Clinical Review

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

There are 3 uncommon types of mechanobullous skin diseases caused by relative reduction or complete loss of functional type VII collagen, which is the main component of anchoring fibrils in the lamina densa of the basement membrane zone (BMZ) of the skin and mucous membrane epithelium.¹ The function of the anchoring fibrils is to maintain adherence of the basement membrane of the epithelium to the connective tissue of the papillary dermis and submucosa.¹ The mechanism of action of the loss of type VII collagen function is via autoimmunity in epidermolysis bullosa acquisita (EBA)² and bullous systemic lupus erythematosus (BSLE).³ In the heritable family of 4 epidermolysis bullosa (EB) variants, only one of the subtypes—dystrophic EB (DEB)—is caused by various recessive and dominant mutations of the type VII collagen gene (COL7A1).⁴ The other 3 diseases in the family—EB simplex, junctional EB, and Kindler syndrome—are caused by diverse mutations that corrupt the integrity of keratinocytes and the BMZ.^5,6 This article provides an overview of these 3 subtypes to help differentiate them from DEB.

Epidermolysis Bullosa

Epidermolysis bullosa consists of a heterogeneous family of 4 major genetic mechanobullous diseases that affect the skin and mucous membranes with more than 30 subtypes.¹ Dystrophic EB is caused by mutations in the COL7A1 gene, which encodes for the α-1 chain of collagen type VII. Classically, EB is divided into 4 main variants based on the location of the cleavage plane or split occurring in the epithelium, which in turn helps to predict the severity of the illness.

Epidermolysis bullosa may be inherited in an ­autosomal-dominant or autosomal-recessive fashion, or it may occur as a spontaneous mutation. All sexes and races are affected equally. Patients present at birth or in early childhood with fragile skin and mucous membranes that may develop blisters, erosions, and ulcerations after minor trauma.⁷ These lesions are marked by slow healing and scar formation and often are associated with itching and pain.

Dystrophic Epidermolysis Bullosa

Dystrophic EB accounts for approximately 25%⁶ of all EB cases in the United States and may be inherited as either a dominant or recessive trait. Hundreds of different pathogenic mutations have been discovered in the COL7A1 gene in the subtypes of DEB.^4,8 Dominant DEB tends to cause milder disease because the patients retain one normal COL7A1 allele and produce some type VII collagen (Figure 1), whereas patients with recessive DEB lack type VII collagen completely.⁹ The cleavage plane is between the lamina densa and the superficial dermis or submucosa. Severity is variable and ranges from ­localization to the hands and feet to severe generalized blistering and painful ulcerations depending on which of the many possible gene mutations have been inherited. Sequelae include mitten deformities, malalignment and tooth decay, and the development of early aggressive squamous cell carcinomas, which may be fatal. The most severe cases of recessive DEB also may have internal organ involvement.

Epidermolysis Bullosa Simplex

Epidermolysis bullosa simplex is the most common variant, comprising approximately 70%of EB cases in the United States.⁶ Epidermolysis bullosa simplex usually is inherited as autosomal-dominant mutations in the keratin 5 or keratin 14 genes,¹⁰ not COL7A1. Skin blistering results from cleavage within the basal cell layer where the keratin genes are primarily expressed. Blisters tend to occur in acral areas such as hands and feet and may heal without scarring in the localized form of epidermolysis bullosa simplex (Figure 2).

Junctional Epidermolysis Bullosa and Kindler Syndrome

Junctional epidermolysis bullosa (JEB) and Kindler syndrome¹¹ are the rarest of the autosomal-recessive EB ­variants.⁶ The plane of cleavage in JEB is through the lamina lucida of the BMZ. Junctional epidermolysis bullosa is caused by mutations of the genes that encode for the 3 chains of laminin 332 protein and type XVII collagen,^5,12 not to be confused with type VII collagen. As with DEB, there is a wide range of severity in JEB, from localized effects on the eyes, oral cavity, and tooth enamel to widespread blistering and skin cancers. In JEB cases involving newborns, nonhealing wounds on the face, buttocks, fingers, and toes may be seen, with devastating complications in the oral cavity, esophagus, and larynx. Life expectancy is limited to 2 years or less.⁶ There have only been approximately 40,013 cases of Kindler syndrome reported worldwide⁶ and there is clinical overlap with DEB. Patients also may demonstrate poikiloderma and photosensitivity. Kindler syndrome is caused by mutations in the FERMT1 gene which encodes for kindlin-1. This protein mediates anchorage between the actin cytoskeleton and the extracellular matrix.^5,11 Loss of function produces variable cleavage planes around the dermoepidermal junction.

Clinical management of all EB variants, especially the severe recessive types, traditionally has been limited to the prevention of trauma to the skin and mucous membranes and supportive care, including dressing changes to erosions and ulcerations, antibiotic ointments as needed, and amelioration of pain and pruritus. Bone marrow and pluripotential stem cell transplants have been attempted.¹² Complications of EB, such as deformities of the hands and feet caused by excessive scarring, esophageal strictures, poor dentition, and squamous cell carcinomas, must be addressed by a multidisciplinary team of specialists, including plastic surgery, gastroenterology, dentistry/oral surgery, ophthalmology, and dermatology/Mohs surgery. 

Until recently, there were no medications approved by the US Food and Drug Administration (FDA) specifically indicated for EB. In 2023, topical gene therapy was approved by the FDA for both recessive and dominant forms of DEB. Normal COL7A1 sequences are delivered by an attenuated herpes simplex virus 1 vector (beremagene geperpavec) in a gel applied directly to the wounds of patients with DEB. In a clinical trial, matching wounds on 31 patients (62 wounds total) were treated with the active agent or placebo gel. After 6 months, complete wound closure was observed in 67% (21/31) of those treated with the active agent and 22% (7/31) of those treated with placebo (P=.002).¹⁴ In a single case report, a patient with recessive DEB and cicatrizing conjunctivitis (Figure 3) was given ophthalmic beremagene geperpavec after surgery and had improved visual acuity.¹⁵ A topical gel consisting of birch triterpenes to promote healing of partial-thickness wounds also was approved for patients with DEB and JEB by the FDA and the European Commission. In a study of 223 patients, 41% of those using active gel and 29% of those using placebo gel achieved the primary end point of percentage of target wounds that had first complete closure at 45 days.¹⁶ 

The most recent FDA approval for DEB involves transferring the functional COL7A1 gene to the patient’s skin cells, then expanding the gene-corrected cells into sheets of keratinocytes that can be surgically applied to the chronic wound sites. In a phase 3 trial of prademagene zamikeracel (pz-cel), 11 patients with 86 matched wounds were randomized to receive pz-cel (50%) or standard wound care (50%). After 24 weeks, 35 wounds treated with pz-cel were at least 50% healed compared to 7 control wounds.¹⁷ The results for healing and reduction of pain were statistically significant (P<.0001 and P<.0002, respectively).¹⁷ Recombinant collagen VII as replacement therapy also is under study to be given by intravenous infusion to increase tissue collagen VII where it is lacking. This treatment has shown early biologic and therapeutic effects.^9,18 Larger long-term follow-up studies are necessary to confirm persistence of the gene-corrected skin cells, the functionality of the replacement collagen VII, and the potential risk for the development of autoantibodies to type VII collagen.

Epidermolysis Bullosa Acquisita

Epidermolysis bullosa acquisita is a rare autoimmune subepithelial bullous disease that primarily affects middle-aged adults but also has been reported in children.¹⁹ Epidermolysis bullosa acquisita is caused by circulating pathogenic IgG autoantibodies that target and bind to type VII collagen in the anchoring fibrils,^20-22 thereby disrupting the attachment of the epithelium to its underlying connective tissue.

The 2 major clinical manifestations of EBA include a mechanobullous disease resembling inherited forms of DEB (Figure 4) and an inflammatory bullous pemphigoid (BP)–like disease,²³ as well as a combination of both types of skin lesions (Figure 5). The skin and mucous membranes of the oral cavity, esophagus, eyes, and urogenital areas are affected in both types; scarring may cause functional disabilities. In the mechanobullous type of EBA, it is common for blisters and erosions to develop in trauma-prone areas such as the hands, feet, elbows, and knees. The blisters tend to heal with scarring and milia formation as might be seen in porphyria cutanea tarda or cicatricial pemphigoid, which are in the differential diagnosis. Dystrophy of the fingernails or complete nail loss may be observed, resembling DEB. In the BP-like presentation, tense blisters arise upon inflamed or urticarial skin and mucous membranes, which may then become generalized. 

Histopathology in both forms of EBA demonstrates subepithelial separation as clefts or blisters. The mechanobullous type shows a sparse inflammatory infiltrate compared to large collections of neutrophils and eosinophils in the blister cavity and in the superficial dermis in the BP-like cases. The final diagnosis rests on the results of immunopathology testing.²⁴ Direct immunofluorescence of perilesional skin and mucosa shows a linear-granular band of IgG and C3 and other conjugates along the BMZ. Deposits of IgA alone in EBA occur in only about 2.4% of cases and are observed more often when there is mucous membrane involvement.² Indirect immunofluorescence of sera against salt-split skin substrates detects immunoreactants in the floor of the blister rather than in the roof, as would be seen in BP. Highly specific and sensitive enzyme-linked immunosorbent assay (ELISA) kits now are commercially available and can detect autoantibodies against the N-terminal domain of type VII collagen in more than 90% of cases of EBA.²⁵ 

Inflammatory bowel disease (IBD), particularly Crohn disease (CD), precedes the onset of EBA in approximately 25% of cases.^26,27 Ulcerative colitis is much less common. Type VII collagen is normally present in the basement membrane of intestinal epithelium. In a survey of patients with IBD, 68% of those with CD and 13% of those with ulcerative colitis had circulating anti–type VII collagen antibodies detected by ELISA without having symptoms of EBA.²⁸ A case report of a patient with both well-proven EBA and CD highlighted the clinical difficulty of controlling EBA: treatment with prednisolone and sulfasalazine improved the CD but had little effect on the skin blisters.²⁹ A variety of malignancies have been reported in association with EBA, including cancers of the uterine cervix,³⁰ thyroid, and pancreas,³¹ lymphoma, and chronic lymphatic leukemia. Some of these cases have met the criteria for classification as paraneoplastic, whereas others may have been coincidental. 

Treatment for chronic EBA generally has been limited.^2,24 Putative antineutrophil drugs such as dapsone and colchicine combined with systemic corticosteroids may be useful in milder or juvenile cases, which tend to have a better prognosis than adult cases.¹⁹ In more severe EBA, systemic corticosteroids and/or immunosuppressive drugs such as azathioprine,²³ cyclophosphamide,²³ mycophenolate mofetil,³¹ methotrexate,²³ cyclosporine,³³ and infliximab²³ have been used. More recently, rituximab infusion monotherapy³³ and rituximab combined with intravenous immunoglobulin or adjuvant immunoadsorption of the pathogenic autoantibodies have induced remission of refractory EBA.³² Adjuvant immunoadsorption therapy is not widely available. Multispecialty care often is required, especially ophthalmology for conjunctival involvement and gastroenterology for potential esophageal stenosis and the early detection and treatment of IBD.

Bullous Systemic Lupus Erythematosus

Bullous systemic lupus erythematosus is a rare and specific autoimmune skin complication that mostly is seen in patients with an established diagnosis of systemic lupus erythematosus (SLE) who are experiencing a disease flare. Although more common in women, it has been reported in all sexes and races as well as in children. Vesicles and bullae may arise on sun-exposed (Figure 6) and sun-protected areas of skin.

Histopathology shows subepidermal separation with collections of neutrophils and nuclear fragments in the blister cavity. The differential diagnosis of BSLE includes EBA, BP, dermatitis herpetiformis, and linear IgA bullous dermatosis. Direct immunofluorescence testing shows linear-granular deposits of IgG and/or IgM and IgA along the BMZ.³⁴ When utilizing the indirect immunofluorescence split-skin assay, the autoantibody to type VII collagen would be detected in the floor of the blister if the serum titer was sufficiently high.³ Proposed criteria for the diagnosis of BSLE have been published: 1) diagnosis of SLE now based on the 2019 European League Against Rheumatism/American College of Rheumatology classification³⁵; 2) vesicles and bullae arising upon but not limited to sun-exposed skin; 3) histopathology featuring neutrophil-rich subepithelial bullae; 4) positive indirect immunofluorescence for circulating BMZ antibodies using separated human skin as substrate; 5) and direct immunofluorescence showing IgG and/or IgM and often IgA at the BMZ.³⁶ Using ELISA to detect circulating antibodies against type VII collagen²⁴ should now be added to the criteria. The new criteria for SLE³⁴ do not include BSLE, perhaps because it occurs in less than 1% of patients with SLE.³⁷ 

Further investigation by Gammon et al³ confirmed that the autoantibodies in BSLE are identical to those found in EBA (ie, directed against type VII collagen in the lamina densa). Bullous systemic lupus erythematosus is not considered to be the coexistence of EBA with SLE but rather a specific entity wherein type VII collagen autoantibodies are expressed in the autoimmune spectrum of SLE. It is especially important to make the diagnosis of BSLE because it is predictive of more serious systemic complications of SLE (eg, hematologic and renal disease is found in up to 90% of cases).³⁸ 

The natural course of BSLE is variable. Treatments include systemic corticosteroids, dapsone, and immunosuppressive drugs such as azathioprine, methotrexate, mycophenolate mofetil, and cyclophosphamide, especially in cases with nephritis.³⁷ There may be spontaneous resolution of the rash as the inflammatory activity of SLE subsides. Rituximab has been used effectively in several refractory cases of BSLE that failed to respond to all other conventional treatments.³⁹

Conclusion

Anchoring fibrils are composed primarily of type VII collagen. Their role is to maintain the attachment of epithelium to the upper dermis and submucosa. The reduction or complete loss of type VII collagen caused by mutations of the COL7A1 gene results in dominant DEB or recessive DEB, respectively. Two distinct non-heritable immunobullous diseases, EBA and BSLE, are caused by autoantibodies that target type VII collagen. A comparison of the 4 type VII collagen disorders can be found in the Table.

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

Humans possess the ability to recognize and distinguish a large range of odors that can be utilized in a wide range of applications. For example, sommeliers can classify more than 88 smells specific to the roughly 800 volatile organic compounds (VOCs) in wine. Thorough physical examination is essential in dermatology, and although sight and touch play the most important diagnostic roles, the sense of smell often is overlooked. Dermatologists are rigorously trained on the many visual aspects of skin disease and have a plethora of terms to describe these features while there is minimal characterization of odors. Research on odors and the role of olfaction in dermatologic practice is limited.^1,2 We conducted a literature review of PubMed and Google Scholar for peer-reviewed articles discussing the role of odors in dermatologic diseases. Keywords included odor + dermatology, smell + dermatology, cutaneous odor, odor + diagnosis, and disease odor. Relevant studies were identified by screening their abstracts, followed by a full-text review. A total of 38 articles written in English that presented information on the odor associated with dermatologic diseases were included. Articles that were unrelated to the topic or written in a language other than English were excluded.

Common Skin Odors

The human body emits odorants—small VOCs—in various forms (skin/sweat, breath, urine, reproductive fluids). Human odor originates from the oxidation and bacterial metabolism of sweat and sebum on the skin.³ While many odors are physiologic and not cause for concern, others can signal underlying dermatologic pathologies.⁴ Odor-producing conditions can be categorized broadly into infectious diseases, disorders of keratinization and acantholysis, metabolic disorders, and organ dysfunction (Table). Infectious causes include bacterial infections and chronic wounds, which commonly emit characteristic offensive odors. For example, coryneform infections produce methanethiol, causing a cheesy odor of putrid fruit, and pseudomonal pyoderma infections emit a grape juice–like or mousy odor.

Bacterial and Fungal Infections

Bacterial and fungal infections often have distinct smells. Coryneform infections emit an odor of sweaty feet, pseudomonal infections emit a grape juice–like or mousy odor, and trichomycosis infections (caused by Corynebacterium tenuis) present with malodor.⁵ Pseudomonas can infect pyoderma gangrenosum lesions, producing a characteristic malodor.⁵ These smells can be clues for infectious etiology and guide further workup.

Pitted keratolysis, a malodorous pitted rash characterized by infection of the stratum corneum by Kytococcus sedentarius, Dermatophilus congolensis, or Corynebacterium species, is associated with a rotten smell. Its pungent odor, clinical location, and characteristic appearance often are enough to make a diagnosis. The amount of bacteria maintained in the stratum corneum is correlated with the extent of the lesion. Controlling excessive moisture in footwear, aluminum chloride, and topical microbial agents work together to eliminate the skin eruption.⁶ 

Hidradenitis suppurativa, a chronic inflammatory disease of apocrine gland–containing skin, can manifest with abscesses, draining sinuses, and nodules that produce a foul-smelling, purulent discharge. The disease can be debilitating, largely impacting patients’ quality of life, making early diagnosis and treatment critical.^7,8 Therapy is dependent on disease severity and includes topical antibiotics, systemic therapies, and biologics.⁸ 

Patients with atopic dermatitis often experience bacterial superinfection with Staphylococcus aureus. A case report described a patient who developed a fishy odor in this setting that resolved with antibiotic treatment, implicating S aureus in the etiology of the smell.⁹ 

A seminal fluid odor has been reported in cases of Pasteurella wound infection. In such cases, Pasteurella multocida subspecies septica was identified in the wounds caused by a dog scratch and a cat bite. The seminal fluid–like odor was apparent hours after the inciting incident and resolved after treatment with antibiotics.¹⁰ 

Fungal infections frequently emit musty or moldy odors. Tinea pedis (athlete’s foot) is the most prevalent cutaneous fungal infection. The presence of tinea pedis is associated with an intense foul-smelling odor, itching, fissuring, scaling, or maceration of the interdigital regions. The rash and odor resolve with use of topical antifungal agents.^11,12 Seborrheic dermatitis, a prevalent and chronic dermatosis, is characterized by yellow greasy scaling on an erythematous base. In severe cases, a greasy crust with an offensive odor can cover the entire scalp.¹³ The specific cause of this odor is unclear, but it is thought that sebum production and the immunological response to specific Malassezia yeast species may play a role.¹⁴

Genetic and Metabolic Disorders

An array of disorders of keratinization and acantholysis can manifest with distinctive smells that dermatologists frequently encounter. For example, Darier disease, characterized by keratotic papules progressing to crusted plaques, has a signature foul-smelling odor associated with cutaneous bacterial colonization.¹⁵ Similarly, Hailey-Hailey disease, an autosomal-dominant disorder with crusted erosions in skinfold areas, produces a distinct foul smell.¹⁶ Disorders such as pemphigus vulgaris and pemphigus foliaceus emit a peculiar fishy odor that can be helpful in making a diagnosis.¹⁷ Additionally, bullous ichthyosiform erythroderma, keratitis-ichthyosis-deafness syndrome, mal de Meleda, and Papillon-Lefèvre syndrome are all associated with malodor.⁵

Certain metabolic disorders can manifest and present initially with identifiable odors. Trimethylaminuria is a psychologically disabling disease known for its rotting fishy smell due to high amounts of trimethylamine appearing in affected individuals’ sweat, urine, and breath. Previously considered to be very rare, Messenger et al¹⁸ reported the disorder is likely underdiagnosed in those with idiopathic malodor production. Detection and treatment can greatly improve patient quality of life.

Phenylketonuria is an autosomal-recessive inborn error of phenylalanine metabolism that produces a musty body and urine odor as well as other neurologic and dermatologic symptoms.^19,20 Patients can present with eczematous rashes, fair skin, and blue eyes. Phenylacetic acid produces the characteristic odor in the bodily fluids, and the disease is treated with a phenylalanine-free diet.²¹ 

Maple syrup urine disease is a disorder of the oxidative decarboxylation of valine, leucine, and isoleucine (branched-chain amino acids) characterized by urine that smells sweet, resembling maple syrup, in afflicted individuals. The odor also can be present in other bodily secretions, such as sweat. Patients present early in infancy with poor feeding and vomiting as well as neurologic symptoms, eventually leading to intellectual disability. These individuals must avoid the branched-chain amino acids in their diets.²¹ 

Other metabolic storage disorders linked with specific odors are methionine adenosyltransferase deficiency (boiled cabbage), hypermethioninemia (fishy, boiled cabbage), isovaleric acidemia (sweaty feet), methionine malabsorption syndrome (pungent malodor), and dimethylglycine dehydrogenase deficiency (fishy).^5,21,22

In diabetic ketoacidosis, a life-threatening complication of diabetes, the excess of ketone bodies produced causes patients to have a distinct fruity breath and urine odor, as well as fatigue, polyuria, polydipsia, nausea, and vomiting.²² Although patients with type 1 diabetes typically comprise the cohort of patients presenting with diabetic ketoacidosis, patients with type 2 diabetes can exhibit cutaneous manifestations such as infection, xerosis, and inflammatory skin diseases.^23,24 

Organ Dysfunction

A peculiar body odor can be a sign of organ dysfunction. Renal dysfunction may present with both an odor and dermatologic manifestations. Patients with end-stage renal disease can have an ammonialike uremic breath odor as the result of excessive nitrogenous waste products and increased concentrations of urea in their saliva.^4,22 These patients also can exhibit pruritus, xerosis, pigmentation changes, nail changes, other dermatoses, and rarely uremic frost with white urate crystals present on the skin.^25,26 

Liver failure has been associated with an ammonialike musty breath odor termed fetor hepaticus. Shimamoto et al²⁷ reported notably higher levels of breath ammonia levels in patients with hepatic encephalopathy, indicating that excess ammonia is responsible for the odor. Fetor hepaticus has unique characteristics that can permit a diagnosis of liver disease, though it has been reported in cases in which a liver injury could not be identified.²⁸ 

Aging patients typically have a distinctive smell. Haze et al²⁹ analyzed the body odor of patients aged 26 to 75 years and discovered the compound 2-nonenal—an unsaturated aldehyde with a smell described as greasy and grassy—was found only in patients older than 40 years. The researchers’ analysis of skin-surface lipids also revealed that the presence of ω7 unsaturated fatty acids and lipid peroxides increased with age. They concluded that 2-nonenal is generated from the oxidative degradation of ω7 unsaturated fatty acids by lipid peroxides, suggesting that 2-nonenal may be a cause of the odor of old age.²⁹

Cutaneous Malignancies 

Research shows that the profiles of the body’s continuously released VOCs change in the presence of malignancy. Some studies suggest that melanoma may have a unique odor. Willis et al³⁰ reported that after a 13-month training period, a dog was able to correctly identify melanoma and distinguish it from basal cell carcinoma, benign nevi, and healthy skin based on olfaction alone. Additional cases have been reported in which dogs have been able to identify melanoma based on smell, suggesting that canine olfactory detection of melanoma could possibly aid in the diagnosis of skin cancer, which warrants further investigation.^31,32 There is limited evidence on the specific odors of other cutaneous malignancies, such as basal cell carcinoma and squamous cell carcinoma. 

Bacterial superinfection of cutaneous malignancy can secrete pungent odors. An offensive rotting odor has been associated with necrotic malignant ulcers of the vagina. This malodor likely is a result of the formation of putrescine, cadaverine, short-chain fatty acids (isovaleric and butyric acids) and sulfur-containing compounds by bacteria.³³ Recognition of similar smells may aid in management of these infections.

Diagnostic Techniques

Evaluating human skin odor is challenging, as the components of VOCs are complicated and typically found at trace levels. Studies indicate that gas chromatography–mass spectrometry is the most effective way to analyze human odor. This method separates, quantifies, and analyzes VOCs from samples containing odors.³⁴ Gas chromatography–mass spectrometry, however, has limitations, as the time for analysis is lengthy, the equipment is large, and the process is expensive.³ Research supports the usefulness and validity of quantitative gas chromatography–olfactometry to detect odorants and evaluate odor activity of VOCs in various samples.³⁵ With this technique, human assessors act in place of more conventional detectors, such as mass spectrometers. This method has been used to evaluate odorants in human urine with the goal of increasing understanding of metabolization and excretion processes.³⁶ However, gas chromatography–olfactometry typically is used in the analysis of food and drink, and future research should be aimed at applying this method to medicine. 

Zheng et al³ proposed a wearable electronic nose as a tool to identify human odor to emulate the odor recognition of a canine’s nose. They developed a sensor array based on the composites of carbon nanotubes and polymers able to examine and identify odors in the air. Study participants wore the electronic nose on the arm with the sensory array facing the armpits while they walked on a treadmill. Although many issues regarding odor measurement were not addressed in this study, the research suggests further studies are warranted to improve analysis of odor.³

Clinical Cases

Patient 1—Arseculeratne et al³⁷ described a 41-year-old man who presented with a fishy odor that others had noticed since the age of 13 years but that the patient could not smell himself. Based on his presentation, he was worked up for trimethylaminuria and found to have elevated levels of urinary trimethylamine (TMA) with a raised TMA/TMA-oxidase ratio. These findings were consistent with a diagnosis of primary trimethylaminuria, and the patient was referred to a dietician for counseling on foods that contain low amounts of choline and lecithin. Initially his urinary TMA level fell but then rose again, indicating possible relaxation of his diet. He then took a 10-day course of metronidazole, which helped reduce some of the malodor. The authors reported that the most impactful therapy for the patient was being able to discuss the disorder with his friends and family members.³⁷ This case highlighted the importance of confirming the diagnosis and early initiation of dietary and pharmacologic interventions in patients with trimethylaminuria. In patients reporting a persistent fishy body odor, trimethylaminuria should be on the differential.

Patient 2—In 1999, Schissel et al⁶ described a 20-year-old active-duty soldier who presented to the dermatology department with smelly trench foot and tinea pedis. The soldier reported having this malodorous pitted rash for more than 10 years. He also reported occasional interdigital burning and itching and noted no improvement despite using various topical antifungals. Physical examination revealed an “overpowering pungent odor” when the patient removed his shoes. He had many tender, white, and wet plaques with scalloped borders coalescing into shallow pits on the plantar surface of the feet and great toes. Potassium hydroxide preparation of the great toe plaques and interdigital web spaces were positive for fungal elements, and bacterial cultures isolated moderate coagulase-negative staphylococcal and Corynebacterium species. Additionally, fungal cultures identified Acremonium species. The patient was started on clotrimazole cream twice daily, clindamycin solution twice daily, and topical ammonium chloride nightly. Two weeks later, the patient reported resolution of symptoms, including the malodor.⁶ In pitted keratolysis, warm and wet environments within boots or shoes allow for the growth of bacteria and fungi. The extent of the lesions is related to the amount of bacteria within the stratum corneum. The diagnosis often is made based on odor, location, and appearance of the rash alone. The most common organisms implicated as causal agents in the condition are Kytococcus sedentarius, Dermatophilus congolensis, and species of Corynebacterium and Actinomyces. It is thought that these organisms release proteolytic enzymes that degrade the horny layer, releasing a mixture of thiols, thioesters, and sulfides, which cause the pungent odor. Familiarity with the characteristic odor aids in prompt diagnosis and treatment, which will ultimately heal the skin eruption. 

Patient 3—Srivastava et al³² described a 43-year-old woman who presented with a nevus on the back since childhood. She noticed that it had changed and grown over the past few years and reported that her dog would often sniff the lesion and try to scratch and bite the lesion. This reaction from her dog led the patient to seek out evaluation from a dermatologist. The patient had no personal history of skin cancer, bad sunburns, tanning bed use, or use of immunosuppressants. She reported that her father had a history of basal cell carcinoma. Physical examination revealed a 1.2×1.5-cm brown patch with an ulcerated nodule located on the lower aspect of the lesion. The patient underwent a wide local excision and sentinel lymph node biopsy with pathology showing a 4-mm-thick melanoma with positive lymph nodes. She then underwent a right axillary lymphadenectomy and was diagnosed with stage IIIB malignant melanoma. Following the surgery, the patient’s dog would sniff the back and calmly rest his head in her lap. She has not had a recurrence and credits her dog for saving her life.³² Canine olfaction may play a role in detecting skin cancers, as evidenced by this case. Patients and dermatologists should pay attention to the behavior of dogs toward skin lesions. Harnessing this sense into a method to noninvasively screen for melanoma in humans should be further investigated.

Patient 4—Matthews et al³⁸ described a 32-year-old woman who presented to an emergency eye clinic with a white “lump” on the left upper eyelid of 6 months’ duration. Physical examination revealed 3 nodular and cystic lesions oozing a thick yellow-white discharge. Cultures were taken, and the patient was started on chloramphenicol ointment once daily to the skin. At follow-up, the lesions had not changed, and the cultures were negative. The patient reported an intermittent malodorous discharge and noted multiple similar lesions on her body. Excisional biopsy demonstrated histologic findings including dyskeratosis, papillomatosis, and suprabasal acantholysis associated with focal underlying chronic inflammatory infiltrate. She was referred to a dermatologist and was diagnosed with Darier disease. She was started on clobetasone butyrate when necessary and adapalene nocte. Understanding the smell associated with Darier disease in conjunction with the cutaneous findings may aid in earlier diagnosis, improving outcomes for affected patients.³⁸ 

Conclusion

The sense of smell may be an overlooked diagnostic tool that dermatologists innately possess. Odors detected when examining patients should be considered, as these odors may help guide a diagnosis. Early diagnosis and treatment are important in many dermatologic diseases, so it is imperative to consider all diagnostic clues. Although physician olfaction may aid in diagnosis, its utility remains challenging, as there is a lack of consensus and terminology regarding odor in disease. A limitation of training to identify disease-specific odors is the requirement of engaging in often unpleasant odors. Methods to objectively measure odor are expensive and still in the early stages of development. Further research and exploration of olfactory-based diagnostic techniques is warranted to potentially improve dermatologic diagnosis. 

Fluoroscopy is an imaging technique that allows for real-time visualization of internal structures in the body using continuous radiography beams. More than 1 million fluoroscopy-guided procedures are performed annually in the United States.¹ Utilization of these procedures continues to increase, and so does the probability of related complications, as prolonged exposure to ionizing radiation can cause skin injuries.² Fortunately, the incidence of radiation-induced skin injuries compared with the total number of fluoroscopic procedures performed remains small,² although one study suggested the incidence may be as high as 8.9% in at-risk populations.³

Radiation dermatitis is well recognized in dermatology as a complication of oncologic management; however, radiation dermatitis as a complication of fluoroscopic procedures is underrecognized.⁴ Fluoroscopy-induced radiation dermatitis can be categorized as acute, subacute, or chronic.⁵ Common fluoroscopic procedures that have been associated with fluoroscopy-induced radiation dermatitis include interventional cardiac procedures, neurovascular procedures, transjugular intrahepatic portosystemic shunt procedures, and endovascular abdominal aortic aneurysm repairs.^6,7

Patients with fluoroscopy-induced radiation dermatitis, particularly fluoroscopy-induced chronic radiation dermatitis (FICRD), can present to dermatology up to several years after the initial fluoroscopy procedure with no awareness of the association between the procedure and their skin findings. This presents a diagnostic challenge, and FICRD often is overlooked.^5,8-10

We conducted a literature search of PubMed articles indexed for MEDLINE using the search terms ­fluoroscopy and dermatitis. In this reappraisal, we will provide a comprehensive overview of fluoroscopy-induced ­radiation dermatitis with an emphasis on FICRD, covering its clinical manifestations, pathophysiology, risk factors, ­differential diagnosis, histology, and management. The aim of this review is to highlight the salient features and mimickers of FICRD and inform readers how to approach suspected cases, leading to accurate diagnosis and ­effective management.

Pathophysiology 

Fluoroscopy-induced radiation dermatitis is the result of dose-dependent radiation-induced tissue damage. As the peak skin dosage (PSD) of radiation increases over the course of a procedure or multiple procedures, the severity of skin injury predictably increases. During fluoroscopic procedures, the standard irradiation dosage ranges from 0.02 Gy/min to 0.05 Gy/min.¹¹ Transient skin changes may start to be seen around 2 Gy of cumulative exposure. Fluoroscopic procedures typically range in duration from 60 to 120 minutes; however, complex cases may exceed that. Additionally, multiple procedures performed within shorter intervals can result in greater PSD accumulation. Shorter intervals between procedures do not allow enough time for damage repair from the previous ­procedure and can result in further severe damage when the skin is re-exposed to radiation.² The American College of Radiology recommends medical follow-up after 10 Gy of cumulative exposure, while cumulative exposure above 15 Gy within a 6- to 12-month period is defined as a sentinel event, according to The Joint Commission.^12-14

Depending on the patient’s total radiation dosage during one or more procedures, the result of the tissue damage manifests differently at varying times: early skin changes are categorized as fluoroscopy-induced acute radiation dermatitis, and late skin changes are categorized as FICRD (Table 1).

Clinical Manifestations

Acute radiation dermatitis from fluoroscopic procedures manifests within hours to days up to 90 days following radiation exposure and can be characterized by erythema with blistering, desquamation, epilation, pigmentation changes, and even necrosis if the accumulated dosage exceeds 15 Gy.¹⁵ Chronic radiation dermatitis (which as related to fluoroscopic procedures is termed FICRD) has a longer onset of weeks to years and is clinically characterized by telangiectasias, permanent erythema, dermal atrophy, or ulcerations. Clinically, subacute radiation dermatitis shares features of both acute and chronic radiation dermatitis; therefore, it is differentiated based on its histologic features.^5,16

Although fluoroscopy-induced acute radiation dermatitis (Table 1) may precede FICRD, acute manifestations of fluoroscopy-related dermatitis can be subtle and often manifest in areas not easily visualized. Because referrals to dermatologists for full-skin examinations after fluoroscopy procedures are not standard, patients may not be aware of the association between these procedures and the development of skin lesions. Nonetheless, some patients may report a history of skin changes such as redness days or weeks after a fluoroscopic procedure with accompanying pain and pruritus limited to the fluoroscopy-exposed region, which tend to self-resolve.¹⁷ The risk for FICRD is thought to increase if a history of fluoroscopy-induced acute radiation dermatitis is present.¹⁸

The location of the skin findings correlates to the area exposed to prolonged radiation during the procedure(s). The most common areas include the scapular and subscapular regions, the right lateral trunk inferior to the axilla, the mid back, and the right anterolateral chest.^16,19,20 These regions are associated with more complex (eg, cardiac) procedures that have been reported to lead to prolonged radiation exposure. The skin findings in FICRD are described as geometric, corresponding to the squarish or rectangular radiography beam that is directed at the patient. Additionally, radiography beams spread outward as they travel in space; therefore, skin injuries are common at the region more distal to the path of origination of the beam.^21-23 Subsequently, a geometric, dyspigmented, indurated or atrophic plaque with telangiectasias and erosions or ulcerations with progressive worsening is a common manifestation of FICRD.^5,16,23 Patients also commonly present with pruritus or severe pain associated with the lesion.^24,25  

Dermatologic Manifestations of FICRD

Skin responses seen weeks to years after a fluoroscopic procedure and typically after cumulative radiation exposure of 10 Gy or greater are categorized as FICRD (Table 2). These changes also can be clinically graded based on the Radiation Therapy Oncology Group classification of radiation dermatitis (Tables 3 and 4).²⁶ Chronic changes in the skin largely result from remodeling of the vasculature and the subcutaneous tissue over time. Unlike acute changes, chronic changes typically persist and continue to worsen.²⁷

Telangiectasias—Anywhere from months to 1 year after exposure to 10 Gy of radiation, proliferation of atypical superficial vessels in the dermis can be seen, typically manifesting as telangiectasias on physical examination. Telangiectasias can increase with time and can even exhibit a dose-dependent relationship to the radiation exposure.²⁸

Atrophy—Atrophic-appearing skin after radiation exposure is the result of direct injury to both the epidermis and fibroblasts in the dermis. The destruction of keratinocytes leads to a thin epidermis, and destruction of dermal fibroblasts causes insufficient collagen production.²⁹ Clinically, this process manifests as an atrophic plaque that can be seen 12 weeks to 1 year after the procedure. 

Fibrosis—Approximately 1 year after the exposure, the initial damage can lead to disruption of molecular pathways, causing fibrosis. Transforming growth factor (TGF) β1 is the main factor involved.²⁹ Damage to the endothelial cells results in increased TGF-β1 levels, which causes increased stimulation of remaining atypical fibroblasts and thus increased irregular collagen deposition.³⁰ Further adding to this knowledge, Wei et al³¹ recently proposed that damage to the epidermal keratinocytes leads to disruption of yes-associated protein 1, which is a protective factor released from keratinocytes that regulates the dermal fibroblasts. However, extensive damage to the keratinocytes can lead to lower yes-associated protein 1 levels and its downstream activity, leading to increased levels of TGF-β1 and fibroblast activity.³¹ Clinically, this fibrotic stage is seen as indurated plaques in patients. 

Necrosis—There are 2 forms of necrosis that can be seen. Ischemic dermal necrosis typically occurs in the acute phase after 10 weeks and approximately 18 Gy of cumulative exposure. It results from substantial skin damage, including microvascular damage and reduction in dermal capillaries, leading to ischemia of the tissue.² Late dermal necrosis is the process seen in the chronic stage of FICRD and radiation dermatitis not related to ­fluoroscopy. It results from the inability of the fibrotic dermis to vascularly support the epidermis above it.² It can be seen anywhere from 1 to 4 years after the procedure. This stage clinically manifests as worsening ulcerations with major pain and increased risk for secondary infections.¹⁶ 

Dyspigmentation—Dyspigmentation at the site of the radiation exposure can be seen acutely and chronically. Dosage above 15 to 18 Gy can lead to destruction of melanocytes, which can cause hypopigmentation in exposed areas. However, melanocytes are relatively resistant to radiation; therefore, dosages below the threshold of destruction of 15 to 18 Gy can cause melanocytic hyperactivity leading to hyperpigmentation.³² Hence, pigmentary changes can vary greatly. Classically, a central area of hypopigmentation with surrounding hyperpigmentation is seen.

Histology 

Histologic appearance of radiation dermatitis varies depending on its stage. Acute radiation dermatitis primarily demonstrates superficial dermal edema, damage to the basal cell layer, small vessel dilation with thrombi, and hemorrhage along with a sparse inflammatory cell infiltrate.³³ Histology typically is the only way to characterize subacute radiation dermatitis.⁵ Lichenoid tissue reaction is its characteristic feature. Mononuclear cells are found adjected to necrotic keratinocytes along with prominent vacuolization of the basal cell layer.³³

The key histologic features of chronic radiation dermatitis include epidermal atrophy, hyperkeratosis, telangiectasias, loss of adnexal structures, and dermal fibrosis along with sparse atypical stellate fibroblasts.³⁴ However, clinical context of fluoroscopic exposure is required for the dermatopathologist to differentiate chronic radiation dermatitis from its histologic differential of morphea and lichen sclerosus. In a cross-sectional study, only 1 of 6 cases (16.7%) was correctly diagnosed as chronic radiation dermatitis in the absence of correlating clinical history.³⁵ 

Risk Factors for FICRD 

Since the diagnosis of FICRD can be a clinical challenge, understanding the risk factors can be helpful. The general likelihood of developing FICRD is related to the duration, frequency, interval, intensity, and area of radiation exposure. Procedures exceeding the normal duration of 60 to 120 minutes have been well documented as a substantial risk factor for radiation dermatitis and FICRD.^36-38 The risk tends to be higher in longer procedures because they result in more radiation exposure and higher accumulated PSD. Obesity (ie, body mass index >26) is the major risk factor that has been associated with longer procedure times, as higher radiation dosages are necessary to penetrate the body of a larger patient and a larger skin surface area is exposed.^37-39

Other risk factors associated with FICRD relate to how prone a patient is to radiation-induced DNA damage. Older patients are at higher risk due to lower intrinsic ability of the tissue to repair itself.¹¹ Patients with a history of connective tissue diseases—particularly lupus, scleroderma, and mixed connective tissue disease—are at an increased risk.⁴⁰ Furthermore, patients with genetic disorders that impair DNA repair are more susceptible to radiation-induced DNA damage; therefore, patients with ataxia-telangiectasia, xeroderma pigmentosum, Fanconi anemia, and hereditary nevoid basal cell carcinoma are at higher risk for FICRD.³⁹ Similarly, medications that can affect DNA repair also have been shown to be risk factors. These medications include chemotherapeutic agents such as actinomycin D, cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil.^2,39 Diabetes, hyperthyroidism, and tobacco use also have been shown to increase a patient’s risk for FICRD.³⁹ It also is reasonable to believe that patients with defects in fibroblasts or with elastin or collagen disorders (eg, Ehlers-Danlos syndrome) would be at higher risk, but there are no known studies highlighting the association in the literature.

Differential Diagnosis of FICRD 

Acute allergic or irritant contact dermatitis manifests with a localized area of erythematous skin accompanied by pruritus.⁴¹ Patients with FICRD can present with a localized area of erythema and hyperpigmentation with minimal atrophy. The lesion may accompany substantial pruritus, which can favor the more common diagnosis of contact dermatitis.^35,42,43

Fixed-drug eruption manifests as a well-defined, hyperpigmented plaque in a fixed location that occurs upon ingestion of a drug.⁴⁴ Fluoroscopy-induced chronic radiation dermatitis lesions are well demarcated and geometrically shaped and therefore can mimic lesions seen in fixed-drug eruptions.⁴⁵ Additionally, the patient population undergoing fluoroscopic procedures tends to have major comorbidities requiring multiple medications.⁴

Decubitus ulcers are a result of vascular compromise to an area of skin due to constant pressure and are most commonly seen in the sacral region of patients with ­obesity.⁴⁶ Ulcerated FICRD lesions can manifest on the lower midback. These lesions can be seen after endovascular repair of abdominal aortic aneurysm or prostatic artery embolization.^20,21 The location of these lesions can mimic decubitus ulcers if fluoroscopic history is unknown. As mentioned, obesity also increases the risk for FICRD. 

Morphea can manifest as a localized area of induration and hyperpigmentation of the skin.⁴⁷ When FICRD has progressed to dermal fibrosis, patients can present with indurated plaques without ulcerations, which can be hard to differentiate from morphea.^16,48 However, the presence of ulcerations or hyperkeratosis can differentiate morphea from FICRD.¹⁶

Ultimately, it is the location of FICRD lesions that remains the biggest diagnostic clue. Any suspicious lesion present on the scapular or subscapular areas, anterolateral chest, and/or mid back should prompt an investigation into recent or remote history of fluoroscopic procedures. 

Management of FICRD

Diagnosis of FICRD should be made clinically based on the history and physical examination whenever possible, since a biopsy is not recommended.³⁵ Wound healing in FICRD is delayed, and biopsies can lead to ulcerations or secondary infections.¹⁷ Therefore, it is important to remain suspicious for FICRD. Management of FICRD should correspond to the clinical findings outlined by a recent Delphi consensus survey.⁴⁹ Regardless, the core of FICRD management framework should always include good hygiene, maintenance of skin hydration to improve epithelialization, and sufficient photoprotection.^49,50

Among the first signs of FICRD are telangiectasias. Although asymptomatic, their appearance can be distressing for patients. Pulsed dye laser therapy is a first-line option that has been studied and has shown clinical efficacy for treatment of telangiectasias and vascular changes in patients with FICRD.^49,51

If patients develop fibrotic changes, treatment options are limited. Fibrosis is hard to reverse, and the management approach is limited to symptomatic relief. Mechanical and deep-friction massages have been shown to be effective at reducing skin induration in patients.⁵² Fractional ablative lasers also may be utilized for skin contractures, especially if range of motion is affected.^53,54 Although it comes with its own challenges, autologous fat grafting has shown promise in reducing postradiation fibrosis and inducing angiogenesis in tissue.⁵⁵ Oral pentoxifylline also has shown mild efficacy, as it may be able to suppress TGF-β1 levels.⁵³ However, prevention of fibrotic changes may be the most important. Wei et al³¹ suggested that low-dose oral prednisolone at 5 mg twice daily for 3 weeks might be an option to prevent the progression of skin changes and even reverse fibrosis to an extent; however, further evidence regarding its efficacy still is necessary. Additionally, no evidence was identified to support the use of topical corticosteroids for fibrotic changes seen in FICRD.⁵⁶

Patients with FICRD or even acute radiation dermatitis after fluoroscopy tend to develop superficial ulcerations from minor traumas. Good wound hygiene, antiseptic care, and absorbent dressings, such as hydrogel and hydrocolloid, may be sufficient for treating these wounds, as seen in the Figure.^42,48 However, once patients develop refractory ulcerations or necrosis, treatment options are then limited to surgical removal with a flap or graft.^5,33,42,45
 

Risk for basal cell carcinomas and squamous cell carcinomas is higher in patients with radiation exposure; however, the exact risk from fluoroscopic procedures is unknown. One study demonstrated an increased risk of 6.9% in development of skin cancer after a median radiation exposure of 15.5 Gy and a mean latency period of 38.3 years,⁵⁷ and in another retrospective study, the risk was higher in Fitzpatrick skin types I and II.⁵⁸ Unlike the development of radiodermatitis itself, which shows a dose-dependent response, development of skin cancers follows a stochastic pattern (not dose dependent).⁵⁹ Therefore, it is important to identify these high-risk patients and establish follow-up.

Conclusion

Fluoroscopy-induced chronic radiation dermatitis can be a diagnostic challenge, as skin changes may not be readily associated with the procedure by patients. Therefore, any lesion with a geometric shape and accompanying chronic radiation dermatitis features located on the scapular or subscapular areas, anterolateral chest, and midback should prompt an investigation into history of fluoroscopic procedures. Treatment of chronic skin changes in FICRD depends on the clinical manifestations. Good hygiene, skin hydration, and sufficient photoprotection are crucial. Finally, long-term monitoring with skin examinations is important to assess for the development of skin cancers in the treated area.

Fluoroscopy is an imaging technique that allows for real-time visualization of internal structures in the body using continuous radiography beams. More than 1 million fluoroscopy-guided procedures are performed annually in the United States.¹ Utilization of these procedures continues to increase, and so does the probability of related complications, as prolonged exposure to ionizing radiation can cause skin injuries.² Fortunately, the incidence of radiation-induced skin injuries compared with the total number of fluoroscopic procedures performed remains small,² although one study suggested the incidence may be as high as 8.9% in at-risk populations.³

Radiation dermatitis is well recognized in dermatology as a complication of oncologic management; however, radiation dermatitis as a complication of fluoroscopic procedures is underrecognized.⁴ Fluoroscopy-induced radiation dermatitis can be categorized as acute, subacute, or chronic.⁵ Common fluoroscopic procedures that have been associated with fluoroscopy-induced radiation dermatitis include interventional cardiac procedures, neurovascular procedures, transjugular intrahepatic portosystemic shunt procedures, and endovascular abdominal aortic aneurysm repairs.^6,7

Patients with fluoroscopy-induced radiation dermatitis, particularly fluoroscopy-induced chronic radiation dermatitis (FICRD), can present to dermatology up to several years after the initial fluoroscopy procedure with no awareness of the association between the procedure and their skin findings. This presents a diagnostic challenge, and FICRD often is overlooked.^5,8-10

We conducted a literature search of PubMed articles indexed for MEDLINE using the search terms ­fluoroscopy and dermatitis. In this reappraisal, we will provide a comprehensive overview of fluoroscopy-induced ­radiation dermatitis with an emphasis on FICRD, covering its clinical manifestations, pathophysiology, risk factors, ­differential diagnosis, histology, and management. The aim of this review is to highlight the salient features and mimickers of FICRD and inform readers how to approach suspected cases, leading to accurate diagnosis and ­effective management.

Pathophysiology 

Fluoroscopy-induced radiation dermatitis is the result of dose-dependent radiation-induced tissue damage. As the peak skin dosage (PSD) of radiation increases over the course of a procedure or multiple procedures, the severity of skin injury predictably increases. During fluoroscopic procedures, the standard irradiation dosage ranges from 0.02 Gy/min to 0.05 Gy/min.¹¹ Transient skin changes may start to be seen around 2 Gy of cumulative exposure. Fluoroscopic procedures typically range in duration from 60 to 120 minutes; however, complex cases may exceed that. Additionally, multiple procedures performed within shorter intervals can result in greater PSD accumulation. Shorter intervals between procedures do not allow enough time for damage repair from the previous ­procedure and can result in further severe damage when the skin is re-exposed to radiation.² The American College of Radiology recommends medical follow-up after 10 Gy of cumulative exposure, while cumulative exposure above 15 Gy within a 6- to 12-month period is defined as a sentinel event, according to The Joint Commission.^12-14

Depending on the patient’s total radiation dosage during one or more procedures, the result of the tissue damage manifests differently at varying times: early skin changes are categorized as fluoroscopy-induced acute radiation dermatitis, and late skin changes are categorized as FICRD (Table 1).

Clinical Manifestations

Acute radiation dermatitis from fluoroscopic procedures manifests within hours to days up to 90 days following radiation exposure and can be characterized by erythema with blistering, desquamation, epilation, pigmentation changes, and even necrosis if the accumulated dosage exceeds 15 Gy.¹⁵ Chronic radiation dermatitis (which as related to fluoroscopic procedures is termed FICRD) has a longer onset of weeks to years and is clinically characterized by telangiectasias, permanent erythema, dermal atrophy, or ulcerations. Clinically, subacute radiation dermatitis shares features of both acute and chronic radiation dermatitis; therefore, it is differentiated based on its histologic features.^5,16

Although fluoroscopy-induced acute radiation dermatitis (Table 1) may precede FICRD, acute manifestations of fluoroscopy-related dermatitis can be subtle and often manifest in areas not easily visualized. Because referrals to dermatologists for full-skin examinations after fluoroscopy procedures are not standard, patients may not be aware of the association between these procedures and the development of skin lesions. Nonetheless, some patients may report a history of skin changes such as redness days or weeks after a fluoroscopic procedure with accompanying pain and pruritus limited to the fluoroscopy-exposed region, which tend to self-resolve.¹⁷ The risk for FICRD is thought to increase if a history of fluoroscopy-induced acute radiation dermatitis is present.¹⁸

The location of the skin findings correlates to the area exposed to prolonged radiation during the procedure(s). The most common areas include the scapular and subscapular regions, the right lateral trunk inferior to the axilla, the mid back, and the right anterolateral chest.^16,19,20 These regions are associated with more complex (eg, cardiac) procedures that have been reported to lead to prolonged radiation exposure. The skin findings in FICRD are described as geometric, corresponding to the squarish or rectangular radiography beam that is directed at the patient. Additionally, radiography beams spread outward as they travel in space; therefore, skin injuries are common at the region more distal to the path of origination of the beam.^21-23 Subsequently, a geometric, dyspigmented, indurated or atrophic plaque with telangiectasias and erosions or ulcerations with progressive worsening is a common manifestation of FICRD.^5,16,23 Patients also commonly present with pruritus or severe pain associated with the lesion.^24,25  

Dermatologic Manifestations of FICRD

Skin responses seen weeks to years after a fluoroscopic procedure and typically after cumulative radiation exposure of 10 Gy or greater are categorized as FICRD (Table 2). These changes also can be clinically graded based on the Radiation Therapy Oncology Group classification of radiation dermatitis (Tables 3 and 4).²⁶ Chronic changes in the skin largely result from remodeling of the vasculature and the subcutaneous tissue over time. Unlike acute changes, chronic changes typically persist and continue to worsen.²⁷

Telangiectasias—Anywhere from months to 1 year after exposure to 10 Gy of radiation, proliferation of atypical superficial vessels in the dermis can be seen, typically manifesting as telangiectasias on physical examination. Telangiectasias can increase with time and can even exhibit a dose-dependent relationship to the radiation exposure.²⁸

Atrophy—Atrophic-appearing skin after radiation exposure is the result of direct injury to both the epidermis and fibroblasts in the dermis. The destruction of keratinocytes leads to a thin epidermis, and destruction of dermal fibroblasts causes insufficient collagen production.²⁹ Clinically, this process manifests as an atrophic plaque that can be seen 12 weeks to 1 year after the procedure. 

Fibrosis—Approximately 1 year after the exposure, the initial damage can lead to disruption of molecular pathways, causing fibrosis. Transforming growth factor (TGF) β1 is the main factor involved.²⁹ Damage to the endothelial cells results in increased TGF-β1 levels, which causes increased stimulation of remaining atypical fibroblasts and thus increased irregular collagen deposition.³⁰ Further adding to this knowledge, Wei et al³¹ recently proposed that damage to the epidermal keratinocytes leads to disruption of yes-associated protein 1, which is a protective factor released from keratinocytes that regulates the dermal fibroblasts. However, extensive damage to the keratinocytes can lead to lower yes-associated protein 1 levels and its downstream activity, leading to increased levels of TGF-β1 and fibroblast activity.³¹ Clinically, this fibrotic stage is seen as indurated plaques in patients. 

Necrosis—There are 2 forms of necrosis that can be seen. Ischemic dermal necrosis typically occurs in the acute phase after 10 weeks and approximately 18 Gy of cumulative exposure. It results from substantial skin damage, including microvascular damage and reduction in dermal capillaries, leading to ischemia of the tissue.² Late dermal necrosis is the process seen in the chronic stage of FICRD and radiation dermatitis not related to ­fluoroscopy. It results from the inability of the fibrotic dermis to vascularly support the epidermis above it.² It can be seen anywhere from 1 to 4 years after the procedure. This stage clinically manifests as worsening ulcerations with major pain and increased risk for secondary infections.¹⁶ 

Dyspigmentation—Dyspigmentation at the site of the radiation exposure can be seen acutely and chronically. Dosage above 15 to 18 Gy can lead to destruction of melanocytes, which can cause hypopigmentation in exposed areas. However, melanocytes are relatively resistant to radiation; therefore, dosages below the threshold of destruction of 15 to 18 Gy can cause melanocytic hyperactivity leading to hyperpigmentation.³² Hence, pigmentary changes can vary greatly. Classically, a central area of hypopigmentation with surrounding hyperpigmentation is seen.

Histology 

Histologic appearance of radiation dermatitis varies depending on its stage. Acute radiation dermatitis primarily demonstrates superficial dermal edema, damage to the basal cell layer, small vessel dilation with thrombi, and hemorrhage along with a sparse inflammatory cell infiltrate.³³ Histology typically is the only way to characterize subacute radiation dermatitis.⁵ Lichenoid tissue reaction is its characteristic feature. Mononuclear cells are found adjected to necrotic keratinocytes along with prominent vacuolization of the basal cell layer.³³

The key histologic features of chronic radiation dermatitis include epidermal atrophy, hyperkeratosis, telangiectasias, loss of adnexal structures, and dermal fibrosis along with sparse atypical stellate fibroblasts.³⁴ However, clinical context of fluoroscopic exposure is required for the dermatopathologist to differentiate chronic radiation dermatitis from its histologic differential of morphea and lichen sclerosus. In a cross-sectional study, only 1 of 6 cases (16.7%) was correctly diagnosed as chronic radiation dermatitis in the absence of correlating clinical history.³⁵ 

Risk Factors for FICRD 

Since the diagnosis of FICRD can be a clinical challenge, understanding the risk factors can be helpful. The general likelihood of developing FICRD is related to the duration, frequency, interval, intensity, and area of radiation exposure. Procedures exceeding the normal duration of 60 to 120 minutes have been well documented as a substantial risk factor for radiation dermatitis and FICRD.^36-38 The risk tends to be higher in longer procedures because they result in more radiation exposure and higher accumulated PSD. Obesity (ie, body mass index >26) is the major risk factor that has been associated with longer procedure times, as higher radiation dosages are necessary to penetrate the body of a larger patient and a larger skin surface area is exposed.^37-39

Other risk factors associated with FICRD relate to how prone a patient is to radiation-induced DNA damage. Older patients are at higher risk due to lower intrinsic ability of the tissue to repair itself.¹¹ Patients with a history of connective tissue diseases—particularly lupus, scleroderma, and mixed connective tissue disease—are at an increased risk.⁴⁰ Furthermore, patients with genetic disorders that impair DNA repair are more susceptible to radiation-induced DNA damage; therefore, patients with ataxia-telangiectasia, xeroderma pigmentosum, Fanconi anemia, and hereditary nevoid basal cell carcinoma are at higher risk for FICRD.³⁹ Similarly, medications that can affect DNA repair also have been shown to be risk factors. These medications include chemotherapeutic agents such as actinomycin D, cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil.^2,39 Diabetes, hyperthyroidism, and tobacco use also have been shown to increase a patient’s risk for FICRD.³⁹ It also is reasonable to believe that patients with defects in fibroblasts or with elastin or collagen disorders (eg, Ehlers-Danlos syndrome) would be at higher risk, but there are no known studies highlighting the association in the literature.

Differential Diagnosis of FICRD 

Acute allergic or irritant contact dermatitis manifests with a localized area of erythematous skin accompanied by pruritus.⁴¹ Patients with FICRD can present with a localized area of erythema and hyperpigmentation with minimal atrophy. The lesion may accompany substantial pruritus, which can favor the more common diagnosis of contact dermatitis.^35,42,43

Fixed-drug eruption manifests as a well-defined, hyperpigmented plaque in a fixed location that occurs upon ingestion of a drug.⁴⁴ Fluoroscopy-induced chronic radiation dermatitis lesions are well demarcated and geometrically shaped and therefore can mimic lesions seen in fixed-drug eruptions.⁴⁵ Additionally, the patient population undergoing fluoroscopic procedures tends to have major comorbidities requiring multiple medications.⁴

Decubitus ulcers are a result of vascular compromise to an area of skin due to constant pressure and are most commonly seen in the sacral region of patients with ­obesity.⁴⁶ Ulcerated FICRD lesions can manifest on the lower midback. These lesions can be seen after endovascular repair of abdominal aortic aneurysm or prostatic artery embolization.^20,21 The location of these lesions can mimic decubitus ulcers if fluoroscopic history is unknown. As mentioned, obesity also increases the risk for FICRD. 

Morphea can manifest as a localized area of induration and hyperpigmentation of the skin.⁴⁷ When FICRD has progressed to dermal fibrosis, patients can present with indurated plaques without ulcerations, which can be hard to differentiate from morphea.^16,48 However, the presence of ulcerations or hyperkeratosis can differentiate morphea from FICRD.¹⁶

Ultimately, it is the location of FICRD lesions that remains the biggest diagnostic clue. Any suspicious lesion present on the scapular or subscapular areas, anterolateral chest, and/or mid back should prompt an investigation into recent or remote history of fluoroscopic procedures. 

Management of FICRD

Diagnosis of FICRD should be made clinically based on the history and physical examination whenever possible, since a biopsy is not recommended.³⁵ Wound healing in FICRD is delayed, and biopsies can lead to ulcerations or secondary infections.¹⁷ Therefore, it is important to remain suspicious for FICRD. Management of FICRD should correspond to the clinical findings outlined by a recent Delphi consensus survey.⁴⁹ Regardless, the core of FICRD management framework should always include good hygiene, maintenance of skin hydration to improve epithelialization, and sufficient photoprotection.^49,50

Among the first signs of FICRD are telangiectasias. Although asymptomatic, their appearance can be distressing for patients. Pulsed dye laser therapy is a first-line option that has been studied and has shown clinical efficacy for treatment of telangiectasias and vascular changes in patients with FICRD.^49,51

If patients develop fibrotic changes, treatment options are limited. Fibrosis is hard to reverse, and the management approach is limited to symptomatic relief. Mechanical and deep-friction massages have been shown to be effective at reducing skin induration in patients.⁵² Fractional ablative lasers also may be utilized for skin contractures, especially if range of motion is affected.^53,54 Although it comes with its own challenges, autologous fat grafting has shown promise in reducing postradiation fibrosis and inducing angiogenesis in tissue.⁵⁵ Oral pentoxifylline also has shown mild efficacy, as it may be able to suppress TGF-β1 levels.⁵³ However, prevention of fibrotic changes may be the most important. Wei et al³¹ suggested that low-dose oral prednisolone at 5 mg twice daily for 3 weeks might be an option to prevent the progression of skin changes and even reverse fibrosis to an extent; however, further evidence regarding its efficacy still is necessary. Additionally, no evidence was identified to support the use of topical corticosteroids for fibrotic changes seen in FICRD.⁵⁶

Patients with FICRD or even acute radiation dermatitis after fluoroscopy tend to develop superficial ulcerations from minor traumas. Good wound hygiene, antiseptic care, and absorbent dressings, such as hydrogel and hydrocolloid, may be sufficient for treating these wounds, as seen in the Figure.^42,48 However, once patients develop refractory ulcerations or necrosis, treatment options are then limited to surgical removal with a flap or graft.^5,33,42,45
 

Risk for basal cell carcinomas and squamous cell carcinomas is higher in patients with radiation exposure; however, the exact risk from fluoroscopic procedures is unknown. One study demonstrated an increased risk of 6.9% in development of skin cancer after a median radiation exposure of 15.5 Gy and a mean latency period of 38.3 years,⁵⁷ and in another retrospective study, the risk was higher in Fitzpatrick skin types I and II.⁵⁸ Unlike the development of radiodermatitis itself, which shows a dose-dependent response, development of skin cancers follows a stochastic pattern (not dose dependent).⁵⁹ Therefore, it is important to identify these high-risk patients and establish follow-up.

Conclusion

Fluoroscopy-induced chronic radiation dermatitis can be a diagnostic challenge, as skin changes may not be readily associated with the procedure by patients. Therefore, any lesion with a geometric shape and accompanying chronic radiation dermatitis features located on the scapular or subscapular areas, anterolateral chest, and midback should prompt an investigation into history of fluoroscopic procedures. Treatment of chronic skin changes in FICRD depends on the clinical manifestations. Good hygiene, skin hydration, and sufficient photoprotection are crucial. Finally, long-term monitoring with skin examinations is important to assess for the development of skin cancers in the treated area.

Fluoroscopy is an imaging technique that allows for real-time visualization of internal structures in the body using continuous radiography beams. More than 1 million fluoroscopy-guided procedures are performed annually in the United States.¹ Utilization of these procedures continues to increase, and so does the probability of related complications, as prolonged exposure to ionizing radiation can cause skin injuries.² Fortunately, the incidence of radiation-induced skin injuries compared with the total number of fluoroscopic procedures performed remains small,² although one study suggested the incidence may be as high as 8.9% in at-risk populations.³

Radiation dermatitis is well recognized in dermatology as a complication of oncologic management; however, radiation dermatitis as a complication of fluoroscopic procedures is underrecognized.⁴ Fluoroscopy-induced radiation dermatitis can be categorized as acute, subacute, or chronic.⁵ Common fluoroscopic procedures that have been associated with fluoroscopy-induced radiation dermatitis include interventional cardiac procedures, neurovascular procedures, transjugular intrahepatic portosystemic shunt procedures, and endovascular abdominal aortic aneurysm repairs.^6,7

Patients with fluoroscopy-induced radiation dermatitis, particularly fluoroscopy-induced chronic radiation dermatitis (FICRD), can present to dermatology up to several years after the initial fluoroscopy procedure with no awareness of the association between the procedure and their skin findings. This presents a diagnostic challenge, and FICRD often is overlooked.^5,8-10

We conducted a literature search of PubMed articles indexed for MEDLINE using the search terms ­fluoroscopy and dermatitis. In this reappraisal, we will provide a comprehensive overview of fluoroscopy-induced ­radiation dermatitis with an emphasis on FICRD, covering its clinical manifestations, pathophysiology, risk factors, ­differential diagnosis, histology, and management. The aim of this review is to highlight the salient features and mimickers of FICRD and inform readers how to approach suspected cases, leading to accurate diagnosis and ­effective management.

Pathophysiology 

Fluoroscopy-induced radiation dermatitis is the result of dose-dependent radiation-induced tissue damage. As the peak skin dosage (PSD) of radiation increases over the course of a procedure or multiple procedures, the severity of skin injury predictably increases. During fluoroscopic procedures, the standard irradiation dosage ranges from 0.02 Gy/min to 0.05 Gy/min.¹¹ Transient skin changes may start to be seen around 2 Gy of cumulative exposure. Fluoroscopic procedures typically range in duration from 60 to 120 minutes; however, complex cases may exceed that. Additionally, multiple procedures performed within shorter intervals can result in greater PSD accumulation. Shorter intervals between procedures do not allow enough time for damage repair from the previous ­procedure and can result in further severe damage when the skin is re-exposed to radiation.² The American College of Radiology recommends medical follow-up after 10 Gy of cumulative exposure, while cumulative exposure above 15 Gy within a 6- to 12-month period is defined as a sentinel event, according to The Joint Commission.^12-14

Depending on the patient’s total radiation dosage during one or more procedures, the result of the tissue damage manifests differently at varying times: early skin changes are categorized as fluoroscopy-induced acute radiation dermatitis, and late skin changes are categorized as FICRD (Table 1).

Clinical Manifestations

Acute radiation dermatitis from fluoroscopic procedures manifests within hours to days up to 90 days following radiation exposure and can be characterized by erythema with blistering, desquamation, epilation, pigmentation changes, and even necrosis if the accumulated dosage exceeds 15 Gy.¹⁵ Chronic radiation dermatitis (which as related to fluoroscopic procedures is termed FICRD) has a longer onset of weeks to years and is clinically characterized by telangiectasias, permanent erythema, dermal atrophy, or ulcerations. Clinically, subacute radiation dermatitis shares features of both acute and chronic radiation dermatitis; therefore, it is differentiated based on its histologic features.^5,16

Although fluoroscopy-induced acute radiation dermatitis (Table 1) may precede FICRD, acute manifestations of fluoroscopy-related dermatitis can be subtle and often manifest in areas not easily visualized. Because referrals to dermatologists for full-skin examinations after fluoroscopy procedures are not standard, patients may not be aware of the association between these procedures and the development of skin lesions. Nonetheless, some patients may report a history of skin changes such as redness days or weeks after a fluoroscopic procedure with accompanying pain and pruritus limited to the fluoroscopy-exposed region, which tend to self-resolve.¹⁷ The risk for FICRD is thought to increase if a history of fluoroscopy-induced acute radiation dermatitis is present.¹⁸

The location of the skin findings correlates to the area exposed to prolonged radiation during the procedure(s). The most common areas include the scapular and subscapular regions, the right lateral trunk inferior to the axilla, the mid back, and the right anterolateral chest.^16,19,20 These regions are associated with more complex (eg, cardiac) procedures that have been reported to lead to prolonged radiation exposure. The skin findings in FICRD are described as geometric, corresponding to the squarish or rectangular radiography beam that is directed at the patient. Additionally, radiography beams spread outward as they travel in space; therefore, skin injuries are common at the region more distal to the path of origination of the beam.^21-23 Subsequently, a geometric, dyspigmented, indurated or atrophic plaque with telangiectasias and erosions or ulcerations with progressive worsening is a common manifestation of FICRD.^5,16,23 Patients also commonly present with pruritus or severe pain associated with the lesion.^24,25  

Dermatologic Manifestations of FICRD

Skin responses seen weeks to years after a fluoroscopic procedure and typically after cumulative radiation exposure of 10 Gy or greater are categorized as FICRD (Table 2). These changes also can be clinically graded based on the Radiation Therapy Oncology Group classification of radiation dermatitis (Tables 3 and 4).²⁶ Chronic changes in the skin largely result from remodeling of the vasculature and the subcutaneous tissue over time. Unlike acute changes, chronic changes typically persist and continue to worsen.²⁷

Telangiectasias—Anywhere from months to 1 year after exposure to 10 Gy of radiation, proliferation of atypical superficial vessels in the dermis can be seen, typically manifesting as telangiectasias on physical examination. Telangiectasias can increase with time and can even exhibit a dose-dependent relationship to the radiation exposure.²⁸

Atrophy—Atrophic-appearing skin after radiation exposure is the result of direct injury to both the epidermis and fibroblasts in the dermis. The destruction of keratinocytes leads to a thin epidermis, and destruction of dermal fibroblasts causes insufficient collagen production.²⁹ Clinically, this process manifests as an atrophic plaque that can be seen 12 weeks to 1 year after the procedure. 

Fibrosis—Approximately 1 year after the exposure, the initial damage can lead to disruption of molecular pathways, causing fibrosis. Transforming growth factor (TGF) β1 is the main factor involved.²⁹ Damage to the endothelial cells results in increased TGF-β1 levels, which causes increased stimulation of remaining atypical fibroblasts and thus increased irregular collagen deposition.³⁰ Further adding to this knowledge, Wei et al³¹ recently proposed that damage to the epidermal keratinocytes leads to disruption of yes-associated protein 1, which is a protective factor released from keratinocytes that regulates the dermal fibroblasts. However, extensive damage to the keratinocytes can lead to lower yes-associated protein 1 levels and its downstream activity, leading to increased levels of TGF-β1 and fibroblast activity.³¹ Clinically, this fibrotic stage is seen as indurated plaques in patients. 

Necrosis—There are 2 forms of necrosis that can be seen. Ischemic dermal necrosis typically occurs in the acute phase after 10 weeks and approximately 18 Gy of cumulative exposure. It results from substantial skin damage, including microvascular damage and reduction in dermal capillaries, leading to ischemia of the tissue.² Late dermal necrosis is the process seen in the chronic stage of FICRD and radiation dermatitis not related to ­fluoroscopy. It results from the inability of the fibrotic dermis to vascularly support the epidermis above it.² It can be seen anywhere from 1 to 4 years after the procedure. This stage clinically manifests as worsening ulcerations with major pain and increased risk for secondary infections.¹⁶ 

Dyspigmentation—Dyspigmentation at the site of the radiation exposure can be seen acutely and chronically. Dosage above 15 to 18 Gy can lead to destruction of melanocytes, which can cause hypopigmentation in exposed areas. However, melanocytes are relatively resistant to radiation; therefore, dosages below the threshold of destruction of 15 to 18 Gy can cause melanocytic hyperactivity leading to hyperpigmentation.³² Hence, pigmentary changes can vary greatly. Classically, a central area of hypopigmentation with surrounding hyperpigmentation is seen.

Histology 

Histologic appearance of radiation dermatitis varies depending on its stage. Acute radiation dermatitis primarily demonstrates superficial dermal edema, damage to the basal cell layer, small vessel dilation with thrombi, and hemorrhage along with a sparse inflammatory cell infiltrate.³³ Histology typically is the only way to characterize subacute radiation dermatitis.⁵ Lichenoid tissue reaction is its characteristic feature. Mononuclear cells are found adjected to necrotic keratinocytes along with prominent vacuolization of the basal cell layer.³³

The key histologic features of chronic radiation dermatitis include epidermal atrophy, hyperkeratosis, telangiectasias, loss of adnexal structures, and dermal fibrosis along with sparse atypical stellate fibroblasts.³⁴ However, clinical context of fluoroscopic exposure is required for the dermatopathologist to differentiate chronic radiation dermatitis from its histologic differential of morphea and lichen sclerosus. In a cross-sectional study, only 1 of 6 cases (16.7%) was correctly diagnosed as chronic radiation dermatitis in the absence of correlating clinical history.³⁵ 

Risk Factors for FICRD 

Since the diagnosis of FICRD can be a clinical challenge, understanding the risk factors can be helpful. The general likelihood of developing FICRD is related to the duration, frequency, interval, intensity, and area of radiation exposure. Procedures exceeding the normal duration of 60 to 120 minutes have been well documented as a substantial risk factor for radiation dermatitis and FICRD.^36-38 The risk tends to be higher in longer procedures because they result in more radiation exposure and higher accumulated PSD. Obesity (ie, body mass index >26) is the major risk factor that has been associated with longer procedure times, as higher radiation dosages are necessary to penetrate the body of a larger patient and a larger skin surface area is exposed.^37-39

Other risk factors associated with FICRD relate to how prone a patient is to radiation-induced DNA damage. Older patients are at higher risk due to lower intrinsic ability of the tissue to repair itself.¹¹ Patients with a history of connective tissue diseases—particularly lupus, scleroderma, and mixed connective tissue disease—are at an increased risk.⁴⁰ Furthermore, patients with genetic disorders that impair DNA repair are more susceptible to radiation-induced DNA damage; therefore, patients with ataxia-telangiectasia, xeroderma pigmentosum, Fanconi anemia, and hereditary nevoid basal cell carcinoma are at higher risk for FICRD.³⁹ Similarly, medications that can affect DNA repair also have been shown to be risk factors. These medications include chemotherapeutic agents such as actinomycin D, cyclophosphamide, doxorubicin, methotrexate, and 5-fluorouracil.^2,39 Diabetes, hyperthyroidism, and tobacco use also have been shown to increase a patient’s risk for FICRD.³⁹ It also is reasonable to believe that patients with defects in fibroblasts or with elastin or collagen disorders (eg, Ehlers-Danlos syndrome) would be at higher risk, but there are no known studies highlighting the association in the literature.

Differential Diagnosis of FICRD 

Acute allergic or irritant contact dermatitis manifests with a localized area of erythematous skin accompanied by pruritus.⁴¹ Patients with FICRD can present with a localized area of erythema and hyperpigmentation with minimal atrophy. The lesion may accompany substantial pruritus, which can favor the more common diagnosis of contact dermatitis.^35,42,43

Fixed-drug eruption manifests as a well-defined, hyperpigmented plaque in a fixed location that occurs upon ingestion of a drug.⁴⁴ Fluoroscopy-induced chronic radiation dermatitis lesions are well demarcated and geometrically shaped and therefore can mimic lesions seen in fixed-drug eruptions.⁴⁵ Additionally, the patient population undergoing fluoroscopic procedures tends to have major comorbidities requiring multiple medications.⁴

Decubitus ulcers are a result of vascular compromise to an area of skin due to constant pressure and are most commonly seen in the sacral region of patients with ­obesity.⁴⁶ Ulcerated FICRD lesions can manifest on the lower midback. These lesions can be seen after endovascular repair of abdominal aortic aneurysm or prostatic artery embolization.^20,21 The location of these lesions can mimic decubitus ulcers if fluoroscopic history is unknown. As mentioned, obesity also increases the risk for FICRD. 

Morphea can manifest as a localized area of induration and hyperpigmentation of the skin.⁴⁷ When FICRD has progressed to dermal fibrosis, patients can present with indurated plaques without ulcerations, which can be hard to differentiate from morphea.^16,48 However, the presence of ulcerations or hyperkeratosis can differentiate morphea from FICRD.¹⁶

Ultimately, it is the location of FICRD lesions that remains the biggest diagnostic clue. Any suspicious lesion present on the scapular or subscapular areas, anterolateral chest, and/or mid back should prompt an investigation into recent or remote history of fluoroscopic procedures. 

Management of FICRD

Diagnosis of FICRD should be made clinically based on the history and physical examination whenever possible, since a biopsy is not recommended.³⁵ Wound healing in FICRD is delayed, and biopsies can lead to ulcerations or secondary infections.¹⁷ Therefore, it is important to remain suspicious for FICRD. Management of FICRD should correspond to the clinical findings outlined by a recent Delphi consensus survey.⁴⁹ Regardless, the core of FICRD management framework should always include good hygiene, maintenance of skin hydration to improve epithelialization, and sufficient photoprotection.^49,50

Among the first signs of FICRD are telangiectasias. Although asymptomatic, their appearance can be distressing for patients. Pulsed dye laser therapy is a first-line option that has been studied and has shown clinical efficacy for treatment of telangiectasias and vascular changes in patients with FICRD.^49,51

If patients develop fibrotic changes, treatment options are limited. Fibrosis is hard to reverse, and the management approach is limited to symptomatic relief. Mechanical and deep-friction massages have been shown to be effective at reducing skin induration in patients.⁵² Fractional ablative lasers also may be utilized for skin contractures, especially if range of motion is affected.^53,54 Although it comes with its own challenges, autologous fat grafting has shown promise in reducing postradiation fibrosis and inducing angiogenesis in tissue.⁵⁵ Oral pentoxifylline also has shown mild efficacy, as it may be able to suppress TGF-β1 levels.⁵³ However, prevention of fibrotic changes may be the most important. Wei et al³¹ suggested that low-dose oral prednisolone at 5 mg twice daily for 3 weeks might be an option to prevent the progression of skin changes and even reverse fibrosis to an extent; however, further evidence regarding its efficacy still is necessary. Additionally, no evidence was identified to support the use of topical corticosteroids for fibrotic changes seen in FICRD.⁵⁶

Patients with FICRD or even acute radiation dermatitis after fluoroscopy tend to develop superficial ulcerations from minor traumas. Good wound hygiene, antiseptic care, and absorbent dressings, such as hydrogel and hydrocolloid, may be sufficient for treating these wounds, as seen in the Figure.^42,48 However, once patients develop refractory ulcerations or necrosis, treatment options are then limited to surgical removal with a flap or graft.^5,33,42,45
 

Risk for basal cell carcinomas and squamous cell carcinomas is higher in patients with radiation exposure; however, the exact risk from fluoroscopic procedures is unknown. One study demonstrated an increased risk of 6.9% in development of skin cancer after a median radiation exposure of 15.5 Gy and a mean latency period of 38.3 years,⁵⁷ and in another retrospective study, the risk was higher in Fitzpatrick skin types I and II.⁵⁸ Unlike the development of radiodermatitis itself, which shows a dose-dependent response, development of skin cancers follows a stochastic pattern (not dose dependent).⁵⁹ Therefore, it is important to identify these high-risk patients and establish follow-up.

Conclusion

Fluoroscopy-induced chronic radiation dermatitis can be a diagnostic challenge, as skin changes may not be readily associated with the procedure by patients. Therefore, any lesion with a geometric shape and accompanying chronic radiation dermatitis features located on the scapular or subscapular areas, anterolateral chest, and midback should prompt an investigation into history of fluoroscopic procedures. Treatment of chronic skin changes in FICRD depends on the clinical manifestations. Good hygiene, skin hydration, and sufficient photoprotection are crucial. Finally, long-term monitoring with skin examinations is important to assess for the development of skin cancers in the treated area.

Mohs micrographic surgery (MMS)—developed by Dr. Frederic Mohs in the 1930s—is the gold standard for treating various cutaneous malignancies. It provides maximal conservation of uninvolved tissues while producing higher cure rates compared to wide local excision.^1,2

We sought to assess the various characteristics that impact patient satisfaction to help Mohs surgeons incorporate relatively simple yet clinically significant practices into their patient encounters. We conducted a systematic literature search of peer-reviewed PubMed articles indexed for MEDLINE from database inception through November 2023 using the terms Mohs micrographic surgery and patient satisfaction. Among the inclusion criteria were studies involving participants having undergone MMS, with objective assessments on patient-reported satisfaction or preferences related to patient education, communication, anxiety-alleviating measures, or QOL in MMS. Studies were excluded if they failed to meet these criteria, were outdated and no longer clinically relevant, or measured unalterable factors with no significant impact on how Mohs surgeons could change clinical practice. Of the 157 nonreplicated studies identified, 34 met inclusion criteria.

Perioperative Patient Communication and Education Techniques

Perioperative Patient Communication—Many studies have evaluated the impact of perioperative patient-provider communication and education on patient satisfaction in those undergoing MMS. Studies focusing on preoperative and postoperative telephone calls, patient consultation formats, and patient-perceived impact of such communication modalities have been well documented (Table 1).^3-8 The importance of the patient follow-up after MMS was further supported by a retrospective study concluding that 88.7% (86/97) of patients regarded follow-up visits as important, and 80% (77/97) desired additional follow-up 3 months after MMS.⁹ Additional studies have highlighted the importance of thorough and open perioperative patient-provider communication during MMS (Table 2).^10-12

Patient-Education Techniques—Many studies have assessed the use of visual models to aid in patient education on MMS, specifically the preprocedural consent process (Table 3).^13-16 Additionally, 2 randomized controlled trials assessing the use of at-home and same-day in-office preoperative educational videos concluded that these interventions increased patient knowledge and confidence regarding procedural risks and benefits, with no statistically significant differences in patient anxiety or satisfaction.^17,18

Despite the availability of these educational videos, many patients often turn to online resources for self-education, which is problematic if reader literacy is incongruent with online readability. One study assessing readability of online MMS resources concluded that the most accessed articles exceeded the recommended reading level for adequate patient comprehension.¹⁹ A survey studying a wide range of variables related to patient satisfaction (eg, demographics, socioeconomics, health status) in 339 MMS patients found that those who considered themselves more involved in the decision-making process were more satisfied in the short-term, and married patients had even higher long-term satisfaction. Interestingly, this study also concluded that undergoing 3 or more MMS stages was associated with higher short- and long-term satisfaction, likely secondary to perceived effects of increased overall care, medical attention, and time spent with the provider.²⁰

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding patient education and communication^13-20:

• Preoperative and same-day postoperative telephone follow-up (TFU) do not show statistically significant impacts on patient satisfaction; however, TFU allows for identification of postoperative concerns and inadequate pain management, which may have downstream effects on long-term perception of the overall patient experience.
• The use of video-assisted consent yields improved patient satisfaction and knowledge, while video content—traditional or didactic—has no impact on satisfaction in new MMS patients.
• The use of at-home or same-day in-office preoperative educational videos can improve procedural knowledge and risk-benefit understanding of MMS while having no impact on satisfaction.
• Bedside manner and effective in-person communication by the provider often takes precedence in the patient experience; however, implementation of additional educational modalities should be considered.

Patient Anxiety and QOL

Reducing Patient Anxiety—The use of perioperative distractors to reduce patient anxiety may play an integral role when patients undergo MMS, as there often are prolonged waiting periods between stages when patients may feel increasingly vulnerable or anxious. Table 4 reviews studies on perioperative distractors that showed a statistically significant reduction in MMS patient anxiety.^21-24

Although not statistically significant, additional studies evaluating the use of intraoperative anxiety-reduction methods in MMS have demonstrated a downtrend in patient anxiety with the following interventions: engaging in small talk with clinic staff, bringing a guest, eating, watching television, communicating surgical expectations with the provider, handholding, use of a stress ball, and use of 3-dimensional educational MMS models.^25-27 Similarly, a survey of 73 patients undergoing MMS found that patients tended to enjoy complimentary beverages preprocedurally in the waiting room, reading, speaking with their guest, watching television, or using their telephone during wait times.²⁸ Table 5 lists additional perioperative factors encompassing specific patient and surgical characteristics that help reduce patient anxiety.^29-32

Patient QOL—Many methods aimed at decreasing MMS-related patient anxiety often show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience. A prospective observational study of MMS patients noted a statistically significant improvement in patient QOL scores 3 months postsurgery (P=.0007), demonstrating that MMS generally results in positive patient outcomes despite preprocedural anxiety.³³ An additional prospective study in MMS patients with nonmelanoma skin cancer concluded that sex, age, and closure type—factors often shown to affect anxiety levels—did not significantly impact patient satisfaction.³⁴ Similarly, high satisfaction levels can be expected among MMS patients undergoing treatment of melanoma in situ, with more than 90% of patients rating their treatment experience a 4 (agree) or 5 (strongly agree) out of 5 in short- and long-term satisfaction assessments (38/41 and 40/42, respectively).³⁵ This assessment, conducted 3 months postoperatively, asked patients to score the statement, “I am completely satisfied with the treatment of my skin problem,” on a scale ranging from 1 (strongly disagree) to 5 (strongly agree).

Lastly, patient perception of their surgeon’s skill may contribute to levels of patient satisfaction. Although suture spacing has not been shown to affect surgical outcomes, it has been demonstrated to impact the patient’s perception of surgical skill and is further supported by a study concluding that closures with 2-mm spacing were ranked significantly lower by patients compared with closures with either 4- or 6-mm spacing (P=.005 and P=.012, respectively).³⁶

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding anxiety-reducing measures and patient-perceived QOL^21-36:

• Factors shown to decrease patient anxiety include patient personalized music, virtual-reality experience, perioperative informational videos, and 3-dimensional–printed MMS models.
• Many methods aimed at decreasing MMS-related patient anxiety show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience.
• Higher anxiety can be associated with worse QOL scores in MMS patients, and additional factors that may have a negative impact on anxiety include female sex, younger age, and tumor location on the face.

Conclusion

Many factors affect patient satisfaction in MMS. Increased awareness and acknowledgement of these factors can foster improved clinical practice and patient experience, which can have downstream effects on patient compliance and overall psychosocial and medical well-being. With the movement toward value-based health care, patient satisfaction ratings are likely to play an increasingly important role in physician reimbursement. Adapting one’s practice to include high-quality, time-efficient, patient-centered care goes hand in hand with increasing MMS patient satisfaction. Careful evaluation and scrutiny of one’s current practices while remaining cognizant of patient population, resource availability, and clinical limitations often reveal opportunities for small adjustments that can have a great impact on patient satisfaction. This thorough assessment and review of the published literature aims to assist MMS surgeons in understanding the role that certain factors—(1) perioperative patient communication and education techniques and (2) patient anxiety, QOL, and additional considerations—have on overall satisfaction with MMS. Specific consideration should be placed on the fact that patient satisfaction is multifactorial, and many different interventions can have a positive impact on the overall patient experience.

Mohs micrographic surgery (MMS)—developed by Dr. Frederic Mohs in the 1930s—is the gold standard for treating various cutaneous malignancies. It provides maximal conservation of uninvolved tissues while producing higher cure rates compared to wide local excision.^1,2

We sought to assess the various characteristics that impact patient satisfaction to help Mohs surgeons incorporate relatively simple yet clinically significant practices into their patient encounters. We conducted a systematic literature search of peer-reviewed PubMed articles indexed for MEDLINE from database inception through November 2023 using the terms Mohs micrographic surgery and patient satisfaction. Among the inclusion criteria were studies involving participants having undergone MMS, with objective assessments on patient-reported satisfaction or preferences related to patient education, communication, anxiety-alleviating measures, or QOL in MMS. Studies were excluded if they failed to meet these criteria, were outdated and no longer clinically relevant, or measured unalterable factors with no significant impact on how Mohs surgeons could change clinical practice. Of the 157 nonreplicated studies identified, 34 met inclusion criteria.

Perioperative Patient Communication and Education Techniques

Perioperative Patient Communication—Many studies have evaluated the impact of perioperative patient-provider communication and education on patient satisfaction in those undergoing MMS. Studies focusing on preoperative and postoperative telephone calls, patient consultation formats, and patient-perceived impact of such communication modalities have been well documented (Table 1).^3-8 The importance of the patient follow-up after MMS was further supported by a retrospective study concluding that 88.7% (86/97) of patients regarded follow-up visits as important, and 80% (77/97) desired additional follow-up 3 months after MMS.⁹ Additional studies have highlighted the importance of thorough and open perioperative patient-provider communication during MMS (Table 2).^10-12

Patient-Education Techniques—Many studies have assessed the use of visual models to aid in patient education on MMS, specifically the preprocedural consent process (Table 3).^13-16 Additionally, 2 randomized controlled trials assessing the use of at-home and same-day in-office preoperative educational videos concluded that these interventions increased patient knowledge and confidence regarding procedural risks and benefits, with no statistically significant differences in patient anxiety or satisfaction.^17,18

Despite the availability of these educational videos, many patients often turn to online resources for self-education, which is problematic if reader literacy is incongruent with online readability. One study assessing readability of online MMS resources concluded that the most accessed articles exceeded the recommended reading level for adequate patient comprehension.¹⁹ A survey studying a wide range of variables related to patient satisfaction (eg, demographics, socioeconomics, health status) in 339 MMS patients found that those who considered themselves more involved in the decision-making process were more satisfied in the short-term, and married patients had even higher long-term satisfaction. Interestingly, this study also concluded that undergoing 3 or more MMS stages was associated with higher short- and long-term satisfaction, likely secondary to perceived effects of increased overall care, medical attention, and time spent with the provider.²⁰

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding patient education and communication^13-20:

• Preoperative and same-day postoperative telephone follow-up (TFU) do not show statistically significant impacts on patient satisfaction; however, TFU allows for identification of postoperative concerns and inadequate pain management, which may have downstream effects on long-term perception of the overall patient experience.
• The use of video-assisted consent yields improved patient satisfaction and knowledge, while video content—traditional or didactic—has no impact on satisfaction in new MMS patients.
• The use of at-home or same-day in-office preoperative educational videos can improve procedural knowledge and risk-benefit understanding of MMS while having no impact on satisfaction.
• Bedside manner and effective in-person communication by the provider often takes precedence in the patient experience; however, implementation of additional educational modalities should be considered.

Patient Anxiety and QOL

Reducing Patient Anxiety—The use of perioperative distractors to reduce patient anxiety may play an integral role when patients undergo MMS, as there often are prolonged waiting periods between stages when patients may feel increasingly vulnerable or anxious. Table 4 reviews studies on perioperative distractors that showed a statistically significant reduction in MMS patient anxiety.^21-24

Although not statistically significant, additional studies evaluating the use of intraoperative anxiety-reduction methods in MMS have demonstrated a downtrend in patient anxiety with the following interventions: engaging in small talk with clinic staff, bringing a guest, eating, watching television, communicating surgical expectations with the provider, handholding, use of a stress ball, and use of 3-dimensional educational MMS models.^25-27 Similarly, a survey of 73 patients undergoing MMS found that patients tended to enjoy complimentary beverages preprocedurally in the waiting room, reading, speaking with their guest, watching television, or using their telephone during wait times.²⁸ Table 5 lists additional perioperative factors encompassing specific patient and surgical characteristics that help reduce patient anxiety.^29-32

Patient QOL—Many methods aimed at decreasing MMS-related patient anxiety often show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience. A prospective observational study of MMS patients noted a statistically significant improvement in patient QOL scores 3 months postsurgery (P=.0007), demonstrating that MMS generally results in positive patient outcomes despite preprocedural anxiety.³³ An additional prospective study in MMS patients with nonmelanoma skin cancer concluded that sex, age, and closure type—factors often shown to affect anxiety levels—did not significantly impact patient satisfaction.³⁴ Similarly, high satisfaction levels can be expected among MMS patients undergoing treatment of melanoma in situ, with more than 90% of patients rating their treatment experience a 4 (agree) or 5 (strongly agree) out of 5 in short- and long-term satisfaction assessments (38/41 and 40/42, respectively).³⁵ This assessment, conducted 3 months postoperatively, asked patients to score the statement, “I am completely satisfied with the treatment of my skin problem,” on a scale ranging from 1 (strongly disagree) to 5 (strongly agree).

Lastly, patient perception of their surgeon’s skill may contribute to levels of patient satisfaction. Although suture spacing has not been shown to affect surgical outcomes, it has been demonstrated to impact the patient’s perception of surgical skill and is further supported by a study concluding that closures with 2-mm spacing were ranked significantly lower by patients compared with closures with either 4- or 6-mm spacing (P=.005 and P=.012, respectively).³⁶

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding anxiety-reducing measures and patient-perceived QOL^21-36:

• Factors shown to decrease patient anxiety include patient personalized music, virtual-reality experience, perioperative informational videos, and 3-dimensional–printed MMS models.
• Many methods aimed at decreasing MMS-related patient anxiety show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience.
• Higher anxiety can be associated with worse QOL scores in MMS patients, and additional factors that may have a negative impact on anxiety include female sex, younger age, and tumor location on the face.

Conclusion

Many factors affect patient satisfaction in MMS. Increased awareness and acknowledgement of these factors can foster improved clinical practice and patient experience, which can have downstream effects on patient compliance and overall psychosocial and medical well-being. With the movement toward value-based health care, patient satisfaction ratings are likely to play an increasingly important role in physician reimbursement. Adapting one’s practice to include high-quality, time-efficient, patient-centered care goes hand in hand with increasing MMS patient satisfaction. Careful evaluation and scrutiny of one’s current practices while remaining cognizant of patient population, resource availability, and clinical limitations often reveal opportunities for small adjustments that can have a great impact on patient satisfaction. This thorough assessment and review of the published literature aims to assist MMS surgeons in understanding the role that certain factors—(1) perioperative patient communication and education techniques and (2) patient anxiety, QOL, and additional considerations—have on overall satisfaction with MMS. Specific consideration should be placed on the fact that patient satisfaction is multifactorial, and many different interventions can have a positive impact on the overall patient experience.

Mohs micrographic surgery (MMS)—developed by Dr. Frederic Mohs in the 1930s—is the gold standard for treating various cutaneous malignancies. It provides maximal conservation of uninvolved tissues while producing higher cure rates compared to wide local excision.^1,2

We sought to assess the various characteristics that impact patient satisfaction to help Mohs surgeons incorporate relatively simple yet clinically significant practices into their patient encounters. We conducted a systematic literature search of peer-reviewed PubMed articles indexed for MEDLINE from database inception through November 2023 using the terms Mohs micrographic surgery and patient satisfaction. Among the inclusion criteria were studies involving participants having undergone MMS, with objective assessments on patient-reported satisfaction or preferences related to patient education, communication, anxiety-alleviating measures, or QOL in MMS. Studies were excluded if they failed to meet these criteria, were outdated and no longer clinically relevant, or measured unalterable factors with no significant impact on how Mohs surgeons could change clinical practice. Of the 157 nonreplicated studies identified, 34 met inclusion criteria.

Perioperative Patient Communication and Education Techniques

Perioperative Patient Communication—Many studies have evaluated the impact of perioperative patient-provider communication and education on patient satisfaction in those undergoing MMS. Studies focusing on preoperative and postoperative telephone calls, patient consultation formats, and patient-perceived impact of such communication modalities have been well documented (Table 1).^3-8 The importance of the patient follow-up after MMS was further supported by a retrospective study concluding that 88.7% (86/97) of patients regarded follow-up visits as important, and 80% (77/97) desired additional follow-up 3 months after MMS.⁹ Additional studies have highlighted the importance of thorough and open perioperative patient-provider communication during MMS (Table 2).^10-12

Patient-Education Techniques—Many studies have assessed the use of visual models to aid in patient education on MMS, specifically the preprocedural consent process (Table 3).^13-16 Additionally, 2 randomized controlled trials assessing the use of at-home and same-day in-office preoperative educational videos concluded that these interventions increased patient knowledge and confidence regarding procedural risks and benefits, with no statistically significant differences in patient anxiety or satisfaction.^17,18

Despite the availability of these educational videos, many patients often turn to online resources for self-education, which is problematic if reader literacy is incongruent with online readability. One study assessing readability of online MMS resources concluded that the most accessed articles exceeded the recommended reading level for adequate patient comprehension.¹⁹ A survey studying a wide range of variables related to patient satisfaction (eg, demographics, socioeconomics, health status) in 339 MMS patients found that those who considered themselves more involved in the decision-making process were more satisfied in the short-term, and married patients had even higher long-term satisfaction. Interestingly, this study also concluded that undergoing 3 or more MMS stages was associated with higher short- and long-term satisfaction, likely secondary to perceived effects of increased overall care, medical attention, and time spent with the provider.²⁰

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding patient education and communication^13-20:

• Preoperative and same-day postoperative telephone follow-up (TFU) do not show statistically significant impacts on patient satisfaction; however, TFU allows for identification of postoperative concerns and inadequate pain management, which may have downstream effects on long-term perception of the overall patient experience.
• The use of video-assisted consent yields improved patient satisfaction and knowledge, while video content—traditional or didactic—has no impact on satisfaction in new MMS patients.
• The use of at-home or same-day in-office preoperative educational videos can improve procedural knowledge and risk-benefit understanding of MMS while having no impact on satisfaction.
• Bedside manner and effective in-person communication by the provider often takes precedence in the patient experience; however, implementation of additional educational modalities should be considered.

Patient Anxiety and QOL

Reducing Patient Anxiety—The use of perioperative distractors to reduce patient anxiety may play an integral role when patients undergo MMS, as there often are prolonged waiting periods between stages when patients may feel increasingly vulnerable or anxious. Table 4 reviews studies on perioperative distractors that showed a statistically significant reduction in MMS patient anxiety.^21-24

Although not statistically significant, additional studies evaluating the use of intraoperative anxiety-reduction methods in MMS have demonstrated a downtrend in patient anxiety with the following interventions: engaging in small talk with clinic staff, bringing a guest, eating, watching television, communicating surgical expectations with the provider, handholding, use of a stress ball, and use of 3-dimensional educational MMS models.^25-27 Similarly, a survey of 73 patients undergoing MMS found that patients tended to enjoy complimentary beverages preprocedurally in the waiting room, reading, speaking with their guest, watching television, or using their telephone during wait times.²⁸ Table 5 lists additional perioperative factors encompassing specific patient and surgical characteristics that help reduce patient anxiety.^29-32

Patient QOL—Many methods aimed at decreasing MMS-related patient anxiety often show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience. A prospective observational study of MMS patients noted a statistically significant improvement in patient QOL scores 3 months postsurgery (P=.0007), demonstrating that MMS generally results in positive patient outcomes despite preprocedural anxiety.³³ An additional prospective study in MMS patients with nonmelanoma skin cancer concluded that sex, age, and closure type—factors often shown to affect anxiety levels—did not significantly impact patient satisfaction.³⁴ Similarly, high satisfaction levels can be expected among MMS patients undergoing treatment of melanoma in situ, with more than 90% of patients rating their treatment experience a 4 (agree) or 5 (strongly agree) out of 5 in short- and long-term satisfaction assessments (38/41 and 40/42, respectively).³⁵ This assessment, conducted 3 months postoperatively, asked patients to score the statement, “I am completely satisfied with the treatment of my skin problem,” on a scale ranging from 1 (strongly disagree) to 5 (strongly agree).

Lastly, patient perception of their surgeon’s skill may contribute to levels of patient satisfaction. Although suture spacing has not been shown to affect surgical outcomes, it has been demonstrated to impact the patient’s perception of surgical skill and is further supported by a study concluding that closures with 2-mm spacing were ranked significantly lower by patients compared with closures with either 4- or 6-mm spacing (P=.005 and P=.012, respectively).³⁶

Synthesis of this information with emphasis on the higher evidence-based studies—including systematic reviews, meta-analyses, and randomized controlled trials—yields the following beneficial interventions regarding anxiety-reducing measures and patient-perceived QOL^21-36:

• Factors shown to decrease patient anxiety include patient personalized music, virtual-reality experience, perioperative informational videos, and 3-dimensional–printed MMS models.
• Many methods aimed at decreasing MMS-related patient anxiety show no direct impact on patient satisfaction, likely due to the multifactorial nature of the patient-perceived experience.
• Higher anxiety can be associated with worse QOL scores in MMS patients, and additional factors that may have a negative impact on anxiety include female sex, younger age, and tumor location on the face.

Conclusion

Many factors affect patient satisfaction in MMS. Increased awareness and acknowledgement of these factors can foster improved clinical practice and patient experience, which can have downstream effects on patient compliance and overall psychosocial and medical well-being. With the movement toward value-based health care, patient satisfaction ratings are likely to play an increasingly important role in physician reimbursement. Adapting one’s practice to include high-quality, time-efficient, patient-centered care goes hand in hand with increasing MMS patient satisfaction. Careful evaluation and scrutiny of one’s current practices while remaining cognizant of patient population, resource availability, and clinical limitations often reveal opportunities for small adjustments that can have a great impact on patient satisfaction. This thorough assessment and review of the published literature aims to assist MMS surgeons in understanding the role that certain factors—(1) perioperative patient communication and education techniques and (2) patient anxiety, QOL, and additional considerations—have on overall satisfaction with MMS. Specific consideration should be placed on the fact that patient satisfaction is multifactorial, and many different interventions can have a positive impact on the overall patient experience.

Pseudofolliculitis barbae (PFB), also known as razor bumps, is a common inflammatory condition characterized by papules and pustules that typically appear in the beard and cheek regions. It occurs when shaved hair regrows and penetrates the skin, leading to irritation and inflammation. While anyone who shaves can develop PFB, it is more prevalent and severe in individuals with naturally tightly coiled, coarse-textured hair.^1,2 PFB is common in individuals who shave frequently due to personal choice or profession, such as members of the US military^3,4 and firefighters, who are required to remain clean shaven for safety (eg, ensuring proper fit of a respirator mask).⁵ Early diagnosis and treatment of PFB are essential to prevent long-term complications such as scarring or hyperpigmentation, which may be more severe in those with darker skin tones.

Epidemiology

PFB is most common in Black men, affecting 45% to 83% of men of African ancestry.^1,2 This condition also can affect individuals of various ethnicities with coarse or curly hair. The spiral shape of the hair increases the likelihood that it will regrow into the skin after shaving.⁶ Women with hirsutism who shave also can develop PFB.

Key Clinical Features

The papules and pustules seen in PFB may be flesh colored, erythematous, hyperpigmented, brown, or violaceous. Erythema may be less pronounced in darker vs lighter skin tones. Persistent and severe postinflammatory hyperpigmentation may occur, and hypertrophic or keloidal scars may develop in affected areas. Dermoscopy may reveal extrafollicular hair penetration as well as follicular or perifollicular pustules accompanied by hyperkeratosis.

Worth Noting

The most effective management for PFB is to discontinue shaving.¹ If shaving is desired or necessary, it is recommended that patients apply lukewarm water to the affected area followed by a generous amount of shaving foam or gel to create a protective antifriction layer that allows the razor to glide more smoothly over the skin and reduces subsequent irritation.² Using the right razor technology also may help alleviate symptoms. Research has shown that multiblade razors used in conjunction with preshave hair hydration and postshave moisturization do not worsen PFB.² A recent study found that multiblade razor technology paired with use of a shave foam or gel actually improved skin appearance in patients with PFB.⁷

It is important to direct patients to shave in the direction of hair growth; however, this may not be possible for individuals with curly or coarse hair, as the hair may grow in many directions.^8,9 Patients also should avoid pulling the skin taut while shaving, as doing so allows the hair to be clipped below the surface, where it can repenetrate the skin and cause further irritation. As an alternative to shaving with a razor, patients can use hair clippers to trim beard hair, which leaves behind stubble and interrupts the cycle of retracted hairs under the skin. Nd:YAG laser therapy has demonstrated efficacy in reduction of PFB papules and pustules.^9-12 Greater mean improvement in inflammatory papules and reduction in hair density was noted in participants who received Nd:YAG laser plus eflornithine compared with those who received the laser or eflornithine alone.¹¹ Patients should not pluck or dig into the skin to remove any ingrown hairs. If a tweezer is used, the patient should gently lift the tip of the ingrown hair with the tweezer to dislodge it from the skin and prevent plucking out the hair completely.

To help manage inflammation after shaving, topical treatments such as benzoyl peroxide 5%/clindamycin 1% gel can be used.^3,13 A low-potency steroid such as topical hydrocortisone 2.5% applied once or twice daily for up to 2 to 3 days may be helpful.^1,14 Adjunctive treatments including keratolytics (eg, topical retinoids, hydroxy acids) reduce perifollicular hyperkeratosis.^14,15 Agents containing alpha hydroxy acids (eg, glycolic acid) also can decrease the curvature of the hair itself by reducing the sulfhydryl bonds.⁶ If secondary bacterial infections occur, oral antibiotics (eg, doxycycline) may be necessary.

Health Disparity Highlight

Individuals with darker skin tones are at higher risk for PFB and associated complications. Limited access to dermatology services may further exacerbate these challenges. Individuals with PFB may not seek medical treatment until the condition becomes severe. Clinicians also may underestimate the severity of PFB—particularly in those with darker skin tones—based on erythema alone because it may be less pronounced in darker vs lighter skin tones.¹⁶

While permanent hair reduction with laser therapy is a treatment option for PFB, it may be inaccessible to some patients because it can be expensive and is coded as a cosmetic procedure. Additionally, patients may not have access to specialists who are experienced in performing the procedure in those with darker skin tones.⁹ Some patients also may not want to permanently reduce the amount of hair that grows in the beard area for personal or religious reasons.¹⁷

Pseudofolliculitis barbae also has been linked to professional disparities. One study found that members of the US Air Force who had medical shaving waivers experienced longer times to promotion than those with no waiver.¹⁸ Delays in promotion may be linked to perceptions of unprofessionalism, exclusion from high-profile duties, and concerns about career progression. While this delay was similar for individuals of all races, the majority of those in the waiver group were Black/African American. In 2021, 4 Black firefighters with PFB were unsuccessful in their bid to get a medical accommodation regarding a New York City Fire Department policy requiring them to be clean shaven where the oxygen mask seals against the skin.⁵ More research is needed on mask safety and efficiency relative to the length of facial hair. Accommodations or tailored masks for facial hair conditions also are necessary so individuals with PFB can meet job requirements while managing their condition.

Pseudofolliculitis barbae (PFB), also known as razor bumps, is a common inflammatory condition characterized by papules and pustules that typically appear in the beard and cheek regions. It occurs when shaved hair regrows and penetrates the skin, leading to irritation and inflammation. While anyone who shaves can develop PFB, it is more prevalent and severe in individuals with naturally tightly coiled, coarse-textured hair.^1,2 PFB is common in individuals who shave frequently due to personal choice or profession, such as members of the US military^3,4 and firefighters, who are required to remain clean shaven for safety (eg, ensuring proper fit of a respirator mask).⁵ Early diagnosis and treatment of PFB are essential to prevent long-term complications such as scarring or hyperpigmentation, which may be more severe in those with darker skin tones.

Epidemiology

PFB is most common in Black men, affecting 45% to 83% of men of African ancestry.^1,2 This condition also can affect individuals of various ethnicities with coarse or curly hair. The spiral shape of the hair increases the likelihood that it will regrow into the skin after shaving.⁶ Women with hirsutism who shave also can develop PFB.

Key Clinical Features

The papules and pustules seen in PFB may be flesh colored, erythematous, hyperpigmented, brown, or violaceous. Erythema may be less pronounced in darker vs lighter skin tones. Persistent and severe postinflammatory hyperpigmentation may occur, and hypertrophic or keloidal scars may develop in affected areas. Dermoscopy may reveal extrafollicular hair penetration as well as follicular or perifollicular pustules accompanied by hyperkeratosis.

Worth Noting

The most effective management for PFB is to discontinue shaving.¹ If shaving is desired or necessary, it is recommended that patients apply lukewarm water to the affected area followed by a generous amount of shaving foam or gel to create a protective antifriction layer that allows the razor to glide more smoothly over the skin and reduces subsequent irritation.² Using the right razor technology also may help alleviate symptoms. Research has shown that multiblade razors used in conjunction with preshave hair hydration and postshave moisturization do not worsen PFB.² A recent study found that multiblade razor technology paired with use of a shave foam or gel actually improved skin appearance in patients with PFB.⁷

It is important to direct patients to shave in the direction of hair growth; however, this may not be possible for individuals with curly or coarse hair, as the hair may grow in many directions.^8,9 Patients also should avoid pulling the skin taut while shaving, as doing so allows the hair to be clipped below the surface, where it can repenetrate the skin and cause further irritation. As an alternative to shaving with a razor, patients can use hair clippers to trim beard hair, which leaves behind stubble and interrupts the cycle of retracted hairs under the skin. Nd:YAG laser therapy has demonstrated efficacy in reduction of PFB papules and pustules.^9-12 Greater mean improvement in inflammatory papules and reduction in hair density was noted in participants who received Nd:YAG laser plus eflornithine compared with those who received the laser or eflornithine alone.¹¹ Patients should not pluck or dig into the skin to remove any ingrown hairs. If a tweezer is used, the patient should gently lift the tip of the ingrown hair with the tweezer to dislodge it from the skin and prevent plucking out the hair completely.

To help manage inflammation after shaving, topical treatments such as benzoyl peroxide 5%/clindamycin 1% gel can be used.^3,13 A low-potency steroid such as topical hydrocortisone 2.5% applied once or twice daily for up to 2 to 3 days may be helpful.^1,14 Adjunctive treatments including keratolytics (eg, topical retinoids, hydroxy acids) reduce perifollicular hyperkeratosis.^14,15 Agents containing alpha hydroxy acids (eg, glycolic acid) also can decrease the curvature of the hair itself by reducing the sulfhydryl bonds.⁶ If secondary bacterial infections occur, oral antibiotics (eg, doxycycline) may be necessary.

Health Disparity Highlight

Individuals with darker skin tones are at higher risk for PFB and associated complications. Limited access to dermatology services may further exacerbate these challenges. Individuals with PFB may not seek medical treatment until the condition becomes severe. Clinicians also may underestimate the severity of PFB—particularly in those with darker skin tones—based on erythema alone because it may be less pronounced in darker vs lighter skin tones.¹⁶

While permanent hair reduction with laser therapy is a treatment option for PFB, it may be inaccessible to some patients because it can be expensive and is coded as a cosmetic procedure. Additionally, patients may not have access to specialists who are experienced in performing the procedure in those with darker skin tones.⁹ Some patients also may not want to permanently reduce the amount of hair that grows in the beard area for personal or religious reasons.¹⁷

Pseudofolliculitis barbae also has been linked to professional disparities. One study found that members of the US Air Force who had medical shaving waivers experienced longer times to promotion than those with no waiver.¹⁸ Delays in promotion may be linked to perceptions of unprofessionalism, exclusion from high-profile duties, and concerns about career progression. While this delay was similar for individuals of all races, the majority of those in the waiver group were Black/African American. In 2021, 4 Black firefighters with PFB were unsuccessful in their bid to get a medical accommodation regarding a New York City Fire Department policy requiring them to be clean shaven where the oxygen mask seals against the skin.⁵ More research is needed on mask safety and efficiency relative to the length of facial hair. Accommodations or tailored masks for facial hair conditions also are necessary so individuals with PFB can meet job requirements while managing their condition.

Pseudofolliculitis barbae (PFB), also known as razor bumps, is a common inflammatory condition characterized by papules and pustules that typically appear in the beard and cheek regions. It occurs when shaved hair regrows and penetrates the skin, leading to irritation and inflammation. While anyone who shaves can develop PFB, it is more prevalent and severe in individuals with naturally tightly coiled, coarse-textured hair.^1,2 PFB is common in individuals who shave frequently due to personal choice or profession, such as members of the US military^3,4 and firefighters, who are required to remain clean shaven for safety (eg, ensuring proper fit of a respirator mask).⁵ Early diagnosis and treatment of PFB are essential to prevent long-term complications such as scarring or hyperpigmentation, which may be more severe in those with darker skin tones.

Epidemiology

PFB is most common in Black men, affecting 45% to 83% of men of African ancestry.^1,2 This condition also can affect individuals of various ethnicities with coarse or curly hair. The spiral shape of the hair increases the likelihood that it will regrow into the skin after shaving.⁶ Women with hirsutism who shave also can develop PFB.

Key Clinical Features

The papules and pustules seen in PFB may be flesh colored, erythematous, hyperpigmented, brown, or violaceous. Erythema may be less pronounced in darker vs lighter skin tones. Persistent and severe postinflammatory hyperpigmentation may occur, and hypertrophic or keloidal scars may develop in affected areas. Dermoscopy may reveal extrafollicular hair penetration as well as follicular or perifollicular pustules accompanied by hyperkeratosis.

Worth Noting

The most effective management for PFB is to discontinue shaving.¹ If shaving is desired or necessary, it is recommended that patients apply lukewarm water to the affected area followed by a generous amount of shaving foam or gel to create a protective antifriction layer that allows the razor to glide more smoothly over the skin and reduces subsequent irritation.² Using the right razor technology also may help alleviate symptoms. Research has shown that multiblade razors used in conjunction with preshave hair hydration and postshave moisturization do not worsen PFB.² A recent study found that multiblade razor technology paired with use of a shave foam or gel actually improved skin appearance in patients with PFB.⁷

It is important to direct patients to shave in the direction of hair growth; however, this may not be possible for individuals with curly or coarse hair, as the hair may grow in many directions.^8,9 Patients also should avoid pulling the skin taut while shaving, as doing so allows the hair to be clipped below the surface, where it can repenetrate the skin and cause further irritation. As an alternative to shaving with a razor, patients can use hair clippers to trim beard hair, which leaves behind stubble and interrupts the cycle of retracted hairs under the skin. Nd:YAG laser therapy has demonstrated efficacy in reduction of PFB papules and pustules.^9-12 Greater mean improvement in inflammatory papules and reduction in hair density was noted in participants who received Nd:YAG laser plus eflornithine compared with those who received the laser or eflornithine alone.¹¹ Patients should not pluck or dig into the skin to remove any ingrown hairs. If a tweezer is used, the patient should gently lift the tip of the ingrown hair with the tweezer to dislodge it from the skin and prevent plucking out the hair completely.

To help manage inflammation after shaving, topical treatments such as benzoyl peroxide 5%/clindamycin 1% gel can be used.^3,13 A low-potency steroid such as topical hydrocortisone 2.5% applied once or twice daily for up to 2 to 3 days may be helpful.^1,14 Adjunctive treatments including keratolytics (eg, topical retinoids, hydroxy acids) reduce perifollicular hyperkeratosis.^14,15 Agents containing alpha hydroxy acids (eg, glycolic acid) also can decrease the curvature of the hair itself by reducing the sulfhydryl bonds.⁶ If secondary bacterial infections occur, oral antibiotics (eg, doxycycline) may be necessary.

Health Disparity Highlight

Individuals with darker skin tones are at higher risk for PFB and associated complications. Limited access to dermatology services may further exacerbate these challenges. Individuals with PFB may not seek medical treatment until the condition becomes severe. Clinicians also may underestimate the severity of PFB—particularly in those with darker skin tones—based on erythema alone because it may be less pronounced in darker vs lighter skin tones.¹⁶

While permanent hair reduction with laser therapy is a treatment option for PFB, it may be inaccessible to some patients because it can be expensive and is coded as a cosmetic procedure. Additionally, patients may not have access to specialists who are experienced in performing the procedure in those with darker skin tones.⁹ Some patients also may not want to permanently reduce the amount of hair that grows in the beard area for personal or religious reasons.¹⁷

Pseudofolliculitis barbae also has been linked to professional disparities. One study found that members of the US Air Force who had medical shaving waivers experienced longer times to promotion than those with no waiver.¹⁸ Delays in promotion may be linked to perceptions of unprofessionalism, exclusion from high-profile duties, and concerns about career progression. While this delay was similar for individuals of all races, the majority of those in the waiver group were Black/African American. In 2021, 4 Black firefighters with PFB were unsuccessful in their bid to get a medical accommodation regarding a New York City Fire Department policy requiring them to be clean shaven where the oxygen mask seals against the skin.⁵ More research is needed on mask safety and efficiency relative to the length of facial hair. Accommodations or tailored masks for facial hair conditions also are necessary so individuals with PFB can meet job requirements while managing their condition.

Spironolactone is increasingly used off label for acne treatment and is now being prescribed for women with acne at a frequency similar to oral antibiotics.^1,2 In this article, we provide an overview of spironolactone use for acne treatment and discuss recent clinical trials and practical strategies for patient selection, dosing, adverse effect management, and monitoring (Table).

History and Mechanism of Action

Because sebaceous gland activity is an important component of acne pathogenesis and is regulated by androgens,³ there has long been interest in identifying treatment strategies that can target the role of hormones in activating the sebaceous gland. In the 1980s, it became apparent that spironolactone, originally developed as a potassium-sparing diuretic, also might possess antiandrogenic properties that could be useful in the treatment of acne.⁴ Spironolactone has been found to decrease testosterone production, inhibit testosterone and dihydrotestosterone binding to androgen receptors,^5-8 and block 5α-reductase receptors of the sebaceous glands of skin.⁹

In 1984, Goodfellow et al¹⁰ conducted a trial in which 36 male and female patients with severe acne were randomized to placebo or spironolactone doses ranging from 50 to 200 mg/d. They found that spironolactone resulted in dose-dependent reductions of sebum production as well as improvement in patient- and clinician-reported assessments of acne. In 1986, another placebo-controlled crossover trial by Muhlemann et al¹¹ provided further support for the effectiveness of spironolactone for acne. This trial randomized 21 women to placebo or spironolactone 200 mg/d and found that spironolactone was associated with statistically significant (P<.001) improvements in acne lesion counts.

Recent Observational Studies and Trials

Following these early trials, several large case series have been published describing the successful use of spironolactone for acne, including a 2020 retrospective case series from the Mayo Clinic describing 395 patients.¹² The investigators found that almost 66% of patients had a complete response and almost 85% had a complete response or a partial response greater than 50%. They also found that the median time to initial response and maximal response were 3 and 5 months, respectively, and that efficacy was observed across acne subtypes, including for nodulocystic acne.¹² In addition, a 2021 case series describing 403 patients treated with spironolactone found that approximately 80% had reduction or complete clearance of acne, with improvements observed for both facial and truncal acne. In this cohort, doses of 100 to 150 mg/d typically were the most successful.¹³ A case series of 80 adolescent females also highlighted the efficacy of spironolactone in younger populations.¹⁴

Adding to these observational data, the multicenter, phase 3, double-blind Spironolactone for Adult Female Acne (SAFA) trial included 410 women (mean age, 29.2 years) who were randomized to receive either placebo or intervention (spironolactone 50 mg/d until week 6 and 100 mg/d until week 24).¹⁵ At 24 weeks, greater improvement in quality of life and participant self-assessed improvement were observed in the spironolactone group. In addition, at 12 weeks, rates of success were higher in the spironolactone group using the Investigator Global Assessment score (adjusted odds ratio 5.18 [95% CI, 2.18- 12.28]). Those randomized to receive spironolactone also had lower rates of oral antibiotic use at 52 weeks than the placebo group did (5.8% vs 13.5%, respectively).

In the SAFA trial, spironolactone was well tolerated; the most common adverse effects relative to placebo were lightheadedness (19% for spironolactone vs 12% for placebo) and headache (20% for spironolactone vs 12% for placebo). Notably, more than 95% of patients were able to increase from 50 mg/d to 100 mg/d at week 6, with greater than 90% tolerating 100 mg/d. As observational data suggest that spironolactone takes 3 to 5 months to reach peak efficacy, these findings provide further support that starting at a dose of at least 100 mg/d is likely optimal for most patients.¹⁶

A Potential Alternative to Oral Antibiotics

Oral antibiotics such as tetracyclines have long played a central role in the treatment of acne and remain a first-line treatment option.¹⁷ In addition, many of these antibiotic courses exceed 6 months in duration.¹ In fact, dermatologists prescribe more antibiotics per capita than any other specialty^1,18-20; however, this can be associated with the development of antibiotic resistance,^21,22 as well as other antibiotic-associated complications, including inflammatory bowel disease,²³ pharyngitis,²⁴Clostridium difficile infections, and cancer.^25-29

In addition to these concerns, many patients may prefer nonantibiotic alternatives to oral antibiotics, with more than 75% preferring a nonantibiotic option if available. For female patients with acne, antiandrogens such as spironolactone have been suggested as a potential alternative.³⁰ A 10-year retrospective study of female patients with acne found that those who had ever received hormonal therapy (ie, spironolactone or a combined oral contraceptive) received fewer cumulative days of oral antibiotics than those who did not (226 days vs 302 days, respectively).³¹ In addition, while oral antibiotics were the most common initial therapy prescribed for patients, as they progressed through their treatment course, more patients ended up on hormonal therapy than oral antibiotics. This study suggests that hormonal therapy such as spironolactone could represent an alternative to the use of systemic antibiotics.³¹

Further supporting the role of spironolactone as an alternative to oral antibiotics, a 2018 analysis of claims data found that spironolactone may have similar effectiveness to oral antibiotics for the treatment of acne.32 After adjusting for age and topical retinoid and oral contraceptive use, this study found that there was no significant difference in the odds of being prescribed a different systemic treatment within 1 year (ie, treatment failure) among those starting spironolactone vs those starting oral tetracycline-class antibiotics as their initial therapy for acne.

A multicenter, randomized, double-blind trial (Female Acne Spironolactone vs doxyCycline Efficacy [FASCE]) also evaluated the comparative effectiveness of doxycycline 100 mg/d for 3 months followed by an oral placebo for 3 months vs spironolactone 150 mg/d for 6 months among 133 adult women with acne. This study found that spironolactone had statistically significantly greater rates of Investigator Global Assessment treatment success after 6 months (odds ratio 2.87 [95% CI, 1.38-5.99; P=.007]).³³ Since spironolactone historically has been prescribed less often than oral antibiotics for women with acne, these findings support spironolactone as an underutilized treatment alternative. The ongoing Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial—a 16-week, blinded trial comparing 100 mg/d doses of both drugs—should provide additional evidence regarding the relative role of spironolactone and oral antibiotics in the management of acne.³⁴

Ultimately, the decision to use spironolactone or other treatments such as oral antibiotics should be based on shared decision making between clinician and patient. Spironolactone has a relatively slow onset of efficacy, and other options such as oral antibiotics might be preferred by those looking for more immediate results; however, as women with acne often have activity that persists into adulthood, spironolactone might be preferable as a long-term maintenance therapy to avoid complications of prolonged antibiotic use.³⁵ Comorbidities also will influence the optimal choice of therapy (eg, spironolactone might be preferred in someone with inflammatory bowel disease, and oral antibiotics might be preferred in someone with orthostatic hypotension).

Patient Selection

Acne occurring along the lower face or jawline in adult women sometimes is referred to as hormonal acne, but this dogma is not particularly evidence based. An observational study of 374 patients found that almost 90% of adult women had acne involving multiple facial zones with a spectrum of facial acne severity similar to that in adolescents.³⁶ Only a small subset of these patients (11.2%) had acne localized solely to the mandibular area. In addition, acne along the lower face is not predictive of hyperandrogenism (eg, polycystic ovary syndrome).³⁷ Antiandrogen therapies such as spironolactone and clascoterone are effective in both men and women with acne^10,38 and in adolescents and adults, suggesting that hormones play a fundamental role in all acne and that addressing this mechanism can be useful broadly. Therefore, hormonal therapies such as spironolactone should not be restricted to only adult women with acne along the lower face.

While spironolactone can be effective for acne treatment in any age group, it may be most effective for adult women with acne. In the SAFA trial, prespecified subgroup analyses showed a statistically significant (P=.005) interaction term for age (categorized as <25 years and ≥25 years), which suggested that spironolactone might be a more effective treatment for women 25 years and older.¹⁵ In addition, subgroup analyses in the aforementioned 2018 analysis of claims data found that spironolactone was more effective relative to oral antibiotics in adults vs adolescents.³² Despite these limitations, several case series have highlighted that spironolactone is effective among adolescent populations with acne. A case series of spironolactone use in 73 patients aged 19 years or younger found that 68% of patients demonstrated resolution or improvement in their acne after spironolactone treatment.³⁹ Another case series among 80 adolescent females reported 80% of patients experiencing improvement of their acne.¹⁴

For those with more severe acne, spironolactone can be combined with other complementary treatment approaches such as topicals, oral antibiotics, or procedural modalities.⁴⁰

Dosing

We recommend starting spironolactone at a dose of 100 mg/d (the patient can take 50 mg/d for 1 week, then increase to 100 mg/d if there are no adverse effects at the lower dose). In the 1984 trial by Goodfellow et al,¹⁰ participants were randomized to doses of 50 mg/d, 100 mg/d, 150 mg/d, and 200 mg/d. In this trial, efficacy assessed by objective and subjective outcomes did not plateau until doses of 100 mg/d to 150 mg/d. In addition, a case series of 403 patients found that the most successful dosage of spironolactone generally was 100 mg/d or higher.¹³ Most of the patients who were started at this dosage either stayed at this level or escalated, whereas patients who started at lower dosages (25-75 mg/d) frequently increased their dosage over time. The SAFA trial also highlighted that most patients can tolerate a spironolactone dose of 100 mg/d.¹⁵ For specific populations, such as patients with polycystic ovary syndrome, a higher dose (mean dosage of 143 mg/d) may be required for efficacy.⁴¹ Given the slow onset of efficacy, typically taking 3 to 5 months, and the low rate of adverse effects, we believe the optimal starting dose is 100 mg/s to 150 mg/d. If adverse effects occur or lesions clear, then the dosage may be reduced.

Adverse Effects

Spironolactone generally is well tolerated; in the SAFA and FASCE trials, fewer than 1% of participants discontinued due to adverse effects.^15,33 Rates of discontinuation due to adverse effects typically have been less than 5% in case series of patients treated in routine clinical practice.^12-14

Because spironolactone is a diuretic and antihypertensive, the most common adverse effects are related to these characteristics. In the SAFA trial, dizziness, lightheadedness, and vertigo were reported more commonly in the spironolactone group than in the placebo group (19% vs 12%, respectively). Similarly, headaches also were reported more frequently in the spironolactone group than in the placebo group (20% vs 12%, respectively).¹⁵ One case series found that, among the 267 patients on spironolactone whose blood pressure was monitored, the mean reduction in systolic blood pressure was 3.5 mm Hg and the mean reduction in diastolic blood pressure was 0.9 mm Hg.¹³ For those with baseline orthostasis or in those who experience adverse effects related to hypotension, reducing the dose often can be helpful. Of note, while doses of 100 mg/d to 150 mg/d often are the most effective, randomized trials have found that spironolactone still can be effective for acne at doses as low as 25 mg/d to 50 mg/d.^10,38

Menstrual irregularities are another commonly cited adverse effect of spironolactone. While a systematic review found that 15% to 30% of patients treated with spironolactone experience menstrual irregularities, it has been difficult to evaluate whether this is due to the medication or other comorbidities, such as polycystic ovary syndrome.⁴² Notably, in the SAFA trial, rates of menstrual irregularities were equivalent between the spironolactone and placebo groups at a dose of 100 mg/d (32% vs 35%, respectively).¹⁵ In contrast, in the FASCE trial, menstrual irregularities were more commonly reported at a dose of 150 mg/d.³³ These findings are consistent with observational data suggesting that menstrual irregularities are much more common at spironolactone doses greater than 100 mg/d.⁴² Additionally, some evidence supports that for some patients these menstrual irregularities may resolve within 2 to 3 months of continued treatment.⁴³ It has been noted in several studies that menstrual irregularities are less likely to occur in patients who are using combined oral contraceptives; therefore, for patients who are amenable and have no contraindications, combined oral contraceptives can be considered to prevent or address menstrual irregularities.^13,42,44

More generally, combined oral contraceptives can be an excellent combination with spironolactone, as they have complementary characteristics. Spironolactone primarily blocks the effects of androgens, while combined oral contraceptives predominantly block the production of androgens. Whereas spironolactone typically causes hypotension and menstrual irregularities, combined oral contraceptives cause hypertension and help to regulate the menstrual cycle.

Spironolactone carries an official US Food and Drug Administration warning regarding possible tumorigenicity that is based on animal studies that used up to 150 times the normal dose of spironolactone used in humans⁴⁵; however, observational studies in humans have not identified such an association when spironolactone is used in normal clinical settings. A systematic review and metanalysis in 2022 reviewed data from a total population of more than 4 million individuals and found that there was no statistically significant association between spironolactone use and the risk for breast, ovarian, bladder, kidney, gastric, or esophageal cancers.⁴⁶ Additional studies also found no association between spironolactone use and cancers.⁴⁸ A more recent cohort study specifically among patients treated with spironolactone for acne also found no significant increased risk for breast cancer.⁴⁹

Combined oral contraceptives are associated with an increased risk for venous thromboembolisms, and there have been concerns that this risk may be greater in combined oral contraceptives that contain drospirenone.⁵⁰ Drospirenone is molecularly related to spironolactone, which has prompted the consideration of whether spironolactone use also conveys a risk for venous thromboembolism. Reassuringly, a retrospective study of claims data found that individuals on spironolactone were not more likely to develop a pulmonary embolism or a deep venous thrombosis than matched controls treated with tetracycline antibiotics, with a point estimate favoring decreased risk.⁵¹

Monitoring

Given that one of spironolactone’s mechanisms of action is aldosterone antagonism and thus the inhibition of potassium excretion, there have been concerns regarding risk for hyperkalemia. A retrospective study analyzing data from 2000 to 2014 found that, among 974 young women receiving spironolactone therapy, the rate of hyperkalemia was 0.72%, which is equivalent to the 0.76% baseline rate of hyperkalemia in the same population.⁵² Subsequent studies also have found that spironolactone does not appear to be associated with a meaningful risk for hyperkalemia among young healthy patients treated for acne.^38,53 These studies suggest that routine potassium monitoring is of low usefulness for healthy young women taking spironolactone for acne. The 2024 American Academy of Dermatology guidelines on the management of acne also state that potassium monitoring is not needed in healthy patients but that potassium testing should be considered for those with risk factors for hyperkalemia (eg, older age, medical comorbidities, medications).⁴⁰ Clinicians should still engage in shared decision making with patients to determine whether to check potassium. If potassium is to be monitored, it should be checked 1 to 2 weeks after spironolactone is started.^45,54

Since drospirenone also has aldosterone antagonistic properties,⁵⁵ there have been concerns about whether concomitant use of spironolactone and drospirenone-containing combined oral contraceptives might increase the risk for hyperkalemia.⁵⁶ However, a retrospective cohort study analyzing data from more than 1 million women found that drospirenone is not any more likely than levonorgestrel to cause hyperkalemia and that there is no interaction between drospirenone and spironolactone for hyperkalemia.⁵⁷ A subsequent prospective study of 27 women treated with combined oral contraceptives containing ethinyl estradiol/drospirenone and spironolactone also did not find any significant elevations in potassium.⁵⁸ Data from these studies suggest that spironolactone can safely be co-administered with drospirenone-containing combined oral contraceptives.

Reproductive Risks

Despite its utility in treating acne, spironolactone should not be used during pregnancy, and appropriate pregnancy prevention is recommended. Spironolactone crosses the placenta, and some animal studies have shown feminization of male fetuses.⁵⁹ While human data are limited to a few case reports that did not demonstrate an association of major malformations,⁶⁰ it generally is recommended to avoid spironolactone during pregnancy. Small studies have found that spironolactone has minimal transfer to breastmilk and is not associated with adverse effects in breastfed infants.^61-63 Accordingly, the World Health Organization considers spironolactone to be compatible with breastfeeding.⁶⁴ Notably, spironolactone may be associated with lactation suppression^65,66; therefore, it may be best if lactating patients ensure that their milk production is established prior to starting spironolactone and to increase their water intake to offset the diuretic effects.

Spironolactone also can result in gynecomastia in men and therefore typically is not prescribed for the treatment of acne in this population in oral form¹⁰; however, topical antiandrogens such as clascoterone can be used in both women and men with acne.⁶⁷

Conclusion

Spironolactone is a well-tolerated and effective treatment for women with acne, both in adult and adolescent populations. It is a potentially underutilized alternative to oral antibiotics. Spironolactone also is affordable, fully covered without any requirements in almost 90% of states under Medicaid and with a monthly cost of only $4.00 when obtained through major retailers in the United States, making it an optimal long-term treatment option for many patients.^52,68 We recommend a starting dose of 100 mg/d, which can be increased to 150 mg/d to 200 mg/d if needed for better acne control or decreased if adverse effects occur or acne clears. Potassium monitoring is of low usefulness in young healthy women, and studies have not identified an association between spironolactone use and increased risk for cancer.

Spironolactone is increasingly used off label for acne treatment and is now being prescribed for women with acne at a frequency similar to oral antibiotics.^1,2 In this article, we provide an overview of spironolactone use for acne treatment and discuss recent clinical trials and practical strategies for patient selection, dosing, adverse effect management, and monitoring (Table).

History and Mechanism of Action

Because sebaceous gland activity is an important component of acne pathogenesis and is regulated by androgens,³ there has long been interest in identifying treatment strategies that can target the role of hormones in activating the sebaceous gland. In the 1980s, it became apparent that spironolactone, originally developed as a potassium-sparing diuretic, also might possess antiandrogenic properties that could be useful in the treatment of acne.⁴ Spironolactone has been found to decrease testosterone production, inhibit testosterone and dihydrotestosterone binding to androgen receptors,^5-8 and block 5α-reductase receptors of the sebaceous glands of skin.⁹

In 1984, Goodfellow et al¹⁰ conducted a trial in which 36 male and female patients with severe acne were randomized to placebo or spironolactone doses ranging from 50 to 200 mg/d. They found that spironolactone resulted in dose-dependent reductions of sebum production as well as improvement in patient- and clinician-reported assessments of acne. In 1986, another placebo-controlled crossover trial by Muhlemann et al¹¹ provided further support for the effectiveness of spironolactone for acne. This trial randomized 21 women to placebo or spironolactone 200 mg/d and found that spironolactone was associated with statistically significant (P<.001) improvements in acne lesion counts.

Recent Observational Studies and Trials

Following these early trials, several large case series have been published describing the successful use of spironolactone for acne, including a 2020 retrospective case series from the Mayo Clinic describing 395 patients.¹² The investigators found that almost 66% of patients had a complete response and almost 85% had a complete response or a partial response greater than 50%. They also found that the median time to initial response and maximal response were 3 and 5 months, respectively, and that efficacy was observed across acne subtypes, including for nodulocystic acne.¹² In addition, a 2021 case series describing 403 patients treated with spironolactone found that approximately 80% had reduction or complete clearance of acne, with improvements observed for both facial and truncal acne. In this cohort, doses of 100 to 150 mg/d typically were the most successful.¹³ A case series of 80 adolescent females also highlighted the efficacy of spironolactone in younger populations.¹⁴

Adding to these observational data, the multicenter, phase 3, double-blind Spironolactone for Adult Female Acne (SAFA) trial included 410 women (mean age, 29.2 years) who were randomized to receive either placebo or intervention (spironolactone 50 mg/d until week 6 and 100 mg/d until week 24).¹⁵ At 24 weeks, greater improvement in quality of life and participant self-assessed improvement were observed in the spironolactone group. In addition, at 12 weeks, rates of success were higher in the spironolactone group using the Investigator Global Assessment score (adjusted odds ratio 5.18 [95% CI, 2.18- 12.28]). Those randomized to receive spironolactone also had lower rates of oral antibiotic use at 52 weeks than the placebo group did (5.8% vs 13.5%, respectively).

In the SAFA trial, spironolactone was well tolerated; the most common adverse effects relative to placebo were lightheadedness (19% for spironolactone vs 12% for placebo) and headache (20% for spironolactone vs 12% for placebo). Notably, more than 95% of patients were able to increase from 50 mg/d to 100 mg/d at week 6, with greater than 90% tolerating 100 mg/d. As observational data suggest that spironolactone takes 3 to 5 months to reach peak efficacy, these findings provide further support that starting at a dose of at least 100 mg/d is likely optimal for most patients.¹⁶

A Potential Alternative to Oral Antibiotics

Oral antibiotics such as tetracyclines have long played a central role in the treatment of acne and remain a first-line treatment option.¹⁷ In addition, many of these antibiotic courses exceed 6 months in duration.¹ In fact, dermatologists prescribe more antibiotics per capita than any other specialty^1,18-20; however, this can be associated with the development of antibiotic resistance,^21,22 as well as other antibiotic-associated complications, including inflammatory bowel disease,²³ pharyngitis,²⁴Clostridium difficile infections, and cancer.^25-29

In addition to these concerns, many patients may prefer nonantibiotic alternatives to oral antibiotics, with more than 75% preferring a nonantibiotic option if available. For female patients with acne, antiandrogens such as spironolactone have been suggested as a potential alternative.³⁰ A 10-year retrospective study of female patients with acne found that those who had ever received hormonal therapy (ie, spironolactone or a combined oral contraceptive) received fewer cumulative days of oral antibiotics than those who did not (226 days vs 302 days, respectively).³¹ In addition, while oral antibiotics were the most common initial therapy prescribed for patients, as they progressed through their treatment course, more patients ended up on hormonal therapy than oral antibiotics. This study suggests that hormonal therapy such as spironolactone could represent an alternative to the use of systemic antibiotics.³¹

Further supporting the role of spironolactone as an alternative to oral antibiotics, a 2018 analysis of claims data found that spironolactone may have similar effectiveness to oral antibiotics for the treatment of acne.32 After adjusting for age and topical retinoid and oral contraceptive use, this study found that there was no significant difference in the odds of being prescribed a different systemic treatment within 1 year (ie, treatment failure) among those starting spironolactone vs those starting oral tetracycline-class antibiotics as their initial therapy for acne.

A multicenter, randomized, double-blind trial (Female Acne Spironolactone vs doxyCycline Efficacy [FASCE]) also evaluated the comparative effectiveness of doxycycline 100 mg/d for 3 months followed by an oral placebo for 3 months vs spironolactone 150 mg/d for 6 months among 133 adult women with acne. This study found that spironolactone had statistically significantly greater rates of Investigator Global Assessment treatment success after 6 months (odds ratio 2.87 [95% CI, 1.38-5.99; P=.007]).³³ Since spironolactone historically has been prescribed less often than oral antibiotics for women with acne, these findings support spironolactone as an underutilized treatment alternative. The ongoing Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial—a 16-week, blinded trial comparing 100 mg/d doses of both drugs—should provide additional evidence regarding the relative role of spironolactone and oral antibiotics in the management of acne.³⁴

Ultimately, the decision to use spironolactone or other treatments such as oral antibiotics should be based on shared decision making between clinician and patient. Spironolactone has a relatively slow onset of efficacy, and other options such as oral antibiotics might be preferred by those looking for more immediate results; however, as women with acne often have activity that persists into adulthood, spironolactone might be preferable as a long-term maintenance therapy to avoid complications of prolonged antibiotic use.³⁵ Comorbidities also will influence the optimal choice of therapy (eg, spironolactone might be preferred in someone with inflammatory bowel disease, and oral antibiotics might be preferred in someone with orthostatic hypotension).

Patient Selection

Acne occurring along the lower face or jawline in adult women sometimes is referred to as hormonal acne, but this dogma is not particularly evidence based. An observational study of 374 patients found that almost 90% of adult women had acne involving multiple facial zones with a spectrum of facial acne severity similar to that in adolescents.³⁶ Only a small subset of these patients (11.2%) had acne localized solely to the mandibular area. In addition, acne along the lower face is not predictive of hyperandrogenism (eg, polycystic ovary syndrome).³⁷ Antiandrogen therapies such as spironolactone and clascoterone are effective in both men and women with acne^10,38 and in adolescents and adults, suggesting that hormones play a fundamental role in all acne and that addressing this mechanism can be useful broadly. Therefore, hormonal therapies such as spironolactone should not be restricted to only adult women with acne along the lower face.

While spironolactone can be effective for acne treatment in any age group, it may be most effective for adult women with acne. In the SAFA trial, prespecified subgroup analyses showed a statistically significant (P=.005) interaction term for age (categorized as <25 years and ≥25 years), which suggested that spironolactone might be a more effective treatment for women 25 years and older.¹⁵ In addition, subgroup analyses in the aforementioned 2018 analysis of claims data found that spironolactone was more effective relative to oral antibiotics in adults vs adolescents.³² Despite these limitations, several case series have highlighted that spironolactone is effective among adolescent populations with acne. A case series of spironolactone use in 73 patients aged 19 years or younger found that 68% of patients demonstrated resolution or improvement in their acne after spironolactone treatment.³⁹ Another case series among 80 adolescent females reported 80% of patients experiencing improvement of their acne.¹⁴

For those with more severe acne, spironolactone can be combined with other complementary treatment approaches such as topicals, oral antibiotics, or procedural modalities.⁴⁰

Dosing

We recommend starting spironolactone at a dose of 100 mg/d (the patient can take 50 mg/d for 1 week, then increase to 100 mg/d if there are no adverse effects at the lower dose). In the 1984 trial by Goodfellow et al,¹⁰ participants were randomized to doses of 50 mg/d, 100 mg/d, 150 mg/d, and 200 mg/d. In this trial, efficacy assessed by objective and subjective outcomes did not plateau until doses of 100 mg/d to 150 mg/d. In addition, a case series of 403 patients found that the most successful dosage of spironolactone generally was 100 mg/d or higher.¹³ Most of the patients who were started at this dosage either stayed at this level or escalated, whereas patients who started at lower dosages (25-75 mg/d) frequently increased their dosage over time. The SAFA trial also highlighted that most patients can tolerate a spironolactone dose of 100 mg/d.¹⁵ For specific populations, such as patients with polycystic ovary syndrome, a higher dose (mean dosage of 143 mg/d) may be required for efficacy.⁴¹ Given the slow onset of efficacy, typically taking 3 to 5 months, and the low rate of adverse effects, we believe the optimal starting dose is 100 mg/s to 150 mg/d. If adverse effects occur or lesions clear, then the dosage may be reduced.

Adverse Effects

Spironolactone generally is well tolerated; in the SAFA and FASCE trials, fewer than 1% of participants discontinued due to adverse effects.^15,33 Rates of discontinuation due to adverse effects typically have been less than 5% in case series of patients treated in routine clinical practice.^12-14

Because spironolactone is a diuretic and antihypertensive, the most common adverse effects are related to these characteristics. In the SAFA trial, dizziness, lightheadedness, and vertigo were reported more commonly in the spironolactone group than in the placebo group (19% vs 12%, respectively). Similarly, headaches also were reported more frequently in the spironolactone group than in the placebo group (20% vs 12%, respectively).¹⁵ One case series found that, among the 267 patients on spironolactone whose blood pressure was monitored, the mean reduction in systolic blood pressure was 3.5 mm Hg and the mean reduction in diastolic blood pressure was 0.9 mm Hg.¹³ For those with baseline orthostasis or in those who experience adverse effects related to hypotension, reducing the dose often can be helpful. Of note, while doses of 100 mg/d to 150 mg/d often are the most effective, randomized trials have found that spironolactone still can be effective for acne at doses as low as 25 mg/d to 50 mg/d.^10,38

Menstrual irregularities are another commonly cited adverse effect of spironolactone. While a systematic review found that 15% to 30% of patients treated with spironolactone experience menstrual irregularities, it has been difficult to evaluate whether this is due to the medication or other comorbidities, such as polycystic ovary syndrome.⁴² Notably, in the SAFA trial, rates of menstrual irregularities were equivalent between the spironolactone and placebo groups at a dose of 100 mg/d (32% vs 35%, respectively).¹⁵ In contrast, in the FASCE trial, menstrual irregularities were more commonly reported at a dose of 150 mg/d.³³ These findings are consistent with observational data suggesting that menstrual irregularities are much more common at spironolactone doses greater than 100 mg/d.⁴² Additionally, some evidence supports that for some patients these menstrual irregularities may resolve within 2 to 3 months of continued treatment.⁴³ It has been noted in several studies that menstrual irregularities are less likely to occur in patients who are using combined oral contraceptives; therefore, for patients who are amenable and have no contraindications, combined oral contraceptives can be considered to prevent or address menstrual irregularities.^13,42,44

More generally, combined oral contraceptives can be an excellent combination with spironolactone, as they have complementary characteristics. Spironolactone primarily blocks the effects of androgens, while combined oral contraceptives predominantly block the production of androgens. Whereas spironolactone typically causes hypotension and menstrual irregularities, combined oral contraceptives cause hypertension and help to regulate the menstrual cycle.

Spironolactone carries an official US Food and Drug Administration warning regarding possible tumorigenicity that is based on animal studies that used up to 150 times the normal dose of spironolactone used in humans⁴⁵; however, observational studies in humans have not identified such an association when spironolactone is used in normal clinical settings. A systematic review and metanalysis in 2022 reviewed data from a total population of more than 4 million individuals and found that there was no statistically significant association between spironolactone use and the risk for breast, ovarian, bladder, kidney, gastric, or esophageal cancers.⁴⁶ Additional studies also found no association between spironolactone use and cancers.⁴⁸ A more recent cohort study specifically among patients treated with spironolactone for acne also found no significant increased risk for breast cancer.⁴⁹

Combined oral contraceptives are associated with an increased risk for venous thromboembolisms, and there have been concerns that this risk may be greater in combined oral contraceptives that contain drospirenone.⁵⁰ Drospirenone is molecularly related to spironolactone, which has prompted the consideration of whether spironolactone use also conveys a risk for venous thromboembolism. Reassuringly, a retrospective study of claims data found that individuals on spironolactone were not more likely to develop a pulmonary embolism or a deep venous thrombosis than matched controls treated with tetracycline antibiotics, with a point estimate favoring decreased risk.⁵¹

Monitoring

Given that one of spironolactone’s mechanisms of action is aldosterone antagonism and thus the inhibition of potassium excretion, there have been concerns regarding risk for hyperkalemia. A retrospective study analyzing data from 2000 to 2014 found that, among 974 young women receiving spironolactone therapy, the rate of hyperkalemia was 0.72%, which is equivalent to the 0.76% baseline rate of hyperkalemia in the same population.⁵² Subsequent studies also have found that spironolactone does not appear to be associated with a meaningful risk for hyperkalemia among young healthy patients treated for acne.^38,53 These studies suggest that routine potassium monitoring is of low usefulness for healthy young women taking spironolactone for acne. The 2024 American Academy of Dermatology guidelines on the management of acne also state that potassium monitoring is not needed in healthy patients but that potassium testing should be considered for those with risk factors for hyperkalemia (eg, older age, medical comorbidities, medications).⁴⁰ Clinicians should still engage in shared decision making with patients to determine whether to check potassium. If potassium is to be monitored, it should be checked 1 to 2 weeks after spironolactone is started.^45,54

Since drospirenone also has aldosterone antagonistic properties,⁵⁵ there have been concerns about whether concomitant use of spironolactone and drospirenone-containing combined oral contraceptives might increase the risk for hyperkalemia.⁵⁶ However, a retrospective cohort study analyzing data from more than 1 million women found that drospirenone is not any more likely than levonorgestrel to cause hyperkalemia and that there is no interaction between drospirenone and spironolactone for hyperkalemia.⁵⁷ A subsequent prospective study of 27 women treated with combined oral contraceptives containing ethinyl estradiol/drospirenone and spironolactone also did not find any significant elevations in potassium.⁵⁸ Data from these studies suggest that spironolactone can safely be co-administered with drospirenone-containing combined oral contraceptives.

Reproductive Risks

Despite its utility in treating acne, spironolactone should not be used during pregnancy, and appropriate pregnancy prevention is recommended. Spironolactone crosses the placenta, and some animal studies have shown feminization of male fetuses.⁵⁹ While human data are limited to a few case reports that did not demonstrate an association of major malformations,⁶⁰ it generally is recommended to avoid spironolactone during pregnancy. Small studies have found that spironolactone has minimal transfer to breastmilk and is not associated with adverse effects in breastfed infants.^61-63 Accordingly, the World Health Organization considers spironolactone to be compatible with breastfeeding.⁶⁴ Notably, spironolactone may be associated with lactation suppression^65,66; therefore, it may be best if lactating patients ensure that their milk production is established prior to starting spironolactone and to increase their water intake to offset the diuretic effects.

Spironolactone also can result in gynecomastia in men and therefore typically is not prescribed for the treatment of acne in this population in oral form¹⁰; however, topical antiandrogens such as clascoterone can be used in both women and men with acne.⁶⁷

Conclusion

Spironolactone is a well-tolerated and effective treatment for women with acne, both in adult and adolescent populations. It is a potentially underutilized alternative to oral antibiotics. Spironolactone also is affordable, fully covered without any requirements in almost 90% of states under Medicaid and with a monthly cost of only $4.00 when obtained through major retailers in the United States, making it an optimal long-term treatment option for many patients.^52,68 We recommend a starting dose of 100 mg/d, which can be increased to 150 mg/d to 200 mg/d if needed for better acne control or decreased if adverse effects occur or acne clears. Potassium monitoring is of low usefulness in young healthy women, and studies have not identified an association between spironolactone use and increased risk for cancer.

Spironolactone is increasingly used off label for acne treatment and is now being prescribed for women with acne at a frequency similar to oral antibiotics.^1,2 In this article, we provide an overview of spironolactone use for acne treatment and discuss recent clinical trials and practical strategies for patient selection, dosing, adverse effect management, and monitoring (Table).

History and Mechanism of Action

Because sebaceous gland activity is an important component of acne pathogenesis and is regulated by androgens,³ there has long been interest in identifying treatment strategies that can target the role of hormones in activating the sebaceous gland. In the 1980s, it became apparent that spironolactone, originally developed as a potassium-sparing diuretic, also might possess antiandrogenic properties that could be useful in the treatment of acne.⁴ Spironolactone has been found to decrease testosterone production, inhibit testosterone and dihydrotestosterone binding to androgen receptors,^5-8 and block 5α-reductase receptors of the sebaceous glands of skin.⁹

In 1984, Goodfellow et al¹⁰ conducted a trial in which 36 male and female patients with severe acne were randomized to placebo or spironolactone doses ranging from 50 to 200 mg/d. They found that spironolactone resulted in dose-dependent reductions of sebum production as well as improvement in patient- and clinician-reported assessments of acne. In 1986, another placebo-controlled crossover trial by Muhlemann et al¹¹ provided further support for the effectiveness of spironolactone for acne. This trial randomized 21 women to placebo or spironolactone 200 mg/d and found that spironolactone was associated with statistically significant (P<.001) improvements in acne lesion counts.

Recent Observational Studies and Trials

Following these early trials, several large case series have been published describing the successful use of spironolactone for acne, including a 2020 retrospective case series from the Mayo Clinic describing 395 patients.¹² The investigators found that almost 66% of patients had a complete response and almost 85% had a complete response or a partial response greater than 50%. They also found that the median time to initial response and maximal response were 3 and 5 months, respectively, and that efficacy was observed across acne subtypes, including for nodulocystic acne.¹² In addition, a 2021 case series describing 403 patients treated with spironolactone found that approximately 80% had reduction or complete clearance of acne, with improvements observed for both facial and truncal acne. In this cohort, doses of 100 to 150 mg/d typically were the most successful.¹³ A case series of 80 adolescent females also highlighted the efficacy of spironolactone in younger populations.¹⁴

Adding to these observational data, the multicenter, phase 3, double-blind Spironolactone for Adult Female Acne (SAFA) trial included 410 women (mean age, 29.2 years) who were randomized to receive either placebo or intervention (spironolactone 50 mg/d until week 6 and 100 mg/d until week 24).¹⁵ At 24 weeks, greater improvement in quality of life and participant self-assessed improvement were observed in the spironolactone group. In addition, at 12 weeks, rates of success were higher in the spironolactone group using the Investigator Global Assessment score (adjusted odds ratio 5.18 [95% CI, 2.18- 12.28]). Those randomized to receive spironolactone also had lower rates of oral antibiotic use at 52 weeks than the placebo group did (5.8% vs 13.5%, respectively).

In the SAFA trial, spironolactone was well tolerated; the most common adverse effects relative to placebo were lightheadedness (19% for spironolactone vs 12% for placebo) and headache (20% for spironolactone vs 12% for placebo). Notably, more than 95% of patients were able to increase from 50 mg/d to 100 mg/d at week 6, with greater than 90% tolerating 100 mg/d. As observational data suggest that spironolactone takes 3 to 5 months to reach peak efficacy, these findings provide further support that starting at a dose of at least 100 mg/d is likely optimal for most patients.¹⁶

A Potential Alternative to Oral Antibiotics

Oral antibiotics such as tetracyclines have long played a central role in the treatment of acne and remain a first-line treatment option.¹⁷ In addition, many of these antibiotic courses exceed 6 months in duration.¹ In fact, dermatologists prescribe more antibiotics per capita than any other specialty^1,18-20; however, this can be associated with the development of antibiotic resistance,^21,22 as well as other antibiotic-associated complications, including inflammatory bowel disease,²³ pharyngitis,²⁴Clostridium difficile infections, and cancer.^25-29

In addition to these concerns, many patients may prefer nonantibiotic alternatives to oral antibiotics, with more than 75% preferring a nonantibiotic option if available. For female patients with acne, antiandrogens such as spironolactone have been suggested as a potential alternative.³⁰ A 10-year retrospective study of female patients with acne found that those who had ever received hormonal therapy (ie, spironolactone or a combined oral contraceptive) received fewer cumulative days of oral antibiotics than those who did not (226 days vs 302 days, respectively).³¹ In addition, while oral antibiotics were the most common initial therapy prescribed for patients, as they progressed through their treatment course, more patients ended up on hormonal therapy than oral antibiotics. This study suggests that hormonal therapy such as spironolactone could represent an alternative to the use of systemic antibiotics.³¹

Further supporting the role of spironolactone as an alternative to oral antibiotics, a 2018 analysis of claims data found that spironolactone may have similar effectiveness to oral antibiotics for the treatment of acne.32 After adjusting for age and topical retinoid and oral contraceptive use, this study found that there was no significant difference in the odds of being prescribed a different systemic treatment within 1 year (ie, treatment failure) among those starting spironolactone vs those starting oral tetracycline-class antibiotics as their initial therapy for acne.

A multicenter, randomized, double-blind trial (Female Acne Spironolactone vs doxyCycline Efficacy [FASCE]) also evaluated the comparative effectiveness of doxycycline 100 mg/d for 3 months followed by an oral placebo for 3 months vs spironolactone 150 mg/d for 6 months among 133 adult women with acne. This study found that spironolactone had statistically significantly greater rates of Investigator Global Assessment treatment success after 6 months (odds ratio 2.87 [95% CI, 1.38-5.99; P=.007]).³³ Since spironolactone historically has been prescribed less often than oral antibiotics for women with acne, these findings support spironolactone as an underutilized treatment alternative. The ongoing Spironolactone versus Doxycycline for Acne: A Comparative Effectiveness, Noninferiority Evaluation trial—a 16-week, blinded trial comparing 100 mg/d doses of both drugs—should provide additional evidence regarding the relative role of spironolactone and oral antibiotics in the management of acne.³⁴

Ultimately, the decision to use spironolactone or other treatments such as oral antibiotics should be based on shared decision making between clinician and patient. Spironolactone has a relatively slow onset of efficacy, and other options such as oral antibiotics might be preferred by those looking for more immediate results; however, as women with acne often have activity that persists into adulthood, spironolactone might be preferable as a long-term maintenance therapy to avoid complications of prolonged antibiotic use.³⁵ Comorbidities also will influence the optimal choice of therapy (eg, spironolactone might be preferred in someone with inflammatory bowel disease, and oral antibiotics might be preferred in someone with orthostatic hypotension).

Patient Selection

Acne occurring along the lower face or jawline in adult women sometimes is referred to as hormonal acne, but this dogma is not particularly evidence based. An observational study of 374 patients found that almost 90% of adult women had acne involving multiple facial zones with a spectrum of facial acne severity similar to that in adolescents.³⁶ Only a small subset of these patients (11.2%) had acne localized solely to the mandibular area. In addition, acne along the lower face is not predictive of hyperandrogenism (eg, polycystic ovary syndrome).³⁷ Antiandrogen therapies such as spironolactone and clascoterone are effective in both men and women with acne^10,38 and in adolescents and adults, suggesting that hormones play a fundamental role in all acne and that addressing this mechanism can be useful broadly. Therefore, hormonal therapies such as spironolactone should not be restricted to only adult women with acne along the lower face.

While spironolactone can be effective for acne treatment in any age group, it may be most effective for adult women with acne. In the SAFA trial, prespecified subgroup analyses showed a statistically significant (P=.005) interaction term for age (categorized as <25 years and ≥25 years), which suggested that spironolactone might be a more effective treatment for women 25 years and older.¹⁵ In addition, subgroup analyses in the aforementioned 2018 analysis of claims data found that spironolactone was more effective relative to oral antibiotics in adults vs adolescents.³² Despite these limitations, several case series have highlighted that spironolactone is effective among adolescent populations with acne. A case series of spironolactone use in 73 patients aged 19 years or younger found that 68% of patients demonstrated resolution or improvement in their acne after spironolactone treatment.³⁹ Another case series among 80 adolescent females reported 80% of patients experiencing improvement of their acne.¹⁴

For those with more severe acne, spironolactone can be combined with other complementary treatment approaches such as topicals, oral antibiotics, or procedural modalities.⁴⁰

Dosing

We recommend starting spironolactone at a dose of 100 mg/d (the patient can take 50 mg/d for 1 week, then increase to 100 mg/d if there are no adverse effects at the lower dose). In the 1984 trial by Goodfellow et al,¹⁰ participants were randomized to doses of 50 mg/d, 100 mg/d, 150 mg/d, and 200 mg/d. In this trial, efficacy assessed by objective and subjective outcomes did not plateau until doses of 100 mg/d to 150 mg/d. In addition, a case series of 403 patients found that the most successful dosage of spironolactone generally was 100 mg/d or higher.¹³ Most of the patients who were started at this dosage either stayed at this level or escalated, whereas patients who started at lower dosages (25-75 mg/d) frequently increased their dosage over time. The SAFA trial also highlighted that most patients can tolerate a spironolactone dose of 100 mg/d.¹⁵ For specific populations, such as patients with polycystic ovary syndrome, a higher dose (mean dosage of 143 mg/d) may be required for efficacy.⁴¹ Given the slow onset of efficacy, typically taking 3 to 5 months, and the low rate of adverse effects, we believe the optimal starting dose is 100 mg/s to 150 mg/d. If adverse effects occur or lesions clear, then the dosage may be reduced.

Adverse Effects

Spironolactone generally is well tolerated; in the SAFA and FASCE trials, fewer than 1% of participants discontinued due to adverse effects.^15,33 Rates of discontinuation due to adverse effects typically have been less than 5% in case series of patients treated in routine clinical practice.^12-14

Because spironolactone is a diuretic and antihypertensive, the most common adverse effects are related to these characteristics. In the SAFA trial, dizziness, lightheadedness, and vertigo were reported more commonly in the spironolactone group than in the placebo group (19% vs 12%, respectively). Similarly, headaches also were reported more frequently in the spironolactone group than in the placebo group (20% vs 12%, respectively).¹⁵ One case series found that, among the 267 patients on spironolactone whose blood pressure was monitored, the mean reduction in systolic blood pressure was 3.5 mm Hg and the mean reduction in diastolic blood pressure was 0.9 mm Hg.¹³ For those with baseline orthostasis or in those who experience adverse effects related to hypotension, reducing the dose often can be helpful. Of note, while doses of 100 mg/d to 150 mg/d often are the most effective, randomized trials have found that spironolactone still can be effective for acne at doses as low as 25 mg/d to 50 mg/d.^10,38

Menstrual irregularities are another commonly cited adverse effect of spironolactone. While a systematic review found that 15% to 30% of patients treated with spironolactone experience menstrual irregularities, it has been difficult to evaluate whether this is due to the medication or other comorbidities, such as polycystic ovary syndrome.⁴² Notably, in the SAFA trial, rates of menstrual irregularities were equivalent between the spironolactone and placebo groups at a dose of 100 mg/d (32% vs 35%, respectively).¹⁵ In contrast, in the FASCE trial, menstrual irregularities were more commonly reported at a dose of 150 mg/d.³³ These findings are consistent with observational data suggesting that menstrual irregularities are much more common at spironolactone doses greater than 100 mg/d.⁴² Additionally, some evidence supports that for some patients these menstrual irregularities may resolve within 2 to 3 months of continued treatment.⁴³ It has been noted in several studies that menstrual irregularities are less likely to occur in patients who are using combined oral contraceptives; therefore, for patients who are amenable and have no contraindications, combined oral contraceptives can be considered to prevent or address menstrual irregularities.^13,42,44

More generally, combined oral contraceptives can be an excellent combination with spironolactone, as they have complementary characteristics. Spironolactone primarily blocks the effects of androgens, while combined oral contraceptives predominantly block the production of androgens. Whereas spironolactone typically causes hypotension and menstrual irregularities, combined oral contraceptives cause hypertension and help to regulate the menstrual cycle.

Spironolactone carries an official US Food and Drug Administration warning regarding possible tumorigenicity that is based on animal studies that used up to 150 times the normal dose of spironolactone used in humans⁴⁵; however, observational studies in humans have not identified such an association when spironolactone is used in normal clinical settings. A systematic review and metanalysis in 2022 reviewed data from a total population of more than 4 million individuals and found that there was no statistically significant association between spironolactone use and the risk for breast, ovarian, bladder, kidney, gastric, or esophageal cancers.⁴⁶ Additional studies also found no association between spironolactone use and cancers.⁴⁸ A more recent cohort study specifically among patients treated with spironolactone for acne also found no significant increased risk for breast cancer.⁴⁹

Combined oral contraceptives are associated with an increased risk for venous thromboembolisms, and there have been concerns that this risk may be greater in combined oral contraceptives that contain drospirenone.⁵⁰ Drospirenone is molecularly related to spironolactone, which has prompted the consideration of whether spironolactone use also conveys a risk for venous thromboembolism. Reassuringly, a retrospective study of claims data found that individuals on spironolactone were not more likely to develop a pulmonary embolism or a deep venous thrombosis than matched controls treated with tetracycline antibiotics, with a point estimate favoring decreased risk.⁵¹

Monitoring

Given that one of spironolactone’s mechanisms of action is aldosterone antagonism and thus the inhibition of potassium excretion, there have been concerns regarding risk for hyperkalemia. A retrospective study analyzing data from 2000 to 2014 found that, among 974 young women receiving spironolactone therapy, the rate of hyperkalemia was 0.72%, which is equivalent to the 0.76% baseline rate of hyperkalemia in the same population.⁵² Subsequent studies also have found that spironolactone does not appear to be associated with a meaningful risk for hyperkalemia among young healthy patients treated for acne.^38,53 These studies suggest that routine potassium monitoring is of low usefulness for healthy young women taking spironolactone for acne. The 2024 American Academy of Dermatology guidelines on the management of acne also state that potassium monitoring is not needed in healthy patients but that potassium testing should be considered for those with risk factors for hyperkalemia (eg, older age, medical comorbidities, medications).⁴⁰ Clinicians should still engage in shared decision making with patients to determine whether to check potassium. If potassium is to be monitored, it should be checked 1 to 2 weeks after spironolactone is started.^45,54

Since drospirenone also has aldosterone antagonistic properties,⁵⁵ there have been concerns about whether concomitant use of spironolactone and drospirenone-containing combined oral contraceptives might increase the risk for hyperkalemia.⁵⁶ However, a retrospective cohort study analyzing data from more than 1 million women found that drospirenone is not any more likely than levonorgestrel to cause hyperkalemia and that there is no interaction between drospirenone and spironolactone for hyperkalemia.⁵⁷ A subsequent prospective study of 27 women treated with combined oral contraceptives containing ethinyl estradiol/drospirenone and spironolactone also did not find any significant elevations in potassium.⁵⁸ Data from these studies suggest that spironolactone can safely be co-administered with drospirenone-containing combined oral contraceptives.

Reproductive Risks

Despite its utility in treating acne, spironolactone should not be used during pregnancy, and appropriate pregnancy prevention is recommended. Spironolactone crosses the placenta, and some animal studies have shown feminization of male fetuses.⁵⁹ While human data are limited to a few case reports that did not demonstrate an association of major malformations,⁶⁰ it generally is recommended to avoid spironolactone during pregnancy. Small studies have found that spironolactone has minimal transfer to breastmilk and is not associated with adverse effects in breastfed infants.^61-63 Accordingly, the World Health Organization considers spironolactone to be compatible with breastfeeding.⁶⁴ Notably, spironolactone may be associated with lactation suppression^65,66; therefore, it may be best if lactating patients ensure that their milk production is established prior to starting spironolactone and to increase their water intake to offset the diuretic effects.

Spironolactone also can result in gynecomastia in men and therefore typically is not prescribed for the treatment of acne in this population in oral form¹⁰; however, topical antiandrogens such as clascoterone can be used in both women and men with acne.⁶⁷

Conclusion

Spironolactone is a well-tolerated and effective treatment for women with acne, both in adult and adolescent populations. It is a potentially underutilized alternative to oral antibiotics. Spironolactone also is affordable, fully covered without any requirements in almost 90% of states under Medicaid and with a monthly cost of only $4.00 when obtained through major retailers in the United States, making it an optimal long-term treatment option for many patients.^52,68 We recommend a starting dose of 100 mg/d, which can be increased to 150 mg/d to 200 mg/d if needed for better acne control or decreased if adverse effects occur or acne clears. Potassium monitoring is of low usefulness in young healthy women, and studies have not identified an association between spironolactone use and increased risk for cancer.

Rosacea is a chronic inflammatory skin condition affecting the central face—including the cheeks, nose, chin, and forehead—that causes considerable discomfort.¹ Its pathogenesis involves immune dysregulation, genetic predisposition, and microbial dysbiosis.² While immune and environmental factors are known triggers of rosacea, recent research highlights the roles of the gut and skin microbiomes in disease progression. While the skin microbiome interacts directly with the immune system to regulate inflammation and skin homeostasis, the gut microbiome also influences cutaneous inflammation, emphasizing the need to address both topical and internal microbiome imbalances.³ In this article, we review gut and skin microbial alterations in rosacea, focusing on the skin microbiome and including the gut-skin axis implications as well as therapeutic strategies aimed at microbiome balance to enhance patient outcomes.

Skin Microbiome Alterations in Rosacea

The human skin microbiome interacts with the immune system, and microbial imbalances have been shown to contribute to immune dysregulation. Several key microbial species have been identified as playing a large role in rosacea, including Demodex folliculorum, Staphylococcus epidermidis, Bacillus oleronius, and Cutibacterium acnes (Figure).

Demodex folliculorum is a microscopic mite is found in hair follicles and sebaceous glands. Patients with rosacea have higher densities of D folliculorum, which trigger follicular occlusion and immune activation.¹Bacillus oleronius be isolated from D folliculorum and can further activate toll-like receptor 2, leading to cytokine production and immune cell infiltration.^3,4 Increased propagation of this mite correlates with shifts in skin microbiome composition, demonstrating increased inflammatory microbial populations.³

Staphylococcus epidermidis normally is commensal but can become pathogenic (pathobiont) in rosacea due to disruptions in the skin microenvironment, where it can form biofilms and produce virulence factors, particularly in papulopustular rosacea.⁵

Bacillus oleronius has been isolated from D folliculorum mites and provokes inflammatory responses in patients with rosacea by triggering toll-like receptor 2 activation and cytokine secretion.⁶

Cutibacterium acnes commonly is associated with acne vulgaris. Its role in rosacea is unclear, but recent research suggests it may have a protective effect. A single-arm trial investigated the effects of minocycline on rosacea and found that treatment significantly reduced C acnes but increased microbial species diversity, improving inflammation.⁷ One longitudinal cohort study of 12 patients with rosacea found that C acnes levels were lower in those older than 60 years. Rosacea severity increased with age and correlated with a decline in C acnes, suggesting that it may confer some protective effect in rosacea.⁸ This finding is supported by studies that have shown a reduction in C acnes levels in patients with rosacea compared to controls.^4,8

Important mechanisms in rosacea include epidermal barrier dysfunction, transepidermal water loss, and decreased stratum corneum hydration, particularly in erythematotelangiectatic and papulopustular subtypes. The resulting alkaline skin pH contributes to barrier instability and heightened inflammation, permitting pathogenic bacteria to proliferate and disrupt skin microbial homeostasis.⁹ A recent study identified metabolic changes in the skin microbiome of patients with rosacea, showing that increased heme and hydrogen sulfide in rosacea skin microbiomes likely drive inflammation, while healthy skin microbiomes produce more anti-inflammatory adenosylcobalamin, thiazole, and L-isoleucine.¹ These findings highlight the link between microbial imbalances and inflammation in rosacea.

The Gut-Skin Axis in Rosacea

Gut microbiota play a critical role in managing systemic inflammation, and microbial dysbiosis in the intestine can influence the skin microbiome in rosacea. Patients with rosacea who have gastrointestinal conditions such as small intestinal bacterial overgrowth and Helicobacter pylori infection experience more severe rosacea symptoms.^3,10

Patients with rosacea have distinctive gut microbiota compositions, with an increased prevalence of proinflammatory bacterial species, potentially affecting the skin microbiome.^8,11 Systemic antibiotics have been shown to modulate the gut microbiome, indirectly influencing the skin microbiome.¹¹ A recent study demonstrated that doxycycline treatment in patients with rosacea altered skin microbial diversity, reducing C acnes while increasing Weissella confusa—highlighting the complicated relationship between systemic antibiotics and the gut-skin axis.⁸

Specific probiotics, such as Escherichia coli Nissle, when given orally shifted gut microbial balance to protective microbiota with increased Lactobacillus and Bifidobacteria species and decreased pathogenic bacteria. This improved rosacea symptoms, normalized immunoglobulin A levels, and suppressed cytokine interleukin 8 levels.¹⁰ Recent studies also suggest oral sarecycline, a narrow-spectrum antibiotic, may improve papulopustular rosacea symptoms through its anti-inflammatory effects while having minimal impact on gut microbiota diversity.^11,12

Gut-derived short-chain fatty acids, which are known to regulate immune function, also have been shown to influence the composition of skin microbiota, suggesting a direct link between gut dysbiosis and skin microbial imbalances. Notably, antibiotic and probiotic treatments targeting the gut microbiome (eg, rifaximin for small intestinal bacterial overgrowth) have been associated with improvements in rosacea symptoms, further underscoring the interconnectedness of the gut-skin axis.¹³ Understanding how gut-derived inflammation alters the skin microbiome may provide new therapeutic avenues for restoring microbial balance and reducing rosacea severity.

Immune Dysregulation and Inflammatory Pathways

Mechanisms of microbiome-driven inflammation via the innate immune system contribute to rosacea pathogenesis. Toll-like receptor 2 is upregulated in rosacea, producing increased peptides including cathelicidins.¹³ When abnormally processed, cathelicidins produce proinflammatory peptides and worsen rosacea symptoms such as erythema, telangiectasias, and neutrophilic infiltration by dysregulating the immune system and the skin barrier.⁶

Heightened levels of cytokines interleukin 8 and interferon α have been identified in patients with rosacea. These cytokines are involved in rosacea pathogenesis, including leukocyte recruitment, angiogenesis, and tissue remodeling and further activate the inflammatory cascade.^8,14

Mendelian randomization studies have provided confirmation of a causal link between skin microbiota alterations and inflammatory skin diseases including rosacea.² Specific alterations in bacteria such as Cutibacterium and Staphylococcus microbial species have been associated with shifts in host immune gene expression, potentially predisposing individuals to abnormal immune activation and inflammation.^2,8 These studies show the potential of leveraging precision medicine to design therapies that target pathways that improve microbial imbalances seen in rosacea.

Environmental and Lifestyle Factors Affecting the Skin Microbiome

Individuals with rosacea often have increased sensitivity to environmental and lifestyle stressors such as high temperatures, UV exposure, and sugar and alcohol consumption. These factors influence the composition of the skin microbiome and potentially contribute to rosacea development and disease exacerbation; therefore, trigger avoidance is an important way to manage rosacea.

High temperatures and UV exposure—Demodex activity increases in response to heat exposure and subsequently worsens rosacea symptoms, while exposure to UV radiation can change the composition of the skin microbiome by encouraging inflammatory responses such as oxidative stress reactions.⁴ This effect on the skin microbiome is driven partly by the increased presence of certain skin microbial species, such as S epidermidis, which secrete virulence factors at higher temperatures and further contribute to inflammation.^1,4

High-glycemic diet and alcohol consumption—High-glycemic diets and alcohol intake have been associated with gut dysbiosis and increased disease severity in rosacea. Processed foods and high sugar consumption can promote proinflammatory reactions that cause skin dysbiosis and exacerbate symptoms.¹⁵ Increased consumption of anti-inflammatory foods or consumption of probiotics and prebiotics can improve microbial balance.

Therapeutic Implications

The influence of the skin and gut microbiome on rosacea have been well described in the medical literature; therefore, many therapeutic strategies aim to address microbiome dysbiosis, including the use of antibiotics, anthelmintics, and a range of topical agents as well as probiotics, microbiome-friendly skin care products, and dietary modifications.

Antibiotics and Anthelmintics—Topical and oral antibiotics such as metronidazole and doxycycline reduce microbial load and inflammation.^5,7,8 Ivermectin, an anthelmintic, has demonstrated efficacy in decreasing Demodex colonization and associated inflammation by interfering with mite survival and reducing bacterial interactions on the skin.⁵ Recent literature also has explored next-generation antibiotics that disrupt biofilm production by bacteria, which could positively affect outcomes while safeguarding antibiotic stewardship.¹⁵ Given its targeted antimicrobial activity and low propensity for microbial resistance, sarecycline represents a promising therapeutic option for managing rosacea symptoms with reduced risk for microbiome-related adverse events.^12,16

Probiotics and Skin Care Interventions—Probiotics, prebiotics, and postbiotics have emerged as promising approaches to improve rosacea outcomes. Topical probiotics have been shown to maintain skin microbiome homeostasis, reduce inflammation, and enhance epidermal barrier function, making them a promising adjunctive therapy for rosacea.^17,18 Physiological pH cleansers and moisturizers formulated with microbiome-friendly ingredients may reduce transepidermal water loss and improve skin hydration, which are critical in microbial equilibrium.⁹ Oral administration of E coli Nissle, Lactobacillus, and Bifidobacterium have shown potential in improving microbial balance and reducing disease severity.¹⁰

Other Topical Therapies—Azelaic acid and benzoyl peroxide can improve rosacea symptoms by decreasing inflammation and also may shift the skin microbiome.^19,20 Formulations of topical therapies, including microencapsulated benzoyl peroxide, show improved efficacy in targeting pathogenic bacteria while maintaining tolerability.¹⁹

Dietary Modifications—Avoiding triggers such as alcohol and high-glycemic foods can help reduce gut and skin dysbiosis.¹³ Polyphenol-rich foods and prebiotic fiber may promote beneficial gut and skin microbial composition and currently are being studied.¹³

Emerging Therapies—Long-pulsed alexandrite laser therapy has been shown to reduce facial erythema and modulate skin microbiota.²¹ Patients with treatment-resistant rosacea may benefit from advanced precision targeted antimicrobials.

The future of rosacea treatment may involve integrating established and emerging microbiome-targeted treatment strategies to improve short- and long-term patient outcomes in rosacea.

Conclusion

As our understanding of rosacea, its pathogenesis, and the role of the skin microbiome continues to grow, so does our ability to develop increasingly effective and well-tolerated treatments. Future research should focus on how changes to the skin microbiome can influence disease progression and treatment responses as well as potential therapies targeting the skin microbiome. Integrating precision treatments that restore microbial balance alongside more traditional therapies may improve outcomes by addressing both inflammation and epidermal barrier dysfunction. Additionally, strategies that support a healthy skin microbiome, such as microbiome-friendly skin care and topical probiotics, should be further explored to enhance long-term disease management. There remains a dearth of literature addressing how the skin microbiome of patients with rosacea can be optimized to maximize treatment, highlighting the need for more research into these interventions.

Rosacea is a chronic inflammatory skin condition affecting the central face—including the cheeks, nose, chin, and forehead—that causes considerable discomfort.¹ Its pathogenesis involves immune dysregulation, genetic predisposition, and microbial dysbiosis.² While immune and environmental factors are known triggers of rosacea, recent research highlights the roles of the gut and skin microbiomes in disease progression. While the skin microbiome interacts directly with the immune system to regulate inflammation and skin homeostasis, the gut microbiome also influences cutaneous inflammation, emphasizing the need to address both topical and internal microbiome imbalances.³ In this article, we review gut and skin microbial alterations in rosacea, focusing on the skin microbiome and including the gut-skin axis implications as well as therapeutic strategies aimed at microbiome balance to enhance patient outcomes.

Skin Microbiome Alterations in Rosacea

The human skin microbiome interacts with the immune system, and microbial imbalances have been shown to contribute to immune dysregulation. Several key microbial species have been identified as playing a large role in rosacea, including Demodex folliculorum, Staphylococcus epidermidis, Bacillus oleronius, and Cutibacterium acnes (Figure).

Demodex folliculorum is a microscopic mite is found in hair follicles and sebaceous glands. Patients with rosacea have higher densities of D folliculorum, which trigger follicular occlusion and immune activation.¹Bacillus oleronius be isolated from D folliculorum and can further activate toll-like receptor 2, leading to cytokine production and immune cell infiltration.^3,4 Increased propagation of this mite correlates with shifts in skin microbiome composition, demonstrating increased inflammatory microbial populations.³

Staphylococcus epidermidis normally is commensal but can become pathogenic (pathobiont) in rosacea due to disruptions in the skin microenvironment, where it can form biofilms and produce virulence factors, particularly in papulopustular rosacea.⁵

Bacillus oleronius has been isolated from D folliculorum mites and provokes inflammatory responses in patients with rosacea by triggering toll-like receptor 2 activation and cytokine secretion.⁶

Cutibacterium acnes commonly is associated with acne vulgaris. Its role in rosacea is unclear, but recent research suggests it may have a protective effect. A single-arm trial investigated the effects of minocycline on rosacea and found that treatment significantly reduced C acnes but increased microbial species diversity, improving inflammation.⁷ One longitudinal cohort study of 12 patients with rosacea found that C acnes levels were lower in those older than 60 years. Rosacea severity increased with age and correlated with a decline in C acnes, suggesting that it may confer some protective effect in rosacea.⁸ This finding is supported by studies that have shown a reduction in C acnes levels in patients with rosacea compared to controls.^4,8

Important mechanisms in rosacea include epidermal barrier dysfunction, transepidermal water loss, and decreased stratum corneum hydration, particularly in erythematotelangiectatic and papulopustular subtypes. The resulting alkaline skin pH contributes to barrier instability and heightened inflammation, permitting pathogenic bacteria to proliferate and disrupt skin microbial homeostasis.⁹ A recent study identified metabolic changes in the skin microbiome of patients with rosacea, showing that increased heme and hydrogen sulfide in rosacea skin microbiomes likely drive inflammation, while healthy skin microbiomes produce more anti-inflammatory adenosylcobalamin, thiazole, and L-isoleucine.¹ These findings highlight the link between microbial imbalances and inflammation in rosacea.

The Gut-Skin Axis in Rosacea

Gut microbiota play a critical role in managing systemic inflammation, and microbial dysbiosis in the intestine can influence the skin microbiome in rosacea. Patients with rosacea who have gastrointestinal conditions such as small intestinal bacterial overgrowth and Helicobacter pylori infection experience more severe rosacea symptoms.^3,10

Patients with rosacea have distinctive gut microbiota compositions, with an increased prevalence of proinflammatory bacterial species, potentially affecting the skin microbiome.^8,11 Systemic antibiotics have been shown to modulate the gut microbiome, indirectly influencing the skin microbiome.¹¹ A recent study demonstrated that doxycycline treatment in patients with rosacea altered skin microbial diversity, reducing C acnes while increasing Weissella confusa—highlighting the complicated relationship between systemic antibiotics and the gut-skin axis.⁸

Specific probiotics, such as Escherichia coli Nissle, when given orally shifted gut microbial balance to protective microbiota with increased Lactobacillus and Bifidobacteria species and decreased pathogenic bacteria. This improved rosacea symptoms, normalized immunoglobulin A levels, and suppressed cytokine interleukin 8 levels.¹⁰ Recent studies also suggest oral sarecycline, a narrow-spectrum antibiotic, may improve papulopustular rosacea symptoms through its anti-inflammatory effects while having minimal impact on gut microbiota diversity.^11,12

Gut-derived short-chain fatty acids, which are known to regulate immune function, also have been shown to influence the composition of skin microbiota, suggesting a direct link between gut dysbiosis and skin microbial imbalances. Notably, antibiotic and probiotic treatments targeting the gut microbiome (eg, rifaximin for small intestinal bacterial overgrowth) have been associated with improvements in rosacea symptoms, further underscoring the interconnectedness of the gut-skin axis.¹³ Understanding how gut-derived inflammation alters the skin microbiome may provide new therapeutic avenues for restoring microbial balance and reducing rosacea severity.

Immune Dysregulation and Inflammatory Pathways

Mechanisms of microbiome-driven inflammation via the innate immune system contribute to rosacea pathogenesis. Toll-like receptor 2 is upregulated in rosacea, producing increased peptides including cathelicidins.¹³ When abnormally processed, cathelicidins produce proinflammatory peptides and worsen rosacea symptoms such as erythema, telangiectasias, and neutrophilic infiltration by dysregulating the immune system and the skin barrier.⁶

Heightened levels of cytokines interleukin 8 and interferon α have been identified in patients with rosacea. These cytokines are involved in rosacea pathogenesis, including leukocyte recruitment, angiogenesis, and tissue remodeling and further activate the inflammatory cascade.^8,14

Mendelian randomization studies have provided confirmation of a causal link between skin microbiota alterations and inflammatory skin diseases including rosacea.² Specific alterations in bacteria such as Cutibacterium and Staphylococcus microbial species have been associated with shifts in host immune gene expression, potentially predisposing individuals to abnormal immune activation and inflammation.^2,8 These studies show the potential of leveraging precision medicine to design therapies that target pathways that improve microbial imbalances seen in rosacea.

Environmental and Lifestyle Factors Affecting the Skin Microbiome

Individuals with rosacea often have increased sensitivity to environmental and lifestyle stressors such as high temperatures, UV exposure, and sugar and alcohol consumption. These factors influence the composition of the skin microbiome and potentially contribute to rosacea development and disease exacerbation; therefore, trigger avoidance is an important way to manage rosacea.

High temperatures and UV exposure—Demodex activity increases in response to heat exposure and subsequently worsens rosacea symptoms, while exposure to UV radiation can change the composition of the skin microbiome by encouraging inflammatory responses such as oxidative stress reactions.⁴ This effect on the skin microbiome is driven partly by the increased presence of certain skin microbial species, such as S epidermidis, which secrete virulence factors at higher temperatures and further contribute to inflammation.^1,4

High-glycemic diet and alcohol consumption—High-glycemic diets and alcohol intake have been associated with gut dysbiosis and increased disease severity in rosacea. Processed foods and high sugar consumption can promote proinflammatory reactions that cause skin dysbiosis and exacerbate symptoms.¹⁵ Increased consumption of anti-inflammatory foods or consumption of probiotics and prebiotics can improve microbial balance.

Therapeutic Implications

The influence of the skin and gut microbiome on rosacea have been well described in the medical literature; therefore, many therapeutic strategies aim to address microbiome dysbiosis, including the use of antibiotics, anthelmintics, and a range of topical agents as well as probiotics, microbiome-friendly skin care products, and dietary modifications.

Antibiotics and Anthelmintics—Topical and oral antibiotics such as metronidazole and doxycycline reduce microbial load and inflammation.^5,7,8 Ivermectin, an anthelmintic, has demonstrated efficacy in decreasing Demodex colonization and associated inflammation by interfering with mite survival and reducing bacterial interactions on the skin.⁵ Recent literature also has explored next-generation antibiotics that disrupt biofilm production by bacteria, which could positively affect outcomes while safeguarding antibiotic stewardship.¹⁵ Given its targeted antimicrobial activity and low propensity for microbial resistance, sarecycline represents a promising therapeutic option for managing rosacea symptoms with reduced risk for microbiome-related adverse events.^12,16

Probiotics and Skin Care Interventions—Probiotics, prebiotics, and postbiotics have emerged as promising approaches to improve rosacea outcomes. Topical probiotics have been shown to maintain skin microbiome homeostasis, reduce inflammation, and enhance epidermal barrier function, making them a promising adjunctive therapy for rosacea.^17,18 Physiological pH cleansers and moisturizers formulated with microbiome-friendly ingredients may reduce transepidermal water loss and improve skin hydration, which are critical in microbial equilibrium.⁹ Oral administration of E coli Nissle, Lactobacillus, and Bifidobacterium have shown potential in improving microbial balance and reducing disease severity.¹⁰

Other Topical Therapies—Azelaic acid and benzoyl peroxide can improve rosacea symptoms by decreasing inflammation and also may shift the skin microbiome.^19,20 Formulations of topical therapies, including microencapsulated benzoyl peroxide, show improved efficacy in targeting pathogenic bacteria while maintaining tolerability.¹⁹

Dietary Modifications—Avoiding triggers such as alcohol and high-glycemic foods can help reduce gut and skin dysbiosis.¹³ Polyphenol-rich foods and prebiotic fiber may promote beneficial gut and skin microbial composition and currently are being studied.¹³

Emerging Therapies—Long-pulsed alexandrite laser therapy has been shown to reduce facial erythema and modulate skin microbiota.²¹ Patients with treatment-resistant rosacea may benefit from advanced precision targeted antimicrobials.

The future of rosacea treatment may involve integrating established and emerging microbiome-targeted treatment strategies to improve short- and long-term patient outcomes in rosacea.

Conclusion

As our understanding of rosacea, its pathogenesis, and the role of the skin microbiome continues to grow, so does our ability to develop increasingly effective and well-tolerated treatments. Future research should focus on how changes to the skin microbiome can influence disease progression and treatment responses as well as potential therapies targeting the skin microbiome. Integrating precision treatments that restore microbial balance alongside more traditional therapies may improve outcomes by addressing both inflammation and epidermal barrier dysfunction. Additionally, strategies that support a healthy skin microbiome, such as microbiome-friendly skin care and topical probiotics, should be further explored to enhance long-term disease management. There remains a dearth of literature addressing how the skin microbiome of patients with rosacea can be optimized to maximize treatment, highlighting the need for more research into these interventions.

Rosacea is a chronic inflammatory skin condition affecting the central face—including the cheeks, nose, chin, and forehead—that causes considerable discomfort.¹ Its pathogenesis involves immune dysregulation, genetic predisposition, and microbial dysbiosis.² While immune and environmental factors are known triggers of rosacea, recent research highlights the roles of the gut and skin microbiomes in disease progression. While the skin microbiome interacts directly with the immune system to regulate inflammation and skin homeostasis, the gut microbiome also influences cutaneous inflammation, emphasizing the need to address both topical and internal microbiome imbalances.³ In this article, we review gut and skin microbial alterations in rosacea, focusing on the skin microbiome and including the gut-skin axis implications as well as therapeutic strategies aimed at microbiome balance to enhance patient outcomes.

Skin Microbiome Alterations in Rosacea

The human skin microbiome interacts with the immune system, and microbial imbalances have been shown to contribute to immune dysregulation. Several key microbial species have been identified as playing a large role in rosacea, including Demodex folliculorum, Staphylococcus epidermidis, Bacillus oleronius, and Cutibacterium acnes (Figure).

Demodex folliculorum is a microscopic mite is found in hair follicles and sebaceous glands. Patients with rosacea have higher densities of D folliculorum, which trigger follicular occlusion and immune activation.¹Bacillus oleronius be isolated from D folliculorum and can further activate toll-like receptor 2, leading to cytokine production and immune cell infiltration.^3,4 Increased propagation of this mite correlates with shifts in skin microbiome composition, demonstrating increased inflammatory microbial populations.³

Staphylococcus epidermidis normally is commensal but can become pathogenic (pathobiont) in rosacea due to disruptions in the skin microenvironment, where it can form biofilms and produce virulence factors, particularly in papulopustular rosacea.⁵

Bacillus oleronius has been isolated from D folliculorum mites and provokes inflammatory responses in patients with rosacea by triggering toll-like receptor 2 activation and cytokine secretion.⁶

Cutibacterium acnes commonly is associated with acne vulgaris. Its role in rosacea is unclear, but recent research suggests it may have a protective effect. A single-arm trial investigated the effects of minocycline on rosacea and found that treatment significantly reduced C acnes but increased microbial species diversity, improving inflammation.⁷ One longitudinal cohort study of 12 patients with rosacea found that C acnes levels were lower in those older than 60 years. Rosacea severity increased with age and correlated with a decline in C acnes, suggesting that it may confer some protective effect in rosacea.⁸ This finding is supported by studies that have shown a reduction in C acnes levels in patients with rosacea compared to controls.^4,8

Important mechanisms in rosacea include epidermal barrier dysfunction, transepidermal water loss, and decreased stratum corneum hydration, particularly in erythematotelangiectatic and papulopustular subtypes. The resulting alkaline skin pH contributes to barrier instability and heightened inflammation, permitting pathogenic bacteria to proliferate and disrupt skin microbial homeostasis.⁹ A recent study identified metabolic changes in the skin microbiome of patients with rosacea, showing that increased heme and hydrogen sulfide in rosacea skin microbiomes likely drive inflammation, while healthy skin microbiomes produce more anti-inflammatory adenosylcobalamin, thiazole, and L-isoleucine.¹ These findings highlight the link between microbial imbalances and inflammation in rosacea.

The Gut-Skin Axis in Rosacea

Gut microbiota play a critical role in managing systemic inflammation, and microbial dysbiosis in the intestine can influence the skin microbiome in rosacea. Patients with rosacea who have gastrointestinal conditions such as small intestinal bacterial overgrowth and Helicobacter pylori infection experience more severe rosacea symptoms.^3,10

Patients with rosacea have distinctive gut microbiota compositions, with an increased prevalence of proinflammatory bacterial species, potentially affecting the skin microbiome.^8,11 Systemic antibiotics have been shown to modulate the gut microbiome, indirectly influencing the skin microbiome.¹¹ A recent study demonstrated that doxycycline treatment in patients with rosacea altered skin microbial diversity, reducing C acnes while increasing Weissella confusa—highlighting the complicated relationship between systemic antibiotics and the gut-skin axis.⁸

Specific probiotics, such as Escherichia coli Nissle, when given orally shifted gut microbial balance to protective microbiota with increased Lactobacillus and Bifidobacteria species and decreased pathogenic bacteria. This improved rosacea symptoms, normalized immunoglobulin A levels, and suppressed cytokine interleukin 8 levels.¹⁰ Recent studies also suggest oral sarecycline, a narrow-spectrum antibiotic, may improve papulopustular rosacea symptoms through its anti-inflammatory effects while having minimal impact on gut microbiota diversity.^11,12

Gut-derived short-chain fatty acids, which are known to regulate immune function, also have been shown to influence the composition of skin microbiota, suggesting a direct link between gut dysbiosis and skin microbial imbalances. Notably, antibiotic and probiotic treatments targeting the gut microbiome (eg, rifaximin for small intestinal bacterial overgrowth) have been associated with improvements in rosacea symptoms, further underscoring the interconnectedness of the gut-skin axis.¹³ Understanding how gut-derived inflammation alters the skin microbiome may provide new therapeutic avenues for restoring microbial balance and reducing rosacea severity.

Immune Dysregulation and Inflammatory Pathways

Mechanisms of microbiome-driven inflammation via the innate immune system contribute to rosacea pathogenesis. Toll-like receptor 2 is upregulated in rosacea, producing increased peptides including cathelicidins.¹³ When abnormally processed, cathelicidins produce proinflammatory peptides and worsen rosacea symptoms such as erythema, telangiectasias, and neutrophilic infiltration by dysregulating the immune system and the skin barrier.⁶

Heightened levels of cytokines interleukin 8 and interferon α have been identified in patients with rosacea. These cytokines are involved in rosacea pathogenesis, including leukocyte recruitment, angiogenesis, and tissue remodeling and further activate the inflammatory cascade.^8,14

Mendelian randomization studies have provided confirmation of a causal link between skin microbiota alterations and inflammatory skin diseases including rosacea.² Specific alterations in bacteria such as Cutibacterium and Staphylococcus microbial species have been associated with shifts in host immune gene expression, potentially predisposing individuals to abnormal immune activation and inflammation.^2,8 These studies show the potential of leveraging precision medicine to design therapies that target pathways that improve microbial imbalances seen in rosacea.

Environmental and Lifestyle Factors Affecting the Skin Microbiome

Individuals with rosacea often have increased sensitivity to environmental and lifestyle stressors such as high temperatures, UV exposure, and sugar and alcohol consumption. These factors influence the composition of the skin microbiome and potentially contribute to rosacea development and disease exacerbation; therefore, trigger avoidance is an important way to manage rosacea.

High temperatures and UV exposure—Demodex activity increases in response to heat exposure and subsequently worsens rosacea symptoms, while exposure to UV radiation can change the composition of the skin microbiome by encouraging inflammatory responses such as oxidative stress reactions.⁴ This effect on the skin microbiome is driven partly by the increased presence of certain skin microbial species, such as S epidermidis, which secrete virulence factors at higher temperatures and further contribute to inflammation.^1,4

High-glycemic diet and alcohol consumption—High-glycemic diets and alcohol intake have been associated with gut dysbiosis and increased disease severity in rosacea. Processed foods and high sugar consumption can promote proinflammatory reactions that cause skin dysbiosis and exacerbate symptoms.¹⁵ Increased consumption of anti-inflammatory foods or consumption of probiotics and prebiotics can improve microbial balance.

Therapeutic Implications

The influence of the skin and gut microbiome on rosacea have been well described in the medical literature; therefore, many therapeutic strategies aim to address microbiome dysbiosis, including the use of antibiotics, anthelmintics, and a range of topical agents as well as probiotics, microbiome-friendly skin care products, and dietary modifications.

Antibiotics and Anthelmintics—Topical and oral antibiotics such as metronidazole and doxycycline reduce microbial load and inflammation.^5,7,8 Ivermectin, an anthelmintic, has demonstrated efficacy in decreasing Demodex colonization and associated inflammation by interfering with mite survival and reducing bacterial interactions on the skin.⁵ Recent literature also has explored next-generation antibiotics that disrupt biofilm production by bacteria, which could positively affect outcomes while safeguarding antibiotic stewardship.¹⁵ Given its targeted antimicrobial activity and low propensity for microbial resistance, sarecycline represents a promising therapeutic option for managing rosacea symptoms with reduced risk for microbiome-related adverse events.^12,16

Probiotics and Skin Care Interventions—Probiotics, prebiotics, and postbiotics have emerged as promising approaches to improve rosacea outcomes. Topical probiotics have been shown to maintain skin microbiome homeostasis, reduce inflammation, and enhance epidermal barrier function, making them a promising adjunctive therapy for rosacea.^17,18 Physiological pH cleansers and moisturizers formulated with microbiome-friendly ingredients may reduce transepidermal water loss and improve skin hydration, which are critical in microbial equilibrium.⁹ Oral administration of E coli Nissle, Lactobacillus, and Bifidobacterium have shown potential in improving microbial balance and reducing disease severity.¹⁰

Other Topical Therapies—Azelaic acid and benzoyl peroxide can improve rosacea symptoms by decreasing inflammation and also may shift the skin microbiome.^19,20 Formulations of topical therapies, including microencapsulated benzoyl peroxide, show improved efficacy in targeting pathogenic bacteria while maintaining tolerability.¹⁹

Dietary Modifications—Avoiding triggers such as alcohol and high-glycemic foods can help reduce gut and skin dysbiosis.¹³ Polyphenol-rich foods and prebiotic fiber may promote beneficial gut and skin microbial composition and currently are being studied.¹³

Emerging Therapies—Long-pulsed alexandrite laser therapy has been shown to reduce facial erythema and modulate skin microbiota.²¹ Patients with treatment-resistant rosacea may benefit from advanced precision targeted antimicrobials.

The future of rosacea treatment may involve integrating established and emerging microbiome-targeted treatment strategies to improve short- and long-term patient outcomes in rosacea.

Conclusion

As our understanding of rosacea, its pathogenesis, and the role of the skin microbiome continues to grow, so does our ability to develop increasingly effective and well-tolerated treatments. Future research should focus on how changes to the skin microbiome can influence disease progression and treatment responses as well as potential therapies targeting the skin microbiome. Integrating precision treatments that restore microbial balance alongside more traditional therapies may improve outcomes by addressing both inflammation and epidermal barrier dysfunction. Additionally, strategies that support a healthy skin microbiome, such as microbiome-friendly skin care and topical probiotics, should be further explored to enhance long-term disease management. There remains a dearth of literature addressing how the skin microbiome of patients with rosacea can be optimized to maximize treatment, highlighting the need for more research into these interventions.