Psoriasis

The estimated prevalence of psoriasis in individuals older than 20 years in the United States has been reported at approximately 3%, or more than 7.5 million people.¹ There currently is no cure for psoriasis, and available therapeutics, including phototherapy,² topical therapies,³ systemic medications,⁴ and biologic agents,⁵ are focused only on controlling symptoms. The National Psoriasis Foundation defines an acceptable treatment response for plaque psoriasis as 3% or lower body surface area (BSA) involvement after 3 months of therapy, with a treat-to-target (TTT) goal of 1% or less BSA involvement.⁶

Cytokines are known to mediate psoriasis pathology, and biologic therapies target the signaling cascade of various cytokines. Biologics approved to treat moderate to severe plaque psoriasis include IgG monoclonal antibodies binding and inhibiting the activity of interleukin (IL)-17 (ixekizumab,⁷ secukinumab⁸), IL-23 (guselkumab,⁹ risankizumab,¹⁰ tildrakizumab¹¹), and IL-12/23 (ustekinumab¹²). Despite targeting these cytokines, biologics may not sufficiently suppress the symptoms of psoriatic disease and their severity in all patients. Adding a topical treatment to biologic therapy can augment clinical response without increasing the incidence of adverse effects^13-15 and may reduce the need to switch biologics due to ineffectiveness. Switching biologics likely would increase cost burden to the health care system and/or patient depending on their insurance plan and possibly introduce new safety and/or tolerability issues.^16,17

In patients who do not adequately respond to biologics, better responses were reported when topical medications including halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam^17,18 were administered. In randomized or open-label, real-world studies, patients with psoriasis responded well when topical medications were added to a biologic, such as tildrakizumab combined with halcinonide ointment 0.1%,¹⁹ etanercept combined with topical clobetasol propionate foam,²⁰ or adalimumab combined with calcipotriene/betamethasone dipropionate foam.²¹ No additional safety concerns were observed with the topical add-ons in any of these studies.

Tapinarof is an aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration for topical treatment of plaque psoriasis in adults.²² It is a first-in-class small molecule with a novel mechanism of action that downregulates IL-17A and IL-17F and normalizes the skin barrier through expression of filaggrin, loricrin, and involucrin; it also has antioxidant activity.²³ In the phase 3 PSOARING 1 and 2 trials, daily application of tapinarof cream was safe and efficacious in patients with plaque psoriasis,^24,25 with a remittive (maintenance) effect of a median of approximately 4 months after discontinuation.²⁵ In these 2 phase 3 studies, tapinarof significantly (P<0.01 at week 12) relieved itch, which was seen rapidly (P<0.05 at week 2),²⁶ improved quality of life,²⁷ and led to high patient satisfaction.²⁷ When tapinarof cream was combined with deucravacitinib in a patient with severe plaque psoriasis, symptoms rapidly cleared, with a 75% decrease in disease severity after 4 weeks.²⁸

The objective of this prospective, open-label, real-world, single-center study was to assess the effectiveness, safety, and remittive (or maintenance) effect of nonsteroidal tapinarof cream 1% added to ongoing biologic therapy in patients with plaque psoriasis who were not adequately responding to a biologic alone.

Methods

Study Design and Participants—This prospective, open-label, real-world, single-center study assessed the safety and effectiveness of once-daily application of tapinarof cream 1% added to ongoing biologic therapy to help reach the National Psoriasis Foundation’s TTT goal of 1% or less BSA involvement at week 12 in patients with 3% or greater BSA involvement after taking the biologic for 24 weeks or more. The study protocol was approved by an institutional review board, and the study was conducted according to the ethical guidelines of the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent before the study began.

Eligible participants were otherwise healthy males and females aged 18 years and older with moderate to severe plaque psoriasis (BSA involvement ≥3%) who had been treated with a biologic for 24 weeks or more. Patients were recruited from the Psoriasis Treatment Center of New Jersey (East Windsor, New Jersey). Exclusion criteria were recent use of oral systemic therapies (within 4 weeks of baseline) or topical therapies (within 2 weeks) to treat psoriasis, recent use of UVB (within 2 weeks) or psoralen plus UVA (within 4 weeks) phototherapy, or use of any investigational drug within 4 weeks of baseline (or within 5 pharmacokinetic/pharmacodynamic half-lives, whichever was longer). Patients who were pregnant or breastfeeding or who had any known hypersensitivity to the excipients of tapinarof cream also were excluded from the study.

Eligible participants received tapinarof cream 1% once daily plus their ongoing biologic for 12 weeks, after which tapinarof was discontinued and the biologic was continued for an additional 4 weeks. A remittive (maintenance) effect was assessed at week 16.

Study Outcomes—Safety and efficacy were evaluated at baseline and weeks 2, 4, 8, 12, and 16. The primary end point was the proportion of patients who reached the TTT goal of 1% or less BSA involvement at week 12. Secondary end points included the proportion of patients with 1% or less BSA involvement at weeks 2, 4, 8, and 16; and PGA scores, composite PGA multiplied by mean percentage of BSA involvement (PGA×BSA), and PASI scores at baseline and weeks 2, 4, 8, 12, and 16. The patient-reported outcomes of Dermatology Life Quality Index (DLQI) and Worst Itch Numeric Rating Scale (WI-NRS) scores also were evaluated at baseline and weeks 2, 4, 8, 12, and 16. In patients who had disease involvement on the scalp or genital region at baseline, Psoriasis Scalp Severity Index (PSSI) and Static Physician’s Global Assessment of Genitalia scores, respectively, were assessed at baseline and weeks 2, 4, 8, 12, and 16. Safety was determined by the incidence, severity, and relatedness of adverse events (AEs) and serious AEs.

Statistical Analysis—Approximately 30 participants were planned for enrollment and recruited consecutively as they were identified during screening against inclusion and exclusion criteria. Changes from baseline in all outcomes were summarized descriptively. Missing data were not imputed. Given the sample size, no formal statistical analyses were conducted. Safety was summarized by descriptively collating AEs and serious AEs, including their frequency, severity, and treatment relatedness.

Results

Thirty participants were enrolled in the study, and 20 fully completed the study. Nine discontinued treatment before week 12 (6 were lost to follow-up, 2 were terminated early by the investigators, and 1 voluntarily withdrew); 1 additional participant was lost to follow-up after week 12. Patients were predominantly male (20/30 [66.7%]) and White (21/30 [70.0%]); the mean age of all participants was 55.4 years, and the mean (SD) duration of psoriasis was 21.4 (15.0) years (Table 1). The mean baseline percentage of BSA involvement and mean baseline PGA, PASI, and DLQI scores are shown in Table 1. Most (19/30 [63.3%]) patients received biologics that inhibited IL-23 activity (guselkumab, risankizumab, tildrakizumab), approximately one-third (9/30 [30.0%]) received biologics that inhibited IL-17 activity (ixekizumab, secukinumab), and 2 (6.7%) received biologics that inhibited IL-12/IL-23 activity (ustekinumab)(Table 1).

For the primary end point, 52.4% (11/21) of patients reached the TTT goal (BSA involvement ≤1% after 12 weeks of treatment with tapinarof cream added to a prescribed biologic). The proportion of patients reaching the TTT goal increased over time with the combined treatment (eFigure 1). Additionally, the mean percentage of BSA involvement (eFigure 2) as well as the mean values for PGA (eFigure 3) and PGA×BSA decreased over time. The mean percentage of BSA involvement was 5.0% at baseline and dropped to 2.0% by week 12. Similar reductions were observed for PGA and PGA×BSA scores at week 12.

After discontinuing tapinarof cream at week 12 and receiving only the biologic for 4 weeks, the proportion of patients maintaining 1% or less BSA involvement fell to 40.0% (8/20) at week 16, which was closer to that observed at week 8 (36% [9/25]) than at week 12 (52.4% [11/21])(eFigure 1).

The mean PASI score was 5.5 at baseline, then decreased over time when tapinarof cream was combined with a biologic (eFigure 4), falling to 3.1 by week 2 and 1.6 by week 12; it was maintained at 1.7 at week 16. Nine (30.0%) participants had psoriasis on the scalp at baseline with a mean PSSI score of 2.6, which decreased to 0.83 by week 2. By week 12, the mean PSSI score remained stable at 0.95 in the 2 (9.5%) participants who still had scalp involvement. The mean PSSI score increased slightly to 1.45 after patients received only the biologic for 4 weeks. At baseline, 3 (10.0%) patients had genital involvement (mean Static Physician’s Global Assessment of Genitalia score, 0.27). Symptoms resolved in 2 (66.7%) of these patients at week 2 and stayed consistent until week 16; the third patient withdrew at week 2.

Both DLQI and WI-NRS scores decreased with use of tapinarof cream added to a biologic up to week 12 (eFigures 5 and 6). Mean DLQI scores were 5.3 at baseline and 3.1 at week 12. At week 16, the mean DLQI score remained stable at 2.8. Mean WI-NRS scores decreased from 4.0 at baseline to 2.7 at week 12 with the therapy combination; at week 16, the mean WI-NRS score fell further to 1.8.

A total of 6 AEs were reported in 5 (16.7%) patients (Table 2). The majority (4/6 [67.0%]) of AEs were considered mild. Two reported cases of COVID-19 were both considered mild and unrelated. Mild folliculitis and moderate worsening of psoriasis in 2 (6.7%) different patients were the only AEs considered related to treatment. No serious AEs were reported, and no patient withdrew from the study due to an AE.

Comment

In this prospective, open-label, real-world study, we found that when a patient’s response to a biologic is unsatisfactory, adding nonsteroidal tapinarof cream can enhance the treatment effect of the biologic. More than half of patients who were not adequately responding to a biologic reached the TTT goal at week 12, which was maintained in most of the responders for 4 weeks after tapinarof discontinuation. All measures of disease activity and quality of life (measured by the DLQI) improved when tapinarof was introduced, and the combination was well tolerated and without any unexpected safety signals.

Disease activity improvements we observed with the nonsteroidal tapinarof cream were consistent with those reported when topical steroidal therapies were given to patients responding poorly to their current biologic. Our primary end point (proportion of patients with BSA involvement ≤1% after 12 weeks) showed that half (52% [11/21]) of patients whose BSA involvement was 3% or greater with a biologic for 24 weeks or more reached the TTT goal after 12 weeks of tapinarof-biologic treatment. Other studies of halobetasol propionate–tazarotene lotion¹⁶ and calcipotriene/betamethasone dipropionate foam^17,18 added to the current biologic of poor responders found 60% to 68% of patients had reductions in their percentage BSA to 1% or lower at 12 to 16 weeks of treatment. Randomized studies showed etanercept plus topical clobetasol propionate foam²⁰ or adalimumab plus calcipotriene/betamethasone dipropionate foam²¹ similarly enhanced treatment effects vs biologic alone.

A phase 3 PSOARING trial demonstrated benefit from treatment with tapinarof alone, with a remittive effect of approximately 4 months after discontinuation.²⁵ Our data are consistent with these findings, with 40% (8/20) of patients demonstrating a remittive effect 4 weeks after discontinuing tapinarof while receiving a biologic. A similar maintenance effect was reported in another study in 50% (9/18) of patients treated with a biologic plus halobetasol propionate–tazarotene lotion.¹⁶ Additionally, when halcinonide ointment was given to patients receiving tildrakizumab, mean percentage of BSA involvement, PGA scores, PGA×BSA, and DLQI scores improved and were maintained 4 weeks after halcinonide ointment was stopped.¹⁹ Thus, topical therapy can augment and extend a biologic’s effect for up to 4 weeks. While a longer remittive effect is possible in our patients based on the 4-month remittive rate observed in the PSOARING trials,²⁵ further patient observation would be needed to confirm.

In our study, tapinarof cream added to a biologic had a good safety and tolerability profile. Few AEs were recorded, with most being mild in nature, and no serious AEs or discontinuations due to AEs were reported. Only 1 case of mild folliculitis and 1 case of moderate worsening of psoriasis were considered treatment related. Further, no unexpected or new safety signals with the tapinarof-biologic combination were observed compared with tapinarof alone.²⁷Prior studies have found that supplementing a biologic with topical therapy can reduce the probability of patients switching to another biologic.^16,19 We previously found that adding halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam¹⁷ to a biologic helped reduce the probability of switching biologics from 88% to 90% at baseline to 12% to 24% after 12 weeks of combined therapy. Such combinations also could prevent a less responsive patient from being prescribed a higher biologic dose.¹⁹ These are important research findings, as patients—even when not responding well to their current biologic—are more likely to be tolerating that biologic well, and switching to a new biologic may introduce new safety or tolerability concerns. Thus, by enhancing the effect of a biologic with a topical therapy, one can avoid increasing the dose of the current biologic or switching to a new biologic, either of which may increase safety and/or tolerability risks. Switching biologics also has increased cost implications to the health care system and/or the patient. When comparing the cost of adding halobetasol propionate–tazarotene lotion to a biologic compared with switching to another biologic, the cost was 1.2 to 2.9 times higher to switch, depending on the biologic, compared with a smaller incremental cost increase to add a topical to the current biologic.¹⁶ Similar observations were reported with calcipotriene/betamethasone dipropionate foam plus a biologic.¹⁷ Although we did not evaluate biologic switching here, we anticipate a similar clinical scenario with a tapinarof-biologic combination.

Limitations of our study included the open-label design, lack of a control arm, and the relatively small study population; however, for studies investigating the safety and effectiveness of a treatment in a real-world setting, these limitations are common and are not unexpected. Our results also are consistent with the overall improvement seen in other studies^16-21 examining the effects of adding a topical to a biologic. Future research is warranted to investigate a longer remittive effect and potential health care system and patient cost savings without having to switch biologics due to lack of effectiveness.

Conclusion

This study demonstrated that adjunctive use of nonsteroidal tapinarof cream 1% may enhance a biologic treatment effect in patients with moderate to severe plaque psoriasis, providing an adequate response for many patients who were not responding well to a biologic alone. Clinical outcomes improved with the tapinarof-biologic combination, and a remittive effect was noted 4 weeks after tapinarof discontinuation without any new safety signals. Adding tapinarof cream to a biologic also may prevent the need to switch biologics when patients do not sufficiently respond, preserving the safety and cost associated with a patient’s current biologic.

The estimated prevalence of psoriasis in individuals older than 20 years in the United States has been reported at approximately 3%, or more than 7.5 million people.¹ There currently is no cure for psoriasis, and available therapeutics, including phototherapy,² topical therapies,³ systemic medications,⁴ and biologic agents,⁵ are focused only on controlling symptoms. The National Psoriasis Foundation defines an acceptable treatment response for plaque psoriasis as 3% or lower body surface area (BSA) involvement after 3 months of therapy, with a treat-to-target (TTT) goal of 1% or less BSA involvement.⁶

Cytokines are known to mediate psoriasis pathology, and biologic therapies target the signaling cascade of various cytokines. Biologics approved to treat moderate to severe plaque psoriasis include IgG monoclonal antibodies binding and inhibiting the activity of interleukin (IL)-17 (ixekizumab,⁷ secukinumab⁸), IL-23 (guselkumab,⁹ risankizumab,¹⁰ tildrakizumab¹¹), and IL-12/23 (ustekinumab¹²). Despite targeting these cytokines, biologics may not sufficiently suppress the symptoms of psoriatic disease and their severity in all patients. Adding a topical treatment to biologic therapy can augment clinical response without increasing the incidence of adverse effects^13-15 and may reduce the need to switch biologics due to ineffectiveness. Switching biologics likely would increase cost burden to the health care system and/or patient depending on their insurance plan and possibly introduce new safety and/or tolerability issues.^16,17

In patients who do not adequately respond to biologics, better responses were reported when topical medications including halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam^17,18 were administered. In randomized or open-label, real-world studies, patients with psoriasis responded well when topical medications were added to a biologic, such as tildrakizumab combined with halcinonide ointment 0.1%,¹⁹ etanercept combined with topical clobetasol propionate foam,²⁰ or adalimumab combined with calcipotriene/betamethasone dipropionate foam.²¹ No additional safety concerns were observed with the topical add-ons in any of these studies.

Tapinarof is an aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration for topical treatment of plaque psoriasis in adults.²² It is a first-in-class small molecule with a novel mechanism of action that downregulates IL-17A and IL-17F and normalizes the skin barrier through expression of filaggrin, loricrin, and involucrin; it also has antioxidant activity.²³ In the phase 3 PSOARING 1 and 2 trials, daily application of tapinarof cream was safe and efficacious in patients with plaque psoriasis,^24,25 with a remittive (maintenance) effect of a median of approximately 4 months after discontinuation.²⁵ In these 2 phase 3 studies, tapinarof significantly (P<0.01 at week 12) relieved itch, which was seen rapidly (P<0.05 at week 2),²⁶ improved quality of life,²⁷ and led to high patient satisfaction.²⁷ When tapinarof cream was combined with deucravacitinib in a patient with severe plaque psoriasis, symptoms rapidly cleared, with a 75% decrease in disease severity after 4 weeks.²⁸

The objective of this prospective, open-label, real-world, single-center study was to assess the effectiveness, safety, and remittive (or maintenance) effect of nonsteroidal tapinarof cream 1% added to ongoing biologic therapy in patients with plaque psoriasis who were not adequately responding to a biologic alone.

Methods

Study Design and Participants—This prospective, open-label, real-world, single-center study assessed the safety and effectiveness of once-daily application of tapinarof cream 1% added to ongoing biologic therapy to help reach the National Psoriasis Foundation’s TTT goal of 1% or less BSA involvement at week 12 in patients with 3% or greater BSA involvement after taking the biologic for 24 weeks or more. The study protocol was approved by an institutional review board, and the study was conducted according to the ethical guidelines of the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent before the study began.

Eligible participants were otherwise healthy males and females aged 18 years and older with moderate to severe plaque psoriasis (BSA involvement ≥3%) who had been treated with a biologic for 24 weeks or more. Patients were recruited from the Psoriasis Treatment Center of New Jersey (East Windsor, New Jersey). Exclusion criteria were recent use of oral systemic therapies (within 4 weeks of baseline) or topical therapies (within 2 weeks) to treat psoriasis, recent use of UVB (within 2 weeks) or psoralen plus UVA (within 4 weeks) phototherapy, or use of any investigational drug within 4 weeks of baseline (or within 5 pharmacokinetic/pharmacodynamic half-lives, whichever was longer). Patients who were pregnant or breastfeeding or who had any known hypersensitivity to the excipients of tapinarof cream also were excluded from the study.

Eligible participants received tapinarof cream 1% once daily plus their ongoing biologic for 12 weeks, after which tapinarof was discontinued and the biologic was continued for an additional 4 weeks. A remittive (maintenance) effect was assessed at week 16.

Study Outcomes—Safety and efficacy were evaluated at baseline and weeks 2, 4, 8, 12, and 16. The primary end point was the proportion of patients who reached the TTT goal of 1% or less BSA involvement at week 12. Secondary end points included the proportion of patients with 1% or less BSA involvement at weeks 2, 4, 8, and 16; and PGA scores, composite PGA multiplied by mean percentage of BSA involvement (PGA×BSA), and PASI scores at baseline and weeks 2, 4, 8, 12, and 16. The patient-reported outcomes of Dermatology Life Quality Index (DLQI) and Worst Itch Numeric Rating Scale (WI-NRS) scores also were evaluated at baseline and weeks 2, 4, 8, 12, and 16. In patients who had disease involvement on the scalp or genital region at baseline, Psoriasis Scalp Severity Index (PSSI) and Static Physician’s Global Assessment of Genitalia scores, respectively, were assessed at baseline and weeks 2, 4, 8, 12, and 16. Safety was determined by the incidence, severity, and relatedness of adverse events (AEs) and serious AEs.

Statistical Analysis—Approximately 30 participants were planned for enrollment and recruited consecutively as they were identified during screening against inclusion and exclusion criteria. Changes from baseline in all outcomes were summarized descriptively. Missing data were not imputed. Given the sample size, no formal statistical analyses were conducted. Safety was summarized by descriptively collating AEs and serious AEs, including their frequency, severity, and treatment relatedness.

Results

Thirty participants were enrolled in the study, and 20 fully completed the study. Nine discontinued treatment before week 12 (6 were lost to follow-up, 2 were terminated early by the investigators, and 1 voluntarily withdrew); 1 additional participant was lost to follow-up after week 12. Patients were predominantly male (20/30 [66.7%]) and White (21/30 [70.0%]); the mean age of all participants was 55.4 years, and the mean (SD) duration of psoriasis was 21.4 (15.0) years (Table 1). The mean baseline percentage of BSA involvement and mean baseline PGA, PASI, and DLQI scores are shown in Table 1. Most (19/30 [63.3%]) patients received biologics that inhibited IL-23 activity (guselkumab, risankizumab, tildrakizumab), approximately one-third (9/30 [30.0%]) received biologics that inhibited IL-17 activity (ixekizumab, secukinumab), and 2 (6.7%) received biologics that inhibited IL-12/IL-23 activity (ustekinumab)(Table 1).

For the primary end point, 52.4% (11/21) of patients reached the TTT goal (BSA involvement ≤1% after 12 weeks of treatment with tapinarof cream added to a prescribed biologic). The proportion of patients reaching the TTT goal increased over time with the combined treatment (eFigure 1). Additionally, the mean percentage of BSA involvement (eFigure 2) as well as the mean values for PGA (eFigure 3) and PGA×BSA decreased over time. The mean percentage of BSA involvement was 5.0% at baseline and dropped to 2.0% by week 12. Similar reductions were observed for PGA and PGA×BSA scores at week 12.

After discontinuing tapinarof cream at week 12 and receiving only the biologic for 4 weeks, the proportion of patients maintaining 1% or less BSA involvement fell to 40.0% (8/20) at week 16, which was closer to that observed at week 8 (36% [9/25]) than at week 12 (52.4% [11/21])(eFigure 1).

The mean PASI score was 5.5 at baseline, then decreased over time when tapinarof cream was combined with a biologic (eFigure 4), falling to 3.1 by week 2 and 1.6 by week 12; it was maintained at 1.7 at week 16. Nine (30.0%) participants had psoriasis on the scalp at baseline with a mean PSSI score of 2.6, which decreased to 0.83 by week 2. By week 12, the mean PSSI score remained stable at 0.95 in the 2 (9.5%) participants who still had scalp involvement. The mean PSSI score increased slightly to 1.45 after patients received only the biologic for 4 weeks. At baseline, 3 (10.0%) patients had genital involvement (mean Static Physician’s Global Assessment of Genitalia score, 0.27). Symptoms resolved in 2 (66.7%) of these patients at week 2 and stayed consistent until week 16; the third patient withdrew at week 2.

Both DLQI and WI-NRS scores decreased with use of tapinarof cream added to a biologic up to week 12 (eFigures 5 and 6). Mean DLQI scores were 5.3 at baseline and 3.1 at week 12. At week 16, the mean DLQI score remained stable at 2.8. Mean WI-NRS scores decreased from 4.0 at baseline to 2.7 at week 12 with the therapy combination; at week 16, the mean WI-NRS score fell further to 1.8.

A total of 6 AEs were reported in 5 (16.7%) patients (Table 2). The majority (4/6 [67.0%]) of AEs were considered mild. Two reported cases of COVID-19 were both considered mild and unrelated. Mild folliculitis and moderate worsening of psoriasis in 2 (6.7%) different patients were the only AEs considered related to treatment. No serious AEs were reported, and no patient withdrew from the study due to an AE.

Comment

In this prospective, open-label, real-world study, we found that when a patient’s response to a biologic is unsatisfactory, adding nonsteroidal tapinarof cream can enhance the treatment effect of the biologic. More than half of patients who were not adequately responding to a biologic reached the TTT goal at week 12, which was maintained in most of the responders for 4 weeks after tapinarof discontinuation. All measures of disease activity and quality of life (measured by the DLQI) improved when tapinarof was introduced, and the combination was well tolerated and without any unexpected safety signals.

Disease activity improvements we observed with the nonsteroidal tapinarof cream were consistent with those reported when topical steroidal therapies were given to patients responding poorly to their current biologic. Our primary end point (proportion of patients with BSA involvement ≤1% after 12 weeks) showed that half (52% [11/21]) of patients whose BSA involvement was 3% or greater with a biologic for 24 weeks or more reached the TTT goal after 12 weeks of tapinarof-biologic treatment. Other studies of halobetasol propionate–tazarotene lotion¹⁶ and calcipotriene/betamethasone dipropionate foam^17,18 added to the current biologic of poor responders found 60% to 68% of patients had reductions in their percentage BSA to 1% or lower at 12 to 16 weeks of treatment. Randomized studies showed etanercept plus topical clobetasol propionate foam²⁰ or adalimumab plus calcipotriene/betamethasone dipropionate foam²¹ similarly enhanced treatment effects vs biologic alone.

A phase 3 PSOARING trial demonstrated benefit from treatment with tapinarof alone, with a remittive effect of approximately 4 months after discontinuation.²⁵ Our data are consistent with these findings, with 40% (8/20) of patients demonstrating a remittive effect 4 weeks after discontinuing tapinarof while receiving a biologic. A similar maintenance effect was reported in another study in 50% (9/18) of patients treated with a biologic plus halobetasol propionate–tazarotene lotion.¹⁶ Additionally, when halcinonide ointment was given to patients receiving tildrakizumab, mean percentage of BSA involvement, PGA scores, PGA×BSA, and DLQI scores improved and were maintained 4 weeks after halcinonide ointment was stopped.¹⁹ Thus, topical therapy can augment and extend a biologic’s effect for up to 4 weeks. While a longer remittive effect is possible in our patients based on the 4-month remittive rate observed in the PSOARING trials,²⁵ further patient observation would be needed to confirm.

In our study, tapinarof cream added to a biologic had a good safety and tolerability profile. Few AEs were recorded, with most being mild in nature, and no serious AEs or discontinuations due to AEs were reported. Only 1 case of mild folliculitis and 1 case of moderate worsening of psoriasis were considered treatment related. Further, no unexpected or new safety signals with the tapinarof-biologic combination were observed compared with tapinarof alone.²⁷Prior studies have found that supplementing a biologic with topical therapy can reduce the probability of patients switching to another biologic.^16,19 We previously found that adding halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam¹⁷ to a biologic helped reduce the probability of switching biologics from 88% to 90% at baseline to 12% to 24% after 12 weeks of combined therapy. Such combinations also could prevent a less responsive patient from being prescribed a higher biologic dose.¹⁹ These are important research findings, as patients—even when not responding well to their current biologic—are more likely to be tolerating that biologic well, and switching to a new biologic may introduce new safety or tolerability concerns. Thus, by enhancing the effect of a biologic with a topical therapy, one can avoid increasing the dose of the current biologic or switching to a new biologic, either of which may increase safety and/or tolerability risks. Switching biologics also has increased cost implications to the health care system and/or the patient. When comparing the cost of adding halobetasol propionate–tazarotene lotion to a biologic compared with switching to another biologic, the cost was 1.2 to 2.9 times higher to switch, depending on the biologic, compared with a smaller incremental cost increase to add a topical to the current biologic.¹⁶ Similar observations were reported with calcipotriene/betamethasone dipropionate foam plus a biologic.¹⁷ Although we did not evaluate biologic switching here, we anticipate a similar clinical scenario with a tapinarof-biologic combination.

Limitations of our study included the open-label design, lack of a control arm, and the relatively small study population; however, for studies investigating the safety and effectiveness of a treatment in a real-world setting, these limitations are common and are not unexpected. Our results also are consistent with the overall improvement seen in other studies^16-21 examining the effects of adding a topical to a biologic. Future research is warranted to investigate a longer remittive effect and potential health care system and patient cost savings without having to switch biologics due to lack of effectiveness.

Conclusion

This study demonstrated that adjunctive use of nonsteroidal tapinarof cream 1% may enhance a biologic treatment effect in patients with moderate to severe plaque psoriasis, providing an adequate response for many patients who were not responding well to a biologic alone. Clinical outcomes improved with the tapinarof-biologic combination, and a remittive effect was noted 4 weeks after tapinarof discontinuation without any new safety signals. Adding tapinarof cream to a biologic also may prevent the need to switch biologics when patients do not sufficiently respond, preserving the safety and cost associated with a patient’s current biologic.

The estimated prevalence of psoriasis in individuals older than 20 years in the United States has been reported at approximately 3%, or more than 7.5 million people.¹ There currently is no cure for psoriasis, and available therapeutics, including phototherapy,² topical therapies,³ systemic medications,⁴ and biologic agents,⁵ are focused only on controlling symptoms. The National Psoriasis Foundation defines an acceptable treatment response for plaque psoriasis as 3% or lower body surface area (BSA) involvement after 3 months of therapy, with a treat-to-target (TTT) goal of 1% or less BSA involvement.⁶

Cytokines are known to mediate psoriasis pathology, and biologic therapies target the signaling cascade of various cytokines. Biologics approved to treat moderate to severe plaque psoriasis include IgG monoclonal antibodies binding and inhibiting the activity of interleukin (IL)-17 (ixekizumab,⁷ secukinumab⁸), IL-23 (guselkumab,⁹ risankizumab,¹⁰ tildrakizumab¹¹), and IL-12/23 (ustekinumab¹²). Despite targeting these cytokines, biologics may not sufficiently suppress the symptoms of psoriatic disease and their severity in all patients. Adding a topical treatment to biologic therapy can augment clinical response without increasing the incidence of adverse effects^13-15 and may reduce the need to switch biologics due to ineffectiveness. Switching biologics likely would increase cost burden to the health care system and/or patient depending on their insurance plan and possibly introduce new safety and/or tolerability issues.^16,17

In patients who do not adequately respond to biologics, better responses were reported when topical medications including halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam^17,18 were administered. In randomized or open-label, real-world studies, patients with psoriasis responded well when topical medications were added to a biologic, such as tildrakizumab combined with halcinonide ointment 0.1%,¹⁹ etanercept combined with topical clobetasol propionate foam,²⁰ or adalimumab combined with calcipotriene/betamethasone dipropionate foam.²¹ No additional safety concerns were observed with the topical add-ons in any of these studies.

Tapinarof is an aryl hydrocarbon receptor agonist approved by the US Food and Drug Administration for topical treatment of plaque psoriasis in adults.²² It is a first-in-class small molecule with a novel mechanism of action that downregulates IL-17A and IL-17F and normalizes the skin barrier through expression of filaggrin, loricrin, and involucrin; it also has antioxidant activity.²³ In the phase 3 PSOARING 1 and 2 trials, daily application of tapinarof cream was safe and efficacious in patients with plaque psoriasis,^24,25 with a remittive (maintenance) effect of a median of approximately 4 months after discontinuation.²⁵ In these 2 phase 3 studies, tapinarof significantly (P<0.01 at week 12) relieved itch, which was seen rapidly (P<0.05 at week 2),²⁶ improved quality of life,²⁷ and led to high patient satisfaction.²⁷ When tapinarof cream was combined with deucravacitinib in a patient with severe plaque psoriasis, symptoms rapidly cleared, with a 75% decrease in disease severity after 4 weeks.²⁸

The objective of this prospective, open-label, real-world, single-center study was to assess the effectiveness, safety, and remittive (or maintenance) effect of nonsteroidal tapinarof cream 1% added to ongoing biologic therapy in patients with plaque psoriasis who were not adequately responding to a biologic alone.

Methods

Study Design and Participants—This prospective, open-label, real-world, single-center study assessed the safety and effectiveness of once-daily application of tapinarof cream 1% added to ongoing biologic therapy to help reach the National Psoriasis Foundation’s TTT goal of 1% or less BSA involvement at week 12 in patients with 3% or greater BSA involvement after taking the biologic for 24 weeks or more. The study protocol was approved by an institutional review board, and the study was conducted according to the ethical guidelines of the Declaration of Helsinki and Good Clinical Practice. All participants provided written informed consent before the study began.

Eligible participants were otherwise healthy males and females aged 18 years and older with moderate to severe plaque psoriasis (BSA involvement ≥3%) who had been treated with a biologic for 24 weeks or more. Patients were recruited from the Psoriasis Treatment Center of New Jersey (East Windsor, New Jersey). Exclusion criteria were recent use of oral systemic therapies (within 4 weeks of baseline) or topical therapies (within 2 weeks) to treat psoriasis, recent use of UVB (within 2 weeks) or psoralen plus UVA (within 4 weeks) phototherapy, or use of any investigational drug within 4 weeks of baseline (or within 5 pharmacokinetic/pharmacodynamic half-lives, whichever was longer). Patients who were pregnant or breastfeeding or who had any known hypersensitivity to the excipients of tapinarof cream also were excluded from the study.

Eligible participants received tapinarof cream 1% once daily plus their ongoing biologic for 12 weeks, after which tapinarof was discontinued and the biologic was continued for an additional 4 weeks. A remittive (maintenance) effect was assessed at week 16.

Study Outcomes—Safety and efficacy were evaluated at baseline and weeks 2, 4, 8, 12, and 16. The primary end point was the proportion of patients who reached the TTT goal of 1% or less BSA involvement at week 12. Secondary end points included the proportion of patients with 1% or less BSA involvement at weeks 2, 4, 8, and 16; and PGA scores, composite PGA multiplied by mean percentage of BSA involvement (PGA×BSA), and PASI scores at baseline and weeks 2, 4, 8, 12, and 16. The patient-reported outcomes of Dermatology Life Quality Index (DLQI) and Worst Itch Numeric Rating Scale (WI-NRS) scores also were evaluated at baseline and weeks 2, 4, 8, 12, and 16. In patients who had disease involvement on the scalp or genital region at baseline, Psoriasis Scalp Severity Index (PSSI) and Static Physician’s Global Assessment of Genitalia scores, respectively, were assessed at baseline and weeks 2, 4, 8, 12, and 16. Safety was determined by the incidence, severity, and relatedness of adverse events (AEs) and serious AEs.

Statistical Analysis—Approximately 30 participants were planned for enrollment and recruited consecutively as they were identified during screening against inclusion and exclusion criteria. Changes from baseline in all outcomes were summarized descriptively. Missing data were not imputed. Given the sample size, no formal statistical analyses were conducted. Safety was summarized by descriptively collating AEs and serious AEs, including their frequency, severity, and treatment relatedness.

Results

Thirty participants were enrolled in the study, and 20 fully completed the study. Nine discontinued treatment before week 12 (6 were lost to follow-up, 2 were terminated early by the investigators, and 1 voluntarily withdrew); 1 additional participant was lost to follow-up after week 12. Patients were predominantly male (20/30 [66.7%]) and White (21/30 [70.0%]); the mean age of all participants was 55.4 years, and the mean (SD) duration of psoriasis was 21.4 (15.0) years (Table 1). The mean baseline percentage of BSA involvement and mean baseline PGA, PASI, and DLQI scores are shown in Table 1. Most (19/30 [63.3%]) patients received biologics that inhibited IL-23 activity (guselkumab, risankizumab, tildrakizumab), approximately one-third (9/30 [30.0%]) received biologics that inhibited IL-17 activity (ixekizumab, secukinumab), and 2 (6.7%) received biologics that inhibited IL-12/IL-23 activity (ustekinumab)(Table 1).

For the primary end point, 52.4% (11/21) of patients reached the TTT goal (BSA involvement ≤1% after 12 weeks of treatment with tapinarof cream added to a prescribed biologic). The proportion of patients reaching the TTT goal increased over time with the combined treatment (eFigure 1). Additionally, the mean percentage of BSA involvement (eFigure 2) as well as the mean values for PGA (eFigure 3) and PGA×BSA decreased over time. The mean percentage of BSA involvement was 5.0% at baseline and dropped to 2.0% by week 12. Similar reductions were observed for PGA and PGA×BSA scores at week 12.

After discontinuing tapinarof cream at week 12 and receiving only the biologic for 4 weeks, the proportion of patients maintaining 1% or less BSA involvement fell to 40.0% (8/20) at week 16, which was closer to that observed at week 8 (36% [9/25]) than at week 12 (52.4% [11/21])(eFigure 1).

The mean PASI score was 5.5 at baseline, then decreased over time when tapinarof cream was combined with a biologic (eFigure 4), falling to 3.1 by week 2 and 1.6 by week 12; it was maintained at 1.7 at week 16. Nine (30.0%) participants had psoriasis on the scalp at baseline with a mean PSSI score of 2.6, which decreased to 0.83 by week 2. By week 12, the mean PSSI score remained stable at 0.95 in the 2 (9.5%) participants who still had scalp involvement. The mean PSSI score increased slightly to 1.45 after patients received only the biologic for 4 weeks. At baseline, 3 (10.0%) patients had genital involvement (mean Static Physician’s Global Assessment of Genitalia score, 0.27). Symptoms resolved in 2 (66.7%) of these patients at week 2 and stayed consistent until week 16; the third patient withdrew at week 2.

Both DLQI and WI-NRS scores decreased with use of tapinarof cream added to a biologic up to week 12 (eFigures 5 and 6). Mean DLQI scores were 5.3 at baseline and 3.1 at week 12. At week 16, the mean DLQI score remained stable at 2.8. Mean WI-NRS scores decreased from 4.0 at baseline to 2.7 at week 12 with the therapy combination; at week 16, the mean WI-NRS score fell further to 1.8.

A total of 6 AEs were reported in 5 (16.7%) patients (Table 2). The majority (4/6 [67.0%]) of AEs were considered mild. Two reported cases of COVID-19 were both considered mild and unrelated. Mild folliculitis and moderate worsening of psoriasis in 2 (6.7%) different patients were the only AEs considered related to treatment. No serious AEs were reported, and no patient withdrew from the study due to an AE.

Comment

In this prospective, open-label, real-world study, we found that when a patient’s response to a biologic is unsatisfactory, adding nonsteroidal tapinarof cream can enhance the treatment effect of the biologic. More than half of patients who were not adequately responding to a biologic reached the TTT goal at week 12, which was maintained in most of the responders for 4 weeks after tapinarof discontinuation. All measures of disease activity and quality of life (measured by the DLQI) improved when tapinarof was introduced, and the combination was well tolerated and without any unexpected safety signals.

Disease activity improvements we observed with the nonsteroidal tapinarof cream were consistent with those reported when topical steroidal therapies were given to patients responding poorly to their current biologic. Our primary end point (proportion of patients with BSA involvement ≤1% after 12 weeks) showed that half (52% [11/21]) of patients whose BSA involvement was 3% or greater with a biologic for 24 weeks or more reached the TTT goal after 12 weeks of tapinarof-biologic treatment. Other studies of halobetasol propionate–tazarotene lotion¹⁶ and calcipotriene/betamethasone dipropionate foam^17,18 added to the current biologic of poor responders found 60% to 68% of patients had reductions in their percentage BSA to 1% or lower at 12 to 16 weeks of treatment. Randomized studies showed etanercept plus topical clobetasol propionate foam²⁰ or adalimumab plus calcipotriene/betamethasone dipropionate foam²¹ similarly enhanced treatment effects vs biologic alone.

A phase 3 PSOARING trial demonstrated benefit from treatment with tapinarof alone, with a remittive effect of approximately 4 months after discontinuation.²⁵ Our data are consistent with these findings, with 40% (8/20) of patients demonstrating a remittive effect 4 weeks after discontinuing tapinarof while receiving a biologic. A similar maintenance effect was reported in another study in 50% (9/18) of patients treated with a biologic plus halobetasol propionate–tazarotene lotion.¹⁶ Additionally, when halcinonide ointment was given to patients receiving tildrakizumab, mean percentage of BSA involvement, PGA scores, PGA×BSA, and DLQI scores improved and were maintained 4 weeks after halcinonide ointment was stopped.¹⁹ Thus, topical therapy can augment and extend a biologic’s effect for up to 4 weeks. While a longer remittive effect is possible in our patients based on the 4-month remittive rate observed in the PSOARING trials,²⁵ further patient observation would be needed to confirm.

In our study, tapinarof cream added to a biologic had a good safety and tolerability profile. Few AEs were recorded, with most being mild in nature, and no serious AEs or discontinuations due to AEs were reported. Only 1 case of mild folliculitis and 1 case of moderate worsening of psoriasis were considered treatment related. Further, no unexpected or new safety signals with the tapinarof-biologic combination were observed compared with tapinarof alone.²⁷Prior studies have found that supplementing a biologic with topical therapy can reduce the probability of patients switching to another biologic.^16,19 We previously found that adding halobetasol propionate–tazarotene lotion¹⁶ or calcipotriene/betamethasone dipropionate foam¹⁷ to a biologic helped reduce the probability of switching biologics from 88% to 90% at baseline to 12% to 24% after 12 weeks of combined therapy. Such combinations also could prevent a less responsive patient from being prescribed a higher biologic dose.¹⁹ These are important research findings, as patients—even when not responding well to their current biologic—are more likely to be tolerating that biologic well, and switching to a new biologic may introduce new safety or tolerability concerns. Thus, by enhancing the effect of a biologic with a topical therapy, one can avoid increasing the dose of the current biologic or switching to a new biologic, either of which may increase safety and/or tolerability risks. Switching biologics also has increased cost implications to the health care system and/or the patient. When comparing the cost of adding halobetasol propionate–tazarotene lotion to a biologic compared with switching to another biologic, the cost was 1.2 to 2.9 times higher to switch, depending on the biologic, compared with a smaller incremental cost increase to add a topical to the current biologic.¹⁶ Similar observations were reported with calcipotriene/betamethasone dipropionate foam plus a biologic.¹⁷ Although we did not evaluate biologic switching here, we anticipate a similar clinical scenario with a tapinarof-biologic combination.

Limitations of our study included the open-label design, lack of a control arm, and the relatively small study population; however, for studies investigating the safety and effectiveness of a treatment in a real-world setting, these limitations are common and are not unexpected. Our results also are consistent with the overall improvement seen in other studies^16-21 examining the effects of adding a topical to a biologic. Future research is warranted to investigate a longer remittive effect and potential health care system and patient cost savings without having to switch biologics due to lack of effectiveness.

Conclusion

This study demonstrated that adjunctive use of nonsteroidal tapinarof cream 1% may enhance a biologic treatment effect in patients with moderate to severe plaque psoriasis, providing an adequate response for many patients who were not responding well to a biologic alone. Clinical outcomes improved with the tapinarof-biologic combination, and a remittive effect was noted 4 weeks after tapinarof discontinuation without any new safety signals. Adding tapinarof cream to a biologic also may prevent the need to switch biologics when patients do not sufficiently respond, preserving the safety and cost associated with a patient’s current biologic.

Psoriasis, one of the most researched diseases in dermatology, has a complex pathogenesis that is not yet fully understood. One of the most important stages of psoriasis pathogenesis is the proliferation of T helper (Th) 17 cells by IL-23 released from myeloid dendritic cells. Cytokines such as tumor necrosis factor (TNF) α released from Th1 cells and IL-17 and IL-22 released from Th17 cells are known to induce the proliferation of keratinocytes and the release of chemokines responsible for neutrophil chemotaxis.¹

Although secondary messengers such as cytokines and chemokines, which provide cell interaction with the extracellular matrix (ECM), have their own specific receptors, it is known that syndecans (SDCs) play a role in ECM and cell interactions and have receptor or coreceptor functions.² In humans, 4 types of SDCs have been identified (SDC1-SDC4), which are type I transmembrane proteoglycans found in all nucleated cells. Syndecans consist of heparan sulfate glycosaminoglycan chains that are structurally linked to a core protein sequence. The molecule has cytoplasmic, transmembrane, and extracellular domains.^2,3 While SDCs often are described as coreceptors for integrins and growth factor and hormone receptors, they also are capable of acting as signaling receptors by engaging intracellular messengers, including actin-related proteins and protein kinases.⁴ 

Prior research has indicated that the release of heparanase from the lysosomes of leukocytes during infection, inflammation, and endothelial damage causes cleavage of heparan sulfate glycosaminoglycans from the extracellular domains of SDCs. The peptide chains at the SDC core then are separated by matrix metalloproteinases in a process known as shedding. The shed SDCs may have either a stimulating or a suppressive effect on their receptor activity. Several cytokines are known to cause SDC shedding.^5,6 Many studies in recent years have reported that SDCs play a role in the pathogenesis of inflammatory diseases, for which serum levels of soluble SDCs can be biomarkers.⁷

In this study, we aimed to evaluate and compare serum SDC1, SDC4, TNF-α, and IL-17A levels in patients with psoriasis vs healthy controls. Additionally, by reviewing the literature data, we analyzed whether SDCs can be implicated in the pathogenesis of psoriasis and their potential role in this process.

Methods

The study population consisted of 40 patients with psoriasis and 40 healthy controls. Age and sex characteristics were similar between the 2 groups, but weight distribution was not. The psoriasis group included patients older than 18 years who had received a clinical and/or ­histologic diagnosis, had no systemic disease other than psoriasis in their medical history, and had not used any systemic treatment or phototherapy for the past 3 months. Healthy patients older than 18 years who had no medical history of inflammatory disease were included in the control group. Participants provided signed consent.

Data such as medical history, laboratory findings, and physical specifications were recorded. A Psoriasis Area and Severity Index (PASI) score of 10 or lower was considered mild disease, and a score higher than 10 was considered moderate to severe disease. An enzyme-linked immunosorbent assay was used to measure SDC1, SDC4, TNF-α, and IL-17A levels. 

The data were evaluated using the IBM SPSS Statistics V22.0 statistical package program. A P value of <.05 was considered statistically significant. The conformity of the data to a normal distribution was examined using a Shapiro-Wilk test. Normally distributed variables were expressed as mean (SD) and nonnormally distributed variables were expressed as median (interquartile range [IQR]). Data were compared between the 2 study groups using either a student t test (normal distribution) or Mann-Whitney U test (nonnormal distribution). Categorical variables were expressed as numbers and percentages. Categorical data were compared using a χ² test. Associations among SDC1, SDC4, TNF-α, IL-17A, and other variables were assessed using Spearman rank correlation. A binary logistic regression analysis was used to determine whether serum SDC1 and SDC4 levels were independent risk factors for psoriasis.

Results

The 2 study groups showed similar demographic characteristics in terms of sex (P=.67) and age (P=.22) distribution. The mean (SD) PASI score in the psoriasis group was 12.33 (7.62); the mean (SD) disease duration was 11.10 (8.00) years. Body weight and BMI were both significantly higher in the psoriasis group (P=.027 and P=.029, respectively) compared with the control group (eTable 1).

The mean (SD) serum SDC1 level was 119.52 ng/mL (69.53 ng/mL) in the psoriasis group, which was significantly higher than the control group (82.81 ng/mL [51.85 ng/mL])(P=.011)(eTable 2)(eFigure 1). The median (IQR) serum SDC4 level also was significantly higher in the psoriasis group compared with the control group (5.78 ng/mL [7.09 ng/mL] vs 3.92 ng/mL [2.88 ng/mL])(P=.030)(eTable 2)(eFigure 2). The median (IQR) IL-17A value was 59.94 pg/mL (12.97 pg/mL) in the psoriasis group, which was significantly higher than the control group (37.74 pg/mL [15.10 pg/mL])(P<.001)(eTable 2)(eFigure 3). The median (IQR) serum TNF-α level was 25.07 pg/mL (41.70 pg/mL) in the psoriasis group and 18.21 pg/mL (48.51 pg/mL) in the control group; however, the difference was not statistically significance (P=.444)(eTable 2)(eFigure 4). 

A significant positive correlation was found between serum SDC1 and PASI score (p=0.064; P=.03). Furthermore, significant positive correlations were ­identified between serum SDC1 and body weight (p=0.404; P<.001), disease duration (p=0.377; P=.008), and C-reactive protein (p=0.327; P=.002). A significant positive correlation also was identified between SDC4 and IL-17A (p=0.265; P=.009). Serum TNF-α was positively correlated with IL-17A (p=0.384; P<.001) and BMI (p=0.234; P=.020)(eTable 3).

Logistic regression analysis showed that high SDC1 levels were independently associated with the development of psoriasis (odds ratio [OR], 1.009; 95% CI, 1.000-1.017; P=.049)(eTable 4).

Comment

Tumor necrosis factor α and IL-17A are key cytokines whose roles in the pathogenesis of psoriasis are well established. Arican et al,⁸ Kyriakou et al,⁹ and Xuan et al¹⁰ previously reported a lack of any correlation between TNF-α and IL-17A in the pathogenesis of psoriasis; however, we observed a positive correlation between TNF-α and IL-17A in our study. This finding may be due to the abundant TNF-α production by myeloid dendritic cells involved in the transformation of naive T lymphocytes into IL-17A–secreting Th17 lymphocytes, which can also secrete TNF-α.

After the molecular cloning of SDCs by Saunders et al¹¹ in 1989, SDCs gained attention and have been the focus of many studies for their part in the pathogenesis of conditions such as inflammatory diseases, carcinogenesis, infections, sepsis, and trauma.^6,12 Among the inflammatory diseases sharing similar pathogenetic features to psoriasis, serum SDC4 levels are found to be elevated in rheumatoid arthritis and are correlated with disease activity.¹³ Cekic et al¹⁴ reported that serum SDC1 levels were significantly higher in patients with Crohn disease than controls (P=.03). Additionally, serum SDC1 levels were higher in patients with active disease compared with those who were in remission. Correlations between SDC1 and disease severity and C-reactive protein also have been found.¹⁴ Serum SDC-1 levels found to be elevated in patients with systemic lupus erythematosus were compared to the controls and were correlated with disease activity.¹⁵ Nakao et al¹⁶ reported that the serum SDC4 levels were significantly higher in patients with atopic dermatitis compared to controls (P<.01); further, SDC4 levels were correlated with severity of the disease.

Jaiswal et al¹⁷ reported that SDC1 is abundant on the surface of IL-17A–secreting γδ T lymphocytes (Tγδ17), whose contribution to psoriasis pathogenesis is known. When subjected to treatment with imiquimod, SDC1-suppressed mice displayed increased psoriasiform dermatitis compared with wild-type counterparts. The authors stated that SDC1 may play a role in controlling homeostasis of Tγδ17.¹⁷

In a study examining changes in the ECM in patients with psoriasis, it was observed that the expression of heparanase and metalloproteinase enzymes, which are responsible for SDC shedding, was higher in psoriasis plaques vs unaffected skin; furthermore, heparanase, metalloproteinases, and SDC1 expression were higher in unaffected skin samples from patients with psoriasis compared with tissues obtained from individuals without psoriasis.¹⁸ These data support our results, as increased serum SDC levels reflect increased shedding from the cell surface by heparanase and metalloproteinase activity. Pointing to the role of SDC1 in psoriasis, another study reported that upregulation of the metalloproteinase meprin β leads to increased SDC1 shedding; in turn, this shedding leads to impaired adhesion and differentiation of keratinocytes, resulting in psoriasislike skin changes in a mouse model.¹⁹

A study conducted by Koliakou et al²⁰ showed that, in healthy skin, SDC1 was expressed in almost the full thickness of the epidermis, but lowest expression was in the basal-layer keratinocytes. In a psoriatic epidermis, unlike the normal epidermis, SDC1 was found to be more intensely expressed in the keratinocytes of the basal layer, where keratinocyte proliferation occurs. In this study, SDC4 was expressed mainly at lower levels in a healthy epidermis, especially in the spinous and the basal layers. In a psoriatic epidermis, SDC4 was absent from all the layers. In the same study, gelatin-based carriers containing anti–TNF-α and anti–IL-17A were applied to a full-thickness epidermis with psoriatic lesions, after which SDC1 expression was observed to decrease almost completely in the psoriatic epidermis; there was no change in SDC4 expression, which also was not seen in the psoriatic epidermis. The authors claimed the application of these gelatin-based carriers could be a possible treatment modality for psoriasis, and the study provides evidence for the involvement of SDC1 and/or SDC4 in the pathogenesis of psoriasis.²⁰ Supporting these findings, another study showed that phototherapy can reduce SDC1 expression in psoriatic skin.²¹ In our study, a significant positive correlation was found between serum SDC4 and IL-17A (P=.009). IL-17A is known to be the key cytokine that stimulates keratinocyte proliferation in affected skin. Koliakou et al²⁰ reported that SDC4 was present on the surface of keratinocytes in normal skin but not in the psoriatic epidermis. This raises the question if IL-17A might lead to an increase in the shedding of SDC4; thus, SDC4 may mediate the effects of IL-17A.

Limitations of the current study include small sample size, lack of longitudinal data, lack of tissue testing of these molecules, and lack of external validation.

Conclusion

Overall, research has shown that SDCs play important roles in inflammatory processes, and more widespread inflammation has been associated with increased shedding of these molecules into the ECM and higher serum levels. In our study, serum SDC1, SDC4, and IL-17A levels were increased in patients with psoriasis compared to the healthy controls. A logistic regression analysis indicated that high serum SDC1 levels may be an independent risk factor for development of psoriasis. The increase in serum SDC1 and SDC4 levels and the positive correlation between SDC1 levels and disease severity observed in our study strongly implicate SDCs in the inflammatory disease psoriasis. The precise role of SDCs in the pathogenesis of psoriasis and the implications of targeting these molecules are the subject of more in-depth studies in the future.

Psoriasis, one of the most researched diseases in dermatology, has a complex pathogenesis that is not yet fully understood. One of the most important stages of psoriasis pathogenesis is the proliferation of T helper (Th) 17 cells by IL-23 released from myeloid dendritic cells. Cytokines such as tumor necrosis factor (TNF) α released from Th1 cells and IL-17 and IL-22 released from Th17 cells are known to induce the proliferation of keratinocytes and the release of chemokines responsible for neutrophil chemotaxis.¹

Although secondary messengers such as cytokines and chemokines, which provide cell interaction with the extracellular matrix (ECM), have their own specific receptors, it is known that syndecans (SDCs) play a role in ECM and cell interactions and have receptor or coreceptor functions.² In humans, 4 types of SDCs have been identified (SDC1-SDC4), which are type I transmembrane proteoglycans found in all nucleated cells. Syndecans consist of heparan sulfate glycosaminoglycan chains that are structurally linked to a core protein sequence. The molecule has cytoplasmic, transmembrane, and extracellular domains.^2,3 While SDCs often are described as coreceptors for integrins and growth factor and hormone receptors, they also are capable of acting as signaling receptors by engaging intracellular messengers, including actin-related proteins and protein kinases.⁴ 

Prior research has indicated that the release of heparanase from the lysosomes of leukocytes during infection, inflammation, and endothelial damage causes cleavage of heparan sulfate glycosaminoglycans from the extracellular domains of SDCs. The peptide chains at the SDC core then are separated by matrix metalloproteinases in a process known as shedding. The shed SDCs may have either a stimulating or a suppressive effect on their receptor activity. Several cytokines are known to cause SDC shedding.^5,6 Many studies in recent years have reported that SDCs play a role in the pathogenesis of inflammatory diseases, for which serum levels of soluble SDCs can be biomarkers.⁷

In this study, we aimed to evaluate and compare serum SDC1, SDC4, TNF-α, and IL-17A levels in patients with psoriasis vs healthy controls. Additionally, by reviewing the literature data, we analyzed whether SDCs can be implicated in the pathogenesis of psoriasis and their potential role in this process.

Methods

The study population consisted of 40 patients with psoriasis and 40 healthy controls. Age and sex characteristics were similar between the 2 groups, but weight distribution was not. The psoriasis group included patients older than 18 years who had received a clinical and/or ­histologic diagnosis, had no systemic disease other than psoriasis in their medical history, and had not used any systemic treatment or phototherapy for the past 3 months. Healthy patients older than 18 years who had no medical history of inflammatory disease were included in the control group. Participants provided signed consent.

Data such as medical history, laboratory findings, and physical specifications were recorded. A Psoriasis Area and Severity Index (PASI) score of 10 or lower was considered mild disease, and a score higher than 10 was considered moderate to severe disease. An enzyme-linked immunosorbent assay was used to measure SDC1, SDC4, TNF-α, and IL-17A levels. 

The data were evaluated using the IBM SPSS Statistics V22.0 statistical package program. A P value of <.05 was considered statistically significant. The conformity of the data to a normal distribution was examined using a Shapiro-Wilk test. Normally distributed variables were expressed as mean (SD) and nonnormally distributed variables were expressed as median (interquartile range [IQR]). Data were compared between the 2 study groups using either a student t test (normal distribution) or Mann-Whitney U test (nonnormal distribution). Categorical variables were expressed as numbers and percentages. Categorical data were compared using a χ² test. Associations among SDC1, SDC4, TNF-α, IL-17A, and other variables were assessed using Spearman rank correlation. A binary logistic regression analysis was used to determine whether serum SDC1 and SDC4 levels were independent risk factors for psoriasis.

Results

The 2 study groups showed similar demographic characteristics in terms of sex (P=.67) and age (P=.22) distribution. The mean (SD) PASI score in the psoriasis group was 12.33 (7.62); the mean (SD) disease duration was 11.10 (8.00) years. Body weight and BMI were both significantly higher in the psoriasis group (P=.027 and P=.029, respectively) compared with the control group (eTable 1).

The mean (SD) serum SDC1 level was 119.52 ng/mL (69.53 ng/mL) in the psoriasis group, which was significantly higher than the control group (82.81 ng/mL [51.85 ng/mL])(P=.011)(eTable 2)(eFigure 1). The median (IQR) serum SDC4 level also was significantly higher in the psoriasis group compared with the control group (5.78 ng/mL [7.09 ng/mL] vs 3.92 ng/mL [2.88 ng/mL])(P=.030)(eTable 2)(eFigure 2). The median (IQR) IL-17A value was 59.94 pg/mL (12.97 pg/mL) in the psoriasis group, which was significantly higher than the control group (37.74 pg/mL [15.10 pg/mL])(P<.001)(eTable 2)(eFigure 3). The median (IQR) serum TNF-α level was 25.07 pg/mL (41.70 pg/mL) in the psoriasis group and 18.21 pg/mL (48.51 pg/mL) in the control group; however, the difference was not statistically significance (P=.444)(eTable 2)(eFigure 4). 

A significant positive correlation was found between serum SDC1 and PASI score (p=0.064; P=.03). Furthermore, significant positive correlations were ­identified between serum SDC1 and body weight (p=0.404; P<.001), disease duration (p=0.377; P=.008), and C-reactive protein (p=0.327; P=.002). A significant positive correlation also was identified between SDC4 and IL-17A (p=0.265; P=.009). Serum TNF-α was positively correlated with IL-17A (p=0.384; P<.001) and BMI (p=0.234; P=.020)(eTable 3).

Logistic regression analysis showed that high SDC1 levels were independently associated with the development of psoriasis (odds ratio [OR], 1.009; 95% CI, 1.000-1.017; P=.049)(eTable 4).

Comment

Tumor necrosis factor α and IL-17A are key cytokines whose roles in the pathogenesis of psoriasis are well established. Arican et al,⁸ Kyriakou et al,⁹ and Xuan et al¹⁰ previously reported a lack of any correlation between TNF-α and IL-17A in the pathogenesis of psoriasis; however, we observed a positive correlation between TNF-α and IL-17A in our study. This finding may be due to the abundant TNF-α production by myeloid dendritic cells involved in the transformation of naive T lymphocytes into IL-17A–secreting Th17 lymphocytes, which can also secrete TNF-α.

After the molecular cloning of SDCs by Saunders et al¹¹ in 1989, SDCs gained attention and have been the focus of many studies for their part in the pathogenesis of conditions such as inflammatory diseases, carcinogenesis, infections, sepsis, and trauma.^6,12 Among the inflammatory diseases sharing similar pathogenetic features to psoriasis, serum SDC4 levels are found to be elevated in rheumatoid arthritis and are correlated with disease activity.¹³ Cekic et al¹⁴ reported that serum SDC1 levels were significantly higher in patients with Crohn disease than controls (P=.03). Additionally, serum SDC1 levels were higher in patients with active disease compared with those who were in remission. Correlations between SDC1 and disease severity and C-reactive protein also have been found.¹⁴ Serum SDC-1 levels found to be elevated in patients with systemic lupus erythematosus were compared to the controls and were correlated with disease activity.¹⁵ Nakao et al¹⁶ reported that the serum SDC4 levels were significantly higher in patients with atopic dermatitis compared to controls (P<.01); further, SDC4 levels were correlated with severity of the disease.

Jaiswal et al¹⁷ reported that SDC1 is abundant on the surface of IL-17A–secreting γδ T lymphocytes (Tγδ17), whose contribution to psoriasis pathogenesis is known. When subjected to treatment with imiquimod, SDC1-suppressed mice displayed increased psoriasiform dermatitis compared with wild-type counterparts. The authors stated that SDC1 may play a role in controlling homeostasis of Tγδ17.¹⁷

In a study examining changes in the ECM in patients with psoriasis, it was observed that the expression of heparanase and metalloproteinase enzymes, which are responsible for SDC shedding, was higher in psoriasis plaques vs unaffected skin; furthermore, heparanase, metalloproteinases, and SDC1 expression were higher in unaffected skin samples from patients with psoriasis compared with tissues obtained from individuals without psoriasis.¹⁸ These data support our results, as increased serum SDC levels reflect increased shedding from the cell surface by heparanase and metalloproteinase activity. Pointing to the role of SDC1 in psoriasis, another study reported that upregulation of the metalloproteinase meprin β leads to increased SDC1 shedding; in turn, this shedding leads to impaired adhesion and differentiation of keratinocytes, resulting in psoriasislike skin changes in a mouse model.¹⁹

A study conducted by Koliakou et al²⁰ showed that, in healthy skin, SDC1 was expressed in almost the full thickness of the epidermis, but lowest expression was in the basal-layer keratinocytes. In a psoriatic epidermis, unlike the normal epidermis, SDC1 was found to be more intensely expressed in the keratinocytes of the basal layer, where keratinocyte proliferation occurs. In this study, SDC4 was expressed mainly at lower levels in a healthy epidermis, especially in the spinous and the basal layers. In a psoriatic epidermis, SDC4 was absent from all the layers. In the same study, gelatin-based carriers containing anti–TNF-α and anti–IL-17A were applied to a full-thickness epidermis with psoriatic lesions, after which SDC1 expression was observed to decrease almost completely in the psoriatic epidermis; there was no change in SDC4 expression, which also was not seen in the psoriatic epidermis. The authors claimed the application of these gelatin-based carriers could be a possible treatment modality for psoriasis, and the study provides evidence for the involvement of SDC1 and/or SDC4 in the pathogenesis of psoriasis.²⁰ Supporting these findings, another study showed that phototherapy can reduce SDC1 expression in psoriatic skin.²¹ In our study, a significant positive correlation was found between serum SDC4 and IL-17A (P=.009). IL-17A is known to be the key cytokine that stimulates keratinocyte proliferation in affected skin. Koliakou et al²⁰ reported that SDC4 was present on the surface of keratinocytes in normal skin but not in the psoriatic epidermis. This raises the question if IL-17A might lead to an increase in the shedding of SDC4; thus, SDC4 may mediate the effects of IL-17A.

Limitations of the current study include small sample size, lack of longitudinal data, lack of tissue testing of these molecules, and lack of external validation.

Conclusion

Overall, research has shown that SDCs play important roles in inflammatory processes, and more widespread inflammation has been associated with increased shedding of these molecules into the ECM and higher serum levels. In our study, serum SDC1, SDC4, and IL-17A levels were increased in patients with psoriasis compared to the healthy controls. A logistic regression analysis indicated that high serum SDC1 levels may be an independent risk factor for development of psoriasis. The increase in serum SDC1 and SDC4 levels and the positive correlation between SDC1 levels and disease severity observed in our study strongly implicate SDCs in the inflammatory disease psoriasis. The precise role of SDCs in the pathogenesis of psoriasis and the implications of targeting these molecules are the subject of more in-depth studies in the future.

Psoriasis, one of the most researched diseases in dermatology, has a complex pathogenesis that is not yet fully understood. One of the most important stages of psoriasis pathogenesis is the proliferation of T helper (Th) 17 cells by IL-23 released from myeloid dendritic cells. Cytokines such as tumor necrosis factor (TNF) α released from Th1 cells and IL-17 and IL-22 released from Th17 cells are known to induce the proliferation of keratinocytes and the release of chemokines responsible for neutrophil chemotaxis.¹

Although secondary messengers such as cytokines and chemokines, which provide cell interaction with the extracellular matrix (ECM), have their own specific receptors, it is known that syndecans (SDCs) play a role in ECM and cell interactions and have receptor or coreceptor functions.² In humans, 4 types of SDCs have been identified (SDC1-SDC4), which are type I transmembrane proteoglycans found in all nucleated cells. Syndecans consist of heparan sulfate glycosaminoglycan chains that are structurally linked to a core protein sequence. The molecule has cytoplasmic, transmembrane, and extracellular domains.^2,3 While SDCs often are described as coreceptors for integrins and growth factor and hormone receptors, they also are capable of acting as signaling receptors by engaging intracellular messengers, including actin-related proteins and protein kinases.⁴ 

Prior research has indicated that the release of heparanase from the lysosomes of leukocytes during infection, inflammation, and endothelial damage causes cleavage of heparan sulfate glycosaminoglycans from the extracellular domains of SDCs. The peptide chains at the SDC core then are separated by matrix metalloproteinases in a process known as shedding. The shed SDCs may have either a stimulating or a suppressive effect on their receptor activity. Several cytokines are known to cause SDC shedding.^5,6 Many studies in recent years have reported that SDCs play a role in the pathogenesis of inflammatory diseases, for which serum levels of soluble SDCs can be biomarkers.⁷

In this study, we aimed to evaluate and compare serum SDC1, SDC4, TNF-α, and IL-17A levels in patients with psoriasis vs healthy controls. Additionally, by reviewing the literature data, we analyzed whether SDCs can be implicated in the pathogenesis of psoriasis and their potential role in this process.

Methods

The study population consisted of 40 patients with psoriasis and 40 healthy controls. Age and sex characteristics were similar between the 2 groups, but weight distribution was not. The psoriasis group included patients older than 18 years who had received a clinical and/or ­histologic diagnosis, had no systemic disease other than psoriasis in their medical history, and had not used any systemic treatment or phototherapy for the past 3 months. Healthy patients older than 18 years who had no medical history of inflammatory disease were included in the control group. Participants provided signed consent.

Data such as medical history, laboratory findings, and physical specifications were recorded. A Psoriasis Area and Severity Index (PASI) score of 10 or lower was considered mild disease, and a score higher than 10 was considered moderate to severe disease. An enzyme-linked immunosorbent assay was used to measure SDC1, SDC4, TNF-α, and IL-17A levels. 

The data were evaluated using the IBM SPSS Statistics V22.0 statistical package program. A P value of <.05 was considered statistically significant. The conformity of the data to a normal distribution was examined using a Shapiro-Wilk test. Normally distributed variables were expressed as mean (SD) and nonnormally distributed variables were expressed as median (interquartile range [IQR]). Data were compared between the 2 study groups using either a student t test (normal distribution) or Mann-Whitney U test (nonnormal distribution). Categorical variables were expressed as numbers and percentages. Categorical data were compared using a χ² test. Associations among SDC1, SDC4, TNF-α, IL-17A, and other variables were assessed using Spearman rank correlation. A binary logistic regression analysis was used to determine whether serum SDC1 and SDC4 levels were independent risk factors for psoriasis.

Results

The 2 study groups showed similar demographic characteristics in terms of sex (P=.67) and age (P=.22) distribution. The mean (SD) PASI score in the psoriasis group was 12.33 (7.62); the mean (SD) disease duration was 11.10 (8.00) years. Body weight and BMI were both significantly higher in the psoriasis group (P=.027 and P=.029, respectively) compared with the control group (eTable 1).

The mean (SD) serum SDC1 level was 119.52 ng/mL (69.53 ng/mL) in the psoriasis group, which was significantly higher than the control group (82.81 ng/mL [51.85 ng/mL])(P=.011)(eTable 2)(eFigure 1). The median (IQR) serum SDC4 level also was significantly higher in the psoriasis group compared with the control group (5.78 ng/mL [7.09 ng/mL] vs 3.92 ng/mL [2.88 ng/mL])(P=.030)(eTable 2)(eFigure 2). The median (IQR) IL-17A value was 59.94 pg/mL (12.97 pg/mL) in the psoriasis group, which was significantly higher than the control group (37.74 pg/mL [15.10 pg/mL])(P<.001)(eTable 2)(eFigure 3). The median (IQR) serum TNF-α level was 25.07 pg/mL (41.70 pg/mL) in the psoriasis group and 18.21 pg/mL (48.51 pg/mL) in the control group; however, the difference was not statistically significance (P=.444)(eTable 2)(eFigure 4). 

A significant positive correlation was found between serum SDC1 and PASI score (p=0.064; P=.03). Furthermore, significant positive correlations were ­identified between serum SDC1 and body weight (p=0.404; P<.001), disease duration (p=0.377; P=.008), and C-reactive protein (p=0.327; P=.002). A significant positive correlation also was identified between SDC4 and IL-17A (p=0.265; P=.009). Serum TNF-α was positively correlated with IL-17A (p=0.384; P<.001) and BMI (p=0.234; P=.020)(eTable 3).

Logistic regression analysis showed that high SDC1 levels were independently associated with the development of psoriasis (odds ratio [OR], 1.009; 95% CI, 1.000-1.017; P=.049)(eTable 4).

Comment

Tumor necrosis factor α and IL-17A are key cytokines whose roles in the pathogenesis of psoriasis are well established. Arican et al,⁸ Kyriakou et al,⁹ and Xuan et al¹⁰ previously reported a lack of any correlation between TNF-α and IL-17A in the pathogenesis of psoriasis; however, we observed a positive correlation between TNF-α and IL-17A in our study. This finding may be due to the abundant TNF-α production by myeloid dendritic cells involved in the transformation of naive T lymphocytes into IL-17A–secreting Th17 lymphocytes, which can also secrete TNF-α.

After the molecular cloning of SDCs by Saunders et al¹¹ in 1989, SDCs gained attention and have been the focus of many studies for their part in the pathogenesis of conditions such as inflammatory diseases, carcinogenesis, infections, sepsis, and trauma.^6,12 Among the inflammatory diseases sharing similar pathogenetic features to psoriasis, serum SDC4 levels are found to be elevated in rheumatoid arthritis and are correlated with disease activity.¹³ Cekic et al¹⁴ reported that serum SDC1 levels were significantly higher in patients with Crohn disease than controls (P=.03). Additionally, serum SDC1 levels were higher in patients with active disease compared with those who were in remission. Correlations between SDC1 and disease severity and C-reactive protein also have been found.¹⁴ Serum SDC-1 levels found to be elevated in patients with systemic lupus erythematosus were compared to the controls and were correlated with disease activity.¹⁵ Nakao et al¹⁶ reported that the serum SDC4 levels were significantly higher in patients with atopic dermatitis compared to controls (P<.01); further, SDC4 levels were correlated with severity of the disease.

Jaiswal et al¹⁷ reported that SDC1 is abundant on the surface of IL-17A–secreting γδ T lymphocytes (Tγδ17), whose contribution to psoriasis pathogenesis is known. When subjected to treatment with imiquimod, SDC1-suppressed mice displayed increased psoriasiform dermatitis compared with wild-type counterparts. The authors stated that SDC1 may play a role in controlling homeostasis of Tγδ17.¹⁷

In a study examining changes in the ECM in patients with psoriasis, it was observed that the expression of heparanase and metalloproteinase enzymes, which are responsible for SDC shedding, was higher in psoriasis plaques vs unaffected skin; furthermore, heparanase, metalloproteinases, and SDC1 expression were higher in unaffected skin samples from patients with psoriasis compared with tissues obtained from individuals without psoriasis.¹⁸ These data support our results, as increased serum SDC levels reflect increased shedding from the cell surface by heparanase and metalloproteinase activity. Pointing to the role of SDC1 in psoriasis, another study reported that upregulation of the metalloproteinase meprin β leads to increased SDC1 shedding; in turn, this shedding leads to impaired adhesion and differentiation of keratinocytes, resulting in psoriasislike skin changes in a mouse model.¹⁹

A study conducted by Koliakou et al²⁰ showed that, in healthy skin, SDC1 was expressed in almost the full thickness of the epidermis, but lowest expression was in the basal-layer keratinocytes. In a psoriatic epidermis, unlike the normal epidermis, SDC1 was found to be more intensely expressed in the keratinocytes of the basal layer, where keratinocyte proliferation occurs. In this study, SDC4 was expressed mainly at lower levels in a healthy epidermis, especially in the spinous and the basal layers. In a psoriatic epidermis, SDC4 was absent from all the layers. In the same study, gelatin-based carriers containing anti–TNF-α and anti–IL-17A were applied to a full-thickness epidermis with psoriatic lesions, after which SDC1 expression was observed to decrease almost completely in the psoriatic epidermis; there was no change in SDC4 expression, which also was not seen in the psoriatic epidermis. The authors claimed the application of these gelatin-based carriers could be a possible treatment modality for psoriasis, and the study provides evidence for the involvement of SDC1 and/or SDC4 in the pathogenesis of psoriasis.²⁰ Supporting these findings, another study showed that phototherapy can reduce SDC1 expression in psoriatic skin.²¹ In our study, a significant positive correlation was found between serum SDC4 and IL-17A (P=.009). IL-17A is known to be the key cytokine that stimulates keratinocyte proliferation in affected skin. Koliakou et al²⁰ reported that SDC4 was present on the surface of keratinocytes in normal skin but not in the psoriatic epidermis. This raises the question if IL-17A might lead to an increase in the shedding of SDC4; thus, SDC4 may mediate the effects of IL-17A.

Limitations of the current study include small sample size, lack of longitudinal data, lack of tissue testing of these molecules, and lack of external validation.

Conclusion

Overall, research has shown that SDCs play important roles in inflammatory processes, and more widespread inflammation has been associated with increased shedding of these molecules into the ECM and higher serum levels. In our study, serum SDC1, SDC4, and IL-17A levels were increased in patients with psoriasis compared to the healthy controls. A logistic regression analysis indicated that high serum SDC1 levels may be an independent risk factor for development of psoriasis. The increase in serum SDC1 and SDC4 levels and the positive correlation between SDC1 levels and disease severity observed in our study strongly implicate SDCs in the inflammatory disease psoriasis. The precise role of SDCs in the pathogenesis of psoriasis and the implications of targeting these molecules are the subject of more in-depth studies in the future.

To the Editor:  

For many years, topical treatment of plaque psoriasis was limited to steroids, calcineurin inhibitors, vitamin D analogs, retinoids, coal tar products, and anthralin. In recent years, 2 new nonsteroidal treatment options with alternative mechanisms of action, roflumilast 0.3% and tapinarof 1%, have been approved by the US Food and Drug Administration.¹ Roflumilast 0.3%, a topical phosphodiesterase 4 inhibitor, was shown in phase 3 clinical trials to reach an Investigator Global Assessment response of 37.5% to 42.2% in 8 weeks using once-daily application with minimal cutaneous adverse effects.¹ Furthermore, it has demonstrated efficacy in treating psoriasis in intertriginous areas in subset analyses.¹ Tapinarof is an aryl hydrocarbon receptor agonist that suppresses Th17 cell differentiation by downregulating IL-17, IL-22, and IL-23.¹ In phase 3 clinical trials, 35% to 40% of patients who used tapinarof cream 1% once daily demonstrated improvement in psoriasis compared with 6% who used the vehicle alone.² In these studies, 18% to 24% of patients who used tapinarof cream 1% experienced folliculitis.²

Acute generalized exanthematous pustulosis (AGEP) is a nonfollicular pustular drug reaction with systemic symptoms that typically occurs within 2 weeks of exposure to an inciting medication. Systemic antibiotics are the most commonly reported cause of AGEP.³ There are few reports in the literature of AGEP induced by topical agents.^4,5 We report a case of AGEP in a young man following the use of tapinarof cream 1%.

A 23-year-old man with a history of psoriasis presented to the emergency department with fever and a pustular rash. One week prior to presentation, he developed a pustular eruption around plaques of psoriasis on the arms and legs. The patient had been prescribed tapinarof cream 1% by an outside dermatologist and was applying the medication to the affected areas once daily for 1 month prior to onset of symptoms. He discontinued tapinarof a few days prior to the eruption starting, but the rash progressed centrifugally and was associated with fevers and fatigue despite treatment with a brief course of empiric cephalexin prescribed by his primary care provider.

At presentation to our institution, the patient had widespread erythematous patches studded with pustules located on the arms, legs, and flexural areas as well as plaques of psoriasis involving approximately 20% of the body surface area (Figure 1). Furthermore, the patient was noted to have large noninflammatory bullae along the legs. The new eruption occurred on areas that were both treated and spared from the tapinarof cream 1%. Laboratory evaluation showed neutrophil-­predominant leukocytosis (white blood cell count, 15.9×10³/µL ­[reference range, 4.0-11.0×10³/µL]; absolute neutrophil count, 10.3×10³/µL [reference range, 1.5-8.0×10³/µL]), absolute eosinophilia (1930/µL [reference range, 0-0.5×10³/µL]), hypocalcemia (8.4 mg/dL ­[reference range, 8.5-10.5 mg/dL]), and a mild transaminitis ­(aspartate aminotransferase, 37 IU/L [reference range, 10-40 IU/L]; alanine aminotransferase, 53 IU/L ­[reference range, 7-56 U/L]). Histopathology demonstrated spongiosis with subcorneal and intraepidermal pustules and mixed dermal inflammation containing eosinophils (Figure 2). Direct immunofluorescence revealed mild granular staining of C3 at the basement membrane zone.

The patient was started on 1 mg/kg/d of prednisone tapered over 20 days, and he rapidly improved. Alanine aminotransferase levels peaked at 120 IU/L 2 weeks later. At that time, he had complete resolution of the original eruption and was transitioned to topical steroids for continued management of the psoriasis (Figure 3).

The differential diagnosis for our patient included AGEP, generalized pustular psoriasis (GPP), miliaria pustulosa, generalized cutaneous candidiasis, exuberant allergic contact dermatitis (ACD), and linear IgA bullous dermatosis (LABD). Based on the clinical manifestations, laboratory results, and histopathologic evaluation, we made the diagnosis of AGEP secondary to tapinarof with systemic absorption. Acute generalized exanthematous pustulosis has been reported with topical use of morphine and diphenhydramine, among other agents.^4,5 To our knowledge, AGEP due to tapinarof cream 1% has not been reported. In the original clinical trials of tapinarof, folliculitis was contained to sites of application.² Our patient developed pustules at sites distant to areas of application, as well as systemic symptoms and laboratory abnormalities, indicating a systemic reaction. It can be difficult to distinguish AGEP clinically and histologically from GPP. Both conditions can manifest with fever, hypocalcemia, and sterile pustules on a background of erythema that favors intertriginous areas.⁶ Infection, rapid oral steroid withdrawal, pregnancy, and rarely oral medications have been reported causes of GPP.⁶ Our patient did not have any of these exposures. There is overlap in the histology of AGEP and GPP. One retrospective series compared histologic samples to help distinguish these 2 entities. Reliable markers that favored AGEP over GPP included eosinophilic spongiosis, interface dermatitis, and dermal eosinophilia (>2/mm²).⁷ In contrast, the presence of CD161 positivity in the dermis with at least 10 cells favored a diagnosis of GPP.⁷ In our case, the presence of spongiosis with eosinophils in the dermis favored a diagnosis of AGEP over GPP. 

Miliaria pustulosa is a benign condition caused by the occlusion of the epidermal portion of eccrine glands related to either high fever or hot and humid environmental conditions. While it can be present in intertriginous areas like AGEP, miliaria pustulosa can be seen extensively on the back, most commonly in immobile hospitalized patients.⁸ Generalized cutaneous candidiasis usually is caused by the yeast Candida albicans and can take on multiple morphologies, including folliculitis.⁹ The eruption may be disseminated but often is accentuated in intertriginous areas and the anogenital folds. Predisposing factors include immunosuppression, endocrinopathies, recent use of systemic antibiotics or steroids, chemotherapy, and indwelling catheters.⁹ Outside of recent antibiotic use, our patient did not have any risk factors for miliaria pustulosa, making this diagnosis unlikely.

Given the presence of overlapping bullae along the lower extremities, an exuberant ACD and LABD were considered. Bullae formation can occur in ACD secondary to robust inflammation and edema leading to acantholysis.¹⁰ While a delayed hypersensitivity reaction to topical tapinarof cream 1% was considered given that the patient used the medication for approximately 1 month prior to the onset of symptoms, it would be unlikely for ACD to present with a concomitant pustular eruption. Linear IgA bullous dermatosis is an autoimmune blistering disease in which antibodies target bullous pemphigoid antigen 2, and there is characteristically linear deposition of IgA at the dermal-epidermal junction that leads to subepidermal blistering.¹¹ This often manifests clinically as widespread tense vesicles in an annular or string-of-pearls appearance. However, morphologies can vary, and large bullae may be seen. In adults, LABD typically is associated with inflammatory bowel disease, malignancy, or medications, notably vancomycin.^11,12 Our patient did not have any of these predisposing factors, and his biopsy for direct immunofluorescence did not reveal the classic pattern described above.

Interestingly, there have been reports in the literature of bullous AGEP in the setting of oral anti-infectives. One report described a 62-year-old woman who developed widespread nonfollicular pustules with multiple tense serous blisters 24 hours after taking oral terbinafine.¹³ Another case described an 80-year-old woman with a similar presentation following a course of ciprofloxacin (although the timeline of medication administration was not described).¹⁴ In this case, patch testing to the culprit medication reproduced the response.¹⁴ In both cases, a biopsy revealed subcorneal and intraepidermal pustules with marked dermal edema.^13,14 As previously described, spongiosis is a common feature of AGEP. We hypothesize that, similar to these reports, our patient had a robust inflammatory response leading to spongiosis, acantholysis, and blister formation secondary to AGEP.

Dermatologists should be aware of this case of AGEP secondary to tapinarof cream 1%, as reports in the literature are rare and it is a reminder that topical medications can cause serious systemic reactions.

To the Editor:  

For many years, topical treatment of plaque psoriasis was limited to steroids, calcineurin inhibitors, vitamin D analogs, retinoids, coal tar products, and anthralin. In recent years, 2 new nonsteroidal treatment options with alternative mechanisms of action, roflumilast 0.3% and tapinarof 1%, have been approved by the US Food and Drug Administration.¹ Roflumilast 0.3%, a topical phosphodiesterase 4 inhibitor, was shown in phase 3 clinical trials to reach an Investigator Global Assessment response of 37.5% to 42.2% in 8 weeks using once-daily application with minimal cutaneous adverse effects.¹ Furthermore, it has demonstrated efficacy in treating psoriasis in intertriginous areas in subset analyses.¹ Tapinarof is an aryl hydrocarbon receptor agonist that suppresses Th17 cell differentiation by downregulating IL-17, IL-22, and IL-23.¹ In phase 3 clinical trials, 35% to 40% of patients who used tapinarof cream 1% once daily demonstrated improvement in psoriasis compared with 6% who used the vehicle alone.² In these studies, 18% to 24% of patients who used tapinarof cream 1% experienced folliculitis.²

Acute generalized exanthematous pustulosis (AGEP) is a nonfollicular pustular drug reaction with systemic symptoms that typically occurs within 2 weeks of exposure to an inciting medication. Systemic antibiotics are the most commonly reported cause of AGEP.³ There are few reports in the literature of AGEP induced by topical agents.^4,5 We report a case of AGEP in a young man following the use of tapinarof cream 1%.

A 23-year-old man with a history of psoriasis presented to the emergency department with fever and a pustular rash. One week prior to presentation, he developed a pustular eruption around plaques of psoriasis on the arms and legs. The patient had been prescribed tapinarof cream 1% by an outside dermatologist and was applying the medication to the affected areas once daily for 1 month prior to onset of symptoms. He discontinued tapinarof a few days prior to the eruption starting, but the rash progressed centrifugally and was associated with fevers and fatigue despite treatment with a brief course of empiric cephalexin prescribed by his primary care provider.

At presentation to our institution, the patient had widespread erythematous patches studded with pustules located on the arms, legs, and flexural areas as well as plaques of psoriasis involving approximately 20% of the body surface area (Figure 1). Furthermore, the patient was noted to have large noninflammatory bullae along the legs. The new eruption occurred on areas that were both treated and spared from the tapinarof cream 1%. Laboratory evaluation showed neutrophil-­predominant leukocytosis (white blood cell count, 15.9×10³/µL ­[reference range, 4.0-11.0×10³/µL]; absolute neutrophil count, 10.3×10³/µL [reference range, 1.5-8.0×10³/µL]), absolute eosinophilia (1930/µL [reference range, 0-0.5×10³/µL]), hypocalcemia (8.4 mg/dL ­[reference range, 8.5-10.5 mg/dL]), and a mild transaminitis ­(aspartate aminotransferase, 37 IU/L [reference range, 10-40 IU/L]; alanine aminotransferase, 53 IU/L ­[reference range, 7-56 U/L]). Histopathology demonstrated spongiosis with subcorneal and intraepidermal pustules and mixed dermal inflammation containing eosinophils (Figure 2). Direct immunofluorescence revealed mild granular staining of C3 at the basement membrane zone.

The patient was started on 1 mg/kg/d of prednisone tapered over 20 days, and he rapidly improved. Alanine aminotransferase levels peaked at 120 IU/L 2 weeks later. At that time, he had complete resolution of the original eruption and was transitioned to topical steroids for continued management of the psoriasis (Figure 3).

The differential diagnosis for our patient included AGEP, generalized pustular psoriasis (GPP), miliaria pustulosa, generalized cutaneous candidiasis, exuberant allergic contact dermatitis (ACD), and linear IgA bullous dermatosis (LABD). Based on the clinical manifestations, laboratory results, and histopathologic evaluation, we made the diagnosis of AGEP secondary to tapinarof with systemic absorption. Acute generalized exanthematous pustulosis has been reported with topical use of morphine and diphenhydramine, among other agents.^4,5 To our knowledge, AGEP due to tapinarof cream 1% has not been reported. In the original clinical trials of tapinarof, folliculitis was contained to sites of application.² Our patient developed pustules at sites distant to areas of application, as well as systemic symptoms and laboratory abnormalities, indicating a systemic reaction. It can be difficult to distinguish AGEP clinically and histologically from GPP. Both conditions can manifest with fever, hypocalcemia, and sterile pustules on a background of erythema that favors intertriginous areas.⁶ Infection, rapid oral steroid withdrawal, pregnancy, and rarely oral medications have been reported causes of GPP.⁶ Our patient did not have any of these exposures. There is overlap in the histology of AGEP and GPP. One retrospective series compared histologic samples to help distinguish these 2 entities. Reliable markers that favored AGEP over GPP included eosinophilic spongiosis, interface dermatitis, and dermal eosinophilia (>2/mm²).⁷ In contrast, the presence of CD161 positivity in the dermis with at least 10 cells favored a diagnosis of GPP.⁷ In our case, the presence of spongiosis with eosinophils in the dermis favored a diagnosis of AGEP over GPP. 

Miliaria pustulosa is a benign condition caused by the occlusion of the epidermal portion of eccrine glands related to either high fever or hot and humid environmental conditions. While it can be present in intertriginous areas like AGEP, miliaria pustulosa can be seen extensively on the back, most commonly in immobile hospitalized patients.⁸ Generalized cutaneous candidiasis usually is caused by the yeast Candida albicans and can take on multiple morphologies, including folliculitis.⁹ The eruption may be disseminated but often is accentuated in intertriginous areas and the anogenital folds. Predisposing factors include immunosuppression, endocrinopathies, recent use of systemic antibiotics or steroids, chemotherapy, and indwelling catheters.⁹ Outside of recent antibiotic use, our patient did not have any risk factors for miliaria pustulosa, making this diagnosis unlikely.

Given the presence of overlapping bullae along the lower extremities, an exuberant ACD and LABD were considered. Bullae formation can occur in ACD secondary to robust inflammation and edema leading to acantholysis.¹⁰ While a delayed hypersensitivity reaction to topical tapinarof cream 1% was considered given that the patient used the medication for approximately 1 month prior to the onset of symptoms, it would be unlikely for ACD to present with a concomitant pustular eruption. Linear IgA bullous dermatosis is an autoimmune blistering disease in which antibodies target bullous pemphigoid antigen 2, and there is characteristically linear deposition of IgA at the dermal-epidermal junction that leads to subepidermal blistering.¹¹ This often manifests clinically as widespread tense vesicles in an annular or string-of-pearls appearance. However, morphologies can vary, and large bullae may be seen. In adults, LABD typically is associated with inflammatory bowel disease, malignancy, or medications, notably vancomycin.^11,12 Our patient did not have any of these predisposing factors, and his biopsy for direct immunofluorescence did not reveal the classic pattern described above.

Interestingly, there have been reports in the literature of bullous AGEP in the setting of oral anti-infectives. One report described a 62-year-old woman who developed widespread nonfollicular pustules with multiple tense serous blisters 24 hours after taking oral terbinafine.¹³ Another case described an 80-year-old woman with a similar presentation following a course of ciprofloxacin (although the timeline of medication administration was not described).¹⁴ In this case, patch testing to the culprit medication reproduced the response.¹⁴ In both cases, a biopsy revealed subcorneal and intraepidermal pustules with marked dermal edema.^13,14 As previously described, spongiosis is a common feature of AGEP. We hypothesize that, similar to these reports, our patient had a robust inflammatory response leading to spongiosis, acantholysis, and blister formation secondary to AGEP.

Dermatologists should be aware of this case of AGEP secondary to tapinarof cream 1%, as reports in the literature are rare and it is a reminder that topical medications can cause serious systemic reactions.

To the Editor:  

For many years, topical treatment of plaque psoriasis was limited to steroids, calcineurin inhibitors, vitamin D analogs, retinoids, coal tar products, and anthralin. In recent years, 2 new nonsteroidal treatment options with alternative mechanisms of action, roflumilast 0.3% and tapinarof 1%, have been approved by the US Food and Drug Administration.¹ Roflumilast 0.3%, a topical phosphodiesterase 4 inhibitor, was shown in phase 3 clinical trials to reach an Investigator Global Assessment response of 37.5% to 42.2% in 8 weeks using once-daily application with minimal cutaneous adverse effects.¹ Furthermore, it has demonstrated efficacy in treating psoriasis in intertriginous areas in subset analyses.¹ Tapinarof is an aryl hydrocarbon receptor agonist that suppresses Th17 cell differentiation by downregulating IL-17, IL-22, and IL-23.¹ In phase 3 clinical trials, 35% to 40% of patients who used tapinarof cream 1% once daily demonstrated improvement in psoriasis compared with 6% who used the vehicle alone.² In these studies, 18% to 24% of patients who used tapinarof cream 1% experienced folliculitis.²

Acute generalized exanthematous pustulosis (AGEP) is a nonfollicular pustular drug reaction with systemic symptoms that typically occurs within 2 weeks of exposure to an inciting medication. Systemic antibiotics are the most commonly reported cause of AGEP.³ There are few reports in the literature of AGEP induced by topical agents.^4,5 We report a case of AGEP in a young man following the use of tapinarof cream 1%.

A 23-year-old man with a history of psoriasis presented to the emergency department with fever and a pustular rash. One week prior to presentation, he developed a pustular eruption around plaques of psoriasis on the arms and legs. The patient had been prescribed tapinarof cream 1% by an outside dermatologist and was applying the medication to the affected areas once daily for 1 month prior to onset of symptoms. He discontinued tapinarof a few days prior to the eruption starting, but the rash progressed centrifugally and was associated with fevers and fatigue despite treatment with a brief course of empiric cephalexin prescribed by his primary care provider.

At presentation to our institution, the patient had widespread erythematous patches studded with pustules located on the arms, legs, and flexural areas as well as plaques of psoriasis involving approximately 20% of the body surface area (Figure 1). Furthermore, the patient was noted to have large noninflammatory bullae along the legs. The new eruption occurred on areas that were both treated and spared from the tapinarof cream 1%. Laboratory evaluation showed neutrophil-­predominant leukocytosis (white blood cell count, 15.9×10³/µL ­[reference range, 4.0-11.0×10³/µL]; absolute neutrophil count, 10.3×10³/µL [reference range, 1.5-8.0×10³/µL]), absolute eosinophilia (1930/µL [reference range, 0-0.5×10³/µL]), hypocalcemia (8.4 mg/dL ­[reference range, 8.5-10.5 mg/dL]), and a mild transaminitis ­(aspartate aminotransferase, 37 IU/L [reference range, 10-40 IU/L]; alanine aminotransferase, 53 IU/L ­[reference range, 7-56 U/L]). Histopathology demonstrated spongiosis with subcorneal and intraepidermal pustules and mixed dermal inflammation containing eosinophils (Figure 2). Direct immunofluorescence revealed mild granular staining of C3 at the basement membrane zone.

The patient was started on 1 mg/kg/d of prednisone tapered over 20 days, and he rapidly improved. Alanine aminotransferase levels peaked at 120 IU/L 2 weeks later. At that time, he had complete resolution of the original eruption and was transitioned to topical steroids for continued management of the psoriasis (Figure 3).

The differential diagnosis for our patient included AGEP, generalized pustular psoriasis (GPP), miliaria pustulosa, generalized cutaneous candidiasis, exuberant allergic contact dermatitis (ACD), and linear IgA bullous dermatosis (LABD). Based on the clinical manifestations, laboratory results, and histopathologic evaluation, we made the diagnosis of AGEP secondary to tapinarof with systemic absorption. Acute generalized exanthematous pustulosis has been reported with topical use of morphine and diphenhydramine, among other agents.^4,5 To our knowledge, AGEP due to tapinarof cream 1% has not been reported. In the original clinical trials of tapinarof, folliculitis was contained to sites of application.² Our patient developed pustules at sites distant to areas of application, as well as systemic symptoms and laboratory abnormalities, indicating a systemic reaction. It can be difficult to distinguish AGEP clinically and histologically from GPP. Both conditions can manifest with fever, hypocalcemia, and sterile pustules on a background of erythema that favors intertriginous areas.⁶ Infection, rapid oral steroid withdrawal, pregnancy, and rarely oral medications have been reported causes of GPP.⁶ Our patient did not have any of these exposures. There is overlap in the histology of AGEP and GPP. One retrospective series compared histologic samples to help distinguish these 2 entities. Reliable markers that favored AGEP over GPP included eosinophilic spongiosis, interface dermatitis, and dermal eosinophilia (>2/mm²).⁷ In contrast, the presence of CD161 positivity in the dermis with at least 10 cells favored a diagnosis of GPP.⁷ In our case, the presence of spongiosis with eosinophils in the dermis favored a diagnosis of AGEP over GPP. 

Miliaria pustulosa is a benign condition caused by the occlusion of the epidermal portion of eccrine glands related to either high fever or hot and humid environmental conditions. While it can be present in intertriginous areas like AGEP, miliaria pustulosa can be seen extensively on the back, most commonly in immobile hospitalized patients.⁸ Generalized cutaneous candidiasis usually is caused by the yeast Candida albicans and can take on multiple morphologies, including folliculitis.⁹ The eruption may be disseminated but often is accentuated in intertriginous areas and the anogenital folds. Predisposing factors include immunosuppression, endocrinopathies, recent use of systemic antibiotics or steroids, chemotherapy, and indwelling catheters.⁹ Outside of recent antibiotic use, our patient did not have any risk factors for miliaria pustulosa, making this diagnosis unlikely.

Given the presence of overlapping bullae along the lower extremities, an exuberant ACD and LABD were considered. Bullae formation can occur in ACD secondary to robust inflammation and edema leading to acantholysis.¹⁰ While a delayed hypersensitivity reaction to topical tapinarof cream 1% was considered given that the patient used the medication for approximately 1 month prior to the onset of symptoms, it would be unlikely for ACD to present with a concomitant pustular eruption. Linear IgA bullous dermatosis is an autoimmune blistering disease in which antibodies target bullous pemphigoid antigen 2, and there is characteristically linear deposition of IgA at the dermal-epidermal junction that leads to subepidermal blistering.¹¹ This often manifests clinically as widespread tense vesicles in an annular or string-of-pearls appearance. However, morphologies can vary, and large bullae may be seen. In adults, LABD typically is associated with inflammatory bowel disease, malignancy, or medications, notably vancomycin.^11,12 Our patient did not have any of these predisposing factors, and his biopsy for direct immunofluorescence did not reveal the classic pattern described above.

Interestingly, there have been reports in the literature of bullous AGEP in the setting of oral anti-infectives. One report described a 62-year-old woman who developed widespread nonfollicular pustules with multiple tense serous blisters 24 hours after taking oral terbinafine.¹³ Another case described an 80-year-old woman with a similar presentation following a course of ciprofloxacin (although the timeline of medication administration was not described).¹⁴ In this case, patch testing to the culprit medication reproduced the response.¹⁴ In both cases, a biopsy revealed subcorneal and intraepidermal pustules with marked dermal edema.^13,14 As previously described, spongiosis is a common feature of AGEP. We hypothesize that, similar to these reports, our patient had a robust inflammatory response leading to spongiosis, acantholysis, and blister formation secondary to AGEP.

Dermatologists should be aware of this case of AGEP secondary to tapinarof cream 1%, as reports in the literature are rare and it is a reminder that topical medications can cause serious systemic reactions.

To the Editor:

Psoriasis is a chronic inflammatory condition that affects individuals in various extracutaneous ways.¹ Prior studies have documented a decrease in exercise intensity among patients with psoriasis²; however, few studies have specifically investigated baseline mobility in this population. Baseline mobility denotes an individual’s fundamental ability to walk or move around without assistance of any kind. Impaired mobility—when baseline mobility is compromised—is an aspect of the wider diversity, equity, and inclusion framework that underscores the significance of recognizing challenges and promoting inclusive measures, both at the point of care and in research.³ study sought to analyze the relationship between psoriasis and baseline mobility among US adults (aged 45 to 80 years) utilizing the latest data from the National Health and Nutrition Examination Survey (NHANES) database for psoriasis.⁴ We used three 2-year cycles of NHANES data to create a 2009-2014 dataset.

The overall NHANES response rate among adults aged 45 to 80 years between 2009 and 2014 was 67.9%. Patients were categorized as having impaired mobility if they responded “yes” to the following question: “Because of a health problem, do you have difficulty walking without using any special equipment?” Psoriasis status was assessed by the following question: “Have you ever been told by a doctor or other health professional that you had psoriasis?” Multivariable logistic regression analyses were performed using Stata/SE 18.0 software (StataCorp LLC) to assess the relationship between psoriasis and impaired mobility. Age, income, education, sex, race, tobacco use, diabetes status, body mass index, and arthritis status were controlled for in our models.

Our analysis initially included 9982 participants; 14 did not respond to questions assessing psoriasis and impaired mobility and were excluded. The prevalence of impaired mobility in patients with psoriasis was 17.1% compared with 10.9% among those without psoriasis (Table 1). There was a significant association between psoriasis and impaired mobility among patients aged 45 to 80 years after adjusting for potential confounding variables (adjusted odds ratio [AOR], 1.54; 95% CI, 1.04- 2.29; P=.032)(Table 2). Analyses of subgroups yielded no statistically significant results.

Our study demonstrated a statistically significant difference in mobility between individuals with psoriasis compared with the general population, which remained significant when controlling for arthritis, obesity, and diabetes (P=.032). This may be the result of several influences. First, the location of the psoriasis may impact mobility. Plantar psoriasis—a manifestation on the soles of the feet—can cause discomfort and pain, which can hinder walking and standing.⁵ Second, a study by Lasselin et al⁶ found that systemic inflammation contributes to mobility impairment through alterations in gait and posture, which suggests that the inflammatory processes inherent in psoriasis could intrinsically modify walking speed and stride, potentially exacerbating mobility difficulties independent of other comorbid conditions. These findings suggest that psoriasis may disproportionately affect individuals with impaired mobility, independent of comorbid arthritis, obesity, and diabetes.

These findings have broad implications for diversity, equity, and inclusion. They should prompt us to consider the practical challenges faced by this patient population and the ways that we can address barriers to care. Offering telehealth appointments, making primary care referrals for impaired mobility workups, and advising patients of direct-to-home delivery of prescriptions are good places to start.

Limitations to our study include the lack of specificity in the survey question, self-reporting bias, and the inability to control for the psoriasis location. Further investigations are warranted in large, representative US adult populations to assess the implications of impaired mobility in patients with psoriasis.

To the Editor:

Psoriasis is a chronic inflammatory condition that affects individuals in various extracutaneous ways.¹ Prior studies have documented a decrease in exercise intensity among patients with psoriasis²; however, few studies have specifically investigated baseline mobility in this population. Baseline mobility denotes an individual’s fundamental ability to walk or move around without assistance of any kind. Impaired mobility—when baseline mobility is compromised—is an aspect of the wider diversity, equity, and inclusion framework that underscores the significance of recognizing challenges and promoting inclusive measures, both at the point of care and in research.³ study sought to analyze the relationship between psoriasis and baseline mobility among US adults (aged 45 to 80 years) utilizing the latest data from the National Health and Nutrition Examination Survey (NHANES) database for psoriasis.⁴ We used three 2-year cycles of NHANES data to create a 2009-2014 dataset.

The overall NHANES response rate among adults aged 45 to 80 years between 2009 and 2014 was 67.9%. Patients were categorized as having impaired mobility if they responded “yes” to the following question: “Because of a health problem, do you have difficulty walking without using any special equipment?” Psoriasis status was assessed by the following question: “Have you ever been told by a doctor or other health professional that you had psoriasis?” Multivariable logistic regression analyses were performed using Stata/SE 18.0 software (StataCorp LLC) to assess the relationship between psoriasis and impaired mobility. Age, income, education, sex, race, tobacco use, diabetes status, body mass index, and arthritis status were controlled for in our models.

Our analysis initially included 9982 participants; 14 did not respond to questions assessing psoriasis and impaired mobility and were excluded. The prevalence of impaired mobility in patients with psoriasis was 17.1% compared with 10.9% among those without psoriasis (Table 1). There was a significant association between psoriasis and impaired mobility among patients aged 45 to 80 years after adjusting for potential confounding variables (adjusted odds ratio [AOR], 1.54; 95% CI, 1.04- 2.29; P=.032)(Table 2). Analyses of subgroups yielded no statistically significant results.

Our study demonstrated a statistically significant difference in mobility between individuals with psoriasis compared with the general population, which remained significant when controlling for arthritis, obesity, and diabetes (P=.032). This may be the result of several influences. First, the location of the psoriasis may impact mobility. Plantar psoriasis—a manifestation on the soles of the feet—can cause discomfort and pain, which can hinder walking and standing.⁵ Second, a study by Lasselin et al⁶ found that systemic inflammation contributes to mobility impairment through alterations in gait and posture, which suggests that the inflammatory processes inherent in psoriasis could intrinsically modify walking speed and stride, potentially exacerbating mobility difficulties independent of other comorbid conditions. These findings suggest that psoriasis may disproportionately affect individuals with impaired mobility, independent of comorbid arthritis, obesity, and diabetes.

These findings have broad implications for diversity, equity, and inclusion. They should prompt us to consider the practical challenges faced by this patient population and the ways that we can address barriers to care. Offering telehealth appointments, making primary care referrals for impaired mobility workups, and advising patients of direct-to-home delivery of prescriptions are good places to start.

Limitations to our study include the lack of specificity in the survey question, self-reporting bias, and the inability to control for the psoriasis location. Further investigations are warranted in large, representative US adult populations to assess the implications of impaired mobility in patients with psoriasis.

To the Editor:

Psoriasis is a chronic inflammatory condition that affects individuals in various extracutaneous ways.¹ Prior studies have documented a decrease in exercise intensity among patients with psoriasis²; however, few studies have specifically investigated baseline mobility in this population. Baseline mobility denotes an individual’s fundamental ability to walk or move around without assistance of any kind. Impaired mobility—when baseline mobility is compromised—is an aspect of the wider diversity, equity, and inclusion framework that underscores the significance of recognizing challenges and promoting inclusive measures, both at the point of care and in research.³ study sought to analyze the relationship between psoriasis and baseline mobility among US adults (aged 45 to 80 years) utilizing the latest data from the National Health and Nutrition Examination Survey (NHANES) database for psoriasis.⁴ We used three 2-year cycles of NHANES data to create a 2009-2014 dataset.

The overall NHANES response rate among adults aged 45 to 80 years between 2009 and 2014 was 67.9%. Patients were categorized as having impaired mobility if they responded “yes” to the following question: “Because of a health problem, do you have difficulty walking without using any special equipment?” Psoriasis status was assessed by the following question: “Have you ever been told by a doctor or other health professional that you had psoriasis?” Multivariable logistic regression analyses were performed using Stata/SE 18.0 software (StataCorp LLC) to assess the relationship between psoriasis and impaired mobility. Age, income, education, sex, race, tobacco use, diabetes status, body mass index, and arthritis status were controlled for in our models.

Our analysis initially included 9982 participants; 14 did not respond to questions assessing psoriasis and impaired mobility and were excluded. The prevalence of impaired mobility in patients with psoriasis was 17.1% compared with 10.9% among those without psoriasis (Table 1). There was a significant association between psoriasis and impaired mobility among patients aged 45 to 80 years after adjusting for potential confounding variables (adjusted odds ratio [AOR], 1.54; 95% CI, 1.04- 2.29; P=.032)(Table 2). Analyses of subgroups yielded no statistically significant results.

Our study demonstrated a statistically significant difference in mobility between individuals with psoriasis compared with the general population, which remained significant when controlling for arthritis, obesity, and diabetes (P=.032). This may be the result of several influences. First, the location of the psoriasis may impact mobility. Plantar psoriasis—a manifestation on the soles of the feet—can cause discomfort and pain, which can hinder walking and standing.⁵ Second, a study by Lasselin et al⁶ found that systemic inflammation contributes to mobility impairment through alterations in gait and posture, which suggests that the inflammatory processes inherent in psoriasis could intrinsically modify walking speed and stride, potentially exacerbating mobility difficulties independent of other comorbid conditions. These findings suggest that psoriasis may disproportionately affect individuals with impaired mobility, independent of comorbid arthritis, obesity, and diabetes.

These findings have broad implications for diversity, equity, and inclusion. They should prompt us to consider the practical challenges faced by this patient population and the ways that we can address barriers to care. Offering telehealth appointments, making primary care referrals for impaired mobility workups, and advising patients of direct-to-home delivery of prescriptions are good places to start.

Limitations to our study include the lack of specificity in the survey question, self-reporting bias, and the inability to control for the psoriasis location. Further investigations are warranted in large, representative US adult populations to assess the implications of impaired mobility in patients with psoriasis.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

THE DIAGNOSIS: Cutaneous Endometriosis

On histopathology, a biopsy specimen of an umbilical papule showed a dermal lymphohistiocyticrich infiltrate, hemorrhage, and ectopic endometrial glands consistent with cutaneous endometriosis (CE)(Figure). Cutaneous endometriosis is a rare condition that typically affects females of reproductive potential and is characterized by endometrial glands and stroma within the dermis and hypodermis. Cutaneous endometriosis is classified as primary or secondary. There is no surgical history of the abdomen or pelvis in primary CE. In contrast, a history of abdominopelvic surgery is the defining characteristic of secondary CE, which is more common than primary CE and typically manifests as painful red, brown, or purple papules along preexisting surgical scars of the umbilicus, lower abdomen, or pelvic region.¹ Our patient may have developed secondary CE related to the laparoscopic cholecystectomy performed 10 years prior. Surgical excision is considered the definitive treatment for CE, and hormonal therapy with danazol or leuprolide may help ameliorate symptoms.¹ Our patient deferred any hormonal or surgical interventions to undergo fertility treatments for pregnancy.

Cyclical bleeding and pain that coincides with menstruation is consistent with CE; however, cyclical symptoms are not always present, which can lead to delayed or incorrect diagnosis. Biopsy and histopathologic analysis are required for definitive diagnosis and are critical for distinguishing CE from other conditions. The differential diagnosis in our patient included pyogenic granuloma, dermatofibrosarcoma protuberans, keloid, and cutaneous metastasis of a primary malignancy. Vascular lesions such as pyogenic granuloma can manifest with bleeding but have a characteristic histopathologic lobular capillary arrangement that was not present in our patient.

Dermatofibrosarcoma protuberans is a rare, slow-growing, malignant soft-tissue sarcoma that most commonly manifests on the trunk, arms, and legs.² It is characterized by a slow-growing, indurated plaque that often is present for years and may suddenly progress into a smooth, red-brown, multinodular mass. Histopathology typically shows spindle cells infiltrating the dermis and subcutaneous tissue in storiform or whorled pattern with variations based on the tumor stage, as well as diffuse CD34 immunoreactivity.²

Keloids are dense, raised, hyperpigmented, fibrous nodules—sometimes with accompanying telangiectasias—that typically grow secondary to trauma and project past the boundaries of the initial trauma site.¹ Keloids are more commonly seen in individuals with darker skin types and tend to grow larger in this population. Histopathology reveals thickened hyalinized collagen bundles, which were not seen in our patient.¹

Metastatic skin lesions of the umbilicus are rare but can arise from internal malignancies including cancers of the lung, colon, and breast.³ We considered Sister Mary Joseph nodule, which is caused most commonly by metastasis of a primary gastrointestinal cancer and signifies poor prognosis. The histopathology of metastatic lesions would reveal the presence of atypical cells with cancer-specific markers. Histopathology along with the patient’s personal and family history, a comprehensive review of symptoms, and cancer screening may help with reaching the correct diagnosis.

The average duration between abdominopelvic surgery and onset of secondary CE symptoms is 3.7 to 5.3 years.⁴ Our patient presented 10 years post surgery and after cessation of oral contraception, which may suggest a potential role of hormonal contraception in delayed CE onset. Diagnosis of CE can be challenging due to atypical signs or symptoms, delayed onset, and lack of awareness among health care professionals. Patients with delayed diagnosis may endure multiple procedures, prolonged physical pain, and emotional distress. Furthermore, 30% to 50% of females with endometriosis experience infertility. Delayed diagnosis of CE compounded with associated age-related increase in oocyte atresia could potentially worsen fecundity as patients age.⁵ It is important to consider CE in the differential diagnosis of females of reproductive age who present with cyclical bleeding and abdominal or umbilical nodules.

To the Editor:

Psoriasis is a chronic systemic inflammatory disease that affects 1% to 3% of the global population.^1,2 Due to dysregulation of the immune system, patients with HIV who have concurrent moderate to severe psoriasis present a clinical therapeutic challenge for dermatologists. Recent guidelines from the American Academy of Dermatology recommended avoiding certain systemic treatments (eg, methotrexate, cyclosporine) in patients who are HIV positive due to their immunosuppressive effects, as well as cautious use of certain biologics in populations with HIV.³ Traditional therapies for managing psoriasis in patients with HIV have included topical agents, antiretroviral therapy (ART), phototherapy, and acitretin; however, phototherapy can be logistically cumbersome for patients, and in the setting of ART, acitretin has the potential to exacerbate hypertriglyceridemia as well as other undesirable adverse effects.³

Apremilast is a phosphodiesterase 4 inhibitor that has emerged as a promising alternative in patients with HIV who require treatment for psoriasis. It has demonstrated clinical efficacy in psoriasis and has minimal immunosuppressive risk.⁴ Despite its potential in this population, reports of apremilast used in patients who are HIV positive are rare, and these patients often are excluded from larges studies. In this study, we reviewed the literature to evaluate outcomes and adverse events in patients with HIV who underwent psoriasis treatment with apremilast.

A search of PubMed articles indexed for MEDLINE from the inception of the database through January 2023 was conducted using the terms psoriasis, human immunodeficiency virus, acquired immunodeficiency syndrome, therapy, apremilast, and adverse events. The inclusion criteria were articles that reported patients with HIV and psoriasis undergoing treatment with apremilast with subsequent follow-up to delineate potential outcomes and adverse effects. Non–English language articles were excluded.

Our search of the literature yielded 7 patients with HIV and psoriasis who were treated with apremilast (eTable).^5-11 All of the patients were male and ranged in age from 31 to 55 years, and all had pretreatment CD4 cell counts greater than 450 cells/mm³. All but 1 patient were confirmed to have undergone ART prior to treatment with apremilast, and all were treated using the traditional apremilast titration from 10 mg to 30 mg orally twice daily.

The mean pretreatment Psoriasis Area and Severity Index (PASI) score in the patients we evaluated was 12.2, with an average reduction in PASI score of 9.3. This equated to achievement of PASI 75 or greater (ie, representing at least a 75% improvement in psoriasis) in 4 (57.1%) patients, with clinical improvement confirmed in all 7 patients (100.0%)(eTable). The average follow-up time was 9.7 months (range, 6 weeks to 24 months). Only 1 (14.3%) patient experienced any adverse effects, which included self-resolving diarrhea and respiratory infections (nonopportunistic) over a follow-up period of 2 years.⁶ Of note, gastrointestinal upset is common with apremilast and usually improves over time.¹²

Apremilast represents a safe and effective alternative systemic therapy for patients with HIV and psoriasis.⁴ As a phosphodiesterase 4 inhibitor, apremilast leads to increased levels of cyclic adenosine monophosphate, which restores an equilibrium between proinflammatory (eg, tumor necrosis factors, interferons, IL-2, IL-6, IL-12, IL-23) and anti-inflammatory (eg, IL-10) cytokines.¹³ Unlike most biologics that target and inhibit a specific proinflammatory cytokine, apremilast’s homeostatic mechanism may explain its minimal immunosuppressive adverse effects.

In the majority of patients we evaluated, initiation of apremilast led to documented clinical improvement. It is worth noting that some patients presented with a relevant medical history and/or comorbidities such as hepatitis and metabolic conditions (eg, obesity, type 2 diabetes mellitus, hypertriglyceridemia). Despite these comorbidities, initiation of apremilast therapy in these patients led to clinical improvement of psoriasis overall. Notable cases from our study included a 41-year-old man with concurrent hepatitis B and psoriatic arthritis who achieved PASI 90 after 24 weeks of apremilast therapy⁸; a 46-year-old man with concurrent hepatitis C who went from 8% to 1.5% body surface area affected after 5 months of treatment with apremilast⁵; and a 54-year-old man with concurrent obesity, type 2 diabetes mellitus, and hypertriglyceridemia who went from a PASI score of 10.2 to 4.1 after 3 months of apremilast treatment and maintained a PASI score of 2.7 at 2 years’ follow up (eTable).⁶

Limitations of this study included the small sample size and homogeneous demographic consisting only of adult males, which restrict the external validity of the findings. Despite limitations, apremilast was utilized effectively for patients with both psoriasis and psoriatic arthritis. The observed effectiveness of apremilast in multiple forms of psoriasis provides valuable insights into the drug’s versatility in this patient population.

The use of apremilast for treatment of psoriasis in patients with HIV represents an important therapeutic development. Its effectiveness in reducing psoriasis symptoms in these immunocompromised patients makes it a viable alternative to traditional systemic therapies that might be contraindicated in this population. While larger studies would be ideal, the exclusion of patients with HIV from clinical trials presents an obstacle and therefore makes case series and reviews helpful for clinicians in bridging the gap with respect to treatment options for these patients. Apremilast may be a safe and effective medication for patients with HIV and psoriasis who require systemic therapy to treat their skin disease.

To the Editor:

Psoriasis is a chronic systemic inflammatory disease that affects 1% to 3% of the global population.^1,2 Due to dysregulation of the immune system, patients with HIV who have concurrent moderate to severe psoriasis present a clinical therapeutic challenge for dermatologists. Recent guidelines from the American Academy of Dermatology recommended avoiding certain systemic treatments (eg, methotrexate, cyclosporine) in patients who are HIV positive due to their immunosuppressive effects, as well as cautious use of certain biologics in populations with HIV.³ Traditional therapies for managing psoriasis in patients with HIV have included topical agents, antiretroviral therapy (ART), phototherapy, and acitretin; however, phototherapy can be logistically cumbersome for patients, and in the setting of ART, acitretin has the potential to exacerbate hypertriglyceridemia as well as other undesirable adverse effects.³

Apremilast is a phosphodiesterase 4 inhibitor that has emerged as a promising alternative in patients with HIV who require treatment for psoriasis. It has demonstrated clinical efficacy in psoriasis and has minimal immunosuppressive risk.⁴ Despite its potential in this population, reports of apremilast used in patients who are HIV positive are rare, and these patients often are excluded from larges studies. In this study, we reviewed the literature to evaluate outcomes and adverse events in patients with HIV who underwent psoriasis treatment with apremilast.

A search of PubMed articles indexed for MEDLINE from the inception of the database through January 2023 was conducted using the terms psoriasis, human immunodeficiency virus, acquired immunodeficiency syndrome, therapy, apremilast, and adverse events. The inclusion criteria were articles that reported patients with HIV and psoriasis undergoing treatment with apremilast with subsequent follow-up to delineate potential outcomes and adverse effects. Non–English language articles were excluded.

Our search of the literature yielded 7 patients with HIV and psoriasis who were treated with apremilast (eTable).^5-11 All of the patients were male and ranged in age from 31 to 55 years, and all had pretreatment CD4 cell counts greater than 450 cells/mm³. All but 1 patient were confirmed to have undergone ART prior to treatment with apremilast, and all were treated using the traditional apremilast titration from 10 mg to 30 mg orally twice daily.

The mean pretreatment Psoriasis Area and Severity Index (PASI) score in the patients we evaluated was 12.2, with an average reduction in PASI score of 9.3. This equated to achievement of PASI 75 or greater (ie, representing at least a 75% improvement in psoriasis) in 4 (57.1%) patients, with clinical improvement confirmed in all 7 patients (100.0%)(eTable). The average follow-up time was 9.7 months (range, 6 weeks to 24 months). Only 1 (14.3%) patient experienced any adverse effects, which included self-resolving diarrhea and respiratory infections (nonopportunistic) over a follow-up period of 2 years.⁶ Of note, gastrointestinal upset is common with apremilast and usually improves over time.¹²

Apremilast represents a safe and effective alternative systemic therapy for patients with HIV and psoriasis.⁴ As a phosphodiesterase 4 inhibitor, apremilast leads to increased levels of cyclic adenosine monophosphate, which restores an equilibrium between proinflammatory (eg, tumor necrosis factors, interferons, IL-2, IL-6, IL-12, IL-23) and anti-inflammatory (eg, IL-10) cytokines.¹³ Unlike most biologics that target and inhibit a specific proinflammatory cytokine, apremilast’s homeostatic mechanism may explain its minimal immunosuppressive adverse effects.

In the majority of patients we evaluated, initiation of apremilast led to documented clinical improvement. It is worth noting that some patients presented with a relevant medical history and/or comorbidities such as hepatitis and metabolic conditions (eg, obesity, type 2 diabetes mellitus, hypertriglyceridemia). Despite these comorbidities, initiation of apremilast therapy in these patients led to clinical improvement of psoriasis overall. Notable cases from our study included a 41-year-old man with concurrent hepatitis B and psoriatic arthritis who achieved PASI 90 after 24 weeks of apremilast therapy⁸; a 46-year-old man with concurrent hepatitis C who went from 8% to 1.5% body surface area affected after 5 months of treatment with apremilast⁵; and a 54-year-old man with concurrent obesity, type 2 diabetes mellitus, and hypertriglyceridemia who went from a PASI score of 10.2 to 4.1 after 3 months of apremilast treatment and maintained a PASI score of 2.7 at 2 years’ follow up (eTable).⁶

Limitations of this study included the small sample size and homogeneous demographic consisting only of adult males, which restrict the external validity of the findings. Despite limitations, apremilast was utilized effectively for patients with both psoriasis and psoriatic arthritis. The observed effectiveness of apremilast in multiple forms of psoriasis provides valuable insights into the drug’s versatility in this patient population.

The use of apremilast for treatment of psoriasis in patients with HIV represents an important therapeutic development. Its effectiveness in reducing psoriasis symptoms in these immunocompromised patients makes it a viable alternative to traditional systemic therapies that might be contraindicated in this population. While larger studies would be ideal, the exclusion of patients with HIV from clinical trials presents an obstacle and therefore makes case series and reviews helpful for clinicians in bridging the gap with respect to treatment options for these patients. Apremilast may be a safe and effective medication for patients with HIV and psoriasis who require systemic therapy to treat their skin disease.

To the Editor:

Psoriasis is a chronic systemic inflammatory disease that affects 1% to 3% of the global population.^1,2 Due to dysregulation of the immune system, patients with HIV who have concurrent moderate to severe psoriasis present a clinical therapeutic challenge for dermatologists. Recent guidelines from the American Academy of Dermatology recommended avoiding certain systemic treatments (eg, methotrexate, cyclosporine) in patients who are HIV positive due to their immunosuppressive effects, as well as cautious use of certain biologics in populations with HIV.³ Traditional therapies for managing psoriasis in patients with HIV have included topical agents, antiretroviral therapy (ART), phototherapy, and acitretin; however, phototherapy can be logistically cumbersome for patients, and in the setting of ART, acitretin has the potential to exacerbate hypertriglyceridemia as well as other undesirable adverse effects.³

Apremilast is a phosphodiesterase 4 inhibitor that has emerged as a promising alternative in patients with HIV who require treatment for psoriasis. It has demonstrated clinical efficacy in psoriasis and has minimal immunosuppressive risk.⁴ Despite its potential in this population, reports of apremilast used in patients who are HIV positive are rare, and these patients often are excluded from larges studies. In this study, we reviewed the literature to evaluate outcomes and adverse events in patients with HIV who underwent psoriasis treatment with apremilast.

A search of PubMed articles indexed for MEDLINE from the inception of the database through January 2023 was conducted using the terms psoriasis, human immunodeficiency virus, acquired immunodeficiency syndrome, therapy, apremilast, and adverse events. The inclusion criteria were articles that reported patients with HIV and psoriasis undergoing treatment with apremilast with subsequent follow-up to delineate potential outcomes and adverse effects. Non–English language articles were excluded.

Our search of the literature yielded 7 patients with HIV and psoriasis who were treated with apremilast (eTable).^5-11 All of the patients were male and ranged in age from 31 to 55 years, and all had pretreatment CD4 cell counts greater than 450 cells/mm³. All but 1 patient were confirmed to have undergone ART prior to treatment with apremilast, and all were treated using the traditional apremilast titration from 10 mg to 30 mg orally twice daily.

The mean pretreatment Psoriasis Area and Severity Index (PASI) score in the patients we evaluated was 12.2, with an average reduction in PASI score of 9.3. This equated to achievement of PASI 75 or greater (ie, representing at least a 75% improvement in psoriasis) in 4 (57.1%) patients, with clinical improvement confirmed in all 7 patients (100.0%)(eTable). The average follow-up time was 9.7 months (range, 6 weeks to 24 months). Only 1 (14.3%) patient experienced any adverse effects, which included self-resolving diarrhea and respiratory infections (nonopportunistic) over a follow-up period of 2 years.⁶ Of note, gastrointestinal upset is common with apremilast and usually improves over time.¹²

Apremilast represents a safe and effective alternative systemic therapy for patients with HIV and psoriasis.⁴ As a phosphodiesterase 4 inhibitor, apremilast leads to increased levels of cyclic adenosine monophosphate, which restores an equilibrium between proinflammatory (eg, tumor necrosis factors, interferons, IL-2, IL-6, IL-12, IL-23) and anti-inflammatory (eg, IL-10) cytokines.¹³ Unlike most biologics that target and inhibit a specific proinflammatory cytokine, apremilast’s homeostatic mechanism may explain its minimal immunosuppressive adverse effects.

In the majority of patients we evaluated, initiation of apremilast led to documented clinical improvement. It is worth noting that some patients presented with a relevant medical history and/or comorbidities such as hepatitis and metabolic conditions (eg, obesity, type 2 diabetes mellitus, hypertriglyceridemia). Despite these comorbidities, initiation of apremilast therapy in these patients led to clinical improvement of psoriasis overall. Notable cases from our study included a 41-year-old man with concurrent hepatitis B and psoriatic arthritis who achieved PASI 90 after 24 weeks of apremilast therapy⁸; a 46-year-old man with concurrent hepatitis C who went from 8% to 1.5% body surface area affected after 5 months of treatment with apremilast⁵; and a 54-year-old man with concurrent obesity, type 2 diabetes mellitus, and hypertriglyceridemia who went from a PASI score of 10.2 to 4.1 after 3 months of apremilast treatment and maintained a PASI score of 2.7 at 2 years’ follow up (eTable).⁶

Limitations of this study included the small sample size and homogeneous demographic consisting only of adult males, which restrict the external validity of the findings. Despite limitations, apremilast was utilized effectively for patients with both psoriasis and psoriatic arthritis. The observed effectiveness of apremilast in multiple forms of psoriasis provides valuable insights into the drug’s versatility in this patient population.

The use of apremilast for treatment of psoriasis in patients with HIV represents an important therapeutic development. Its effectiveness in reducing psoriasis symptoms in these immunocompromised patients makes it a viable alternative to traditional systemic therapies that might be contraindicated in this population. While larger studies would be ideal, the exclusion of patients with HIV from clinical trials presents an obstacle and therefore makes case series and reviews helpful for clinicians in bridging the gap with respect to treatment options for these patients. Apremilast may be a safe and effective medication for patients with HIV and psoriasis who require systemic therapy to treat their skin disease.

Biologic therapies have transformed the treatment of psoriasis. Current biologics approved for psoriasis include monoclonal antibodies targeting various pathways: tumor necrosis factor α (TNF-α) inhibitors (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit common to IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17 receptor A (brodalumab), and dual IL-17A/IL-17F inhibition (bimekizumab). Recent research showed that risankizumab achieved the highest Psoriasis Area and Severity Index (PASI) 90 scores in short- and long-term treatment periods (4 and 16 weeks, respectively) compared to other biologics, and IL-23 inhibitors demonstrated the lowest short- and long-term adverse event rates and the most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.¹

Although these monoclonal antibodies have revolutionized psoriasis treatment, they are large proteins that must be administered subcutaneously or via intravenous injection. Emerging biologics are smaller proteins administered orally via a tablet or pill. In clinical trials, oral biologics have demonstrated efficacy (eTable), suggesting that oral biologics may be the future for psoriasis treatment, as this noninvasive delivery method may help improve patient compliance with treatment.

A major inflammatory pathway in psoriasis, IL-23 has been an effective and safe drug target. The novel oral IL-23 inhibitor, JNJ-2113, was discovered in 2017 and currently is being compared to deucravacitinib in the phase III ICONIC-LEAD trial (ClinicalTrials. gov Identifier NCT06095115) in patients with moderate to severe plaque psoriasis.^2,3 In the phase IIb FRONTIER 1 trial, treatment with either 3 once-daily (25 mg, 50 mg, 100 mg) and 2 twice-daily (25 mg, 100 mg) doses of JNJ-2113 led to significant improvements in PASI 75 response at 16 weeks compared to placebo (P<.001).⁴ In the phase IIb long-term extension FRONTIER 2 trial, JNJ-2113 maintained high rates of skin clearance through 52 weeks in adults with moderate to severe plaque psoriasis, with the highest PASI 75 response observed in the 100-mg twice-daily group (32/42 [76.2%]).⁵ Responses were maintained through week 52 for all JNJ-2113 treatment groups for PASI 90 and PASI 100 endpoints. In addition to ICONIC-LEAD, JNJ-2113 is being evaluated in the phase III multicenter, randomized, double-blind, placebo-controlled trial ICONIC-TOTAL (NCT06095102) in patients with special area psoriasis and ANTHEM-UC (NCT06049017) in patients with ulcerative colitis to evaluate its efficacy and safety. The most common adverse events associated with JNJ-77242113 were mild to moderate and included COVID-19 infection and nasopharyngitis.⁶ Higher rates of COVID-19 infection likely were due to immune compromise in the setting of the recent pandemic. Similar percentages of at least 1 adverse event were found in JNJ-77242113 and placebo groups (52%-58.6% and 51%-65.7%, respectively).^4,5,7

An orally administered small-molecule inhibitor of IL-17A, LY3509754, may represent a convenient alternative to IL-17A–targeting monoclonal antibodies. In a study of 91 participants,⁸ LY3509754 showed strong target engagement indicated by elevated plasma IL-17A levels within 12 hours of dosing. Despite strong target engagement and a pharmacokinetics profile that supports once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated, as 4.4% (4/91) of participants (3 receiving 1000 mg once daily and 1 receiving 400 mg once daily) had increased liver transaminases or acute hepatitis (onset, ≥12 days following the last dose), which was consistent with drug-induced liver injury.⁸

The small potent molecule SAR441566 inhibits TNF-α by stabilizing an asymmetrical form of the soluble TNF trimer. As the asymmetrical trimer is the biologically active form of TNF-α, stabilization of the trimer compromises downstream signaling and inhibits the functions of TNF-α in vitro and in vivo. Recently, SAR441566 was found to be safe and well tolerated in healthy participants, showing efficacy in mild to moderate psoriasis in a phase Ib trial.⁹ A phase II trial of SAR441566 (NCT06073119) is being developed to create a more convenient orally bioavailable treatment option for patients with psoriasis compared to established biologic drugs targeting TNF-α.¹⁰

Few trials have focused on investigating the antipsoriatic effects of orally administered small molecules. Some of these small molecules can enter cells and inhibit the activation of T lymphocytes, leukocyte trafficking, leukotriene activity/production and angiogenesis, and promote apoptosis. Oral administration of small molecules is the future of effective and affordable psoriasis treatment, but safety and efficacy must first be assessed in clinical trials. JNJ-77242113 has shown a more promising safety profile, has recently undergone phase III trials, and may represent the newest wave for psoriasis treatment. While LY3509754 had a strong pharmacokinetics profile, it was poorly tolerated, and study participants' laboratory results suggested the drug to be hepatotoxic.⁸ SAR441566 has been shown to be safe and well tolerated in treating psoriasis, and phase II readouts are expected later in 2025. We can expect a new wave of psoriasis treatments with emerging oral therapies.

Biologic therapies have transformed the treatment of psoriasis. Current biologics approved for psoriasis include monoclonal antibodies targeting various pathways: tumor necrosis factor α (TNF-α) inhibitors (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit common to IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17 receptor A (brodalumab), and dual IL-17A/IL-17F inhibition (bimekizumab). Recent research showed that risankizumab achieved the highest Psoriasis Area and Severity Index (PASI) 90 scores in short- and long-term treatment periods (4 and 16 weeks, respectively) compared to other biologics, and IL-23 inhibitors demonstrated the lowest short- and long-term adverse event rates and the most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.¹

Although these monoclonal antibodies have revolutionized psoriasis treatment, they are large proteins that must be administered subcutaneously or via intravenous injection. Emerging biologics are smaller proteins administered orally via a tablet or pill. In clinical trials, oral biologics have demonstrated efficacy (eTable), suggesting that oral biologics may be the future for psoriasis treatment, as this noninvasive delivery method may help improve patient compliance with treatment.

A major inflammatory pathway in psoriasis, IL-23 has been an effective and safe drug target. The novel oral IL-23 inhibitor, JNJ-2113, was discovered in 2017 and currently is being compared to deucravacitinib in the phase III ICONIC-LEAD trial (ClinicalTrials. gov Identifier NCT06095115) in patients with moderate to severe plaque psoriasis.^2,3 In the phase IIb FRONTIER 1 trial, treatment with either 3 once-daily (25 mg, 50 mg, 100 mg) and 2 twice-daily (25 mg, 100 mg) doses of JNJ-2113 led to significant improvements in PASI 75 response at 16 weeks compared to placebo (P<.001).⁴ In the phase IIb long-term extension FRONTIER 2 trial, JNJ-2113 maintained high rates of skin clearance through 52 weeks in adults with moderate to severe plaque psoriasis, with the highest PASI 75 response observed in the 100-mg twice-daily group (32/42 [76.2%]).⁵ Responses were maintained through week 52 for all JNJ-2113 treatment groups for PASI 90 and PASI 100 endpoints. In addition to ICONIC-LEAD, JNJ-2113 is being evaluated in the phase III multicenter, randomized, double-blind, placebo-controlled trial ICONIC-TOTAL (NCT06095102) in patients with special area psoriasis and ANTHEM-UC (NCT06049017) in patients with ulcerative colitis to evaluate its efficacy and safety. The most common adverse events associated with JNJ-77242113 were mild to moderate and included COVID-19 infection and nasopharyngitis.⁶ Higher rates of COVID-19 infection likely were due to immune compromise in the setting of the recent pandemic. Similar percentages of at least 1 adverse event were found in JNJ-77242113 and placebo groups (52%-58.6% and 51%-65.7%, respectively).^4,5,7

An orally administered small-molecule inhibitor of IL-17A, LY3509754, may represent a convenient alternative to IL-17A–targeting monoclonal antibodies. In a study of 91 participants,⁸ LY3509754 showed strong target engagement indicated by elevated plasma IL-17A levels within 12 hours of dosing. Despite strong target engagement and a pharmacokinetics profile that supports once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated, as 4.4% (4/91) of participants (3 receiving 1000 mg once daily and 1 receiving 400 mg once daily) had increased liver transaminases or acute hepatitis (onset, ≥12 days following the last dose), which was consistent with drug-induced liver injury.⁸

The small potent molecule SAR441566 inhibits TNF-α by stabilizing an asymmetrical form of the soluble TNF trimer. As the asymmetrical trimer is the biologically active form of TNF-α, stabilization of the trimer compromises downstream signaling and inhibits the functions of TNF-α in vitro and in vivo. Recently, SAR441566 was found to be safe and well tolerated in healthy participants, showing efficacy in mild to moderate psoriasis in a phase Ib trial.⁹ A phase II trial of SAR441566 (NCT06073119) is being developed to create a more convenient orally bioavailable treatment option for patients with psoriasis compared to established biologic drugs targeting TNF-α.¹⁰

Few trials have focused on investigating the antipsoriatic effects of orally administered small molecules. Some of these small molecules can enter cells and inhibit the activation of T lymphocytes, leukocyte trafficking, leukotriene activity/production and angiogenesis, and promote apoptosis. Oral administration of small molecules is the future of effective and affordable psoriasis treatment, but safety and efficacy must first be assessed in clinical trials. JNJ-77242113 has shown a more promising safety profile, has recently undergone phase III trials, and may represent the newest wave for psoriasis treatment. While LY3509754 had a strong pharmacokinetics profile, it was poorly tolerated, and study participants' laboratory results suggested the drug to be hepatotoxic.⁸ SAR441566 has been shown to be safe and well tolerated in treating psoriasis, and phase II readouts are expected later in 2025. We can expect a new wave of psoriasis treatments with emerging oral therapies.

Biologic therapies have transformed the treatment of psoriasis. Current biologics approved for psoriasis include monoclonal antibodies targeting various pathways: tumor necrosis factor α (TNF-α) inhibitors (infliximab, adalimumab, certolizumab, etanercept), the p40 subunit common to IL-12 and IL-23 (ustekinumab), the p19 subunit of IL-23 (guselkumab, tildrakizumab, risankizumab), IL-17A (secukinumab, ixekizumab), IL-17 receptor A (brodalumab), and dual IL-17A/IL-17F inhibition (bimekizumab). Recent research showed that risankizumab achieved the highest Psoriasis Area and Severity Index (PASI) 90 scores in short- and long-term treatment periods (4 and 16 weeks, respectively) compared to other biologics, and IL-23 inhibitors demonstrated the lowest short- and long-term adverse event rates and the most favorable long-term risk-benefit profile compared to IL-17, IL-12/23, and TNF-α inhibitors.¹

Although these monoclonal antibodies have revolutionized psoriasis treatment, they are large proteins that must be administered subcutaneously or via intravenous injection. Emerging biologics are smaller proteins administered orally via a tablet or pill. In clinical trials, oral biologics have demonstrated efficacy (eTable), suggesting that oral biologics may be the future for psoriasis treatment, as this noninvasive delivery method may help improve patient compliance with treatment.

A major inflammatory pathway in psoriasis, IL-23 has been an effective and safe drug target. The novel oral IL-23 inhibitor, JNJ-2113, was discovered in 2017 and currently is being compared to deucravacitinib in the phase III ICONIC-LEAD trial (ClinicalTrials. gov Identifier NCT06095115) in patients with moderate to severe plaque psoriasis.^2,3 In the phase IIb FRONTIER 1 trial, treatment with either 3 once-daily (25 mg, 50 mg, 100 mg) and 2 twice-daily (25 mg, 100 mg) doses of JNJ-2113 led to significant improvements in PASI 75 response at 16 weeks compared to placebo (P<.001).⁴ In the phase IIb long-term extension FRONTIER 2 trial, JNJ-2113 maintained high rates of skin clearance through 52 weeks in adults with moderate to severe plaque psoriasis, with the highest PASI 75 response observed in the 100-mg twice-daily group (32/42 [76.2%]).⁵ Responses were maintained through week 52 for all JNJ-2113 treatment groups for PASI 90 and PASI 100 endpoints. In addition to ICONIC-LEAD, JNJ-2113 is being evaluated in the phase III multicenter, randomized, double-blind, placebo-controlled trial ICONIC-TOTAL (NCT06095102) in patients with special area psoriasis and ANTHEM-UC (NCT06049017) in patients with ulcerative colitis to evaluate its efficacy and safety. The most common adverse events associated with JNJ-77242113 were mild to moderate and included COVID-19 infection and nasopharyngitis.⁶ Higher rates of COVID-19 infection likely were due to immune compromise in the setting of the recent pandemic. Similar percentages of at least 1 adverse event were found in JNJ-77242113 and placebo groups (52%-58.6% and 51%-65.7%, respectively).^4,5,7

An orally administered small-molecule inhibitor of IL-17A, LY3509754, may represent a convenient alternative to IL-17A–targeting monoclonal antibodies. In a study of 91 participants,⁸ LY3509754 showed strong target engagement indicated by elevated plasma IL-17A levels within 12 hours of dosing. Despite strong target engagement and a pharmacokinetics profile that supports once-daily administration, this study showed that oral dosing with LY3509754 was poorly tolerated, as 4.4% (4/91) of participants (3 receiving 1000 mg once daily and 1 receiving 400 mg once daily) had increased liver transaminases or acute hepatitis (onset, ≥12 days following the last dose), which was consistent with drug-induced liver injury.⁸

The small potent molecule SAR441566 inhibits TNF-α by stabilizing an asymmetrical form of the soluble TNF trimer. As the asymmetrical trimer is the biologically active form of TNF-α, stabilization of the trimer compromises downstream signaling and inhibits the functions of TNF-α in vitro and in vivo. Recently, SAR441566 was found to be safe and well tolerated in healthy participants, showing efficacy in mild to moderate psoriasis in a phase Ib trial.⁹ A phase II trial of SAR441566 (NCT06073119) is being developed to create a more convenient orally bioavailable treatment option for patients with psoriasis compared to established biologic drugs targeting TNF-α.¹⁰

Few trials have focused on investigating the antipsoriatic effects of orally administered small molecules. Some of these small molecules can enter cells and inhibit the activation of T lymphocytes, leukocyte trafficking, leukotriene activity/production and angiogenesis, and promote apoptosis. Oral administration of small molecules is the future of effective and affordable psoriasis treatment, but safety and efficacy must first be assessed in clinical trials. JNJ-77242113 has shown a more promising safety profile, has recently undergone phase III trials, and may represent the newest wave for psoriasis treatment. While LY3509754 had a strong pharmacokinetics profile, it was poorly tolerated, and study participants' laboratory results suggested the drug to be hepatotoxic.⁸ SAR441566 has been shown to be safe and well tolerated in treating psoriasis, and phase II readouts are expected later in 2025. We can expect a new wave of psoriasis treatments with emerging oral therapies.

To the Editor:

UV light plays an essential role in various environmental and biological processes.¹ Excessive exposure to UV radiation can lead to sunburn, which is marked by skin erythema and pain.² A study of more than 31,000 individuals found that 34.2% of adults aged 18 years and older reported at least 1 sunburn during the survey year.³ A lack of research regarding the incidence of sunburns in patients with psoriasis is particularly important considering the heightened incidence of skin cancer observed in this population.⁴ Thus, the aim of our study was to analyze the prevalence of sunburns among US adults with psoriasis utilizing data from the National Health and Nutrition Examination Survey (NHANES) database.⁵

Our analysis initially included 11,842 participants ranging in age from 20 to 59 years; 35 did not respond to questions assessing psoriasis and sunburn prevalence and thus were excluded. Multivariable logistic regression analyses were performed using Stata/SE 18 (StataCorp LLC) to assess the relationship between psoriasis and sunburns. Our models controlled for patient age, sex, income, race, education, diabetes status, tobacco use, and body mass index. A P value <.05 was considered statistically significant. The study period from January 2009 to December 2014 was chosen based on the availability of the most recent and comprehensive psoriasis data within the NHANES database.

In the NHANES data we evaluated, psoriasis status was assessed by asking, “Have you ever been told by a doctor or other health professional that you had psoriasis?” History of sunburns in the survey year was assessed by the question, “How many times in the past year have you had sunburn?” Patients who reported 1 or more sunburns were included in the sunburn cohort, while those who did not report a sunburn were included in the no sunburn cohort.

In our analysis, the prevalence of at least 1 sunburn in the survey year in patients with psoriasis was 55.4% (weighted), compared to 45.6% (weighted) among those without psoriasis (eTable 1). Although there was no statistically significant relationship between psoriasis and history of sunburn in patients aged 20 to 59 years, a subgroup analysis revealed a significant association between psoriasis and sunburn in adults aged 20 to 39 years after adjusting for potential confounding variables (adjusted OR, 1.57 [95% CI, 1.00-2.45]; P=.049)(eTable 2). Further analysis of subgroups showed no statistically significant results with adjustment of the logistic regression model. Characterizing response rates is important for assessing the validity of survey studies. The NHANES response rate from 2009 to 2014 was 72.9%, enhancing the reliability of our findings.

Our study revealed an increased prevalence of sunburn in US adults with psoriasis. A trend of increased sunburn prevalence among younger adults regardless of psoriasis status is corroborated by the literature. Surveys conducted in the United States in 2005, 2010, and 2015 showed that 43% to 50% of adults aged 18 to 39 years and 28% to 42% of those aged 40 to 59 years reported experiencing at least 1 sunburn within the respective survey year.⁶ Furthermore, in our study, patients with psoriasis reported higher rates of sunburn than their counterparts without psoriasis, both in those aged 20 to 39 years (psoriasis, 62.8% [73/136]; no psoriasis, 51.1% [2425/5840]) and those aged 40 to 59 years (psoriasis, 50.5% [n=75/179]; no psoriasis, 40.2% [1613/5652]), though it was only statistically significant in the 20-to-39 age group. This discrepancy may be attributed to differences in sun-protective behaviors in younger vs older adults. A study from the NHANES database found that, among individuals aged 20 to 39 years, 75.9% [4225/5493] reported staying in the shade, 50.0% [2346/5493] reported using sunscreen, and 31.2% [1874/5493] reported wearing sun-protective clothing.⁷ Interestingly, the likelihood of engaging in all 3 behaviors was 28% lower in the 20-to-39 age group vs the 40-to-59 age group (adjusted OR, 0.72; 95% CI, 0.62-0.83).⁷

While our analysis adjusted for age, race/ethnicity, and tobacco use to mitigate potential confounding, we acknowledge the statistically significant differences observed in these variables between study groups as presented in eTable 2. These differences may reflect inherent disparities in the study population. We employed multivariable regression analysis to control for these covariates in our primary analyses. Of note, there was a statistically significant difference associated with race/ethnicity when comparing non-Hispanic White individuals with psoriasis (77.0% [n=182/315]) and those without psoriasis (62.5% [n=4516/11,492])(P<.0001)(eTable 1). The higher proportion of non-Hispanic White patients in the psoriasis group may reflect an increased susceptibility to sunburn given their typically lighter skin pigmentation; however, our analysis controlled for race/ethnicity (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of racial/ethnic differences. There also were statistically significant differences in tobacco use (P=.0026) and age (P=.002) in our unadjusted findings (eTable 1). Again, our analysis controlled for these factors (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of tobacco use and age differences. This approach enhanced the reliability of our findings.

The association between psoriasis and skin cancer has previously been evaluated using the NHANES database—one study found that patients with psoriasis had a significantly higher prevalence of nonmelanoma skin cancer compared with those without psoriasis (3.0% vs 1.3%; relative risk, 2.29; P<.001).⁸ This difference remained significant after adjusting for confounding variables, as it was found that psoriasis was independently associated with a 1.5-fold increased risk for nonmelanoma skin cancer (adjusted relative risk, 2.06; P=.004).⁸

The relationship between psoriasis and sunburn may be due to behavioral choices, such as the use of phototherapy for managing psoriasis due to its recognized advantages.⁹ Patients may seek out both artificial and natural light sources more frequently, potentially increasing the risk for sunburn.¹⁰ Psoriasis-related sunburn susceptibility may stem from biological factors, including vitamin D insufficiency, as vitamin D is crucial for keratinocyte differentiation, immune function, and UV protection and repair.¹¹ One study examined the effects of high-dose vitamin D3 on sunburn-induced inflammation.¹² Patients who received high-dose vitamin D3 exhibited reduced skin inflammation, enhanced skin barrier repair, and increased anti-inflammatory response compared with those who did not receive the supplement. This improvement was associated with upregulation of arginase 1, an anti-inflammatory enzyme, leading to decreased levels of pro-inflammatory mediators such as tumor necrosis factor α and inducible nitric oxide synthase, thereby promoting tissue repair and reducing prolonged inflammation.¹² These findings suggest that vitamin D insufficiency coupled with dysregulated immune responses may contribute to the heightened susceptibility of individuals with psoriasis to sunburn.

The established correlation between sunburn and skin cancer^4,8 coupled with our findings of increased prevalence of sunburn in individuals with psoriasis underscores the need for additional research to clarify the underlying biological and behavioral factors that may contribute to a higher prevalence of sunburn in these patients, along with the implications for skin cancer development. Limitations of our study included potential recall bias, as individuals self-reported their clinical conditions and the inability to incorporate psoriasis severity into our analysis, as this was not consistently captured in the NHANES questionnaire during the study period.

To the Editor:

UV light plays an essential role in various environmental and biological processes.¹ Excessive exposure to UV radiation can lead to sunburn, which is marked by skin erythema and pain.² A study of more than 31,000 individuals found that 34.2% of adults aged 18 years and older reported at least 1 sunburn during the survey year.³ A lack of research regarding the incidence of sunburns in patients with psoriasis is particularly important considering the heightened incidence of skin cancer observed in this population.⁴ Thus, the aim of our study was to analyze the prevalence of sunburns among US adults with psoriasis utilizing data from the National Health and Nutrition Examination Survey (NHANES) database.⁵

Our analysis initially included 11,842 participants ranging in age from 20 to 59 years; 35 did not respond to questions assessing psoriasis and sunburn prevalence and thus were excluded. Multivariable logistic regression analyses were performed using Stata/SE 18 (StataCorp LLC) to assess the relationship between psoriasis and sunburns. Our models controlled for patient age, sex, income, race, education, diabetes status, tobacco use, and body mass index. A P value <.05 was considered statistically significant. The study period from January 2009 to December 2014 was chosen based on the availability of the most recent and comprehensive psoriasis data within the NHANES database.

In the NHANES data we evaluated, psoriasis status was assessed by asking, “Have you ever been told by a doctor or other health professional that you had psoriasis?” History of sunburns in the survey year was assessed by the question, “How many times in the past year have you had sunburn?” Patients who reported 1 or more sunburns were included in the sunburn cohort, while those who did not report a sunburn were included in the no sunburn cohort.

In our analysis, the prevalence of at least 1 sunburn in the survey year in patients with psoriasis was 55.4% (weighted), compared to 45.6% (weighted) among those without psoriasis (eTable 1). Although there was no statistically significant relationship between psoriasis and history of sunburn in patients aged 20 to 59 years, a subgroup analysis revealed a significant association between psoriasis and sunburn in adults aged 20 to 39 years after adjusting for potential confounding variables (adjusted OR, 1.57 [95% CI, 1.00-2.45]; P=.049)(eTable 2). Further analysis of subgroups showed no statistically significant results with adjustment of the logistic regression model. Characterizing response rates is important for assessing the validity of survey studies. The NHANES response rate from 2009 to 2014 was 72.9%, enhancing the reliability of our findings.

Our study revealed an increased prevalence of sunburn in US adults with psoriasis. A trend of increased sunburn prevalence among younger adults regardless of psoriasis status is corroborated by the literature. Surveys conducted in the United States in 2005, 2010, and 2015 showed that 43% to 50% of adults aged 18 to 39 years and 28% to 42% of those aged 40 to 59 years reported experiencing at least 1 sunburn within the respective survey year.⁶ Furthermore, in our study, patients with psoriasis reported higher rates of sunburn than their counterparts without psoriasis, both in those aged 20 to 39 years (psoriasis, 62.8% [73/136]; no psoriasis, 51.1% [2425/5840]) and those aged 40 to 59 years (psoriasis, 50.5% [n=75/179]; no psoriasis, 40.2% [1613/5652]), though it was only statistically significant in the 20-to-39 age group. This discrepancy may be attributed to differences in sun-protective behaviors in younger vs older adults. A study from the NHANES database found that, among individuals aged 20 to 39 years, 75.9% [4225/5493] reported staying in the shade, 50.0% [2346/5493] reported using sunscreen, and 31.2% [1874/5493] reported wearing sun-protective clothing.⁷ Interestingly, the likelihood of engaging in all 3 behaviors was 28% lower in the 20-to-39 age group vs the 40-to-59 age group (adjusted OR, 0.72; 95% CI, 0.62-0.83).⁷

While our analysis adjusted for age, race/ethnicity, and tobacco use to mitigate potential confounding, we acknowledge the statistically significant differences observed in these variables between study groups as presented in eTable 2. These differences may reflect inherent disparities in the study population. We employed multivariable regression analysis to control for these covariates in our primary analyses. Of note, there was a statistically significant difference associated with race/ethnicity when comparing non-Hispanic White individuals with psoriasis (77.0% [n=182/315]) and those without psoriasis (62.5% [n=4516/11,492])(P<.0001)(eTable 1). The higher proportion of non-Hispanic White patients in the psoriasis group may reflect an increased susceptibility to sunburn given their typically lighter skin pigmentation; however, our analysis controlled for race/ethnicity (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of racial/ethnic differences. There also were statistically significant differences in tobacco use (P=.0026) and age (P=.002) in our unadjusted findings (eTable 1). Again, our analysis controlled for these factors (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of tobacco use and age differences. This approach enhanced the reliability of our findings.

The association between psoriasis and skin cancer has previously been evaluated using the NHANES database—one study found that patients with psoriasis had a significantly higher prevalence of nonmelanoma skin cancer compared with those without psoriasis (3.0% vs 1.3%; relative risk, 2.29; P<.001).⁸ This difference remained significant after adjusting for confounding variables, as it was found that psoriasis was independently associated with a 1.5-fold increased risk for nonmelanoma skin cancer (adjusted relative risk, 2.06; P=.004).⁸

The relationship between psoriasis and sunburn may be due to behavioral choices, such as the use of phototherapy for managing psoriasis due to its recognized advantages.⁹ Patients may seek out both artificial and natural light sources more frequently, potentially increasing the risk for sunburn.¹⁰ Psoriasis-related sunburn susceptibility may stem from biological factors, including vitamin D insufficiency, as vitamin D is crucial for keratinocyte differentiation, immune function, and UV protection and repair.¹¹ One study examined the effects of high-dose vitamin D3 on sunburn-induced inflammation.¹² Patients who received high-dose vitamin D3 exhibited reduced skin inflammation, enhanced skin barrier repair, and increased anti-inflammatory response compared with those who did not receive the supplement. This improvement was associated with upregulation of arginase 1, an anti-inflammatory enzyme, leading to decreased levels of pro-inflammatory mediators such as tumor necrosis factor α and inducible nitric oxide synthase, thereby promoting tissue repair and reducing prolonged inflammation.¹² These findings suggest that vitamin D insufficiency coupled with dysregulated immune responses may contribute to the heightened susceptibility of individuals with psoriasis to sunburn.

The established correlation between sunburn and skin cancer^4,8 coupled with our findings of increased prevalence of sunburn in individuals with psoriasis underscores the need for additional research to clarify the underlying biological and behavioral factors that may contribute to a higher prevalence of sunburn in these patients, along with the implications for skin cancer development. Limitations of our study included potential recall bias, as individuals self-reported their clinical conditions and the inability to incorporate psoriasis severity into our analysis, as this was not consistently captured in the NHANES questionnaire during the study period.

To the Editor:

UV light plays an essential role in various environmental and biological processes.¹ Excessive exposure to UV radiation can lead to sunburn, which is marked by skin erythema and pain.² A study of more than 31,000 individuals found that 34.2% of adults aged 18 years and older reported at least 1 sunburn during the survey year.³ A lack of research regarding the incidence of sunburns in patients with psoriasis is particularly important considering the heightened incidence of skin cancer observed in this population.⁴ Thus, the aim of our study was to analyze the prevalence of sunburns among US adults with psoriasis utilizing data from the National Health and Nutrition Examination Survey (NHANES) database.⁵

Our analysis initially included 11,842 participants ranging in age from 20 to 59 years; 35 did not respond to questions assessing psoriasis and sunburn prevalence and thus were excluded. Multivariable logistic regression analyses were performed using Stata/SE 18 (StataCorp LLC) to assess the relationship between psoriasis and sunburns. Our models controlled for patient age, sex, income, race, education, diabetes status, tobacco use, and body mass index. A P value <.05 was considered statistically significant. The study period from January 2009 to December 2014 was chosen based on the availability of the most recent and comprehensive psoriasis data within the NHANES database.

In the NHANES data we evaluated, psoriasis status was assessed by asking, “Have you ever been told by a doctor or other health professional that you had psoriasis?” History of sunburns in the survey year was assessed by the question, “How many times in the past year have you had sunburn?” Patients who reported 1 or more sunburns were included in the sunburn cohort, while those who did not report a sunburn were included in the no sunburn cohort.

In our analysis, the prevalence of at least 1 sunburn in the survey year in patients with psoriasis was 55.4% (weighted), compared to 45.6% (weighted) among those without psoriasis (eTable 1). Although there was no statistically significant relationship between psoriasis and history of sunburn in patients aged 20 to 59 years, a subgroup analysis revealed a significant association between psoriasis and sunburn in adults aged 20 to 39 years after adjusting for potential confounding variables (adjusted OR, 1.57 [95% CI, 1.00-2.45]; P=.049)(eTable 2). Further analysis of subgroups showed no statistically significant results with adjustment of the logistic regression model. Characterizing response rates is important for assessing the validity of survey studies. The NHANES response rate from 2009 to 2014 was 72.9%, enhancing the reliability of our findings.

Our study revealed an increased prevalence of sunburn in US adults with psoriasis. A trend of increased sunburn prevalence among younger adults regardless of psoriasis status is corroborated by the literature. Surveys conducted in the United States in 2005, 2010, and 2015 showed that 43% to 50% of adults aged 18 to 39 years and 28% to 42% of those aged 40 to 59 years reported experiencing at least 1 sunburn within the respective survey year.⁶ Furthermore, in our study, patients with psoriasis reported higher rates of sunburn than their counterparts without psoriasis, both in those aged 20 to 39 years (psoriasis, 62.8% [73/136]; no psoriasis, 51.1% [2425/5840]) and those aged 40 to 59 years (psoriasis, 50.5% [n=75/179]; no psoriasis, 40.2% [1613/5652]), though it was only statistically significant in the 20-to-39 age group. This discrepancy may be attributed to differences in sun-protective behaviors in younger vs older adults. A study from the NHANES database found that, among individuals aged 20 to 39 years, 75.9% [4225/5493] reported staying in the shade, 50.0% [2346/5493] reported using sunscreen, and 31.2% [1874/5493] reported wearing sun-protective clothing.⁷ Interestingly, the likelihood of engaging in all 3 behaviors was 28% lower in the 20-to-39 age group vs the 40-to-59 age group (adjusted OR, 0.72; 95% CI, 0.62-0.83).⁷

While our analysis adjusted for age, race/ethnicity, and tobacco use to mitigate potential confounding, we acknowledge the statistically significant differences observed in these variables between study groups as presented in eTable 2. These differences may reflect inherent disparities in the study population. We employed multivariable regression analysis to control for these covariates in our primary analyses. Of note, there was a statistically significant difference associated with race/ethnicity when comparing non-Hispanic White individuals with psoriasis (77.0% [n=182/315]) and those without psoriasis (62.5% [n=4516/11,492])(P<.0001)(eTable 1). The higher proportion of non-Hispanic White patients in the psoriasis group may reflect an increased susceptibility to sunburn given their typically lighter skin pigmentation; however, our analysis controlled for race/ethnicity (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of racial/ethnic differences. There also were statistically significant differences in tobacco use (P=.0026) and age (P=.002) in our unadjusted findings (eTable 1). Again, our analysis controlled for these factors (eTable 2), thereby allowing us to isolate the effect of psoriasis on sunburn prevalence independent of tobacco use and age differences. This approach enhanced the reliability of our findings.

The association between psoriasis and skin cancer has previously been evaluated using the NHANES database—one study found that patients with psoriasis had a significantly higher prevalence of nonmelanoma skin cancer compared with those without psoriasis (3.0% vs 1.3%; relative risk, 2.29; P<.001).⁸ This difference remained significant after adjusting for confounding variables, as it was found that psoriasis was independently associated with a 1.5-fold increased risk for nonmelanoma skin cancer (adjusted relative risk, 2.06; P=.004).⁸

The relationship between psoriasis and sunburn may be due to behavioral choices, such as the use of phototherapy for managing psoriasis due to its recognized advantages.⁹ Patients may seek out both artificial and natural light sources more frequently, potentially increasing the risk for sunburn.¹⁰ Psoriasis-related sunburn susceptibility may stem from biological factors, including vitamin D insufficiency, as vitamin D is crucial for keratinocyte differentiation, immune function, and UV protection and repair.¹¹ One study examined the effects of high-dose vitamin D3 on sunburn-induced inflammation.¹² Patients who received high-dose vitamin D3 exhibited reduced skin inflammation, enhanced skin barrier repair, and increased anti-inflammatory response compared with those who did not receive the supplement. This improvement was associated with upregulation of arginase 1, an anti-inflammatory enzyme, leading to decreased levels of pro-inflammatory mediators such as tumor necrosis factor α and inducible nitric oxide synthase, thereby promoting tissue repair and reducing prolonged inflammation.¹² These findings suggest that vitamin D insufficiency coupled with dysregulated immune responses may contribute to the heightened susceptibility of individuals with psoriasis to sunburn.

The established correlation between sunburn and skin cancer^4,8 coupled with our findings of increased prevalence of sunburn in individuals with psoriasis underscores the need for additional research to clarify the underlying biological and behavioral factors that may contribute to a higher prevalence of sunburn in these patients, along with the implications for skin cancer development. Limitations of our study included potential recall bias, as individuals self-reported their clinical conditions and the inability to incorporate psoriasis severity into our analysis, as this was not consistently captured in the NHANES questionnaire during the study period.

Psoriasis treatments have come a long way in the past 20 years. We now have more than a dozen systemic targeted treatments for psoriatic disease, with more on the way; however, with each successive class of medications introduced, the gap has narrowed in terms of increasing efficacy. In an era of medications reporting complete clearance rates in the 70% range, the average improvement in Psoriasis Area and Severity Index (PASI) for most biologics has remained at 90% to 95% in the past half-decade. While this is a far cry from the mean PASI improvements of 70% seen with the first biologics,¹ it is becoming more challenging to base our treatment decisions solely on PASI outcome measures.

How, then, do we approach rational selection of a systemic psoriasis treatment? We could try to delineate based on mechanism of action, but it may be disingenuous to dissect minor differences in pathways (eg, IL-17 vs IL-23) that are fundamentally related and on the same continuum in psoriasis pathophysiology. Therefore, the most meaningful way to select an appropriate therapeutic may be to adopt a patient-centered approach that accounts for both individual preferences and specific medical needs by evaluating for other comorbidities² to exclude or select certain medicines or types of treatments. We have long known to avoid tumor necrosis factor (TNF) α inhibitors in patients with congestive heart failure or a history of demyelinating disorders while regularly considering the presence of psoriatic arthritis and family planning when making treatment decisions. Now, we can be more nuanced in our approaches to psoriasis biologics. Specifically, the most important comorbidities to consider broadly encompass cardiometabolic disorders, gastrointestinal conditions, and psychiatric conditions.

Cardiometabolic Disorders

Possibly the hottest topic in psoriasis for some years now, the relationship between cardiometabolic disorders and psoriasis is of great interest to clinicians, scientists, and patients alike. There is a clear link between development of atherosclerosis and Th17-related immune mechanisms that also are implicated in the pathogenesis of psoriasis.³ Furthermore, the incidence of cardiovascular disease is markedly increased in patients with psoriasis, which is an independent risk factor for myocardial infarction, particularly among younger patients.^4,5 Although several retrospective studies^6-8 have shown that TNF-α inhibitors are associated with a reduction in cardiovascular outcomes, it is yet to be seen whether biologic treatment actually has a direct impact on cardiovascular outcomes, multiple studies investigating the effect of biologics on arterial inflammation markers notwithstanding.⁹

There are some direct factors to keep in mind when considering cardiometabolic comorbidities in patients with psoriasis. Obesity is common in the psoriasis population and can have a direct negative effect on cardiovascular health.¹⁰ However, the data on obesity and psoriasis are somewhat mixed with regard to treatment outcomes. In general, with increased volumes of distribution for biologics in patients with obesity, it has been shown that treatment success is more difficult to achieve in those with a body mass index greater than 30.¹¹ Rather surprisingly, a separate nationwide study in South Korea found that patients on biologics for psoriasis were more likely to experience weight gain, even after controlling for factors such as exercise, smoking, and drinking,¹² but it is unclear whether this is driven mostly by a known connection between weight gain and TNF-α inhibitors.¹³ These contrasting results point to the need for further studies in this area, as our intuitive approach would involve promoting weight loss while starting on a systemic treatment for psoriasis—but perhaps it is important not to assume that one will come with the other in tow, reinforcing the need to discuss a healthy diet with our patients with psoriasis regardless of treatment decisions.

The data that we have do not directly answer the big questions about biologic treatment and cardiovascular health, but we are starting to see interesting signals. For example, in a report of tildrakizumab treatment in patients with and without metabolic syndrome, the rates of major adverse cardiovascular events as well as cardiac disorders were essentially the same in both groups after receiving treatment for up to 244 weeks.¹⁴ This is interesting, more because of the lack of an increase in cardiovascular adverse events in the metabolic syndrome group, who entered the trial on average 25 kg to 30 kg heavier than those without metabolic syndrome. There is an increased risk for adverse cardiovascular events among patients with metabolic syndrome, a roughly 2-fold relative risk in as few as 5 to 6 years of follow-up.¹⁵ While the cohorts in the tildrakizumab study¹⁴ were too small to draw firm conclusions, the data are interesting and a step in the right direction; we need much larger data sets for analysis. Among other agents, similar efficacy and safety have been reported for guselkumab in a long-term psoriasis study; as a class, IL-23 inhibitors also tend to perform well from an efficacy standpoint in patients with obesity.¹⁶

Overall, when assessing the evidence for cardiometabolic disorders, it is reasonable to consider starting a biologic from the IL-17 or IL-23 inhibitor classes— thus avoiding both the potential downside of weight gain and contraindication in patients with congestive heart failure associated with TNF-α inhibitors. It is important to counsel patients about weight loss in conjunction with these treatments, both to improve efficacy and reduce cardiovascular risk factors. There may be a preference for IL-23 inhibitors in patients with obesity, as this class of medications maintains efficacy particularly well in these patients. Patients with psoriasis should be counseled to follow up with a primary care physician given their higher risk for metabolic syndrome and adverse cardiovascular outcomes.

Gastrointestinal Conditions

Psoriasis and inflammatory bowel disease (IBD) have a bidirectional association, and patients with psoriasis are about 1.7 times more likely to have either Crohn disease or ulcerative colitis.^17,18 This association may be related to a shared pathogenesis with regard to immune dysregulation and overactivated inflammatory pathways, but there are some important differences to consider from a therapeutic standpoint. Given the increased expression of IL-17 in patients with IBD,¹⁹ a phase II trial of secukinumab yielded surprising results—not only was secukinumab ineffective in treating Crohn disease, but there also were higher rates of adverse events²⁰ (as noted on the product label for all IL-17 inhibitors). We have come to understand that there are regulatory subsets of IL-17 cells that are important in mucosal homeostasis and also regulate IL-10, which generally is considered an anti-inflammatory cytokine.²¹ Thus, while IL-17 inhibition can reduce some component of inflammatory signaling, it also can increase inflammatory signaling through indirect pathways while increasing intestinal permeability to microbes. Importantly, this process seems to occur via IL-23–independent pathways; as such, while direct inhibition of IL-17 can be deleterious, IL-23 inhibitors have become important therapeutics for IBD.²²

IL-17 family, IL-17A clearly is the culprit for worsening colitis as evidenced by both human and animal models. On the contrary, IL-17F blockade has been shown to ameliorate colitis in a murine model, whereas IL-17A inhibition worsens it.²³ Furthermore, dual blockade of IL-17A and IL-17F has a protective effect against colitis, suggesting that the IL-17F inhibition is dominant. This interesting finding has some mechanistic backing, since blockade of IL-17F induces Treg cells that serve to maintain gut epithelium homeostasis and integrity.²⁴

Overall, IL-17A inhibitors should be avoided in patients with a history of IBD—namely, secukinumab and ixekizumab. While there may be theoretical reasons that brodalumab or bimekizumab may confer a somewhat different risk for IBD exacerbation, there may be better choices that would be expected to effectively treat both the psoriasis and IBD manifestations. Given the US Food and Drug Administration approval of IL-23 inhibitors for IBD and their high levels of efficacy in treating psoriasis, these likely will be the best choice for most patients. Another mainstay of IBD treatment is TNF-α inhibitors, but they come with other risks such as increased immunosuppression and increased risk for nonmelanoma skin cancer.

An important question remains: What about patients who do not have known IBD? Do we proactively change our treatment choice due to fear of IBD development given the higher incidence of both Crohn disease and ulcerative colitis in patients with psoriasis? What about patients with a family history of IBD? First-degree relatives of patients with Crohn disease and ulcerative colitis have an 8- and 4-fold higher risk for those same conditions, respectively.²⁵ Postmarketing surveillance and database findings of low rates of IBD development with IL-17 inhibitors gives only modest reassurance, as dermatologists generally know to avoid these medications for patients with even questionable IBD symptoms. It is important to emphasize to our patients that in no case do we believe that a psoriasis medication actually will cause IBD—rather, someone with subclinical IBD could experience a flare and a first manifestation of colitis. The drug is not the culprit in inducing IBD but rather may serve to unmask existing disease.

One study suggested that for patients who move on to the IL-17 inhibitor secukinumab after being treated with TNF-α inhibitors for psoriasis, the rates of IBD development are higher (4.8%) than in those who start IL-17A inhibition without prior treatment (1%)(OR, 8.38; P=.018).²⁶ This begs the question of whether subclinical IBD in many patients with psoriasis who are treated with TNF-α inhibitors can be unmasked later when they are transitioned to a treatment that either does not treat the IBD or could worsen it. There may be a mechanistic drive behind this sequencing of treatments that predisposes patients to colitis, which would suggest selecting an IL-23 inhibitor after failing/trying a TNF-α inhibitor. However, the data are very preliminary, and in real practice, other concerns such as severe psoriatic arthritis may outweigh these considerations, as the IL-17 inhibitor class still is considered to be more effective than IL-23 inhibition at treating psoriatic arthritis overall. For most patients with no personal history of IBD and no strong family history of IBD (ie, first-degree relatives), the choice of biologic should not be affected by concern over gastrointestinal issues.

Psychiatric Conditions

It has been well established that psoriasis is linked to higher rates of depression, anxiety, and suicidality.²⁷ How do we take this into account when treating patients with psoriasis, especially when we have biologics with a warning label for suicidality and a Risk Evaluation and Mitigation Strategies program (brodalumab) and language around suicidal ideation in the label (bimekizumab)? While it is challenging to discuss mental health, it is not a conversation that we as dermatologists should shy away from. Appropriate treatment of psoriasis is an important tool to get our patients on the path to better mental health. A recent database study of more than 4000 patients showed that patients with psoriasis treated with biologics had a 17% lower risk for depression than those treated with conventional disease-modifying drugs such as methotrexate.²⁸ The comparator of the conventional disease-modifying drug class is important as it serves as a control for disease severity. Too often, a higher rate of depression, anxiety, or suicidality can be attributed to a medication when we in fact may just be capturing the background of higher incidence of all 3 in patients with severe psoriasis.

Indeed, even with the medication that many worry about on this front (brodalumab), multiple studies have confirmed that the effect on mental health generally is a positive one, with decreases in depressive symptoms.²⁹ In a cohort switched from TNF-α inhibitors to brodalumab, symptoms of depression actually improved,³⁰ so attributing a direct treatment effect to negative mental health outcomes does not seem to be justified, especially in light of the low number of suicide events in global postmarketing surveillance for brodalumab, comparable to or lower than other biologics for psoriasis.³¹ Similarly, bimekizumab has language in the label about discussing suicidality with patients, although the rates of suicidal ideation and behavior are no different from other biologics and rates of depression improved with its use.³²

Heightened awareness of our patients’ mental health is something that we as providers should embrace, even when it seems that we do not have much time to see each patient. The priority when a patient comes in with mental health symptoms should be to treat what is within our scope (ie, psoriasis) as quickly and effectively as possible— with a newer-generation biologic such as an IL-17 or IL-23 inhibitor—while encouraging the patient to seek care from a mental health professional. In these cases, one might even argue that the rapidity of action of IL-17 inhibitors may be of additional benefit.

Final Thoughts

We as dermatologists generally are tasked with seeing high volumes of patients, and an initial psoriasis consultation can be a lengthy visit; however, it is rewarding to establish this relationship with patients and a reminder of why we practice medicine to begin with. Psoriasis can be satisfying to treat, and we have so many highly effective medicines that can completely transform our patients’ lives. Applying an understanding of the interplay between psoriasis, its related comorbidities, and treatment choices can be a fulfilling exercise that captures the essence of shared decision-making, which can lead to better outcomes and satisfaction for both providers and patients.

Psoriasis treatments have come a long way in the past 20 years. We now have more than a dozen systemic targeted treatments for psoriatic disease, with more on the way; however, with each successive class of medications introduced, the gap has narrowed in terms of increasing efficacy. In an era of medications reporting complete clearance rates in the 70% range, the average improvement in Psoriasis Area and Severity Index (PASI) for most biologics has remained at 90% to 95% in the past half-decade. While this is a far cry from the mean PASI improvements of 70% seen with the first biologics,¹ it is becoming more challenging to base our treatment decisions solely on PASI outcome measures.

How, then, do we approach rational selection of a systemic psoriasis treatment? We could try to delineate based on mechanism of action, but it may be disingenuous to dissect minor differences in pathways (eg, IL-17 vs IL-23) that are fundamentally related and on the same continuum in psoriasis pathophysiology. Therefore, the most meaningful way to select an appropriate therapeutic may be to adopt a patient-centered approach that accounts for both individual preferences and specific medical needs by evaluating for other comorbidities² to exclude or select certain medicines or types of treatments. We have long known to avoid tumor necrosis factor (TNF) α inhibitors in patients with congestive heart failure or a history of demyelinating disorders while regularly considering the presence of psoriatic arthritis and family planning when making treatment decisions. Now, we can be more nuanced in our approaches to psoriasis biologics. Specifically, the most important comorbidities to consider broadly encompass cardiometabolic disorders, gastrointestinal conditions, and psychiatric conditions.

Cardiometabolic Disorders

Possibly the hottest topic in psoriasis for some years now, the relationship between cardiometabolic disorders and psoriasis is of great interest to clinicians, scientists, and patients alike. There is a clear link between development of atherosclerosis and Th17-related immune mechanisms that also are implicated in the pathogenesis of psoriasis.³ Furthermore, the incidence of cardiovascular disease is markedly increased in patients with psoriasis, which is an independent risk factor for myocardial infarction, particularly among younger patients.^4,5 Although several retrospective studies^6-8 have shown that TNF-α inhibitors are associated with a reduction in cardiovascular outcomes, it is yet to be seen whether biologic treatment actually has a direct impact on cardiovascular outcomes, multiple studies investigating the effect of biologics on arterial inflammation markers notwithstanding.⁹

There are some direct factors to keep in mind when considering cardiometabolic comorbidities in patients with psoriasis. Obesity is common in the psoriasis population and can have a direct negative effect on cardiovascular health.¹⁰ However, the data on obesity and psoriasis are somewhat mixed with regard to treatment outcomes. In general, with increased volumes of distribution for biologics in patients with obesity, it has been shown that treatment success is more difficult to achieve in those with a body mass index greater than 30.¹¹ Rather surprisingly, a separate nationwide study in South Korea found that patients on biologics for psoriasis were more likely to experience weight gain, even after controlling for factors such as exercise, smoking, and drinking,¹² but it is unclear whether this is driven mostly by a known connection between weight gain and TNF-α inhibitors.¹³ These contrasting results point to the need for further studies in this area, as our intuitive approach would involve promoting weight loss while starting on a systemic treatment for psoriasis—but perhaps it is important not to assume that one will come with the other in tow, reinforcing the need to discuss a healthy diet with our patients with psoriasis regardless of treatment decisions.

The data that we have do not directly answer the big questions about biologic treatment and cardiovascular health, but we are starting to see interesting signals. For example, in a report of tildrakizumab treatment in patients with and without metabolic syndrome, the rates of major adverse cardiovascular events as well as cardiac disorders were essentially the same in both groups after receiving treatment for up to 244 weeks.¹⁴ This is interesting, more because of the lack of an increase in cardiovascular adverse events in the metabolic syndrome group, who entered the trial on average 25 kg to 30 kg heavier than those without metabolic syndrome. There is an increased risk for adverse cardiovascular events among patients with metabolic syndrome, a roughly 2-fold relative risk in as few as 5 to 6 years of follow-up.¹⁵ While the cohorts in the tildrakizumab study¹⁴ were too small to draw firm conclusions, the data are interesting and a step in the right direction; we need much larger data sets for analysis. Among other agents, similar efficacy and safety have been reported for guselkumab in a long-term psoriasis study; as a class, IL-23 inhibitors also tend to perform well from an efficacy standpoint in patients with obesity.¹⁶

Overall, when assessing the evidence for cardiometabolic disorders, it is reasonable to consider starting a biologic from the IL-17 or IL-23 inhibitor classes— thus avoiding both the potential downside of weight gain and contraindication in patients with congestive heart failure associated with TNF-α inhibitors. It is important to counsel patients about weight loss in conjunction with these treatments, both to improve efficacy and reduce cardiovascular risk factors. There may be a preference for IL-23 inhibitors in patients with obesity, as this class of medications maintains efficacy particularly well in these patients. Patients with psoriasis should be counseled to follow up with a primary care physician given their higher risk for metabolic syndrome and adverse cardiovascular outcomes.

Gastrointestinal Conditions

Psoriasis and inflammatory bowel disease (IBD) have a bidirectional association, and patients with psoriasis are about 1.7 times more likely to have either Crohn disease or ulcerative colitis.^17,18 This association may be related to a shared pathogenesis with regard to immune dysregulation and overactivated inflammatory pathways, but there are some important differences to consider from a therapeutic standpoint. Given the increased expression of IL-17 in patients with IBD,¹⁹ a phase II trial of secukinumab yielded surprising results—not only was secukinumab ineffective in treating Crohn disease, but there also were higher rates of adverse events²⁰ (as noted on the product label for all IL-17 inhibitors). We have come to understand that there are regulatory subsets of IL-17 cells that are important in mucosal homeostasis and also regulate IL-10, which generally is considered an anti-inflammatory cytokine.²¹ Thus, while IL-17 inhibition can reduce some component of inflammatory signaling, it also can increase inflammatory signaling through indirect pathways while increasing intestinal permeability to microbes. Importantly, this process seems to occur via IL-23–independent pathways; as such, while direct inhibition of IL-17 can be deleterious, IL-23 inhibitors have become important therapeutics for IBD.²²

IL-17 family, IL-17A clearly is the culprit for worsening colitis as evidenced by both human and animal models. On the contrary, IL-17F blockade has been shown to ameliorate colitis in a murine model, whereas IL-17A inhibition worsens it.²³ Furthermore, dual blockade of IL-17A and IL-17F has a protective effect against colitis, suggesting that the IL-17F inhibition is dominant. This interesting finding has some mechanistic backing, since blockade of IL-17F induces Treg cells that serve to maintain gut epithelium homeostasis and integrity.²⁴

Overall, IL-17A inhibitors should be avoided in patients with a history of IBD—namely, secukinumab and ixekizumab. While there may be theoretical reasons that brodalumab or bimekizumab may confer a somewhat different risk for IBD exacerbation, there may be better choices that would be expected to effectively treat both the psoriasis and IBD manifestations. Given the US Food and Drug Administration approval of IL-23 inhibitors for IBD and their high levels of efficacy in treating psoriasis, these likely will be the best choice for most patients. Another mainstay of IBD treatment is TNF-α inhibitors, but they come with other risks such as increased immunosuppression and increased risk for nonmelanoma skin cancer.

An important question remains: What about patients who do not have known IBD? Do we proactively change our treatment choice due to fear of IBD development given the higher incidence of both Crohn disease and ulcerative colitis in patients with psoriasis? What about patients with a family history of IBD? First-degree relatives of patients with Crohn disease and ulcerative colitis have an 8- and 4-fold higher risk for those same conditions, respectively.²⁵ Postmarketing surveillance and database findings of low rates of IBD development with IL-17 inhibitors gives only modest reassurance, as dermatologists generally know to avoid these medications for patients with even questionable IBD symptoms. It is important to emphasize to our patients that in no case do we believe that a psoriasis medication actually will cause IBD—rather, someone with subclinical IBD could experience a flare and a first manifestation of colitis. The drug is not the culprit in inducing IBD but rather may serve to unmask existing disease.

One study suggested that for patients who move on to the IL-17 inhibitor secukinumab after being treated with TNF-α inhibitors for psoriasis, the rates of IBD development are higher (4.8%) than in those who start IL-17A inhibition without prior treatment (1%)(OR, 8.38; P=.018).²⁶ This begs the question of whether subclinical IBD in many patients with psoriasis who are treated with TNF-α inhibitors can be unmasked later when they are transitioned to a treatment that either does not treat the IBD or could worsen it. There may be a mechanistic drive behind this sequencing of treatments that predisposes patients to colitis, which would suggest selecting an IL-23 inhibitor after failing/trying a TNF-α inhibitor. However, the data are very preliminary, and in real practice, other concerns such as severe psoriatic arthritis may outweigh these considerations, as the IL-17 inhibitor class still is considered to be more effective than IL-23 inhibition at treating psoriatic arthritis overall. For most patients with no personal history of IBD and no strong family history of IBD (ie, first-degree relatives), the choice of biologic should not be affected by concern over gastrointestinal issues.

Psychiatric Conditions

It has been well established that psoriasis is linked to higher rates of depression, anxiety, and suicidality.²⁷ How do we take this into account when treating patients with psoriasis, especially when we have biologics with a warning label for suicidality and a Risk Evaluation and Mitigation Strategies program (brodalumab) and language around suicidal ideation in the label (bimekizumab)? While it is challenging to discuss mental health, it is not a conversation that we as dermatologists should shy away from. Appropriate treatment of psoriasis is an important tool to get our patients on the path to better mental health. A recent database study of more than 4000 patients showed that patients with psoriasis treated with biologics had a 17% lower risk for depression than those treated with conventional disease-modifying drugs such as methotrexate.²⁸ The comparator of the conventional disease-modifying drug class is important as it serves as a control for disease severity. Too often, a higher rate of depression, anxiety, or suicidality can be attributed to a medication when we in fact may just be capturing the background of higher incidence of all 3 in patients with severe psoriasis.

Indeed, even with the medication that many worry about on this front (brodalumab), multiple studies have confirmed that the effect on mental health generally is a positive one, with decreases in depressive symptoms.²⁹ In a cohort switched from TNF-α inhibitors to brodalumab, symptoms of depression actually improved,³⁰ so attributing a direct treatment effect to negative mental health outcomes does not seem to be justified, especially in light of the low number of suicide events in global postmarketing surveillance for brodalumab, comparable to or lower than other biologics for psoriasis.³¹ Similarly, bimekizumab has language in the label about discussing suicidality with patients, although the rates of suicidal ideation and behavior are no different from other biologics and rates of depression improved with its use.³²

Heightened awareness of our patients’ mental health is something that we as providers should embrace, even when it seems that we do not have much time to see each patient. The priority when a patient comes in with mental health symptoms should be to treat what is within our scope (ie, psoriasis) as quickly and effectively as possible— with a newer-generation biologic such as an IL-17 or IL-23 inhibitor—while encouraging the patient to seek care from a mental health professional. In these cases, one might even argue that the rapidity of action of IL-17 inhibitors may be of additional benefit.

Final Thoughts

We as dermatologists generally are tasked with seeing high volumes of patients, and an initial psoriasis consultation can be a lengthy visit; however, it is rewarding to establish this relationship with patients and a reminder of why we practice medicine to begin with. Psoriasis can be satisfying to treat, and we have so many highly effective medicines that can completely transform our patients’ lives. Applying an understanding of the interplay between psoriasis, its related comorbidities, and treatment choices can be a fulfilling exercise that captures the essence of shared decision-making, which can lead to better outcomes and satisfaction for both providers and patients.

Psoriasis treatments have come a long way in the past 20 years. We now have more than a dozen systemic targeted treatments for psoriatic disease, with more on the way; however, with each successive class of medications introduced, the gap has narrowed in terms of increasing efficacy. In an era of medications reporting complete clearance rates in the 70% range, the average improvement in Psoriasis Area and Severity Index (PASI) for most biologics has remained at 90% to 95% in the past half-decade. While this is a far cry from the mean PASI improvements of 70% seen with the first biologics,¹ it is becoming more challenging to base our treatment decisions solely on PASI outcome measures.

How, then, do we approach rational selection of a systemic psoriasis treatment? We could try to delineate based on mechanism of action, but it may be disingenuous to dissect minor differences in pathways (eg, IL-17 vs IL-23) that are fundamentally related and on the same continuum in psoriasis pathophysiology. Therefore, the most meaningful way to select an appropriate therapeutic may be to adopt a patient-centered approach that accounts for both individual preferences and specific medical needs by evaluating for other comorbidities² to exclude or select certain medicines or types of treatments. We have long known to avoid tumor necrosis factor (TNF) α inhibitors in patients with congestive heart failure or a history of demyelinating disorders while regularly considering the presence of psoriatic arthritis and family planning when making treatment decisions. Now, we can be more nuanced in our approaches to psoriasis biologics. Specifically, the most important comorbidities to consider broadly encompass cardiometabolic disorders, gastrointestinal conditions, and psychiatric conditions.

Cardiometabolic Disorders

Possibly the hottest topic in psoriasis for some years now, the relationship between cardiometabolic disorders and psoriasis is of great interest to clinicians, scientists, and patients alike. There is a clear link between development of atherosclerosis and Th17-related immune mechanisms that also are implicated in the pathogenesis of psoriasis.³ Furthermore, the incidence of cardiovascular disease is markedly increased in patients with psoriasis, which is an independent risk factor for myocardial infarction, particularly among younger patients.^4,5 Although several retrospective studies^6-8 have shown that TNF-α inhibitors are associated with a reduction in cardiovascular outcomes, it is yet to be seen whether biologic treatment actually has a direct impact on cardiovascular outcomes, multiple studies investigating the effect of biologics on arterial inflammation markers notwithstanding.⁹

There are some direct factors to keep in mind when considering cardiometabolic comorbidities in patients with psoriasis. Obesity is common in the psoriasis population and can have a direct negative effect on cardiovascular health.¹⁰ However, the data on obesity and psoriasis are somewhat mixed with regard to treatment outcomes. In general, with increased volumes of distribution for biologics in patients with obesity, it has been shown that treatment success is more difficult to achieve in those with a body mass index greater than 30.¹¹ Rather surprisingly, a separate nationwide study in South Korea found that patients on biologics for psoriasis were more likely to experience weight gain, even after controlling for factors such as exercise, smoking, and drinking,¹² but it is unclear whether this is driven mostly by a known connection between weight gain and TNF-α inhibitors.¹³ These contrasting results point to the need for further studies in this area, as our intuitive approach would involve promoting weight loss while starting on a systemic treatment for psoriasis—but perhaps it is important not to assume that one will come with the other in tow, reinforcing the need to discuss a healthy diet with our patients with psoriasis regardless of treatment decisions.

The data that we have do not directly answer the big questions about biologic treatment and cardiovascular health, but we are starting to see interesting signals. For example, in a report of tildrakizumab treatment in patients with and without metabolic syndrome, the rates of major adverse cardiovascular events as well as cardiac disorders were essentially the same in both groups after receiving treatment for up to 244 weeks.¹⁴ This is interesting, more because of the lack of an increase in cardiovascular adverse events in the metabolic syndrome group, who entered the trial on average 25 kg to 30 kg heavier than those without metabolic syndrome. There is an increased risk for adverse cardiovascular events among patients with metabolic syndrome, a roughly 2-fold relative risk in as few as 5 to 6 years of follow-up.¹⁵ While the cohorts in the tildrakizumab study¹⁴ were too small to draw firm conclusions, the data are interesting and a step in the right direction; we need much larger data sets for analysis. Among other agents, similar efficacy and safety have been reported for guselkumab in a long-term psoriasis study; as a class, IL-23 inhibitors also tend to perform well from an efficacy standpoint in patients with obesity.¹⁶

Overall, when assessing the evidence for cardiometabolic disorders, it is reasonable to consider starting a biologic from the IL-17 or IL-23 inhibitor classes— thus avoiding both the potential downside of weight gain and contraindication in patients with congestive heart failure associated with TNF-α inhibitors. It is important to counsel patients about weight loss in conjunction with these treatments, both to improve efficacy and reduce cardiovascular risk factors. There may be a preference for IL-23 inhibitors in patients with obesity, as this class of medications maintains efficacy particularly well in these patients. Patients with psoriasis should be counseled to follow up with a primary care physician given their higher risk for metabolic syndrome and adverse cardiovascular outcomes.

Gastrointestinal Conditions

Psoriasis and inflammatory bowel disease (IBD) have a bidirectional association, and patients with psoriasis are about 1.7 times more likely to have either Crohn disease or ulcerative colitis.^17,18 This association may be related to a shared pathogenesis with regard to immune dysregulation and overactivated inflammatory pathways, but there are some important differences to consider from a therapeutic standpoint. Given the increased expression of IL-17 in patients with IBD,¹⁹ a phase II trial of secukinumab yielded surprising results—not only was secukinumab ineffective in treating Crohn disease, but there also were higher rates of adverse events²⁰ (as noted on the product label for all IL-17 inhibitors). We have come to understand that there are regulatory subsets of IL-17 cells that are important in mucosal homeostasis and also regulate IL-10, which generally is considered an anti-inflammatory cytokine.²¹ Thus, while IL-17 inhibition can reduce some component of inflammatory signaling, it also can increase inflammatory signaling through indirect pathways while increasing intestinal permeability to microbes. Importantly, this process seems to occur via IL-23–independent pathways; as such, while direct inhibition of IL-17 can be deleterious, IL-23 inhibitors have become important therapeutics for IBD.²²

IL-17 family, IL-17A clearly is the culprit for worsening colitis as evidenced by both human and animal models. On the contrary, IL-17F blockade has been shown to ameliorate colitis in a murine model, whereas IL-17A inhibition worsens it.²³ Furthermore, dual blockade of IL-17A and IL-17F has a protective effect against colitis, suggesting that the IL-17F inhibition is dominant. This interesting finding has some mechanistic backing, since blockade of IL-17F induces Treg cells that serve to maintain gut epithelium homeostasis and integrity.²⁴

Overall, IL-17A inhibitors should be avoided in patients with a history of IBD—namely, secukinumab and ixekizumab. While there may be theoretical reasons that brodalumab or bimekizumab may confer a somewhat different risk for IBD exacerbation, there may be better choices that would be expected to effectively treat both the psoriasis and IBD manifestations. Given the US Food and Drug Administration approval of IL-23 inhibitors for IBD and their high levels of efficacy in treating psoriasis, these likely will be the best choice for most patients. Another mainstay of IBD treatment is TNF-α inhibitors, but they come with other risks such as increased immunosuppression and increased risk for nonmelanoma skin cancer.

An important question remains: What about patients who do not have known IBD? Do we proactively change our treatment choice due to fear of IBD development given the higher incidence of both Crohn disease and ulcerative colitis in patients with psoriasis? What about patients with a family history of IBD? First-degree relatives of patients with Crohn disease and ulcerative colitis have an 8- and 4-fold higher risk for those same conditions, respectively.²⁵ Postmarketing surveillance and database findings of low rates of IBD development with IL-17 inhibitors gives only modest reassurance, as dermatologists generally know to avoid these medications for patients with even questionable IBD symptoms. It is important to emphasize to our patients that in no case do we believe that a psoriasis medication actually will cause IBD—rather, someone with subclinical IBD could experience a flare and a first manifestation of colitis. The drug is not the culprit in inducing IBD but rather may serve to unmask existing disease.

One study suggested that for patients who move on to the IL-17 inhibitor secukinumab after being treated with TNF-α inhibitors for psoriasis, the rates of IBD development are higher (4.8%) than in those who start IL-17A inhibition without prior treatment (1%)(OR, 8.38; P=.018).²⁶ This begs the question of whether subclinical IBD in many patients with psoriasis who are treated with TNF-α inhibitors can be unmasked later when they are transitioned to a treatment that either does not treat the IBD or could worsen it. There may be a mechanistic drive behind this sequencing of treatments that predisposes patients to colitis, which would suggest selecting an IL-23 inhibitor after failing/trying a TNF-α inhibitor. However, the data are very preliminary, and in real practice, other concerns such as severe psoriatic arthritis may outweigh these considerations, as the IL-17 inhibitor class still is considered to be more effective than IL-23 inhibition at treating psoriatic arthritis overall. For most patients with no personal history of IBD and no strong family history of IBD (ie, first-degree relatives), the choice of biologic should not be affected by concern over gastrointestinal issues.

Psychiatric Conditions

It has been well established that psoriasis is linked to higher rates of depression, anxiety, and suicidality.²⁷ How do we take this into account when treating patients with psoriasis, especially when we have biologics with a warning label for suicidality and a Risk Evaluation and Mitigation Strategies program (brodalumab) and language around suicidal ideation in the label (bimekizumab)? While it is challenging to discuss mental health, it is not a conversation that we as dermatologists should shy away from. Appropriate treatment of psoriasis is an important tool to get our patients on the path to better mental health. A recent database study of more than 4000 patients showed that patients with psoriasis treated with biologics had a 17% lower risk for depression than those treated with conventional disease-modifying drugs such as methotrexate.²⁸ The comparator of the conventional disease-modifying drug class is important as it serves as a control for disease severity. Too often, a higher rate of depression, anxiety, or suicidality can be attributed to a medication when we in fact may just be capturing the background of higher incidence of all 3 in patients with severe psoriasis.

Indeed, even with the medication that many worry about on this front (brodalumab), multiple studies have confirmed that the effect on mental health generally is a positive one, with decreases in depressive symptoms.²⁹ In a cohort switched from TNF-α inhibitors to brodalumab, symptoms of depression actually improved,³⁰ so attributing a direct treatment effect to negative mental health outcomes does not seem to be justified, especially in light of the low number of suicide events in global postmarketing surveillance for brodalumab, comparable to or lower than other biologics for psoriasis.³¹ Similarly, bimekizumab has language in the label about discussing suicidality with patients, although the rates of suicidal ideation and behavior are no different from other biologics and rates of depression improved with its use.³²

Heightened awareness of our patients’ mental health is something that we as providers should embrace, even when it seems that we do not have much time to see each patient. The priority when a patient comes in with mental health symptoms should be to treat what is within our scope (ie, psoriasis) as quickly and effectively as possible— with a newer-generation biologic such as an IL-17 or IL-23 inhibitor—while encouraging the patient to seek care from a mental health professional. In these cases, one might even argue that the rapidity of action of IL-17 inhibitors may be of additional benefit.

Final Thoughts

We as dermatologists generally are tasked with seeing high volumes of patients, and an initial psoriasis consultation can be a lengthy visit; however, it is rewarding to establish this relationship with patients and a reminder of why we practice medicine to begin with. Psoriasis can be satisfying to treat, and we have so many highly effective medicines that can completely transform our patients’ lives. Applying an understanding of the interplay between psoriasis, its related comorbidities, and treatment choices can be a fulfilling exercise that captures the essence of shared decision-making, which can lead to better outcomes and satisfaction for both providers and patients.

TOPLINE:

Tildrakizumab was well tolerated and achieved sustained response in patients with moderate to severe plaque psoriasis of the scalp in a phase 3 study.

METHODOLOGY:

• A 72-week, multicenter, randomized, double-blind, placebo-controlled phase 3b trial enrolled 231 patients with moderate to severe plaque psoriasis of the scalp.
• Patients were randomly assigned to receive placebo (n = 114) or tildrakizumab (n = 117) until week 16, when patients in the placebo group switched to receive tildrakizumab.
• The primary endpoint, Investigator Global Assessment modified 2011 (IGA) scalp response, was defined as a score of 0 (clear) or 1 (almost clear) or an improvement of at least two points at week 16.
• The treatment was stopped at week 52, and participants were observed for another 20 weeks for safety and tolerability.

TAKEAWAY:

• At week 16, the response rate was higher in the tildrakizumab group than in the placebo group (49.4% vs 7.3%; P < .00001), and it increased to 62.9% and 56.1% (after crossover), respectively, at week 52.
• Psoriasis Scalp Severity Index 90 (PSSI 90) response rates were 60.7% and 4.9% at week 16 in the tildrakizumab and placebo groups, rising to 65.2% and 57.3%, respectively, at week 52.
• More than 80% of the week 16 responders maintained IGA and PSSI 90 responses at week 52.
• More than 50% of patients in both groups experienced adverse events, with no treatment-related serious toxicity.

IN PRACTICE:

“Tildrakizumab maintains improvements in scalp psoriasis for up to 52 weeks,” the authors wrote.

SOURCE:

Howard L. Sofen, MD, University of California, Los Angeles, led the study, which was published online on December 22, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

This study excluded patients with predominantly scalp involvement and minimal whole body psoriasis, who might respond differently to the treatment. Results were obtained under controlled clinical conditions and may not be generalizable to clinical practice.

DISCLOSURES:

This study and analyses were funded by Sun Pharma. Sofen reported serving as a clinical investigator for various pharmaceutical companies, including Sun Pharma. Five authors were current or former employees of Sun Pharma and associated companies. Others also disclosed financial ties outside this work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Tildrakizumab was well tolerated and achieved sustained response in patients with moderate to severe plaque psoriasis of the scalp in a phase 3 study.

METHODOLOGY:

• A 72-week, multicenter, randomized, double-blind, placebo-controlled phase 3b trial enrolled 231 patients with moderate to severe plaque psoriasis of the scalp.
• Patients were randomly assigned to receive placebo (n = 114) or tildrakizumab (n = 117) until week 16, when patients in the placebo group switched to receive tildrakizumab.
• The primary endpoint, Investigator Global Assessment modified 2011 (IGA) scalp response, was defined as a score of 0 (clear) or 1 (almost clear) or an improvement of at least two points at week 16.
• The treatment was stopped at week 52, and participants were observed for another 20 weeks for safety and tolerability.

TAKEAWAY:

• At week 16, the response rate was higher in the tildrakizumab group than in the placebo group (49.4% vs 7.3%; P < .00001), and it increased to 62.9% and 56.1% (after crossover), respectively, at week 52.
• Psoriasis Scalp Severity Index 90 (PSSI 90) response rates were 60.7% and 4.9% at week 16 in the tildrakizumab and placebo groups, rising to 65.2% and 57.3%, respectively, at week 52.
• More than 80% of the week 16 responders maintained IGA and PSSI 90 responses at week 52.
• More than 50% of patients in both groups experienced adverse events, with no treatment-related serious toxicity.

IN PRACTICE:

“Tildrakizumab maintains improvements in scalp psoriasis for up to 52 weeks,” the authors wrote.

SOURCE:

Howard L. Sofen, MD, University of California, Los Angeles, led the study, which was published online on December 22, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

This study excluded patients with predominantly scalp involvement and minimal whole body psoriasis, who might respond differently to the treatment. Results were obtained under controlled clinical conditions and may not be generalizable to clinical practice.

DISCLOSURES:

This study and analyses were funded by Sun Pharma. Sofen reported serving as a clinical investigator for various pharmaceutical companies, including Sun Pharma. Five authors were current or former employees of Sun Pharma and associated companies. Others also disclosed financial ties outside this work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.

TOPLINE:

Tildrakizumab was well tolerated and achieved sustained response in patients with moderate to severe plaque psoriasis of the scalp in a phase 3 study.

METHODOLOGY:

• A 72-week, multicenter, randomized, double-blind, placebo-controlled phase 3b trial enrolled 231 patients with moderate to severe plaque psoriasis of the scalp.
• Patients were randomly assigned to receive placebo (n = 114) or tildrakizumab (n = 117) until week 16, when patients in the placebo group switched to receive tildrakizumab.
• The primary endpoint, Investigator Global Assessment modified 2011 (IGA) scalp response, was defined as a score of 0 (clear) or 1 (almost clear) or an improvement of at least two points at week 16.
• The treatment was stopped at week 52, and participants were observed for another 20 weeks for safety and tolerability.

TAKEAWAY:

• At week 16, the response rate was higher in the tildrakizumab group than in the placebo group (49.4% vs 7.3%; P < .00001), and it increased to 62.9% and 56.1% (after crossover), respectively, at week 52.
• Psoriasis Scalp Severity Index 90 (PSSI 90) response rates were 60.7% and 4.9% at week 16 in the tildrakizumab and placebo groups, rising to 65.2% and 57.3%, respectively, at week 52.
• More than 80% of the week 16 responders maintained IGA and PSSI 90 responses at week 52.
• More than 50% of patients in both groups experienced adverse events, with no treatment-related serious toxicity.

IN PRACTICE:

“Tildrakizumab maintains improvements in scalp psoriasis for up to 52 weeks,” the authors wrote.

SOURCE:

Howard L. Sofen, MD, University of California, Los Angeles, led the study, which was published online on December 22, 2024, in the Journal of the American Academy of Dermatology.

LIMITATIONS:

This study excluded patients with predominantly scalp involvement and minimal whole body psoriasis, who might respond differently to the treatment. Results were obtained under controlled clinical conditions and may not be generalizable to clinical practice.

DISCLOSURES:

This study and analyses were funded by Sun Pharma. Sofen reported serving as a clinical investigator for various pharmaceutical companies, including Sun Pharma. Five authors were current or former employees of Sun Pharma and associated companies. Others also disclosed financial ties outside this work.

This article was created using several editorial tools, including artificial intelligence, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.