Article

Chronic obstructive pulmonary disease (COPD) affects about 25% of the veteran population and is the third-leading cause of death globally.^1,2 In patients with COPD, cigarette smoking leads to increased respiratory symptoms, a greater annual rate of decline in forced expiratory volume in 1 second (FEV₁), and an increase in COPD mortality rate vs nonsmokers.³ Veterans are at a higher risk of COPD due to increased prevalence of smoking within this population as well as military activities leading to environmental and occupational exposure.⁴

According to the 2024 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, the primary treatment goals of COPD therapy are to reduce symptoms and future risk of exacerbations.³ Bronchodilators are recommended for initial COPD pharmacotherapy, including long-acting muscarinic antagonists (LAMAs) and/or long-acting Β₂-agonists (LABAs). In some cases, treatment may include inhaled corticosteroids (ICS). Evidence supports ICS therapy in patients with COPD experiencing hospitalizations for exacerbations, ≥ 2 moderate exacerbations per year, blood eosinophil count ≥ 300 cells/μL or concomitant asthma.³

While the 2024 GOLD guidelines caution against the use of ICS outside of certain patient groups, previous GOLD guidelines recommended the use of ICS more broadly.⁵ Due to these changes, many patients may be using ICS therapy unnecessarily. At the Sioux Falls Veterans Affairs Health Care System (SFVAHCS), ICS overuse was identified as a driver of increased medication burden and potential adverse effects (AEs). To help reduce unnecessary ICS use, a data dashboard was created to identify potential candidates for ICS deprescribing. SFVAHCS clinical pharmacy practitioners are licensed pharmacists who work as independent practitioners with a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics. Pharmacists contacted dashboard patients to de-escalate ICS therapy when appropriate.

The SUNSET trial directly compared the continuation of triple therapy (tiotropium + salmeterol/fluticasone propionate) vs deprescribing to LABA/LAMA (indacaterol/ glycopyrronium) in patients with COPD.⁶ It evaluated whether LABA/LAMA was noninferior to LABA/LAMA/ICS therapy when comparing COPD exacerbations in patients whose COPD exacerbations were infrequent. Participants were randomized to triple therapy continuation or indacaterol/glycopyrronium and followed for 26 weeks. Patients on indacaterol/glycopyrronium did not have a significant difference in exacerbations than patients utilizing triple therapy.

The Implementation of a Targeted ICS De-Escalation in Patients with COPD in the Primary Care Setting trial evaluated the success of pharmacist-led ICS deprescribing in appropriate patients with COPD.⁷ Pharmacists followed GOLD guidelines to recommend ICS deprescribing and have risk vs benefit discussions with certain patients. Patients were considered for ICS deprescribing if they had a history of recurrent pneumonia or had no exacerbations within the previous year and eosinophils < 300 cells/μL (risk-benefit discussion if no eosinophil count available). This study found that 19.6% of patients were unable to tolerate ICS withdrawal and resumed either a standard or reduced dose of ICS therapy.⁷

Current guidelines and evidence recommend deprescribing ICS for appropriate patients. There is no current literature defining the impact of pharmacists on ICS deprescribing within the US Department of Veterans Affairs (VA) system. This study will allow for a quantifiable measure of pharmacists’ impact on reducing AEs associated with unnecessary ICS use.

Methods

This retrospective, single-center study was conducted at the SFVAHCS. Data were collected through manual chart review of SFVAHCS electronic health records. Veterans aged ≥ 18 years with a COPD diagnosis who underwent ICS deprescribing by a SFVAHCS pharmacist between February 2022 and December 2023 were included. Records were examined for 52 weeks prior to ICS withdrawal (baseline) and 52 weeks following withdrawal. Patients were excluded from the study if they had a history of asthma or ICS was used for < 52 weeks before deprescribing. Baseline characteristics were collected, including age, race, sex, current tobacco use, eosinophil count, COPD maintenance therapy, FEV₁/forced vital capacity (FVC) ratio, and mean postbronchodilator FEV₁ improvement.

The primary endpoint was number of COPD exacerbations at 52 weeks before vs after deprescribing. Secondary endpoints included the number of patients restarted on an ICS within 52 weeks of deprescribing, as well as ICS AEs, including pneumonia, oral candidiasis, and throat hoarseness.

Statistical Analysis

The primary endpoint was analyzed using the Wilcoxon signed rank test and secondary endpoints were analyzed using the McNemar exact test. Results with P < .05 were considered statistically significant for both tests.

Results

Seventy-six patients were included. Patients had a mean age of 75 years and 91% identified as White, which is representative of the SFVAHCS patient population (Table 1). Twenty-nine (38%) patients were current tobacco users and 55 patients (72%) used LAMA/LABA therapy (after ICS deprescribing) with an eosinophil count < 300 cells/μL. There was no significant difference in exacerbations before vs after ICS deprescribing (P = .78) (Table 2). There were 7 AEs reported before ICS deprescribing vs 0 following ICS deprescribing (P < .001). Five patients (7%) reported throat hoarseness, 1 (1%) reported pneumonia, and 1 (1%) reported oral candidiasis. Eighteen patients were reinitiated on ICS (24%). ICS reinitiation was most commonly due to patients reporting worsening symptoms (56%) (Table 3).

Discussion

This study sought to determine the impact of pharmacist-led ICS deprescribing on AEs and exacerbations experienced by patients with COPD. COPD exacerbations were not significantly different before vs after ICS deprescribing. The pharmacist-led ICS deprescribing program did not lead to increased COPD exacerbations. Similar to the SUNSET trial, the results of this study showed exacerbations did not significantly increase upon ICS deprescribing; however, this study differed by specifying pharmacist- led intervention.⁶

There was a decrease in ICS-related AEs following ICS deprescribing. Several patients were reinitiated on an ICS. As expected with deprescribing, some patients were not able to tolerate ICS withdrawal or had clinical indications to resume therapy (ie, an exacerbation). Similar results were found in another study where 8.9% of patients were restarted on ICS and 10.9% were de-escalated to a lower dose but were unable to stop completely.⁷ A 2024 systematic review by Georgiou et al found a wide range of patients resumed ICS therapy following withdrawal (21%-74%). Of note, only 2 of the randomized controlled trials and 3 observational studies included this meta-analysis included data on ICS reinitiation. Georgiou et al concluded there was insufficient evidence to determine the proportion of patients reinitiated on ICS but patients were commonly resumed on ICS therapy due to worsening symptoms, experiencing an exacerbation or decline in FEV₁.⁸ Although the rate of ICS reinitiation was unclear in the Georgiou et al meta-analysis, reasons for re-initiation were similar to what was found in our study.⁸

Strengths and Limitations

The retrospective nature of this study and its small sample size of 76 patients limit its findings. The retrospective nature of the study required researchers to rely on proper chart documentation, which is not always accurate or up to date. Lack of documentation of COPD exacerbations or patients who received care outside the VA following initial deprescribing could have biased study results. This patient population is representative of the veteran population in South Dakota but is not representative of the female or non-White patient population which may be more prevalent at other VA Health Care Systems as well as nonveteran patient populations. Additionally, this study was limited to a review of 52 weeks pre- and post-ICS deprescribing which may have impacted results. Patients may have had a COPD exacerbation or were restarted on ICS therapy beyond 52 weeks. Finally, the retrospective nature and small sample size limited the findings for the primary endpoint which could have been improved with a larger sample size and a randomized controlled design.

The comparison of patients with themselves before and after ICS deprescribing reduced the potential for bias seen in retrospective studies. This method did not require a second control group which would potentially introduce confounding factors.

Conclusions

This study found that in a small population of veterans with COPD, pharmacist-led ICS deprescribing did not lead to an increase in COPD exacerbations and decreased the risk of AEs related to ICS therapy. Some patients were reinitiated on ICS therapy; however, reinitiation was rarely attributable to a COPD exacerbation. This study suggests that pharmacists were able to appropriately identify candidates for ICS deprescribing without increasing their risk of exacerbations. By de-escalating ICS therapy, pharmacists decreased medication burden and potential AEs caused by ICS therapy. These findings support expanding the role of clinical pharmacists in COPD management, particularly in identifying candidates for safe ICS deprescribing.

Chronic obstructive pulmonary disease (COPD) affects about 25% of the veteran population and is the third-leading cause of death globally.^1,2 In patients with COPD, cigarette smoking leads to increased respiratory symptoms, a greater annual rate of decline in forced expiratory volume in 1 second (FEV₁), and an increase in COPD mortality rate vs nonsmokers.³ Veterans are at a higher risk of COPD due to increased prevalence of smoking within this population as well as military activities leading to environmental and occupational exposure.⁴

According to the 2024 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, the primary treatment goals of COPD therapy are to reduce symptoms and future risk of exacerbations.³ Bronchodilators are recommended for initial COPD pharmacotherapy, including long-acting muscarinic antagonists (LAMAs) and/or long-acting Β₂-agonists (LABAs). In some cases, treatment may include inhaled corticosteroids (ICS). Evidence supports ICS therapy in patients with COPD experiencing hospitalizations for exacerbations, ≥ 2 moderate exacerbations per year, blood eosinophil count ≥ 300 cells/μL or concomitant asthma.³

While the 2024 GOLD guidelines caution against the use of ICS outside of certain patient groups, previous GOLD guidelines recommended the use of ICS more broadly.⁵ Due to these changes, many patients may be using ICS therapy unnecessarily. At the Sioux Falls Veterans Affairs Health Care System (SFVAHCS), ICS overuse was identified as a driver of increased medication burden and potential adverse effects (AEs). To help reduce unnecessary ICS use, a data dashboard was created to identify potential candidates for ICS deprescribing. SFVAHCS clinical pharmacy practitioners are licensed pharmacists who work as independent practitioners with a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics. Pharmacists contacted dashboard patients to de-escalate ICS therapy when appropriate.

The SUNSET trial directly compared the continuation of triple therapy (tiotropium + salmeterol/fluticasone propionate) vs deprescribing to LABA/LAMA (indacaterol/ glycopyrronium) in patients with COPD.⁶ It evaluated whether LABA/LAMA was noninferior to LABA/LAMA/ICS therapy when comparing COPD exacerbations in patients whose COPD exacerbations were infrequent. Participants were randomized to triple therapy continuation or indacaterol/glycopyrronium and followed for 26 weeks. Patients on indacaterol/glycopyrronium did not have a significant difference in exacerbations than patients utilizing triple therapy.

The Implementation of a Targeted ICS De-Escalation in Patients with COPD in the Primary Care Setting trial evaluated the success of pharmacist-led ICS deprescribing in appropriate patients with COPD.⁷ Pharmacists followed GOLD guidelines to recommend ICS deprescribing and have risk vs benefit discussions with certain patients. Patients were considered for ICS deprescribing if they had a history of recurrent pneumonia or had no exacerbations within the previous year and eosinophils < 300 cells/μL (risk-benefit discussion if no eosinophil count available). This study found that 19.6% of patients were unable to tolerate ICS withdrawal and resumed either a standard or reduced dose of ICS therapy.⁷

Current guidelines and evidence recommend deprescribing ICS for appropriate patients. There is no current literature defining the impact of pharmacists on ICS deprescribing within the US Department of Veterans Affairs (VA) system. This study will allow for a quantifiable measure of pharmacists’ impact on reducing AEs associated with unnecessary ICS use.

Methods

This retrospective, single-center study was conducted at the SFVAHCS. Data were collected through manual chart review of SFVAHCS electronic health records. Veterans aged ≥ 18 years with a COPD diagnosis who underwent ICS deprescribing by a SFVAHCS pharmacist between February 2022 and December 2023 were included. Records were examined for 52 weeks prior to ICS withdrawal (baseline) and 52 weeks following withdrawal. Patients were excluded from the study if they had a history of asthma or ICS was used for < 52 weeks before deprescribing. Baseline characteristics were collected, including age, race, sex, current tobacco use, eosinophil count, COPD maintenance therapy, FEV₁/forced vital capacity (FVC) ratio, and mean postbronchodilator FEV₁ improvement.

The primary endpoint was number of COPD exacerbations at 52 weeks before vs after deprescribing. Secondary endpoints included the number of patients restarted on an ICS within 52 weeks of deprescribing, as well as ICS AEs, including pneumonia, oral candidiasis, and throat hoarseness.

Statistical Analysis

The primary endpoint was analyzed using the Wilcoxon signed rank test and secondary endpoints were analyzed using the McNemar exact test. Results with P < .05 were considered statistically significant for both tests.

Results

Seventy-six patients were included. Patients had a mean age of 75 years and 91% identified as White, which is representative of the SFVAHCS patient population (Table 1). Twenty-nine (38%) patients were current tobacco users and 55 patients (72%) used LAMA/LABA therapy (after ICS deprescribing) with an eosinophil count < 300 cells/μL. There was no significant difference in exacerbations before vs after ICS deprescribing (P = .78) (Table 2). There were 7 AEs reported before ICS deprescribing vs 0 following ICS deprescribing (P < .001). Five patients (7%) reported throat hoarseness, 1 (1%) reported pneumonia, and 1 (1%) reported oral candidiasis. Eighteen patients were reinitiated on ICS (24%). ICS reinitiation was most commonly due to patients reporting worsening symptoms (56%) (Table 3).

Discussion

This study sought to determine the impact of pharmacist-led ICS deprescribing on AEs and exacerbations experienced by patients with COPD. COPD exacerbations were not significantly different before vs after ICS deprescribing. The pharmacist-led ICS deprescribing program did not lead to increased COPD exacerbations. Similar to the SUNSET trial, the results of this study showed exacerbations did not significantly increase upon ICS deprescribing; however, this study differed by specifying pharmacist- led intervention.⁶

There was a decrease in ICS-related AEs following ICS deprescribing. Several patients were reinitiated on an ICS. As expected with deprescribing, some patients were not able to tolerate ICS withdrawal or had clinical indications to resume therapy (ie, an exacerbation). Similar results were found in another study where 8.9% of patients were restarted on ICS and 10.9% were de-escalated to a lower dose but were unable to stop completely.⁷ A 2024 systematic review by Georgiou et al found a wide range of patients resumed ICS therapy following withdrawal (21%-74%). Of note, only 2 of the randomized controlled trials and 3 observational studies included this meta-analysis included data on ICS reinitiation. Georgiou et al concluded there was insufficient evidence to determine the proportion of patients reinitiated on ICS but patients were commonly resumed on ICS therapy due to worsening symptoms, experiencing an exacerbation or decline in FEV₁.⁸ Although the rate of ICS reinitiation was unclear in the Georgiou et al meta-analysis, reasons for re-initiation were similar to what was found in our study.⁸

Strengths and Limitations

The retrospective nature of this study and its small sample size of 76 patients limit its findings. The retrospective nature of the study required researchers to rely on proper chart documentation, which is not always accurate or up to date. Lack of documentation of COPD exacerbations or patients who received care outside the VA following initial deprescribing could have biased study results. This patient population is representative of the veteran population in South Dakota but is not representative of the female or non-White patient population which may be more prevalent at other VA Health Care Systems as well as nonveteran patient populations. Additionally, this study was limited to a review of 52 weeks pre- and post-ICS deprescribing which may have impacted results. Patients may have had a COPD exacerbation or were restarted on ICS therapy beyond 52 weeks. Finally, the retrospective nature and small sample size limited the findings for the primary endpoint which could have been improved with a larger sample size and a randomized controlled design.

The comparison of patients with themselves before and after ICS deprescribing reduced the potential for bias seen in retrospective studies. This method did not require a second control group which would potentially introduce confounding factors.

Conclusions

This study found that in a small population of veterans with COPD, pharmacist-led ICS deprescribing did not lead to an increase in COPD exacerbations and decreased the risk of AEs related to ICS therapy. Some patients were reinitiated on ICS therapy; however, reinitiation was rarely attributable to a COPD exacerbation. This study suggests that pharmacists were able to appropriately identify candidates for ICS deprescribing without increasing their risk of exacerbations. By de-escalating ICS therapy, pharmacists decreased medication burden and potential AEs caused by ICS therapy. These findings support expanding the role of clinical pharmacists in COPD management, particularly in identifying candidates for safe ICS deprescribing.

Chronic obstructive pulmonary disease (COPD) affects about 25% of the veteran population and is the third-leading cause of death globally.^1,2 In patients with COPD, cigarette smoking leads to increased respiratory symptoms, a greater annual rate of decline in forced expiratory volume in 1 second (FEV₁), and an increase in COPD mortality rate vs nonsmokers.³ Veterans are at a higher risk of COPD due to increased prevalence of smoking within this population as well as military activities leading to environmental and occupational exposure.⁴

According to the 2024 Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines, the primary treatment goals of COPD therapy are to reduce symptoms and future risk of exacerbations.³ Bronchodilators are recommended for initial COPD pharmacotherapy, including long-acting muscarinic antagonists (LAMAs) and/or long-acting Β₂-agonists (LABAs). In some cases, treatment may include inhaled corticosteroids (ICS). Evidence supports ICS therapy in patients with COPD experiencing hospitalizations for exacerbations, ≥ 2 moderate exacerbations per year, blood eosinophil count ≥ 300 cells/μL or concomitant asthma.³

While the 2024 GOLD guidelines caution against the use of ICS outside of certain patient groups, previous GOLD guidelines recommended the use of ICS more broadly.⁵ Due to these changes, many patients may be using ICS therapy unnecessarily. At the Sioux Falls Veterans Affairs Health Care System (SFVAHCS), ICS overuse was identified as a driver of increased medication burden and potential adverse effects (AEs). To help reduce unnecessary ICS use, a data dashboard was created to identify potential candidates for ICS deprescribing. SFVAHCS clinical pharmacy practitioners are licensed pharmacists who work as independent practitioners with a scope of practice that allows them to initiate, modify, or discontinue medication therapy within medication management clinics. Pharmacists contacted dashboard patients to de-escalate ICS therapy when appropriate.

The SUNSET trial directly compared the continuation of triple therapy (tiotropium + salmeterol/fluticasone propionate) vs deprescribing to LABA/LAMA (indacaterol/ glycopyrronium) in patients with COPD.⁶ It evaluated whether LABA/LAMA was noninferior to LABA/LAMA/ICS therapy when comparing COPD exacerbations in patients whose COPD exacerbations were infrequent. Participants were randomized to triple therapy continuation or indacaterol/glycopyrronium and followed for 26 weeks. Patients on indacaterol/glycopyrronium did not have a significant difference in exacerbations than patients utilizing triple therapy.

The Implementation of a Targeted ICS De-Escalation in Patients with COPD in the Primary Care Setting trial evaluated the success of pharmacist-led ICS deprescribing in appropriate patients with COPD.⁷ Pharmacists followed GOLD guidelines to recommend ICS deprescribing and have risk vs benefit discussions with certain patients. Patients were considered for ICS deprescribing if they had a history of recurrent pneumonia or had no exacerbations within the previous year and eosinophils < 300 cells/μL (risk-benefit discussion if no eosinophil count available). This study found that 19.6% of patients were unable to tolerate ICS withdrawal and resumed either a standard or reduced dose of ICS therapy.⁷

Current guidelines and evidence recommend deprescribing ICS for appropriate patients. There is no current literature defining the impact of pharmacists on ICS deprescribing within the US Department of Veterans Affairs (VA) system. This study will allow for a quantifiable measure of pharmacists’ impact on reducing AEs associated with unnecessary ICS use.

Methods

This retrospective, single-center study was conducted at the SFVAHCS. Data were collected through manual chart review of SFVAHCS electronic health records. Veterans aged ≥ 18 years with a COPD diagnosis who underwent ICS deprescribing by a SFVAHCS pharmacist between February 2022 and December 2023 were included. Records were examined for 52 weeks prior to ICS withdrawal (baseline) and 52 weeks following withdrawal. Patients were excluded from the study if they had a history of asthma or ICS was used for < 52 weeks before deprescribing. Baseline characteristics were collected, including age, race, sex, current tobacco use, eosinophil count, COPD maintenance therapy, FEV₁/forced vital capacity (FVC) ratio, and mean postbronchodilator FEV₁ improvement.

The primary endpoint was number of COPD exacerbations at 52 weeks before vs after deprescribing. Secondary endpoints included the number of patients restarted on an ICS within 52 weeks of deprescribing, as well as ICS AEs, including pneumonia, oral candidiasis, and throat hoarseness.

Statistical Analysis

The primary endpoint was analyzed using the Wilcoxon signed rank test and secondary endpoints were analyzed using the McNemar exact test. Results with P < .05 were considered statistically significant for both tests.

Results

Seventy-six patients were included. Patients had a mean age of 75 years and 91% identified as White, which is representative of the SFVAHCS patient population (Table 1). Twenty-nine (38%) patients were current tobacco users and 55 patients (72%) used LAMA/LABA therapy (after ICS deprescribing) with an eosinophil count < 300 cells/μL. There was no significant difference in exacerbations before vs after ICS deprescribing (P = .78) (Table 2). There were 7 AEs reported before ICS deprescribing vs 0 following ICS deprescribing (P < .001). Five patients (7%) reported throat hoarseness, 1 (1%) reported pneumonia, and 1 (1%) reported oral candidiasis. Eighteen patients were reinitiated on ICS (24%). ICS reinitiation was most commonly due to patients reporting worsening symptoms (56%) (Table 3).

Discussion

This study sought to determine the impact of pharmacist-led ICS deprescribing on AEs and exacerbations experienced by patients with COPD. COPD exacerbations were not significantly different before vs after ICS deprescribing. The pharmacist-led ICS deprescribing program did not lead to increased COPD exacerbations. Similar to the SUNSET trial, the results of this study showed exacerbations did not significantly increase upon ICS deprescribing; however, this study differed by specifying pharmacist- led intervention.⁶

There was a decrease in ICS-related AEs following ICS deprescribing. Several patients were reinitiated on an ICS. As expected with deprescribing, some patients were not able to tolerate ICS withdrawal or had clinical indications to resume therapy (ie, an exacerbation). Similar results were found in another study where 8.9% of patients were restarted on ICS and 10.9% were de-escalated to a lower dose but were unable to stop completely.⁷ A 2024 systematic review by Georgiou et al found a wide range of patients resumed ICS therapy following withdrawal (21%-74%). Of note, only 2 of the randomized controlled trials and 3 observational studies included this meta-analysis included data on ICS reinitiation. Georgiou et al concluded there was insufficient evidence to determine the proportion of patients reinitiated on ICS but patients were commonly resumed on ICS therapy due to worsening symptoms, experiencing an exacerbation or decline in FEV₁.⁸ Although the rate of ICS reinitiation was unclear in the Georgiou et al meta-analysis, reasons for re-initiation were similar to what was found in our study.⁸

Strengths and Limitations

The retrospective nature of this study and its small sample size of 76 patients limit its findings. The retrospective nature of the study required researchers to rely on proper chart documentation, which is not always accurate or up to date. Lack of documentation of COPD exacerbations or patients who received care outside the VA following initial deprescribing could have biased study results. This patient population is representative of the veteran population in South Dakota but is not representative of the female or non-White patient population which may be more prevalent at other VA Health Care Systems as well as nonveteran patient populations. Additionally, this study was limited to a review of 52 weeks pre- and post-ICS deprescribing which may have impacted results. Patients may have had a COPD exacerbation or were restarted on ICS therapy beyond 52 weeks. Finally, the retrospective nature and small sample size limited the findings for the primary endpoint which could have been improved with a larger sample size and a randomized controlled design.

The comparison of patients with themselves before and after ICS deprescribing reduced the potential for bias seen in retrospective studies. This method did not require a second control group which would potentially introduce confounding factors.

Conclusions

This study found that in a small population of veterans with COPD, pharmacist-led ICS deprescribing did not lead to an increase in COPD exacerbations and decreased the risk of AEs related to ICS therapy. Some patients were reinitiated on ICS therapy; however, reinitiation was rarely attributable to a COPD exacerbation. This study suggests that pharmacists were able to appropriately identify candidates for ICS deprescribing without increasing their risk of exacerbations. By de-escalating ICS therapy, pharmacists decreased medication burden and potential AEs caused by ICS therapy. These findings support expanding the role of clinical pharmacists in COPD management, particularly in identifying candidates for safe ICS deprescribing.

Bullous pemphigoid (BP) is an autoimmune blistering disorder characterized by the development of tense subepidermal blisters and erosions primarily on the skin, commonly affecting the elderly.¹ It is attributed to autoantibodies targeting 2 hemidesmosomal components within the dermoepidermal junction—transmembrane collagen XVII (BP180/BPAG2) and plakin family protein BP230 (BPAG1)—resulting in blister formation due to loss of structural integrity.² Typically, patients present with pruritic urticarial plaques and tense bullae localized on flexural areas, but cutaneous manifestations vary and can be nonspecific. Histologically, a subepidermal blister with eosinophilic infiltration is characteristic, and detection of circulating autoantibodies against BP180 and BP230 antigens aids in diagnosis.^3,4

Drug-induced BP (DIBP) is a subset triggered by medications, including immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1) or its ligand, programmed death ligand-1 (PD-L1).^5,6 Often overexpressed in malignant tumors, PD-L1 inhibits host lymphocytic and apoptotic immune responses. Anti‒PD-1 and anti‒PD-L1 agents, designed to enhance the immune system’s ability to recognize and eliminate cancer cells,^7,8 have improved oncologic outcomes for various cancers, including urothelial cancer.^9-11 Before 2016, platinum-based chemotherapy was the mainstay for metastatic urothelial cancer management, but US Food and Drug Administration approval of 5 ICIs—nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab—­transformed treatment options.¹²Despite robust antitumor responses to ICIs, these medications are increasingly associated with immune-related adverse events (IRAEs), including DIBP, due to inhibition of negative regulators of immunity crucial for maintaining immunologic homeostasis.^13,14 Up to 30% to 40% of patients treated with PD-1 inhibitors experience dermatologic complications, such as lichenoid reactions, eczema, vitiligo, and pruritus,¹⁵ and patients undergoing treatment with the PD-1 inhibitor pembrolizumab are estimated to be 2.6 times more likely to develop a rash than those receiving standard chemotherapy.^16,17 The pathogenesis of DIBP involves autoreactive T-cell activation and subsequent autoantibody production against BP antigens.¹⁸ We present the case of DIBP secondary to pembrolizumab immunotherapy in a man with PD-L1–negative metastatic bladder cancer.

Case Report

An 81-year-old man with metastatic urothelial carcinoma presented to dermatology with a pruritic rash characterized by blisters of 5 months’ duration following treatment with pembrolizumab. He had a history of non–muscle invasive urothelial carcinoma and underwent intravesical bacillus Calmette-Guerin treatment. Thirty years later, after surveillance cystoscopies, the patient developed hematuria, which prompted pelvic ultrasonography and cystoscopy that revealed a tumor. Transurethral resection of the bladder tumor confirmed invasive, high-grade papillary urothelial carcinoma with vascular and muscle invasion (clinical stage T2NxMx). Due to elevated creatinine levels, neoadjuvant chemotherapy was contraindicated. Instead, the patient underwent cystoprostatectomy with ureteroileal conduit creation and pelvic lymphadenectomy one month later; final pathology revealed pT2aN0M0 disease with multifocal carcinoma in situ. At that time, there was no evidence of distant metastasis. Surveillance 5 months later identified pulmonary nodules that were confirmed as metastatic urothelial cancer by positron emission ­tomography/computed tomography (CT). The patient received 6 cycles of paclitaxel (175 mg/m² on day 1) and gemcitabine (1000 mg/m² on days 1 and 8 every 21 days), with progressive disease 16 months later. Despite 0% PD-L1 expression, pembrolizumab 400 mg intravenous (IV) treatment every 6 weeks was initiated 2 months later, and subsequent positron emission tomography/CT showed a positive response at 3 and 7 months after treatment initiation. After the patient’s sixth cycle of pembrolizumab, a generalized maculopapular rash involving approximately 50% of the body surface area led to discontinuation of pembrolizumab, initiation of multiple courses of prednisone and prednisolone, and a dermatology referral.

At the current presentation, the patient exhibited excoriated red patches on the abdomen, wrists, arms, upper chest, and legs (Figure 1). Tense blisters were observed on various areas, including the ear and arms. The provisional diagnosis was pembrolizumab-induced BP, supported by the clinical history, presentation, and an initial positive response to steroids. Treatment included topical triamcinolone 0.1% ointment and prednisone 40 mg daily. Biopsies revealed subepidermal blisters with underlying eosinophils on histopathology (Figure 2). Direct immunofluorescence showed strong linear basement membrane zone staining with IgG and C3, consistent with a diagnosis of BP.

One month later, the patient was given the first of two 1-g doses of rituximab, chosen as a treatment due to metastatic cancer history and ongoing severity of the DIBP. In addition, a slow prednisone taper was initiated. Atovaquone 1500 mg daily was ordered for Pneumocystis jirovecii prophylaxis. Following the first rituximab dose, the patient became clear of DIBP but required treatment for a chronic urinary tract infection, delaying the second rituximab dose. The prednisone taper continued, however, and the patient reported re-emergence of several blisters, followed by resolution of pruritus following the second rituximab dose. Bilateral pulmonary embolisms were noted on a restaging CT, attributed to the underlying malignancy and inflammation from DIBP. Doxycycline was initiated at 100 mg twice daily, and prednisone was slowly tapered (as tolerated by the patient’s symptoms) down to 2.5 mg daily approximately 6 months after rituximab initiation. The patient remains in clinical remission at last follow-up; however, considerations for further treatments have included intravenous immunoglobulin.

Comment

This case highlights major clinical challenges in the diagnosis and management of DIBP in a patient with metastatic urothelial carcinoma receiving ICI therapy. Our patient’s clinical course offers several high-yield lessons regarding diagnostic latency, treatment resistance, and a multidisciplinary approach to management.

Pruritus as a Precursor—Since an initial report in 2015, the emergence of DIBP postpembrolizumab has been well described in the literature.^19-22 Pruritus is frequently the earliest symptom, preceding bullous eruption. Similar to our case—in which DIBP developed 30 weeks after pembrolizumab initiation—the classic clinical presentation and formation of bullae often are delayed, typically occurring 28 and 39 weeks.

Beyond Corticosteroids to Manage Refractory DIBP—Our patient’s DIBP persisted despite multiple interventions, including pembrolizumab discontinuation, corticosteroid therapy, and rituximab administration. Although cases of DIBP in pembrolizumab-treated metastatic urothelial carcinoma patients have been reported, they did not exhibit similar treatment resistance.^23-25 As observed in our patient, immunotherapy discontinuation has been reported in at least 40% of all ICI-mediated cases of BP.¹⁴ Subsequent management involves low-dose oral corticosteroids and potent topical corticosteroids; the duration of steroid treatment varies widely, ranging from a few weeks to longer than 12 months, with no standardized approach.²⁶ In cases where ICI withdrawal and corticosteroids fail to produce a complete response, monoclonal antibodies such as rituximab, dupilumab, and omalizumab have been used as alternative treatments, with dupilumab recently receiving US Food and Drug Administration approval for moderate to severe BP.^27-31 These biologics selectively inhibit autoantibody formation and the inflammatory cascade, and research has pointed toward them as safe and effective options for refractory BP. Although robust randomized, controlled clinical trials on rituximab for DIBP still are lacking, prospective and retrospective cohort studies have shown promising results, including complete remission rates of 67% to 90%, along with a decline in circulating BP180-specific B lymphocytes, anti-BP180 IgG, and the expression of proinflammatory IL-15 and IL-6.³²

Despite receiving 2 doses of rituximab, our patient experienced recurrence of blisters when prednisone was tapered, prompting discussions about alternative tapering timelines and additional therapies such as doxycycline³³ or intravenous immunoglobulin,³⁴ which have emerged as steroid-sparing agents for BP following initial steroid therapy.

Systemic Barriers and the Need for Multidisciplinary Care—This case underscores systemic barriers within the health care system that impede prompt diagnosis and management of conditions such as DIBP. The 5-month delay between the patient’s referral to dermatology and the actual consultation, potentially due to shortages of dermatologists, highlights the need for more systematic urgent dermatologic referrals and streamlined diagnostic pathways in suspected cases of IRAEs. Diagnosis requires comprehensive evaluation, including skin biopsy for histopathologic examination and immunofluorescence studies. Ruling out alternative blistering disorders, such as epidermolysis bullosa acquisita, is crucial before confirming a BP diagnosis. Encouraging direct communication between referring physicians and consultants often can expedite the process, as a call from the referring physician can alert the consultant and speed up scheduling. Notably, the patient’s daughter, who was a patient of the dermatologist herself, played a crucial role in advocating for the dermatology referral. Although this should not be necessary, it highlights the pivotal role families can play in ensuring timely access to specialized care for challenging conditions such as BP.

Lastly, the refractory nature of the patient’s condition, coupled with concurrent chronic urinary tract infection and bilateral pulmonary embolisms, emphasizes the necessity of multidisciplinary collaboration among oncology, dermatology, and primary care in managing DIBP. Consulting experts on IRAEs and coordinating with the oncologist were essential for making informed treatment decisions and facilitating the timely exchange of clinical information.

Conclusion

This case underscores the importance of timely recognition and diagnosis of DIBP in patients undergoing ICI therapy but also highlights the need for individualized treatment approaches and multidisciplinary collaboration when managing adverse cutaneous reactions.

Bullous pemphigoid (BP) is an autoimmune blistering disorder characterized by the development of tense subepidermal blisters and erosions primarily on the skin, commonly affecting the elderly.¹ It is attributed to autoantibodies targeting 2 hemidesmosomal components within the dermoepidermal junction—transmembrane collagen XVII (BP180/BPAG2) and plakin family protein BP230 (BPAG1)—resulting in blister formation due to loss of structural integrity.² Typically, patients present with pruritic urticarial plaques and tense bullae localized on flexural areas, but cutaneous manifestations vary and can be nonspecific. Histologically, a subepidermal blister with eosinophilic infiltration is characteristic, and detection of circulating autoantibodies against BP180 and BP230 antigens aids in diagnosis.^3,4

Drug-induced BP (DIBP) is a subset triggered by medications, including immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1) or its ligand, programmed death ligand-1 (PD-L1).^5,6 Often overexpressed in malignant tumors, PD-L1 inhibits host lymphocytic and apoptotic immune responses. Anti‒PD-1 and anti‒PD-L1 agents, designed to enhance the immune system’s ability to recognize and eliminate cancer cells,^7,8 have improved oncologic outcomes for various cancers, including urothelial cancer.^9-11 Before 2016, platinum-based chemotherapy was the mainstay for metastatic urothelial cancer management, but US Food and Drug Administration approval of 5 ICIs—nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab—­transformed treatment options.¹²Despite robust antitumor responses to ICIs, these medications are increasingly associated with immune-related adverse events (IRAEs), including DIBP, due to inhibition of negative regulators of immunity crucial for maintaining immunologic homeostasis.^13,14 Up to 30% to 40% of patients treated with PD-1 inhibitors experience dermatologic complications, such as lichenoid reactions, eczema, vitiligo, and pruritus,¹⁵ and patients undergoing treatment with the PD-1 inhibitor pembrolizumab are estimated to be 2.6 times more likely to develop a rash than those receiving standard chemotherapy.^16,17 The pathogenesis of DIBP involves autoreactive T-cell activation and subsequent autoantibody production against BP antigens.¹⁸ We present the case of DIBP secondary to pembrolizumab immunotherapy in a man with PD-L1–negative metastatic bladder cancer.

Case Report

An 81-year-old man with metastatic urothelial carcinoma presented to dermatology with a pruritic rash characterized by blisters of 5 months’ duration following treatment with pembrolizumab. He had a history of non–muscle invasive urothelial carcinoma and underwent intravesical bacillus Calmette-Guerin treatment. Thirty years later, after surveillance cystoscopies, the patient developed hematuria, which prompted pelvic ultrasonography and cystoscopy that revealed a tumor. Transurethral resection of the bladder tumor confirmed invasive, high-grade papillary urothelial carcinoma with vascular and muscle invasion (clinical stage T2NxMx). Due to elevated creatinine levels, neoadjuvant chemotherapy was contraindicated. Instead, the patient underwent cystoprostatectomy with ureteroileal conduit creation and pelvic lymphadenectomy one month later; final pathology revealed pT2aN0M0 disease with multifocal carcinoma in situ. At that time, there was no evidence of distant metastasis. Surveillance 5 months later identified pulmonary nodules that were confirmed as metastatic urothelial cancer by positron emission ­tomography/computed tomography (CT). The patient received 6 cycles of paclitaxel (175 mg/m² on day 1) and gemcitabine (1000 mg/m² on days 1 and 8 every 21 days), with progressive disease 16 months later. Despite 0% PD-L1 expression, pembrolizumab 400 mg intravenous (IV) treatment every 6 weeks was initiated 2 months later, and subsequent positron emission tomography/CT showed a positive response at 3 and 7 months after treatment initiation. After the patient’s sixth cycle of pembrolizumab, a generalized maculopapular rash involving approximately 50% of the body surface area led to discontinuation of pembrolizumab, initiation of multiple courses of prednisone and prednisolone, and a dermatology referral.

At the current presentation, the patient exhibited excoriated red patches on the abdomen, wrists, arms, upper chest, and legs (Figure 1). Tense blisters were observed on various areas, including the ear and arms. The provisional diagnosis was pembrolizumab-induced BP, supported by the clinical history, presentation, and an initial positive response to steroids. Treatment included topical triamcinolone 0.1% ointment and prednisone 40 mg daily. Biopsies revealed subepidermal blisters with underlying eosinophils on histopathology (Figure 2). Direct immunofluorescence showed strong linear basement membrane zone staining with IgG and C3, consistent with a diagnosis of BP.

One month later, the patient was given the first of two 1-g doses of rituximab, chosen as a treatment due to metastatic cancer history and ongoing severity of the DIBP. In addition, a slow prednisone taper was initiated. Atovaquone 1500 mg daily was ordered for Pneumocystis jirovecii prophylaxis. Following the first rituximab dose, the patient became clear of DIBP but required treatment for a chronic urinary tract infection, delaying the second rituximab dose. The prednisone taper continued, however, and the patient reported re-emergence of several blisters, followed by resolution of pruritus following the second rituximab dose. Bilateral pulmonary embolisms were noted on a restaging CT, attributed to the underlying malignancy and inflammation from DIBP. Doxycycline was initiated at 100 mg twice daily, and prednisone was slowly tapered (as tolerated by the patient’s symptoms) down to 2.5 mg daily approximately 6 months after rituximab initiation. The patient remains in clinical remission at last follow-up; however, considerations for further treatments have included intravenous immunoglobulin.

Comment

This case highlights major clinical challenges in the diagnosis and management of DIBP in a patient with metastatic urothelial carcinoma receiving ICI therapy. Our patient’s clinical course offers several high-yield lessons regarding diagnostic latency, treatment resistance, and a multidisciplinary approach to management.

Pruritus as a Precursor—Since an initial report in 2015, the emergence of DIBP postpembrolizumab has been well described in the literature.^19-22 Pruritus is frequently the earliest symptom, preceding bullous eruption. Similar to our case—in which DIBP developed 30 weeks after pembrolizumab initiation—the classic clinical presentation and formation of bullae often are delayed, typically occurring 28 and 39 weeks.

Beyond Corticosteroids to Manage Refractory DIBP—Our patient’s DIBP persisted despite multiple interventions, including pembrolizumab discontinuation, corticosteroid therapy, and rituximab administration. Although cases of DIBP in pembrolizumab-treated metastatic urothelial carcinoma patients have been reported, they did not exhibit similar treatment resistance.^23-25 As observed in our patient, immunotherapy discontinuation has been reported in at least 40% of all ICI-mediated cases of BP.¹⁴ Subsequent management involves low-dose oral corticosteroids and potent topical corticosteroids; the duration of steroid treatment varies widely, ranging from a few weeks to longer than 12 months, with no standardized approach.²⁶ In cases where ICI withdrawal and corticosteroids fail to produce a complete response, monoclonal antibodies such as rituximab, dupilumab, and omalizumab have been used as alternative treatments, with dupilumab recently receiving US Food and Drug Administration approval for moderate to severe BP.^27-31 These biologics selectively inhibit autoantibody formation and the inflammatory cascade, and research has pointed toward them as safe and effective options for refractory BP. Although robust randomized, controlled clinical trials on rituximab for DIBP still are lacking, prospective and retrospective cohort studies have shown promising results, including complete remission rates of 67% to 90%, along with a decline in circulating BP180-specific B lymphocytes, anti-BP180 IgG, and the expression of proinflammatory IL-15 and IL-6.³²

Despite receiving 2 doses of rituximab, our patient experienced recurrence of blisters when prednisone was tapered, prompting discussions about alternative tapering timelines and additional therapies such as doxycycline³³ or intravenous immunoglobulin,³⁴ which have emerged as steroid-sparing agents for BP following initial steroid therapy.

Systemic Barriers and the Need for Multidisciplinary Care—This case underscores systemic barriers within the health care system that impede prompt diagnosis and management of conditions such as DIBP. The 5-month delay between the patient’s referral to dermatology and the actual consultation, potentially due to shortages of dermatologists, highlights the need for more systematic urgent dermatologic referrals and streamlined diagnostic pathways in suspected cases of IRAEs. Diagnosis requires comprehensive evaluation, including skin biopsy for histopathologic examination and immunofluorescence studies. Ruling out alternative blistering disorders, such as epidermolysis bullosa acquisita, is crucial before confirming a BP diagnosis. Encouraging direct communication between referring physicians and consultants often can expedite the process, as a call from the referring physician can alert the consultant and speed up scheduling. Notably, the patient’s daughter, who was a patient of the dermatologist herself, played a crucial role in advocating for the dermatology referral. Although this should not be necessary, it highlights the pivotal role families can play in ensuring timely access to specialized care for challenging conditions such as BP.

Lastly, the refractory nature of the patient’s condition, coupled with concurrent chronic urinary tract infection and bilateral pulmonary embolisms, emphasizes the necessity of multidisciplinary collaboration among oncology, dermatology, and primary care in managing DIBP. Consulting experts on IRAEs and coordinating with the oncologist were essential for making informed treatment decisions and facilitating the timely exchange of clinical information.

Conclusion

This case underscores the importance of timely recognition and diagnosis of DIBP in patients undergoing ICI therapy but also highlights the need for individualized treatment approaches and multidisciplinary collaboration when managing adverse cutaneous reactions.

Bullous pemphigoid (BP) is an autoimmune blistering disorder characterized by the development of tense subepidermal blisters and erosions primarily on the skin, commonly affecting the elderly.¹ It is attributed to autoantibodies targeting 2 hemidesmosomal components within the dermoepidermal junction—transmembrane collagen XVII (BP180/BPAG2) and plakin family protein BP230 (BPAG1)—resulting in blister formation due to loss of structural integrity.² Typically, patients present with pruritic urticarial plaques and tense bullae localized on flexural areas, but cutaneous manifestations vary and can be nonspecific. Histologically, a subepidermal blister with eosinophilic infiltration is characteristic, and detection of circulating autoantibodies against BP180 and BP230 antigens aids in diagnosis.^3,4

Drug-induced BP (DIBP) is a subset triggered by medications, including immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1 (PD-1) or its ligand, programmed death ligand-1 (PD-L1).^5,6 Often overexpressed in malignant tumors, PD-L1 inhibits host lymphocytic and apoptotic immune responses. Anti‒PD-1 and anti‒PD-L1 agents, designed to enhance the immune system’s ability to recognize and eliminate cancer cells,^7,8 have improved oncologic outcomes for various cancers, including urothelial cancer.^9-11 Before 2016, platinum-based chemotherapy was the mainstay for metastatic urothelial cancer management, but US Food and Drug Administration approval of 5 ICIs—nivolumab, pembrolizumab, avelumab, atezolizumab, and durvalumab—­transformed treatment options.¹²Despite robust antitumor responses to ICIs, these medications are increasingly associated with immune-related adverse events (IRAEs), including DIBP, due to inhibition of negative regulators of immunity crucial for maintaining immunologic homeostasis.^13,14 Up to 30% to 40% of patients treated with PD-1 inhibitors experience dermatologic complications, such as lichenoid reactions, eczema, vitiligo, and pruritus,¹⁵ and patients undergoing treatment with the PD-1 inhibitor pembrolizumab are estimated to be 2.6 times more likely to develop a rash than those receiving standard chemotherapy.^16,17 The pathogenesis of DIBP involves autoreactive T-cell activation and subsequent autoantibody production against BP antigens.¹⁸ We present the case of DIBP secondary to pembrolizumab immunotherapy in a man with PD-L1–negative metastatic bladder cancer.

Case Report

An 81-year-old man with metastatic urothelial carcinoma presented to dermatology with a pruritic rash characterized by blisters of 5 months’ duration following treatment with pembrolizumab. He had a history of non–muscle invasive urothelial carcinoma and underwent intravesical bacillus Calmette-Guerin treatment. Thirty years later, after surveillance cystoscopies, the patient developed hematuria, which prompted pelvic ultrasonography and cystoscopy that revealed a tumor. Transurethral resection of the bladder tumor confirmed invasive, high-grade papillary urothelial carcinoma with vascular and muscle invasion (clinical stage T2NxMx). Due to elevated creatinine levels, neoadjuvant chemotherapy was contraindicated. Instead, the patient underwent cystoprostatectomy with ureteroileal conduit creation and pelvic lymphadenectomy one month later; final pathology revealed pT2aN0M0 disease with multifocal carcinoma in situ. At that time, there was no evidence of distant metastasis. Surveillance 5 months later identified pulmonary nodules that were confirmed as metastatic urothelial cancer by positron emission ­tomography/computed tomography (CT). The patient received 6 cycles of paclitaxel (175 mg/m² on day 1) and gemcitabine (1000 mg/m² on days 1 and 8 every 21 days), with progressive disease 16 months later. Despite 0% PD-L1 expression, pembrolizumab 400 mg intravenous (IV) treatment every 6 weeks was initiated 2 months later, and subsequent positron emission tomography/CT showed a positive response at 3 and 7 months after treatment initiation. After the patient’s sixth cycle of pembrolizumab, a generalized maculopapular rash involving approximately 50% of the body surface area led to discontinuation of pembrolizumab, initiation of multiple courses of prednisone and prednisolone, and a dermatology referral.

At the current presentation, the patient exhibited excoriated red patches on the abdomen, wrists, arms, upper chest, and legs (Figure 1). Tense blisters were observed on various areas, including the ear and arms. The provisional diagnosis was pembrolizumab-induced BP, supported by the clinical history, presentation, and an initial positive response to steroids. Treatment included topical triamcinolone 0.1% ointment and prednisone 40 mg daily. Biopsies revealed subepidermal blisters with underlying eosinophils on histopathology (Figure 2). Direct immunofluorescence showed strong linear basement membrane zone staining with IgG and C3, consistent with a diagnosis of BP.

One month later, the patient was given the first of two 1-g doses of rituximab, chosen as a treatment due to metastatic cancer history and ongoing severity of the DIBP. In addition, a slow prednisone taper was initiated. Atovaquone 1500 mg daily was ordered for Pneumocystis jirovecii prophylaxis. Following the first rituximab dose, the patient became clear of DIBP but required treatment for a chronic urinary tract infection, delaying the second rituximab dose. The prednisone taper continued, however, and the patient reported re-emergence of several blisters, followed by resolution of pruritus following the second rituximab dose. Bilateral pulmonary embolisms were noted on a restaging CT, attributed to the underlying malignancy and inflammation from DIBP. Doxycycline was initiated at 100 mg twice daily, and prednisone was slowly tapered (as tolerated by the patient’s symptoms) down to 2.5 mg daily approximately 6 months after rituximab initiation. The patient remains in clinical remission at last follow-up; however, considerations for further treatments have included intravenous immunoglobulin.

Comment

This case highlights major clinical challenges in the diagnosis and management of DIBP in a patient with metastatic urothelial carcinoma receiving ICI therapy. Our patient’s clinical course offers several high-yield lessons regarding diagnostic latency, treatment resistance, and a multidisciplinary approach to management.

Pruritus as a Precursor—Since an initial report in 2015, the emergence of DIBP postpembrolizumab has been well described in the literature.^19-22 Pruritus is frequently the earliest symptom, preceding bullous eruption. Similar to our case—in which DIBP developed 30 weeks after pembrolizumab initiation—the classic clinical presentation and formation of bullae often are delayed, typically occurring 28 and 39 weeks.

Beyond Corticosteroids to Manage Refractory DIBP—Our patient’s DIBP persisted despite multiple interventions, including pembrolizumab discontinuation, corticosteroid therapy, and rituximab administration. Although cases of DIBP in pembrolizumab-treated metastatic urothelial carcinoma patients have been reported, they did not exhibit similar treatment resistance.^23-25 As observed in our patient, immunotherapy discontinuation has been reported in at least 40% of all ICI-mediated cases of BP.¹⁴ Subsequent management involves low-dose oral corticosteroids and potent topical corticosteroids; the duration of steroid treatment varies widely, ranging from a few weeks to longer than 12 months, with no standardized approach.²⁶ In cases where ICI withdrawal and corticosteroids fail to produce a complete response, monoclonal antibodies such as rituximab, dupilumab, and omalizumab have been used as alternative treatments, with dupilumab recently receiving US Food and Drug Administration approval for moderate to severe BP.^27-31 These biologics selectively inhibit autoantibody formation and the inflammatory cascade, and research has pointed toward them as safe and effective options for refractory BP. Although robust randomized, controlled clinical trials on rituximab for DIBP still are lacking, prospective and retrospective cohort studies have shown promising results, including complete remission rates of 67% to 90%, along with a decline in circulating BP180-specific B lymphocytes, anti-BP180 IgG, and the expression of proinflammatory IL-15 and IL-6.³²

Despite receiving 2 doses of rituximab, our patient experienced recurrence of blisters when prednisone was tapered, prompting discussions about alternative tapering timelines and additional therapies such as doxycycline³³ or intravenous immunoglobulin,³⁴ which have emerged as steroid-sparing agents for BP following initial steroid therapy.

Systemic Barriers and the Need for Multidisciplinary Care—This case underscores systemic barriers within the health care system that impede prompt diagnosis and management of conditions such as DIBP. The 5-month delay between the patient’s referral to dermatology and the actual consultation, potentially due to shortages of dermatologists, highlights the need for more systematic urgent dermatologic referrals and streamlined diagnostic pathways in suspected cases of IRAEs. Diagnosis requires comprehensive evaluation, including skin biopsy for histopathologic examination and immunofluorescence studies. Ruling out alternative blistering disorders, such as epidermolysis bullosa acquisita, is crucial before confirming a BP diagnosis. Encouraging direct communication between referring physicians and consultants often can expedite the process, as a call from the referring physician can alert the consultant and speed up scheduling. Notably, the patient’s daughter, who was a patient of the dermatologist herself, played a crucial role in advocating for the dermatology referral. Although this should not be necessary, it highlights the pivotal role families can play in ensuring timely access to specialized care for challenging conditions such as BP.

Lastly, the refractory nature of the patient’s condition, coupled with concurrent chronic urinary tract infection and bilateral pulmonary embolisms, emphasizes the necessity of multidisciplinary collaboration among oncology, dermatology, and primary care in managing DIBP. Consulting experts on IRAEs and coordinating with the oncologist were essential for making informed treatment decisions and facilitating the timely exchange of clinical information.

Conclusion

This case underscores the importance of timely recognition and diagnosis of DIBP in patients undergoing ICI therapy but also highlights the need for individualized treatment approaches and multidisciplinary collaboration when managing adverse cutaneous reactions.

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer and ranks sixth in prevalence among all cancers in the United Kingdom.^1,2 The etiologic factors underlying cSCC are well established, with major efforts undertaken by governments and public health organizations over the past 2 decades to increase public awareness globally. Known risk factors for cSCC include chronic exposure to UV radiation, radiotherapy, chemical injury, and immunosuppression. The first 3 risk factors amplify risk by increasing accumulation of abnormal gene mutations. Immunosuppression hampers the immune system’s ability to eradicate cells bearing malignant genetic aberrations. Notable gene mutations implicated in cSCC include p53, p16, telomerase reverse transcriptase, NOTCH1, ROS1, mitogen-activated protein kinases, forkhead box M1, and cyclooxygenase 2, in addition to matrix metalloproteinases, which are most commonly associated with Marjolin ulcers.³

The incidence of cSCC continues to surge worldwide,^3,4 with more patients presenting with advanced stages of disease and a notable increase in those presenting with unresectable cSCC due to either locally advanced disease or distant metastases.⁵ Existing therapies for cSCC include surgical excision (including Mohs micrographic surgery); radiotherapy (indicated for cosmetic reasons, locally advanced disease, and/or patient factors); and systemic treatments, encompassing chemotherapy (eg, ­5-fluorouracil), and epidermal growth factor receptor inhibitors (indicated locally advanced disease or distant metastases).⁴

In recent years, immunotherapy has emerged as a potent and effective treatment modality for unresectable cSCC, both locally advanced and metastatic. The success of immunotherapy in cSCC treatment can be attributed to the unique tumor microenvironment of cSCC, which is characterized by high tumor mutational burden, increased density of tumor-infiltrating lymphocytes (TILs), and heightened programmed cell death ligand 1 (PD-L1) expression on neoplastic cells. The elevated TIL density enables a robust immune response, rendering checkpoint inhibitors particularly effective. Greater tumor mutational burden further augments this enhanced TIL activity, amplifying the response to checkpoint inhibitors. Additionally, heightened PD-L1 expression facilitates more effective unmasking by checkpoint inhibitors, thereby enhancing the immune response.⁶

Cemiplimab is a programmed cell death protein 1/PD-L1 that was approved by the US Food and Drug Administration in September 2018 for treatment of cSCC. It also gained a European Union endorsement in June 2019 and National Institute for Health and Care Excellence approval in August 2019 based on the highly promising results of a phase 2 trial that involved only 59 adult patients with metastatic cSCC.⁷ The trial reported an overall response rate (ORR) of 47%, durable disease control in 61% of patients, a median time to response of 1.9 months, and response duration exceeding 6 months in 57% of patients. The phase 2 trials reported an estimated 12-month progression-free survival (PFS) of 53% and an estimated 12-month overall survival (OS) of 81%.⁷

Despite the noteworthy response statistics demonstrated by these studies, it is imperative to recognize that immunotherapies, while potent, are not without challenges. They can precipitate severe immune-related adverse events (AEs), including myocarditis, adrenal failure, and pneumonitis, which can negatively impact patient health outcomes and lead to early treatment cessation. The initial trials reported high-grade AEs such as pneumonitis, pleural effusion, and, notably 11 total deaths, with 8 (72.7%) attributed to disease progression and 3 (27.3%) to AEs.⁷ Additionally, cost and access to immunotherapy are inherent limitations of the treatment; immunotherapy agents are expensive, and not all centers or patients are able to access them.

The aim of this study was to assess the efficacy of cemiplimab in patients with inoperable cSCC, including locally advanced and metastatic disease, treated at a tertiary referral center in the United Kingdom, and to compare outcomes with the pivotal phase 2 trial that supported regulatory approval of cemiplimab.⁷ The primary objective was ORR, with secondary objectives including PFS, OS, and AEs.

Methods

The patients included in this study had unresectable cSCC and therefore were not candidates for surgery or radiotherapy. Patient demographics are presented in Table 1. The main indications for cemiplimab in place of surgery or radiotherapy included local recurrence, locally advanced disease involving deep structures, advanced nodal disease, and distant metastatic disease. Patients meeting these criteria and the following inclusion criteria for cemiplimab treatment from November 2018 through March 2023 at a single tertiary referral center were included in the study:

• Age 18 years or older
• Histologically confirmed cSCC with locoregional recurrence after surgery or radiotherapy, or histologically confirmed advanced or metastatic disease deemed to be inoperable
• Eastern Cooperative Oncology Group performance status of 0 to 2

All enrolled patients received intravenous infusions of cemiplimab 3 times weekly at a dosage of 350 mg. Treatment was continued until complete response, unacceptable toxicity, or disease progression, with a maximum duration of 2 years or 35 cycles. Patients underwent regular follow-up, typically 3 weeks preceding each treatment cycle. Monitoring adhered to the Common Terminology Criteria for Adverse Events, version 4.0, as outlined by the National Cancer Institute.⁸ Response to treatment was reported according to the guidelines stipulated by the Response Evaluation Criteria in Solid Tumours, version 1.1.⁹ Written informed consent was obtained for all patients.

Comprehensive patient demographics, histologic profiles, and clinical data were meticulously captured on a retrospective basis. The primary objective centered on elucidating the ORR. Secondary objectives encompassed evaluating PFS, OS, and a comprehensive analysis of AEs. Progression-free survival and OS were calculated by generating Kaplan-Meier curves using Python 3.9 (Python Software Foundation).

Results

Patient Characteristics—From November 2018 through March 2023, a cohort of 31 patients with inoperable cSCC underwent treatment with cemiplimab at our tertiary referral center. The median duration of follow-up was 13 months. Clinical characteristics are outlined in the Table 2. Four (12.9%) patients successfully completed the full 2-year treatment course. Nine (29.0%) continued to receive cemiplimab therapy at the conclusion of this study in March 2023, with treatment courses ranging from 2 to 11 months since initiation. Ten (32.3%) patients discontinued treatment due to AEs, while 5 (16.1%) regrettably ceased treatment due to mortality. Two (6.5%) patients terminated treatment due to the COVID-19 pandemic, and 1 (3.2%) discontinued treatment as a result of disease progression.

Clinical Efficacy—Of the 31 enrolled patients, a substantial proportion experienced positive clinical outcomes, with 20 (64.5%) achieving complete response and 6 (19.4%) achieving partial response. A total of 26 patients achieved a response on cemiplimab, with an ORR of 83.9% (95% CI, 66.3%-94.6%). Regrettably, 2 (6.5%) patients experienced disease progression, while 3 (9.7%) died before response to cemiplimab could be assessed. Following a median follow-up period of 13 months, the median PFS and OS remained unreached, emphasizing the efficacy of cemiplimab in treating inoperable cSCC (Figures 1 and 2).

In our cohort, 2-year PFS was 57.5% (95% CI, 33.9%-75.5%) with cemiplimab and 2-year OS was 70.6% (95% CI, 46.5%-85.4%). For PFS, we observed the steepest drops at onset and at the 23-month mark (Figure 1), while for OS we observed the steepest drop at the 38-month mark (Figure 2). Clinically, we observed cemiplimab causing near-complete regression of previously large, ulcerating, fungating cSCC in patients who responded to cemiplimab, mirroring results seen elsewhere.⁷

Adverse Events and Treatment Cessation—A substantial proportion of patients (24/31 [77.4%]) reported AEs during treatment. Notably, treatment discontinuation was necessary in 10 (32.3%) patients due to a range of AEs, including myocarditis, atrial flutter, pneumonitis, nephritis, derangement of liver function tests, and arthritis. Additional relevant side effects included adrenal insufficiency (3/31 [9.7%]), fatigue (3/31 [9.7%]), diarrhea (2/31 [6.5%]), and type 1 diabetes 1/31 [3.2%]). These outcomes emphasize the importance of vigilance and monitoring when administering cemiplimab in the context of advanced cSCC.

Comment

Historically, advanced cSCC has had a bleak prognosis. The nature of the disease generally meant these patients could not be operated on due to metastatic spread or local invasion, and radiotherapy was not curative. The only option remaining was palliation, but new therapies have shown promise due to specific inherent characteristics of advanced cSCC; for example, the characteristic high mutation burden prevalent in advanced cSCC has paved the way for the emergence of immunotherapy as a promising avenue for intervention.¹⁰ Cemiplimab in particular has emerged as a feasible treatment for patients who would otherwise be confined to palliation. Our findings derived from a local cohort reinforce this notion, with a remarkable 83.9% (26/31) exhibiting a favorable response to cemiplimab. Although this local sample of 31 patients is small in absolute terms, in the context of the trial with 59 participants⁷ that gained global approval for the use of cemiplimab, our study adds a substantial amount of data to the growing body of evidence on the long-term efficacy of cemiplimab. Notably, our results emphasize the potential applicability of cemiplimab among elderly patients and individuals with lower performance statuses: populations historically excluded from immunotherapeutic considerations.

Immunotherapeutic AEs and Tolerance­—As anticipated with immunotherapeutic agents, cemiplimab is associated with AEs that also are seen in its counterparts.¹¹ A total of 77.4% (24/31) of our cohort reported immune-related AEs, although the severity warranted treatment discontinuation in only 10 (10/24 [41.7%]) patients, representing less than half of those who encountered side effects and less than a third of the entire cohort. Furthermore, most of these immune-related AEs were managed effectively with short courses of oral steroids, further substantiating the notion that cemiplimab is generally well tolerated across patients of diverse performance statuses. Even for patients who discontinued treatment early due to immune-related side effects, benefits persisted despite the partial course of cemiplimab. Of the 10 patients who discontinued treatment due to immune AEs, 6 (60%) demonstrated stable complete response, 2 (20%) experienced relapse after stopping cemiplimab, and 2 (20%) demonstrated a partial response with stable disease.

Challenges in the Most Vulnerable Patient—Of the 5 recorded mortalities, 2 (40%) were attributed to disease progression, while 3 (60%) occurred before response assessment could be undertaken. The 3 patients who died prior to response evaluation were among the most medically fragile in the cohort, characterized by extensive metastatic cSCC and major comorbidities that, in isolation, posed life-threatening risks. For individuals grappling with widespread metastatic cSCC and substantial life-threatening comorbidities, it is plausible that the necessary physiologic resilience necessary for cemiplimab therapy may be absent. We hypothesize that an immune reconstitution syndrome–like response may be responsible for this early mortality, and these patients may lack the necessary physiological resilience to tolerate this response. This subset of patients warrants careful consideration when considering therapy with cemiplimab.

Conclusion

In summary, our results underscore the efficacy of cemiplimab, as it supported a response in more than three-quarters of our patient cohort. Additionally, the associated AEs, similar to those with other programmed cell death protein 1 inhibitors, generally were manageable with medical intervention. Our findings corroborate earlier studies that have demonstrated the therapeutic potential of cemiplimab in advanced, inoperable cSCC management. In addition to efficacy, our results also suggest that cemiplimab holds promise as a therapeutic option for patients who might not be amenable to the stresses of general anesthesia, surgery, or prolonged hospitalization, although cemiplimab should likely be used with caution in patients with severe, life-threatening medical comorbidities and/or concurrent severe illness. Furthermore, our data demonstrate that the benefits persist not only beyond the completion of the full 2-year course, but also after partial treatment courses discontinued due to patient-specific factors. Future studies would be useful to better understand and optimize dose and duration of cemiplimab treatment to maximize therapeutic effectiveness while minimizing risk of immune-related AEs. Among individuals confronting advanced, inoperable cSCC, cemiplimab is emerging as a viable and beneficial intervention.

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer and ranks sixth in prevalence among all cancers in the United Kingdom.^1,2 The etiologic factors underlying cSCC are well established, with major efforts undertaken by governments and public health organizations over the past 2 decades to increase public awareness globally. Known risk factors for cSCC include chronic exposure to UV radiation, radiotherapy, chemical injury, and immunosuppression. The first 3 risk factors amplify risk by increasing accumulation of abnormal gene mutations. Immunosuppression hampers the immune system’s ability to eradicate cells bearing malignant genetic aberrations. Notable gene mutations implicated in cSCC include p53, p16, telomerase reverse transcriptase, NOTCH1, ROS1, mitogen-activated protein kinases, forkhead box M1, and cyclooxygenase 2, in addition to matrix metalloproteinases, which are most commonly associated with Marjolin ulcers.³

The incidence of cSCC continues to surge worldwide,^3,4 with more patients presenting with advanced stages of disease and a notable increase in those presenting with unresectable cSCC due to either locally advanced disease or distant metastases.⁵ Existing therapies for cSCC include surgical excision (including Mohs micrographic surgery); radiotherapy (indicated for cosmetic reasons, locally advanced disease, and/or patient factors); and systemic treatments, encompassing chemotherapy (eg, ­5-fluorouracil), and epidermal growth factor receptor inhibitors (indicated locally advanced disease or distant metastases).⁴

In recent years, immunotherapy has emerged as a potent and effective treatment modality for unresectable cSCC, both locally advanced and metastatic. The success of immunotherapy in cSCC treatment can be attributed to the unique tumor microenvironment of cSCC, which is characterized by high tumor mutational burden, increased density of tumor-infiltrating lymphocytes (TILs), and heightened programmed cell death ligand 1 (PD-L1) expression on neoplastic cells. The elevated TIL density enables a robust immune response, rendering checkpoint inhibitors particularly effective. Greater tumor mutational burden further augments this enhanced TIL activity, amplifying the response to checkpoint inhibitors. Additionally, heightened PD-L1 expression facilitates more effective unmasking by checkpoint inhibitors, thereby enhancing the immune response.⁶

Cemiplimab is a programmed cell death protein 1/PD-L1 that was approved by the US Food and Drug Administration in September 2018 for treatment of cSCC. It also gained a European Union endorsement in June 2019 and National Institute for Health and Care Excellence approval in August 2019 based on the highly promising results of a phase 2 trial that involved only 59 adult patients with metastatic cSCC.⁷ The trial reported an overall response rate (ORR) of 47%, durable disease control in 61% of patients, a median time to response of 1.9 months, and response duration exceeding 6 months in 57% of patients. The phase 2 trials reported an estimated 12-month progression-free survival (PFS) of 53% and an estimated 12-month overall survival (OS) of 81%.⁷

Despite the noteworthy response statistics demonstrated by these studies, it is imperative to recognize that immunotherapies, while potent, are not without challenges. They can precipitate severe immune-related adverse events (AEs), including myocarditis, adrenal failure, and pneumonitis, which can negatively impact patient health outcomes and lead to early treatment cessation. The initial trials reported high-grade AEs such as pneumonitis, pleural effusion, and, notably 11 total deaths, with 8 (72.7%) attributed to disease progression and 3 (27.3%) to AEs.⁷ Additionally, cost and access to immunotherapy are inherent limitations of the treatment; immunotherapy agents are expensive, and not all centers or patients are able to access them.

The aim of this study was to assess the efficacy of cemiplimab in patients with inoperable cSCC, including locally advanced and metastatic disease, treated at a tertiary referral center in the United Kingdom, and to compare outcomes with the pivotal phase 2 trial that supported regulatory approval of cemiplimab.⁷ The primary objective was ORR, with secondary objectives including PFS, OS, and AEs.

Methods

The patients included in this study had unresectable cSCC and therefore were not candidates for surgery or radiotherapy. Patient demographics are presented in Table 1. The main indications for cemiplimab in place of surgery or radiotherapy included local recurrence, locally advanced disease involving deep structures, advanced nodal disease, and distant metastatic disease. Patients meeting these criteria and the following inclusion criteria for cemiplimab treatment from November 2018 through March 2023 at a single tertiary referral center were included in the study:

• Age 18 years or older
• Histologically confirmed cSCC with locoregional recurrence after surgery or radiotherapy, or histologically confirmed advanced or metastatic disease deemed to be inoperable
• Eastern Cooperative Oncology Group performance status of 0 to 2

All enrolled patients received intravenous infusions of cemiplimab 3 times weekly at a dosage of 350 mg. Treatment was continued until complete response, unacceptable toxicity, or disease progression, with a maximum duration of 2 years or 35 cycles. Patients underwent regular follow-up, typically 3 weeks preceding each treatment cycle. Monitoring adhered to the Common Terminology Criteria for Adverse Events, version 4.0, as outlined by the National Cancer Institute.⁸ Response to treatment was reported according to the guidelines stipulated by the Response Evaluation Criteria in Solid Tumours, version 1.1.⁹ Written informed consent was obtained for all patients.

Comprehensive patient demographics, histologic profiles, and clinical data were meticulously captured on a retrospective basis. The primary objective centered on elucidating the ORR. Secondary objectives encompassed evaluating PFS, OS, and a comprehensive analysis of AEs. Progression-free survival and OS were calculated by generating Kaplan-Meier curves using Python 3.9 (Python Software Foundation).

Results

Patient Characteristics—From November 2018 through March 2023, a cohort of 31 patients with inoperable cSCC underwent treatment with cemiplimab at our tertiary referral center. The median duration of follow-up was 13 months. Clinical characteristics are outlined in the Table 2. Four (12.9%) patients successfully completed the full 2-year treatment course. Nine (29.0%) continued to receive cemiplimab therapy at the conclusion of this study in March 2023, with treatment courses ranging from 2 to 11 months since initiation. Ten (32.3%) patients discontinued treatment due to AEs, while 5 (16.1%) regrettably ceased treatment due to mortality. Two (6.5%) patients terminated treatment due to the COVID-19 pandemic, and 1 (3.2%) discontinued treatment as a result of disease progression.

Clinical Efficacy—Of the 31 enrolled patients, a substantial proportion experienced positive clinical outcomes, with 20 (64.5%) achieving complete response and 6 (19.4%) achieving partial response. A total of 26 patients achieved a response on cemiplimab, with an ORR of 83.9% (95% CI, 66.3%-94.6%). Regrettably, 2 (6.5%) patients experienced disease progression, while 3 (9.7%) died before response to cemiplimab could be assessed. Following a median follow-up period of 13 months, the median PFS and OS remained unreached, emphasizing the efficacy of cemiplimab in treating inoperable cSCC (Figures 1 and 2).

In our cohort, 2-year PFS was 57.5% (95% CI, 33.9%-75.5%) with cemiplimab and 2-year OS was 70.6% (95% CI, 46.5%-85.4%). For PFS, we observed the steepest drops at onset and at the 23-month mark (Figure 1), while for OS we observed the steepest drop at the 38-month mark (Figure 2). Clinically, we observed cemiplimab causing near-complete regression of previously large, ulcerating, fungating cSCC in patients who responded to cemiplimab, mirroring results seen elsewhere.⁷

Adverse Events and Treatment Cessation—A substantial proportion of patients (24/31 [77.4%]) reported AEs during treatment. Notably, treatment discontinuation was necessary in 10 (32.3%) patients due to a range of AEs, including myocarditis, atrial flutter, pneumonitis, nephritis, derangement of liver function tests, and arthritis. Additional relevant side effects included adrenal insufficiency (3/31 [9.7%]), fatigue (3/31 [9.7%]), diarrhea (2/31 [6.5%]), and type 1 diabetes 1/31 [3.2%]). These outcomes emphasize the importance of vigilance and monitoring when administering cemiplimab in the context of advanced cSCC.

Comment

Historically, advanced cSCC has had a bleak prognosis. The nature of the disease generally meant these patients could not be operated on due to metastatic spread or local invasion, and radiotherapy was not curative. The only option remaining was palliation, but new therapies have shown promise due to specific inherent characteristics of advanced cSCC; for example, the characteristic high mutation burden prevalent in advanced cSCC has paved the way for the emergence of immunotherapy as a promising avenue for intervention.¹⁰ Cemiplimab in particular has emerged as a feasible treatment for patients who would otherwise be confined to palliation. Our findings derived from a local cohort reinforce this notion, with a remarkable 83.9% (26/31) exhibiting a favorable response to cemiplimab. Although this local sample of 31 patients is small in absolute terms, in the context of the trial with 59 participants⁷ that gained global approval for the use of cemiplimab, our study adds a substantial amount of data to the growing body of evidence on the long-term efficacy of cemiplimab. Notably, our results emphasize the potential applicability of cemiplimab among elderly patients and individuals with lower performance statuses: populations historically excluded from immunotherapeutic considerations.

Immunotherapeutic AEs and Tolerance­—As anticipated with immunotherapeutic agents, cemiplimab is associated with AEs that also are seen in its counterparts.¹¹ A total of 77.4% (24/31) of our cohort reported immune-related AEs, although the severity warranted treatment discontinuation in only 10 (10/24 [41.7%]) patients, representing less than half of those who encountered side effects and less than a third of the entire cohort. Furthermore, most of these immune-related AEs were managed effectively with short courses of oral steroids, further substantiating the notion that cemiplimab is generally well tolerated across patients of diverse performance statuses. Even for patients who discontinued treatment early due to immune-related side effects, benefits persisted despite the partial course of cemiplimab. Of the 10 patients who discontinued treatment due to immune AEs, 6 (60%) demonstrated stable complete response, 2 (20%) experienced relapse after stopping cemiplimab, and 2 (20%) demonstrated a partial response with stable disease.

Challenges in the Most Vulnerable Patient—Of the 5 recorded mortalities, 2 (40%) were attributed to disease progression, while 3 (60%) occurred before response assessment could be undertaken. The 3 patients who died prior to response evaluation were among the most medically fragile in the cohort, characterized by extensive metastatic cSCC and major comorbidities that, in isolation, posed life-threatening risks. For individuals grappling with widespread metastatic cSCC and substantial life-threatening comorbidities, it is plausible that the necessary physiologic resilience necessary for cemiplimab therapy may be absent. We hypothesize that an immune reconstitution syndrome–like response may be responsible for this early mortality, and these patients may lack the necessary physiological resilience to tolerate this response. This subset of patients warrants careful consideration when considering therapy with cemiplimab.

Conclusion

In summary, our results underscore the efficacy of cemiplimab, as it supported a response in more than three-quarters of our patient cohort. Additionally, the associated AEs, similar to those with other programmed cell death protein 1 inhibitors, generally were manageable with medical intervention. Our findings corroborate earlier studies that have demonstrated the therapeutic potential of cemiplimab in advanced, inoperable cSCC management. In addition to efficacy, our results also suggest that cemiplimab holds promise as a therapeutic option for patients who might not be amenable to the stresses of general anesthesia, surgery, or prolonged hospitalization, although cemiplimab should likely be used with caution in patients with severe, life-threatening medical comorbidities and/or concurrent severe illness. Furthermore, our data demonstrate that the benefits persist not only beyond the completion of the full 2-year course, but also after partial treatment courses discontinued due to patient-specific factors. Future studies would be useful to better understand and optimize dose and duration of cemiplimab treatment to maximize therapeutic effectiveness while minimizing risk of immune-related AEs. Among individuals confronting advanced, inoperable cSCC, cemiplimab is emerging as a viable and beneficial intervention.

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer and ranks sixth in prevalence among all cancers in the United Kingdom.^1,2 The etiologic factors underlying cSCC are well established, with major efforts undertaken by governments and public health organizations over the past 2 decades to increase public awareness globally. Known risk factors for cSCC include chronic exposure to UV radiation, radiotherapy, chemical injury, and immunosuppression. The first 3 risk factors amplify risk by increasing accumulation of abnormal gene mutations. Immunosuppression hampers the immune system’s ability to eradicate cells bearing malignant genetic aberrations. Notable gene mutations implicated in cSCC include p53, p16, telomerase reverse transcriptase, NOTCH1, ROS1, mitogen-activated protein kinases, forkhead box M1, and cyclooxygenase 2, in addition to matrix metalloproteinases, which are most commonly associated with Marjolin ulcers.³

The incidence of cSCC continues to surge worldwide,^3,4 with more patients presenting with advanced stages of disease and a notable increase in those presenting with unresectable cSCC due to either locally advanced disease or distant metastases.⁵ Existing therapies for cSCC include surgical excision (including Mohs micrographic surgery); radiotherapy (indicated for cosmetic reasons, locally advanced disease, and/or patient factors); and systemic treatments, encompassing chemotherapy (eg, ­5-fluorouracil), and epidermal growth factor receptor inhibitors (indicated locally advanced disease or distant metastases).⁴

In recent years, immunotherapy has emerged as a potent and effective treatment modality for unresectable cSCC, both locally advanced and metastatic. The success of immunotherapy in cSCC treatment can be attributed to the unique tumor microenvironment of cSCC, which is characterized by high tumor mutational burden, increased density of tumor-infiltrating lymphocytes (TILs), and heightened programmed cell death ligand 1 (PD-L1) expression on neoplastic cells. The elevated TIL density enables a robust immune response, rendering checkpoint inhibitors particularly effective. Greater tumor mutational burden further augments this enhanced TIL activity, amplifying the response to checkpoint inhibitors. Additionally, heightened PD-L1 expression facilitates more effective unmasking by checkpoint inhibitors, thereby enhancing the immune response.⁶

Cemiplimab is a programmed cell death protein 1/PD-L1 that was approved by the US Food and Drug Administration in September 2018 for treatment of cSCC. It also gained a European Union endorsement in June 2019 and National Institute for Health and Care Excellence approval in August 2019 based on the highly promising results of a phase 2 trial that involved only 59 adult patients with metastatic cSCC.⁷ The trial reported an overall response rate (ORR) of 47%, durable disease control in 61% of patients, a median time to response of 1.9 months, and response duration exceeding 6 months in 57% of patients. The phase 2 trials reported an estimated 12-month progression-free survival (PFS) of 53% and an estimated 12-month overall survival (OS) of 81%.⁷

Despite the noteworthy response statistics demonstrated by these studies, it is imperative to recognize that immunotherapies, while potent, are not without challenges. They can precipitate severe immune-related adverse events (AEs), including myocarditis, adrenal failure, and pneumonitis, which can negatively impact patient health outcomes and lead to early treatment cessation. The initial trials reported high-grade AEs such as pneumonitis, pleural effusion, and, notably 11 total deaths, with 8 (72.7%) attributed to disease progression and 3 (27.3%) to AEs.⁷ Additionally, cost and access to immunotherapy are inherent limitations of the treatment; immunotherapy agents are expensive, and not all centers or patients are able to access them.

The aim of this study was to assess the efficacy of cemiplimab in patients with inoperable cSCC, including locally advanced and metastatic disease, treated at a tertiary referral center in the United Kingdom, and to compare outcomes with the pivotal phase 2 trial that supported regulatory approval of cemiplimab.⁷ The primary objective was ORR, with secondary objectives including PFS, OS, and AEs.

Methods

The patients included in this study had unresectable cSCC and therefore were not candidates for surgery or radiotherapy. Patient demographics are presented in Table 1. The main indications for cemiplimab in place of surgery or radiotherapy included local recurrence, locally advanced disease involving deep structures, advanced nodal disease, and distant metastatic disease. Patients meeting these criteria and the following inclusion criteria for cemiplimab treatment from November 2018 through March 2023 at a single tertiary referral center were included in the study:

• Age 18 years or older
• Histologically confirmed cSCC with locoregional recurrence after surgery or radiotherapy, or histologically confirmed advanced or metastatic disease deemed to be inoperable
• Eastern Cooperative Oncology Group performance status of 0 to 2

All enrolled patients received intravenous infusions of cemiplimab 3 times weekly at a dosage of 350 mg. Treatment was continued until complete response, unacceptable toxicity, or disease progression, with a maximum duration of 2 years or 35 cycles. Patients underwent regular follow-up, typically 3 weeks preceding each treatment cycle. Monitoring adhered to the Common Terminology Criteria for Adverse Events, version 4.0, as outlined by the National Cancer Institute.⁸ Response to treatment was reported according to the guidelines stipulated by the Response Evaluation Criteria in Solid Tumours, version 1.1.⁹ Written informed consent was obtained for all patients.

Comprehensive patient demographics, histologic profiles, and clinical data were meticulously captured on a retrospective basis. The primary objective centered on elucidating the ORR. Secondary objectives encompassed evaluating PFS, OS, and a comprehensive analysis of AEs. Progression-free survival and OS were calculated by generating Kaplan-Meier curves using Python 3.9 (Python Software Foundation).

Results

Patient Characteristics—From November 2018 through March 2023, a cohort of 31 patients with inoperable cSCC underwent treatment with cemiplimab at our tertiary referral center. The median duration of follow-up was 13 months. Clinical characteristics are outlined in the Table 2. Four (12.9%) patients successfully completed the full 2-year treatment course. Nine (29.0%) continued to receive cemiplimab therapy at the conclusion of this study in March 2023, with treatment courses ranging from 2 to 11 months since initiation. Ten (32.3%) patients discontinued treatment due to AEs, while 5 (16.1%) regrettably ceased treatment due to mortality. Two (6.5%) patients terminated treatment due to the COVID-19 pandemic, and 1 (3.2%) discontinued treatment as a result of disease progression.

Clinical Efficacy—Of the 31 enrolled patients, a substantial proportion experienced positive clinical outcomes, with 20 (64.5%) achieving complete response and 6 (19.4%) achieving partial response. A total of 26 patients achieved a response on cemiplimab, with an ORR of 83.9% (95% CI, 66.3%-94.6%). Regrettably, 2 (6.5%) patients experienced disease progression, while 3 (9.7%) died before response to cemiplimab could be assessed. Following a median follow-up period of 13 months, the median PFS and OS remained unreached, emphasizing the efficacy of cemiplimab in treating inoperable cSCC (Figures 1 and 2).

In our cohort, 2-year PFS was 57.5% (95% CI, 33.9%-75.5%) with cemiplimab and 2-year OS was 70.6% (95% CI, 46.5%-85.4%). For PFS, we observed the steepest drops at onset and at the 23-month mark (Figure 1), while for OS we observed the steepest drop at the 38-month mark (Figure 2). Clinically, we observed cemiplimab causing near-complete regression of previously large, ulcerating, fungating cSCC in patients who responded to cemiplimab, mirroring results seen elsewhere.⁷

Adverse Events and Treatment Cessation—A substantial proportion of patients (24/31 [77.4%]) reported AEs during treatment. Notably, treatment discontinuation was necessary in 10 (32.3%) patients due to a range of AEs, including myocarditis, atrial flutter, pneumonitis, nephritis, derangement of liver function tests, and arthritis. Additional relevant side effects included adrenal insufficiency (3/31 [9.7%]), fatigue (3/31 [9.7%]), diarrhea (2/31 [6.5%]), and type 1 diabetes 1/31 [3.2%]). These outcomes emphasize the importance of vigilance and monitoring when administering cemiplimab in the context of advanced cSCC.

Comment

Historically, advanced cSCC has had a bleak prognosis. The nature of the disease generally meant these patients could not be operated on due to metastatic spread or local invasion, and radiotherapy was not curative. The only option remaining was palliation, but new therapies have shown promise due to specific inherent characteristics of advanced cSCC; for example, the characteristic high mutation burden prevalent in advanced cSCC has paved the way for the emergence of immunotherapy as a promising avenue for intervention.¹⁰ Cemiplimab in particular has emerged as a feasible treatment for patients who would otherwise be confined to palliation. Our findings derived from a local cohort reinforce this notion, with a remarkable 83.9% (26/31) exhibiting a favorable response to cemiplimab. Although this local sample of 31 patients is small in absolute terms, in the context of the trial with 59 participants⁷ that gained global approval for the use of cemiplimab, our study adds a substantial amount of data to the growing body of evidence on the long-term efficacy of cemiplimab. Notably, our results emphasize the potential applicability of cemiplimab among elderly patients and individuals with lower performance statuses: populations historically excluded from immunotherapeutic considerations.

Immunotherapeutic AEs and Tolerance­—As anticipated with immunotherapeutic agents, cemiplimab is associated with AEs that also are seen in its counterparts.¹¹ A total of 77.4% (24/31) of our cohort reported immune-related AEs, although the severity warranted treatment discontinuation in only 10 (10/24 [41.7%]) patients, representing less than half of those who encountered side effects and less than a third of the entire cohort. Furthermore, most of these immune-related AEs were managed effectively with short courses of oral steroids, further substantiating the notion that cemiplimab is generally well tolerated across patients of diverse performance statuses. Even for patients who discontinued treatment early due to immune-related side effects, benefits persisted despite the partial course of cemiplimab. Of the 10 patients who discontinued treatment due to immune AEs, 6 (60%) demonstrated stable complete response, 2 (20%) experienced relapse after stopping cemiplimab, and 2 (20%) demonstrated a partial response with stable disease.

Challenges in the Most Vulnerable Patient—Of the 5 recorded mortalities, 2 (40%) were attributed to disease progression, while 3 (60%) occurred before response assessment could be undertaken. The 3 patients who died prior to response evaluation were among the most medically fragile in the cohort, characterized by extensive metastatic cSCC and major comorbidities that, in isolation, posed life-threatening risks. For individuals grappling with widespread metastatic cSCC and substantial life-threatening comorbidities, it is plausible that the necessary physiologic resilience necessary for cemiplimab therapy may be absent. We hypothesize that an immune reconstitution syndrome–like response may be responsible for this early mortality, and these patients may lack the necessary physiological resilience to tolerate this response. This subset of patients warrants careful consideration when considering therapy with cemiplimab.

Conclusion

In summary, our results underscore the efficacy of cemiplimab, as it supported a response in more than three-quarters of our patient cohort. Additionally, the associated AEs, similar to those with other programmed cell death protein 1 inhibitors, generally were manageable with medical intervention. Our findings corroborate earlier studies that have demonstrated the therapeutic potential of cemiplimab in advanced, inoperable cSCC management. In addition to efficacy, our results also suggest that cemiplimab holds promise as a therapeutic option for patients who might not be amenable to the stresses of general anesthesia, surgery, or prolonged hospitalization, although cemiplimab should likely be used with caution in patients with severe, life-threatening medical comorbidities and/or concurrent severe illness. Furthermore, our data demonstrate that the benefits persist not only beyond the completion of the full 2-year course, but also after partial treatment courses discontinued due to patient-specific factors. Future studies would be useful to better understand and optimize dose and duration of cemiplimab treatment to maximize therapeutic effectiveness while minimizing risk of immune-related AEs. Among individuals confronting advanced, inoperable cSCC, cemiplimab is emerging as a viable and beneficial intervention.

Compared to later-onset procedures, early diagnosis of melanoma using affordable skin biopsies can result in better patient outcomes, lower health care expenditures, and enhanced psychological well-being.¹ Numerous research and economic evaluations that highlight the possible advantages of early intervention in melanoma care lend support to this strategy. In health care systems, the cost of early identification and screening for skin cancer is a critical factor.¹ There has been debate in the literature regarding performing more frequent biopsies earlier for skin cancers, which may greatly improve patient outcomes at the expense of increased financial cost, compared with performing fewer biopsies, which reduces costs at the potential expense of managing later-onset melanoma.^1,2 We sought to summarize the current literature and address some considerations that may help bring more clarity to this topic.

According to a study of a large health care system, the average cost of a skin cancer screening visit was $150, of which $105 (70%) went toward the costs of the office visit and $45 (30%) went toward the costs of the biopsy.¹ In the changing health care landscape, it is crucial to take into account the possible compounded savings from early diagnosis and treatment. While biopsies do involve some expenses, consideration of immunotherapy costs for advanced melanoma also should be considered, as they provide an alternative viewpoint on the financial effects of melanoma treatment.² The use of new systemic treatments such as immunotherapy has led to a notable rise in Medicare users’ first-year melanoma treatment expenses. The average expense of treating stage IV melanoma rose from $47,739 in 2007 through 2012 to $117,450 in 2018 through 2019. This sharp rise highlights how much more expensive treating advanced melanoma is than performing biopsies for early detection and treatment. Hundreds of biopsies might be carried out for the cost of a single advanced melanoma therapy, possibly identifying several cases at an earlier, more manageable stage.²

Patient quality of life and survival rates also can be considerably improved by early melanoma detection through screening.³ Compared to patients with later-stage diagnoses, those with early-stage melanoma reported a higher overall quality of life. Better physical functioning and reduced levels of anxiety and sadness were linked to early identification using skin biopsies. Patients with more advanced melanoma who had later-onset procedures, on the other hand, experience worsening psychological symptoms and physical health.³

A cost-effectiveness analysis using a Markov cohort model compared the long-term economic impact of early detection and primary prevention of melanoma. It found that daily use of sunscreen could prevent a substantial number of new skin tumors and melanoma deaths and reduce health care costs when compared to early detection strategies such as performing extra biopsies.⁴ There already are programs across the United States that aim to educate the public on the importance of wearing sunscreen; this has, in turn, reduced the prevalence of skin cancer in certain communities. Primary prevention resulted in just 1364 new melanomas and more than $430 million in expenditures per 100,000 individuals, whereas early diagnosis produced 2446 new melanomas and more than $660 million in economic expenses per 100,000 individuals.⁴ It is imperative to acknowledge that skin biopsies remain a vital tool for the early identification of melanoma, particularly in high-risk groups.

By using technologies such as teledermoscopy, the cost-effectiveness of skin cancer referral and consultation can be further enhanced; for example, teledermoscopy for skin cancer referral and triage would result in faster clinical resolution at an average cost of $54.64 per case. This method may reduce the need for redundant in-person consultations and increase the effectiveness of melanoma identification.⁵

Large-scale public health initiatives in skin cancer prevention and early detection have the potential to be very effective, as evidenced by the War on Melanoma project at Oregon Health & Science University (Portland, Oregon). This all-encompassing strategy, which uses cutting-edge technologies, public education, and health care professional training, has improved melanoma outcomes and decreased health care expenditures with encouraging results.⁶

A few tactics can be used to best balance the costs of later-onset procedures and early skin biopsies. These include using advanced technologies such as teledermoscopy and dermoscopy, provider training to increase diagnostic accuracy, public health campaigns to raise awareness and promote prevention, and a comprehensive strategy combining targeted early detection strategies with primary prevention.^5,6 Health care systems can optimize the financial efficiency and clinical results of melanoma treatment by putting these principles into practice.

Compared to later-onset melanoma procedures, early skin biopsies typically are more cost-effective, produce better patient outcomes, and offer psychological advantages, even if they may have a higher initial cost. Health care systems can optimize the trade-off between early detection and cost effectiveness in melanoma management by putting sophisticated technology to use, enhancing provider training, and implementing focused screening programs.^5,6 To support evidence-based policies and guidelines, future research should assess the long-term economic impact of different melanoma prevention and detection measures.

Compared to later-onset procedures, early diagnosis of melanoma using affordable skin biopsies can result in better patient outcomes, lower health care expenditures, and enhanced psychological well-being.¹ Numerous research and economic evaluations that highlight the possible advantages of early intervention in melanoma care lend support to this strategy. In health care systems, the cost of early identification and screening for skin cancer is a critical factor.¹ There has been debate in the literature regarding performing more frequent biopsies earlier for skin cancers, which may greatly improve patient outcomes at the expense of increased financial cost, compared with performing fewer biopsies, which reduces costs at the potential expense of managing later-onset melanoma.^1,2 We sought to summarize the current literature and address some considerations that may help bring more clarity to this topic.

According to a study of a large health care system, the average cost of a skin cancer screening visit was $150, of which $105 (70%) went toward the costs of the office visit and $45 (30%) went toward the costs of the biopsy.¹ In the changing health care landscape, it is crucial to take into account the possible compounded savings from early diagnosis and treatment. While biopsies do involve some expenses, consideration of immunotherapy costs for advanced melanoma also should be considered, as they provide an alternative viewpoint on the financial effects of melanoma treatment.² The use of new systemic treatments such as immunotherapy has led to a notable rise in Medicare users’ first-year melanoma treatment expenses. The average expense of treating stage IV melanoma rose from $47,739 in 2007 through 2012 to $117,450 in 2018 through 2019. This sharp rise highlights how much more expensive treating advanced melanoma is than performing biopsies for early detection and treatment. Hundreds of biopsies might be carried out for the cost of a single advanced melanoma therapy, possibly identifying several cases at an earlier, more manageable stage.²

Patient quality of life and survival rates also can be considerably improved by early melanoma detection through screening.³ Compared to patients with later-stage diagnoses, those with early-stage melanoma reported a higher overall quality of life. Better physical functioning and reduced levels of anxiety and sadness were linked to early identification using skin biopsies. Patients with more advanced melanoma who had later-onset procedures, on the other hand, experience worsening psychological symptoms and physical health.³

A cost-effectiveness analysis using a Markov cohort model compared the long-term economic impact of early detection and primary prevention of melanoma. It found that daily use of sunscreen could prevent a substantial number of new skin tumors and melanoma deaths and reduce health care costs when compared to early detection strategies such as performing extra biopsies.⁴ There already are programs across the United States that aim to educate the public on the importance of wearing sunscreen; this has, in turn, reduced the prevalence of skin cancer in certain communities. Primary prevention resulted in just 1364 new melanomas and more than $430 million in expenditures per 100,000 individuals, whereas early diagnosis produced 2446 new melanomas and more than $660 million in economic expenses per 100,000 individuals.⁴ It is imperative to acknowledge that skin biopsies remain a vital tool for the early identification of melanoma, particularly in high-risk groups.

By using technologies such as teledermoscopy, the cost-effectiveness of skin cancer referral and consultation can be further enhanced; for example, teledermoscopy for skin cancer referral and triage would result in faster clinical resolution at an average cost of $54.64 per case. This method may reduce the need for redundant in-person consultations and increase the effectiveness of melanoma identification.⁵

Large-scale public health initiatives in skin cancer prevention and early detection have the potential to be very effective, as evidenced by the War on Melanoma project at Oregon Health & Science University (Portland, Oregon). This all-encompassing strategy, which uses cutting-edge technologies, public education, and health care professional training, has improved melanoma outcomes and decreased health care expenditures with encouraging results.⁶

A few tactics can be used to best balance the costs of later-onset procedures and early skin biopsies. These include using advanced technologies such as teledermoscopy and dermoscopy, provider training to increase diagnostic accuracy, public health campaigns to raise awareness and promote prevention, and a comprehensive strategy combining targeted early detection strategies with primary prevention.^5,6 Health care systems can optimize the financial efficiency and clinical results of melanoma treatment by putting these principles into practice.

Compared to later-onset melanoma procedures, early skin biopsies typically are more cost-effective, produce better patient outcomes, and offer psychological advantages, even if they may have a higher initial cost. Health care systems can optimize the trade-off between early detection and cost effectiveness in melanoma management by putting sophisticated technology to use, enhancing provider training, and implementing focused screening programs.^5,6 To support evidence-based policies and guidelines, future research should assess the long-term economic impact of different melanoma prevention and detection measures.

Compared to later-onset procedures, early diagnosis of melanoma using affordable skin biopsies can result in better patient outcomes, lower health care expenditures, and enhanced psychological well-being.¹ Numerous research and economic evaluations that highlight the possible advantages of early intervention in melanoma care lend support to this strategy. In health care systems, the cost of early identification and screening for skin cancer is a critical factor.¹ There has been debate in the literature regarding performing more frequent biopsies earlier for skin cancers, which may greatly improve patient outcomes at the expense of increased financial cost, compared with performing fewer biopsies, which reduces costs at the potential expense of managing later-onset melanoma.^1,2 We sought to summarize the current literature and address some considerations that may help bring more clarity to this topic.

According to a study of a large health care system, the average cost of a skin cancer screening visit was $150, of which $105 (70%) went toward the costs of the office visit and $45 (30%) went toward the costs of the biopsy.¹ In the changing health care landscape, it is crucial to take into account the possible compounded savings from early diagnosis and treatment. While biopsies do involve some expenses, consideration of immunotherapy costs for advanced melanoma also should be considered, as they provide an alternative viewpoint on the financial effects of melanoma treatment.² The use of new systemic treatments such as immunotherapy has led to a notable rise in Medicare users’ first-year melanoma treatment expenses. The average expense of treating stage IV melanoma rose from $47,739 in 2007 through 2012 to $117,450 in 2018 through 2019. This sharp rise highlights how much more expensive treating advanced melanoma is than performing biopsies for early detection and treatment. Hundreds of biopsies might be carried out for the cost of a single advanced melanoma therapy, possibly identifying several cases at an earlier, more manageable stage.²

Patient quality of life and survival rates also can be considerably improved by early melanoma detection through screening.³ Compared to patients with later-stage diagnoses, those with early-stage melanoma reported a higher overall quality of life. Better physical functioning and reduced levels of anxiety and sadness were linked to early identification using skin biopsies. Patients with more advanced melanoma who had later-onset procedures, on the other hand, experience worsening psychological symptoms and physical health.³

A cost-effectiveness analysis using a Markov cohort model compared the long-term economic impact of early detection and primary prevention of melanoma. It found that daily use of sunscreen could prevent a substantial number of new skin tumors and melanoma deaths and reduce health care costs when compared to early detection strategies such as performing extra biopsies.⁴ There already are programs across the United States that aim to educate the public on the importance of wearing sunscreen; this has, in turn, reduced the prevalence of skin cancer in certain communities. Primary prevention resulted in just 1364 new melanomas and more than $430 million in expenditures per 100,000 individuals, whereas early diagnosis produced 2446 new melanomas and more than $660 million in economic expenses per 100,000 individuals.⁴ It is imperative to acknowledge that skin biopsies remain a vital tool for the early identification of melanoma, particularly in high-risk groups.

By using technologies such as teledermoscopy, the cost-effectiveness of skin cancer referral and consultation can be further enhanced; for example, teledermoscopy for skin cancer referral and triage would result in faster clinical resolution at an average cost of $54.64 per case. This method may reduce the need for redundant in-person consultations and increase the effectiveness of melanoma identification.⁵

Large-scale public health initiatives in skin cancer prevention and early detection have the potential to be very effective, as evidenced by the War on Melanoma project at Oregon Health & Science University (Portland, Oregon). This all-encompassing strategy, which uses cutting-edge technologies, public education, and health care professional training, has improved melanoma outcomes and decreased health care expenditures with encouraging results.⁶

A few tactics can be used to best balance the costs of later-onset procedures and early skin biopsies. These include using advanced technologies such as teledermoscopy and dermoscopy, provider training to increase diagnostic accuracy, public health campaigns to raise awareness and promote prevention, and a comprehensive strategy combining targeted early detection strategies with primary prevention.^5,6 Health care systems can optimize the financial efficiency and clinical results of melanoma treatment by putting these principles into practice.

Compared to later-onset melanoma procedures, early skin biopsies typically are more cost-effective, produce better patient outcomes, and offer psychological advantages, even if they may have a higher initial cost. Health care systems can optimize the trade-off between early detection and cost effectiveness in melanoma management by putting sophisticated technology to use, enhancing provider training, and implementing focused screening programs.^5,6 To support evidence-based policies and guidelines, future research should assess the long-term economic impact of different melanoma prevention and detection measures.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.

Transthyretin amyloid cardiomyopathy (ATTR-CM) is caused by the misfolding of the TTR protein, which results in aggregation of amyloid fibrils that deposit in the myocardium and causes restrictive cardiomyopathy. Though it remains underdiagnosed, ATTR-CM is increasingly being recognized as a cause of heart failure in geriatric patients.¹ There are 2 categories of ATTRCM: wild-type ATTR-CM (wtATTR-CM), in which there is no mutation in the TTR gene, and hereditary ATTR-CM (hATTR-CM), in which a mutation is present in the TTR gene. Research has shown that wtATTR-CM accounted for as many as 30% of cases of heart failure (HF) with preserved ejection fraction (HFpEF) in patients aged > 75 years.² A significant percentage of the veteran patient population consists of older males. Given their age, these patients are at greater risk for ATTR diagnosis.³

Identifying red flags for patients within this population may allow clinicians to make earlier diagnoses and improve outcomes. A high index of suspicion is needed to diagnose ATTR because many early signs and symptoms are extracardiac, which leads to delayed diagnoses and worse outcomes. This article describes 8 cases of ATTR-CM within the US Department of Veterans Affairs (VA) New York Harbor Healthcare System-Brooklyn (VANYHHSB).

Methods

This retrospective case series was reviewed and approved by the VANYHHSB Institutional Review Board where it was conducted. Patients diagnosed with ATTR between 2017 and 2024 were identified using International Classification of Diseases, Tenth Revision codes. Eleven patients were identified; 3 were excluded due to insufficient medical records. The remaining 8 patient records were retrospectively reviewed and included.

Case 1

A 67-year-old male with a history of carpal tunnel syndrome (CTS) presented following a syncopal episode. Initial electrocardiogram (ECG) showed sinus rhythm, first-degree atrioventricular block, and a bifascicular block. Transthoracic echocardiogram (TTE) showed moderate asymmetric left ventricular (LV) hypertrophy (LVH) and biatrial enlargement with an ejection fraction (EF) > 55%. The patient was discharged with a loop recorder and an outpatient follow-up appointment scheduled. One month later, he presented with worsening dyspnea on exertion with clinical signs of hypervolemia. A repeat TTE showed global LV wall thickening, moderately reduced LV systolic function (EF 40%), and moderate pulmonary hypertension. Given these findings, the patient underwent cardiac magnetic resonance imaging (CMR), which suggested an infiltrative cardiomyopathy. Amyloid light-chain (AL) amyloidosis evaluation, technetium-99m (^99mTC) pyrophosphate imaging, and a fat pad biopsy were unrevealing. An endomyocardial biopsy was performed with electron microscopy, which confirmed amyloidosis. Genetic testing was negative, and the patient began taking tafamidis. There were no later admissions for decompensated HF; however, the patient developed atrial fibrillation (AF) and an interval TTE demonstrated no improvement in his EF. He died at age 73 years.

Case 2

A 78-year-old male with a history of CTS presented with lightheadedness. Initial ECG showed rate-controlled AF and TTE revealed a moderately thickened LV wall with normal LV size, mild left atrial enlargement, and an EF of 65%. The patient was discharged with a scheduled outpatient CMR appointment; however, he defaulted from follow-up. Two years later, he presented with recurrent syncopal episodes and physical examination was consistent with hypervolemia. Repeat TTE revealed moderate LVH, biatrial enlargement, and an EF of 55%. An inpatient CMR was suggestive of cardiac amyloidosis, and a pyrophosphate scan was diagnostic for ATTR. The patient started taking tafamidis, but continued to have recurrent admissions for HF exacerbation. He died at age 81 years.

Case 3

A 71-year-old male with a history of CTS presented with exertional dyspnea. The initial ECG showed sinus rhythm with left atrial enlargement and left axis deviation. Subsequent TTE revealed severe LVH, mildly reduced LV cavity size, moderate to severe biatrial enlargement, and an EF of 25% to 30%. Outpatient ^99mTC pyrophosphate imaging suggested cardiac amyloidosis, and laboratory testing showed no evidence of monoclonal proteins. The patient was started on tafamidis for ATTR. At 2-year follow-up, he had new AF and to date has had no further hospitalizations for acute decompensated HF.

Case 4

A 92-year-old male with a history of AF and bilateral CTS presented with lightheadedness. An ECG revealed AF with a slowed ventricular response. Subsequent Holter monitoring demonstrated pauses exceeding 3 seconds, and a permanent pacemaker was recommended. During his preoperative evaluation, TTE revealed severe concentric LVH with a speckled appearance of the myocardium, mild-tomoderate biatrial enlargement, and an EF of 50% to 55%. 99mTC pyrophosphate imaging was positive for amyloidosis and the patient started taking tafamidis. Recurrent hospital admissions for decompensated HF complicated his progression. The patient died at age 95 years.

Case 5

A 72-year-old male with a history of bilateral CTS and cervical spinal stenosis presented with dyspnea on exertion. An ECG revealed a normal sinus rhythm. A TTE found severely reduced systolic function with an EF ≤ 25%, mild concentric LVH, grade 3 diastolic dysfunction, mild-tomoderate biatrial enlargement, and moderate pulmonary hypertension (Figure 1). He was started on guideline-directed medical therapy (GDMT) for HF, which included sacubitril/valsartan, metoprolol succinate, and empagliflozin. The patient’s dyspnea improved, and a workup for nonischemic cardiomyopathy was initiated. 99mTC pyrophosphate imaging 1 year after his initial presentation was positive, leading to ATTR-CM diagnosis. The patient started taking tafamidis and he has since had a stable progression and continued to demonstrate good exercise tolerance with no hospitalizations. His most recent TTE indicated an EF of 40% to 45%.

Case 6

A 76-year-old male with a history of paroxysmal AF status after multiple ablations, bilateral CTS, and severe cervical spinal stenosis presented with dyspnea on exertion. The patient’s ECG showed normal sinus rhythm and left axis deviation with concern for left anterior hemiblock. A TTE revealed moderate LVH with a speckled appearance of the myocardium and grade 3 diastolic dysfunction with preserved EF. Before completing the workup for underlying cardiomyopathy, the patient underwent an interventional radiology procedure for an angiomyolipoma, and his postoperative course was complicated by pulmonary edema, requiring admission to the coronary care unit for diuresis. A repeat TTE revealed a reduced EF of 35%, and he was discharged on GDMT. No monoclonal protein was seen in the serum or urine. The patient’s progression was complicated by recurrent admissions for acute decompensated HF and supraventricular tachycardia despite being on amiodarone, which led to a delay in obtaining 99mTC pyrophosphate imaging. Due to hypotension, the patient was unable to tolerate GDMT. He eventually underwent 99mTC pyrophosphate imaging that confirmed ATTR-CM and was started on tafamidis. One year following initial presentation, the patient’s EF progressively declined to 20% to 25%, and he died shortly after discharge to subacute rehabilitation.

Case 7

A 95-year-old male with a history of longstanding persistent AF and bilateral CTS presented with dyspnea on exertion, bendopnea, and worsening bilateral pedal edema for a week. An ECG showed AF with a controlled ventricular response and low-voltage QRS waves (Figure 2). A TTE showed biatrial enlargement, LVH, and preserved EF > 55%. He started taking furosemide and was discharged with a diagnosis of HFpEF. The patient missed cardiology follow-up and presented 1 year later with decompensated HF. An amyloidosis workup was recommended, but due to intermittent periods of being lost to follow-up, the patient did not pursue this workup until 3 years after his initial presentation when 99mTC pyrophosphate imaging confirmed ATTR-CM. The patient declined tafamidis and continued to be followed by the cardiology team. His HF is managed with furosemide as needed due to intolerance to GDMT.

Case 8

A 74-year-old male with history of bilateral CTS presented with right-sided chest pain associated with shortness of breath, diaphoresis, dizziness, and worsening abdominal pain. He was found to have inferior wall myocardial infarction on ECG with later percutaneous coronary intervention to the left circumflex. His hospital course was complicated by decompensated HF (EF 45% to 50%) and AF with rapid ventricular response. He was treated and discharged with follow-up visits scheduled in the cardiology clinic. Multiple attempts were made to place him on GDMT; however, the patient was unable to tolerate these medications due to recurrent admissions for syncope. During a cardiology clinic visit 3 years after his initial presentation, an amyloidosis workup was initiated. 99mTC pyrophosphate imaging was positive for ATTR-CM, and he started taking tafamidis. Before this diagnosis, ECG indicated low-voltage QRS complexes. His progression has since been complicated by admissions for decompensated HF, recurrent episodes of AF requiring atrioventricular node ablation, and biventricular implantable cardioverter-defibrillator implantation after failed attempts at electrical cardioversion. He continued to follow up in the HF clinic.

Discussion

ATTR-CM is an underdiagnosed cause of cardiomyopathy, particularly in older adults. TTR is a transport protein produced in the liver, and misfolding can occur due to age-related instability of the wild-type protein (wtATTR) or pathologic variants in the TTR (hATTR). The misfolding leads to restrictive physiology, HF (often with preserved EF) arrhythmias, and conduction system disease.¹ It is likely that the predominantly older male veteran population would be predisposed to wtATTR cardiomyopathy given that misfolding in the condition is believed to be age-related.

Current criteria for ATTR diagnosis require a combination of clinical suspicion, imaging, laboratory testing, and, in some cases, tissue biopsy confirmation and genetic testing.^1,4,5 The diagnostic algorithm is as follows:

Clinical suspicion. Consider ATTR in patients with unexplained HFpEF, LV wall thickness ≥ 12 to 14 mm, discordance between ECG voltage and wall thickness, or associated extracardiac manifestations such as CTS, lumbar spinal stenosis, or peripheral/ autonomic neuropathy.

Exclusion of AL amyloidosis. Bone scintigraphy alone cannot distinguish between AL amyloidosis and ATTR, so patients with suspected amyloid cardiomyopathy should undergo serum and urine immunofixation electrophoresis and serum free light chain assay to rule out a monoclonal gammopathy as seen in AL amyloidosis.

Cardiac scintigraphy. Once AL amyloidosis is excluded, a positive 99mTC-labeled boneavid tracer image (such as a pyrophosphate scan) with grade 2 or grade 3 myocardial uptake is diagnostic of ATTR.

Tissue biopsy. If there is monoclonal gammopathy or equivocal imaging, tissue biopsy (eg, endomyocardial) with Congo red staining and amyloid typing by mass spectrometry or immunohistochemistry is necessary.

Genetic testing. Once ATTR is confirmed, genetic testing distinguishes hATTR from wtATTR, which impacts management and determines the need to screen family members.

Currently, there are 3 therapies approved by the US Food and Drug Administration (FDA) to treat ATTR-CM: tafamidis, acoramidis, and vutrisiran.^6-8 Tafamidis and acoramidis stabilize the TTR tetramer, preventing amyloid formation. Vutrisiran uses RNA interference to silence the gene that produces TTR. Tafamidis has been found to improve cardiovascular outcomes in ATTR-CM. In the ATTR-ACT trial, it reduced all-cause mortality and cardiovascular hospitalizations in patients with ATTR-CM and New York Heart Association class I-III symptoms.⁶ There are other disease-modifying therapies, such the TTR gene silencers inotersen and patisiran; however, these are only FDA-approved for hATTR polyneuropathy and not for ATTRCM; ongoing trials are evaluating their cardiac efficacy.

The mean age of ATTR-CM diagnosis in the patients described in this case series was 79 years, which is older than the mean age of 74 years reported in prior research.⁴ All patients were male, and the most common presenting symptom was dyspnea on exertion. Table 1 outlines baseline characteristics and associated comorbidities of patients in this case series. The patients presented with many red-flag signs of ATTR-CM (Figure 3). Among them included syncope (4 of 8 patients), spinal stenosis (2 of 8 patients), arrhythmia (7 of 8 patients), heart failure (7 of 8 patients), and bilateral CTS (all patients).

Bilateral CTS was diagnosed in all patients before their diagnosis of ATTR-CM. Patient 7 had a diagnosis of CTS 9 years before his ATTR-CM diagnosis, underscoring a subtle, yet important extracardiac sign that may increase clinical suspicion for ATTR-CM. Previous research found that the probability of having CTS is highest 5 to 9 years prior to the development of cardiomyopathy. Its presence is also a prognostic marker in ATTR, independent of cardiac involvement.⁹ The median interval between CTS diagnosis and cardiomyopathy diagnosis was 5 years in this series.

Although screening criteria for ATTR have been proposed, none have been incorporated into formal guidelines.^10,11 We propose that a baseline ECG and screening TTE be obtained in any patient aged > 65 years with cardiac risk equivalents such as hypertension and diabetes, presenting with ≥ 1 extracardiac red-flag signs, such as bilateral CTS and spinal stenosis. This will likely facilitate an earlier diagnosis of ATTR-CM, leading to earlier treatment initiation and better patient outcomes. This initiative can be started in the primary care setting and facilitates early cardiology referral. This recommendation is based on literature supporting clinical patterns and observations the authors have made in clinical practice.

Obstructive sleep apnea (OSA) was a comorbidity present in 50% of the patients described in this case series. The literature describing this association is sparse; however, a prospective observational study reported that disorders of sleep inclusive of OSA are frequent in patients with cardiac amyloidosis.¹² A theory behind this association is that amyloid deposits in the upper airway tissues lead to airway narrowing. ¹³ More research is needed to further assess the relationship between OSA and cardiac amyloidosis, particularly with respect to the timing of OSA prior to the development of cardiomyopathy as it may be a potential early sign for clinicians to acknowledge.

An important observation from this case series is the variability in the timing of tafamidis initiation relative to symptom onset and confirmed diagnosis of ATTR-CM (Table 2). Although tafamidis has been found to slow disease progression, several patients in this series began treatment at advanced stages or years after the onset of cardiac symptoms, potentially limiting its clinical benefit.

For example, patient 1 was diagnosed with ATTR 2 years before tafamidis became available on the market and was initially treated with diflunisal. Patients who started tafamidis earlier in the disease course (eg, patients 3 and 5) appeared to have better long-term outcomes, including an absence of heart failure hospitalizations after initiation. In contrast, patients with delayed treatment initiation (eg, patients 2, 6, and 8) experienced ongoing decompensations or early mortality. Patient 7 declined tafamidis, underscoring challenges in medication uptake among older adults. Randomized controlled trials are warranted to compare the effectiveness of tafamidis with other recently FDA-approved therapies, such as acoramidis and vutrisiran, particularly in terms of cardiovascular outcomes.

AF was the most common arrhythmia observed in these patients and may occur years before the development of HF symptoms in the setting of ATTR-CM. Due to inherent conduction system disease, AF in this population may have a controlled or slow ventricular response, as observed in patient 4. Patients with atrial fibrillation and cardiac amyloidosis should receive anticoagulation regardless of CHA2DS2- VASc score due to their high risk of intracardiac thrombus formation.⁴

Limitations

This case series lacked genetic testing following a confirmed ATTR-CM diagnosis. Although much of the treatment is the same regardless of the presence of a TTR mutation, knowing the specific subtype of ATTR-CM has implications for prognosis and for screening family members.

Conclusions

Following analysis of 8 patients diagnosed with ATTR, this case series could serve as a blueprint for research into ATTR in veterans. In clinical practice, following military service, veterans may not be routinely seen by an outpatient physician and may present with sequelae of advanced stages of ATTR. Early identification of red-flag symptoms can lead to a higher clinical suspicion, prompting early diagnostic evaluation and treatment initiation and ultimately mitigating adverse outcomes. Future research that includes genetic testing for those with confirmed ATTR-CM may prove useful as a foundation for detailed and informed discussions with patients and their families regarding prognosis and, if indicated, screening for family members.