Mixed Topics

To the Editor:

Indeterminate cell histiocytosis (ICH) is a rare neoplastic dendritic cell disorder with a poorly understood histogenesis and pathogenesis.¹ The clinical manifestation of ICH is broad and can include isolated or multiple papules or nodules on the face, neck, trunk, arms, or legs. Our case demonstrates a rare occurrence of ICH that initially was misdiagnosed and highlights the use of cobimetinib, a MEK inhibitor, as a potential new therapeutic option for ICH.

A 74-year-old man with a history of type 2 diabetes mellitus presented for evaluation of a progressive pruritic rash of approximately 5 years’ duration. The eruption previously had been diagnosed as Langerhans cell histiocytosis. It started on the chest and spread to the face, neck, trunk, and arms. The patient denied systemic symptoms and had no known history of malignancy.

Physical examination revealed pink to orange smooth papules, nodules, and small plaques on the ears, cheeks, trunk, neck, and arms (Figure 1). Baseline laboratory results showed a normal complete blood count and comprehensive metabolic panel, elevated lactate dehydrogenase and erythrocyte sedimentation rate, and hyperlipidemia. Serology for hepatitis B and C was negative. Bone marrow biopsy was normal, and positron emission tomography/ computed tomography demonstrated no evidence of extracutaneous disease. A punch biopsy of a lesion on the left forearm revealed epithelioid histiocytic proliferation in the dermis extending into the subcutis with a background infiltrate of small lymphocytes. Immunohistochemistry was positive for CD1a and CD56 and was variably positive for CD4 but negative for CD163, CD68, S100, Langerin, cyclin D1, myeloperoxidase, CD21, and CD23. No mutation was detected in BRAF codon 600. Given the negative Langerin stain, these findings were compatible with a diagnosis of ICH. After considering the lack of standard treatment options as well as the recent approval of cobimetinib for histiocytic disorders, we initiated treatment with cobimetinib at the standard dose of 60 mg daily for 21 days followed by a 7-day break.

One month into treatment, the patient’s lesions were less erythematous, and he reported improvement in pruritus. Two months into treatment, there was continued improvement in cutaneous symptoms with flattening of the lesions on the chest and back. At this time, the patient developed edema of the face and ears (Figure 2) and reported weakness, blurred vision, and decreased appetite. He was advised to take an additional 7-day treatment break before resuming cobimetinib at a decreased dose of 40 mg daily. The patient returned to the clinic 1 month later with improved systemic symptoms and continued flattening of the lesions. Five months into treatment, the lesions had continued to improve with complete resolution of the facial plaques (Figure 3).

Indeterminate cell histiocytosis is a rarely diagnosed condition characterized by the proliferation of indeterminate histiocytes that morphologically and immunophenotypically resemble Langerhans cells but lack their characteristic Birbeck granules.² There is no standard treatment for ICH, but previous reports have described improvement with a variety of treatment options including methotrexate,^3,4 UVB phototherapy,⁵ and topical delgocitinib 0.5%.⁶

Because histiocytic disorders are characterized by mutations in the mitogen-activated protein kinase pathway, it is possible that they would be responsive to MEK inhibition. Cobimetinib, a MEK inhibitor initially approved to treat metastatic melanoma, was approved by the US Food and Drug Administration to treat histiocytic disorders in October 2022.⁷ The approval followed the release of data from a phase 2 trial of cobimetinib in 18 adults with various histiocytic disorders, which demonstrated an 89% (16/18) overall response rate with 94% (17/18) of patients remaining progression free at 1 year.⁸ While cobimetinib has not specifically been studied in ICH, given the high response rate in histiocytic disorders and the lack of standard treatment options for ICH, the decision was made to initiate treatment with cobimetinib in our patient. Based on the observed improvement in our patient, we propose cobimetinib as a treatment option for patients with cutaneous ICH and recommend additional studies to confirm its safety and efficacy in patients with this disorder.

To the Editor:

Indeterminate cell histiocytosis (ICH) is a rare neoplastic dendritic cell disorder with a poorly understood histogenesis and pathogenesis.¹ The clinical manifestation of ICH is broad and can include isolated or multiple papules or nodules on the face, neck, trunk, arms, or legs. Our case demonstrates a rare occurrence of ICH that initially was misdiagnosed and highlights the use of cobimetinib, a MEK inhibitor, as a potential new therapeutic option for ICH.

A 74-year-old man with a history of type 2 diabetes mellitus presented for evaluation of a progressive pruritic rash of approximately 5 years’ duration. The eruption previously had been diagnosed as Langerhans cell histiocytosis. It started on the chest and spread to the face, neck, trunk, and arms. The patient denied systemic symptoms and had no known history of malignancy.

Physical examination revealed pink to orange smooth papules, nodules, and small plaques on the ears, cheeks, trunk, neck, and arms (Figure 1). Baseline laboratory results showed a normal complete blood count and comprehensive metabolic panel, elevated lactate dehydrogenase and erythrocyte sedimentation rate, and hyperlipidemia. Serology for hepatitis B and C was negative. Bone marrow biopsy was normal, and positron emission tomography/ computed tomography demonstrated no evidence of extracutaneous disease. A punch biopsy of a lesion on the left forearm revealed epithelioid histiocytic proliferation in the dermis extending into the subcutis with a background infiltrate of small lymphocytes. Immunohistochemistry was positive for CD1a and CD56 and was variably positive for CD4 but negative for CD163, CD68, S100, Langerin, cyclin D1, myeloperoxidase, CD21, and CD23. No mutation was detected in BRAF codon 600. Given the negative Langerin stain, these findings were compatible with a diagnosis of ICH. After considering the lack of standard treatment options as well as the recent approval of cobimetinib for histiocytic disorders, we initiated treatment with cobimetinib at the standard dose of 60 mg daily for 21 days followed by a 7-day break.

One month into treatment, the patient’s lesions were less erythematous, and he reported improvement in pruritus. Two months into treatment, there was continued improvement in cutaneous symptoms with flattening of the lesions on the chest and back. At this time, the patient developed edema of the face and ears (Figure 2) and reported weakness, blurred vision, and decreased appetite. He was advised to take an additional 7-day treatment break before resuming cobimetinib at a decreased dose of 40 mg daily. The patient returned to the clinic 1 month later with improved systemic symptoms and continued flattening of the lesions. Five months into treatment, the lesions had continued to improve with complete resolution of the facial plaques (Figure 3).

Indeterminate cell histiocytosis is a rarely diagnosed condition characterized by the proliferation of indeterminate histiocytes that morphologically and immunophenotypically resemble Langerhans cells but lack their characteristic Birbeck granules.² There is no standard treatment for ICH, but previous reports have described improvement with a variety of treatment options including methotrexate,^3,4 UVB phototherapy,⁵ and topical delgocitinib 0.5%.⁶

Because histiocytic disorders are characterized by mutations in the mitogen-activated protein kinase pathway, it is possible that they would be responsive to MEK inhibition. Cobimetinib, a MEK inhibitor initially approved to treat metastatic melanoma, was approved by the US Food and Drug Administration to treat histiocytic disorders in October 2022.⁷ The approval followed the release of data from a phase 2 trial of cobimetinib in 18 adults with various histiocytic disorders, which demonstrated an 89% (16/18) overall response rate with 94% (17/18) of patients remaining progression free at 1 year.⁸ While cobimetinib has not specifically been studied in ICH, given the high response rate in histiocytic disorders and the lack of standard treatment options for ICH, the decision was made to initiate treatment with cobimetinib in our patient. Based on the observed improvement in our patient, we propose cobimetinib as a treatment option for patients with cutaneous ICH and recommend additional studies to confirm its safety and efficacy in patients with this disorder.

To the Editor:

Indeterminate cell histiocytosis (ICH) is a rare neoplastic dendritic cell disorder with a poorly understood histogenesis and pathogenesis.¹ The clinical manifestation of ICH is broad and can include isolated or multiple papules or nodules on the face, neck, trunk, arms, or legs. Our case demonstrates a rare occurrence of ICH that initially was misdiagnosed and highlights the use of cobimetinib, a MEK inhibitor, as a potential new therapeutic option for ICH.

A 74-year-old man with a history of type 2 diabetes mellitus presented for evaluation of a progressive pruritic rash of approximately 5 years’ duration. The eruption previously had been diagnosed as Langerhans cell histiocytosis. It started on the chest and spread to the face, neck, trunk, and arms. The patient denied systemic symptoms and had no known history of malignancy.

Physical examination revealed pink to orange smooth papules, nodules, and small plaques on the ears, cheeks, trunk, neck, and arms (Figure 1). Baseline laboratory results showed a normal complete blood count and comprehensive metabolic panel, elevated lactate dehydrogenase and erythrocyte sedimentation rate, and hyperlipidemia. Serology for hepatitis B and C was negative. Bone marrow biopsy was normal, and positron emission tomography/ computed tomography demonstrated no evidence of extracutaneous disease. A punch biopsy of a lesion on the left forearm revealed epithelioid histiocytic proliferation in the dermis extending into the subcutis with a background infiltrate of small lymphocytes. Immunohistochemistry was positive for CD1a and CD56 and was variably positive for CD4 but negative for CD163, CD68, S100, Langerin, cyclin D1, myeloperoxidase, CD21, and CD23. No mutation was detected in BRAF codon 600. Given the negative Langerin stain, these findings were compatible with a diagnosis of ICH. After considering the lack of standard treatment options as well as the recent approval of cobimetinib for histiocytic disorders, we initiated treatment with cobimetinib at the standard dose of 60 mg daily for 21 days followed by a 7-day break.

One month into treatment, the patient’s lesions were less erythematous, and he reported improvement in pruritus. Two months into treatment, there was continued improvement in cutaneous symptoms with flattening of the lesions on the chest and back. At this time, the patient developed edema of the face and ears (Figure 2) and reported weakness, blurred vision, and decreased appetite. He was advised to take an additional 7-day treatment break before resuming cobimetinib at a decreased dose of 40 mg daily. The patient returned to the clinic 1 month later with improved systemic symptoms and continued flattening of the lesions. Five months into treatment, the lesions had continued to improve with complete resolution of the facial plaques (Figure 3).

Indeterminate cell histiocytosis is a rarely diagnosed condition characterized by the proliferation of indeterminate histiocytes that morphologically and immunophenotypically resemble Langerhans cells but lack their characteristic Birbeck granules.² There is no standard treatment for ICH, but previous reports have described improvement with a variety of treatment options including methotrexate,^3,4 UVB phototherapy,⁵ and topical delgocitinib 0.5%.⁶

Because histiocytic disorders are characterized by mutations in the mitogen-activated protein kinase pathway, it is possible that they would be responsive to MEK inhibition. Cobimetinib, a MEK inhibitor initially approved to treat metastatic melanoma, was approved by the US Food and Drug Administration to treat histiocytic disorders in October 2022.⁷ The approval followed the release of data from a phase 2 trial of cobimetinib in 18 adults with various histiocytic disorders, which demonstrated an 89% (16/18) overall response rate with 94% (17/18) of patients remaining progression free at 1 year.⁸ While cobimetinib has not specifically been studied in ICH, given the high response rate in histiocytic disorders and the lack of standard treatment options for ICH, the decision was made to initiate treatment with cobimetinib in our patient. Based on the observed improvement in our patient, we propose cobimetinib as a treatment option for patients with cutaneous ICH and recommend additional studies to confirm its safety and efficacy in patients with this disorder.

Hidradenitis suppurativa (HS) is a debilitating dermatologic condition characterized by recurrent episodes of neutrophilic inflammation affecting the apocrine and pilosebaceous units that most commonly affects individuals aged 20 to 40 years. Originating from the hair follicles, inflammation initiates the formation of painful nodules and abscesses that can progress to sinus tracts or fistulas accompanied by the development of extensive scarring, exquisite pain, and malodorous drainage.¹ The lesions most commonly occur in intertriginous zones as well as areas rich in apocrine glands. The distinctive and sometimes irreversible clinical features of HS profoundly influence patients’ well-being and have lasting social, personal, and emotional impacts on their lives.²

Bimekizumab is a monoclonal antibody that specifically targets IL-17A and IL-17F, aiming to inhibit the downstream effects responsible for the chronic inflammation and tissue damage characteristic of HS.³ In HS lesions, IL-17 cytokines produced by T helper 17 (Th17) cells stimulate the production of chemokines (such as CC motif chemokine ligand 20) and neutrophil-attracting chemokines (including C-X-C motif chemokine ligands 1 and 8), cytokines (such as granulocyte colony-stimulating factor and IL-19), and epidermal antimicrobial proteins.^1,2 This cascade results in the chemotaxis of monocytes and neutrophils in the skin, recruiting additional Th17 and myeloid cells and further amplifying IL-17 production.¹

Bimekizumab’s mechanism of action strategically disrupts this feed-forward inflammatory loop, decreasing the transcription of neutrophil-attracting chemokines, IL-19, and epidermal antimicrobial proteins (Figure).^1,2 This leads to diminished recruitment of Th17 cells and inhibits the chemotaxis of monocytes and neutrophils in the skin, effectively addressing the chronic inflammation and tissue damage characteristic of HS.

We present a comprehensive review of the current standards of care, the underlying molecular pathophysiology of HS, and evaluation of the efficacy and safety of bimekizumab.

Evaluating HS Severity

The Hurley staging system provides a valuable framework for evaluating the severity of HS based on lesion characteristics. Stage I is characterized by abscess formation without tracts or scars. Stage II is characterized by recurrent abscesses with sinus tracts and scarring. Stage III is characterized by diffuse involvement, multiple interconnected sinus tracts, and abscesses across an entire area, leaving little to no uninvolved skin.⁴

Treatment strategies for HS vary based on Hurley staging (eTable).^5-11 For mild cases (stage I), topical and intralesional therapies are common, while moderate to severe cases (stages II and III) may require extensive surgical approaches or systemic drugs such as antibiotics, hormonal therapies, retinoids, or immunosuppressive/biologic agents.²

Adalimumab, an anti–tumor necrosis factor (TNF) α monoclonal antibody, was the first US Food and Drug Administration (FDA)–approved biologic for HS. Secukinumab, a monoclonal antibody against IL-17A, subsequently was approved by the FDA for moderate to severe HS.¹² Off-label use of biologics including infliximab and ustekinumab expands the available treatment options for HS. In one Phase II randomized clinical trial (RCT), infliximab showed efficacy in reducing Hidradenitis Suppurativa Severity Index scores, with 26.7% (4/15) of patients achieving a 50% or greater reduction compared to placebo, although this was not statistically significant. Similarly, ustekinumab demonstrated promising results, with 47.1% (8/17) of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at week 40.² This multifaceted approach aims to address the varying degrees of severity and optimize outcomes for individuals with HS.

Molecular Pathophysiology of HS

The pathogenesis of HS is multifactorial, involving a complex interplay of genetic, environmental, and behavioral factors.² Approximately 33% to 40% of patients with HS worldwide report a first-degree relative with the condition, indicating a hereditary element with an autosomal-dominant transmission pattern and highlighting the global relevance of genetic factors in HS.⁴ Hidradenitis suppurativa is highly prevalent in individuals with obesity, likely due to increased intertriginous surface area, skin friction, sweat production, and hormonal changes in these patients. Smoking also commonly is associated with HS, with nicotine potentially contributing to increased follicular plugging.¹ Hormonal influences also play a role, as evidenced by a greater prevalence of HS in females, disease onset typically occurring between puberty and menopause, and symptomatic fluctuations correlating with menstrual cycles and exogenous hormones.⁴

Altered infundibular keratinization with subsequent hyperkeratosis/occlusion and innate immune pathway activation are key events leading to development of HS.¹ These events are mediated by release of pathogen- and danger-associated molecular patterns, leading to inflammasome-mediated IL-1α release, followed by downstream cytokine release.² Elevated levels of TNF-α, IL-1Β, IL-10, IL-17, and particularly IL-17A have been detected in HS lesional skin. The IL-17 family comprises multiple members, namely IL-17A, IL-17C, IL-17E, and IL17F. IL-17A and IL-17F often are co-expressed and secreted predominantly by a subset of CD4+ T helper cells, namely Th17 cells.² IL-17 cytokines exert pro-inflammatory effects, influencing immune cell activity and contributing to skin inflammation, particularly in HS.

Given the pivotal role of IL-17 in the pathogenesis of HS, the exploration of IL-17–targeted agents has become a focal point in clinical research. Bimekizumab, a novel IL-17 inhibitor, has emerged as a promising candidate, offering a potential breakthrough in the treatment landscape for individuals affected by HS.

Bimekizumab for HS Management

A phase II, double-blind, placebo-controlled RCT included 90 patients with moderate to severe HS (age range, 18-70 years) who were randomly assigned in a 2:1:1 ratio to receive either bimekizumab 320 mg every 2 weeks (with a 640-mg loading dose at baseline)(n=46), placebo (n=21), or adalimumab 40 mg once weekly from week 4 onward (following an initial 160-mg loading dose at baseline and 80-mg dose at week 2)(n=21). The study included a 12-week treatment period followed by a 20-week safety follow-up period. The primary endpoint was the achievement of HiSCR₅₀—defined as a reduction of at least 50% nodules, coupled with no increase in the number of abscesses or draining fistulas relative to baseline—at week 12. Additionally, the study assessed the number of patients who achieved a modified HiSCR with 75% reduction (HiSCR₇₅) of combined abscess and inflammatory nodule count or a modified HiSCR with 90% reduction (HiSCR₉₀). At week 12, the modeled response rates were estimated using a Bayesian logistic regression model. For HiSCR₅₀, the modeled rate for bimekizumab was 57.3%, with an observed rate of 62.5% (25/40), compared to a modeled rate of 26.1% for placebo (observed rate, 27.8% [5/18]). The posterior probability of superiority for bimekizumab over placebo was 0.998. By week 12, bimekizumab-treated patients achieved modeled HiSCR₇₅ and HiSCR₉₀ rates of 46.0% and 32.0%, respectively, with observed rates of 50.0% (20/40) for HiSCR₇₅ and 35.0% (14/40) for HiSCR₉₀. In comparison, placebo-treated patients achieved modeled HiSCR75 and HiSCR₉₀ rates of 10.0% and 0%, respectively, with observed rates of 11.1% (2/18) for HiSCR₇₅ and 0% (0/18) for HiSCR₉₀. Adalimumab-treated participants demonstrated intermediate results, achieving modeled HiSCR₇₅ and HiSCR₉₀ rates of 35.0% and 15.0%, respectively, with observed rates of 38.88% (7/18) for HiSCR₇₅ and 16.66% (3/18) for HiSCR₉₀.⁷

Bimekizumab was effective in the treatment of moderate to severe HS with comparable results to adalimumab.⁷ The incidence of treatment-emergent adverse events was similar across treatment arms (bimekizumab, 69.6% [32/46]; placebo, 61.9% [13/21]; adalimumab, 71.4% [15/21]). The most common treatment-emergent adverse events in the biologic treatment arms were infections (43.5% [20/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), skin and subcutaneous tissue disorders (28.3% [13/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), and general disorders/administration site conditions (21.7% [10/46] in the bimekizumab group and 23.8% [5/21] in the adalimumab group). Serious adverse events occurred in 4.3% (2/46) of patients in the bimekizumab group, 9.5% (2/21) of patients in the placebo group, and 4.8% (1/21) of patients in the adalimumab group. Serious adverse events that required hospitalization were due to anemia and empyema in the bimekizumab group; worsening HS in the adalimumab group; and myocardial infarction, hypoesthesia, headache, and dizziness in the placebo group. No deaths occurred in this study. Overall, bimekizumab was well tolerated, and discontinuation rates were low across all arms. The primary reason for discontinuation was withdrawal of consent (not due to an adverse event) or loss to follow-up.⁷

Two completed 48-week phase III RCTs, BE HEARD I and BE HEARD II, evaluated the efficacy and safety of bimekizumab in patients with moderate to severe HS.¹³ In both trials, 2 bimekizumab dosing regimens (320 mg every 2 weeks and 320 mg every 4 weeks) were compared with placebo during the 16-week initial and 32-week maintenance treatment periods. The primary endpoint of week 16 was achieved by 47.8% (138/289) and 51.9% (151/291) of patients receiving bimekizumab every 2 weeks in BE HEARD I (n=505) and BE HEARD II (n=509), respectively, compared with 29.2% (21/72) and 32.4% (24/74) of the placebo group. The bimekizumab 320 mg every 4 weeks dosing regimen met the primary endpoint only in BE HEARD II, with 53.5% (77/144) of patients achieving HiSCR₅₀ compared to 32.4% (24/74) with placebo (P=0.0038).¹³ Both trials met the key secondary endpoint of HiSCR₇₅ at week 16 for bimekizumab 320 mg every 2 weeks vs placebo. In BE HEARD I, 33.6% (97/289) of patients receiving bimekizumab achieved HiSCR₇₅ versus 18.1% (13/72) taking placebo. In BE HEARD II, 35.7% (104/291) of patients receiving bimekizumab achieved HiSCR₇₅ vs 16.2% (12/74) taking placebo. Responses were maintained or increased through week 48 in both trials. The most common treatment-emergent adverse events through week 48 were worsening HS, COVID-19 infection, diarrhea, oral candidiasis, and headache.¹³

A smaller scale case series investigated the use of bimekizumab in 4 female patients aged 20 to 62 years with moderate to severe HS and concomitant plaque or inverse psoriasis.⁸ A monthly loading dose of 320 mg was given during weeks 0 to 12 followed by a maintenance dose of 320 mg administered every 8 weeks. The International Hidradenitis Suppurativa Score System, visual analogue scale, and Dermatology Life Quality Index were used to assess the effectiveness of therapy by comparing scores before and after 4 and 16 weeks of treatment. A reduction of pain and improvement of HS lesions was observed in 3 (75.0%) patients after the first dosage of bimekizumab, with completed remission of HS by week 16. The fourth patient (25.0%) experienced substantial improvement in all measures, although not complete remission. All 4 patients remained on bimekizumab, and no adverse effects were reported.⁸

A meta-analysis evaluated 16 RCTs of 9 biologics and 3 small-molecule inhibitors in 2076 patients with HS.¹⁰ Secukinumab was not included in this meta-analysis. Only adalimumab (risk ratio, 1.77; 95% CI, 1.44-2.17) and bimekizumab (risk ratio, 2.25; 95% CI, 1.03-4.92) were superior to placebo in achieving HiSCR response at weeks 12 to 16 in 5 RCTs and 1 RCT, respectively; however, no statistically significant differences were noted between adalimumab and bimekizumab (P=.56). This analysis concluded that adalimumab and bimekizumab are the only 2 biologics efficacious in reaching HiSCR and consistently improved both disease severity and quality of life in patients with HS with an acceptable safety profile.¹⁰ Furthermore, these biologics had no increase in serious adverse events when compared to placebo.¹⁰

A network meta-analysis of 10 clinical trials involving more than 900 total participants evaluated nonsurgical therapies for HS. The analysis used Surface Under the Cumulative Ranking curve (SUCRA) values to estimate the efficacy of treatments in achieving clinical response according to HiSCR criteria. These values range from 0% to 100%, with 100% representing the best possible ranking for efficacy. Bimekizumab showed the highest estimated efficacy with a SUCRA value of 67%, followed by adalimumab (64%), anakinra (49%), and placebo (19%). These SUCRA values indicate the relative ranking of treatments, with higher values suggesting greater likelihood of achieving clinical response, rather than representing the actual percentage of patients achieving HiSCR. Bimekizumab was found to be more efficacious than placebo (P<.05).¹⁴

Building on the initial evidence of bimekizumab’s efficacy, BE HEARD I and BE HEARD II addressed some limitations of prior studies, including small sample sizes and insufficient stratification.¹³ Notably, stratification by baseline Hurley stage severity (ie, the most severe stage of disease assigned at baseline) and baseline systemic antibiotic use helped mitigate bias and ensured a more robust assessment of treatment efficacy; however, certain limitations persist. While the trials demonstrated rapid and clinically meaningful responses maintained up to 48 weeks, longer-term data beyond this period are limited, leaving gaps in understanding the durability of treatment effects over years. Additionally, despite appropriate stratification, the generalizability of the findings to broader patient populations remains unclear, as trial participants may not fully represent the diversity of patients seen in clinical practice.¹³

Future research is needed to address these limitations. The use of validated HS biomarkers as endpoints could enhance the ability to evaluate biologic efficacy and identify predictors of response. Comparative studies with other biologics also are warranted to establish the relative efficacy of bimekizumab within the growing therapeutic landscape for HS. Finally, real-world evidence from larger and more diverse populations will be critical to confirm the trial findings and assess long-term safety and effectiveness in routine clinical practice.¹³

Conclusion

The existing literature and recent phase III RCTs, BE HEARD I and BE HEARD II, demonstrate that bimekizumab is an effective treatment for moderate to severe HS, with robust efficacy according to HiSCR scores and sustained responses through 48 weeks. These trials addressed some prior limitations, including small sample sizes and insufficient stratification, providing a more comprehensive evaluation of bimekizumab’s clinical impact. The safety profile of bimekizumab remains favorable, with low discontinuation rates and manageable adverse events, such as infection, gastrointestinal upset, headache, and injection-site reactions. Long-term efficacy and safety data beyond 48 weeks still are needed to fully establish its durability and impact in diverse populations. The recent FDA approval of bimekizumab for moderate to severe HS provides patients with a new treatment option, offering a more positive clinical outlook.

Hidradenitis suppurativa (HS) is a debilitating dermatologic condition characterized by recurrent episodes of neutrophilic inflammation affecting the apocrine and pilosebaceous units that most commonly affects individuals aged 20 to 40 years. Originating from the hair follicles, inflammation initiates the formation of painful nodules and abscesses that can progress to sinus tracts or fistulas accompanied by the development of extensive scarring, exquisite pain, and malodorous drainage.¹ The lesions most commonly occur in intertriginous zones as well as areas rich in apocrine glands. The distinctive and sometimes irreversible clinical features of HS profoundly influence patients’ well-being and have lasting social, personal, and emotional impacts on their lives.²

Bimekizumab is a monoclonal antibody that specifically targets IL-17A and IL-17F, aiming to inhibit the downstream effects responsible for the chronic inflammation and tissue damage characteristic of HS.³ In HS lesions, IL-17 cytokines produced by T helper 17 (Th17) cells stimulate the production of chemokines (such as CC motif chemokine ligand 20) and neutrophil-attracting chemokines (including C-X-C motif chemokine ligands 1 and 8), cytokines (such as granulocyte colony-stimulating factor and IL-19), and epidermal antimicrobial proteins.^1,2 This cascade results in the chemotaxis of monocytes and neutrophils in the skin, recruiting additional Th17 and myeloid cells and further amplifying IL-17 production.¹

Bimekizumab’s mechanism of action strategically disrupts this feed-forward inflammatory loop, decreasing the transcription of neutrophil-attracting chemokines, IL-19, and epidermal antimicrobial proteins (Figure).^1,2 This leads to diminished recruitment of Th17 cells and inhibits the chemotaxis of monocytes and neutrophils in the skin, effectively addressing the chronic inflammation and tissue damage characteristic of HS.

We present a comprehensive review of the current standards of care, the underlying molecular pathophysiology of HS, and evaluation of the efficacy and safety of bimekizumab.

Evaluating HS Severity

The Hurley staging system provides a valuable framework for evaluating the severity of HS based on lesion characteristics. Stage I is characterized by abscess formation without tracts or scars. Stage II is characterized by recurrent abscesses with sinus tracts and scarring. Stage III is characterized by diffuse involvement, multiple interconnected sinus tracts, and abscesses across an entire area, leaving little to no uninvolved skin.⁴

Treatment strategies for HS vary based on Hurley staging (eTable).^5-11 For mild cases (stage I), topical and intralesional therapies are common, while moderate to severe cases (stages II and III) may require extensive surgical approaches or systemic drugs such as antibiotics, hormonal therapies, retinoids, or immunosuppressive/biologic agents.²

Adalimumab, an anti–tumor necrosis factor (TNF) α monoclonal antibody, was the first US Food and Drug Administration (FDA)–approved biologic for HS. Secukinumab, a monoclonal antibody against IL-17A, subsequently was approved by the FDA for moderate to severe HS.¹² Off-label use of biologics including infliximab and ustekinumab expands the available treatment options for HS. In one Phase II randomized clinical trial (RCT), infliximab showed efficacy in reducing Hidradenitis Suppurativa Severity Index scores, with 26.7% (4/15) of patients achieving a 50% or greater reduction compared to placebo, although this was not statistically significant. Similarly, ustekinumab demonstrated promising results, with 47.1% (8/17) of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at week 40.² This multifaceted approach aims to address the varying degrees of severity and optimize outcomes for individuals with HS.

Molecular Pathophysiology of HS

The pathogenesis of HS is multifactorial, involving a complex interplay of genetic, environmental, and behavioral factors.² Approximately 33% to 40% of patients with HS worldwide report a first-degree relative with the condition, indicating a hereditary element with an autosomal-dominant transmission pattern and highlighting the global relevance of genetic factors in HS.⁴ Hidradenitis suppurativa is highly prevalent in individuals with obesity, likely due to increased intertriginous surface area, skin friction, sweat production, and hormonal changes in these patients. Smoking also commonly is associated with HS, with nicotine potentially contributing to increased follicular plugging.¹ Hormonal influences also play a role, as evidenced by a greater prevalence of HS in females, disease onset typically occurring between puberty and menopause, and symptomatic fluctuations correlating with menstrual cycles and exogenous hormones.⁴

Altered infundibular keratinization with subsequent hyperkeratosis/occlusion and innate immune pathway activation are key events leading to development of HS.¹ These events are mediated by release of pathogen- and danger-associated molecular patterns, leading to inflammasome-mediated IL-1α release, followed by downstream cytokine release.² Elevated levels of TNF-α, IL-1Β, IL-10, IL-17, and particularly IL-17A have been detected in HS lesional skin. The IL-17 family comprises multiple members, namely IL-17A, IL-17C, IL-17E, and IL17F. IL-17A and IL-17F often are co-expressed and secreted predominantly by a subset of CD4+ T helper cells, namely Th17 cells.² IL-17 cytokines exert pro-inflammatory effects, influencing immune cell activity and contributing to skin inflammation, particularly in HS.

Given the pivotal role of IL-17 in the pathogenesis of HS, the exploration of IL-17–targeted agents has become a focal point in clinical research. Bimekizumab, a novel IL-17 inhibitor, has emerged as a promising candidate, offering a potential breakthrough in the treatment landscape for individuals affected by HS.

Bimekizumab for HS Management

A phase II, double-blind, placebo-controlled RCT included 90 patients with moderate to severe HS (age range, 18-70 years) who were randomly assigned in a 2:1:1 ratio to receive either bimekizumab 320 mg every 2 weeks (with a 640-mg loading dose at baseline)(n=46), placebo (n=21), or adalimumab 40 mg once weekly from week 4 onward (following an initial 160-mg loading dose at baseline and 80-mg dose at week 2)(n=21). The study included a 12-week treatment period followed by a 20-week safety follow-up period. The primary endpoint was the achievement of HiSCR₅₀—defined as a reduction of at least 50% nodules, coupled with no increase in the number of abscesses or draining fistulas relative to baseline—at week 12. Additionally, the study assessed the number of patients who achieved a modified HiSCR with 75% reduction (HiSCR₇₅) of combined abscess and inflammatory nodule count or a modified HiSCR with 90% reduction (HiSCR₉₀). At week 12, the modeled response rates were estimated using a Bayesian logistic regression model. For HiSCR₅₀, the modeled rate for bimekizumab was 57.3%, with an observed rate of 62.5% (25/40), compared to a modeled rate of 26.1% for placebo (observed rate, 27.8% [5/18]). The posterior probability of superiority for bimekizumab over placebo was 0.998. By week 12, bimekizumab-treated patients achieved modeled HiSCR₇₅ and HiSCR₉₀ rates of 46.0% and 32.0%, respectively, with observed rates of 50.0% (20/40) for HiSCR₇₅ and 35.0% (14/40) for HiSCR₉₀. In comparison, placebo-treated patients achieved modeled HiSCR75 and HiSCR₉₀ rates of 10.0% and 0%, respectively, with observed rates of 11.1% (2/18) for HiSCR₇₅ and 0% (0/18) for HiSCR₉₀. Adalimumab-treated participants demonstrated intermediate results, achieving modeled HiSCR₇₅ and HiSCR₉₀ rates of 35.0% and 15.0%, respectively, with observed rates of 38.88% (7/18) for HiSCR₇₅ and 16.66% (3/18) for HiSCR₉₀.⁷

Bimekizumab was effective in the treatment of moderate to severe HS with comparable results to adalimumab.⁷ The incidence of treatment-emergent adverse events was similar across treatment arms (bimekizumab, 69.6% [32/46]; placebo, 61.9% [13/21]; adalimumab, 71.4% [15/21]). The most common treatment-emergent adverse events in the biologic treatment arms were infections (43.5% [20/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), skin and subcutaneous tissue disorders (28.3% [13/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), and general disorders/administration site conditions (21.7% [10/46] in the bimekizumab group and 23.8% [5/21] in the adalimumab group). Serious adverse events occurred in 4.3% (2/46) of patients in the bimekizumab group, 9.5% (2/21) of patients in the placebo group, and 4.8% (1/21) of patients in the adalimumab group. Serious adverse events that required hospitalization were due to anemia and empyema in the bimekizumab group; worsening HS in the adalimumab group; and myocardial infarction, hypoesthesia, headache, and dizziness in the placebo group. No deaths occurred in this study. Overall, bimekizumab was well tolerated, and discontinuation rates were low across all arms. The primary reason for discontinuation was withdrawal of consent (not due to an adverse event) or loss to follow-up.⁷

Two completed 48-week phase III RCTs, BE HEARD I and BE HEARD II, evaluated the efficacy and safety of bimekizumab in patients with moderate to severe HS.¹³ In both trials, 2 bimekizumab dosing regimens (320 mg every 2 weeks and 320 mg every 4 weeks) were compared with placebo during the 16-week initial and 32-week maintenance treatment periods. The primary endpoint of week 16 was achieved by 47.8% (138/289) and 51.9% (151/291) of patients receiving bimekizumab every 2 weeks in BE HEARD I (n=505) and BE HEARD II (n=509), respectively, compared with 29.2% (21/72) and 32.4% (24/74) of the placebo group. The bimekizumab 320 mg every 4 weeks dosing regimen met the primary endpoint only in BE HEARD II, with 53.5% (77/144) of patients achieving HiSCR₅₀ compared to 32.4% (24/74) with placebo (P=0.0038).¹³ Both trials met the key secondary endpoint of HiSCR₇₅ at week 16 for bimekizumab 320 mg every 2 weeks vs placebo. In BE HEARD I, 33.6% (97/289) of patients receiving bimekizumab achieved HiSCR₇₅ versus 18.1% (13/72) taking placebo. In BE HEARD II, 35.7% (104/291) of patients receiving bimekizumab achieved HiSCR₇₅ vs 16.2% (12/74) taking placebo. Responses were maintained or increased through week 48 in both trials. The most common treatment-emergent adverse events through week 48 were worsening HS, COVID-19 infection, diarrhea, oral candidiasis, and headache.¹³

A smaller scale case series investigated the use of bimekizumab in 4 female patients aged 20 to 62 years with moderate to severe HS and concomitant plaque or inverse psoriasis.⁸ A monthly loading dose of 320 mg was given during weeks 0 to 12 followed by a maintenance dose of 320 mg administered every 8 weeks. The International Hidradenitis Suppurativa Score System, visual analogue scale, and Dermatology Life Quality Index were used to assess the effectiveness of therapy by comparing scores before and after 4 and 16 weeks of treatment. A reduction of pain and improvement of HS lesions was observed in 3 (75.0%) patients after the first dosage of bimekizumab, with completed remission of HS by week 16. The fourth patient (25.0%) experienced substantial improvement in all measures, although not complete remission. All 4 patients remained on bimekizumab, and no adverse effects were reported.⁸

A meta-analysis evaluated 16 RCTs of 9 biologics and 3 small-molecule inhibitors in 2076 patients with HS.¹⁰ Secukinumab was not included in this meta-analysis. Only adalimumab (risk ratio, 1.77; 95% CI, 1.44-2.17) and bimekizumab (risk ratio, 2.25; 95% CI, 1.03-4.92) were superior to placebo in achieving HiSCR response at weeks 12 to 16 in 5 RCTs and 1 RCT, respectively; however, no statistically significant differences were noted between adalimumab and bimekizumab (P=.56). This analysis concluded that adalimumab and bimekizumab are the only 2 biologics efficacious in reaching HiSCR and consistently improved both disease severity and quality of life in patients with HS with an acceptable safety profile.¹⁰ Furthermore, these biologics had no increase in serious adverse events when compared to placebo.¹⁰

A network meta-analysis of 10 clinical trials involving more than 900 total participants evaluated nonsurgical therapies for HS. The analysis used Surface Under the Cumulative Ranking curve (SUCRA) values to estimate the efficacy of treatments in achieving clinical response according to HiSCR criteria. These values range from 0% to 100%, with 100% representing the best possible ranking for efficacy. Bimekizumab showed the highest estimated efficacy with a SUCRA value of 67%, followed by adalimumab (64%), anakinra (49%), and placebo (19%). These SUCRA values indicate the relative ranking of treatments, with higher values suggesting greater likelihood of achieving clinical response, rather than representing the actual percentage of patients achieving HiSCR. Bimekizumab was found to be more efficacious than placebo (P<.05).¹⁴

Building on the initial evidence of bimekizumab’s efficacy, BE HEARD I and BE HEARD II addressed some limitations of prior studies, including small sample sizes and insufficient stratification.¹³ Notably, stratification by baseline Hurley stage severity (ie, the most severe stage of disease assigned at baseline) and baseline systemic antibiotic use helped mitigate bias and ensured a more robust assessment of treatment efficacy; however, certain limitations persist. While the trials demonstrated rapid and clinically meaningful responses maintained up to 48 weeks, longer-term data beyond this period are limited, leaving gaps in understanding the durability of treatment effects over years. Additionally, despite appropriate stratification, the generalizability of the findings to broader patient populations remains unclear, as trial participants may not fully represent the diversity of patients seen in clinical practice.¹³

Future research is needed to address these limitations. The use of validated HS biomarkers as endpoints could enhance the ability to evaluate biologic efficacy and identify predictors of response. Comparative studies with other biologics also are warranted to establish the relative efficacy of bimekizumab within the growing therapeutic landscape for HS. Finally, real-world evidence from larger and more diverse populations will be critical to confirm the trial findings and assess long-term safety and effectiveness in routine clinical practice.¹³

Conclusion

The existing literature and recent phase III RCTs, BE HEARD I and BE HEARD II, demonstrate that bimekizumab is an effective treatment for moderate to severe HS, with robust efficacy according to HiSCR scores and sustained responses through 48 weeks. These trials addressed some prior limitations, including small sample sizes and insufficient stratification, providing a more comprehensive evaluation of bimekizumab’s clinical impact. The safety profile of bimekizumab remains favorable, with low discontinuation rates and manageable adverse events, such as infection, gastrointestinal upset, headache, and injection-site reactions. Long-term efficacy and safety data beyond 48 weeks still are needed to fully establish its durability and impact in diverse populations. The recent FDA approval of bimekizumab for moderate to severe HS provides patients with a new treatment option, offering a more positive clinical outlook.

Hidradenitis suppurativa (HS) is a debilitating dermatologic condition characterized by recurrent episodes of neutrophilic inflammation affecting the apocrine and pilosebaceous units that most commonly affects individuals aged 20 to 40 years. Originating from the hair follicles, inflammation initiates the formation of painful nodules and abscesses that can progress to sinus tracts or fistulas accompanied by the development of extensive scarring, exquisite pain, and malodorous drainage.¹ The lesions most commonly occur in intertriginous zones as well as areas rich in apocrine glands. The distinctive and sometimes irreversible clinical features of HS profoundly influence patients’ well-being and have lasting social, personal, and emotional impacts on their lives.²

Bimekizumab is a monoclonal antibody that specifically targets IL-17A and IL-17F, aiming to inhibit the downstream effects responsible for the chronic inflammation and tissue damage characteristic of HS.³ In HS lesions, IL-17 cytokines produced by T helper 17 (Th17) cells stimulate the production of chemokines (such as CC motif chemokine ligand 20) and neutrophil-attracting chemokines (including C-X-C motif chemokine ligands 1 and 8), cytokines (such as granulocyte colony-stimulating factor and IL-19), and epidermal antimicrobial proteins.^1,2 This cascade results in the chemotaxis of monocytes and neutrophils in the skin, recruiting additional Th17 and myeloid cells and further amplifying IL-17 production.¹

Bimekizumab’s mechanism of action strategically disrupts this feed-forward inflammatory loop, decreasing the transcription of neutrophil-attracting chemokines, IL-19, and epidermal antimicrobial proteins (Figure).^1,2 This leads to diminished recruitment of Th17 cells and inhibits the chemotaxis of monocytes and neutrophils in the skin, effectively addressing the chronic inflammation and tissue damage characteristic of HS.

We present a comprehensive review of the current standards of care, the underlying molecular pathophysiology of HS, and evaluation of the efficacy and safety of bimekizumab.

Evaluating HS Severity

The Hurley staging system provides a valuable framework for evaluating the severity of HS based on lesion characteristics. Stage I is characterized by abscess formation without tracts or scars. Stage II is characterized by recurrent abscesses with sinus tracts and scarring. Stage III is characterized by diffuse involvement, multiple interconnected sinus tracts, and abscesses across an entire area, leaving little to no uninvolved skin.⁴

Treatment strategies for HS vary based on Hurley staging (eTable).^5-11 For mild cases (stage I), topical and intralesional therapies are common, while moderate to severe cases (stages II and III) may require extensive surgical approaches or systemic drugs such as antibiotics, hormonal therapies, retinoids, or immunosuppressive/biologic agents.²

Adalimumab, an anti–tumor necrosis factor (TNF) α monoclonal antibody, was the first US Food and Drug Administration (FDA)–approved biologic for HS. Secukinumab, a monoclonal antibody against IL-17A, subsequently was approved by the FDA for moderate to severe HS.¹² Off-label use of biologics including infliximab and ustekinumab expands the available treatment options for HS. In one Phase II randomized clinical trial (RCT), infliximab showed efficacy in reducing Hidradenitis Suppurativa Severity Index scores, with 26.7% (4/15) of patients achieving a 50% or greater reduction compared to placebo, although this was not statistically significant. Similarly, ustekinumab demonstrated promising results, with 47.1% (8/17) of patients achieving Hidradenitis Suppurativa Clinical Response (HiSCR) at week 40.² This multifaceted approach aims to address the varying degrees of severity and optimize outcomes for individuals with HS.

Molecular Pathophysiology of HS

The pathogenesis of HS is multifactorial, involving a complex interplay of genetic, environmental, and behavioral factors.² Approximately 33% to 40% of patients with HS worldwide report a first-degree relative with the condition, indicating a hereditary element with an autosomal-dominant transmission pattern and highlighting the global relevance of genetic factors in HS.⁴ Hidradenitis suppurativa is highly prevalent in individuals with obesity, likely due to increased intertriginous surface area, skin friction, sweat production, and hormonal changes in these patients. Smoking also commonly is associated with HS, with nicotine potentially contributing to increased follicular plugging.¹ Hormonal influences also play a role, as evidenced by a greater prevalence of HS in females, disease onset typically occurring between puberty and menopause, and symptomatic fluctuations correlating with menstrual cycles and exogenous hormones.⁴

Altered infundibular keratinization with subsequent hyperkeratosis/occlusion and innate immune pathway activation are key events leading to development of HS.¹ These events are mediated by release of pathogen- and danger-associated molecular patterns, leading to inflammasome-mediated IL-1α release, followed by downstream cytokine release.² Elevated levels of TNF-α, IL-1Β, IL-10, IL-17, and particularly IL-17A have been detected in HS lesional skin. The IL-17 family comprises multiple members, namely IL-17A, IL-17C, IL-17E, and IL17F. IL-17A and IL-17F often are co-expressed and secreted predominantly by a subset of CD4+ T helper cells, namely Th17 cells.² IL-17 cytokines exert pro-inflammatory effects, influencing immune cell activity and contributing to skin inflammation, particularly in HS.

Given the pivotal role of IL-17 in the pathogenesis of HS, the exploration of IL-17–targeted agents has become a focal point in clinical research. Bimekizumab, a novel IL-17 inhibitor, has emerged as a promising candidate, offering a potential breakthrough in the treatment landscape for individuals affected by HS.

Bimekizumab for HS Management

A phase II, double-blind, placebo-controlled RCT included 90 patients with moderate to severe HS (age range, 18-70 years) who were randomly assigned in a 2:1:1 ratio to receive either bimekizumab 320 mg every 2 weeks (with a 640-mg loading dose at baseline)(n=46), placebo (n=21), or adalimumab 40 mg once weekly from week 4 onward (following an initial 160-mg loading dose at baseline and 80-mg dose at week 2)(n=21). The study included a 12-week treatment period followed by a 20-week safety follow-up period. The primary endpoint was the achievement of HiSCR₅₀—defined as a reduction of at least 50% nodules, coupled with no increase in the number of abscesses or draining fistulas relative to baseline—at week 12. Additionally, the study assessed the number of patients who achieved a modified HiSCR with 75% reduction (HiSCR₇₅) of combined abscess and inflammatory nodule count or a modified HiSCR with 90% reduction (HiSCR₉₀). At week 12, the modeled response rates were estimated using a Bayesian logistic regression model. For HiSCR₅₀, the modeled rate for bimekizumab was 57.3%, with an observed rate of 62.5% (25/40), compared to a modeled rate of 26.1% for placebo (observed rate, 27.8% [5/18]). The posterior probability of superiority for bimekizumab over placebo was 0.998. By week 12, bimekizumab-treated patients achieved modeled HiSCR₇₅ and HiSCR₉₀ rates of 46.0% and 32.0%, respectively, with observed rates of 50.0% (20/40) for HiSCR₇₅ and 35.0% (14/40) for HiSCR₉₀. In comparison, placebo-treated patients achieved modeled HiSCR75 and HiSCR₉₀ rates of 10.0% and 0%, respectively, with observed rates of 11.1% (2/18) for HiSCR₇₅ and 0% (0/18) for HiSCR₉₀. Adalimumab-treated participants demonstrated intermediate results, achieving modeled HiSCR₇₅ and HiSCR₉₀ rates of 35.0% and 15.0%, respectively, with observed rates of 38.88% (7/18) for HiSCR₇₅ and 16.66% (3/18) for HiSCR₉₀.⁷

Bimekizumab was effective in the treatment of moderate to severe HS with comparable results to adalimumab.⁷ The incidence of treatment-emergent adverse events was similar across treatment arms (bimekizumab, 69.6% [32/46]; placebo, 61.9% [13/21]; adalimumab, 71.4% [15/21]). The most common treatment-emergent adverse events in the biologic treatment arms were infections (43.5% [20/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), skin and subcutaneous tissue disorders (28.3% [13/46] in the bimekizumab group and 42.9% [9/21] in the adalimumab group), and general disorders/administration site conditions (21.7% [10/46] in the bimekizumab group and 23.8% [5/21] in the adalimumab group). Serious adverse events occurred in 4.3% (2/46) of patients in the bimekizumab group, 9.5% (2/21) of patients in the placebo group, and 4.8% (1/21) of patients in the adalimumab group. Serious adverse events that required hospitalization were due to anemia and empyema in the bimekizumab group; worsening HS in the adalimumab group; and myocardial infarction, hypoesthesia, headache, and dizziness in the placebo group. No deaths occurred in this study. Overall, bimekizumab was well tolerated, and discontinuation rates were low across all arms. The primary reason for discontinuation was withdrawal of consent (not due to an adverse event) or loss to follow-up.⁷

Two completed 48-week phase III RCTs, BE HEARD I and BE HEARD II, evaluated the efficacy and safety of bimekizumab in patients with moderate to severe HS.¹³ In both trials, 2 bimekizumab dosing regimens (320 mg every 2 weeks and 320 mg every 4 weeks) were compared with placebo during the 16-week initial and 32-week maintenance treatment periods. The primary endpoint of week 16 was achieved by 47.8% (138/289) and 51.9% (151/291) of patients receiving bimekizumab every 2 weeks in BE HEARD I (n=505) and BE HEARD II (n=509), respectively, compared with 29.2% (21/72) and 32.4% (24/74) of the placebo group. The bimekizumab 320 mg every 4 weeks dosing regimen met the primary endpoint only in BE HEARD II, with 53.5% (77/144) of patients achieving HiSCR₅₀ compared to 32.4% (24/74) with placebo (P=0.0038).¹³ Both trials met the key secondary endpoint of HiSCR₇₅ at week 16 for bimekizumab 320 mg every 2 weeks vs placebo. In BE HEARD I, 33.6% (97/289) of patients receiving bimekizumab achieved HiSCR₇₅ versus 18.1% (13/72) taking placebo. In BE HEARD II, 35.7% (104/291) of patients receiving bimekizumab achieved HiSCR₇₅ vs 16.2% (12/74) taking placebo. Responses were maintained or increased through week 48 in both trials. The most common treatment-emergent adverse events through week 48 were worsening HS, COVID-19 infection, diarrhea, oral candidiasis, and headache.¹³

A smaller scale case series investigated the use of bimekizumab in 4 female patients aged 20 to 62 years with moderate to severe HS and concomitant plaque or inverse psoriasis.⁸ A monthly loading dose of 320 mg was given during weeks 0 to 12 followed by a maintenance dose of 320 mg administered every 8 weeks. The International Hidradenitis Suppurativa Score System, visual analogue scale, and Dermatology Life Quality Index were used to assess the effectiveness of therapy by comparing scores before and after 4 and 16 weeks of treatment. A reduction of pain and improvement of HS lesions was observed in 3 (75.0%) patients after the first dosage of bimekizumab, with completed remission of HS by week 16. The fourth patient (25.0%) experienced substantial improvement in all measures, although not complete remission. All 4 patients remained on bimekizumab, and no adverse effects were reported.⁸

A meta-analysis evaluated 16 RCTs of 9 biologics and 3 small-molecule inhibitors in 2076 patients with HS.¹⁰ Secukinumab was not included in this meta-analysis. Only adalimumab (risk ratio, 1.77; 95% CI, 1.44-2.17) and bimekizumab (risk ratio, 2.25; 95% CI, 1.03-4.92) were superior to placebo in achieving HiSCR response at weeks 12 to 16 in 5 RCTs and 1 RCT, respectively; however, no statistically significant differences were noted between adalimumab and bimekizumab (P=.56). This analysis concluded that adalimumab and bimekizumab are the only 2 biologics efficacious in reaching HiSCR and consistently improved both disease severity and quality of life in patients with HS with an acceptable safety profile.¹⁰ Furthermore, these biologics had no increase in serious adverse events when compared to placebo.¹⁰

A network meta-analysis of 10 clinical trials involving more than 900 total participants evaluated nonsurgical therapies for HS. The analysis used Surface Under the Cumulative Ranking curve (SUCRA) values to estimate the efficacy of treatments in achieving clinical response according to HiSCR criteria. These values range from 0% to 100%, with 100% representing the best possible ranking for efficacy. Bimekizumab showed the highest estimated efficacy with a SUCRA value of 67%, followed by adalimumab (64%), anakinra (49%), and placebo (19%). These SUCRA values indicate the relative ranking of treatments, with higher values suggesting greater likelihood of achieving clinical response, rather than representing the actual percentage of patients achieving HiSCR. Bimekizumab was found to be more efficacious than placebo (P<.05).¹⁴

Building on the initial evidence of bimekizumab’s efficacy, BE HEARD I and BE HEARD II addressed some limitations of prior studies, including small sample sizes and insufficient stratification.¹³ Notably, stratification by baseline Hurley stage severity (ie, the most severe stage of disease assigned at baseline) and baseline systemic antibiotic use helped mitigate bias and ensured a more robust assessment of treatment efficacy; however, certain limitations persist. While the trials demonstrated rapid and clinically meaningful responses maintained up to 48 weeks, longer-term data beyond this period are limited, leaving gaps in understanding the durability of treatment effects over years. Additionally, despite appropriate stratification, the generalizability of the findings to broader patient populations remains unclear, as trial participants may not fully represent the diversity of patients seen in clinical practice.¹³

Future research is needed to address these limitations. The use of validated HS biomarkers as endpoints could enhance the ability to evaluate biologic efficacy and identify predictors of response. Comparative studies with other biologics also are warranted to establish the relative efficacy of bimekizumab within the growing therapeutic landscape for HS. Finally, real-world evidence from larger and more diverse populations will be critical to confirm the trial findings and assess long-term safety and effectiveness in routine clinical practice.¹³

Conclusion

The existing literature and recent phase III RCTs, BE HEARD I and BE HEARD II, demonstrate that bimekizumab is an effective treatment for moderate to severe HS, with robust efficacy according to HiSCR scores and sustained responses through 48 weeks. These trials addressed some prior limitations, including small sample sizes and insufficient stratification, providing a more comprehensive evaluation of bimekizumab’s clinical impact. The safety profile of bimekizumab remains favorable, with low discontinuation rates and manageable adverse events, such as infection, gastrointestinal upset, headache, and injection-site reactions. Long-term efficacy and safety data beyond 48 weeks still are needed to fully establish its durability and impact in diverse populations. The recent FDA approval of bimekizumab for moderate to severe HS provides patients with a new treatment option, offering a more positive clinical outlook.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

The cutting edge of treating solid tumors with cell therapies got notably sharper in 2024.

First came the US Food and Drug Administration (FDA) approval in February 2024 of the tumor-infiltrating lymphocyte (TIL) therapy lifileucel in unresectable or metastatic melanoma that had progressed on prior immunotherapy, the first cellular therapy for any solid tumor. Then came the August FDA approval of afamitresgene autoleucel in unresectable or metastatic synovial sarcoma with failed chemotherapy, the first engineered T-cell therapy for cancers in soft tissue. 

“This was a pipe dream just a decade ago,” Alison Betof Warner, MD, PhD, lead author of a lifileucel study (NCT05640193), said in an interview with Medscape Medical News. “At the start of 2024, we had no approvals of these kinds of products in solid cancers. Now we have two.”

As the director of Solid Tumor Cell Therapy and leader of Stanford Medicine’s Melanoma and Cutaneous Oncology Clinical Research Group, Betof Warner has been at the forefront of developing commercial cell therapy using tumor-infiltrating lymphocytes (TILs). 

“The approval of lifileucel increases confidence that we can get these therapies across the regulatory finish line and to patients,” Betof Warner said during the interview. She was not involved in the development of afamitresgene autoleucel.

 

‘Reverse Engineering’

In addition to her contributions to the work that led to lifileucel’s approval, Betof Warner was the lead author on the first consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. 

Betof Warner began studying TILs after doing research with her mentors in immuno-oncology, Jedd D. Wolchok and Michael A. Postow. Their investigations — including one that Betof Warner coauthored — into how monoclonal antibodies and checkpoint inhibitors, such as ipilimumab or nivolumab, might extend the lives of people with advanced unresectable or metastatic melanoma inspired her to push further to find ways to minimize treatment while maximizing outcomes for patients. Betof Warner’s interest overall, she said in the interview, is in capitalizing on what can be learned about how the immune system controls cancer.

“What we know is that the immune system has the ability to kill cancer,” Betof Warner said. “Therefore we need to be thinking about how we can increase immune surveillance. How can we enhance that before a patient develops advanced cancer? 

Betof Warner said that although TILs are now standard treatment in melanoma, there is about a 30% response rate compared with about a 50% response rate in immunotherapy, and the latter is easier for the patient to withstand. 

“Antibodies on the frontline are better than going through a surgery and then waiting weeks to get your therapy,” Betof Warner said in the interview. “You can come into my clinic and get an antibody therapy in 30 minutes and go straight to work. TILs require patients to be in the hospital for weeks at a time and out of work for months at a time.”

In an effort to combine therapies to maximize best outcomes, a phase 3 trial (NCT05727904) is currently recruiting. The TILVANCE-301 trial will compare immunotherapy plus adoptive cell therapy vs immunotherapy alone in untreated unresectable or metastatic melanoma. Betof Warner is not a part of this study.

 

Cell Therapies Include CAR T Cells and TCRT

In general, adoptive T-cell therapies such as TILs involve the isolation of autologous immune cells that are removed from the body and either expanded or modified to optimize their efficacy in fighting antigens, before their transfer to the patient as a living drug by infusion.

In addition to TILs, adoptive cell therapies for antitumor therapeutics include chimeric antigen receptor (CAR) T cells and engineered T-cell receptor therapy (TCRT).

In CAR T-cell therapy and TCRT, naive T cells are harvested from the patient’s blood then engineered to target a tumor. In TIL therapy, tumor-specific T cells are taken from the patient’s tumor. Once extracted, the respective cells are expanded billions of times and then delivered back to the patient’s body, said Betof Warner. 

“The main promise of this approach is to generate responses in what we know as ‘cold’ tumors, or tumors that do not have a lot of endogenous T-cell infiltration or where the T cells are not working well, to bring in tumor targeting T cells and then trigger an immune response,” Betof Warner told an audience at the American Society of Clinical Oncology (ASCO) 2024 annual meeting.

TIL patients also receive interleukin (IL)-2 infusions to further stimulate the cells. In patients being treated with TCRT, they either receive low or no IL-2, Betof Warner said in her ASCO presentation, “Adopting Cutting-Edge Cell Therapies in Melanoma,” part of the session Beyond the Tip of the Iceberg: Next-Generation Cell-Based Therapies. 

Betof Warner takes Medscape Medical News through the history and ongoing investigations of cellular therapies for solid tumors, including her own research on these treatments. 

 

Decades in the Making

The National Cancer Institute began investigating TILs in the late 1980s, with the current National Cancer Institute (NCI) surgery chief, Steven Rosenberg, MD, PhD, leading the first-ever trials that showed TILs could shrink tumors in people with advanced melanoma.

Since then, NCI staff and others have also investigated TILs beyond melanoma and additional cell therapies based on CAR T cells and TCRT for antitumor therapeutics. 

“TCRs are different from CAR Ts because they go after intracellular antigens instead of extracellular antigens,” said Betof Warner. “That has appeal because many of the tumor antigens we’re looking for will be intracellular.” 

Because CAR T cells only target extracellular antigens, their utility is somewhat limited. Although several CAR T-cell therapies exist for blood cancers, there currently are no approved CAR T-cell therapies for solid tumors. However, several trials of CAR T cells in gastrointestinal cancers and melanoma are ongoing, said Betof Warner, who is not a part of these studies.

“We are starting to see early-phase efficacy in pediatric gliomas,” Betof Warner said, mentioning a study conducted by colleagues at Stanford who demonstrated potential for anti-GD2 CAR T-cell therapy in deadly pediatric diffuse midline gliomas, tumors on the spine and brain.

In their study, nine out of 11 participants (median age, 15 years) showed benefit from the cell therapy, with one participant’s tumors resolving completely. The results paved the way for the FDA to grant a Regenerative Medicine Advanced Therapy designation for use of anti-GD2 CAR T cells in H3K27M-positive diffuse midline gliomas. 

The investigators are now recruiting for a phase 1 trial (NCT04196413). Results of the initial study were published in Nature last month.

Another lesser-known cell therapy expected to advance at some point in the future for solid tumors is use of the body’s natural killer (NK) cells. “They’ve been known about for a long time, but they are more difficult to regulate, which is one reason why it has taken longer to make NK cell therapies,” said Betof Warner, who is not involved in the study of NK cells. “One of their advantages is that, potentially, there could be an ‘off the shelf’ NK product. They don’t necessarily have to be made with autologous cells.”

 

Risk-Benefit Profiles Depend on Mechanism of Action

If the corresponding TCR sequence of a tumor antigen is known, said Betof Warner, it is possible to use leukapheresis to generate naive circulating lymphocytes. Once infused, the manufactured TCRTs will activate in the body the same as native cells because the signaling is the same.
An advantage to TCRT compared with CAR T-cell therapy is that it targets intracellular proteins, which are significantly present in the tumor, Betof Warner said in her presentation at ASCO 2024. She clarified that tumors will usually be screened for the presence of this antigen before a patient is selected for treatment with that particular therapy, because not all antigens are highly expressed in every tumor. 

“Furthermore, the tumor antigen has to be presented by a major histocompatibility complex, meaning there are human leukocyte antigen restrictions, which impacts patient selection,” she said.

A risk with both TCRT and CAR T-cell therapy, according to Betof Warner, is that because there are often shared antigens between tumor and normal tissues, on-target/off-tumor toxicity is a risk.

“TILs are different because they are nonengineered, at least not for antigen recognition. They are polyclonal and go after multiple targets,” Betof Warner said. “TCRs and CARs are engineered to go after one target. So, TILs have much lower rates of on-tumor/off-target effects, vs when you engineer a very high affinity receptor like a TCR or CAR.”

A good example of how this amplification of TCR affinity can lead to poor outcomes is in metastatic melanoma, said Betof Warner. 

In investigations (NCI-07-C-0174 and NCI-07-C-0175) of TCRT in metastatic melanoma, for example, the researchers were targeting MART-1 or gp100, which are expressed in melanocytes. 

“The problem was that these antigens are also expressed in the eyes and ears, so it caused eye inflammation and hearing loss in a number of patients because it wasn’t specific enough for the tumor,” said Betof Warner. “So, if that target is highly expressed on normal tissue, then you have a high risk.”

 

Promise of PRAME

Betof Warner said the most promising TCRT at present is the investigational autologous cell therapy IMA203 (NCT03688124), which targets the preferentially expressed antigen (PRAME). Although PRAME is found in many tumors, this testis antigen does not tend to express in normal, healthy adult tissues. Betof Warner is not affiliated with this study. 

“It’s maybe the most exciting TCRT cell in melanoma,” Betof Warner told her audience at the ASCO 2024 meeting. Because the expression rate of PRAME in cutaneous and uveal melanoma is at or above 95% and 90%, respectively, she said “it is a really good target in melanoma.”

Phase 1a results reported in late 2023 from a first-in-human trial of IMA203 involving 13 persons with highly advanced melanoma and a median of 5.5 previous treatments showed a 50% objective response rate in the 12 evaluable results. The duration of response ranged between 2.2 and 14.7 months (median follow-up, 14 months).

The safety profile of the treatment was favorable, with no grade 3 adverse events occurring in more than 10% of the cohort, and no grade 5 adverse events at all.

Phase 1b results published in October by maker Immatics showed that in 28 heavily pretreated metastatic melanoma patients, IMA203 had a confirmed objective response rate of 54% with a median duration of response of 12.1 months, while maintaining a favorable tolerability profile. 

 

Accelerated Approvals, Boxed Warnings

The FDA granted accelerated approvals for both lifileucel, the TIL therapy, and afamitresgene autoleucel, the TCRT. 

Both were approved with boxed warnings. Lifileucel’s warning is for treatment-related mortality, prolonged severe cytopenia, severe infection, and cardiopulmonary and renal impairment. Afamitresgene autoleucel’s boxed warning is for serious or fatal cytokine release syndrome, which may be severe or life-threatening.

With these approvals, the bar is now raised on TILs and TCRTs, said Betof Warner.

The lifileucel trial studied 73 patients whose melanoma had continued to metastasize despite treatment with a programmed cell death protein (PD-1)/ programmed death-ligand (PD-L1)–targeted immune checkpoint inhibitor and a BRAF inhibitor (if appropriate based on tumor mutation status), and whose lifileucel dose was at least 7.5 billion cells (the approved dose). The cohort also received a median of six IL-2 (aldesleukin) doses. 

The objective response rate was 31.5% (95% CI, 21.1-43.4), and median duration of response was not reached (lower bound of 95% CI, 4.1).

In the afamitresgene autoleucel study, 44 of 52 patients with synovial sarcoma received leukapheresis and a single infusion of afamitresgene autoleucel. 

The overall response rate was 43.2% (95% CI, 28.4-59.0). The median time to response was 4.9 weeks (95% CI, 4.4-8), and the median duration of response was 6 months (lower bound of 95% CI, 4.6). Among patients who were responsive to the treatment, 45.6% and 39.0% had a duration of response of 6 months or longer and 12 months or longer, respectively.

 

New Hope for Patients

Betof Warner and her colleagues are now recruiting for an open-label, phase 1/2 investigation of the safety and efficacy of the TIL therapy OBX-115 in adult advanced solid tumors in melanoma or non–small cell lung cancer. The first-in-human results of a previous trial were presented at the ASCO 2024 meeting, and OBX-115 received FDA fast track designation in July.

“I think the results are really promising,” said Betof Warner. “This is an engineered TIL that does not require administering IL-2 to the patient. There were four out of the nine patients who responded to the treatment and there were no dose-limiting toxicities, no cytokine and no intracranial — all of which is excellent.”

For Betof Warner, the possibility that by using their own immune system, patients with advanced and refractory cancers could soon have a one-time treatment with a cell therapy rather than innumerable bouts of chemotherapy pushes her onward.

“The idea that we can treat cancer one time and have it not recur for years — that’s pushing the start of saying there’s a cure of cancer. That a person could move on from cancer like they move on from an infection. That is the potential of this work. We’re not there yet, but that’s where we need to think and dream big,” she said.

Betof Warner disclosed consulting/advisory roles with BluePath Solutions, Bristol-Myers Squibb/Medarex, Immatics, Instil Bio, Iovance Biotherapeutics, Lyell Immunopharma, Merck, Novartis, and Pfizer and research funding and travel expenses from Iovance Biotherapeutics.

 

A version of this article appeared on Medscape.com.

PRACTICE GAP

Photography is an essential tool in modern dermatologic practice, aiding in the evaluation, documentation, and monitoring of nevi, skin cancers, and other cutaneous pathologies.¹ With the rapid technologic advancement of smartphone cameras, high-quality clinical and dermoscopic images have become increasingly easy to attain; however, best practices for optimizing smartphone photography are limited in the medical literature. We have collated a series of recommendations to help fill this knowledge gap.

A search of PubMed articles indexed for MEDLINE was conducted using the terms clinical imaging AND smartphone, clinical photography AND smartphone, dermatology AND photography, dermatology AND imaging, dermoscopy AND photography, and dermoscopy AND imaging. We also consulted with Elizabeth Seiverling, MD (Annville, Pennsylvania) and Jennifer Stein, MD (New York, New York)—both renowned experts in the fields of dermatology, dermoscopy, and medical photography—via email and video meetings conducted during the period from June 1, 2022, through August 20, 2022. Our goal in creating this guide is to facilitate standardized yet simple ways to integrate smartphone photography into current dermatologic practice.

THE TECHNIQUE

Clinical Photography

Clinical images should be captured in a space with ample indirect natural light, such as a patient examination room with frosted or draped windows, ensuring patient privacy is maintained.^1,2 The smartphone’s flash can be used if natural lighting is insufficient, but caution should be exercised when photographing patients with darker skin types, as the flash may create an undesired glare. To combat this, consider using a small clip-on light-emitting diode ring light positioned at a 45° angle for more uniform lighting and reduced glare (eFigures 1 and 2).² This additional light source helps to distribute light evenly across the patient’s skin, enhancing detail visibility, minimizing harsh shadows, and ensuring a more accurate representation of skin pigmentation.²

When a magnified image is required (eg, to capture suspicious lesions with unique and detailed findings such as irregular borders or atypical pigmentation), use the smartphone’s digital zoom function rather than physically moving the camera lens closer to the subject. Moving the camera too close can cause proximity distortion, artificially enlarging objects close to the lens and degrading the quality of the image.^1,2 Unnecessary camera features such as portrait mode, live focus, and filters should be turned off to maintain image accuracy. It also is important to avoid excessive manual adjustments to exposure and brightness settings.^1,2 The tap-to-focus feature that is integrated into many smartphone cameras can be utilized to ensure the capture of sharp, focused images. After verifying the image preview on the smartphone display, take the photograph. Immediately review the captured image to ensure it is clear and well lit and accurately depicts the area of interest, including its color, texture, and any relevant details, without glare or distortion. If the image does not meet these criteria, promptly reattempt to achieve the desired quality.

Dermoscopic Photography

Dermoscopy, which enables magnified examination of skin lesions, is increasingly being utilized in dermatology. While traditional dermoscopic photography requires specialized equipment, such as large single-lens reflex cameras with dedicated dermoscopic lens attachments, smartphone cameras now can be used to obtain dermoscopic images of reasonable quality.^3,4 Adhering to specific practices can help to optimize the quality of dermoscopic images obtained via this technique.

Before capturing an image, it is essential to prepare both the lesion and the surrounding skin. Ensure the area is cleaned thoroughly and trim any hairs that may obscure the image. Apply an interface fluid such as rubbing alcohol or ultrasonography gel to improve image clarity by reducing surface tension and reflections, minimizing glare, and ensuring even light transmission throughout the lesion.⁵ As recommended for clinical photography, images should be captured in a space with ample indirect light. For best results, we recommend utilizing the primary photo capture option instead of portrait or panoramic mode or additional settings. It is crucial to disable features such as live focus, filters, night mode, and flash, as they may alter image accuracy; however, use of the tap-to-focus feature or manual settings adjustment is encouraged to ensure a high-resolution photograph.

Once these smartphone settings have been verified, position the dermatoscope directly over the lesion of interest. Next, place the smartphone camera lens directly against the eyepiece of the dermatoscope (Figure). Center the lesion in the field of view on the screen. Most smartphones enable adjustment to the image magnification on the photo capture screen. A single tap on the screen should populate the zoom options (eg, ×0.5, ×1, ×3) and allow for adjustment. For the majority of dermoscopic photographs, we recommend standard ×1 magnification, as it typically provides a clear and accurate representation of the lesion without introducing the possibility of image distortion. To obtain a close-up image, use the smartphone’s digital zoom function prior to taking the photograph rather than zooming in on the image after it has been captured; however, to minimize proximity distortion and maintain optimal image quality, avoid exceeding the halfway point on the camera’s zoom dial. After verifying the image preview on the smartphone display, capture the photograph. Immediate review is recommended to allow for prompt reattempt at capturing the image if needed.

PRACTICE IMPLICATIONS

The inherent convenience and accessibility offered by smartphone photography further solidifies its status as a valuable tool in modern dermatologic practice. By adhering to the best practices outlined in this guide, dermatologists can utilize smartphones to capture high-quality clinical and dermoscopic images that support accurate diagnosis and enhance patient care. This approach helps streamline workflows, enhance consistency in image quality, and standardize image capture across different settings and providers.

Additionally, smartphone photography can enhance both education and telemedicine by enabling physicians to easily share high-quality images with colleagues for virtual consultations, second opinions, and collaborative diagnoses. This sharing of images fosters learning opportunities, supports knowledge exchange, and allows for real-time feedback—all of which can improve clinical decision-making. Moreover, it broadens access to dermatologic expertise, strengthens communication between health care providers, and facilitates timely decision-making. As a result, patients benefit from more efficient, accurate, and collaborative care.

PRACTICE GAP

Photography is an essential tool in modern dermatologic practice, aiding in the evaluation, documentation, and monitoring of nevi, skin cancers, and other cutaneous pathologies.¹ With the rapid technologic advancement of smartphone cameras, high-quality clinical and dermoscopic images have become increasingly easy to attain; however, best practices for optimizing smartphone photography are limited in the medical literature. We have collated a series of recommendations to help fill this knowledge gap.

A search of PubMed articles indexed for MEDLINE was conducted using the terms clinical imaging AND smartphone, clinical photography AND smartphone, dermatology AND photography, dermatology AND imaging, dermoscopy AND photography, and dermoscopy AND imaging. We also consulted with Elizabeth Seiverling, MD (Annville, Pennsylvania) and Jennifer Stein, MD (New York, New York)—both renowned experts in the fields of dermatology, dermoscopy, and medical photography—via email and video meetings conducted during the period from June 1, 2022, through August 20, 2022. Our goal in creating this guide is to facilitate standardized yet simple ways to integrate smartphone photography into current dermatologic practice.

THE TECHNIQUE

Clinical Photography

Clinical images should be captured in a space with ample indirect natural light, such as a patient examination room with frosted or draped windows, ensuring patient privacy is maintained.^1,2 The smartphone’s flash can be used if natural lighting is insufficient, but caution should be exercised when photographing patients with darker skin types, as the flash may create an undesired glare. To combat this, consider using a small clip-on light-emitting diode ring light positioned at a 45° angle for more uniform lighting and reduced glare (eFigures 1 and 2).² This additional light source helps to distribute light evenly across the patient’s skin, enhancing detail visibility, minimizing harsh shadows, and ensuring a more accurate representation of skin pigmentation.²

When a magnified image is required (eg, to capture suspicious lesions with unique and detailed findings such as irregular borders or atypical pigmentation), use the smartphone’s digital zoom function rather than physically moving the camera lens closer to the subject. Moving the camera too close can cause proximity distortion, artificially enlarging objects close to the lens and degrading the quality of the image.^1,2 Unnecessary camera features such as portrait mode, live focus, and filters should be turned off to maintain image accuracy. It also is important to avoid excessive manual adjustments to exposure and brightness settings.^1,2 The tap-to-focus feature that is integrated into many smartphone cameras can be utilized to ensure the capture of sharp, focused images. After verifying the image preview on the smartphone display, take the photograph. Immediately review the captured image to ensure it is clear and well lit and accurately depicts the area of interest, including its color, texture, and any relevant details, without glare or distortion. If the image does not meet these criteria, promptly reattempt to achieve the desired quality.

Dermoscopic Photography

Dermoscopy, which enables magnified examination of skin lesions, is increasingly being utilized in dermatology. While traditional dermoscopic photography requires specialized equipment, such as large single-lens reflex cameras with dedicated dermoscopic lens attachments, smartphone cameras now can be used to obtain dermoscopic images of reasonable quality.^3,4 Adhering to specific practices can help to optimize the quality of dermoscopic images obtained via this technique.

Before capturing an image, it is essential to prepare both the lesion and the surrounding skin. Ensure the area is cleaned thoroughly and trim any hairs that may obscure the image. Apply an interface fluid such as rubbing alcohol or ultrasonography gel to improve image clarity by reducing surface tension and reflections, minimizing glare, and ensuring even light transmission throughout the lesion.⁵ As recommended for clinical photography, images should be captured in a space with ample indirect light. For best results, we recommend utilizing the primary photo capture option instead of portrait or panoramic mode or additional settings. It is crucial to disable features such as live focus, filters, night mode, and flash, as they may alter image accuracy; however, use of the tap-to-focus feature or manual settings adjustment is encouraged to ensure a high-resolution photograph.

Once these smartphone settings have been verified, position the dermatoscope directly over the lesion of interest. Next, place the smartphone camera lens directly against the eyepiece of the dermatoscope (Figure). Center the lesion in the field of view on the screen. Most smartphones enable adjustment to the image magnification on the photo capture screen. A single tap on the screen should populate the zoom options (eg, ×0.5, ×1, ×3) and allow for adjustment. For the majority of dermoscopic photographs, we recommend standard ×1 magnification, as it typically provides a clear and accurate representation of the lesion without introducing the possibility of image distortion. To obtain a close-up image, use the smartphone’s digital zoom function prior to taking the photograph rather than zooming in on the image after it has been captured; however, to minimize proximity distortion and maintain optimal image quality, avoid exceeding the halfway point on the camera’s zoom dial. After verifying the image preview on the smartphone display, capture the photograph. Immediate review is recommended to allow for prompt reattempt at capturing the image if needed.

PRACTICE IMPLICATIONS

The inherent convenience and accessibility offered by smartphone photography further solidifies its status as a valuable tool in modern dermatologic practice. By adhering to the best practices outlined in this guide, dermatologists can utilize smartphones to capture high-quality clinical and dermoscopic images that support accurate diagnosis and enhance patient care. This approach helps streamline workflows, enhance consistency in image quality, and standardize image capture across different settings and providers.

Additionally, smartphone photography can enhance both education and telemedicine by enabling physicians to easily share high-quality images with colleagues for virtual consultations, second opinions, and collaborative diagnoses. This sharing of images fosters learning opportunities, supports knowledge exchange, and allows for real-time feedback—all of which can improve clinical decision-making. Moreover, it broadens access to dermatologic expertise, strengthens communication between health care providers, and facilitates timely decision-making. As a result, patients benefit from more efficient, accurate, and collaborative care.

PRACTICE GAP

Photography is an essential tool in modern dermatologic practice, aiding in the evaluation, documentation, and monitoring of nevi, skin cancers, and other cutaneous pathologies.¹ With the rapid technologic advancement of smartphone cameras, high-quality clinical and dermoscopic images have become increasingly easy to attain; however, best practices for optimizing smartphone photography are limited in the medical literature. We have collated a series of recommendations to help fill this knowledge gap.

A search of PubMed articles indexed for MEDLINE was conducted using the terms clinical imaging AND smartphone, clinical photography AND smartphone, dermatology AND photography, dermatology AND imaging, dermoscopy AND photography, and dermoscopy AND imaging. We also consulted with Elizabeth Seiverling, MD (Annville, Pennsylvania) and Jennifer Stein, MD (New York, New York)—both renowned experts in the fields of dermatology, dermoscopy, and medical photography—via email and video meetings conducted during the period from June 1, 2022, through August 20, 2022. Our goal in creating this guide is to facilitate standardized yet simple ways to integrate smartphone photography into current dermatologic practice.

THE TECHNIQUE

Clinical Photography

Clinical images should be captured in a space with ample indirect natural light, such as a patient examination room with frosted or draped windows, ensuring patient privacy is maintained.^1,2 The smartphone’s flash can be used if natural lighting is insufficient, but caution should be exercised when photographing patients with darker skin types, as the flash may create an undesired glare. To combat this, consider using a small clip-on light-emitting diode ring light positioned at a 45° angle for more uniform lighting and reduced glare (eFigures 1 and 2).² This additional light source helps to distribute light evenly across the patient’s skin, enhancing detail visibility, minimizing harsh shadows, and ensuring a more accurate representation of skin pigmentation.²

When a magnified image is required (eg, to capture suspicious lesions with unique and detailed findings such as irregular borders or atypical pigmentation), use the smartphone’s digital zoom function rather than physically moving the camera lens closer to the subject. Moving the camera too close can cause proximity distortion, artificially enlarging objects close to the lens and degrading the quality of the image.^1,2 Unnecessary camera features such as portrait mode, live focus, and filters should be turned off to maintain image accuracy. It also is important to avoid excessive manual adjustments to exposure and brightness settings.^1,2 The tap-to-focus feature that is integrated into many smartphone cameras can be utilized to ensure the capture of sharp, focused images. After verifying the image preview on the smartphone display, take the photograph. Immediately review the captured image to ensure it is clear and well lit and accurately depicts the area of interest, including its color, texture, and any relevant details, without glare or distortion. If the image does not meet these criteria, promptly reattempt to achieve the desired quality.

Dermoscopic Photography

Dermoscopy, which enables magnified examination of skin lesions, is increasingly being utilized in dermatology. While traditional dermoscopic photography requires specialized equipment, such as large single-lens reflex cameras with dedicated dermoscopic lens attachments, smartphone cameras now can be used to obtain dermoscopic images of reasonable quality.^3,4 Adhering to specific practices can help to optimize the quality of dermoscopic images obtained via this technique.

Before capturing an image, it is essential to prepare both the lesion and the surrounding skin. Ensure the area is cleaned thoroughly and trim any hairs that may obscure the image. Apply an interface fluid such as rubbing alcohol or ultrasonography gel to improve image clarity by reducing surface tension and reflections, minimizing glare, and ensuring even light transmission throughout the lesion.⁵ As recommended for clinical photography, images should be captured in a space with ample indirect light. For best results, we recommend utilizing the primary photo capture option instead of portrait or panoramic mode or additional settings. It is crucial to disable features such as live focus, filters, night mode, and flash, as they may alter image accuracy; however, use of the tap-to-focus feature or manual settings adjustment is encouraged to ensure a high-resolution photograph.

Once these smartphone settings have been verified, position the dermatoscope directly over the lesion of interest. Next, place the smartphone camera lens directly against the eyepiece of the dermatoscope (Figure). Center the lesion in the field of view on the screen. Most smartphones enable adjustment to the image magnification on the photo capture screen. A single tap on the screen should populate the zoom options (eg, ×0.5, ×1, ×3) and allow for adjustment. For the majority of dermoscopic photographs, we recommend standard ×1 magnification, as it typically provides a clear and accurate representation of the lesion without introducing the possibility of image distortion. To obtain a close-up image, use the smartphone’s digital zoom function prior to taking the photograph rather than zooming in on the image after it has been captured; however, to minimize proximity distortion and maintain optimal image quality, avoid exceeding the halfway point on the camera’s zoom dial. After verifying the image preview on the smartphone display, capture the photograph. Immediate review is recommended to allow for prompt reattempt at capturing the image if needed.

PRACTICE IMPLICATIONS

The inherent convenience and accessibility offered by smartphone photography further solidifies its status as a valuable tool in modern dermatologic practice. By adhering to the best practices outlined in this guide, dermatologists can utilize smartphones to capture high-quality clinical and dermoscopic images that support accurate diagnosis and enhance patient care. This approach helps streamline workflows, enhance consistency in image quality, and standardize image capture across different settings and providers.

Additionally, smartphone photography can enhance both education and telemedicine by enabling physicians to easily share high-quality images with colleagues for virtual consultations, second opinions, and collaborative diagnoses. This sharing of images fosters learning opportunities, supports knowledge exchange, and allows for real-time feedback—all of which can improve clinical decision-making. Moreover, it broadens access to dermatologic expertise, strengthens communication between health care providers, and facilitates timely decision-making. As a result, patients benefit from more efficient, accurate, and collaborative care.

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

THE DIAGNOSIS: Trichodiscoma

Histologic evaluation revealed an unremarkable epidermal surface and a subjacent well-demarcated superficial dermal nodule showing a proliferation, sometimes fascicular, of wavy and spindled fibroblasts with some stellate forms within a variably loose fibrous stroma. Some angioplasia and vascular ectasia also were seen (Figure). A diagnosis of trichodiscoma was made based on these histologic findings.

While the patient’s personal and family history of pneumothorax originally had been attributed to other causes, the diagnosis of trichodiscoma raised suspicion for Birt-Hogg-Dubé syndrome due to the classic association of skin lesions (often trichodiscomas), renal cell carcinoma, and spontaneous pneumothorax in this condition. The patient was sent for genetic testing for the associated folliculin (FLCN) gene, which was positive and thereby confirmed the diagnosis of Birt-Hogg-Dubé syndrome. At the most recent follow-up almost 2 years after initial presentation, the lesions on the earlobe were stable. The patient has since undergone screening for abdominal and renal neoplasia with negative results, and he has had no other occurrences of pneumothorax.

Our case highlights the association between trichodiscomas and Birt-Hogg-Dubé syndrome, which necessitates screening for renal cell carcinoma, pneumothorax, and lung cysts.¹ Birt-Hogg-Dubé syndrome is an autosomal- dominant disorder of the skin and lungs that is characterized by a predisposition for renal carcinoma, pneumothorax, and colon polyps as well as cutaneous markers that include fibrofolliculomas, acrochordons, and trichodiscomas; the trichodiscomas tend to manifest as numerous smooth, flesh-colored or grayish-white papules on the face, ears, neck, and/or upper trunk.¹

Trichodiscomas are benign lesions and do not require treatment²; however, if they are cosmetically bothersome to the patient, surgical excision is an option for single lesions. For more widespread cutaneous disease, combination therapy with a CO₂ laser and erbium-doped yttrium aluminum garnet laser may be utilized.³ The differential diagnosis for trichodiscoma includes basal cell carcinoma, fibrous papule, dermal nevus, and trichofolliculoma.

Basal cell carcinoma is the most common type of skin cancer.⁴ Clinically, it typically manifests as pink or flesh-colored papules on the head or neck, often with overlying ulceration or telangiectasia. Due to its association with chronic sun exposure, the median age of diagnosis for basal cell carcinoma is 68 years. Histopathologically, basal cell carcinoma is characterized by islands or nests of atypical basaloid cells with palisading cells at the periphery.⁴ Treatment depends on the location and size of the lesion, but Mohs micrographic surgery is the most common intervention on the face and ears.⁵

In contrast, fibrous papules are benign lesions that manifest clinically as small, firm, flesh-colored papules that most commonly are found on the nose.^6,7 On dermatopathology, classic findings include fibrovascular proliferation and scattered multinucleated triangular or stellate cells in the upper dermis.⁷ Due to the benign nature of the lesion, treatment is not required⁶; however, shave excision, electrodessication, and laser therapies can be attempted if the patient chooses to pursue treatment.⁸

Dermal nevus is a type of benign acquired melanocytic nevus that manifests clinically as a light-brown to flesh-colored, dome-shaped or papillomatous papule.⁹ It typically develops in areas that are exposed to the sun, including the face.¹⁰ There also have been cases of dermal nevi on the ear.¹¹ Histopathology shows melanocytic nevus cells that have completely detached from the epidermis and are located entirely in the dermis.¹² While dermal nevi are benign and treatment is not necessary, surgical excision is an option for patients who request removal.¹³

Trichofolliculoma is a benign tumor of the adnexa that shows follicular differentiation on histopathology.¹⁴ On physical examination, it manifests as an isolated flesh-colored papule or nodule with a central pore from which tufted hairs protrude. These lesions usually appear on the face or scalp and occur more commonly in women than in men. While these may be clinically indistinguishable from trichodiscomas, the absence of protruding hair in our patient’s case makes trichofolliculoma less likely. When biopsied, histopathology classically shows a cystically dilated hair follicle with keratinous material and several mature and immature branched follicular structures. Preferred treatment for trichofolliculomas is surgical excision, and recurrence is rare.¹⁴

The advent of social media has revolutionized the way patients access and consume health information. While this increased access has its merits, it also has given rise to the proliferation of medical myths, which have considerable effects on patient-physician interactions.¹ Myths are prevalent across all fields of health care, ranging from misconceptions about disease etiology and prevention to the efficacy and safety of treatments. This influx of misinformation can derail the clinical encounter, shifting the focus from evidence-based medicine to myth-busting.² The COVID-19 pandemic exacerbated this issue, as widespread lockdowns and social distancing measures limited access to in-person medical consultations, prompting patients to increasingly turn to online sources for health information that often were unreliable, thereby bypassing professional medical advice.³ Herein, we highlight the challenges and implications of common dermatology myths and provide strategies for effectively debunking these myths to enhance patient care.

Common Dermatology Myths

In dermatology, where visible and often distressing conditions such as acne and hair loss are common, the impact of myths on patient perceptions and treatment outcomes can be particularly profound. Patients often arrive for consultations with preconceived notions that are not grounded in scientific evidence. Common dermatologic myths include eczema and the efficacy of topical corticosteroids, the causes and treatment of hair loss, and risk factors associated with skin cancer.

Eczema and Topical Corticosteroids—Topical corticosteroids for eczema are safe and effective, but nonadherence due to phobias stemming from misinformation online can impede treatment.⁴ Myths such as red skin syndrome and topical corticosteroid addiction are prevalent. Red skin syndrome refers to claims that prolonged use of topical corticosteroids causes severe redness and burning of the skin and worsening eczema symptoms upon withdrawal. Topical corticosteroid addiction suggests that patients become dependent on corticosteroids, requiring higher doses over time to maintain efficacy. These misconceptions contribute to fear and avoidance of prescribed treatments.

Eczema myths often divert focus from its true etiology as a genetic inflammatory skin disease, suggesting instead that it is caused by leaky gut or food intolerances.⁴ Risks such as skin thinning and stunted growth often are exaggerated on social media and other nonmedical platforms, though these adverse effects rarely are seen when topical corticosteroids are used appropriately under medical supervision. Misinformation often is linked to companies promoting unregulated consultations, tests, or supposedly natural treatments, including herbal remedies that may surreptitiously contain corticosteroids without clear labeling. This fosters distrust of US Food and Drug Administration– approved and dermatologist-prescribed treatments, as patients may cite concerns based on experiences with or claims about unapproved products.⁴

Sunscreen and Skin Cancer—In 2018, the American Academy of Dermatology prioritized skin cancer prevention due to suboptimal public adoption of photoprotection measures.⁵ However, the proliferation of misinformation regarding sunscreen and its potential to cause skin cancer is a more pressing issue. Myths range from claims that sunscreen is ineffective to warnings that it is dangerous, with some social media influencers even suggesting that sunscreen causes skin cancer due to toxic ingredients.⁶ Oxybenzone, typically found in chemical sunscreens, has been criticized by some advocacy groups and social media influencers as a potential hormone disruptor (ie, a chemical that could interfere with hormone production).⁷ However, no conclusive evidence has shown that oxybenzone is harmful to humans. Consumer concerns often are based on animal studies in which rats are fed oxybenzone, but mathematical modeling has indicated it would take 277 years of sunscreen use by humans to match the doses used in these studies.⁸ The false association between sunscreen use and skin cancer is based on flawed studies that found higher rates of skin cancer—including melanoma—in sunscreen users compared to those who did not use sunscreen. However, those using sunscreen also were more likely to travel to sunnier climates and engage in sunbathing, and it may have been this increased sun exposure that elevated their risk for skin cancer.⁷ It is imperative that the dermatology community counteract this type of misinformation with evidence-based advice.

Hair Loss—Some patients believe that hair loss is caused by wearing hats, frequent shampooing, or even stress in a way that oversimplifies complex physiological processes. Biotin, which commonly is added to supplements for hair, skin, and nails, has been linked to potential risks, such as interference with laboratory testing and false-positive or false-negative results in critical medical tests, which can lead to misdiagnosis or inappropriate treatment.⁹ Biotin interference can result in falsely low troponin readings, which are critical in diagnosing acute myocardial infarction. Tests for other hormones such as cortisol and parathyroid hormone also are affected, potentially impacting the evaluation and management of endocrine disorders. The US Food and Drug Administration has issued warnings for patients on this topic, emphasizing the importance of informing health care providers about any biotin supplementation prior to laboratory testing. Despite its popularity, there is no substantial scientific evidence to suggest that biotin supplementation promotes hair growth in anyone other than those with deficiency, which is quite rare.⁹

Myths and the Patient-Physician Relationship

The proliferation of medical myths and misinformation affects the dynamic between patients and dermatologists in several ways. Research across various medical fields has demonstrated that misinformation can substantially impact patient behavior and treatment adherence. Like many other specialists, dermatologists often spend considerable time during consultations with patients debunking myths and correcting misconceptions, which can detract from discussing more critical aspects of the patient’s condition and treatment plan and lead to frustration and anxiety among patients. It also can be challenging for physicians to have these conversations without alienating patients, who may distrust medical recommendations and believe that natural or alternative treatments are superior. This can lead to noncompliance with prescribed treatments, and patients may instead opt to try unproven remedies they encounter online, ultimately resulting in poorer health outcomes.

Strategies to Debunk Myths

By implementing the following strategies, dermatologists can combat the spread of myths, foster trust among patients, and promote adherence to evidence-based treatments:

• Provide educational outreach. Preemptively address myths by giving patients accurate and accessible resources. Including a dedicated section on your clinic’s website with articles, frequently asked questions, videos, and links to reputable sources can be effective. Sharing patient testimonials and before-and-after photographs to demonstrate the success of evidence-based treatments also is recommended, as real-life stories can be powerful tools in dispelling myths.
• Practice effective communication. Involve patients in the decision-making process by discussing their treatment goals, preferences, and concerns. It is important to present all options clearly, including the potential benefits and adverse effects. Discuss the expected outcomes and timelines, and be transparent about the limitations of certain treatment—honesty helps build trust and sets realistic expectations.
• Conduct structured consultations. Ensure that consultations with patients follow a structured format—history, physical examination, and discussion—to help keep the focus on evidence-based practice.
• Leverage technology. Guide patients toward reliable digital patient education tools to empower them with accurate information. Hosting live sessions on social media platforms during which patients can ask questions and receive evidence-based answers also can be beneficial.

Final Thoughts

In summary, the rise of medical myths poses a considerable challenge to dermatologic practice. By understanding the sources and impacts of these myths and employing strategies to dispel them, dermatologists can better navigate the complexities of modern patient interactions and ensure that care remains grounded in scientific evidence.

The advent of social media has revolutionized the way patients access and consume health information. While this increased access has its merits, it also has given rise to the proliferation of medical myths, which have considerable effects on patient-physician interactions.¹ Myths are prevalent across all fields of health care, ranging from misconceptions about disease etiology and prevention to the efficacy and safety of treatments. This influx of misinformation can derail the clinical encounter, shifting the focus from evidence-based medicine to myth-busting.² The COVID-19 pandemic exacerbated this issue, as widespread lockdowns and social distancing measures limited access to in-person medical consultations, prompting patients to increasingly turn to online sources for health information that often were unreliable, thereby bypassing professional medical advice.³ Herein, we highlight the challenges and implications of common dermatology myths and provide strategies for effectively debunking these myths to enhance patient care.

Common Dermatology Myths

In dermatology, where visible and often distressing conditions such as acne and hair loss are common, the impact of myths on patient perceptions and treatment outcomes can be particularly profound. Patients often arrive for consultations with preconceived notions that are not grounded in scientific evidence. Common dermatologic myths include eczema and the efficacy of topical corticosteroids, the causes and treatment of hair loss, and risk factors associated with skin cancer.

Eczema and Topical Corticosteroids—Topical corticosteroids for eczema are safe and effective, but nonadherence due to phobias stemming from misinformation online can impede treatment.⁴ Myths such as red skin syndrome and topical corticosteroid addiction are prevalent. Red skin syndrome refers to claims that prolonged use of topical corticosteroids causes severe redness and burning of the skin and worsening eczema symptoms upon withdrawal. Topical corticosteroid addiction suggests that patients become dependent on corticosteroids, requiring higher doses over time to maintain efficacy. These misconceptions contribute to fear and avoidance of prescribed treatments.

Eczema myths often divert focus from its true etiology as a genetic inflammatory skin disease, suggesting instead that it is caused by leaky gut or food intolerances.⁴ Risks such as skin thinning and stunted growth often are exaggerated on social media and other nonmedical platforms, though these adverse effects rarely are seen when topical corticosteroids are used appropriately under medical supervision. Misinformation often is linked to companies promoting unregulated consultations, tests, or supposedly natural treatments, including herbal remedies that may surreptitiously contain corticosteroids without clear labeling. This fosters distrust of US Food and Drug Administration– approved and dermatologist-prescribed treatments, as patients may cite concerns based on experiences with or claims about unapproved products.⁴

Sunscreen and Skin Cancer—In 2018, the American Academy of Dermatology prioritized skin cancer prevention due to suboptimal public adoption of photoprotection measures.⁵ However, the proliferation of misinformation regarding sunscreen and its potential to cause skin cancer is a more pressing issue. Myths range from claims that sunscreen is ineffective to warnings that it is dangerous, with some social media influencers even suggesting that sunscreen causes skin cancer due to toxic ingredients.⁶ Oxybenzone, typically found in chemical sunscreens, has been criticized by some advocacy groups and social media influencers as a potential hormone disruptor (ie, a chemical that could interfere with hormone production).⁷ However, no conclusive evidence has shown that oxybenzone is harmful to humans. Consumer concerns often are based on animal studies in which rats are fed oxybenzone, but mathematical modeling has indicated it would take 277 years of sunscreen use by humans to match the doses used in these studies.⁸ The false association between sunscreen use and skin cancer is based on flawed studies that found higher rates of skin cancer—including melanoma—in sunscreen users compared to those who did not use sunscreen. However, those using sunscreen also were more likely to travel to sunnier climates and engage in sunbathing, and it may have been this increased sun exposure that elevated their risk for skin cancer.⁷ It is imperative that the dermatology community counteract this type of misinformation with evidence-based advice.

Hair Loss—Some patients believe that hair loss is caused by wearing hats, frequent shampooing, or even stress in a way that oversimplifies complex physiological processes. Biotin, which commonly is added to supplements for hair, skin, and nails, has been linked to potential risks, such as interference with laboratory testing and false-positive or false-negative results in critical medical tests, which can lead to misdiagnosis or inappropriate treatment.⁹ Biotin interference can result in falsely low troponin readings, which are critical in diagnosing acute myocardial infarction. Tests for other hormones such as cortisol and parathyroid hormone also are affected, potentially impacting the evaluation and management of endocrine disorders. The US Food and Drug Administration has issued warnings for patients on this topic, emphasizing the importance of informing health care providers about any biotin supplementation prior to laboratory testing. Despite its popularity, there is no substantial scientific evidence to suggest that biotin supplementation promotes hair growth in anyone other than those with deficiency, which is quite rare.⁹

Myths and the Patient-Physician Relationship

The proliferation of medical myths and misinformation affects the dynamic between patients and dermatologists in several ways. Research across various medical fields has demonstrated that misinformation can substantially impact patient behavior and treatment adherence. Like many other specialists, dermatologists often spend considerable time during consultations with patients debunking myths and correcting misconceptions, which can detract from discussing more critical aspects of the patient’s condition and treatment plan and lead to frustration and anxiety among patients. It also can be challenging for physicians to have these conversations without alienating patients, who may distrust medical recommendations and believe that natural or alternative treatments are superior. This can lead to noncompliance with prescribed treatments, and patients may instead opt to try unproven remedies they encounter online, ultimately resulting in poorer health outcomes.

Strategies to Debunk Myths

By implementing the following strategies, dermatologists can combat the spread of myths, foster trust among patients, and promote adherence to evidence-based treatments:

• Provide educational outreach. Preemptively address myths by giving patients accurate and accessible resources. Including a dedicated section on your clinic’s website with articles, frequently asked questions, videos, and links to reputable sources can be effective. Sharing patient testimonials and before-and-after photographs to demonstrate the success of evidence-based treatments also is recommended, as real-life stories can be powerful tools in dispelling myths.
• Practice effective communication. Involve patients in the decision-making process by discussing their treatment goals, preferences, and concerns. It is important to present all options clearly, including the potential benefits and adverse effects. Discuss the expected outcomes and timelines, and be transparent about the limitations of certain treatment—honesty helps build trust and sets realistic expectations.
• Conduct structured consultations. Ensure that consultations with patients follow a structured format—history, physical examination, and discussion—to help keep the focus on evidence-based practice.
• Leverage technology. Guide patients toward reliable digital patient education tools to empower them with accurate information. Hosting live sessions on social media platforms during which patients can ask questions and receive evidence-based answers also can be beneficial.

Final Thoughts

In summary, the rise of medical myths poses a considerable challenge to dermatologic practice. By understanding the sources and impacts of these myths and employing strategies to dispel them, dermatologists can better navigate the complexities of modern patient interactions and ensure that care remains grounded in scientific evidence.

The advent of social media has revolutionized the way patients access and consume health information. While this increased access has its merits, it also has given rise to the proliferation of medical myths, which have considerable effects on patient-physician interactions.¹ Myths are prevalent across all fields of health care, ranging from misconceptions about disease etiology and prevention to the efficacy and safety of treatments. This influx of misinformation can derail the clinical encounter, shifting the focus from evidence-based medicine to myth-busting.² The COVID-19 pandemic exacerbated this issue, as widespread lockdowns and social distancing measures limited access to in-person medical consultations, prompting patients to increasingly turn to online sources for health information that often were unreliable, thereby bypassing professional medical advice.³ Herein, we highlight the challenges and implications of common dermatology myths and provide strategies for effectively debunking these myths to enhance patient care.

Common Dermatology Myths

In dermatology, where visible and often distressing conditions such as acne and hair loss are common, the impact of myths on patient perceptions and treatment outcomes can be particularly profound. Patients often arrive for consultations with preconceived notions that are not grounded in scientific evidence. Common dermatologic myths include eczema and the efficacy of topical corticosteroids, the causes and treatment of hair loss, and risk factors associated with skin cancer.

Eczema and Topical Corticosteroids—Topical corticosteroids for eczema are safe and effective, but nonadherence due to phobias stemming from misinformation online can impede treatment.⁴ Myths such as red skin syndrome and topical corticosteroid addiction are prevalent. Red skin syndrome refers to claims that prolonged use of topical corticosteroids causes severe redness and burning of the skin and worsening eczema symptoms upon withdrawal. Topical corticosteroid addiction suggests that patients become dependent on corticosteroids, requiring higher doses over time to maintain efficacy. These misconceptions contribute to fear and avoidance of prescribed treatments.

Eczema myths often divert focus from its true etiology as a genetic inflammatory skin disease, suggesting instead that it is caused by leaky gut or food intolerances.⁴ Risks such as skin thinning and stunted growth often are exaggerated on social media and other nonmedical platforms, though these adverse effects rarely are seen when topical corticosteroids are used appropriately under medical supervision. Misinformation often is linked to companies promoting unregulated consultations, tests, or supposedly natural treatments, including herbal remedies that may surreptitiously contain corticosteroids without clear labeling. This fosters distrust of US Food and Drug Administration– approved and dermatologist-prescribed treatments, as patients may cite concerns based on experiences with or claims about unapproved products.⁴

Sunscreen and Skin Cancer—In 2018, the American Academy of Dermatology prioritized skin cancer prevention due to suboptimal public adoption of photoprotection measures.⁵ However, the proliferation of misinformation regarding sunscreen and its potential to cause skin cancer is a more pressing issue. Myths range from claims that sunscreen is ineffective to warnings that it is dangerous, with some social media influencers even suggesting that sunscreen causes skin cancer due to toxic ingredients.⁶ Oxybenzone, typically found in chemical sunscreens, has been criticized by some advocacy groups and social media influencers as a potential hormone disruptor (ie, a chemical that could interfere with hormone production).⁷ However, no conclusive evidence has shown that oxybenzone is harmful to humans. Consumer concerns often are based on animal studies in which rats are fed oxybenzone, but mathematical modeling has indicated it would take 277 years of sunscreen use by humans to match the doses used in these studies.⁸ The false association between sunscreen use and skin cancer is based on flawed studies that found higher rates of skin cancer—including melanoma—in sunscreen users compared to those who did not use sunscreen. However, those using sunscreen also were more likely to travel to sunnier climates and engage in sunbathing, and it may have been this increased sun exposure that elevated their risk for skin cancer.⁷ It is imperative that the dermatology community counteract this type of misinformation with evidence-based advice.

Hair Loss—Some patients believe that hair loss is caused by wearing hats, frequent shampooing, or even stress in a way that oversimplifies complex physiological processes. Biotin, which commonly is added to supplements for hair, skin, and nails, has been linked to potential risks, such as interference with laboratory testing and false-positive or false-negative results in critical medical tests, which can lead to misdiagnosis or inappropriate treatment.⁹ Biotin interference can result in falsely low troponin readings, which are critical in diagnosing acute myocardial infarction. Tests for other hormones such as cortisol and parathyroid hormone also are affected, potentially impacting the evaluation and management of endocrine disorders. The US Food and Drug Administration has issued warnings for patients on this topic, emphasizing the importance of informing health care providers about any biotin supplementation prior to laboratory testing. Despite its popularity, there is no substantial scientific evidence to suggest that biotin supplementation promotes hair growth in anyone other than those with deficiency, which is quite rare.⁹

Myths and the Patient-Physician Relationship

The proliferation of medical myths and misinformation affects the dynamic between patients and dermatologists in several ways. Research across various medical fields has demonstrated that misinformation can substantially impact patient behavior and treatment adherence. Like many other specialists, dermatologists often spend considerable time during consultations with patients debunking myths and correcting misconceptions, which can detract from discussing more critical aspects of the patient’s condition and treatment plan and lead to frustration and anxiety among patients. It also can be challenging for physicians to have these conversations without alienating patients, who may distrust medical recommendations and believe that natural or alternative treatments are superior. This can lead to noncompliance with prescribed treatments, and patients may instead opt to try unproven remedies they encounter online, ultimately resulting in poorer health outcomes.

Strategies to Debunk Myths

By implementing the following strategies, dermatologists can combat the spread of myths, foster trust among patients, and promote adherence to evidence-based treatments:

• Provide educational outreach. Preemptively address myths by giving patients accurate and accessible resources. Including a dedicated section on your clinic’s website with articles, frequently asked questions, videos, and links to reputable sources can be effective. Sharing patient testimonials and before-and-after photographs to demonstrate the success of evidence-based treatments also is recommended, as real-life stories can be powerful tools in dispelling myths.
• Practice effective communication. Involve patients in the decision-making process by discussing their treatment goals, preferences, and concerns. It is important to present all options clearly, including the potential benefits and adverse effects. Discuss the expected outcomes and timelines, and be transparent about the limitations of certain treatment—honesty helps build trust and sets realistic expectations.
• Conduct structured consultations. Ensure that consultations with patients follow a structured format—history, physical examination, and discussion—to help keep the focus on evidence-based practice.
• Leverage technology. Guide patients toward reliable digital patient education tools to empower them with accurate information. Hosting live sessions on social media platforms during which patients can ask questions and receive evidence-based answers also can be beneficial.

Final Thoughts

In summary, the rise of medical myths poses a considerable challenge to dermatologic practice. By understanding the sources and impacts of these myths and employing strategies to dispel them, dermatologists can better navigate the complexities of modern patient interactions and ensure that care remains grounded in scientific evidence.

For almost 2 decades, antidepressants have carried boxed warnings linking the medications to an increased risk for suicidal thoughts and behaviors in young people. Paradoxically, and for almost as long, evidence suggests these warnings may have led to fewer depression diagnoses, reduced prescriptions, and, ultimately, higher suicide rates.

With mounting evidence of these negative unintended consequences, some clinicians and researchers are urging the Food and Drug Administration (FDA) to consider revising — or even eliminating — boxed warnings on these medications.

The latest report challenging the utility of the 2005 warnings was particularly sobering. Published in October in Health Affairs, the systematic review of studies from 2003 to 2022 showed a 20%-40% decline in physician visits for depression, a 20%-50% decline in antidepressant use, and an abrupt increase in psychotropic drug poisonings and suicides — all after the warnings were added.

“FDA officials should review the totality of evidence and err on the side of caution in acknowledging possible harms of the antidepressant warnings,” lead author Stephen Soumerai, ScD, professor of population medicine at Harvard Medical School at Harvard Pilgrim Health Care Institute, Boston, Massachusetts and colleagues wrote. They called on the FDA to replace the boxed warnings with a routine warning in labeling.

While good prospective data on the risks and benefits of antidepressants in youth were limited when the boxed warnings were instituted, there is more information now, said Jeffrey Strawn, MD, professor of psychiatry and pediatrics at the University of Cincinnati College of Medicine in Ohio. Strawn, whose research on the topic has been cited frequently over the years, said the new evidence suggests it is time for the FDA to reevaluate the warnings.

“I don’t think that they’ve been useful. They’ve actually been harmful,” Strawn told this news organization. “These boxed warnings have decreased physicians’ and other clinicians’ comfort and tendency to prescribe.”

 

Decline in Diagnoses

The FDA issued its first warning about the potential for suicidal thoughts and behavior in children in 2003. After an advisory panel weighed the evidence, the agency added a boxed warning in 2005 to all antidepressants for children younger than 18 years. The warning was expanded in 2007 to include young adults through age 24.

Data suggesting that the warnings have had unintended effects can be found going back to just after they were issued. For instance, in 2009, after rising for years, the rate of new pediatric depression diagnoses fell precipitously after the warning was added, with primary care physicians diagnosing 44% fewer cases.

In 2014, citing evidence of fewer diagnoses and rising psychotropic drug poisonings, Weill Cornell Medicine Professor Richard A. Friedman, MD, called on the FDA in a perspective to remove the boxed warnings.

Strawn and colleagues reported in an often-cited 2014 systematic review and meta-analysis that, in nine trials involving 1673 patients and six medications, antidepressants were superior to placebo, with no increased risk for suicidal thoughts or behavior.

He has also studied adverse effects of the medications, reporting in Pharmacotherapy that suicidality risk might be more likely with some medications, such as paroxetine and venlafaxine, and that it could be influenced by baseline suicidality, among many other factors. A Swedish register study found that risk was highest the month before starting a medication, Strawn and colleagues wrote.

Dara Sakolsky, MD, PhD, associate professor of psychiatry and associate medical director, Services for Teens at Risk at the University of Pittsburgh School of Medicine, Pennsylvania, told this news organization that, because of “these negative unintended consequences,” the FDA should lower the temperature by putting the warnings in labeling.

“It makes sense based on the data that we have at hand now,” said Sakolsky.

 

The Dangers of Untreated Depression

Even with this new information, lingering concerns about earlier studies that pointed to increased suicidality risk may discourage prescribing by primary care physicians and pediatricians, and that worries researchers and psychiatrists.

“My concern is that the risk for suicide and suicidal behavior may be higher in untreated depression than the risk of suicidal thoughts or behaviors from antidepressants,” Jeffrey Bridge, PhD, director of the Center for Suicide Prevention and Research at Nationwide Children’s Hospital, Columbus, Ohio, told this news organization.

Bridge is the lead author of a much-cited 2007 meta-analysis in JAMA that showed that the benefits of antidepressants in children and adolescents appeared to be greater than the risks for suicidality. “The concern about antidepressants must be considered in the context of possible benefit,” wrote Bridge, who also is professor of pediatrics, psychiatry, and behavioral health at Ohio State University College of Medicine, Columbus.

Depression and suicide are a scourge for those younger than 25 years. A 2021 literature review noted that the prevalence of depression — which has been increasing for all Americans — has risen more among adolescents than adults. Depression is “strongly associated with suicide,” the authors wrote.

In 2021, the National Institute of Mental Health reported suicide was the second leading cause of death among 10- to 14-year-olds and the third leading cause of death among those aged 15-24 years.

Suicide kills more kids aged between 10 and 24 years than cancer and all other illnesses combined, John Campo, MD, director of child and adolescent psychiatry at Johns Hopkins University School of Medicine and vice president of psychiatric services at Kennedy Krieger Institute, told this news organization.

Meanwhile, he added, the medications work and clinicians balance risk and benefit in prescribing.

The landmark 2007 Treatment for Adolescents with Depression Study showed that fluoxetine, especially in combination with cognitive-behavioral therapy (CBT), was significantly better than placebo. Since that time, legions of trials have shown the drugs’ effectiveness.

The most effective treatment for teen depression is a combination of CBT and a selective serotonin reuptake inhibitor, said Sakolsky.

“We know that the evidence for that is pretty good,” she said. “On the flip side, we know the risk of having an adverse outcome is pretty low.”

Sakolsky tells patients and families that perhaps 1 in 146 will have a suicidal thought or behavior. “That’s pretty rare when we know how effective these medicines are.” 

Strawn said he always notes that no suicides took place in the trials that led to the warning and stresses that he closely monitors patients. “While the more recent prospective data are reassuring,” the suicidality risk “is something that we still talk about,” he said. He also discusses how some antidepressants seem to increase risk more than others.

For Campo, the discussion is based on his reading of the evidence, not the presence of the FDA warning.

“Based on what we know, I still think it’s fair to proceed with the idea that there is a small, but real risk,” he said. However, “at the same time, the medications might be exceptionally helpful for some kids.”

 

‘What Do We Do Now?’

When the FDA issued its warning in 2005, the agency said it identified the risk for suicidality in a combined analysis of short-term placebo-controlled trials of nine antidepressants. It ultimately included 24 trials involving more than 4400 patients. The risk was highest in the first few months. The average risk for those taking antidepressants was 4%, twice the placebo risk of 2%. There were no suicides in these trials, however.

The trials relied on spontaneous reports of adverse events, not predetermined measures, Campo said. Even so, that 2% difference is “nothing to sneeze at,” he noted.

Bridge’s meta-analysis showed a smaller difference — closer to 0.7%. “But it was still statistically significant,” Campo said. “I have trouble ignoring that.”

The unintended consequences of the warning can’t be studied in a randomized controlled trial. Studies have shown an association but not a direct cause-and-effect relationship between the warning and a decline in treatment and rise in suicides.

But the potential for suicidal thoughts and behavior with antidepressants has been studied prospectively. Some older studies found a significant risk, while more recent trials have not.

While the Health Affairs analysis “certainly makes a strong case,” it is observational data, Campo said.

“The question is, what do we do now in retrospect? Do you say, ‘Never mind. We don’t need the black box warning anymore?’ ” he said. “That would require a pretty careful look.”

The Health Affairs paper “makes me think that there are other areas of research that that need to be completed and done and updated, and then there should be an assessment, a reevaluation from the FDA,” said Bridge. A new meta-analysis “would be very informative,” he said.

 

What’s Next?

When asked about the Health Affairs paper and whether the agency would review the warnings, an FDA spokesperson told this news organization that the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

Sakolsky said the data clearly point to the damage that the warning has done over the past 2 decades, but that things might be improving. Studies conducted more recently might not have captured some changes in practice.

For instance, she noted, in 2022, the US Preventive Services Task Force recommended screening for major depressive disorder in adolescents aged 12-18 years. In turn, she has seen more patients in her office who were referred by pediatricians who had conducted the screening, said Sakolsky.

Strawn said the time for pontificating is long past due. “We’re withholding medications and other treatments that could potentially be effective for disorders that, in and of themselves, are associated with a significant increase in the risk of suicide.” 

After the FDA instituted the warning, “we were all very nervous,” about the potential fallout, said Campo, adding that a part of him wishes that the warnings had been “more mundane and less dramatic.”

Despite the unintended consequences, “it’s going to be hard to put the genie back in the bottle,” he said.

Campo and Sakolsky reported no relevant financial relationships. Strawn disclosed that his institution has received research funding from the National Institute of Child Health and Human Development, the Patient-Centered Outcomes Research Institute (PCORI), and AbbVie. Bridge reported that he received grant support from the National Institute of Mental Health, Centers for Disease Control and Prevention, and PCORI; is a scientific adviser to Clarigent Health; and is on the Scientific Council of the American Foundation for Suicide Prevention.

A version of this article first appeared on Medscape.com.

For almost 2 decades, antidepressants have carried boxed warnings linking the medications to an increased risk for suicidal thoughts and behaviors in young people. Paradoxically, and for almost as long, evidence suggests these warnings may have led to fewer depression diagnoses, reduced prescriptions, and, ultimately, higher suicide rates.

With mounting evidence of these negative unintended consequences, some clinicians and researchers are urging the Food and Drug Administration (FDA) to consider revising — or even eliminating — boxed warnings on these medications.

The latest report challenging the utility of the 2005 warnings was particularly sobering. Published in October in Health Affairs, the systematic review of studies from 2003 to 2022 showed a 20%-40% decline in physician visits for depression, a 20%-50% decline in antidepressant use, and an abrupt increase in psychotropic drug poisonings and suicides — all after the warnings were added.

“FDA officials should review the totality of evidence and err on the side of caution in acknowledging possible harms of the antidepressant warnings,” lead author Stephen Soumerai, ScD, professor of population medicine at Harvard Medical School at Harvard Pilgrim Health Care Institute, Boston, Massachusetts and colleagues wrote. They called on the FDA to replace the boxed warnings with a routine warning in labeling.

While good prospective data on the risks and benefits of antidepressants in youth were limited when the boxed warnings were instituted, there is more information now, said Jeffrey Strawn, MD, professor of psychiatry and pediatrics at the University of Cincinnati College of Medicine in Ohio. Strawn, whose research on the topic has been cited frequently over the years, said the new evidence suggests it is time for the FDA to reevaluate the warnings.

“I don’t think that they’ve been useful. They’ve actually been harmful,” Strawn told this news organization. “These boxed warnings have decreased physicians’ and other clinicians’ comfort and tendency to prescribe.”

 

Decline in Diagnoses

The FDA issued its first warning about the potential for suicidal thoughts and behavior in children in 2003. After an advisory panel weighed the evidence, the agency added a boxed warning in 2005 to all antidepressants for children younger than 18 years. The warning was expanded in 2007 to include young adults through age 24.

Data suggesting that the warnings have had unintended effects can be found going back to just after they were issued. For instance, in 2009, after rising for years, the rate of new pediatric depression diagnoses fell precipitously after the warning was added, with primary care physicians diagnosing 44% fewer cases.

In 2014, citing evidence of fewer diagnoses and rising psychotropic drug poisonings, Weill Cornell Medicine Professor Richard A. Friedman, MD, called on the FDA in a perspective to remove the boxed warnings.

Strawn and colleagues reported in an often-cited 2014 systematic review and meta-analysis that, in nine trials involving 1673 patients and six medications, antidepressants were superior to placebo, with no increased risk for suicidal thoughts or behavior.

He has also studied adverse effects of the medications, reporting in Pharmacotherapy that suicidality risk might be more likely with some medications, such as paroxetine and venlafaxine, and that it could be influenced by baseline suicidality, among many other factors. A Swedish register study found that risk was highest the month before starting a medication, Strawn and colleagues wrote.

Dara Sakolsky, MD, PhD, associate professor of psychiatry and associate medical director, Services for Teens at Risk at the University of Pittsburgh School of Medicine, Pennsylvania, told this news organization that, because of “these negative unintended consequences,” the FDA should lower the temperature by putting the warnings in labeling.

“It makes sense based on the data that we have at hand now,” said Sakolsky.

 

The Dangers of Untreated Depression

Even with this new information, lingering concerns about earlier studies that pointed to increased suicidality risk may discourage prescribing by primary care physicians and pediatricians, and that worries researchers and psychiatrists.

“My concern is that the risk for suicide and suicidal behavior may be higher in untreated depression than the risk of suicidal thoughts or behaviors from antidepressants,” Jeffrey Bridge, PhD, director of the Center for Suicide Prevention and Research at Nationwide Children’s Hospital, Columbus, Ohio, told this news organization.

Bridge is the lead author of a much-cited 2007 meta-analysis in JAMA that showed that the benefits of antidepressants in children and adolescents appeared to be greater than the risks for suicidality. “The concern about antidepressants must be considered in the context of possible benefit,” wrote Bridge, who also is professor of pediatrics, psychiatry, and behavioral health at Ohio State University College of Medicine, Columbus.

Depression and suicide are a scourge for those younger than 25 years. A 2021 literature review noted that the prevalence of depression — which has been increasing for all Americans — has risen more among adolescents than adults. Depression is “strongly associated with suicide,” the authors wrote.

In 2021, the National Institute of Mental Health reported suicide was the second leading cause of death among 10- to 14-year-olds and the third leading cause of death among those aged 15-24 years.

Suicide kills more kids aged between 10 and 24 years than cancer and all other illnesses combined, John Campo, MD, director of child and adolescent psychiatry at Johns Hopkins University School of Medicine and vice president of psychiatric services at Kennedy Krieger Institute, told this news organization.

Meanwhile, he added, the medications work and clinicians balance risk and benefit in prescribing.

The landmark 2007 Treatment for Adolescents with Depression Study showed that fluoxetine, especially in combination with cognitive-behavioral therapy (CBT), was significantly better than placebo. Since that time, legions of trials have shown the drugs’ effectiveness.

The most effective treatment for teen depression is a combination of CBT and a selective serotonin reuptake inhibitor, said Sakolsky.

“We know that the evidence for that is pretty good,” she said. “On the flip side, we know the risk of having an adverse outcome is pretty low.”

Sakolsky tells patients and families that perhaps 1 in 146 will have a suicidal thought or behavior. “That’s pretty rare when we know how effective these medicines are.” 

Strawn said he always notes that no suicides took place in the trials that led to the warning and stresses that he closely monitors patients. “While the more recent prospective data are reassuring,” the suicidality risk “is something that we still talk about,” he said. He also discusses how some antidepressants seem to increase risk more than others.

For Campo, the discussion is based on his reading of the evidence, not the presence of the FDA warning.

“Based on what we know, I still think it’s fair to proceed with the idea that there is a small, but real risk,” he said. However, “at the same time, the medications might be exceptionally helpful for some kids.”

 

‘What Do We Do Now?’

When the FDA issued its warning in 2005, the agency said it identified the risk for suicidality in a combined analysis of short-term placebo-controlled trials of nine antidepressants. It ultimately included 24 trials involving more than 4400 patients. The risk was highest in the first few months. The average risk for those taking antidepressants was 4%, twice the placebo risk of 2%. There were no suicides in these trials, however.

The trials relied on spontaneous reports of adverse events, not predetermined measures, Campo said. Even so, that 2% difference is “nothing to sneeze at,” he noted.

Bridge’s meta-analysis showed a smaller difference — closer to 0.7%. “But it was still statistically significant,” Campo said. “I have trouble ignoring that.”

The unintended consequences of the warning can’t be studied in a randomized controlled trial. Studies have shown an association but not a direct cause-and-effect relationship between the warning and a decline in treatment and rise in suicides.

But the potential for suicidal thoughts and behavior with antidepressants has been studied prospectively. Some older studies found a significant risk, while more recent trials have not.

While the Health Affairs analysis “certainly makes a strong case,” it is observational data, Campo said.

“The question is, what do we do now in retrospect? Do you say, ‘Never mind. We don’t need the black box warning anymore?’ ” he said. “That would require a pretty careful look.”

The Health Affairs paper “makes me think that there are other areas of research that that need to be completed and done and updated, and then there should be an assessment, a reevaluation from the FDA,” said Bridge. A new meta-analysis “would be very informative,” he said.

 

What’s Next?

When asked about the Health Affairs paper and whether the agency would review the warnings, an FDA spokesperson told this news organization that the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

Sakolsky said the data clearly point to the damage that the warning has done over the past 2 decades, but that things might be improving. Studies conducted more recently might not have captured some changes in practice.

For instance, she noted, in 2022, the US Preventive Services Task Force recommended screening for major depressive disorder in adolescents aged 12-18 years. In turn, she has seen more patients in her office who were referred by pediatricians who had conducted the screening, said Sakolsky.

Strawn said the time for pontificating is long past due. “We’re withholding medications and other treatments that could potentially be effective for disorders that, in and of themselves, are associated with a significant increase in the risk of suicide.” 

After the FDA instituted the warning, “we were all very nervous,” about the potential fallout, said Campo, adding that a part of him wishes that the warnings had been “more mundane and less dramatic.”

Despite the unintended consequences, “it’s going to be hard to put the genie back in the bottle,” he said.

Campo and Sakolsky reported no relevant financial relationships. Strawn disclosed that his institution has received research funding from the National Institute of Child Health and Human Development, the Patient-Centered Outcomes Research Institute (PCORI), and AbbVie. Bridge reported that he received grant support from the National Institute of Mental Health, Centers for Disease Control and Prevention, and PCORI; is a scientific adviser to Clarigent Health; and is on the Scientific Council of the American Foundation for Suicide Prevention.

A version of this article first appeared on Medscape.com.

For almost 2 decades, antidepressants have carried boxed warnings linking the medications to an increased risk for suicidal thoughts and behaviors in young people. Paradoxically, and for almost as long, evidence suggests these warnings may have led to fewer depression diagnoses, reduced prescriptions, and, ultimately, higher suicide rates.

With mounting evidence of these negative unintended consequences, some clinicians and researchers are urging the Food and Drug Administration (FDA) to consider revising — or even eliminating — boxed warnings on these medications.

The latest report challenging the utility of the 2005 warnings was particularly sobering. Published in October in Health Affairs, the systematic review of studies from 2003 to 2022 showed a 20%-40% decline in physician visits for depression, a 20%-50% decline in antidepressant use, and an abrupt increase in psychotropic drug poisonings and suicides — all after the warnings were added.

“FDA officials should review the totality of evidence and err on the side of caution in acknowledging possible harms of the antidepressant warnings,” lead author Stephen Soumerai, ScD, professor of population medicine at Harvard Medical School at Harvard Pilgrim Health Care Institute, Boston, Massachusetts and colleagues wrote. They called on the FDA to replace the boxed warnings with a routine warning in labeling.

While good prospective data on the risks and benefits of antidepressants in youth were limited when the boxed warnings were instituted, there is more information now, said Jeffrey Strawn, MD, professor of psychiatry and pediatrics at the University of Cincinnati College of Medicine in Ohio. Strawn, whose research on the topic has been cited frequently over the years, said the new evidence suggests it is time for the FDA to reevaluate the warnings.

“I don’t think that they’ve been useful. They’ve actually been harmful,” Strawn told this news organization. “These boxed warnings have decreased physicians’ and other clinicians’ comfort and tendency to prescribe.”

 

Decline in Diagnoses

The FDA issued its first warning about the potential for suicidal thoughts and behavior in children in 2003. After an advisory panel weighed the evidence, the agency added a boxed warning in 2005 to all antidepressants for children younger than 18 years. The warning was expanded in 2007 to include young adults through age 24.

Data suggesting that the warnings have had unintended effects can be found going back to just after they were issued. For instance, in 2009, after rising for years, the rate of new pediatric depression diagnoses fell precipitously after the warning was added, with primary care physicians diagnosing 44% fewer cases.

In 2014, citing evidence of fewer diagnoses and rising psychotropic drug poisonings, Weill Cornell Medicine Professor Richard A. Friedman, MD, called on the FDA in a perspective to remove the boxed warnings.

Strawn and colleagues reported in an often-cited 2014 systematic review and meta-analysis that, in nine trials involving 1673 patients and six medications, antidepressants were superior to placebo, with no increased risk for suicidal thoughts or behavior.

He has also studied adverse effects of the medications, reporting in Pharmacotherapy that suicidality risk might be more likely with some medications, such as paroxetine and venlafaxine, and that it could be influenced by baseline suicidality, among many other factors. A Swedish register study found that risk was highest the month before starting a medication, Strawn and colleagues wrote.

Dara Sakolsky, MD, PhD, associate professor of psychiatry and associate medical director, Services for Teens at Risk at the University of Pittsburgh School of Medicine, Pennsylvania, told this news organization that, because of “these negative unintended consequences,” the FDA should lower the temperature by putting the warnings in labeling.

“It makes sense based on the data that we have at hand now,” said Sakolsky.

 

The Dangers of Untreated Depression

Even with this new information, lingering concerns about earlier studies that pointed to increased suicidality risk may discourage prescribing by primary care physicians and pediatricians, and that worries researchers and psychiatrists.

“My concern is that the risk for suicide and suicidal behavior may be higher in untreated depression than the risk of suicidal thoughts or behaviors from antidepressants,” Jeffrey Bridge, PhD, director of the Center for Suicide Prevention and Research at Nationwide Children’s Hospital, Columbus, Ohio, told this news organization.

Bridge is the lead author of a much-cited 2007 meta-analysis in JAMA that showed that the benefits of antidepressants in children and adolescents appeared to be greater than the risks for suicidality. “The concern about antidepressants must be considered in the context of possible benefit,” wrote Bridge, who also is professor of pediatrics, psychiatry, and behavioral health at Ohio State University College of Medicine, Columbus.

Depression and suicide are a scourge for those younger than 25 years. A 2021 literature review noted that the prevalence of depression — which has been increasing for all Americans — has risen more among adolescents than adults. Depression is “strongly associated with suicide,” the authors wrote.

In 2021, the National Institute of Mental Health reported suicide was the second leading cause of death among 10- to 14-year-olds and the third leading cause of death among those aged 15-24 years.

Suicide kills more kids aged between 10 and 24 years than cancer and all other illnesses combined, John Campo, MD, director of child and adolescent psychiatry at Johns Hopkins University School of Medicine and vice president of psychiatric services at Kennedy Krieger Institute, told this news organization.

Meanwhile, he added, the medications work and clinicians balance risk and benefit in prescribing.

The landmark 2007 Treatment for Adolescents with Depression Study showed that fluoxetine, especially in combination with cognitive-behavioral therapy (CBT), was significantly better than placebo. Since that time, legions of trials have shown the drugs’ effectiveness.

The most effective treatment for teen depression is a combination of CBT and a selective serotonin reuptake inhibitor, said Sakolsky.

“We know that the evidence for that is pretty good,” she said. “On the flip side, we know the risk of having an adverse outcome is pretty low.”

Sakolsky tells patients and families that perhaps 1 in 146 will have a suicidal thought or behavior. “That’s pretty rare when we know how effective these medicines are.” 

Strawn said he always notes that no suicides took place in the trials that led to the warning and stresses that he closely monitors patients. “While the more recent prospective data are reassuring,” the suicidality risk “is something that we still talk about,” he said. He also discusses how some antidepressants seem to increase risk more than others.

For Campo, the discussion is based on his reading of the evidence, not the presence of the FDA warning.

“Based on what we know, I still think it’s fair to proceed with the idea that there is a small, but real risk,” he said. However, “at the same time, the medications might be exceptionally helpful for some kids.”

 

‘What Do We Do Now?’

When the FDA issued its warning in 2005, the agency said it identified the risk for suicidality in a combined analysis of short-term placebo-controlled trials of nine antidepressants. It ultimately included 24 trials involving more than 4400 patients. The risk was highest in the first few months. The average risk for those taking antidepressants was 4%, twice the placebo risk of 2%. There were no suicides in these trials, however.

The trials relied on spontaneous reports of adverse events, not predetermined measures, Campo said. Even so, that 2% difference is “nothing to sneeze at,” he noted.

Bridge’s meta-analysis showed a smaller difference — closer to 0.7%. “But it was still statistically significant,” Campo said. “I have trouble ignoring that.”

The unintended consequences of the warning can’t be studied in a randomized controlled trial. Studies have shown an association but not a direct cause-and-effect relationship between the warning and a decline in treatment and rise in suicides.

But the potential for suicidal thoughts and behavior with antidepressants has been studied prospectively. Some older studies found a significant risk, while more recent trials have not.

While the Health Affairs analysis “certainly makes a strong case,” it is observational data, Campo said.

“The question is, what do we do now in retrospect? Do you say, ‘Never mind. We don’t need the black box warning anymore?’ ” he said. “That would require a pretty careful look.”

The Health Affairs paper “makes me think that there are other areas of research that that need to be completed and done and updated, and then there should be an assessment, a reevaluation from the FDA,” said Bridge. A new meta-analysis “would be very informative,” he said.

 

What’s Next?

When asked about the Health Affairs paper and whether the agency would review the warnings, an FDA spokesperson told this news organization that the agency “does not comment on specific studies but evaluates them as part of the body of evidence to further our understanding about a particular issue and assist in our mission to protect public health.”

Sakolsky said the data clearly point to the damage that the warning has done over the past 2 decades, but that things might be improving. Studies conducted more recently might not have captured some changes in practice.

For instance, she noted, in 2022, the US Preventive Services Task Force recommended screening for major depressive disorder in adolescents aged 12-18 years. In turn, she has seen more patients in her office who were referred by pediatricians who had conducted the screening, said Sakolsky.

Strawn said the time for pontificating is long past due. “We’re withholding medications and other treatments that could potentially be effective for disorders that, in and of themselves, are associated with a significant increase in the risk of suicide.” 

After the FDA instituted the warning, “we were all very nervous,” about the potential fallout, said Campo, adding that a part of him wishes that the warnings had been “more mundane and less dramatic.”

Despite the unintended consequences, “it’s going to be hard to put the genie back in the bottle,” he said.

Campo and Sakolsky reported no relevant financial relationships. Strawn disclosed that his institution has received research funding from the National Institute of Child Health and Human Development, the Patient-Centered Outcomes Research Institute (PCORI), and AbbVie. Bridge reported that he received grant support from the National Institute of Mental Health, Centers for Disease Control and Prevention, and PCORI; is a scientific adviser to Clarigent Health; and is on the Scientific Council of the American Foundation for Suicide Prevention.

A version of this article first appeared on Medscape.com.

TOPLINE:

Age-standardized mortality rates for hepatocellular carcinoma (HCC) in the United States are expected to rise from 5.03 per 100,000 persons in 2022 to 6.39 per 100,000 persons by 2040. Alcohol-associated liver disease (ALD) will likely become the leading cause of HCC-related mortality by 2026, and metabolic dysfunction–associated steatotic liver disease (MASLD) is projected to become the second leading cause by 2032, a new analysis found. 

METHODOLOGY:

• HCC accounts for 75%-85% of primary liver cancers and most liver cancer deaths. Researchers have observed an upward trend in the incidence of and mortality from HCC in the past 2 decades.
• This cross-sectional study analyzed 188,280 HCC-related deaths among adults aged 25 and older to determine trends in mortality rates and project age-standardized mortality rates through 2040. Data came from the National Vital Statistics System database from 2006 to 2022.
• Researchers stratified mortality data by etiology of liver disease (ALD, hepatitis B virus, hepatitis C virus, and MASLD), age groups (25-64 or 65 and older years), sex, and race/ethnicity.
• Demographic data showed that 77.4% of deaths occurred in men, 55.6% in individuals aged 65 years or older, and 62.3% in White individuals.

TAKEAWAY:

• Overall, the age-standardized mortality rate for HCC-related deaths increased from 3.65 per 100,000 persons in 2006 to 5.03 in 2022 and was projected to increase to 6.39 per 100,000 persons by 2040.
• Sex- and age-related disparities were substantial. Men had much higher rates of HCC-related mortality than women (8.15 vs 2.33 per 100,000 persons), with a projected rate among men of 9.78 per 100,000 persons by 2040. HCC-related mortality rates for people aged 65 years or older were 10 times higher than for those aged 25-64 years (18.37 vs 1.79 per 100,000 persons) in 2022 and was projected to reach 32.81 per 100,000 persons by 2040 in the older group.
• Although hepatitis C virus–related deaths were projected to decline from 0.69 to 0.03 per 100,000 persons by 2034, ALD- and MASLD-related deaths showed increasing trends, with both projected to become the two leading causes of HCC-related mortality in the next few years.
• Racial disparities were also evident. By 2040, the American Indian/Alaska Native population showed the highest increase in projected HCC-related mortality rates, which went from 5.46 per 100,000 persons in 2006 to a project increase to 14.71 per 100,000 persons.

IN PRACTICE:

“HCC mortality was projected to continue increasing in the US, primarily due to rising rates of deaths attributable to ALD and MASLD,” the authors wrote. 

This “study highlights the importance of addressing these conditions to decrease the burden of liver disease and liver disease mortality in the future,” Emad Qayed, MD, MPH, Emory University School of Medicine, Atlanta, wrote in an accompanying editorial.

SOURCE:

The study was led by Sikai Qiu, MM, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, and was published online in JAMA Network Open.
 

LIMITATIONS:

The National Vital Statistics System database used in this study captured only mortality data without access to detailed clinical records or individual medical histories. Researchers could not analyze socioeconomic factors or individual-level risk factors owing to data anonymization requirements. Additionally, the inclusion of the COVID-19 pandemic period could have influenced observed trends and reliability of future projections.
 

DISCLOSURES:

This study was supported by grants from the National Natural Science Foundation of China. Several authors reported receiving consulting fees, speaking fees, or research support from various sources.

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

TOPLINE:

Age-standardized mortality rates for hepatocellular carcinoma (HCC) in the United States are expected to rise from 5.03 per 100,000 persons in 2022 to 6.39 per 100,000 persons by 2040. Alcohol-associated liver disease (ALD) will likely become the leading cause of HCC-related mortality by 2026, and metabolic dysfunction–associated steatotic liver disease (MASLD) is projected to become the second leading cause by 2032, a new analysis found. 

METHODOLOGY:

• HCC accounts for 75%-85% of primary liver cancers and most liver cancer deaths. Researchers have observed an upward trend in the incidence of and mortality from HCC in the past 2 decades.
• This cross-sectional study analyzed 188,280 HCC-related deaths among adults aged 25 and older to determine trends in mortality rates and project age-standardized mortality rates through 2040. Data came from the National Vital Statistics System database from 2006 to 2022.
• Researchers stratified mortality data by etiology of liver disease (ALD, hepatitis B virus, hepatitis C virus, and MASLD), age groups (25-64 or 65 and older years), sex, and race/ethnicity.
• Demographic data showed that 77.4% of deaths occurred in men, 55.6% in individuals aged 65 years or older, and 62.3% in White individuals.

TAKEAWAY:

• Overall, the age-standardized mortality rate for HCC-related deaths increased from 3.65 per 100,000 persons in 2006 to 5.03 in 2022 and was projected to increase to 6.39 per 100,000 persons by 2040.
• Sex- and age-related disparities were substantial. Men had much higher rates of HCC-related mortality than women (8.15 vs 2.33 per 100,000 persons), with a projected rate among men of 9.78 per 100,000 persons by 2040. HCC-related mortality rates for people aged 65 years or older were 10 times higher than for those aged 25-64 years (18.37 vs 1.79 per 100,000 persons) in 2022 and was projected to reach 32.81 per 100,000 persons by 2040 in the older group.
• Although hepatitis C virus–related deaths were projected to decline from 0.69 to 0.03 per 100,000 persons by 2034, ALD- and MASLD-related deaths showed increasing trends, with both projected to become the two leading causes of HCC-related mortality in the next few years.
• Racial disparities were also evident. By 2040, the American Indian/Alaska Native population showed the highest increase in projected HCC-related mortality rates, which went from 5.46 per 100,000 persons in 2006 to a project increase to 14.71 per 100,000 persons.

IN PRACTICE:

“HCC mortality was projected to continue increasing in the US, primarily due to rising rates of deaths attributable to ALD and MASLD,” the authors wrote. 

This “study highlights the importance of addressing these conditions to decrease the burden of liver disease and liver disease mortality in the future,” Emad Qayed, MD, MPH, Emory University School of Medicine, Atlanta, wrote in an accompanying editorial.

SOURCE:

The study was led by Sikai Qiu, MM, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, and was published online in JAMA Network Open.
 

LIMITATIONS:

The National Vital Statistics System database used in this study captured only mortality data without access to detailed clinical records or individual medical histories. Researchers could not analyze socioeconomic factors or individual-level risk factors owing to data anonymization requirements. Additionally, the inclusion of the COVID-19 pandemic period could have influenced observed trends and reliability of future projections.
 

DISCLOSURES:

This study was supported by grants from the National Natural Science Foundation of China. Several authors reported receiving consulting fees, speaking fees, or research support from various sources.

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

TOPLINE:

Age-standardized mortality rates for hepatocellular carcinoma (HCC) in the United States are expected to rise from 5.03 per 100,000 persons in 2022 to 6.39 per 100,000 persons by 2040. Alcohol-associated liver disease (ALD) will likely become the leading cause of HCC-related mortality by 2026, and metabolic dysfunction–associated steatotic liver disease (MASLD) is projected to become the second leading cause by 2032, a new analysis found. 

METHODOLOGY:

• HCC accounts for 75%-85% of primary liver cancers and most liver cancer deaths. Researchers have observed an upward trend in the incidence of and mortality from HCC in the past 2 decades.
• This cross-sectional study analyzed 188,280 HCC-related deaths among adults aged 25 and older to determine trends in mortality rates and project age-standardized mortality rates through 2040. Data came from the National Vital Statistics System database from 2006 to 2022.
• Researchers stratified mortality data by etiology of liver disease (ALD, hepatitis B virus, hepatitis C virus, and MASLD), age groups (25-64 or 65 and older years), sex, and race/ethnicity.
• Demographic data showed that 77.4% of deaths occurred in men, 55.6% in individuals aged 65 years or older, and 62.3% in White individuals.

TAKEAWAY:

• Overall, the age-standardized mortality rate for HCC-related deaths increased from 3.65 per 100,000 persons in 2006 to 5.03 in 2022 and was projected to increase to 6.39 per 100,000 persons by 2040.
• Sex- and age-related disparities were substantial. Men had much higher rates of HCC-related mortality than women (8.15 vs 2.33 per 100,000 persons), with a projected rate among men of 9.78 per 100,000 persons by 2040. HCC-related mortality rates for people aged 65 years or older were 10 times higher than for those aged 25-64 years (18.37 vs 1.79 per 100,000 persons) in 2022 and was projected to reach 32.81 per 100,000 persons by 2040 in the older group.
• Although hepatitis C virus–related deaths were projected to decline from 0.69 to 0.03 per 100,000 persons by 2034, ALD- and MASLD-related deaths showed increasing trends, with both projected to become the two leading causes of HCC-related mortality in the next few years.
• Racial disparities were also evident. By 2040, the American Indian/Alaska Native population showed the highest increase in projected HCC-related mortality rates, which went from 5.46 per 100,000 persons in 2006 to a project increase to 14.71 per 100,000 persons.

IN PRACTICE:

“HCC mortality was projected to continue increasing in the US, primarily due to rising rates of deaths attributable to ALD and MASLD,” the authors wrote. 

This “study highlights the importance of addressing these conditions to decrease the burden of liver disease and liver disease mortality in the future,” Emad Qayed, MD, MPH, Emory University School of Medicine, Atlanta, wrote in an accompanying editorial.

SOURCE:

The study was led by Sikai Qiu, MM, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, and was published online in JAMA Network Open.
 

LIMITATIONS:

The National Vital Statistics System database used in this study captured only mortality data without access to detailed clinical records or individual medical histories. Researchers could not analyze socioeconomic factors or individual-level risk factors owing to data anonymization requirements. Additionally, the inclusion of the COVID-19 pandemic period could have influenced observed trends and reliability of future projections.
 

DISCLOSURES:

This study was supported by grants from the National Natural Science Foundation of China. Several authors reported receiving consulting fees, speaking fees, or research support from various sources.

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

A new US Department of Veterans Affairs (VA) outreach campaign is encouraging all eligible veterans to enroll in VA health care, aiming to connect the roughly 1 million unenrolled veterans to care.  
 

The campaign was prompted following reports of concerns from veterans about health issues—including mental health hurdles and thoughts of suicide—potentially related to repeated low-level artillery blasts, improvised explosive devices, missile launches, heavy fire, and other blast exposures.  
 

Veterans enrolled in VA health care have access to specialty screenings and services to address issues related to blast exposure. Those who served in Vietnam, the Gulf War, Iraq, Afghanistan, and other specific locations are eligible for these benefits based on their deployments. They do not need to have any health conditions specifically associated with their service to be eligible. 
 

“We take veteran concerns about repeated blast exposure very seriously, and we are studying this matter urgently to learn more about potential health impacts,” VA Secretary Denis McDonough said. “While we do that, we don’t want veterans to wait—they should enroll in VA health care today to get full access to primary care, mental health care, regular screenings, specialty care, and more. That’s what this outreach effort is all about: getting veterans in our care, because veterans who come to VA are proven to do better.”  
 

The campaign will consist of text messages and emails sent directly to veterans, in addition to thousands of nationwide events, advertising, and social media campaigns. It is the latest effort to appeal to more veterans and is part of the largest outreach campaign in VA history, which began when President Joseph R. Biden signed the PACT Act into law in 2022. As a result > 835,000 veterans have enrolled in VA health care (a 37% increase), > 900,000 veterans have upgraded their priority groups, making them eligible for health care with fewer copays (a record), and > 4.4 million veterans and survivors have applied for disability compensation benefits (another record).  
 

Increased enrollment benefits not only the individuals enrolled in VA health care, but those who come after.

"[W]e are constantly looking for ways to improve that care as science and research tells us about new concerns," said VA Under Secretary for Health Shereef Elnahal, MD. "The more veterans who enroll, the more we can learn about the impact of blast exposure—and the better care we can ultimately provide those who served."

A new US Department of Veterans Affairs (VA) outreach campaign is encouraging all eligible veterans to enroll in VA health care, aiming to connect the roughly 1 million unenrolled veterans to care.  
 

The campaign was prompted following reports of concerns from veterans about health issues—including mental health hurdles and thoughts of suicide—potentially related to repeated low-level artillery blasts, improvised explosive devices, missile launches, heavy fire, and other blast exposures.  
 

Veterans enrolled in VA health care have access to specialty screenings and services to address issues related to blast exposure. Those who served in Vietnam, the Gulf War, Iraq, Afghanistan, and other specific locations are eligible for these benefits based on their deployments. They do not need to have any health conditions specifically associated with their service to be eligible. 
 

“We take veteran concerns about repeated blast exposure very seriously, and we are studying this matter urgently to learn more about potential health impacts,” VA Secretary Denis McDonough said. “While we do that, we don’t want veterans to wait—they should enroll in VA health care today to get full access to primary care, mental health care, regular screenings, specialty care, and more. That’s what this outreach effort is all about: getting veterans in our care, because veterans who come to VA are proven to do better.”  
 

The campaign will consist of text messages and emails sent directly to veterans, in addition to thousands of nationwide events, advertising, and social media campaigns. It is the latest effort to appeal to more veterans and is part of the largest outreach campaign in VA history, which began when President Joseph R. Biden signed the PACT Act into law in 2022. As a result > 835,000 veterans have enrolled in VA health care (a 37% increase), > 900,000 veterans have upgraded their priority groups, making them eligible for health care with fewer copays (a record), and > 4.4 million veterans and survivors have applied for disability compensation benefits (another record).  
 

Increased enrollment benefits not only the individuals enrolled in VA health care, but those who come after.

"[W]e are constantly looking for ways to improve that care as science and research tells us about new concerns," said VA Under Secretary for Health Shereef Elnahal, MD. "The more veterans who enroll, the more we can learn about the impact of blast exposure—and the better care we can ultimately provide those who served."

A new US Department of Veterans Affairs (VA) outreach campaign is encouraging all eligible veterans to enroll in VA health care, aiming to connect the roughly 1 million unenrolled veterans to care.  
 

The campaign was prompted following reports of concerns from veterans about health issues—including mental health hurdles and thoughts of suicide—potentially related to repeated low-level artillery blasts, improvised explosive devices, missile launches, heavy fire, and other blast exposures.  
 

Veterans enrolled in VA health care have access to specialty screenings and services to address issues related to blast exposure. Those who served in Vietnam, the Gulf War, Iraq, Afghanistan, and other specific locations are eligible for these benefits based on their deployments. They do not need to have any health conditions specifically associated with their service to be eligible. 
 

“We take veteran concerns about repeated blast exposure very seriously, and we are studying this matter urgently to learn more about potential health impacts,” VA Secretary Denis McDonough said. “While we do that, we don’t want veterans to wait—they should enroll in VA health care today to get full access to primary care, mental health care, regular screenings, specialty care, and more. That’s what this outreach effort is all about: getting veterans in our care, because veterans who come to VA are proven to do better.”  
 

The campaign will consist of text messages and emails sent directly to veterans, in addition to thousands of nationwide events, advertising, and social media campaigns. It is the latest effort to appeal to more veterans and is part of the largest outreach campaign in VA history, which began when President Joseph R. Biden signed the PACT Act into law in 2022. As a result > 835,000 veterans have enrolled in VA health care (a 37% increase), > 900,000 veterans have upgraded their priority groups, making them eligible for health care with fewer copays (a record), and > 4.4 million veterans and survivors have applied for disability compensation benefits (another record).  
 

Increased enrollment benefits not only the individuals enrolled in VA health care, but those who come after.

"[W]e are constantly looking for ways to improve that care as science and research tells us about new concerns," said VA Under Secretary for Health Shereef Elnahal, MD. "The more veterans who enroll, the more we can learn about the impact of blast exposure—and the better care we can ultimately provide those who served."