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Research Summary: Lipid‑Related Metabolites as Causal Contributors to Androgenic Alopecia

Tue, 20 Jan 2026 17:56:12 GMT

Featured Student: Sundus Malik

Sundus Malik is a medical student at the University of Missouri–Kansas City School of Medicine and a Master of International Health candidate. Her academic interests span internal medicine and dermatology, with a focus on the metabolic and systemic factors that influence cutaneous disease. She also served as Executive Director of the Sojourner Health Clinic, where she leads initiatives aimed at improving access to comprehensive, patient‑centered care.

Coordinating Editor: Demi Elrond

Androgenic alopecia (AGA) is the most common form of hair loss in adults and represents a significant source of psychosocial distress for patients. Traditionally, AGA has been conceptualized as a hormonally mediated disorder driven by dihydrotestosterone‑dependent follicular miniaturization in genetically susceptible individuals. However, emerging evidence suggests that metabolic factors may also play a meaningful role in disease pathogenesis. A 2024 review of major dermatologic studies highlighted a Mendelian‑randomization analysis demonstrating that elevated lipid‑related metabolites are causally associated with increased risk of androgenic alopecia. This finding reframes AGA as not only a hormonally influenced condition but also one with important metabolic underpinnings, opening new avenues for prevention and treatment.

The study employed a Mendelian randomization (MR) design, a method that uses genetic variants as instrumental variables to infer causality between an exposure and an outcome. This approach helps overcome limitations of observational studies, such as confounding and reverse causation. By integrating large‑scale genomic and metabolomic datasets, the investigators identified specific lipid‑related metabolites whose genetically predicted elevations increased the likelihood of developing AGA. The causal nature of this association strengthens the hypothesis that lipid dysregulation contributes directly to follicular miniaturization rather than merely co‑occurring with hair loss.

These findings align with a growing body of literature linking metabolic syndrome, dyslipidemia, and cardiovascular risk factors with hair disorders. Prior observational studies have reported higher rates of insulin resistance, hypertension, and abnormal lipid profiles among individuals with AGA. However, such studies cannot establish whether metabolic abnormalities cause hair loss or simply share common risk factors. The MR approach used in this 2024 study provides stronger evidence that lipid abnormalities may play a mechanistic role in AGA pathophysiology. This insight is clinically meaningful, as it suggests that metabolic health may influence the onset and progression of hair loss.

The study’s strengths include its use of large, well‑characterized genomic datasets and the methodological rigor inherent to Mendelian randomization. By relying on genetic instruments, the analysis reduces confounding and strengthens causal inference. Additionally, the identification of specific lipid‑related metabolites provides a more granular understanding of metabolic pathways that may influence follicular

biology. These findings may help guide future mechanistic studies exploring how lipid metabolism interacts with androgen signaling, inflammation, and follicular cycling.

However, several limitations warrant consideration. First, MR analyses depend on the validity of the selected genetic instruments. If the genetic variants influence AGA through pathways unrelated to lipid metabolism, the results may be biased. Second, the study population likely consisted predominantly of individuals of European ancestry, which may limit generalizability to more diverse populations. Third, while MR can establish causality, it cannot delineate the precise biological mechanisms linking lipid metabolites to hair follicle miniaturization. Further laboratory and clinical research is needed to clarify these pathways and determine whether modifying lipid levels can meaningfully alter disease course.

Despite these limitations, the study has important implications for dermatologic practice. If lipid abnormalities contribute causally to AGA, clinicians may consider incorporating metabolic screening into the evaluation of patients presenting with early hair thinning. This could include lipid panels, assessment of metabolic syndrome components, and counseling on lifestyle modifications. Moreover, the findings raise the possibility that lipid‑lowering therapies—such as statins, PCSK9 inhibitors, or dietary interventions—could serve as adjunctive treatments for AGA. While such interventions are not yet evidence‑based for hair loss, the study provides a strong rationale for future clinical trials exploring metabolic‑targeted therapies alongside established treatments such as minoxidil, finasteride, and low‑level laser therapy.

In conclusion, the 2024 study identifying lipid‑related metabolites as causal contributors to androgenic alopecia represents a significant advancement in understanding the pathophysiology of this common condition. By demonstrating a metabolic component to AGA risk, the research expands the conceptual framework of hair loss beyond androgen signaling alone and highlights the importance of systemic health in dermatologic disease. As the field continues to integrate insights from genomics, metabolomics, and epidemiology, studies such as this underscore the value of interdisciplinary approaches in improving patient care and developing novel therapeutic strategies.

Citations:

Dermatology Times. (2024). Reviewing major dermatologic studies of the year: 2024 . Key findings include the causal link between elevated lipid‑related metabolites and increased androgenic alopecia risk.

Advancing Repigmentation Therapy: Extended Phase Three Results for Ruxolitinib Cream

Wed, 10 Dec 2025 19:00:02 GMT

Featured Student: Zoya Siddiqui

Zoya Siddiqui is a fifth-year medical student in the B.A./M.D. program at the University of Missouri-Kansas City. She enjoys rollerblading, playing tennis, and exploring local coffee shops. Her research interests include inflammatory skin conditions and health disparities in dermatologic care. Writing this research summary has helped her develop a deeper appreciation for study design and its role in translating clinical evidence into patient-centered treatment decisions.

Coordinating Editor: Demi Elrond

Introduction

Vitiligo is an acquired disorder of skin pigmentation marked by progressive loss of melanocytes. It carries a significant psychosocial burden and has historically been difficult to treat, with few approved therapies. A major advance came with the JAK inhibitor ruxolitinib cream, which received FDA approval in 2022 for nonsegmental vitiligo in patients aged twelve years and older. A study published in the New England Journal of Medicine in late 2023 by Dr. David Rosmarin and colleagues expanded on this work by evaluating the longer-term efficacy and safety of ruxolitinib cream over a full year of treatment. The trial offers valuable insight into the durability of repigmentation and real-world therapeutic potential.

Methodology

This randomized, double blind trial enrolled 674 participants with nonsegmental vitiligo affecting at least 0.5% of facial surface area or 1% of total body surface area. Participants were assigned in a two-to-one ratio to receive ruxolitinib cream 1.5% percent twice daily or vehicle cream. At week twenty-four, responders continued active treatment, and the vehicle group was crossed over to receive ruxolitinib in an open-label extension period through week fifty-two.

The primary endpoint was the Facial Vitiligo Area Scoring Index (FVASI-75) response at week twenty-four, defined as at least a 75% improvement from baseline. Secondary endpoints included total body repigmentation using the VASI, patient-reported outcome measures, and safety assessments such as application site reactions, acne, laboratory changes, and any systemic adverse events that might signal percutaneous absorption.

Findings

At week twenty four, 50% of patients receiving ruxolitinib cream achieved FVASI-75 compared with 8% in the vehicle group. Improvements continued with ongoing therapy. By week fifty-two, almost 60% of patients on continuous ruxolitinib reached FVASI-75, and many also achieved meaningful improvement in total body VASI scores.

Adverse events were mild and most often included acne at the application site, mild erythema, or pruritus. Laboratory monitoring did not show systemic JAK inhibitor-related effects, and the safety profile remained stable through one year.

Strengths and Weaknesses

The study is strengthened by its large sample size, double-blinded design, and long duration of follow-up. Use of validated vitiligo scoring systems improves clarity and clinical relevance. The extension phase also provides valuable insight into the sustained benefit of treatment, which is essential for a chronic depigmenting disorder.

Limitations include the absence of a direct comparison to other treatments, such as topical calcineurin inhibitors or phototherapy. The population consisted mainly of patients with mild to moderate disease, leaving questions about efficacy in those with extensive involvement. Additionally, repigmentation varied widely, reminding clinicians that response remains patient dependent.

Applications to Future Practice

This study reinforces the role of ruxolitinib cream as an effective and well-tolerated therapy for nonsegmental vitiligo. The continued improvement beyond six months suggests that patients may benefit from prolonged treatment, and the favorable safety profile supports its use as a first-line topical option. As interest grows in targeted therapies for pigmentary disorders, this trial provides important evidence that topical JAK inhibition can deliver meaningful repigmentation without systemic risk. Further studies will be useful to guide treatment sequencing, combination therapy with phototherapy, and management of more extensive disease.

Citations:

1. Bae JM, et al. Facial Vitiligo Area Scoring Index reliable for facial involvement. J Am Acad Dermatol. 2022. DermSquared

2. Ezzedine K, et al. Psychometric Properties and Meaningful Thresholds of the Vitiligo Area Scoring Index (VASI). JAMA Dermatol. 2025. JAMA Network

3. Merhi R, et al. Assessment of Vitiligo Area Scoring Index (VASI), Facial‐VASI, and VES scores using full body photographs. Br J Dermatol. 2022. OUP Academic

4. Pourang A, et al. Reliability of the Vitiligo Area Scoring Index measurement in vitiligo. JAAD Int. 2024. jaadinternational.org

5. Rosmarin D, Passeron T, Pandya AG, et al. Two Phase 3, Randomized, Controlled Trials of Ruxolitinib Cream for Vitiligo. N Engl J Med. 2022;387:1445–1455. New England Journal of Medicine+2PubMed+2

A Letter From President Matthew Fink

Mon, 17 Nov 2025 20:24:11 GMT

Letter from the President Matthew Fink, MD

It is an honor to serve as the newly elected president of the Kansas Society of Dermatology and Dermatologic Surgery. I practice general dermatology with University Health Physicians in Kansas City, where I also serve as Medical Director of our Eastland Dermatology Clinic and as an Assistant Professor at the UMKC School of Medicine. Over the years, the relationships built through this Society have shaped my own professional path, and I am grateful for the opportunity to support our community in the year ahead.

The Kansas Society of Dermatology and Dermatologic Surgery plays a vital role for dermatologists, Mohs surgeons, dermatology physician assistants, and dermatology nurse practitioners across our region. Our annual meeting offers more than continuing medical education. It is a place to share ideas, strengthen collegial ties, and learn from one another in an environment that is collegial, supportive, and intellectually engaging. The opportunity to gather each year strengthens our statewide dermatology community and ensures that we continue to advance patient care across Kansas through shared knowledge and collaboration.

As we look ahead to our October 2026 conference in Overland Park, I am excited about the program we are assembling. We are fortunate to welcome Dr. Benjamin Stoff, Chair of Dermatology at Emory University and a nationally recognized dermatologist and bioethicist, who will deliver two lectures. We will also be joined by Dr. Michael Sargen, a melanoma researcher at the National Institutes of Health whose training at Stanford and Emory has shaped his cutting-edge work in cutaneous oncology. Finally, Dr. Elizabeth Niemann from the University of North Carolina will speak on advances in pediatric dermatology. Dr. Niemann previously served both as Pediatric Dermatology Fellowship Program Director and as Dermatology Residency Program Director at UNC, and she brings a depth of experience that will enrich our meeting.

I am grateful for the chance to serve this Society and look forward to a productive, collaborative, and inspiring year together.

Warm regards,

Matthew Fink, MD, FAAD

President, Kansas Society of Dermatology and Dermatologic Surgery

Research Summary: Hydrocolloid Dressing vs Petroleum Ointment for Scar Appearance After Dermatologic Surgery, A Randomized Clinical Trial

Mon, 17 Nov 2025 19:47:33 GMT

Featured Student: Demi Elrond

Demi Elrod is a fifth-year student in the B.A./M.D. program at the University of Missouri-Kansas City. She enjoys junk journaling, babysitting, and exploring Kansas City's vast food scene in her spare time. Her favorite research subjects are underserved populations and psoriasis treatment developments. She enjoys keeping up with recent publications in dermatology so that she can gain more experience with evaluating the quality and clinical applications of studies.

Coordinating Editor: Demi Elrond

The 2025 study, Hydrocolloid Dressing vs Petroleum Ointment for Scar Appearance After Dermatologic Surgery, published in JAMA Dermatology, investigated whether a one-time application of a hydrocolloid dressing (HCD) for one week following dermatologic surgery would improve scar appearance and wound healing outcomes compared to standard daily petroleum ointment application. Hydrocolloid dressings are occlusive wound coverings composed of gelatin, pectin, and carboxymethylcellulose that maintain a moist wound environment, promote epithelialization, and enhance angiogenesis. They have been widely used in the management of chronic wounds such as pressure ulcers and donor sites and even for acne treatment; However, their efficacy following acute dermatologic excisions have not been well established. This study aimed to provide higher quality evidence through a randomized clinical trial assessing both patient-reported and physician-assessed scar outcomes, as well as safety and patient satisfaction.

This investigator-blinded, single-center, randomized clinical trial was conducted at Indiana University between October 2022 and October 2023. A total of 146 adult patients undergoing excision or Mohs micrographic surgery followed by linear bilayered repair were enrolled and randomized to one of two post operative wound care interventions. The experimental group received a single application of a hydrocolloid dressing, which was left in place for one week. The control group followed standard wound care involving daily washing, reapplication of petroleum ointment, and fresh dressing changes for the same duration. The primary outcome was patient reported scar appearance measured using a modified Visual Analog Scale (VAS) assessing color, texture, scar line, and overall appearance. Secondary outcomes included surgeon-assessed VAS scores, postoperative complications such as bleeding or wound dehiscence, and patient-reported comfort and convenience associated with each dressing type.

The results demonstrated that, even at seven days postoperatively, patients in the hydrocolloid dressing group reported slightly higher overall scar appearance scores compared to those in the petroleum group (7.4 versus 6.6 P=.02). However, this difference did not persist at 30 or 90 days, when both groups showed comparable improvements in scar appearance. Surgeon assessed scores mirrored the patient results, indicating no statistically significant differences between groups across all time points. Complication rates were also similar between the two groups. Although the hydrocolloid group reported higher rates of postoperative bleeding (20.6 versus 8.8%), wound dehiscence (6.2% versus 0%), and pain (21.2% versus 12.3%). Of note,these findings were not statistically significant, and no postoperative infections or antibiotic use occurred in either group. Importantly, patients in the hydrocolloid group reported significantly greater satisfaction, with 86.9% describing the dressing as convenient or extremely convenient and 73.8% rating it as comfortable or extremely comfortable. These findings suggest that hydrocolloid dressings are well tolerated and preferred by patients due to reduced dressing maintenance and overall ease of use.

The study had several notable strengths. It was randomized and investigator-blinded, which minimized bias and enhanced internal validity. Surgical techniques and suture types were standardized across all procedures, ensuring consistency in closure and healing conditions. The use of a validated, image-based scar assessment scale allowed for objective and repeatable evaluation of scar outcomes while facilitating participation for patients living far from the study site. Additionally, the study was able to maintain a high follow-up rate of 78% which reinforced the reliability of the results. By incorporating both subjective patient assessments and blinded surgeon evaluations, the study provided a comprehensive analysis of postoperative wound outcomes.

However, the study also had limitations that affect generalizability. It was conducted at a single academic center, which limits external validity and may not reflect outcomes in community or multi-site clinical settings. Because all included cases involved linear closures, the results may not apply to more complex repairs such as flaps or grafts. The reliance on photographic rather than in person scar assessments also restricted evaluation of certain tactile qualities, such as firmness or raised scar texture. Additionally, differences in wound care frequency between the continuous hydrocolloid application and daily petroleum changes introduced a variable that may have influenced patient perception and wound environment.

In conclusion, this study found that a one time application of a hydrocolloid dressing for one week after dermatologic surgery produced scar appearance outcomes and complication rates comparable to daily petroleum ointment use. Although hydrocolloid dressings did not significantly improve long term scar appearance, they provided greater comfort and convenience for patients, suggesting an important role in patient centered wound care. These findings support the use of hydrocolloid dressings as a reasonable alternative for postoperative management, particularly for patients who prefer to avoid daily dressing changes or have limitations that make frequent wound care difficult. Future research should focus on multi-center trials with larger sample sizes, inclusion of more complex surgical repairs and longer follow up durations. Collectively, this study contributes valuable evidence supporting the safety and practicality of hydrocolloid dressings in dermatologic surgery and emphasizes the importance of aligning wound care strategies with patient comfort and quality of life outcomes.

References

Bell MC, Gangodawila TW, Morr CS, et al. Hydrocolloid Dressing vs Petroleum Ointment for Scar Appearance After Dermatologic Surgery: A Randomized Clinical Trial. JAMA Dermatol. Published online October 22, 2025. doi:10.1001/jamadermatol.2025.4051

Rituximab Dosing in Pemphigus: A Review of a 52-Week Clinical Trial

Tue, 09 Sep 2025 18:29:38 GMT

Featured Student: Joey Cascone

Joey Cascone is a 4th-year medical student in the MD-only program at the University of Missouri-Kansas City rural satellite campus. His research and clinical interests are focused on narrowing the gap in health care disparities for underserved populations, both rural and urban. Joey is particularly interested in the cutaneous manifestations of autoimmune disease and malignancy. He enjoys cooking and baking, playing piano, and playing golf in his spare time.

Coordinating Editor: Demi Elrond

Introduction

Pemphigus represents a group of autoimmune blistering skin diseases affecting the skin and/or mucous membranes. It results from autoantibodies targeting desmogleins, leading to the disruption of epidermal desmosomes and subsequent blister formation. This debilitating and potentially life-threatening condition carries a mortality rate of up to 26.5%. Historically, pemphigus has been treated with systemic corticosteroids and steroid-sparing immunosuppressants like rituximab (RTX). The rheumatoid arthritis protocol for RTX (2 x 1000 mg, administered two weeks apart) has shown promising results for pemphigus treatment. However, this high dose is associated with adverse effects such as infusion reactions and infections. This study, led by Dr. Shan Cao and colleagues in JAAD, aimed to identify the optimal RTX dosing strategy for moderate-to-severe pemphigus, assessing the safety and effectiveness of ultralow-dose RTX (ULRTX), low-dose RTX (LRTX), and standard-dose RTX (SDRTX).

Study Design and Methods
This prospective, open-label, nonrandomized clinical trial involved 52 adult patients with moderate or severe pemphigus vulgaris or pemphigus foliaceus. The patients were mostly middle-aged and mainly had pemphigus vulgaris. Severity was measured by the Pemphigus Disease Area Index (PDAI). Ten patients had moderate disease (PDAI 15-45), and 41 had severe disease (PDAI > 45). Participants were divided into three non-randomized groups, each receiving RTX at baseline and two weeks later, with doses of ULRTX (100 mg, n = 26), LRTX (500 mg, n = 13), and SDRTX (1000 mg, n = 13). Patients were monitored for 52 weeks. Those in the ULRTX group received an additional 100 mg RTX infusion at 26 weeks if CD20+ B-cell reconstitution rates greatly exceeded those of the other groups. All patients received oral glucocorticoids at a dosage of 0.5 mg/kg/day for moderate disease and 1.0 mg/kg/day for severe disease, with dosages tapered according to S2k guidelines.

The primary end goal of this study was to determine complete remission after disease control for the doses mentioned above, defined as the absence of new lesions, healing of existing lesions, and the ability to taper glucocorticoids safely. Secondary endpoints included reduction in PDAI score, cumulative glucocorticoid dose required for each group, relapse rates, partial remission with minimal therapy, and autoantibody seroconversion.

Results

All patients reached disease control by week 52, with complete remission rates of 92.3% in the ULRTX group and 100% in the LRTX and SDRTX groups. This difference was not statistically significant (p = 0.35). The time to disease control varied significantly: ULRTX at 15.5 days, LRTX at 14.0 days, and SDRTX at 13.0 days (p = 0.02).

The duration to complete remission off therapy was longer in ULRTX (median 224 days) than in LRTX (172 days) or SDRTX (183 days), yet the difference was not significant (p = 0.84). All groups achieved near-complete CD20+ B-cell depletion at two weeks post-treatment. B-cell percentages at 26 weeks were 8.88% for ULRTX, 1.25% for LRTX, and 0.51% for SDRTX. The ULRTX group showed significant B-cell reconstitution at week 26 compared to LRTX (p = 0.026) and SDRTX (p = 0.018), prompting additional 100 mg RTX infusions for all ULRTX patients. No significant differences were seen in PDAI score reduction, cumulative glucocorticoid doses, or relapse rates. A small proportion (7.7%) of ULRTX patients achieved partial remission on minimal therapy, an outcome observed only in this group. All groups exhibited downward trends in anti-desmoglein 1/3 antibody titers; approximately half of each group became seronegative, with no significant variation. Adverse event rates were lowest in ULRTX (11.5%) compared to LRTX (30.8%) and SDRTX (38.5%), though these differences were not statistically significant (p = 0.15). ULRTX also resulted in significant total hospitalization cost savings of 32% compared to LRTX and 53% compared to SDRTX (p < 0.05).

Limitations

The lack of random assignment and the observational nature of this prospective cohort study mean that causality cannot be definitively established. The uneven patient distribution (26 subjects in ULRTX and only 13 in each of the other groups) further weakens the comparison strength. The authors also note additional limitations, including the small sample size from a single center.

Significance

Overall, ultralow-dose rituximab may be as effective as higher-dose regimens for pemphigus with the added benefit of saving costs. Although the lack of a significant difference in adverse events limits definitive clinical conclusions, ULRTX showed the lowest rate of adverse events, supporting a favorable safety profile. Clinicians should also consider that complete remission off therapy took longer in the ULRTX group, although this difference was also not statistically significant. Together, the comparable efficacy, low adverse event rate, and cost benefits suggest that the future of pemphigus treatment may lie in lower doses of rituximab. However, larger studies will be needed to confirm these findings.

References

Cao S, Yang B, Wang Z, et al. Efficacy, safety, and B-cell depletion capacity of three rituximab dosing regimens in the treatment of moderate-to-severe pemphigus vulgaris and pemphigus foliaceus: a 52-week clinical trial. Journal of the American Academy of Dermatology . Published online May 1, 2025. doi:10.1016/j.jaad.2025.05.1374

Atopic Dermatitis

Fri, 15 Aug 2025 14:43:37 GMT

Featured Student: Joey Cascone

Coordinating Editor: Demi Elrond

Introduction

Atopic dermatitis (AD) is one of the most prevalent chronic skin diseases worldwide. It is characterized by recurrent, relapsing skin rashes and potentially intense pruritus. The pathogenesis is multifaceted but ultimately marked by impaired epidermal barrier function and aberrant immune responses. Medicines that target both of these aspects offer the best chance at sustainable treatment. Dupilumab is a monoclonal antibody that targets the IL-4 receptor alpha. It modulates both the type 2 immune response and improves skin barrier function in AD. Abrocitinib is a JAK inhibitor capable of modulating the cytokine signals implicated in type 2 immunity. While JAK inhibitors have previously demonstrated a quicker onset of action compared to dupilumab in AD, their role in restoring impaired skin barrier function has not previously been identified. The purpose of this study, published by Dr. Jui-Wen Chang and colleagues in JAAD, was to determine whether JAK inhibitors differ from dupilumab in restoring skin barrier function in AD patients.

S tudy Design and Methods
This small prospective cohort study evaluated 33 adult patients with moderate-to-severe AD along with 17 age and gender matched healthy controls from March 2023 to March 2024. AD patients were assigned to either the dupilumab group (N = 16) or the abrocitinib group (N = 17). Itch intensity using the Peak Pruritus Numeric Rating Scale (PP-NRS) and lesion severity using the Eczema Area and Severity Index (EASI) were measured at baseline, week 4, and week 12. Skin samples from lesional and non-lesional skin were collected for proteomic analysis at these time points. All patients used emollients twice daily for the duration of the study, except within 3 hours before skin sample collection.

R esults

Both dupilumab and abrocitinib significantly improved skin lesions, with EASI scores significantly decreasing by week 4 in both groups. There was no statistically significant difference in EASI score between the two groups. Both treatments significantly reduced pruritus by week 4 and demonstrated meaningful reduction in itch overall. However, the abrocitinib group demonstrated a greater reduction in itch compared to the dupilumab group at week 12, though within-group analysis showed no significant reduction in itch for both groups at that time point.

Abrocitinib was associated with a greater decrease in lesional transepidermal water loss (TEWL) at week 4 and decreased non-lesional TEWL overall compared to dupilumab. Within-group analysis showed statistically significant improvements in lesional and non-lesional hydration by week 4 in abrocitinib only. Neither drug showed statistically significant improvements in skin hydration at week 12. No significant differences were observed between the two groups in skin hydration.

Proteomic analysis revealed widespread differences in protein expression between AD and healthy skin in both lesional and non-lesional areas. After 12 weeks of treatment, skin protein

profiles for both lesional and non-lesional skin in the abrocitinib group showed greater improvement toward healthy control profiles compared to those in the dupilumab group. In lesional skin, abrocitinib increased expression of proteins involved in keratinocyte differentiation and integrity, including filaggrin-2, PSMB6, KRT10, and KRT5, while dupilumab only increased expression of PSMB6. Expression of inflammatory proteins such as IL-18 and STAT1, and KRT16, a protein associated with keratinocyte barrier dysfunction, were significantly decreased only in the abrocitinib group. For non-lesional skin, KRT16, IL-18, and involucrin were significantly decreased only in the abrocitinib group.

Limitations

This study is clearly limited by the relatively small number of cases and controls. For this reason, further research is required to determine the mechanistic roles of each aforementioned biomarker and their significance in AD and skin barrier function. Additionally, while emollient use was standardized, other uncontrollable factors could influence skin barrier measures at each time point. Further research with larger cohorts and longer observation is necessary to better determine any differences in benefit between abrocitinib and dupilumab.

Significance

While both dupilumab and abrocitinib demonstrated improved skin barrier function, abrocitinib had a stronger effect in this measure overall through expanded modulation of skin barrier proteins and inflammatory markers. Abrocitinib may also demonstrate a modest clinical improvement in terms of itch reduction after 12 weeks of treatment compared to dupilumab. Regardless, both medicines are effective for the treatment of atopic dermatitis as there was improvement in EASI score with no statistically significant difference between the two groups at any measured time point. These findings contribute to a better understanding of how these two therapies affect the pathophysiology of AD.

References

Chang JW, Huang X, Jiang W, et al. Abrocitinib versus dupilumab: impact on skin barrier function and proteomics in atopic dermatitis. Journal of the American Academy of Dermatology. Published online April 1, 2025. doi:10.1016/j.jaad.2025.04.027

Efficacy and Safety of Secukinumab for Moderate to Severe Hidradenitis Suppurativa: A Review of a Phase 3 Randomized Clinical Trial

Mon, 07 Jul 2025 17:00:43 GMT

Featured Student: Zoya Siddiqui

Coordinating Editor: Demi Elrond

Introduction

Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease characterized by painful nodules, abscesses, and sinus tract formation, most commonly affecting intertriginous areas. Despite increasing awareness and research, treatment options remain limited, and many patients experience inadequate symptom control. A study published in JAMA Dermatology in January 2024 by Dr. Haley B. Naik and colleagues examined the use of secukinumab, an IL-17A inhibitor, for moderate to severe HS in a randomized clinical trial. .

Methodology

This multicenter, phase 3, randomized, double-blind, placebo-controlled trial enrolled 540 adult patients with moderate to severe HS. Participants were randomized in a 2:2:1:1 ratio to receive either 300 mg of secukinumab every 2 weeks, every 4 weeks, or a matching placebo. Treatment was administered subcutaneously over 16 weeks. The primary endpoint was the Hidradenitis Suppurativa Clinical Response (HiSCR) at week 16, which required at least a 50% reduction in the combined count of abscesses and inflammatory nodules (AN count) from baseline with no increase in abscess or draining fistula counts. Secondary endpoints included changes in the International Hidradenitis Suppurativa Severity Score System (IHS4), pain numeric rating scores, and quality of life measures such as the Dermatology Life Quality Index (DLQI). Safety assessments included monitoring adverse events, laboratory values, and injection site reactions throughout the treatment and follow-up periods.

Findings

At week 16, 45% of participants receiving secukinumab every 2 weeks achieved HiSCR compared to 34% in the every-4-week group and 25% in the placebo group. The difference was statistically significant, particularly in the biweekly group. Common adverse events included nasopharyngitis and headache, with no new safety concerns reported. The study concluded that secukinumab was both effective and well tolerated, particularly when administered biweekly.

Strengths and Weaknesses

This study has several strengths, including its large sample size and randomized, double-blind, placebo-controlled design, which support the reliability of the findings. The use of a validated clinical endpoint (HiSCR) and inclusion of both biweekly and monthly dosing regimens improve the clinical applicability of the results. The multicenter approach and diverse patient population also enhance generalizability.

However, the study does have some limitations. The 16-week study period provides limited information on long-term outcomes, and the exclusion of patients with mild HS may reduce applicability to the broader HS population. While secukinumab outperformed placebo, many participants did not achieve HiSCR, suggesting that response rates could still be improved. Additionally, the study did not directly compare secukinumab to other biologic treatments, such as adalimumab, which would have helped clarify its relative effectiveness.

Applications to Future Practice

This study highlights secukinumab as a promising treatment for patients with moderate to severe HS, particularly those who have not responded to antibiotics or TNF-alpha inhibitors. Its favorable safety profile and efficacy suggest it could be a valuable addition to existing management strategies. While further long-term studies are needed to evaluate the durability of response and define optimal treatment duration, these findings offer a strong foundation for future clinical application.

References

Naik HB, Liu H, Huang KP, et al. Efficacy and Safety of Secukinumab in Adults With Moderate to Severe Hidradenitis Suppurativa: A Phase 3 Randomized Clinical Trial. JAMA Dermatol. 2024;160(1):19-27. doi:10.1001/jamadermatol.2023.5321
Jemec GBE. Clinical Practice. Hidradenitis Suppurativa. N Engl J Med. 2012;366(2):158-164. doi:10.1056/NEJMcp1014163
Alavi A, Kirsner RS, Shah N, et al. Hidradenitis Suppurativa: A Review of Pathogenesis, Diagnosis, and Management. J Am Acad Dermatol. 2015;73(5 Suppl 1):S5-S7. doi:10.1016/j.jaad.2015.07.045
Zouboulis CC, Okun MM, Prens EP, et al. Adalimumab for the Treatment of Hidradenitis Suppurativa: Long-term Outcomes from the PIONEER Trials. Br J Dermatol. 2019;181(4):723-732. doi:10.1111/bjd.17771

Extended Half-life Antibodies: The Future of Biologic Therapy in Atopic Dermatitis?

Thu, 19 Jun 2025 16:47:18 GMT

Featured Student: Yeanna Moon

Yeanna Moon is a fourth-year student in the B.A./M.D. Program at the University of Missouri-Kansas City with an interest in dermatology and a strong commitment to addressing health care equities. Her academic interests like at the intersection of clinical dermatology, basic science, and public health, with ongoing work in translational research and advocacy. Outside of her studies, she finds balance through music, volunteering and exploring new coffee shops.

Introduction

Biologics have dramatically transformed the care of atopic dermatitis (AD) in the past decade and raised the bar for a new standard of care for many patients. However, they have some important limitations. One sizable limitation is that they require injections with fairly high frequency, currently from every 2-4 weeks initially. Excitingly, the most recent addition to the armamentarium offers an extended 8-week dosing schedule for patients who have achieved an adequate clinical response.1 However, the future holds the possibility for far fewer injections: new technologies are making once- or twice-yearly injections a true possibility, opening up biologic therapy in a whole new way.1

While biologics have revolutionized AD treatment, their administration presents several challenges that can increase patient burden and healthcare costs. Needle phobia, affecting approximately 24% of adults and 63% of children, leads to immunization non-compliance in 7% and 8% of these groups, respectively, potentially resulting in treatment avoidance and compromised disease management.2,3 In particular, children exhibit higher rates of needle phobia, with studies indicating that 63% of those aged 6-17 years experience this anxiety.3 Additionally, many biologic medications require strict refrigeration between 2°C and 8°C to maintain efficacy, posing significant challenges for patients who travel or lack consistent access to refrigeration. Maintaining the cold chain during transport is both costly and logistically complex. Studies have shown that over 80% of patients inadvertently expose their biologic therapies to temperatures outside the recommended range, which can compromise the effectiveness of treatment and negatively impact patient outcomes.4 Addressing these issues is crucial to enhance patient adherence, reduce healthcare costs, and improve overall treatment outcomes for individuals with AD.

Current Therapies

Several biologic therapies are currently available for AD, each targeting key inflammatory pathways with varying dosing schedules and pharmacokinetics. Dupilumab, the first approved biologic, inhibits IL-4 and IL-13 signaling through IL-4Rα and is administered every other week in adults after a loading dose, and has a half-life of approximately 14 days (Note: the elimination is non-linear and depends on factors such as age, weight, and concentration).5 IL-13 inhibitors lebrikizumab and tralokinumab follow similar regimens, with initial dosing every 2 weeks and then maintenance doses every 4 weeks and exhibit half-lives of 25 and 18 days, respectively.6,7 Nemolizumab, targeting IL-31, with a half-life of 19 days, is given every four weeks initially with possible maintenance doing at 8 week intervals.8 Newer OX40-targeting biologics Amlitelimab, Telazorlimab, and Roxatinlimab, are currently in clinical trials phase 2b, 2b, and 3 respectively. Amlitelimab is dosed every two weeks and has a 24-day half-life while Telazorlimab has a median half-life of 10–15 days.9,10 Rocatinlimab is given every four weeks, with a half-life of approximately 17 days.11 Despite their effectiveness, the frequent injection schedules required for these biologics remain a significant barrier to patient adherence and long-term success.

Challenges of Frequent Injections

Frequent injection schedules for biologic therapies in AD can pose challenges to patient adherence. A study on biologic treatments for severe asthma, a condition that like AD often requires regular injections, found that only 54% of patients treated with dupilumab achieved an adherence rate of 75% or higher, suggesting that the frequency of injections may impact adherence rates.12 Additionally, studies have demonstrated that extending dosing intervals for biologics in AD can reduce the number of injections, potentially improving patient adherence and satisfaction.1 These findings highlight the importance of developing biologic therapies with extended dosing intervals to enhance treatment adherence and patient outcomes in AD.

New Technologies

Emerging technologies focused on extending antibody half-life aim to address this challenge by reducing the frequency of injections, with the potential to decrease the need for injections to nearly twice a year. One promising approach involves optimizing antibody interactions with the neonatal Fc receptor (FcRn). By modifying the Fc region of monoclonal antibodies, their affinity for FcRn is enhanced, allowing for increased recycling and reduced degradation (Figure 1). This approach is exemplified by extended half-life biologics like APG777, an IL-13 inhibitor with a half-life of approximately 75 days, far surpassing the 18-day half-life of lebrikizumab.6,13,14 Similarly, IMG-007, an OX40 inhibitor, utilizes FcRn-based modifications to extend its presence in circulation, reducing the need for frequent dosing.13

Alternative methods for extending antibody half-life include PEGylation and albumin binding. PEGylation involves attaching polyethylene glycol (PEG) chains to therapeutic proteins, increasing their molecular size and reducing renal clearance (Figure 1).15 While PEGylation can improve pharmacokinetic properties, it may also lead to immunogenic responses, including the development of anti-PEG antibodies, which can accelerate drug clearance.16 Another approach, albumin binding, involves genetic fusion of therapeutic proteins to human serum albumin or chemical conjugation to albumin-binding domains. This approach leverages albumin's long circulation time to enhance the persistence of therapeutic antibodies, potentially reducing dosing frequency (Figure 1).17 These technologies aim to improve pharmacokinetics and enhance patient adherence by reducing the need for frequent injections.

Conclusion

The development of extended half-life biologics represents a transformative shift in the treatment of atopic dermatitis.13 Currently, biologics require frequent injections, which can be burdensome for patients and hinder long-term treatment success. However, the advent of technologies such as FcRn optimization, PEGylation, and albumin binding promises to reduce injection frequency to just once or twice per year. This groundbreaking shift will not only alleviate the burden of frequent clinic visits and injections but also improve patient convenience, adherence, and overall satisfaction with treatment. As these technologies evolve, they hold the potential to revolutionize biologic therapy for AD and other chronic inflammatory diseases, offering a more sustainable and accessible treatment paradigm that could reshape the future of care and management for these conditions. This breakthrough represents a major leap forward in chronic disease treatment, making therapies more accessible and sustainable for patients.

References:

Jacobson ME, Boesjes CM, de Bruin-Weller MS, de Graaf M, Morimoto RY, Simpson EL. Increasing dosing intervals for biologics in atopic dermatitis-why, who, when and how? J Eur Acad Dermatol Venereol. 2025 Jan 22. doi: 10.1111/jdv.20534. Epub ahead of print. PMID: 39840710.
Taddio A, Ipp M, Thivakaran S, Jamal A, Parikh C, Smart S, Sovran J, Stephens D, Katz J. Survey of the prevalence of immunization non-compliance due to needle fears in children and adults. Vaccine. 2012 Jul 6;30(32):4807-12. doi: 10.1016/j.vaccine.2012.05.011. Epub 2012 May 19. PMID: 22617633.
Orenius T, LicPsych, Säilä H, Mikola K, Ristolainen L. Fear of Injections and Needle Phobia Among Children and Adolescents: An Overview of Psychological, Behavioral, and Contextual Factors. SAGE Open Nursing. 2018;4. doi:10.1177/2377960818759442
Yu YB, Briggs KT, Taraban MB, Brinson RG, Marino JP. Grand Challenges in Pharmaceutical Research Series: Ridding the Cold Chain for Biologics. Pharm Res. 2021 Jan;38(1):3-7. doi: 10.1007/s11095-021-03008-w. Epub 2021 Feb 8. PMID: 33555493; PMCID: PMC7869771.
Le Floc'h A, Allinne J, Nagashima K, Scott G, Birchard D, Asrat S, Bai Y, Lim WK, Martin J, Huang T, Potocky TB, Kim JH, Rafique A, Papadopoulos NJ, Stahl N, Yancopoulos GD, Murphy AJ, Sleeman MA, Orengo JM. Dual blockade of IL-4 and IL-13 with dupilumab, an IL-4Rα antibody, is required to broadly inhibit type 2 inflammation. Allergy. 2020 May;75(5):1188-1204. doi: 10.1111/all.14151. Epub 2020 Jan 3. PMID: 31838750; PMCID: PMC7317958.
Andrew Blauvelt, Jacob P Thyssen, Emma Guttman-Yassky, Thomas Bieber, Esther Serra-Baldrich, Eric Simpson, David Rosmarin, Hany Elmaraghy, Eric Meskimen, Chitra R Natalie, Zhuqing Liu, Chenjia Xu, Evangeline Pierce, MaryAnn Morgan-Cox, Esther Garcia Gil, Jonathan I Silverberg, Efficacy and safety of lebrikizumab in moderate-to-severe atopic dermatitis: 52-week results of two randomized double-blinded placebo-controlled phase III trials, British Journal of Dermatology, Volume 188, Issue 6, June 2023, Pages 740–748, https://doi.org/10.1093/bjd/ljad022
Ratnarajah K, Le M, Muntyanu A, et al. Inhibition of IL-13: A New Pathway for Atopic Dermatitis . Journal of Cutaneous Medicine and Surgery. 2020;25(3):315-328. doi:10.1177/1203475420982553
Serra-Baldrich E, Santamaría-Babí LF, Francisco Silvestre J. Nemolizumab: An Innovative Biologic Treatment to Control Interleukin 31, a Key Mediator in Atopic Dermatitis and Prurigo Nodularis. Actas Dermosifiliogr. 2022 Jul-Aug;113(7):674-684. English, Spanish. doi: 10.1016/j.ad.2021.12.014. Epub 2021 Dec 23. PMID: 35842249.
Saghari M, Gal P, Gilbert S, Yateman M, Porter-Brown B, Brennan N, Quaratino S, Wilson R, Grievink HW, Klaassen ES, Bergmann KR, Burggraaf J, van Doorn MBA, Powell J, Moerland M, Rissmann R. OX40L Inhibition Suppresses KLH-driven Immune Responses in Healthy Volunteers: A Randomized Controlled Trial Demonstrating Proof-of-Pharmacology for KY1005. Clin Pharmacol Ther. 2022 May;111(5):1121-1132. doi: 10.1002/cpt.2539. Epub 2022 Mar 1. PMID: 35092305; PMCID: PMC9314635.
Rewerska B, Sher LD, Alpizar S, Pauser S, Pulka G, Mozaffarian N, Salhi Y, Martinet C, Jabert W, Gudi G, Ca V, Gn S, Macoin J, Anstett V, Turrini R, Doucey MA, Blein S, Konto C, Machkova M. Phase 2b randomized trial of OX40 inhibitor telazorlimab for moderate-to-severe atopic dermatitis. J Allergy Clin Immunol Glob. 2023 Nov 22;3(1):100195. doi: 10.1016/j.jacig.2023.100195. PMID: 38187863; PMCID: PMC10770725.
Guttman-Yassky, E., Simpson, E., Bissonnette, R., Eichenfield, L. F., Kabashima, K., Luna, P. C., Kricorian, G. (2025). ROCKET: a phase 3 program evaluating the efficacy and safety of rocatinlimab in moderate-to-severe atopic dermatitis. Immunotherapy, 17(2), 83–94. https://doi.org/10.1080/1750743X.2025.2464528
Real-world severe asthma biologic administration and adherence differs by biologic
Ledford, Dennis K. et al. Annals of Allergy, Asthma & Immunology, Volume 131, Issue 5, 598 - 605.
Yilmaz, O., Torres, T. Extended Half-life Antibodies: A Narrative Review of a New Approach in the Management of Atopic Dermatitis. Dermatol Ther (Heidelb) 14, 2393–2406 (2024). https://doi.org/10.1007/s13555-024-01253-6
Binder, U., & Skerra, A. (2024). Strategies for extending the half-life of biotherapeutics: successes and complications. Expert Opinion on Biological Therapy, 25(1), 93–118. https://doi.org/10.1080/14712598.2024.2436094
Batra J, Robinson J, Mehner C, et al. PEGylation extends circulation half-life while preserving in vitro and in vivo activity of tissue inhibitor of metalloproteinases-1 (TIMP-1). PloS One. 2012;7(11):e50028.
Chapman AP. PEGylated antibodies and antibody fragments for improved therapy: a review. Adv Drug Deliv Rev. 2002 Jun 17;54(4):531-45. doi: 10.1016/s0169-409x(02)00026-1. PMID: 12052713.
Tan, H., Sattler, M., & Zou, P. (2024). Albumin-binding as a universal strategy for half-life extension. Journal of Biopharmaceutical Sciences, 1(1), 1-9. https://doi.org/10.33425/2690-8077.1043

Dupilumab for Prurigo Nodularis: A Randomized Clinical Trial

Wed, 14 May 2025 14:27:27 GMT

Featured Student: Zoya Siddiqui

Introduction

Prurigo nodularis (PN) is a chronic, intensely pruritic skin condition characterized by multiple hyperkeratotic nodules that significantly impair patients’ quality of life. The pathogenesis involves neuroimmune dysregulation, and until recently, treatment options have been limited and often ineffective. A phase 3 trial published in JAMA Dermatology in September 2022 by Dr. Gil Yosipovitch and colleagues investigated the safety and efficacy of dupilumab, an IL-4Rα inhibitor, in managing moderate-to-severe PN.

Methodology

This multicenter, double-blind, placebo-controlled trial enrolled 151 adults with moderate-to-severe prurigo nodularis from diverse racial and ethnic backgrounds. Participants were randomized to receive either weekly subcutaneous dupilumab (300 mg following a 600 mg loading dose) or placebo for 24 weeks. The primary endpoint was the proportion of patients achieving a ≥4-point reduction on the Worst Itch Numeric Rating Scale (WI-NRS)—a patient-reported scale from 0 to 10 measuring itch severity—by week 12. Key secondary endpoints included reduction in lesion count, sleep disturbance improvement, and changes in Dermatology Life Quality Index (DLQI) scores, a validated 10-question survey measuring the impact of skin disease on quality of life.

Findings

The study demonstrated that 60% of patients in the dupilumab group achieved the primary endpoint, compared to 18% in the placebo group (p < 0.001). Dupilumab also significantly reduced lesion burden and improved patient-reported outcomes such as sleep quality and overall dermatologic quality of life. The medication was well-tolerated, with conjunctivitis being the most frequently reported adverse event, consistent with previous dupilumab studies.

Strengths and Weaknesses

One notable strength of this study is its well-structured design. By using a randomized, double-blind, placebo-controlled approach conducted across multiple centers, the investigators minimized bias and enhanced both the reliability and generalizability of the findings. The use of validated outcome measures such as WI-NRS, lesion counts, and DLQI provides meaningful insight into both clinical and patient-reported outcomes. Another notable strength is the inclusion of a racially and ethnically diverse patient population, which improves the applicability of the results to real-world settings. However, the study has several limitations, including its 24-week duration, which may not adequately capture long-term safety, durability of response, or the risk of disease recurrence after treatment discontinuation. Patients with mild disease were excluded, which limits the ability to generalize these findings to all individuals with PN. Additionally, while the study establishes dupilumab’s efficacy, it does not provide guidance on optimal treatment duration or how to manage partial responders. Cost and access to biologic therapy, which are highly relevant to clinical implementation, were also not addressed.

Applications to Future Practice

This study provides encouraging evidence for the use of dupilumab in treating prurigo nodularis, a condition with limited systemic treatment options. Dupilumab offers a well-tolerated and clinically meaningful option for patients with moderate-to-severe disease, and its success in this trial may signal a broader shift toward the use of targeted biologics in chronic pruritic disorders. Further research will be important to clarify long-term outcomes, real-world effectiveness, and strategies to improve accessibility for patients who could benefit from this treatment.

References

Yosipovitch G, Kwatra SG, Peguero A, et al. Dupilumab for the treatment of prurigo nodularis: A randomized, double-blind, placebo-controlled phase 3 trial. JAMA Dermatol. 2022;158(10):1083–1090. doi:10.1001/jamadermatol.2022.2819
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)—a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210–216. doi:10.1111/j.1365-2230.1994.tb01167.x
Phan NQ, Blome C, Fritz F, et al. Assessment of pruritus intensity: Prospective study on validity and reliability of the visual analogue scale, numeric rating scale and verbal rating scale in 471 patients with chronic pruritus. Acta Derm Venereol. 2012;92(5):502–507. doi:10.2340/00015555-1265

Cost-Effectiveness Analysis of 3D Total-Body Photography for People at High Risk of Melanoma

Wed, 16 Apr 2025 14:14:05 GMT

Featured Student: Fatima Iqbal

Fatima Iqbal is a first-year student in the B.A./M.D. program at the University of Missouri–Kansas City. She loves hanging out with friends, baking, and participating in debate tournaments. Her research experiences have strengthened her understanding of how innovation can address challenges in healthcare. Fatima is particularly interested in dermatology, with a specific focus on Mohs surgery and its clinical applications. She is eager to pursue research in Mohs surgery to better understand its role in skin cancer treatment. Fatima hopes to integrate her passion for advocacy and medicine to improve equitable healthcare outcomes on both clinical and policy levels.

Introduction

Melanoma is a fast-growing form of skin cancer that’s especially dangerous when detected late. For patients who are considered high-risk like those with a personal history of melanoma or many atypical moles consistent and accurate skin monitoring is essential. But routine skin exams and even 2D photography can miss early changes.

A recent study published in JAMA Dermatology (March 2025) by Lindsay explored whether 3D total-body photography (3D TBP) combined with sequential digital dermoscopy imaging (SDDI) could improve melanoma surveillance outcomes—and whether it’s a cost-eective strategy in the long run. The study blends clinical care, economics, and tech to answer a question that’s becoming more relevant as imaging tools become more advanced.

Methodology

The researchers used a cost-effectiveness model to simulate the long-term impact of three different surveillance methods for high-risk individuals:

Standard care – regular full-body skin exams.
2D TBP with SDDI – traditional flat photography with dermoscopic follow-up.
3D TBP with SDDI – an immersive 3D scanning system that maps the skin’s surface, tracks lesions over time, and flags any subtle changes for further evaluation.

The model accounted for patient outcomes over a lifespan and included factors like:

Number of melanomas detected early
Reduction in unnecessary biopsies
Long-term treatment costs
Patient quality of life, measured in quality-adjusted life years (QALYs)
Healthcare spending thresholds (specifically, whether the cost per QALY was under $100,000, which is commonly used as a benchmark for value)

Findings

The results showed that 3D TBP with SDDI had the highest upfront costs, mainly due to the technology itself and the setup required. But over time, it actually saved money by catching melanomas earlier, when they’re easier and less expensive to treat. It also reduced unnecessary procedures, like biopsies, that can cause stress, discomfort, and costs for patients.

Here’s the part that stood out: the incremental cost-effectiveness ratio (ICER) for 3D TBP was around $50,000 per QALY, well below the $100,000 threshold, making it a cost-effective strategy for high-risk patients. It also offered more QALYs than the other methods, showing both clinical and economic benefit.

Strengths and Weaknesses

Strengths:

This study was strong in its design. It looked at both outcomes and cost, two things that matter a lot in real-world decision-making. The use of lifetime modeling, along with established cost thresholds, gave a clear picture of how 3D TBP could be applied in actual practice.

Weaknesses:

One of the study’s limitations is that it’s based on modeling, not a randomized clinical trial. That means it relied on previously published data and assumptions about patient behavior, follow-up, and disease progression. Also, the model focused on high-risk patients, so we don’t know yet how these fi ndings would translate to people at average risk or in underserved areas where access to 3D imaging might be limited.

Applications to Future Practice

This study suggests that 3D total-body photography, when paired with SDDI, could be a valuable tool in dermatology especially for patients at high risk of melanoma. As the technology becomes more available, it could change the way providers approach skin cancer checkings. Early detection means better outcomes, fewer invasive procedures, and ultimately, lower costs for patients and the healthcare system.

For students like me, this study was a reminder that medicine doesn’t happen in a vacuum. The best tools are the ones that work and make sense for patients, clinics, and the system as a whole. 3D TBP could be one of those tools, and I’m excited to see how it fi ts into future practice.

Reference

Lindsay, H., et al. (2025). Cost-Effectiveness Analysis of 3D Total-Body Photography for Melanoma Surveillance. JAMA Dermatology. Published March 26, 2025. https://jamanetwork.com/journals/jamadermatology/fullarticle/2831499

A Review on an “Association of Childhood Obesity or Weight Change with Early-Onset Follicular Occlusion Triad in Children”

Fri, 07 Mar 2025 15:23:59 GMT

Featured Student: Demi Elrod

Demi Elrod is a fifth-year student in the B.A./M.D. program at the University of Missouri-Kansas City. She enjoys crafting, babysitting, and exploring Kansas City's vast food scene in her spare time. Her favorite research subjects are underserved populations and psoriasis treatment developments. She enjoys keeping up with recent publications in dermatology so that she can gain more experience with evaluating the quality and clinical applications of studies.

Childhood obesity has long been recognized as a contributor to various health conditions, but its role in dermatologic diseases is an evolving area of study. A recent nationwide population-based cohort study from Korea has provided significant insights into the relationship between childhood obesity, weight fluctuations, and the development of early-onset follicular occlusion triad (FOT). This triad includes hidradenitis suppurativa (HS), acne conglobata (AC), and dissecting cellulitis of the scalp (DCS), all of which involve chronic inflammation and follicular blockage. Understanding this link is crucial for early intervention and management strategies in pediatric dermatology.

The study analyzed data from over two million Korean children who underwent health screenings between 30 to 36 months and 42 to 48 months of age from 2009 to 2020. By tracking changes in body mass index (BMI), researchers aimed to determine whether obesity and weight gain increase the risk of developing FOT. The study identified 1,283 cases of early-onset FOT, including 143 cases of HS, 1,068 cases of AC, and 72 cases of DCS. Obesity at an early age increased the risk of FOT, with children who were obese having a 49% higher likelihood of developing the condition compared to those with a normal weight. The risk was particularly pronounced for HS and AC. Additionally, weight gain was strongly associated with an increased risk of FOT, while weight loss was found to be protective, particularly against HS. Children who transitioned from obesity to a normal weight had a significantly lower risk of developing FOT compared to those who remained obese.

This study has several notable strengths, including its large sample size, longitudinal design, and use of a nationwide health database, all of which enhance the reliability and generalizability of its findings. The study also presents a clear dose-response relationship, showing a progressive trend where increasing BMI correlates with higher FOT risk. However, some limitations exist, such as the lack of genetic and environmental factors in the analysis, the homogeneity of the study population, a relatively short follow-up period, and reliance on BMI as a measure of body composition. These factors suggest that additional research is needed to confirm and expand upon these findings.

The implications of this study are significant for dermatologists, particularly those treating pediatric and adolescent patients. Given the strong association between obesity and FOT, dermatologists should incorporate BMI assessments into routine skin evaluations for children, allowing for early identification and intervention. A multidisciplinary approach involving pediatricians, nutritionists, and endocrinologists may be necessary to develop comprehensive weight management plans for at-risk children. Education is also critical, as dermatologists can play a key role in discussing weight control strategies with parents and caregivers, emphasizing that maintaining a healthy weight can help prevent severe dermatologic conditions. Future research should focus on the biological mechanisms linking obesity to follicular occlusion disorders, investigate these associations in diverse populations, and extend follow-up periods to determine the long-term effects of early childhood obesity on dermatologic health. This study provides compelling evidence that childhood obesity and weight gain significantly increase the risk of early-onset follicular occlusion triad, particularly hidradenitis suppurativa and acne conglobata. More importantly, weight loss appears to be protective, suggesting that early intervention and weight management strategies can play a crucial role in preventing these chronic skin conditions. By integrating weight assessment and management into dermatologic practice, physicians can take proactive steps in reducing the burden of obesity-related dermatologic diseases in children.

Works Cited

Kim, S. R., Koh, S. J., & Park, H. (2025). Association of childhood obesity or weight change with early-onset follicular occlusion triad in children. The British journal of dermatology, 192(3), 430–439. https://doi.org/10.1093/bjd/ljae414

CAR T-cell Therapy in Autoimmune Diseases

Mon, 17 Feb 2025 22:05:46 GMT

Featured Student: Gustavo Rodrigues de Moraes

Gustavo Rodrigues de Moraes is a second-year medical student at Kansas City University College of Osteopathic Medicine. His interests include dermatology, with a particular focus on autoimmune diseases with cutaneous manifestations and the intersection of dermatological conditions and mental health. Gustavo is also passionate about providing care to LGBTQ+ and underserved populations. In his free time, he enjoys spending time with his dogs, watching shows on Netflix, mixology, and traveling whenever possible.

Introduction

Autoimmune diseases are a heterogeneous group of disorders that are characterised by a breach of immune tolerance. The sensitisation against antigens leads to the formation of autoreactive T cells and B cells, as well as autoantibodies that trigger organ damage. Autoimmune diseases include rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, pemphigus, and multiple sclerosis. In all autoimmune diseases, autoreactive B-cell clones and autoantibodies directed against a patient’s own antigens are formed long before the onset of clinical symptoms. However, not all chronic inflammatory diseases are autoimmune diseases. For instance, diseases like psoriasis, Crohn’s disease, or ankylosing spondylitis have no B-cell-mediated pathophysiology but clinically present as chronic inflammation. This group of diseases usually genetically associated with major histocompatibility class I alleles, whereas autoimmune diseases are often associated with specific MHC class-II alleles.In this paper, we focus on the treatment of autoimmune diseases by using chimeric antigen receptor (CAR) T cells directed against B cells. Autoimmune diseases are also susceptible to the therapeutic targeting of B cells by monoclonal antibodies. However, to some extent, results on the treatment of autoimmune disease by monoclonal B-cell- depleting antibodies were disappointing, as some trials failed their clinical endpoints and induction of drug-free remission or cure has not been shown. CAR T cells, on the other hand, might have curative potential, at least in malignant diseases, as implied by data from clinical trials.

Current management of autoimmune diseases Autoimmune diseases are usually not chronic and drive organ damage when no therapeutic intervention is

initiated. Autoimmune T-cell and B-cell clones trigger disease and autoantibodies by inductions of autoantibodies that act as effectors driving target cell lysis (such as in autoimmune haemolytic anaemia), mediating cell activation (like in Graves’ disease), disturbing cell communication (like in pemphigus), or leading to immune complex formation and inflammation (like in systemic lupus erythematosus). Controlling altered T-cell and B-cell function is of the utmost importance in the treatment of autoimmune disease. Conventional immune suppressants (eg, azathioprine, inhibiting purine synthesis or mycophenolate blocking the enzyme inosine-5’-monophosphate dehydrogenase and depleting guanosine nucleotides) and calcineurin inhibitors (eg, ciclosporin A tacrolimus and voclosporin, which downregulate the production of T-cell-derived cytokines through binding to cytoplasmic receptors cyclophilin and FK binding protein) are widely used for the treatment of autoimmune disease. In addition, targeted drugs that block T-cell migration to inflammatory sites, such as natalizumab and vedolizumab, blocking integrin a4 and a4b7, respectively, and those modulating the sphingosine-1 phosphate receptor, have been developed to treat autoimmune diseases. These agents often sufficiently attenuate the inflammatory process, but treatment with the need to be given continuously over years, or even lifelong. Even when remission is reached, recurrence of disease often happens when immunosuppression is discontinued. Furthermore, suboptimal control of autoimmune disease by immune suppressants requires additional use of glucocorticoids to dampen inflammation, which is associated with considerable side-effects. Selectively interfering with B-cell activation and autoantibody production in autoimmune diseases is a promising approach. The breakthrough work by Edwards and colleagues in 2004 showed that B-cell depletion with rituximab—a monoclonal antibody directed against CD20 antigen—showed efficacy in the treatment of rheumatoid arthritis. Despite this success of rituximab, a substantial proportion of patients do not show sufficient improvement of disease activity of rheumatoid arthritis. Some studies on the use of rituximab in autoimmune diseases, including a randomised controlled trial in systemic lupus erythematosus, showed no clinically or statistically significant effect in ameliorating the disease, suggesting escape mechanisms that prevent eradication of autoimmunity in patients with an autoimmune disease. Also, the disease often relapses after cessation of rituximab, necessitating repeated application to sufficiently control disease. This observation also applies to treatments that inhibit B-cell activation, such as belimumab, a monoclonal antibody that blocks the B-cell activating factor, which is used in the treatment of systemic lupus erythematosus. Furthermore, long-term use of B-cell depleting antibodies is associated with low serum immunoglobulin G levels, which increases the risk of infections.

Limitations of current B-cell targeting approaches and the concept of deep B-cell depletion in autoimmunity

Control of autoimmune diseases and even a potential

immunological reset in autoimmunity might require deep B-cell depletion. Rituximab mediates effects via antibody-dependent cytotoxicity. However, treatment does not always fully eliminate circulating B cells, which has been observed to be associated with the level of therapeutic efficacy in systemic lupus erythematosus. Circulating B cells are the most susceptible to antibody-mediated B-cell depletion, as effector cells (ie, monocytes and natural killer cells) and complement factors are readily available.

However, effector cells that mediate antibody-induced cellular toxicity might not always be present in the tissues, and antibody concentrations are eventually lower (eg, because of uptake through marginal zone macrophages), which could contribute to insufficient target cell clearance. In the case of systemic lupus erythematosus, complement factors are consumed, and there is evidence of lower phagocytic activity of

myeloid cells. In accordance with this concept, several studies have shown that memory B cells escape depletion by rituximab. For instance, in the abdominal lymph nodes, numbers of CD19+ B cells were not reduced after rituximab treatment, when the drug was administered to prevent rejection of kidney transplants. Furthermore, B cells have been detected in the synovial membrane of patients with rheumatoid arthritis upon rituximab treatment, while peripheral B cells were depleted. Finally, in tonsils of patients with systemic lupus erythematosus, memory B cells can reside in niches after rituximab treatment, which indicates that tissue B cells can escape antibody-mediated targeting.

These data clearly show that depletion of tissue-resident B cells poses a greater challenge compared with depletion of their circulating counterparts, suggesting that memory B cells in the tissues might have a greater resistance to depletion. This lack of complete depletion of B cells within the tissues might explain the inconsistent results of rituximab therapy in systemic lupus erythematosus. Also, negative studies showed in post-hoc analyses that patients with complete peripheral B-cell depletion had better responses to treatment than those with only partial depletion. In accordance, newer anti-CD20 antibodies with higher antibody-dependent cellular cytotoxicity activity, such as the humanised ocrelizumab and, in particular, the glycoengineered IgG1 type 2 obinutuzumab, show clinical efficacy in systemic lupus erythematosus. However, in the case of ocrelizumab, treatment of systemic lupus erythematosus was associated with an increased risk of severe infections. Although the degree of B-cell depletion might be better with obinutuzumab and ocrelizumab than with rituximab, the need to recruit functional effector cells to the site of B cells, or absence of complement factors might still limit efficacy and allow autoreactive B-cell populations to survive in their respective niches. Another open question is the ideal target antigen. For example, CD20 antigen is not expressed on plasmablasts and plasma cells. A high cell proportion of plasmablasts are found in post-rituximab systemic lupus erythematosus flares. Targeted elimination of CD38+ plasma cells through the monoclonal anti-CD38 antibody daratumumab has shown efficacy in patients with refractory systemic lupus erythematosus.

Principle of targeting B-cell-derived malignant cells with CAR T cells

Researchers have been trying to develop strategies to reset autoimmune disease in the way that leads to abrogation of disease by deeply resetting the immune system and allowing patients to permanently stop immunosuppressive drugs. Such concepts of rebooting the immune system in autoimmune disease have been previously attempted by autologous haematopoietic stem cell transplantation (auto-HSCT) following high- dose chemotherapy. However, significant toxic effects have restricted the use of auto-HSCT in systemic lupus erythematosus. Cell-based therapy has undergone a fast evolution over the years thanks to the development of genetically engineered receptors, such as CARs. The term chimeric is based on the different origins of the individual CAR components: an extracellular antigen recognition domain derived from antibodies, a transmembrane domain, and an intracellular activation domain derived from T cells. The CAR-encoding DNA can be transferred into ex-vivo immune cells, such as T cells, to generate CAR T cells (figure 2). Upon infusion of CAR T cell into the host the cells recognise the antigen, become activated, and destroy the target. In malignancies, such as B-cell-derived acute lymphoblastic leukaemia or non-Hodgkin lymphoma, it is of utmost importance to eliminate malignant clones to prevent relapse. To achieve this goal, targeting of hard-to-reach, tissue-resident tumour cells is a prerequisite. CAR T cells represent a suitable tool for that thanks to the T cells’ natural ability to infiltrate tissues, their high-affinity specific target binding, and their anti-tumor effector functions. Engagement of the CAR expressed on the plasma membrane of T cells, or alternatively of natural killer cells, by the target antigen leads to their activation and subsequent killing of tumour cells. Surface molecules restricted to B-cell lineage, such as CD19, CD20, and CD22, serve as the tumour-associated antigens. These antigens are recognised by the extracellular domain of the CAR that represents a single-chain variable fragment of an antibody specific to the respective antigen. The cytoplasmic part of CAR contains signalling (CD3 zeta-chain of the T-cell receptor) and co-stimulatory (4–1BB or CD28) domains to ensure proper expansion and activation of CAR T cells, as well as target cell killing. CAR T cells expand and survive in the tissues, where they are exposed to their target antigens.Another key factor for the expansion and persistence of CAR T cells is the lymphodepleting chemotherapy (usually cyclophosphamide and fludarabine) before CAR T-cell infusion. The resulting lymphopenia leads to a compensatory homoeostatic proliferation of CAR T cells and the preferential formation of a memory phenotype. Under ideal circumstances, CAR-expressing cells can survive for many years in the tissues. CAR T cells have become a powerful tool in cancer therapy, leading to a deep and sustained eradication of target antigen-expressing cells. The most advanced CAR-based treatments are those directed against malignant B cells, allowing long-lasting remissions in up to 50% of the patients. In fact, all CD19 CAR T-cell products approved by the US Food and Drug Administration (ie, axicabtagene ciloleucel/axi-cel, tisagenlecleucel/tisa-cel, lisocabtagene maraleucel/liso-cel, and brexucabtagene autoleucel/brexu-cell) are directed against B-cell-derived malignancies, such as B-cell-derived acute lymphoblastic leukaemia, large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. For treatment of refractory and relapsed diseases CAR T cells are superior in inducing remission over the standard treatments, and lead to long-term remissions (up to 10 years), indicating CAR T cells’ curative therapeutic potential. In consequence, CD19 CAR T cells have become an established tool in haematology practice. In the context of malignant diseases, the risk of immune escape with reappearance of the tumour and toxic effects are among the strongest limitations of CAR T-cell therapy.

Cytokine release syndrome is of particular concern as a toxic effect of CAR T-cell therapy. Mild cytokine release syndrome manifests as fever, headache, arthralgia, and myalgia, but can also lead to hypotension and even cytotoxic shock in severe cases. Cytokine release syndrome rates, including milder forms of the condition, range from 42% to 93% across all therapeutic cell products, and life-threatening and lethal events have occurred. Mechanistically, cytokine release syndrome is mediated by CAR T-cell activation upon target cell engagement and the release of proinflammatory mediators, such as IL-6. Another typical side-effect is the immune effector cell-associated neurotoxicity syndrome, which can manifest as fine motor impairment leading to dysgraphia and speech alterations. Headache, confusion, seizures, and behavioural changes have also been reported in conjunction with immune effector cell- associated neurotoxicity syndrome. The pathophysiology of this condition is not well understood, but there is evidence that endothelial activation and disruption of the blood-brain barrier are involved. The key risk factor for both cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome is a high target cell (tumour) burden. Treatment of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome is based on antipyretics, glucocorticoids, and IL-6 receptor blockade with the monoclonal antibody tocilizumab.

Autoimmune diseases that might benefit from CAR T-cell-based therapy

Autoimmune diseases can potentially be treated with CAR T cells that recognise B-cell-specific surface molecules. However, the pathophysiological role of B cells in individual autoimmune diseases is not entirely clear apart from the fact that autoantibodies are formed. B-cell activation and autoantibody formation might just represent an epiphenomenon of underlying T-cell-mediated autoimmunity, rather than being the causal factor in triggering disease. In such cases, even complete B-cell depletion might not be an effective treatment, as remaining autoreactive T cells would still sustain the disease. Furthermore, it is not entirely clear whether B-cell-derived plasmablasts or long-lived plasma cells are the main source of autoantibodies in individual autoimmune diseases. As plasma cells have different antigens from B cells and plasmablasts, they might escape treatment with B-cell-directed CAR T cells and therefore still maintain the autoimmune disease process. Finally, clinical symptoms in autoimmune diseases might not only be the result of ongoing inflammation, but to some extent also result from permanent organ damage limiting the reversibility of the symptoms even after successful CAR T-cell treatment. Examples for this include kidney damage in systemic lupus erythematosus, lung fibrosis in systemic sclerosis, muscle atrophy in myositis, secretory gland fibrosis in Sjögren’s syndrome, neuronal damage in multiple sclerosis, and disappearance of β cells in the pancreatic islets in diabetes. For this reason, it might be particularly important to use CAR T cells as early as possible in the treatment of autoimmune diseases, in order not to miss the window of opportunity for reversibility of the symptoms and to minimise the risk of permanent organ damage. Clinical CAR T-cell treatment in cancer is currently limited to autologous cells (extracted from the same patient), which require manufacturing of an individual advanced therapy medicinal product. Off-the-shelf allogeneic CAR T-cell products (cells extracted from the same patient) are not yet commercially available but are yielding encouraging results in ongoing clinical trials. The manufacturing of autologous CAR T cells requires leukapheresis of sufficient numbers of functional lymphocytes, cell transfection using viral vectors, and in-vitro expansion of CAR T cells following strict quality controls in each patient. Correct identification of patients who might benefit the most from such complex intervention and who are in the highest need of CAR T cells is of utmost importance.

Evidence for efficacy of CAR T-cell therapy in autoimmune diseases

CAR T-cell therapy for the treatment of autoimmune diseases is promising. In the last 2 years, substantial progress has been achieved in making the therapy available to patients CAR T-cell therapy to patients with autoimmune diseases. Landmark work in pre-clinical models has strongly supported the use of CAR T cells targeting B cells in autoimmune diseases, showing that CD19 CAR T cells abrogate disease-specific B-cell autoimmunity and organ (ie, kidney) inflammation in murine models of systemic lupus erythematosus. These findings have led to the concept that deep cell-based depletion of (autoreactive) B cells might induce remission of systemic lupus erythematosus and potentially also other autoimmune diseases. Rolling out CAR T-cell treatment of patients with autoimmune diseases has been challenging for several reasons. First, patients with autoimmune diseases, particularly those with severe manifestations of the diseases, have usually been exposed to glucocorticoids and other drugs, such as mycophenolate or cyclophosphamide, that have an effect on T-cell quantity and quality. Therefore, retrieving sufficient amounts of functional T cells and expanding them in patients with autoimmune diseases might be impossible, especially because lymphopenia is not uncommon in autoimmune diseases. Second, the T-cell compartment in autoimmune disease patients contains autoreactive T-cell clones, which might also expand during the manufacturing of CAR T cells. In fact, reinfusion of CAR T cells that also carry autoreactive T-cell receptors could aggravate autoimmune diseases. Finally, cytokine release syndrome resulting from activated CAR T cells, which in turn activate macrophages and other immune cells, is a serious complication for cancer patients receiving CAR T cells. Risk factors for cytokine release syndrome include elevated inflammatory parameters, such as C-reactive protein, which is also seen in active autoimmune diseases. Similarly, immune effector cell-associated neurotoxicity syndrome is more prevalent in patients with previous CNS dysfunction, and many autoimmune diseases display CNS involvement. Such events, especially if they are severe, might prevent applicability of CAR T cells in the treatment of non-malignant diseases and autoimmune diseases. In autoimmune diseases, CD19-directed CAR T cells were used for the first time in 2021, in the treatment of a woman aged 20 years with severe treatment-refractory systemic lupus erythematosus.55 The approach showed that CAR T-cell production from patients with autoimmune diseases is feasible, allowing a stable transfection of T cells with the CAR construct and generation of sufficient numbers of CAR T cells to be applied for therapy. CAR T-cell infusion was well tolerated by the patient and did not lead to any high-grade toxic effects. This first CAR T-cell-based approach in autoimmune disease treatment led to fast depletion of B cells in vivo, which was accompanied by a rapid and robust expansion of CAR T cells in peripheral blood. With respect to the manifestations of the autoimmune disease, complete clinical remission, including cessation of proteinuria, was reached after 3 months and seroconversion of disease-associated antibodies against double-stranded DNA was observed. Furthermore, all immunosuppressive agents, including glucocorticoids, could be successfully discontinued in this patient without signs of disease relapse for up to 18 months. A deeper analysis of the effects of CD19 CAR T-cell therapy in systemic lupus erythematosus was done in a group of five patients with severe treatment resistance. This study showed stable and reproducible production of CD19 CAR T cells from the peripheral blood, despite pre-treatment with T-cell targeting agents, such as mycophenolate and glucocorticoids, as part of systemic lupus erythematosus therapy. These agents do not seem to impair the production of CAR T cells when readily stopped (in the case of mycophenolate) or tapered to lower doses (in the case of glucocorticoids). Furthermore, the temporal dynamics of the expansion of CAR T cells in vivo were similar among these treated patients, with a peak in circulating CAR T cells around 1 week after administration. Clinical manifestations of systemic lupus erythematosus rapidly ceased in all five patients, reaching a state of remission according to DORIS criteria. This remission was accompanied by seroconversion of several systemic lupus erythematosus-associated antibodies, such as those against double-stranded DNA, nucleosomes, and Smith antigen, but long-standing vaccination responses (ie, those against measles, rubella, and tetanus) were mostly stable or only slightly decreased. This observation indicated that at least some autoantibody species seem to stem from the memory B cell and plasmablast compartment and not from the CD19-negative plasma cells. Vice versa, antibody responses against vaccines that the patients received before CAR T-cell therapy seem to primarily stem from the long-lived CD19-negative plasma cell compartment, which should not be affected by CD19 CAR T cells. The finding is also important given that humoral vaccination responses are seriously impaired during the B-cell aplasia phase after CD19 CAR T-cell therapy, highlighting the importance of previous vaccinations and the stability of anti-vaccine antibody titres after CAR T-cell treatment. Another key finding of the impact of CAR T-cell therapy in these patients with systemic lupus erythematosus was that no long-term B-cell aplasia was observed as B cells reconstituted around 100 days after the infusion. Analysis of these B cells showed that memory B cells and plasmablasts virtually disappeared, and the newly emerging B cells in the circulation revealed a naive phenotype with expression of IgM and IgD heavy chains, indicating a pre-class switched naive B-cell phenotype. The B-cell recurrence after CAR-T cell therapy was not associated with disease recurrence, as all patients remained in treatment-free remission and did not produce double-stranded DNA autoantibodies. This finding is important, as it has been shown that after antibody-mediated B-cell depletion with rituximab, the rising levels of B-cell-activating factor can perpetuate autoreactive B cells and plasmablasts, stimulate T follicular helper cells, and trigger flares of systemic lupus erythematosus.60 Tolerability of CAR T-cell therapy in this small group of patients with systemic lupus erythematosus seems good, as no high-grade cytokine release syndrome, neurotoxicity, haematotoxicity, or infectious complications occurred. Hence, the key lessons from these first patients with autoimmune disease treated with CAR T cells are that the procedure is feasible, well tolerated, and allows induction of longer treatment-free remissions with clear indications of a rebooting of the B-cell compartment. As these results were gathered from a small group of patients, the risk of infections in conjunction with conditioning therapy and B-cell depletion by CAR T cells remains to be determined. In addition to patients with systemic lupus erythematosus, a patient with severe multidrug-resistant dermatomyositis (anti-synthetase syndrome) has been treated with CD19 CAR T cells.61 The patient was in drug- free remission after infusion with CD19 CAR T cells. Deep abrogation of B cells was followed by normalisation of concentrations of creatine kinase, seroconversion of anti-Jo-1 autoantibodies, regression of muscle and lung inflammation, and complete regain of physical function. The observed changes suggest that the effect of CD19 CAR T-cell therapy might not be limited to systemic lupus erythematosus but might also work in several different B-cell-mediated and autoantibody-driven human autoimmune diseases.

Required length of CAR T-cell activity and duration of response in autoimmune diseases

The length of expected drug-free remission after CAR T-cell therapy for an autoimmune disease remains to be determined. Disease-free observational periods extend to up to 2 years for some patients with systemic lupus erythematosus, with patients being in the state of full B-cell reconstitution for the majority of this period. Hence, it might well be that some patients receiving CAR T-cell therapy can be cured of autoimmune diseases; however, longer follow-up is necessary. New B cells mature in response to infections and vaccinations, and it will be important to know whether this maturation process is not accompanied by the formation of autoreactive B-cell clones, autoantibodies, and eventually the recurrence of the disease. The genetic links (eg, HLA- DR2 and DR3 alleles) for systemic lupus erythematosus are still in place. Furthermore, it is not known how CAR T-cell treatment affects the aberrant T-cell responses in systemic lupus erythematosus, particularly the type I interferon signature associated with autoimmune diseases.62 If the autoimmune disease does not recur for years, however, CAR T-cell therapy has restored an important immune checkpoint that could be associated with the permanent absence of symptoms and even a cure of the underlying disease. Such a scenario would push the use of CAR T-cell treatment as an early intervention strategy in selected patients with severe forms of autoimmune diseases. In the context of treatment of B-cell malignancies, CAR T cells must have the potential to survive in the body for many years. Whether such long survival of CAR T cells is possible and necessary in autoimmune diseases’ treatment is unclear. Consistent and stable repopulation of patients with an autoimmune disease with B cells following CAR T-cell treatment speaks against the CAR T-cells’ long-term persistence, either suggesting contraction, activation-induced cell death, or exhaustion. The underlying mechanism remains unclear, however, unlike patients with cancer, patients with autoimmune diseases have received less cytotoxic agents with the corresponding effects on stem cells and immune cells. Thus, it is conceivable that the reconstructing cells (after lymphodepletion) more successfully compete for niches (ie, bone marrow or lymphoid tissues) than the substantially pre-damaged cells of patients with cancer. Another straightforward explanation could be the rapid elimination of cells carrying the target antigen (ie, CD19), as the B-cell load is many times lower in autoimmune disease than in patients with tumours. Hence, loss of the target antigen could trigger early contraction of the CAR T-cell population. The value of long-term persistence of functional CAR T cells in autoimmune diseases appears questionable as the time-limited deep B-cell depletion was shown to be sufficient to fully abrogate disease activity and reboot the B-cell system. Long-term B-cell depletion might not be desirable in autoimmune diseases, as B cells provide humoral protection and are involved in immunological homoeostasis (eg, as regulatory B cells). If poor CAR T-cell persistence leads to autoimmune disease relapse, retreatment with ready-to-use CAR T cells, which had been cryopreserved during the initial production round, could be considered. A similar strategy is also exploited in B-cell-derived malignancies.64 Although not observed to date, relapse of autoimmune disease might occur with the disappearance or exhaustion of CAR T cells. Relapses of B-cell lymphoma have been described several years after CAR T-cell treatment and autologous stem cell transplantation.65 Hence, long-term observation of patients with autoimmune disease receiving CAR T-cell therapy is of the utmost importance.

Challenges regarding safety and cost-effectiveness

Although mortality is increased in patients with autoimmune diseases, it is substantially lower than in patients with relapsed or refractory B-cell malignancies, which inevitably cause death of the affected patient if they do not respond to treatment. Hence, safety considerations for CAR T-cell therapy in autoimmune diseases are different from considerations in cancer therapy. Life-threatening or even fatal cytokine release syndrome and neurotoxicity (ie, immune effector cell-associated neurotoxicity syndrome) is not acceptable in autoimmune disease patients. Therefore, a low rate of higher-grade side effects, which also include haematotoxicity, hypogammaglobulinemia, and infectious complications, is of utmost importance for making the use of CAR T cells an acceptable treatment option in the future. In the small number of patients with autoimmune diseases who have been treated with CAR T cells, good tolerability of the treatment was observed, with no cytokine release syndrome greater than grade 1 (fever) and no immune effector cell-associated neurotoxicity syndrome. Although this low toxicity might be based on the much lower target engagement of CAR T cells in autoimmune diseases than in B-cell malignancies, the effects of standard treatments for cytokine release syndrome, including glucocorticoids and the IL-6 receptor antibody tocilizumab, must be carefully assessed in patients with autoimmune disease. The use of glucocorticoids has not shown any negative effects on CAR T-cell function in patients with cancer, and it remains to be shown whether this is also true for patients with autoimmune diseases. In addition, there is the possibility of exacerbating T-cell-mediated autoimmunity by co-expanding autoimmune T-cell clones from patients with autoimmune disease during the process of CAR T-cell manufacturing. However, the chance of such a scenario is low, as CAR T cells are likely to quickly become exhausted by simultaneous T-cell receptor and CAR engagement, which has also been shown for donor-derived alloreactive T cells, which are unable to trigger graft-versus-host disease.71 Given the high cost of CAR T cells manufacturing, the therapy might initially be available only to patients with particularly severe forms of autoimmune disease. However, since CAR T cells have allowed discontinuation of all other immunosuppressive agents in patients with systemic lupus erythematosus, the treatment of which is associated with substantial cumulative drug costs (up to US$100 000 per year), CAR T cells could actually reach their break-even point over a few years. Since this type of cellular therapy holds promise to achieve a long-term, if not permanent, reset of the immune system in autoimmune diseases, CAR T cells might be cost-effective for autoimmune disease treatment.

Future strategies for CAR T-cell therapies against autoimmune diseases

The feasibility of CAR T-cell treatment in autoimmune diseases will strongly depend on a multidisciplinary collaboration between different specialists (ie, immunologists and hematologists, together with colleagues specialized in rheumatology, nephrology, and neurology). Highly specialised centres will have a key role in the selection of suitable patients with autoimmune diseases, the planning and execution of individualised therapeutic concepts, and the prevention and management of treatment-related toxic effects.72 If the safety data for CAR T cells in autoimmune diseases documented so far are confirmed, studies in the outpatient setting, similar to the approaches in malignant diseases, would be the next step. The best procedure to treat an autoimmune disease with CAR T cells is unknown. Clinical tolerability and efficacy data for CAR T-cell therapy in autoimmune disease are so far confined to one construct targeting CD19 and one containing a 4–1BB co-stimulatory domain. CD19 seems to be a promising target, as it is highly specific for the B-cell lineage and is expressed widely across different B-cell differentiation stages, including plasmablasts and potentially a small portion of plasma cells.74 CD20 and CD22 also represent interesting antigens for CAR T cells in systemic lupus erythematosus and other autoimmune diseases. However, it is unclear how CD20 and CD22 would be a better target than CD19, as their expression overlaps with CD19 but is low or absent in plasmablasts and plasma cells. Some patients with an autoimmune disease might also respond to CAR T cells targeting plasma cells. CAR T cells directed against CD38 and B-cell maturation antigen (BCMA), both of which are antigens expressed on plasmablasts and plasma cells, have been developed for the treatment of malignant plasma cell disease (multiple myeloma). CAR T cells directed against CD38 or BCMA could also be interesting for application in autoimmune diseases after the first evidence for the efficacy of CD38 antibodies in systemic lupus rythematosus.25 Stable antibody titres against vaccinations that the patients had before CART-cell therapy and only a mild decrease in immunoglobulin concentration suggest that most of the plasma cell compartment remains intact upon treatment with CD19 CAR T cells, which might be a major advantage, as the CD19-directed approach was sufficient to eliminate double-stranded DNA and nucleosome antibodies. However, long-lived plasma cells in the bone marrow, which contribute to antibody and probably to autoantibody production, are usually CD19-negative and would, therefore, escape elimination by CD19 CAR T cells. Some forms of systemic lupus erythematosus and other autoimmune diseases might show a higher dependence on plasma cells and, therefore, might benefit more from plasma cell targeting rather than deep B-cell (and plasmablast) depletion. In these patients, using BCMA-targeted CAR T cells or CD38-targeted CAR T cells might be beneficial. Newer constructs, such as CAR T cells that simultaneously target B cells and plasmablasts through CD19 and plasma cells through CD38, might be interesting in the treatment of autoimmune diseases.81 The safety of CD38-targeted and BCMA-targeted CAR T cells in autoimmune disease treatment is unknown, and specific features for BCMA-targeted CAR T cells regarding safety in hematological malignancies such as neurocognitive and hypokinetic disorders82 and lung changes need to be considered. Apart from the target-binding domains, other features of the CAR vector might also affect the therapeutic efficacy of CAR T-cell treatment in autoimmune diseases. First-generation CAR T cells without co-stimulatory domains did not proliferate sufficiently in vivo and had poor lasting efficacy.84 In the currently approved second-generation CD19 CAR T cells, CD28 or 4–1BB co-stimulatory domains are used. Which domain has better suitability for the treatment of malignancies and autoimmune diseases has not been determined. CD28-driven CARs are considered to elicit faster and more intense downstream signalling, promoting differentiation into effector memory CAR T cells, than 4–1BB-driven CARs.85 However, CD28-driven tonic signaling favors early exhaustion.86 In contrast, 4–1BB-driven CARs lead to slower and more persistent signalling, skewing T cells towards a central memory phenotype.87 Some studies have reported that CD28-costimulated CAR T cells might have higher rates of cytokine release syndrome, but this observation is not reproducible. In fact, a comprehensive review has not supported consistent differences between 4–1BB-containing and CD28-containing CARs with respect to efficacy and safety in the treatment of B-cell-derived malignancies. A short-term but very deep depletion of the B-cell compartment seems to be sufficient for an immunological reset, as autoimmune disease does not recur despite the reconstitution of B cells and the halting of immune-suppressive drug therapy. Thus, construct modifications for the prolongation of CAR T-cell persistence might not be crucial for the treatment of autoimmune diseases. However, in cases of early recurrence of autoimmune diseases, such modifications could be necessary, such as the use of third-generation CARs that combine 4–1BB and CD28 co-stimulation to improve the robust signaling that is important for better longevity and effector functions of CAR T cells. Another important component of CAR T-cell treatment is the preparatory conditioning regimen, which for most patients is composed of a short course of cyclophosphamide and fludarabine. The current doses of cyclophosphamide (usually a cumulative dose of about 1 g/m²) used in conjunction with CAR T-cell treatment are lower than the cumulative doses usually applied for treating autoimmune diseases and in some systemic lupus erythematosus patients receiving CAR treatment had been non-responsive. Data on fludarabine in autoimmune diseases, and particularly on systemic lupus erythematosus, are anecdotal and suggest that the medication showed substantial toxicity if used over longer periods of time. Overall, conditioning chemotherapy might have some short-term effects in autoimmune diseases as it reduces immune cell count (including B cells) for approximately 1 week. However, lymphodepletion might not be responsible for the long-term effects of CAR T-cell therapy in autoimmune diseases, including sustained B-cell depletion, disappearance of autoantibodies, rebooting of the B-cell compartment, and resolution of disease symptoms. The effect is regarded as necessary to empty niches for CAR T cells (eg, in the bone marrow and in secondary lymphoid organs), which allows them to better proliferate and survive.

Conclusions

CAR T cells have been successfully introduced into the treatment of autoimmune diseases. This approach is unique not only because it is based on complex manufacturing of a personalized genetically modified autologous cell product but also because it is con conceptualized as a single-shot intervention to induce long-standing drug-free remission; this ambitious approach could herald a new era of autoimmune disease treatment, transforming the current principle of long-term immunosuppression into a strategy that induces an immune reset with no need for further treatment. Further studies addressing the potential of CAR T-cells’ applications for the treatment of autoimmune diseases are underway and will shed more light on the potential of this treatment approach.

Citation

Schett G, Mackensen A, Mougiakakos D. CAR T-cell therapy in autoimmune diseases. Lancet. 2023 Nov 25;402(10416):2034-2044. doi: 10.1016/S0140-6736(23)01126-1.

Epub 2023 Sep 22. PMID: 37748491.

Zasocitinib and Plaque Psoriasis

Wed, 15 Jan 2025 17:01:33 GMT

Featured Student: Demi Elrod

Introduction

Plaque psoriasis is a chronic autoimmune skin condition that can have a significant impact on both physical and emotional well-being. While biologic treatments have been a game-changer for many patients, there’s still a need for effective oral therapies, especially for those who prefer not to use injections. Zasocitinib, a TYK2 inhibitor, offers a promising approach by targeting specific inflammatory pathways involved in psoriasis. This study explored its potential to address the gap in oral treatment options for moderate to severe plaque psoriasis.

Methodology

In this Phase 2 trial, adults aged 18–75 with moderate to severe plaque psoriasis were randomly assigned to receive different doses of zasocitinib or a placebo for 12 weeks. The main goal was to see how many participants achieved a 75% reduction in their psoriasis severity (PASI 75) by week 12. Researchers also looked at higher levels of improvement (PASI 90), quality of life changes, and monitored for any side effects. The trial’s design helped ensure reliable comparisons between the treatment and placebo groups.

Findings

The results showed a clear benefit for zasocitinib, especially at higher doses. A significant number of participants in the high-dose group achieved PASI 75, and many even saw improvements beyond that. Quality of life scores improved as well, reflecting the treatment’s

impact on daily living. The medication was generally well-tolerated, with side effects mostly mild and similar to those seen in the placebo group. These findings suggest that zasocitinib could be an effective oral option for managing moderate to severe psoriasis.

Strengths and Weaknesses

Strengths: The study was well-structured, with randomization and blinding to ensure reliable results. Using multiple doses allowed the researchers to understand how well the drug worked at different levels, and the use of PASI scores provided a standard way to measure improvement.

Weaknesses: However, the trial was relatively short at just 12 weeks, so we don’t know much about how the drug performs in the long term. The study size, typical of early-phase trials, was smaller, and it didn’t compare zasocitinib directly with established therapies like biologics. These factors make it harder to fully understand how it fits into current treatment options.

Applications for Future Practice

If further studies confirm its benefits, zasocitinib could be a valuable option for patients who want an effective oral treatment for psoriasis. It may also be useful for those who can’t or don’t want to use injectable therapies. Future research should focus on longer-term safety and

effectiveness, as well as comparing zasocitinib with other treatments to clarify its role in clinical practice. Expanding oral options would help meet a real need for patients and improve overall care.

Reference

Novartis Institutes for BioMedical Research, Stieglitz, E., et al. (2024). Zasocitinib, an oral TYK2 inhibitor, in patients with moderate-to-severe plaque psoriasis: A phase 2 randomized clinical trial. Journal of the American Academy of Dermatology, 91(6), 1157-1167.

https://doi.org/10.1016/j.jaad.2024.08.058

Neurocutaneous Melanosis (NCM)

Thu, 19 Dec 2024 18:14:25 GMT

Featured Student: Manisha Vadali

Manisha Vadali is a second-year medical student at the University of Missouri-Kansas City School of Medicine. Her work on a case report about neurocutaneous melanosis deepened her knowledge of rare dermatologic disorders and the intricacies of presenting pediatric cases, particularly in dermatology. Manisha is especially drawn to pediatric dermatology with a focus on addressing the needs of skin of color and underserved communities. Beyond her medical studies, she finds joy in practicing hot yoga and watching Shark Tank.

Neurocutaneous melanosis (NCM) is a rare congenital disorder characterized by melanocytic nevi, leptomeningeal melanosis, and severe neurological complications. Malignant transformation of leptomeningeal melanosis is associated with poor prognosis due to its aggressive progression and resistance to treatment.

This case report describes an 18-month-old boy with NCM, who presented with altered gait, recurrent falls, and neurological deficits, including hyperreflexia, bilateral Babinski signs, and reduced lower limb sensation. Imaging revealed a 4 cm intradural extramedullary mass in the lumbar region, causing significant syringohydromyelia and spinal canal compression.

Histopathological analysis of the mass confirmed malignant melanoma, with large, atypical cells showing high mitotic rates. Immunohistochemistry was positive for Melan-A, HMB-45, and vimentin, consistent with the primary cutaneous lesions.

Cytogenetic studies identified genetic alterations, including a loss of PTEN and RAD51B genes and an NRAS Q61K mutation, which supported targeted therapy with a MEK inhibitor (trametinib). Despite initial treatment, the patient developed new metastatic lesions within two months, necessitating a switch to immunotherapy with ipilimumab and nivolumab. Surgical resection was attempted but was incomplete due to the infiltrative nature of the tumor. The disease progressed rapidly, and the patient passed away 163 days after diagnosis.

This case underscores the aggressive nature of NCM-associated melanoma and the challenges posed by its invasive growth patterns and genetic complexity. Current therapeutic strategies, including MEK inhibitors and immunotherapy, have limited efficacy in such cases. This highlights the need for further research to identify novel therapeutic targets, develop effective treatments, and refine diagnostic protocols to improve outcomes in this devastating pediatric condition.

Recent Study in Low-Dose Naltrexone Use in Biopsy-Proven Lichen Planus of the Nails

Fri, 08 Nov 2024 15:39:17 GMT

Featured Student: Sundus Malik

Sundus Malik is a fifth-year medical student in the B.A./M.D. program at the University of Missouri-Kansas City. In her spare time, she likes to paint and track race. Her research summary underscores the value of rigorous methodology in clinical trials and highlights the potential of low-dose naltrexone as a novel therapy. Through this process, she has learned to appreciate the significance of patient-centered approaches and the necessity of considering both short-term and long-term outcomes when evaluating new treatments.

KSDDS Newsletter Educational Coordinator - Demi Elrod (UMKC - SOM)

Introduction

Lichen planus of the nails is a chronic inflammatory condition that can lead to significant nail dystrophy and discomfort for patients. Traditional treatments often fall short in effectively managing this condition, prompting the need for alternative therapeutic approaches. In a study published in JAMA Dermatology in October 2024, Dr. Eric R. Bray and colleagues explored the efficacy and safety of low-dose naltrexone (LDN) as a treatment for biopsy-proven lichen planus of the nails.

Methodology

The study utilized a double-blind, placebo-controlled design to ensure the reliability of its findings. Participants were randomly assigned to either an LDN treatment group or a placebo group. The treatment group received a low dose of naltrexone daily, while the control group received a placebo. Both groups were monitored over a specified period, with regular assessments of nail appearance and symptom severity.

Findings

The results of the study indicated a significant improvement in the nail appearance and symptoms for those in the LDN treatment group compared to the placebo group. Participants receiving LDN reported reduced discomfort and visible improvement in nail dystrophy. Importantly, the treatment was well-tolerated, with minimal side effects, suggesting LDN as a viable option for managing this condition.

Strengths and Weaknesses

One of the major strengths of the study was its robust methodology. The double-blind, placebo-controlled design minimized bias and ensured the accuracy of the results. Additionally, the focus on a condition that is often challenging to manage highlights the study's clinical relevance and potential impact on patient care. However, the study also had limitations. The small sample size may limit the generalizability of the findings, and the relatively short follow-up period did not allow for an assessment of long-term effects.

Applications to Future Practice

The findings from this study suggest that low-dose naltrexone could be a promising treatment for lichen planus of the nails. This offers a new avenue for patients who may not respond well to traditional therapies. The research paves the way for further studies to explore the long-term efficacy and safety of LDN, as well as its potential application in other dermatological conditions. Integrating LDN into clinical practice could improve patient outcomes and offer a new therapeutic option for managing this often debilitating condition.

References:

Bray, E. R., & Morrison, B. W. (2024). Low-Dose Naltrexone Use in Biopsy-Proven Lichen Planus of the Nails. JAMA Dermatology. https://doi.org/10.1001/jamadermatol.2024.4098

2024 Poster Presentation Winners

Tue, 15 Oct 2024 15:33:53 GMT

Congratulations to this year's Poster Presentation winners!

Judging and awards took place at the 2024 Annual KSDDS Conference on October 12th.

Pictured from left to right: Dominique Tarantino, Joycie Chang, Victoria Shi, Riya Bhat

Clinical practice guidelines for cosmetic procedures in minors: Consensus amongst experts

Victoria Shi

Generalized Verrucosis Developing in Two Adult Females Receiving Chronic 6-Mercaptopurine Therapy for the Treatment of Inflammatory Bowel Disease

Dominique Tarantino

Survival Outcomes in Pediatric Squamous Cell Carcinoma: A Retrospective Analysis of Demographics and Treatments

Riya Bhat

340B Program in Dermatology: A Single-Center, Cross- Sectional Study

Joycie Chang

Kaposi Sarcoma in a Men-Who-Have-Sex-with-Men Patient Without Human Immunodeficiency Virus who was Treated with Upadacitinib for Ulcerative Colitis

Mon, 14 Oct 2024 15:04:16 GMT

Featured Student: Yeanna Moon

Yeanna Moon is a third-year student in the 6-year medical program at UMKC with a focus on dermatology. Her first case study involved an MSM patient without HIV who developed Kaposi sarcoma after treatment with Upadacitinib for ulcerative colitis, highlighting the malignancy risks associated with JAK inhibitors and the importance of careful monitoring”

Authors: Jacob T. Tribble, BA; Mckinzie Johnson, MD; Yeanna Moon, BA; Anand Rajpara, MD; and Jacob Whitsitt, MD

KSDDS Newsletter Educational Coordinator - Demi Elrod (UMKC - SOM)

Abbreviations used:

HHV-8: human herpesvirus 8
JAK: Janus kinase
KS: Kaposi sarcoma
MSM: men-who-have-sex-with-men
UC: ulcerative colitis

Introduction

Kaposi sarcoma (KS) is a rare neoplasm of lymphatic endothelium-derived cells infected with human herpesvirus 8 (HHV-8).1 There are 4 variant forms of KS: classic, AIDS-related, endemic (African), and iatrogenic.1 Recent literature has noted an emerging fifth variant of KS seen in men-whohave-sex-with-men (MSM) but who are HIV-seronegative.2 With the growing use of immune modulating medications such as Janus kinase (JAK) inhibitors for a range of inflammatory diseases, there have been an increasing number of reported iatrogenic KS cases associated with these medications.3 We report a case of KS in a patient who is MSM with a history of severe ulcerative colitis (UC) treated with upadacitinib, highlighting both the potential risk of malignancy associated with JAK inhibitors and risk of KS in MSM patients without HIV.

Case Report

A 45-year-old man presented to the dermatology clinic with a 6-month history of slowly progressive violaceous plaques on his bilateral lower extremities. Medical history was significant for preexposure prophylaxis use for HIV prevention because he has male sexual partners and severe UC that failed to improve with adalimumab therapy. He was switched to upadacitinib 15 mg daily for treatment resistant UC 1 year before his presentation to the dermatology clinic. Six months before he presented to the clinic, his dose of upadacitinib was increased to 30 mg daily. After his dose was increased, over the next 6 months he developed slowly progressive asymptomatic violaceous papules and plaques, first involving his bilateral ankles, with later involvement of his bilateral calves. Physical examination on the day of presentation to the dermatology clinic was congruent with these findings (Fig 1). Skin biopsy was taken of the lesion on the patient’s left calf, and histopathology showed the proliferation of spindled cells infiltrating collagen bundles and native vascular structures throughout the dermis (Fig 2). Immunohistochemistry showed neoplastic cells diffusely positive for HHV-8, confirming the diagnosis of KS (Fig 3). HIV-1/2 antigen/antibody testing 2 weeks after the skin biopsy was collected was negative. Upper and lower gastrointestinal endoscopy along with a computed tomography of chest, abdomen, and pelvis with contrast were all negative for visceral KS involvement. At this point, medical oncology was consulted and believed the best course of action would be to discontinue the upadacitinib and monitor the KS for progression while switching him to vedolizumab for management of his UC. At the time of this case report, the patient had canceled his appointments and was no longer able to be monitored.

Discussion

Most commonly, iatrogenic KS is seen in solid organ transplant recipients.1 However, as JAK inhibitors have received approval for a wide range of diseases throughout the past decade, there have been a growing number of KS cases related to their use.3 JAK inhibitors act by targeting JAKs, which are tyrosine kinases that have a pivotal role in cellular signal transduction for a wide range of systems.4 JAK inhibitors have quickly revolutionized the management of autoimmune and inflammatory dermatologic disease. Because of their immunosuppressive properties, there are a range of adverse effects seen with these medications.4

JAK inhibitors have been demonstrated to increase the risk of herpes zoster, with a recent systematic review looking at 47 randomized controlled trials showing a 3 times higher odds of shingles in those treated with upadacitinib compared with those without treatment.5 Basic science studies have demonstrated the crucial role of JAK pathways in the proliferation of CD41 lymphocytes for optimal antiviral functions.6 It is possible that downregulation of these pathways by JAK inhibitors could cause varicella-zoster virus reactivation and lead to increased herpes zoster incidence.6 Theoretically, the same could be said about HHV-8 reactivation leading to KS development in patients treated with JAK inhibitors. This report contributes to a growing number of iatrogenic KS reports. Although there are too few cases to be assessed systematically, there are at least 7 other reported cases of KS associated with JAK inhibitors to date.3 Interestingly, in 3 of these KS cases, regression was seen with discontinuation of the JAK inhibitor without any other therapies, indicating a causal role of JAK inhibitors in the pathogenesis.3

Aside from KS, JAK inhibitors have been associated with an increased risk of malignancy. A recent meta-analysis found an increased risk of malignancies in patients using JAK inhibitors compared with those using tumor necrosis factor-alfa inhibitors, but no difference when compared with placebo or those using methotrexate.7 Because of the relatively small number of cancer events and short amount of follow-up time for placebos, this metaanalyses was limited in examining more detailed analyses on the risk of individual cancer subtypes.7 As more data becomes available, future research should examining the risk of KS and other virus induced cancers in those using JAK inhibitors, as we know the JAK pathway plays a critical role in the immune system.

A novel form of KS appears to be arising in the population of MSM without HIV, of which our case is another example. Epidemiologic studies in the United States have shown increased prevalence of HHV-8 in MSM ranging from 30% to 70% compared with the general population at 4%.8,9 Although this is increased prevalence of HHV-8 is known, it is difficult to quantify the risk MSM without HIV have in KS development compared with the general population because cancer registries do not routinely collect information on sexual orientation and gender identity.

This case highlights the potential risk of KS among those using JAK inhibitors and those who are MSM without HIV. Future studies should aim to assess the risk of KS development in patients using JAK inhibitors and collect information on sexual orientation and gender identity. Additional reports may inform practitioners on the utility of screening for HHV-8 among MSM before starting immunomodulatory medicines. Lastly, physician’s prescribing JAK inhibitors should be aware of and monitor for potential KS development along with other malignancies and opportunistic infections.

From the Department of Dermatology, University of Missouri e Kansas City School of Medicine, Kansas City, Missouri(a) ; Department of Pathology, University of Colorado School of Medicine, Aurora, Colorado(b) ; and UCHealth Medical Group, Denver, Colorado.(c)

Funding sources: None.

Patient consent: The authors attest that they have obtained written consent from patient/s, their legal guardian/s or person/s with legal authority, for their photographs and medical information to be published in print and online and with the understanding that this information may be publicly available. Patient consent forms were not provided to the journal but are retained by the authors to be made available upon request.

IRB approval status: Not applicable.

Correspondence to: Jacob T. Tribble, BA, University of Missouri e Kansas City School of Medicine, 2411 Holmes St, Kansas City, MO 64108.

E-mail: jttbkh@mail.umkc.edu.

JAAD Case Reports 2024;50:119-22. 2352-5126 ©, 2024 by the American Academy of Dermatology, Inc. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

https://doi.org/10.1016/j.jdcr.2024.06.005

References:

Lebbe C, Garbe C, Stratigos AJ, et al. Diagnosis and treatment of Kaposi’s sarcoma: European consensus-based interdisciplinary guideline (EDF/EADO/EORTC). Eur J Cancer. 2019;114:117-127. https://doi.org/10.1016/j.ejca.2018.12.036
Vangipuram R, Tyring SK. Epidemiology of Kaposi sarcoma: review and description of the nonepidemic variant. Int J Dermatol. 2019;58(5):538-542. https://doi.org/10.1111/ijd.14080
Fournier C, Sauder MB, Kamil ZS, Butler MO. Kaposi sarcoma in a patient treated with upadacitinib for rheumatoid arthritis. JAAD Case Rep. 2023;39:145-149. https://doi.org/10.1016/j.jdcr.2023. 07.019
McLornan DP, Pope JE, Gotlib J, Harrison CN. Current and future status of JAK inhibitors. Lancet. 2021;398(10302):803-816. https: //doi.org/10.1016/S0140-6736(21)00438-4
Xu Q, He L, Yin Y. Risk of herpes zoster associated with JAK inhibitors in immune-mediated inflammatory diseases: a systematic review and network meta-analysis. Front Pharmacol. 2023;14:1241954. https://doi.org/10.3389/fphar.2023.1241954
Sunzini F, McInnes I, Siebert S. JAK inhibitors and infections risk: focus on herpes zoster. Ther Adv Musculoskelet Dis. 2020; 12:1759720X20936059. https://doi.org/10.1177/1759720X2093 6059
Russell MD, Stovin C, Alveyn E, et al. JAK inhibitors and the risk of malignancy: a meta-analysis across disease indications. Ann Rheum Dis. 2023;82(8):1059-1067. https://doi.org/10.1136/ard2023-224049
Mesri EA, Cesarman E, Boshoff C. Kaposi’s sarcoma and its associated herpesvirus. Nat Rev Cancer. 2010;10(10):707-719. https://doi.org/10.1038/nrc2888
Salyards M, Nijhawan AE, Kuo J, et al. Prevalence, incidence, and predictors of Kaposi sarcoma-associated herpesvirus infection among young men who have sex with men in the Southern United States. J Infect Dis. 2024;229(5):1387-1392. https: //doi.org/10.1093/infdis/jiad384