⚡First Evidence β-HPV Can Cause cSCC

Good morning — it’s Saturday, August 16, and we’re covering the first documented case of β-HPV driving cutaneous SCC in an immunodeficient patient, the largest-ever comparison of advanced chronic urticaria treatments, and more.

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For the first time, beta-human papillomavirus (β-HPV) has been shown to directly cause cutaneous squamous cell carcinoma (cSCC) in a patient with defective T-cell immunity.

This finding challenges the long-standing view that β-HPV is merely an early facilitator of ultraviolet radiation–induced tumorigenesis. In contrast, α-HPV plays a well-established oncogenic role in mucosal SCC, such as at anogenital and oropharyngeal sites.

The case study, published in NEJM, describes a 34-year-old woman with a germline ZAP70 mutation that causes defective proximal T-cell receptor signaling, thereby impairing adaptive T-cell function. She developed widespread benign and malignant HPV-related diseases, including an aggressive, treatment-refractory cSCC on her forehead.

Molecular analysis of the cSCC revealed β1-HPV19 integration into the tumor genome with high E6/E7 oncogene expression, despite no prior published reports of β-HPV expression in advanced cutaneous SCC.

The tumor lacked common somatic SCC driver mutations (e.g., TP53) and had only a modest ultraviolet radiation mutational burden.

Following allogeneic hematopoietic-cell transplantation, T-cell receptor signaling was restored, HPV-specific T cells expanded, and all HPV-related lesions, including the aggressive cSCC, cleared (before-and-after photos here). The patient remains disease-free nearly three years later.

The discovery could reshape our understanding of cSCC pathogenesis and treatment in patients with impaired T-cell responses.

> Largest-ever meta-analysis ranks advanced systemic treatments for chronic urticaria: A network meta-analysis in the Journal of Allergy and Clinical Immunology (JACI) offers the most comprehensive efficacy–safety comparison to date for biologics and systemic immunomodulators in chronic urticaria. The analysis included 42 treatments studied in 11,398 patients across 83 randomized trials and 10 observational studies. The anti-IgE monoclonal antibody omalizumab (standard dose: 300 mg every 4 weeks) and the investigational Bruton’s tyrosine kinase inhibitor remibrutinib ranked highest, with high-certainty evidence, for improving urticaria activity, angioedema-free weeks, and quality of life. Low-dose omalizumab showed intermediate efficacy. The IL-4/IL-13 blocker dupilumab was also highly effective in reducing urticaria activity, though no trials assessed angioedema outcomes. All three agents had favorable safety profiles. Cyclosporine was effective but had high adverse event rates. The evidence for other agents was uncertain. Limitations include sparse data for several immunomodulators, few head-to-head trials, and short follow-up that hindered long-term safety assessment. These results are expected to inform the imminent AAAAI/ACAAI Joint Task Force chronic urticaria guideline update.

> Amlitelimab improves disease control in atopic dermatitis and sustains response after stopping treatment: A post hoc analysis of the Phase 2b STREAM-AD trial in moderate-to-severe atopic dermatitis found that amlitelimab improved clinician- and patient-reported outcomes, with efficacy persisting after treatment withdrawal. The findings were published in JEADV. Amlitelimab is an investigational OX40 ligand–blocking antibody that inhibits T-cell–mediated inflammation without depleting T cells. In Part 1 of the trial, 390 adults received subcutaneous amlitelimab or placebo every 4 weeks for 24 weeks. At Week 24, the most effective dose reduced SCORing Atopic Dermatitis (SCORAD) scores by 47% and Patient-Oriented Eczema Measure (POEM) scores by 43%, vs 18% and 6% with placebo. In Part 2, responders either continued or stopped therapy for 28 weeks. Among those with a clinically meaningful SCORAD improvement (≥8.7 points) at Week 24, 83% who continued therapy and 79% who stopped therapy maintained their response through Week 52. Phase 3 trials are underway to confirm efficacy and test extended dosing every 12 weeks. Watch a quick breakdown of OX40/OX40L’s role in atopic dermatitis here.

> First head-to-head trial comparing topical tofacitinib with topical tacrolimus in localized vitiligo: A randomized trial in the British Journal of Dermatology found that topical tofacitinib had similar efficacy to topical tacrolimus in localized vitiligo. However, tofacitinib showed a nonsignificant trend toward earlier, better responses and fewer local reactions. Thirty patients with vitiligo affecting <5% body surface area had 60 symmetrical patches randomized to twice daily tofacitinib 2% or tacrolimus 0.1% ointment. Treatment success corresponded to a Vitiligo Noticeability Scale score of 4 or 5 on a 5-point scale, indicating the patch was “a lot less noticeable” or “no longer noticeable.” At Week 16, 47% of tofacitinib-treated patches vs 37% of tacrolimus-treated patches achieved this outcome (P = 0.60). Median time to success was non-significantly shorter with tofacitinib (8 vs 12 weeks, P = 0.18). Overall, facial lesions responded best (63%), followed by trunk (43%) and acral sites (18%). Both drugs were well tolerated, though local reactions such as burning and itch were more common with tacrolimus (seven patients) than with tofacitinib (two patients). Limitations include the small sample size, short study duration, and lack of patient blinding.

> Aclaris’ ITK/JAK3 inhibitor shows clinical activity in early eczema study: Aclaris Therapeutics reported positive topline results from its open-label, single-arm Phase 2a trial of ATI-2138 in moderate-to-severe atopic dermatitis. The analysis was based on per-protocol data from 10 adults. ATI-2138 is an investigational oral inhibitor of interleukin-2–inducible T cell kinase (ITK) and Janus kinase 3 (JAK3), key enzymes in pathways involved in T cell differentiation, activation, and proliferation. At Week 12, mean and median Eczema Area and Severity Index (EASI) score improvements were 61% and 77%, rising to 77% and 82% after excluding one outlier. Improvements were evident as early as Week 1. Skin tape strip analyses showed downregulation of Th2, Th17, TCR (ITK), and Th1 pathways. The drug was well tolerated, with no severe adverse events. The study’s small, uncontrolled design limits interpretation. Even so, the company believes efficacy is on par with current therapies, and a favorable safety profile supports plans to explore higher doses in future trials. Development in alopecia areata is also planned.

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