Secukinumab for the treatment of adult-onset pityriasis rubra pilaris: a single-arm clinical trial with transcriptomic analysis.

BACKGROUND: The pathogenesis of pityriasis rubra pilaris (PRP) is not completely understood, but interleukin (IL)-17 has been shown to play a critical role. There are no reliable immunomodulatory agents to treat PRP. We conducted an open-label, single-arm clinical trial of secukinumab, a monoclonal antibody that inhibits IL-17A, for the treatment of PRP. OBJECTIVES: To evaluate the clinical efficacy of secukinumab and define the transcriptomic landscape of PRP and its response to IL-17A blockade. METHODS: Twelve patients with PRP were recruited for an open-label trial of secukinumab. Patients received a 24-week course of secukinumab. The primary endpoint was a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) from baseline to week 28. Secondary endpoints included PASI 90, change in Physician's Global Assessment (PGA), and change in Dermatology Life Quality Index (DLQI). RNA sequencing was performed on lesional and nonlesional skin biopsies obtained at baseline and week 2. Sample groups were compared to identify differential gene expression and pathway enrichment. This trial was registered with ClinicalTrials.gov: 'Cosentyx (secukinumab) for the treatment of adult onset pityriasis rubra pilaris' - NCT03342573. RESULTS: At week 28, six of 11 patients (55%) achieved PASI 75, and three patients (27%) achieved PASI 90. PGA (P = 0.008) and DLQI scores (P = 0.010) showed significant improvement with treatment. No serious treatment-related adverse events were encountered. Treatment with secukinumab normalized transcriptional differences between lesional and nonlesional skin. Transcriptomic data from nonresponsive patients suggest that overactivity of innate immune pathways may be driving resistance to secukinumab. CONCLUSIONS: Secukinumab appears to be an effective treatment for PRP and warrants further investigation. PRP is a transcriptionally heterogeneous disease, reflecting its variable response to therapy. Agents targeting other IL-17 isoforms and innate immune mediators should be considered for future clinical trials. What is already known about this topic? The pathogenesis of pityriasis rubra pilaris is incompletely understood. Successful treatment has been reported with a variety of immunomodulatory agents, but disease is often refractory to therapy. Interleukin (IL)-17 is thought to drive keratinocyte proliferation and vascular dysfunction in this disease. A previous trial demonstrated efficacy of the anti-IL-17A drug ixekizumab for pityriasis rubra pilaris. What does this study add? Herein we describe the findings of a clinical trial of secukinumab, an anti-IL-17A monoclonal antibody, for the treatment of pityriasis rubra pilaris. Secukinumab was effective in treating pityriasis rubra pilaris. Our transcriptomic data give new insight into the expressional changes that occur in response to secukinumab and suggest mechanisms of treatment resistance.

Histopathologic features of necrobiosis lipoidica.

BACKGROUND: Necrobiosis lipoidica (NL) is an uncommon granulomatous dermatosis that can occur in patients with or without associated diabetes mellitus (DM). Prior studies have attempted to determine distinctive histopathologic features of NL in patients with and without DM. METHODS: A retrospective review of 97 patients with NL was performed to determine the similar and distinctive histopathologic features in patients with DM and without DM. RESULTS: Of the 97 patients, 32% (n = 31) had DM. Epidermal acanthosis was seen more commonly in diabetics than nondiabetics (32.3% vs. 12.1%; p = 0.017). Naked (sarcoidal/tuberculoid) granulomas were more frequently observed in nondiabetics than diabetics (22.7% vs. 3.2%; p = 0.016). Eosinophils were more common in nondiabetics than diabetics (38.5% vs. 9.7%; p = 0.004), while neutrophilic infiltration was more common in diabetics than nondiabetics (45.2% vs. 17.5%; p = 0.004). CONCLUSIONS: This study corroborates well-documented histopathologic features of NL and shows distinctive histopathologic features of NL among patients with DM-I, DM-II, and without DM. These results support the hypothesis that there are different underlying drivers of NL between diabetics and nondiabetics.

Trifarotene for the Treatment of Facial and Truncal Acne.

OBJECTIVE: This article reviews clinical trials to assess the efficacy, safety, and clinical application of trifarotene 0.005% cream (Aklief). DATA SOURCES: A systematic review of the literature was performed using the terms trifarotene OR Aklief OR CD5789 in MEDLINE (PubMed) and EMBASE databases. Articles prior to May 2020 were considered for inclusion. Bibliographies and ClinicalTrials.gov were also searched to identify further studies. STUDY SELECTION AND DATA EXTRACTION: Relevant English language and human studies related to pharmacology, clinical trials, and safety were considered. DATA SYNTHESIS: In the 52-week phase III trial, treatment success rates for facial acne (Investigator Global Assessment [IGA] rating of no or almost no acne) and truncal acne (Physician's Global Assessment [PGA] rating of no or almost no acne) were 65.1% and 66.9%, respectively. Overall success rates (IGA and PGA success in the same patient) were 57.9%; 52.8% of patients had a Dermatology Quality of Life Index score of 0 or 1, compared with 22.6% at baseline. Trifarotene was well tolerated, with pruritus, irritation, and sunburn as the most common adverse effects. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Trifarotene is a newly Food and Drug Administration-labeled fourth-generation topical retinoid that shows particular promise in the treatment of facial and truncal acne vulgaris. It is an effective and safe addition to currently available retinoids. CONCLUSION: Trifarotene is effective and safe for treatment of facial and truncal acne. Future trials should compare its efficacy and tolerability with that of the older, clinically established retinoids. Despite efficacy, cost may be a prohibitive factor.

How to Sequence Therapies in Mycosis Fungoides.

OPINION STATEMENT: Choice of therapy in mycosis fungoides is based on both patient- and lymphoma-specific factors, such as disease characteristics, comorbidities, symptoms and effect on quality of life, potential associated toxicities of therapy, response and tolerance to prior lines of therapy, and convenience and practicality. Generally, we sequence therapies from least toxic, targeted, nonimmunosuppressive to more toxic, immunosuppressive and from single agent to multiple agents, as necessary. If more toxic, immunosuppressive agents are required to alleviate disease burden or symptoms, we generally use them just long enough to control the disease, then transition to a maintenance regimen with less toxic, less immunosuppressive agents.

Cutaneous B cell pseudolymphoma treated with rituximab and methotrexate.

Cutaneous B cell pseudolymphoma (CBPL), or cutaneous lymphoid hyperplasia, is the most common pseudolymphoma. It typically responds well to local treatment and follows a benign course. Herein, we describe the unique case of a patient with CBPL that was refractory to a variety of treatments, with subsequent response to rituximab followed by methotrexate. This case explores the complex interplay of T and B lymphocytes, and the potential role of perifollicular T cells in treatment resistant CBPL. Further, it describes the additive therapeutic effect of rituximab and methotrexate to target both B cell and T cell populations in CBPL, a strategy already employed in a number of other conditions.

Granulomatous Panniculitis as a Complication of Subcutaneous Testosterone Pellet Therapy.

A 51-year-old man with a 3-year history of exogenous testosterone pellet injections to the left buttock presented for routine skin examination. While the patient reported recurrent drainage from the site of testosterone replacement therapy (TRT) injections, he continued to receive repeated implantations every 6 months. On physical examination, a 12-mm irregular, brown macule was identified within a poorly demarcated, ecchymotic, and fluctuant subcutaneous plaque on the left buttock with a sinus tract draining serosanguinous fluid. The pigmented lesion was biopsied, revealing malignant melanoma in situ; hence, a wide local excision was scheduled. During the procedure, necrotic subcutaneous fat was observed surrounding the site of biopsy, and a region measuring 18 cm2 approximately was debrided and submitted for pathologic evaluation. Histopathologic examination revealed a diffused subcutaneous granulomatous infiltrate with septal and lobular panniculitis and fat necrosis as well as peripherally palisading histiocytes and hemosiderin deposition (Figures 1A and B). Similar findings were observed in another specimen from the same segment of debrided tissue, compatible with granulomatous panniculitis. Periodic acid-Schiff (PAS), Gram's, and acid-fast bacilli (AFB) stains revealed no microorganisms. During surgical exploration, six foreign bodies were discovered and identified as undissolved testosterone pellets. The patient was referred to a wound care center, but ultimately lost to follow-up.

Skin Cancer Knowledge, Attitudes and Sun Protection Practices in the Hispanic Population: A Cross-Sectional Survey.

Hispanics are more likely to be diagnosed with skin cancer at a later stage and experience worse overall survival than Whites. The objective of this cross-sectional study was to assess the skin cancer knowledge, attitudes, perceived risk, and sun protection practices among an underserved population in the Phoenix area. We recruited participants from the greater Phoenix area to undergo skin examination and complete a questionnaire. 208 participants were included. The majority were Hispanic (64.9%). Of this Hispanic group, most were from Mexico (87.9%). The Hispanic cohort had an overall mean skin cancer knowledge score of 3.68/6, the lowest of any other racial/ethnic group, but had the highest desire to learn more about skin cancer (64.6%, "strongly agree"). They were the most concerned about developing skin cancer (50.4%, "very concerned") but had relatively lower rates of sun protection practices (7.9% "always use" sunscreen, 22.0% "always use" sun-protective clothing). Limitations of this study include a small sample size, lack of validation for the skin cancer knowledge score, lack of season as a covariate in the multivariate analysis, lack of follow-up, and lack of robust skin cancer risk assessment. In conclusion, despite poorer skin cancer knowledge and sun protection practices, the Hispanic population had the highest concern for developing skin cancer and desire to learn more about skin cancer. Targeted and culturally relevant skin cancer and sun protection education for this group is needed.

Current perspectives of and potential reforms to the dermatology residency application process: A nationwide survey of program directors and applicants.

The COVID-19 pandemic has accelerated discussions about reforms needed in the dermatology residency application process. We sought to evaluate the perspectives of dermatology program directors (PDs) and applicants regarding changes implemented during the 2020-2021 application cycle and measure support for potential reforms. Two online surveys were distributed to PDs and applicants who participated in the 2020-2021 dermatology residency match. Responses were collected from a total of 79 PDs (73.8% response rate, 83.5% complete responses) and 232 applicants (83.6% complete responses). The top 3 reforms supported by PDs were application caps (89.4% in favor), interview caps (86.4% in favor), and token preference signaling (81.8% in favor). The top 3 reforms supported by applicants were coordinated interview invite release (89.7% in favor), national webinars with PDs and/or faculty to discuss the application process (86.6% in favor), and formalized mentorship programs with PDs and/or faculty (78.4% in favor). This study was limited by the inability to capture responses from more dermatology applicants, possibly affecting the generalizability of the results. We identified broad support for multiple proposed reforms to the dermatology residency application process, particularly to improve the efficiency of application review and strengthen communication between programs and applicants.

Differences in Underrepresented in Medicine Applicant Backgrounds and Outcomes in the 2020-2021 Dermatology Residency Match.

Dermatology is one of the least diverse medical specialties. Although there have been studies addressing barriers faced by underrepresented in medicine (UIM) applicants to dermatology, there is little information about how UIM applicants approach and fare in the dermatology residency match process. This study aimed to assess differences between UIM and non-UIM applicants in the dermatology match process. A survey was administered to 2020-2021 dermatology applicants (N=232) to evaluate applicant characteristics, approaches, and outcomes in the match process. Survey responses were analyzed to determine if differences between variables were statistically significant. An additional survey was administered to dermatology residency program directors to evaluate their approach to the 2020-2021 application process. Our findings are important in identifying interventions to improve equity in the dermatology application process and to improve diversity in the dermatology workforce.

Ruxolitinib Cream in the Treatment of Cutaneous Lichen Planus: A Prospective, Open-Label Study.

Ruxolitinib is a Janus kinase 1/2 inhibitor that blocks signal transduction of interferon-gamma, a critical cytokine involved in the pathogenesis of cutaneous lichen planus (LP). In this prospective phase II study, we investigated the efficacy of topical ruxolitinib in cutaneous LP and performed transcriptomic analysis before and after therapy. Twelve patients with cutaneous LP applied topical ruxolitinib twice daily for 8 weeks. Primary endpoints were changes in total lesion count and changes in modified Composite Assessment of Index Lesion Severity score in index treated and untreated index control lesions at week 4. Total lesion count decreased by a median of 50 lesions (interquartile range 25, 723; P < 0.001). modified Composite Assessment of Index Lesion Severity scores decreased by a mean difference of 7.6 (standard deviation 8.8, P = 0.016) between index treated and control lesions. Type I and II interferon pathways were enriched in LP, and responsive disease displayed downregulation of interferon-stimulated genes. In this small pilot study, topical ruxolitinib was highly effective in the treatment of cutaneous LP. Transcriptomic analysis confirmed LP as an interferon-driven disease and downregulation of interferon-stimulated genes correlated with disease response.

Dermatologic manifestations of COVID-19-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) affects a small percentage of pediatric patients infected with COVID-19 and is characterized by fever, laboratory evidence of inflammation, multisystem involvement, and severe illness necessitating hospitalization. Skin findings are often present in these patients, and when initially compared with Kawasaki disease, they likely represent distinct phenomena and overall remain poorly characterized. In this retrospective review of 34 case reports and series, we identified cutaneous manifestations documented in 417 of 736 patients (57%) with MIS-C associated with COVID-19. "Rash" was the sole descriptor of skin findings in nearly half of patients. Case reports and smaller case series provided more detail, outlining a broad range of lesion morphologies (polymorphic, maculopapular, morbilliform, erythrodermic, urticarial, reticular, petechial, purpuric) in variable anatomic distribution. More thorough descriptions of dermatologic manifestations in patients with MIS-C are warranted to better characterize this syndrome, as they may lend important insight into pathogenic mechanisms of disease.

Cutaneous Desmoplastic Leiomyosarcoma Development at Smallpox Vaccination Site.

An 81-year-old man presented to the clinic with a 2.1 cm firm, skin-colored subcutaneous tumor on the left upper arm (Figure 1). The lesion arose at the site of a past smallpox vaccination and had been slowly enlarging for approximately 4 years. The differential diagnosis included sympastic leiomyoma, and a variety of desmoplastic spindle cell lesions such as desmoplastic melanoma, cutaneous spindle cell carcinoma, and desmoplastic leiomyosarcoma. Punch biopsy and immunohistochemical staining revealed positive spindle cells for desmin and caldesmon (Figures 2 and 3). Immunostain for p53 was also strongly and uniformly positive. Owing to poor circumscription on histopathology, symplastic leiomyosarcoma was ruled out. Demoplastic melanoma was also excluded due to positive immunoreaction to muscle markers (desmin and caldesmon) and negative S-100 staining. Additionally, cutaneous spinde cell carcinoma was also ruled out due to negative p63 and cytokeratin staining. Ultimately, clinicopathologic correlation favored a diagnosis of desmoplastic leiomyosarcoma. Staged excisions were performed to eradicate the lesion.