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.

Deep learning for dermatologists: Part II. Current applications.

Because of a convergence of the availability of large data sets, graphics-specific computer hardware, and important theoretical advancements, artificial intelligence has recently contributed to dramatic progress in medicine. One type of artificial intelligence known as deep learning has been particularly impactful for medical image analysis. Deep learning applications have shown promising results in dermatology and other specialties, including radiology, cardiology, and ophthalmology. The modern clinician will benefit from an understanding of the basic features of deep learning to effectively use new applications and to better gauge their utility and limitations. In this second article of a 2-part series, we review the existing and emerging clinical applications of deep learning in dermatology and discuss future opportunities and limitations. Part 1 of this series offered an introduction to the basic concepts of deep learning to facilitate effective communication between clinicians and technical experts.

Deep learning for dermatologists: Part I. Fundamental concepts.

Artificial intelligence is generating substantial interest in the field of medicine. One form of artificial intelligence, deep learning, has led to rapid advances in automated image analysis. In 2017, an algorithm demonstrated the ability to diagnose certain skin cancers from clinical photographs with the accuracy of an expert dermatologist. Subsequently, deep learning has been applied to a range of dermatology applications. Although experts will never be replaced by artificial intelligence, it will certainly affect the specialty of dermatology. In this first article of a 2-part series, the basic concepts of deep learning will be reviewed with the goal of laying the groundwork for effective communication between clinicians and technical colleagues. In part 2 of the series, the clinical applications of deep learning in dermatology will be reviewed and limitations and opportunities will be considered.

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.

Levels of secretory leukocyte protease inhibitor expression in acute wounds.

OBJECTIVE: Even with our best practices, we are frequently unable to prevent slow and stalled wound healing-particularly in people with impaired circulation and conditions such as diabetes. As a result, greater insight into the nature of wound healing and alternative treatment approaches is needed. An avenue that may be of particular promise is increasing understanding of the role of secretory leukocyte protease inhibitor (SLPI) as there is evidence that it enhances wound healing, its expression increases in response to inflammation and infection, and it exhibits anti-protease, anti-inflammatory, antiviral antibacterial and antifungal activities. METHOD: The response of SLPI levels to wounding and skin injury was assessed by taking punch skin biopsies from healthy volunteers and assessing the levels of SLPI at the site of injury at the time of wounding (baseline) as well as one, two, three, four, seven, nine and 12 weeks later. RESULTS: A total of 35 volunteers took part in the study. Significant elevations were found: levels of SLPI were greatly increased, 12 times that at baseline, and remained elevated at three weeks despite re-epithelialisation having occurred. CONCLUSION: These findings not only suggest that levels of SLPI rise rapidly following wounding, but that these elevations are sustained, and continue to increase even when re-epithelialisation has occurred. These results suggest that the role and potential benefits of this protease inhibitor deserve further exploration.

Panniculitis in a patient with metastatic renal cell carcinoma on a tyrosine kinase inhibitor.

A 71-year-old female was diagnosed with localized renal cell carcinoma in July 2008 with subsequent metastasis in 2012 to the right adrenal gland, lungs, and brain. Due to disease progression, she was started on pazopanib 800 mg daily in October 2012. In November 2016, the patient developed an ill-defined, red, 10 × 15 cm indurated plaque on the left lateral upper thigh with a discrete 3 cm firm tender tumor without ulceration. An incisional biopsy was performed and showed panniculitis with features resembling sclerosing lipogranuloma. Alternative causes including rheumatologic disease and trauma were ruled out. We report the first case of pazopanib-induced panniculitis. Key clinical and histopathological features include tender subcutaneous nodules, exclusion of other causes, and fatty microcysts within a densely sclerotic background on pathology. As targeted therapies are becoming increasingly common in the field of oncology, prompt identification and reporting of adverse reactions is critical for proper management.

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.

Prognostic value of inositol polyphosphate-5-phosphatase expression in recurrent and metastatic cutaneous squamous cell carcinoma.

BACKGROUND: Inositol polyphosphate-5-phosphatase (INPP5A) has been shown to play a role in the progression of actinic keratosis to cutaneous squamous cell carcinoma (cSCC) and the progression of localized disease to metastatic disease. Currently, no cSCC biomarkers are able to risk stratify recurrent and metastatic disease. OBJECTIVE: To determine the prognostic value of INPP5A expression in cSCC recurrent and metastatic disease. METHODS: We conducted a multicenter, single-institutional, retrospective cohort study within the Mayo Clinic Health System on the use of immunohistochemical staining to examine cSCC INPP5A protein expression in primary tumors and recurrent and metastatic disease. Dermatologists and dermatopathologists were blinded to outcome. RESULTS: Low staining expression of INPP5A in recurrent and metastatic disease tumors was associated with poor overall survival (OS) (31.0 months for low versus 62.0 months for high expression; P = .0272). A composite risk score (calculated as score of primary tumor + score of recurrent or metastatic disease tumor, with tumors with high expression scoring a zero and low expression a 1, score range 0-2) of 0 was predictive of improved OS compared with a composite risk score of ≥1 (hazard ratio 0.42, 95% confidence interval 0.21-0.84; P = .0113). LIMITATIONS: This is a multicenter but single institution study of a white population. CONCLUSION: Loss of INPP5A expression predicts poor OS in recurrent and metastatic disease of cSCC.

A case of pediatric lymphomatoid papulosis treated with photodynamic therapy and narrowband ultraviolet B.

We report a case of a 13-year-old boy with extensive lymphomatoid papulosis (LyP) involving his elbows, forearms, proximal thighs, and right hip, with treatment-resistant nodules on his right forearm. He was treated with full-body narrowband ultraviolet B and targeted photodynamic therapy (PDT) with 20% aminolevulinic acid (ALA). After two months, there was complete resolution of the right forearm nodules. Due to its minimal toxicity, PDT offers unique advantages and may be considered for pediatric LyP patients with symptomatic, localized disease resistant to conventional treatments.

Improving Access to Care Through the Establishment of a Local, Teledermatology Network.

Introduction: Access to dermatologic care is a major issue in the United States, especially within the un- and underinsured populations; technology, including teledermatology, will pay a role in improving access to care. Methods: We performed a prospective study between November 2016 and September 2017. We leveraged a partnership between Mayo Clinic and Mountain Park Health Clinic, a community clinic that primarily serves un- and underinsured populations. We implemented a mobile phone-based store and forward (SAF) teledermatology service, which integrated an external community health clinic to an existing electronic health record (EHR) using standardized data capture forms, real-time support, and simple workflows. Results: Thirty-seven patients were enrolled in the study, 65% female and 35% male with an average age of 47.9 (SD = 15.9). The ethnic breakdown was: 81.1% Hispanic, 13.5% Caucasian, and 5.4% African American. The majority, 62.2%, did not have a high school education, 45.9% were unemployed, and 51.4% were uninsured. 64.9% earned less than $25,000 for annual household income. Teledermatology consultation increased the absolute diagnostic and management concordance by 36.6% (p = 0.01, 95% CI 12.2%-61.0%) and 34.2% (p < 0.01, 95% CI 11%-57%), respectively. Primary care providers had a significant increase in mean confidence in the diagnosis and management of dermatology conditions pre and poststudy (3.60 vs. 3.70 and 3.21 vs. 3.60, respectively; p < 0.01). Ninety-six percent of the primary care providers agreed (52.0%) and strongly agreed (44.0%) that they would send another patient for teleconsultation.Conclusion: We successfully implemented a SAF teledermatology consultative service in a community health clinic outside our EHR. A similar approach can be used by other large health care organizations to provide integrated, high-quality consultation to clinics with rural, un- and underinsured populations.

The prognostic value of inositol polyphosphate 5-phosphatase in cutaneous squamous cell carcinoma.

BACKGROUND: Inositol polyphosphate 5-phosphatase (INPP5A) has been shown to play a role in development and progression of cutaneous squamous cell carcinoma (cSCC). The goal of the current study was to explore the prognostic value of INPP5A expression in cSCC. METHODS: A total of 189 cases of actinic keratosis and SCC in 174 patients were identified; clinical and outcome data were abstracted, histopathology was rereviewed, and immunohistochemical staining and interpretation was performed for INPP5A. RESULTS: The majority of tumors (89.4%) had an INPP5A score of 2 or 3. No patients had complete loss of INPP5A. Tumors with an INPP5A score of 1 were more likely to be intermediate- to high-risk tumors (Brigham and Women's Hospital stage ≥T2a 85.0% vs 23.7% [P < .0001]) characterized by a larger diameter (2.4 cm vs 1.3 cm [P = .0004]), moderate-to-poor differentiation (86.7% vs 17.6% [P < .0001]), and perineural invasion (37.5% vs 5.3%, [P < .0001]). An INPP5A score of 1 was associated with a worse 3-year survival (a rate of 42.3% [hazard ratio, 2.81, P = .0006]) and a local metastasis rate of 48.0% (hazard ratio, 4.71; P < .0001). CONCLUSIONS: Low INPP5A scores are predictive of aggressive tumors and may be a useful adjunct to guide clinical management of cSCC.

Clinical and histopathologic features of paraneoplastic granuloma annulare in association with solid organ malignancies: A case-control study.

BACKGROUND: Granuloma annulare (GA) is a granulomatous skin eruption rarely associated with cancer. We report seven cases of paraneoplastic GA in association with solid organ malignancy. OBJECTIVE: To compare the clinical and histopathological features of paraneoplastic GA to case-matched controls of classic GA. METHODS: Retrospective chart and histopathological review of 7 individuals and 13 age- and sex-matched controls. Paraneoplastic GA was defined as GA occurring within 6 months of the diagnosis of solid organ malignancy and/or persistent GA that resolved with cancer treatment. RESULTS: Most cases of paraneoplastic GA were associated with lung cancer (4/7). The clinical and histopathological features of paraneoplastic and classic GA were similar. Compared to classic GA, paraneoplastic GA cases were more often generalized disease (6/7 vs 6/13), refractory to treatment, and had a perivascular inflammatory cell infiltrate (5/7 vs 2/13). All cases of paraneoplastic GA that underwent definitive treatment of their cancer improved. LIMITATIONS: Single-institution, retrospective review with a small sample size. CONCLUSION: Paraneoplastic GA is rare, similar to classic GA, and refractory to treatment. We advocate for age-appropriate screening in individuals with GA that is nonresponsive to multiple lines of systemic treatment and evaluating patients with concerning signs or symptoms for an underlying neoplasm.

Sézary syndrome without erythroderma: A review of 16 cases at Mayo Clinic.

BACKGROUND: Sézary syndrome (SS) is characterized by erythroderma with leukemic involvement. In atypical SS, leukemic involvement is present without erythroderma. Little is known about the presentation, prognosis, and outcome in these patients. OBJECTIVE: We sought to describe our experience with patients with SS without erythroderma. METHODS: We retrospectively identified patients with SS, but without erythroderma, at Mayo Clinic from 1976 to 2010. Patients all met criteria for high blood tumor burden. Their clinical characteristics, disease course, and prognosis were reviewed and compared with a previously described cohort of 176 patients with SS from this institution. RESULTS: Among 16 patients identified, all had cutaneous findings consistent with cutaneous T-cell lymphoma, most commonly erythematous patches (n = 6) and plaques (n = 12). All 16 patients were deceased at the time of the study. Median time from diagnosis of SS without erythroderma to the date of death was 3.6 years (range, 0.5-8.7 years). Survival was not different between patients with SS with and without erythroderma (hazard ratio 1.58; 95% confidence interval 0.94-2.66; P = .08). LIMITATIONS: This was a single-institution retrospective study. CONCLUSION: Leukemic involvement may confer shortened survival in patients with SS, because the presence of erythroderma did not affect survival. These atypical cases could potentially be more accurately described using the TNMB classification.

Early clinical manifestations of Sézary syndrome: A multicenter retrospective cohort study.

BACKGROUND: Classic Sézary syndrome (SS) is defined by erythroderma, generalized lymphadenopathy, and leukemic blood involvement. Clinical observations suggest that SS begins as a nonerythrodermic disease. OBJECTIVE: To describe the early clinical characteristics of patients with SS. METHODS: A retrospective, multicenter chart review was performed for 263 confirmed cases of SS diagnosed during 1976-2015. RESULTS: Erythroderma was the earliest recorded skin sign of SS in only 25.5% of cases, although most patients (86.3%) eventually developed erythroderma. In patients without erythroderma during their initial visit, the first cutaneous signs of SS were nonspecific dermatitis (49%), atopic dermatitis-like eruption (4.9%), or patches and plaques of mycosis fungoides (10.6%). The mean diagnostic delay was 4.2 years overall, 2.2 years for cases involving erythroderma at the initial presentation, and 5.0 years for cases not involving erythroderma at the initial presentation. LIMITATIONS: This study is retrospective. CONCLUSION: Erythroderma is uncommon as an initial sign of SS. Early SS should be considered in cases of nonerythrodermic dermatitis that is refractory to conventional treatments. In these cases, examination of the blood by PCR for monoclonal T-cell receptor rearrangement and by flow cytometry to identify an expanded or aberrant T-cell population should be considered.