Radiation Recall Dermatitis With Bruton Tyrosine Kinase Inhibitor Therapy.

This case report describes a woman in her 70s with a history of breast cancer and chronic lymphocytic leukemia who presented with a painful rash of the bilateral chest extending onto the flanks.

Efficacy and safety of subcutaneous spesolimab for the prevention of generalised pustular psoriasis flares (Effisayil 2): an international, multicentre, randomised, placebo-controlled trial.

BACKGROUND: Spesolimab is an anti-interleukin-36 receptor monoclonal antibody approved to treat generalised pustular psoriasis (GPP) flares. We aimed to assess the efficacy and safety of spesolimab for GPP flare prevention. METHODS: This multicentre, randomised, placebo-controlled, phase 2b trial was done at 60 hospitals and clinics in 20 countries. Eligible study participants were aged between 12 and 75 years with a documented history of GPP as per the European Rare and Severe Psoriasis Expert Network criteria, with a history of at least two past GPP flares, and a GPP Physician Global Assessment (GPPGA) score of 0 or 1 at screening and random assignment. Patients were randomly assigned (1:1:1:1) to receive subcutaneous placebo, subcutaneous low-dose spesolimab (300 mg loading dose followed by 150 mg every 12 weeks), subcutaneous medium-dose spesolimab (600 mg loading dose followed by 300 mg every 12 weeks), or subcutaneous high-dose spesolimab (600 mg loading dose followed by 300 mg every 4 weeks) over 48 weeks. The primary objective was to demonstrate a non-flat dose-response curve on the primary endpoint, time to first GPP flare. FINDINGS: From June 8, 2020, to Nov 23, 2022, 157 patients were screened, of whom 123 were randomly assigned. 92 were assigned to receive spesolimab (30 high dose, 31 medium dose, and 31 low dose) and 31 to placebo. All patients were either Asian (79 [64%] of 123) or White (44 [36%]). Patient groups were similar in sex distribution (76 [62%] female and 47 [38%] male), age (mean 40·4 years, SD 15·8), and GPP Physician Global Assessment score. A non-flat dose-response relationship was established on the primary endpoint. By week 48, 35 patients had GPP flares; seven (23%) of 31 patients in the low-dose spesolimab group, nine (29%) of 31 patients in the medium-dose spesolimab group, three (10%) of 30 patients in the high-dose spesolimab group, and 16 (52%) of 31 patients in the placebo group. High-dose spesolimab was significantly superior versus placebo on the primary outcome of time to GPP flare (hazard ratio [HR]=0·16, 95% CI 0·05-0·54; p=0·0005) endpoint. HRs were 0·35 (95% CI 0·14-0·86, nominal p=0·0057) in the low-dose spesolimab group and 0·47 (0·21-1·06, p=0·027) in the medium-dose spesolimab group. We established a non-flat dose-response relationship for spesolimab compared with placebo, with statistically significant p values for each predefined model (linear p=0·0022, emax1 p=0·0024, emax2 p=0·0023, and exponential p=0·0034). Infection rates were similar across treatment arms; there were no deaths and no hypersensitivity reactions leading to discontinuation. INTERPRETATION: High-dose spesolimab was superior to placebo in GPP flare prevention, significantly reducing the risk of a GPP flare and flare occurrence over 48 weeks. Given the chronic nature of GPP, a treatment for flare prevention is a significant shift in the clinical approach, and could ultimately lead to improvements in patient morbidity and quality of life. FUNDING: Boehringer Ingelheim.

Rare missense variants in the SH3 domain of PSTPIP1 are associated with hidradenitis suppurativa.

Hidradenitis suppurativa (HS) is a chronic, debilitating skin disease for which few treatment options are available. While most HS is sporadic, some rare kindred show a high-penetrance, autosomal-dominant inheritance. We wanted to identify rare variants that could contribute to HS risk in sporadic cases using candidate gene sequencing. We ultimately identified 21 genes for our capture panel. We included genes of the γ-secretase complex (n = 6) because rare variants in these genes sometimes cause familial HS. We added Notch receptor and ligand genes (n = 13) because γ-secretase is critical for processing Notch receptor signaling. Clinically, some people with PAPA (pyogenic arthritis, pyoderma gangrenosum, and acne) syndrome, a rare inflammatory disease, have concurrent HS. Rare variants in PSTPIP1 are known to cause PAPA syndrome, so we included PSTPIP1 and PSTPIP2 in the capture panel. We screened 117 individuals with HS for rare variations and calculated the expected burden using Genome Aggregation Database (gnomAD) allele frequencies. We discovered two pathogenic loss-of-function variants in NCSTN. This class of NCSTN variant can cause familial HS. There was no increased burden of rare variations in any γ-secretase complex gene. We did find that individuals with HS had a significantly increased number of rare missense variants in the SH3 domain of PSTPIP1. This finding, therefore, implicates PSTPIP1 variation in sporadic HS and further supports dysregulated immunity in HS. Our data also suggests that population-scale HS genetic research will yield valuable insights into disease pathology.

Rapid and sustained improvements in Generalized Pustular Psoriasis Physician Global Assessment scores with spesolimab for treatment of generalized pustular psoriasis flares in the randomized, placebo-controlled Effisayil 1 study.

BACKGROUND: Effisayil 1 was a randomized, placebo-controlled study of spesolimab, which is an anti-IL-36 receptor antibody, in patients presenting with a generalized pustular psoriasis flare. OBJECTIVE: To assess the effects of spesolimab over the 12-week study. METHODS: The primary endpoint of the study was Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 at week 1. Patients (N = 53) were randomized (2:1) to receive a single intravenous dose of 900 mg spesolimab or placebo on day 1. Patients could receive open-label spesolimab for persistent flare symptoms on day 8. RESULTS: Most patients receiving spesolimab achieved a GPPGA pustulation subscore of 0 (60.0%) and GPPGA total score of 0 or 1 (60.0%) by week 12. In patients randomized to placebo who received open-label spesolimab on day 8, the proportion with GPPGA pustulation subscore of 0 increased from 5.6% at day 8 to 83.3% at week 2. No factors predictive of spesolimab response were identified in patient demographics or clinical characteristics. LIMITATIONS: The effect of initial randomization was not determined conventionally beyond week 1 due to patients receiving open-label spesolimab. CONCLUSION: Rapid control of generalized pustular psoriasis flare symptoms with spesolimab was sustained over 12 weeks, further supporting its potential use as a therapeutic option for patients.

Design of Effisayil™ 2: A Randomized, Double-Blind, Placebo-Controlled Study of Spesolimab in Preventing Flares in Patients with Generalized Pustular Psoriasis.

INTRODUCTION: Generalized pustular psoriasis (GPP) is a rare autoinflammatory skin disease characterized by flares of widespread erythema with sterile pustules, and can be relapsing with recurrent flares, or persistent with intermittent flares. Spesolimab, a humanized anti-interleukin-36 (IL-36) receptor monoclonal antibody, targets the key IL-36 pathogenetic pathway in GPP. A previous study showed that spesolimab treatment led to rapid pustular and skin clearance in patients with GPP flares, which was sustained for up to 12 weeks. This study investigates the long-term effects of spesolimab on GPP flares, for which no specific treatments are currently available. The Effisayil™ 2 study will assess whether maintenance treatment with subcutaneous spesolimab prevents the occurrence of GPP flares and determine the optimal dosing regimen to achieve this aim. METHODS: Patients will have a documented history of GPP with a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear) at screening and randomization. Patients will be randomized 1:1:1:1 to three groups receiving a 600-mg subcutaneous loading dose of spesolimab followed by a 300-mg maintenance dose administered every 4 or 12 weeks, or a 300-mg loading dose followed by a 150-mg maintenance dose administered every 12 weeks, and one group receiving placebo, for 48 weeks. The primary endpoint is time to first GPP flare. If a patient experiences a GPP flare during the randomized maintenance treatment period, an open-label intravenous dose of 900-mg spesolimab will be administered, with an option for a second intravenous dose after 1 week. CONCLUSIONS: Effisayil™ 2 is the first placebo-controlled study in patients with GPP to investigate whether maintenance treatment with spesolimab can prevent flares and provide sustained disease control. This study will provide valuable insights on the long-term management of patients with this potentially life-threatening skin disease. TRIAL REGISTRATION NUMBER: NCT04399837.

The aim of the Effisayil™ 2 study is to see whether long-term treatment with the antibody spesolimab helps prevent skin flares in people with generalized pustular psoriasis (GPP). Patients can take part in the Effisayil™ 2 study if they have well-controlled GPP before they begin treatment in the study; that is, they will have skin that is clear or almost clear. Patients will be randomly divided into four groups, with similar numbers of patients in each group. In three of the four groups, patients will be given different doses of spesolimab for 48 weeks. In the fourth group, patients will be given a placebo for 48 weeks. The main goal of the study is to see how long it takes patients to have a GPP flare, while they are being given spesolimab or placebo. If any patient has a GPP flare during the study, they can be treated with another dose of spesolimab (and possibly a second dose 1 week later if needed), to help control the GPP flare. In this way, the Effisayil™ 2 study will help doctors and patients to learn how to manage GPP over time, so that GPP flares can be avoided.

Factors Associated With Dermatologic Follow-up vs Emergency Department Return in Patients With Hidradenitis Suppurativa After an Initial Emergency Department Visit.

Importance: Emergency department (ED) visitation is common for the treatment of hidradenitis suppurativa (HS), whereas dermatology outpatient care is low. The reasons underlying this differential follow-up have not been elucidated. Objective: To assess the interventions and patient factors associated with ED return following an initial ED visit for HS. Design, Setting, and Participants: This retrospective cohort study used data from the IBM® MarketScan® Commercial and Multi-State Medicaid databases (trademark symbols retained per database owner requirement). An HS cohort was formed from patients who had 2 or more claims for HS during the study period of 2010 to 2019 and with at least 1 ED visit for their HS or a defined proxy. Data were analyzed from November 2021 to May 2022. Exposures: Factors analyzed included those associated with the ED visit and patient characteristics. Main Outcomes and Measures: Primary outcomes were return to the ED or dermatology outpatient follow-up for HS or related proxy within 30 or 180 days of index ED visit. Results: This retrospective cohort study included 20 269 patients with HS (median [IQR] age, 32 [25-41] years; 16 804 [82.9%] female patients), of which 7455 (36.8%) had commercial insurance and 12 814 (63.2%) had Medicaid. A total of 9737 (48.0%) patients had incision and drainage performed at the index ED visit, 14 725 (72.6%) received an oral antibiotic prescription, and 9913 (48.9%) received an opioid medication prescription. A total of 3484 (17.2%) patients had at least 1 return ED visit for HS or proxy within 30 days, in contrast with 483 (2.4%) who had a dermatology visit (P < .001). Likewise, 6893 (34.0%) patients had a return ED visit for HS or proxy within 180 days, as opposed to 1374 (6.8%) with a dermatology visit (P < .001). Patients with Medicaid and patients who had an opioid prescribed were more likely to return to the ED for treatment of their disease (odds ratio [OR], 1.48; 95% CI, 1.38-1.58; and OR, 1.48; 95% CI, 1.39-1.58, respectively, within 180 days) and, conversely, less likely to have dermatology follow-up (OR, 0.16; 95% CI, 0.14-0.18; and OR, 0.81; 95% CI, 0.71-0.91, respectively, within 180 days). Conclusions and Relevance: This cohort study suggests that many patients with HS frequent the ED for their disease but are not subsequently seen in the dermatology clinic for ongoing care. The findings in this study raise the opportunity for cross-specialty interventions that could be implemented to better connect patients with HS to longitudinal care.

Recurrent Onychomadesis of the Toenails in Children and Adults: A Case Series.

INTRODUCTION: Onychomadesis occurs when the nail plate separates from the nail matrix and nail bed, eventually leading to shedding of the nail. This condition has been attributed to viral infections, autoimmune disorders, drug side effects, and physical trauma. A subset of patients has a recurrent form of onychomadesis without a clear trigger; this phenomenon is not well characterized in the literature. CASE PRESENTATION: We present a case series of pediatric and adult patients with recurrent toenail onychomadesis in order to better characterize the disorder and explore possible etiologies, risk factors, and treatments. DISCUSSION/CONCLUSION: For the cases herein, we propose microtrauma associated with footwear as the underlying etiology given the periodicity of nail shedding, exclusion of other etiological factors, and presence of predisposing risk factors in certain patients. Many patients saw improvement with application of urea 40% cream, suggesting this can be a valuable part of a treatment strategy, in addition to minimizing injury to involved digits.

Expert guidance on prophylaxis and treatment of dermatologic adverse events with Tumor Treating Fields (TTFields) therapy in the thoracic region.

Tumor Treating Fields (TTFields) are electric fields, delivered via wearable arrays placed on or near the tumor site, that exert physical forces to disrupt cellular processes critical for cancer cell viability and tumor progression. As a first-in-class treatment, TTFields therapy is approved for use in newly diagnosed glioblastoma, recurrent glioblastoma, and pleural mesothelioma. Additionally, TTFields therapy is being investigated in non-small cell lung cancer (NSCLC), brain metastases from NSCLC, pancreatic cancer, ovarian cancer, hepatocellular carcinoma, and gastric adenocarcinoma. Because TTFields therapy is well tolerated and delivery is locoregional, there is low risk of additive systemic adverse events (AEs) when used with other cancer treatment modalities. The most common AE associated with TTFields therapy is mild-to-moderate skin events, which can be treated with topical agents and may be managed without significant treatment interruptions. Currently, there are no guidelines for oncologists regarding the management of TTFields therapy-related skin AEs in the thoracic region, applicable for patients with pleural mesothelioma or NSCLC. This publication aims to provide guidance on preventing, minimizing, and managing dermatologic AEs in the thoracic region to help improve patient quality of life and reduce treatment interruptions that may impact outcomes with TTFields therapy.

Trial of Spesolimab for Generalized Pustular Psoriasis.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, life-threatening, inflammatory skin disease characterized by widespread eruption of sterile pustules. Interleukin-36 signaling is involved in the pathogenesis of this disorder. Spesolimab, a humanized anti-interleukin-36 receptor monoclonal antibody, is being studied for the treatment of GPP flares. METHODS: In a phase 2 trial, we randomly assigned patients with a GPP flare in a 2:1 ratio to receive a single 900-mg intravenous dose of spesolimab or placebo. Patients in both groups could receive an open-label dose of spesolimab on day 8, an open-label dose of spesolimab as a rescue medication after day 8, or both and were followed to week 12. The primary end point was a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) pustulation subscore of 0 (range, 0 [no visible pustules] to 4 [severe pustulation]) at the end of week 1. The key secondary end point was a GPPGA total score of 0 or 1 (clear or almost clear skin) at the end of week 1; scores range from 0 to 4, with higher scores indicating greater disease severity. RESULTS: A total of 53 patients were enrolled: 35 were assigned to receive spesolimab and 18 to receive placebo. At baseline, 46% of the patients in the spesolimab group and 39% of those in the placebo group had a GPPGA pustulation subscore of 3, and 37% and 33%, respectively, had a pustulation subscore of 4. At the end of week 1, a total of 19 of 35 patients (54%) in the spesolimab group had a pustulation subscore of 0, as compared with 1 of 18 patients (6%) in the placebo group (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001). A total of 15 of 35 patients (43%) had a GPPGA total score of 0 or 1, as compared with 2 of 18 patients (11%) in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Drug reactions were reported in 2 patients who received spesolimab, in 1 of them concurrently with a drug-induced hepatic injury. Among patients assigned to the spesolimab group, infections occurred in 6 of 35 (17%) through the first week; among patients who received spesolimab at any time in the trial, infections had occurred in 24 of 51 (47%) at week 12. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab. CONCLUSIONS: In a phase 2 randomized trial involving patients with GPP, the interleukin-36 receptor inhibitor spesolimab resulted in a higher incidence of lesion clearance at 1 week than placebo but was associated with infections and systemic drug reactions. Longer and larger trials are warranted to determine the effect and risks of spesolimab in patients with pustular psoriasis. (Funded by Boehringer Ingelheim; Effisayil 1 ClinicalTrials.gov number, NCT03782792.).

Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline.

PURPOSE: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy. METHODS: A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021. RESULTS: The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS: The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell-related toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell-associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell-associated neurotoxicity syndrome should be managed with corticosteroids and supportive care.Additional information is available at www.asco.org/supportive-care-guidelines.

Management of Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor Therapy: ASCO Guideline Update.

PURPOSE: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy. METHODS: A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021. RESULTS: A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus. RECOMMENDATIONS: Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines.

Reducing Skin Toxicities from EGFR Inhibitors with Topical BRAF Inhibitor Therapy.

Treatment of cancer with EGFR inhibitors is limited by on-target skin toxicities induced by inhibition of the MAPK pathway. BRAF inhibitors are known to paradoxically activate the MAPK downstream of EGFR, which we confirmed using human skin keratinocytes. We then conducted a phase I clinical trial testing the hypothesis that topical therapy with the BRAF inhibitor LUT014 could improve skin toxicities induced by EGFR inhibitors. Ten patients with metastatic colorectal cancer who had developed acneiform rash while being treated with cetuximab or panitumumab were enrolled in three cohorts. LUT014 was well tolerated, and there were no dose-limiting toxicities. The acneiform rash improved in the 6 patients who started with grade 2 rash in the low and intermediate cohorts. We conclude that topical LUT014 is safe and efficacious in improving rash from EGFR inhibitors, consistent with the mechanism of action inducting paradoxical MAPK activation. SIGNIFICANCE: BRAF inhibitor topical therapy could avoid dose reductions of EGFR inhibitors, locally treating the main dose-limiting skin toxicity of this class of agents.This article is highlighted in the In This Issue feature, p. 2113.

Psoriasis and mortality in the United States: Data from the National Health and Nutrition Examination Survey.

BACKGROUND: Psoriasis is a multifactorial disease that has been associated with multiple systemic disorders. Despite its role in mediating cardiovascular, metabolic, and pulmonary disorders, few studies have examined the independent mortality risk associated with psoriasis. OBJECTIVE: To determine the independent relationship between psoriasis and all-cause mortality in a nationally representative sample of the US population. METHODS: Retrospective population-based cohort study of adults and adolescents older than 10 years (N = 13 031) who participated in National Health and Nutrition Examination Surveys (2003-2006 and 2009-2010). Psoriasis status was determined from a self-reported medical history questionnaire. Mortality data are linked from national databases. RESULTS: Psoriasis was present in 2.7% of the study population. Over an average median follow-up of 52.3 months, psoriasis was significantly associated with increased mortality risk (HR, 1.99; 95% CI, 1.01-3.93; P = .047) with adjustment for demographics, smoking, and comorbidities including cardiovascular disease, diabetes, chronic obstructive pulmonary disease, cancer, chronic kidney disease, and stroke. These comorbidities mediated 15.5%, 5.9%, 8.7%, 11.7%, 4.2%, and 4.7% of the association between psoriasis and mortality, respectively. CONCLUSION: Psoriasis is independently associated with an increased risk of mortality. This relationship is partially mediated by an increased prevalence of the cardiovascular, infectious, and neoplastic disorders seen among patients with psoriasis.