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.

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.).

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.

Dermatologic Adverse Events Associated with Selective Fibroblast Growth Factor Receptor Inhibitors: Overview, Prevention, and Management Guidelines.

Fibroblast growth factor receptor (FGFR) tyrosine kinases, which are expressed on the cell membrane, are involved in a wide range of biological functions such as cell proliferation, survival, migration, and differentiation. The identification of FGFR fusions and other alterations in a wide range of solid tumors, including cholangiocarcinoma and bladder cancer, has resulted in the development of several selective FGFR inhibitors for use in these indications, for example, infigratinib, erdafitinib, derazantinib, pemigatinib, and futibatinib. In addition to the typical adverse events associated with tyrosine kinases, the FGFR inhibitors appear to give rise to a number of adverse events affecting the skin. Here we describe these skin events, which include the more common nail adverse events (e.g., onycholysis), palmar-plantar erythrodysesthesia syndrome, and stomatitis, as well as less common reactions such as calciphylaxis. This review aims to provide oncologists with an understanding of these dermatologic events and proposes guidelines for the management of treatment-emergent dermatologic adverse events. Awareness of possible adverse events associated with specific drugs should allow physicians to educate patients as to what to expect and implement effective management plans at the earliest possible opportunity, thereby preventing premature discontinuation while maintaining patient quality of life. IMPLICATIONS FOR PRACTICE: Identification of fibroblast growth factor receptor (FGFR) aberrations in cholangiocarcinoma and bladder cancer led to development of selective FGFR inhibitors for these indications, based on clinical benefit and safety profiles. The most frequent adverse events (AEs) include those affecting skin, hair, and nails, a unique class effect of these agents. These are usually mild to moderate in severity. This work reviewed skin AEs reported with FGFR inhibitors and provides management guidelines for physicians, aiming to increase awareness of skin events and provide effective treatment strategies. Early intervention and effective management may improve treatment adherence, optimize outcomes, and improve quality of life.

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.

First-in-human phase 1 clinical study of the IL-15 superagonist complex ALT-803 to treat relapse after transplantation.

New therapies for patients with hematologic malignancies who relapse after allogeneic hematopoietic cell transplantation (allo-HCT) are needed. Interleukin 15 (IL-15) is a cytokine that stimulates CD8+ T-cell and natural killer (NK) cell antitumor responses, and we hypothesized this cytokine may augment antileukemia/antilymphoma immunity in vivo. To test this, we performed a first-in-human multicenter phase 1 trial of the IL-15 superagonist complex ALT-803 in patients who relapsed >60 days after allo-HCT. ALT-803 was administered to 33 patients via the IV or subcutaneous (SQ) routes once weekly for 4 doses (dose levels of 1, 3, 6, and 10 µg/kg). ALT-803 was well tolerated, and no dose-limiting toxicities or treatment-emergent graft-versus-host disease requiring systemic therapy was observed in this clinical setting. Adverse events following IV administration included constitutional symptoms temporally related to increased serum IL-6 and interferon-γ. To mitigate these effects, the SQ route was tested. SQ delivery resulted in self-limited injection site rashes infiltrated with lymphocytes without acute constitutional symptoms. Pharmacokinetic analysis revealed prolonged (>96 hour) serum concentrations following SQ, but not IV, injection. ALT-803 stimulated the activation, proliferation, and expansion of NK cells and CD8+ T cells without increasing regulatory T cells. Responses were observed in 19% of evaluable patients, including 1 complete remission lasting 7 months. Thus, ALT-803 is a safe, well-tolerated agent that significantly increased NK and CD8+ T cell numbers and function. This immunostimulatory IL-15 superagonist warrants further investigation to augment antitumor immunity alone and combined with other immunotherapies. This trial was registered at www.clinicaltrials.gov as #NCT01885897.

Navigating immunosuppression in a pandemic: A guide for the dermatologist from the COVID Task Force of the Medical Dermatology Society and Society of Dermatology Hospitalists.

Dermatologists treating immune-mediated skin disease must now contend with the uncertainties associated with immunosuppressive use in the context of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Although the risk of infection with many commonly used immunosuppressive agents remains low, direct data evaluating the safety of such agents in coronavirus disease 2019 (COVID-19) are scarce. This article reviews and offers guidance based on currently available safety data and the most recent COVID-19 outcome data in patients with immune-mediated dermatologic disease. The interdisciplinary panel of experts emphasizes a stepwise, shared decision-making approach in the management of immunosuppressive therapy. The goal of this article is to help providers minimize the risk of disease flares while simultaneously minimizing the risk of iatrogenic harm during an evolving pandemic.

Pemphigus foliaceus in a patient with gastrointestinal stromal tumor treated with adjuvant imatinib mesylate.

Pemphigus is an autoimmune bullous disease with a number of described associations, including medications, which have been grouped into three structural categories - thiol drugs, phenol drugs, and drugs with neither functional group [1]. Discontinuation of the offending medication is considered a mainstay of therapy. We report a patient in whom the onset of pemphigus foliaceus was associated with initiation of imatinib mesylate adjuvant therapy in a patient with resected gastrointestinal stromal tumor (GIST). Imatinib was continued because of the survival benefit to the patient with a resected, high risk GIST. Treatment with rituximab resulted in near resolution of his blistering rash and follow up enzyme-linked immunosorbent assay (ELISA) demonstrated reference range immunoreactivity for both desmoglein 1 and desmoglein 3. After dose increase of imatinib therapy owing to tumor growth, the patient subsequently again developed a similar eruption. Re-biopsy and ELISA were consistent with recurrence of pemphigus. In conclusion, although the patient's pemphigus was cleared with a single cycle of rituximab infusions while continuing imatinib therapy, the disease returned after imatinib dose was increased a year later, suggesting a dose-response relationship.

Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.

Acute graft-versus-host disease following lung transplantation in a patient with a novel TERT mutation.

Familial pulmonary fibrosis is associated with loss-of-function mutations in telomerase reverse transcriptase (TERT) and short telomeres. Interstitial lung diseases have become the leading indication for lung transplantation in the USA, and recent data indicate that pathogenic mutations in telomerase may cause unfavourable outcomes following lung transplantation. Although a rare occurrence, solid organ transplant recipients who develop acute graft-versus-host disease (GVHD) have very poor survival. This case report describes the detection of a novel mutation in TERT in a patient who had lung transplantation for familial pulmonary fibrosis and died from complications of acute GVHD.

The effect of smoking and age on the response to first-line therapy of hidradenitis suppurativa: An institutional retrospective cohort study.

BACKGROUND: Treatment for hidradenitis suppurativa is often empiric and inadequate, and determining which patients will respond is difficult. OBJECTIVE: We sought to determine which patient factors are associated with a positive response to first-line medical therapy. METHODS: A single-center retrospective cohort study of all patients with hidradenitis suppurativa seen between January 1, 1992, and October 1, 2014, was conducted. Response to first-line medical therapy (oral/topical antibiotics, intralesional corticosteroids, and topical washes) was examined at follow-up within 6 months of initiating therapy. A multivariate binary logistic regression model was built examining response to treatment and the interplay of patient factors and treatment initiated. RESULTS: In all, 198 patients were included in the final model. Nonsmokers (odds ratio 2.634, 95% confidence interval 1.301-5.332, P = .007) and older individuals (odds ratio 1.046 for each additional year, 95% confidence interval 1.020-1.072, P < .001) were more likely to have improvement at follow-up. In addition, current smokers differed significantly from nonsmokers in several regards. LIMITATIONS: The retrospective nature of this study is a limitation, as is relying on classification of disease severity from physical examination findings in some patients. CONCLUSIONS: The results of this study suggest that clinicians may be able to more accurately predict which patients with hidradenitis suppurativa will respond to first-line medical therapy, and which patients may require therapy escalation.

EGFR inhibitor-induced skin reactions: differentiating acneiform rash from superimposed bacterial infections.

PURPOSE: Epidermal growth factor receptor (EGFR) inhibitors are approved for use as targeted chemotherapeutic agents against multiple solid-organ malignancies. The most common side effect associated with EGFR inhibitor therapy is a papulopustular eruption, which can easily be confused with bacterial folliculitis. In this study, we examine the relative timing and location of the EGFR-induced papulopustular eruption compared to the associated bacterial superinfections. METHODS: In this retrospective chart review, patients enrolled in our institution's IRB-approved prospective registry of cutaneous reactions to chemotherapy were screened for inclusion. All patients who received an EGFR inhibitor and developed either a papulopustular eruption or bacterial superinfection at some point during treatment were included. RESULTS: Of the 157 patients who met inclusion criteria, 36 (23 %) developed bacterial superinfections at some point during EGFR therapy. Papulopustular eruptions developed in a highly predictable time course, with a mean time to onset of 1.5 weeks and mean duration of 9.4 weeks. Bacterial superinfections occurred at widely variable time points during therapy with a mean time to onset of 27.7 weeks. Papulopustular eruptions much more frequently affected the face (97 %), chest (75 %), and back (61 %), while bacterial superinfections occurred more commonly on the upper extremity (64 %), lower extremity (47 %), and abdomen (39 %). CONCLUSIONS: The EGFR inhibitor-induced papulopustular eruption has a stereotypical time course and occurs in a characteristic distribution affecting the central face, upper chest, and back. Bacterial superinfections more frequently affect the extremities, abdomen, and groin and may occur at any point during EGFR therapy.

Palmoplantar pustules and osteoarticular pain in a 42-year-old woman.

Key teaching points • Synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is characterized by distinctive osteoarticular manifestations and a spectrum of neutrophilic dermatoses. • The most common dermatologic manifestations include palmoplantar pustulosis, acne conglobata, and acne fulminans. • SAPHO syndrome should be considered in patients presenting osteoarticular pain, particularly involving the anterior chest wall and/or spine, and neutrophilic skin lesions.

Life-threatening dermatologic adverse events in oncology.

The incidences of life-threatening toxicities such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are inconsistently reported. The potential association of anticancer agents with SJS or TEN has not been systematically investigated. We searched the literature (Ovid: 1950 to June 2013 and PubMed: 1948 to June 2013) using terms for SJS/TEN and anticancer therapies. Primary case reports, case series, and clinical trials were included. In addition, MedWatch, the Food and Drug Administration Adverse Event Reporting System (FAERS), was searched (1968 to August 2012) for SJS/TEN reports associated with anticancer therapies. Proportional reporting ratios (PRR>2, N>3), empirical Bayes geometric mean (EBGM>2, N>3), and lower 95% confidence interval (EBGM0.05>2) were used as thresholds to constitute a signal of association between SJS/TEN and anticancer drugs. There were 46 SJS and 37 TEN cases associated with 18 and 22 anticancer drugs in the literature, respectively. Among cases in the FAERS, significant signals were associated with SJS for bendamustine and with TEN for bendamustine, busulfan, chlorambucil, fludarabine, lomustine, and procarbazine. Several drugs reported in the published literature to be associated with SJS/TEN were not found to have significant signals in FAERS. Proactive pharmacovigilance to detect and define safety signals serves to aid oncology practitioners in the recognition of possible, yet uncommon, serious, and/or life-threatening skin reactions.

Dermatologic adverse events to chemotherapeutic agents, part 1: cytotoxics, epidermal growth factor receptors, multikinase inhibitors, and proteasome inhibitors.

Dermatologic toxicities have profound effects on patients receiving chemotherapy for cancer treatment. Cytotoxic chemotherapies are associated with a number of nonspecific dermatologic adverse events including alopecia, mucositis, and onychodystrophy. Targeted therapies including epidermal growth factor inhibitors, multikinase inhibitors, and proteasome inhibitors are associated with different skin reactions that are class-specific. In Part 1 of this review, we examine the presentations of the most common dermatologic adverse events associated with the above drugs and discuss the strategies used for their prevention and treatment.

Histopathology of acneiform eruptions in patients treated with epidermal growth factor receptor inhibitors.

BACKGROUND: Epidermal growth factor receptor inhibitors (EGFRIs) are anticancer agents that have been approved for use in a variety of solid tumors. EGFR-inhibiting agents produce a variety of cutaneous adverse events: most commonly a follicular papulopustular (acneiform) eruption on the face, scalp, chest and upper back. OBJECTIVE: The goal of this manuscript is to elucidate the histopathologic findings associated with this most common adverse event. METHODS: The histopathological findings of 10 patients with papulopustular eruptions induced by EGFRIs are described and compared to the four prior published case series of acneiform rashes attributed to EGFRIs. RESULTS: All 10 patients in our case series showed a superficial, predominantly neutrophilic suppurative folliculitis with ectatic follicular infundibula and rupture of the epithelial lining. Similar pathology was found in the four other case series discussing this phenomenon. CONCLUSION: While the characteristic clinical appearance of this rash precludes the need for a biopsy in most cases, this knowledge promotes our understanding of the pathophysiologic process. As the use of EGFRIs expands, dermatopathologists will see these reactions more commonly and will need to recognize this pattern.