Clinical Pearls & Morning Reports
Published December 22, 2021
Biologic agents are approved for the treatment of generalized pustular psoriasis (GPP) in Japan, Taiwan, and Thailand on the basis of small trials of these drugs involving patients with plaque psoriasis and small, nonrandomized trials involving patients with GPP. There are no approved therapies for the disease in the United States or Europe. Bachelez et al. conducted a phase 2 randomized, placebo-controlled trial that investigated the efficacy and safety of spesolimab in patients presenting with a GPP flare. Read the NEJM Original Article here.
Q: What are some of the features of GPP?
A: GPP is a rare, potentially life-threatening, autoinflammatory skin disease characterized by widespread eruption of sterile, visible pustules that occurs with or without systemic symptoms of pain, fever, general malaise, fatigue, and extracutaneous manifestations such as arthritis and neutrophilic cholangitis. The clinical course of GPP can be relapsing with recurrent flares or persistent with intermittent flares. Mortality ranges from 2 to 16%, and deaths have been attributed to septic shock and cardiorespiratory failure. The frequency of flares varies among patients, and flares may be spontaneous or triggered by upper respiratory tract infections, stress, medication, medication withdrawal, and pregnancy.
Q: What is the target of spesolimab?
A: The role of the interleukin-36 pathway in GPP is supported by the finding of loss-of-function mutations in the interleukin-36 receptor antagonist gene (IL36RN) and associated genes (CARD14, AP1S3, SERPINA3, and MPO) and by the overexpression of interleukin-36 cytokines in GPP skin lesions. Clinical improvements with spesolimab, a humanized anti–interleukin-36 receptor monoclonal antibody, were observed in an open-label phase 1 study involving seven patients presenting with a GPP flare.
A: This randomized trial of a single intravenous dose of spesolimab in patients with a flare of GPP showed that at 1 week there was better clearance of lesions with spesolimab than with placebo. At the end of week 1, a total of 19 of the 35 patients (54%) who were assigned to the spesolimab group and 1 of the 18 patients (6%) who were assigned to the placebo group had a Generalized Pustular Psoriasis Physician Global Assessment pustulation subscore of 0 (no visible pustules) (difference, 49 percentage points; 95% confidence interval, 21 to 67; P<0.001). Because 15 of the 18 patients who were assigned to the placebo group received open-label spesolimab, the effect of spesolimab as compared with that of placebo could not be determined after week 1. Longer and larger trials are warranted to determine the effect of spesolimab in patients with pustular psoriasis.
A: Through the first week of treatment, adverse events were reported in 66% of the patients assigned to the spesolimab group and 56% of those assigned to the placebo group. Infections were reported in 17% of the patients in the spesolimab group and in 6% of those in the placebo group through the first week. Symptoms that were observed in two patients who received spesolimab were reported as a drug reaction with eosinophilia and systemic symptoms (DRESS) with RegiSCAR (European Registry of Severe Cutaneous Adverse Reactions) scores of 1 and 3. Antidrug antibodies were detected at a median of 2.3 weeks after spesolimab administration. Antidrug antibodies were detected in 23 of 50 patients (46%) who received at least one dose of spesolimab.