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In a randomized trial involving patients with the rare but disabling disorder generalized pustular psoriasis, the anti–interleukin-36 monoclonal antibody spesolimab greatly curtailed disease activity as compared with placebo over a period of 1 week. Systemic drug reactions and infections occurred with spesolimab.

In two identical trials of treatment for psoriasis with the topical aryl hydrocarbon receptor–modulating agent tapinarof, clearance or near-clearance of lesions occurred in a larger proportion of patients who used tapinarof cream than of those who used placebo. Side effects included folliculitis, contact dermatitis, and headache.

Biologics that neutralize specific cytokines have improved outcomes for several immune-mediated disorders but may also increase risks for particular side effects. This article postulates potential immunologic consequences of inhibiting components of the IL-23/T-helper cell 17 pathway–the target of next-generation biologics for treating psoriasis–based on clinical phenotypes of inherent or acquired deficiencies in this pathway. Generally, downstream deficiencies (e.g., IL-17A, IL-17F) are associated with fewer disorders compared with upstream deficiencies, suggesting that selectively blocking downstream targets may result in a narrower range of side effects. However, safety of these specific inhibitions must be established in long-term studies.

Vitiligo is a chronic autoimmune disease that causes skin depigmentation. A cream formulation of ruxolitinib (an inhibitor of Janus kinase 1 and 2) resulted in repigmentation in a phase 2 trial involving adults with vitiligo. We conducted two phase 3, double-blind, vehicle-controlled trials (Topical Ruxolitinib Evaluation in Vitiligo Study 1 [TRuE-V1] and 2 [TRuE-V2]) in North America and Europe that involved patients 12 years of age or older who had nonsegmental vitiligo with depigmentation covering 10% or less of total body-surface area. Patients were randomly assigned in a 2:1 ratio to apply 1.5% ruxolitinib cream or vehicle control twice daily for 24 weeks to all vitiligo areas on the face and body, after which all patients could apply 1.5% ruxolitinib cream through week 52. The primary end point was a decrease (improvement) of at least 75% from baseline in the facial Vitiligo Area Scoring Index (F-VASI; range, 0 to 3, with higher scores indicating a greater area of facial depigmentation), or F-VASI75 response, at week 24. There were five key secondary end points, including improved responses on the Vitiligo Noticeability Scale. A total of 674 patients were enrolled, 330 in TRuE-V1 and 344 in TRuE-V2. In TRuE-V1, the percentage of patients with an F-VASI75 response at week 24 was 29.8% in the ruxolitinib-cream group and 7.4% in the vehicle group (relative risk, 4.0; 95% confidence interval [CI], 1.9 to 8.4; P<0.001). In TRuE-V2, the percentages were 30.9% and 11.4%, respectively (relative risk, 2.7; 95% CI, 1.5 to 4.9; P<0.001). The results for key secondary end points showed superiority of ruxolitinib cream over vehicle control. Among patients who applied ruxolitinib cream throughout 52 weeks, adverse events occurred in 54.8% in TRuE-V1 and 62.3% in TRuE-V2; the most common adverse events were application-site acne (6.3% and 6.6%, respectively), nasopharyngitis (5.4% and 6.1%), and application-site pruritus (5.4% and 5.3%). In two phase 3 trials, application of ruxolitinib cream resulted in greater repigmentation of vitiligo lesions than vehicle control through 52 weeks, but it was associated with acne and pruritus at the application site. Larger and longer trials are required to determine the effect and safety of ruxolitinib cream in patients with vitiligo. (Funded by Incyte; TRuE-V1 and TRuE-V2 ClinicalTrials.gov numbers, NCT04052425 and NCT04057573.).

Background The Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP), a population-based survey of patients, dermatologists, and rheumatologists, was conducted for better understanding of the unmet needs of psoriasis and psoriatic arthritis (PsA) patients. Objective To report results from US physicians and patients. Methods Adults were contacted by household telephone, using random digit dialing, and asked to participate if they had ever been diagnosed with psoriasis or PsA. Physicians were identified through national databases and contacted through random sampling methods. Results In the USA, 1005 patients, 101 dermatologists, and 100 rheumatologists were surveyed. PsA had been diagnosed in 270 patients (26.9 %). Of those with psoriasis alone, fewer than 60 % (versus 85.6 % of PsA patients) had seen a healthcare provider within 12 months. Joint pain was reported by 51.8 % of psoriasis patients without a diagnosis of PsA, and 37.6 % of dermatologists cited their greatest challenge in managing PsA patients as being differentiating PsA from other arthritic diseases. Itching was reported by 36 % of psoriasis patients versus 12 % of dermatologists as the most important factor contributing to disease severity. Patients reported lower rates of current treatment than did dermatologists and rheumatologists. Conventional oral and biologic therapies were used by 24.9 and 17.7 % of patients, respectively. Among patients who had received injectable biologics, treatment dissatisfaction was related to long-term safety/tolerability, injection-related anxiety/fear, and cost. Conclusion This large, population-based survey identified unmet needs in the management of psoriasis and PsA patients in the USA, including assessment of disease severity, PsA diagnosis, undertreatment, and satisfaction with therapy.

There is an unmet need for a treatment for psoriasis that results in complete skin clearance with a reliably quick response. Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. We aimed to compare the efficacy and safety of bimekizumab with placebo and ustekinumab in patients with moderate to severe plaque psoriasis over 52 weeks. BE VIVID was a multicentre, randomised, double-blind, active comparator and placebo controlled phase 3 trial done across 105 sites (clinics, hospitals, research units, and private practices) in 11 countries in Asia, Australia, Europe, and North America. Adults aged 18 years or older with moderate to severe plaque psoriasis (Psoriasis Area and Severity Index [PASI] score ≥12, ≥10% body surface area affected by psoriasis, and Investigator's Global Assessment [IGA] score ≥3 on a five point scale) were included. Randomisation was stratified by geographical region and previous exposure to biologics; patients, investigators, and sponsors were masked to treatment assignment. Patients were randomly assigned (4:2:1) using an interactive response technology to bimekizumab 320 mg every 4 weeks, ustekinumab 45 mg or 90 mg (baseline weight-dependent dosing) at weeks 0 and 4, then every 12 weeks, or placebo every 4 weeks. At week 16, patients receiving placebo switched to bimekizumab 320 mg every 4 weeks. All study treatments were administered as two subcutaneous injections. Coprimary endpoints were the proportion of patients with 90% improvement in the PASI (PASI90) and the proportion of patients with an IGA response of clear or almost clear (score 0 or 1) at week 16 (non-responder imputation). Efficacy analyses included the intention-to-treat population; safety analysis included patients who received at least one dose of study treatment. This trial was registered at ClinicalTrials.gov, NCT03370133 (completed). Between Dec 6, 2017, and Dec 13, 2019, 735 patients were screened and 567 were enrolled and randomly assigned (bimekizumab 320 mg every 4 weeks n=321, ustekinumab 45 mg or 90 mg every 12 weeks n=163, placebo n=83). At week 16, 273 (85%) of 321 patients in the bimekizumab group had PASI90 versus 81 (50%) of 163 in the ustekinumab group (risk difference 35 [95% CI 27–43]; p<0·0001) and four (5%) of 83 in the placebo group (risk difference 80 [74–86]; p<0·0001). At week 16, 270 (84%) patients in the bimekizumab group had an IGA response versus 87 (53%) in the ustekinumab group (risk difference 30 [95% CI 22–39]; p<0·0001) and four (5%) in the placebo group (risk difference 79 [73–85]; p<0·0001). Over 52 weeks, serious treatment-emergent adverse events were reported in 24 (6%) of 395 patients in the bimekizumab group (including those who switched from placebo at week 16) and 13 (8%) of 163 in the ustekinumab group. Bimekizumab was more efficacious than ustekinumab and placebo in the treatment of moderate to severe plaque psoriasis. The bimekizumab safety profile was consistent with that observed in previous studies. UCB Pharma.

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. 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. 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. 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. Boehringer Ingelheim.

In two trials in patients with moderate-to-severe plaque psoriasis, the anti–interleukin-17A monoclonal antibody secukinumab was more effective than placebo and etanercept. Infectious complications occurred more often with secukinumab than with placebo. Psoriasis is a chronic, immune-mediated inflammatory skin disease that is associated with substantial impairment of physical and psychological quality of life. 1 , 2 Our understanding of the pathogenesis of psoriasis was advanced by the discovery of the class of type 17 helper T (Th17) cells, which regulates innate and adaptive immunity. The proinflammatory cytokine interleukin-17A is the primary effector of Th17 cells, but it is also produced by other cell types in psoriatic lesions, including γδ T cells, neutrophils, and possibly mast cells. 3 – 7 Interleukin-17A stimulates keratinocytes to secrete chemokines and other proinflammatory mediators that recruit additional inflammatory cells, including neutrophils, . . .

Generalized pustular psoriasis (GPP) is a rare, chronic, inflammatory skin disease characterized by persistent symptoms and sudden flares of painful, sterile pustules, and may be accompanied by systemic inflammation. Ongoing symptoms of GPP can have a serious impact on patient quality of life, morbidity, and mortality, and severe flares may be life-threatening if left untreated. Guidelines have been developed for the treatment of GPP flares; however, health care professionals and patients are lacking guidance on the management of long-term, persistent symptoms of GPP. Spesolimab is the only FDA-approved treatment for GPP and is approved for use in adults and pediatric patients aged 12 years or older and weighing at least 40 kg. Spesolimab recently gained FDA approval as a subcutaneous injection to treat GPP when patients are not experiencing a flare. In this podcast episode, we discuss what is known about the chronic disease burden of GPP and how persistent symptoms affect quality of life when patients are not experiencing a flare. We address the need for treatment guidelines for chronic GPP and discuss the results of the EFFISAYIL 2 clinical trial, which led to the approval of the subcutaneous formulation of spesolimab to treat GPP when patients are not experiencing a flare. Finally, we discuss what can be done to improve the treatment of patients with chronic GPP, both while experiencing a flare, and while living with persistent symptoms.