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.).

Generalized pustular psoriasis: A nationwide population-based study using the National Health Data System in France.

BACKGROUND: GPP is a rare, chronic, neutrophilic skin disease, with limited real-world data characterizing patients with flares and the impact of flares on disease progression and morbidity. OBJECTIVE: Describe the clinical characteristics of patients with GPP, comorbidities, disease epidemiology and frequency and severity of flares, and compare patients with GPP with a matched severe psoriasis population. METHODS: In this population-based real-world cohort study an algorithm was developed to identify patients with GPP flares. Three cohorts were identified using the Système National des Données de Santé (SNDS) database covering almost the entire French population; a prevalent cohort (2010-2018), an incident cohort (2012-2015). A severe psoriasis cohort was compared with the GPP incident cohort using propensity score matching. RESULTS: The prevalent and incident cohorts comprised 4195 and 1842 patients, respectively. In both cohorts, mean age was 58 years; 53% were male. Comorbidities were significantly more common in the incident cohort versus matched psoriasis cohort, respectively, including hypertension (44% vs. 26%), ischaemic heart disease (26% vs. 18%) and hyperlipidaemia (25% vs. 15%). In the incident cohort, the flare rate was 0.1 flares/person-year and 0.4 flares/person-year among the 569 out of 1842 patients hospitalized with flares. These patients had a mean (±SD) stay of 11.6 ± 10.4 days; 25% were admitted to the intensive care unit. In 2017, the cumulative incidence and cumulative GPP age-sex standardized prevalence were 7.1 and 45.2 per million, respectively. CONCLUSIONS: Patients with GPP had a distinct comorbidity profile compared to patients with severe psoriasis, and GPP flares were associated with long hospitalizations.

Efficacy of long-term risankizumab treatment for moderate-to-severe plaque psoriasis: Subgroup analyses by baseline characteristics and psoriatic disease manifestations through 256 weeks (LIMMitless trial).

BACKGROUND: Psoriasis is an inflammatory skin disease that impacts a heterogeneous group of patients and can have multiple clinical manifestations. Risankizumab is approved for the treatment of moderate-to-severe plaque psoriasis. OBJECTIVES: To evaluate the long-term efficacy of risankizumab according to baseline patient characteristics, and for the treatment of high-impact disease manifestations (nail, scalp and palmoplantar psoriasis), through 256 weeks of continuous treatment in the phase 3 LIMMitless study. METHODS: This subgroup analysis evaluated pooled data from patients with moderate-to-severe plaque psoriasis who were randomized to risankizumab 150 mg during two double-blind, phase 3, 52-week base studies (UltIMMa-1/2; NCT02684370/NCT02684357) and were enrolled in the phase 3 LIMMitless open-label extension study (NCT03047395). Subgroup assessments included the proportion of patients who achieved ≥90%/100% improvement in Psoriasis Area and Severity Index (PASI 90/100). Among patients with nail, scalp and/or palmoplantar psoriasis in addition to skin psoriasis, assessments included changes from baseline in and resolution of these three psoriatic manifestations. RESULTS: Overall, a numerically similar proportion of patients (N = 525) achieved PASI 90/100 through Week 256, regardless of their baseline age, sex, body mass index, weight, PASI or psoriatic arthritis status. Patients with nail, scalp and/or palmoplantar psoriasis experienced substantial improvements in manifestation-specific indices (mean improvement from baseline to Week 256 of >81%, >94% and >97%, respectively); in patients with all three manifestations (N = 121), 44.6% achieved complete clearance of these manifestations at Week 256. CONCLUSIONS: Risankizumab demonstrated generally consistent efficacy through 256 weeks across patient subgroups and showed durable long-term efficacy for psoriatic disease manifestations.

Human papilloma virus-16-specific CD8+ T-cell expansions characterize different clinical forms of lichen planus and not lichen sclerosus et atrophicus.

Lichen planus (LP) is a cutaneomucosal chronic inflammatory disease characterized by a CD8+ cytotoxic T-lymphocytes (CTL) infiltrate. In erosive oral LP, we found HPV16-specific activated CTL in lesions, supporting a pathogenic contribution of HPV16. Here, we investigated whether a similar scenario occurs in other clinical forms of LP and in lichen sclerosus et atrophicus (LSA), another chronic disease also affecting the mucosa and/or the skin. Blood CTL from LP and LSA patients expressed significant higher levels of granzyme B, perforin and CD107a proteins than healthy donors. Expansions of TCRVß3+ CTL, with presence of TCR clonotypes identical to those previously detected in erosive oral LP, were found both in blood and mucosal/skin lesions of LP, and not of LSA patients. These expansions were enriched with HPV16-specific CD8+ T-cells as shown by their recognition of the E711-20 immunodominant epitope. In LSA patients, the peripheral repertoire of CTL was oligoclonal for TCRVß6+ CTL. Finally, although patients with LP and LSA have developed antibodies against HPV16 capsid L1, antibodies against HPV16 E6 were only observed in patients with LP. Overall, our data collectively suggest an involvement of HPV16-specific CTL in different clinical forms of LP, not only in erosive oral LP, while a different scenario operates in LSA.

Nonadherence to systemic immune-modifying therapy in people with psoriasis during the COVID-19 pandemic: findings from a global cross-sectional survey.

BACKGROUND: Nonadherence to immune-modifying therapy is a complex behaviour which, before the COVID-19 pandemic, was shown to be associated with mental health disorders in people with immune-mediated diseases. The COVID-19 pandemic has led to a rise in the global prevalence of anxiety and depression, and limited data exist on the association between mental health and nonadherence to immune-modifying therapy during the pandemic. OBJECTIVES: To assess the extent of and reasons underlying nonadherence to systemic immune-modifying therapy during the COVID-19 pandemic in individuals with psoriasis, and the association between mental health and nonadherence. METHODS: Online self-report surveys (PsoProtectMe), including validated screens for anxiety and depression, were completed globally during the first year of the pandemic. We assessed the association between anxiety or depression and nonadherence to systemic immune-modifying therapy using binomial logistic regression, adjusting for potential cofounders (age, sex, ethnicity, comorbidity) and country of residence. RESULTS: Of 3980 participants from 77 countries, 1611 (40.5%) were prescribed a systemic immune-modifying therapy. Of these, 408 (25.3%) reported nonadherence during the pandemic, most commonly due to concerns about their immunity. In the unadjusted model, a positive anxiety screen was associated with nonadherence to systemic immune-modifying therapy [odds ratio (OR) 1.37, 95% confidence interval (CI) 1.07-1.76]. Specifically, anxiety was associated with nonadherence to targeted therapy (OR 1.41, 95% CI 1.01-1.96) but not standard systemic therapy (OR 1.16, 95% CI 0.81-1.67). In the adjusted model, although the directions of the effects remained, anxiety was not significantly associated with nonadherence to overall systemic (OR 1.20, 95% CI 0.92-1.56) or targeted (OR 1.33, 95% CI 0.94-1.89) immune-modifying therapy. A positive depression screen was not strongly associated with nonadherence to systemic immune-modifying therapy in the unadjusted (OR 1.22, 95% CI 0.94-1.57) or adjusted models (OR 1.14, 95% CI 0.87-1.49). CONCLUSIONS: These data indicate substantial nonadherence to immune-modifying therapy in people with psoriasis during the pandemic, with attenuation of the association with mental health after adjusting for confounders. Future research in larger populations should further explore pandemic-specific drivers of treatment nonadherence. Clear communication of the reassuring findings from population-based research regarding immune-modifying therapy-associated adverse COVID-19 risks to people with psoriasis is essential, to optimize adherence and disease outcomes.

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.

Clinical Characteristics and Outcomes of Generalized Pustular Psoriasis Flares.

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare, neutrophilic skin disease that can become life-threatening if flares are untreated. There are limited data describing the characteristics and clinical course of GPP disease flares with current treatment options. OBJECTIVE: The aim of the study was to describe the characteristics and outcomes of GPP flares using historical medical information from patients enrolled in the Effisayil™ 1 trial. METHODS: Investigators collected retrospective medical data characterizing patients' GPP flares prior to clinical trial enrollment. Data on overall historical flares were collected, as well as information on patients' typical, most severe, and longest past flares. This included data on systemic symptoms, flare duration, treatment, hospitalization, and time to clearance of skin lesions. RESULTS: In this cohort (N = 53), patients with GPP experienced a mean of 3.4 flares per year. Flares were painful, associated with systemic symptoms, and often triggered by stress, infections, or treatment withdrawal. Resolution of flares was longer than 3 weeks in 57.1%, 71.0%, and 85.7% of documented (or identified) typical, most severe, and longest flares, respectively. GPP flares led to patient hospitalization in 35.1%, 74.2%, and 64.3% of patients for their typical, most severe, and longest flares, respectively. For the majority of patients, pustules took up to 2 weeks to clear for a typical flare and 3-8 weeks to clear for the most severe and longest flares. CONCLUSION: Our findings highlight that current treatment options are slow to control GPP flares and provide context for assessing the efficacy of new therapeutic strategies in patients with a GPP flare.

Clinical features, therapeutic choice and response by phototype in psoriasis: analysis of the French PsoBioTeq cohort.

BACKGROUND: Little is known about phototype and the response to systemic treatment in psoriasis. OBJECTIVES: To assess the characteristics of psoriasis, the therapeutic choice and its efficacy according to phototype. METHODS: We included patients from the PsoBioTeq cohort initiating a first biologic. Patients were classified according to their phototype. The evaluation included disease characteristics, choice of the initial biologic and therapeutic response at 12 months based on 90% improvement from baseline in Psoriasis Area and Severity Index (PASI 90) and Dermatology Life Quality Index (DLQI) 0/1. RESULTS: Of the 1400 patients included, 423 (30.2%), 904 (64.6%) and 73 (5.2%) were in the phototype I-II, III-IV and V-VI groups, respectively. The V-VI group had a higher initial DLQI, and more frequently initiated ustekinumab. Patients in the V-VI group maintained the initial biologic prescribed as did the other phototype groups, even though the proportion of patients reaching PASI 90 and DLQI 0/1 at 12 months was lower in this group than the other groups. CONCLUSIONS: Patient phototype seems associated with quality of life and choice of the initial biologic in psoriasis. The phototype V-VI group less frequently switched treatments than did the other groups when the response was not efficient.

Psychometric validation of the generalized pustular psoriasis physician global assessment (GPPGA) and generalized pustular psoriasis area and severity index (GPPASI).

BACKGROUND: Generalized pustular psoriasis (GPP) is a rare and life-threatening skin disease often accompanied by systemic inflammation. There are currently no standardized or validated GPP-specific measures for assessing severity. OBJECTIVE: To evaluate the reliability, validity and responder definitions of the Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) and Generalized Pustular Psoriasis Area and Severity Index (GPPASI). METHODS: The GPPGA and GPPASI were validated using outcome data from Week 1 of the Effisayil™ 1 study. The psychometric analyses performed included confirmatory factor analysis, item-to-item/item-to-total correlations, internal consistency reliability, test-retest reliability, convergent validity, known-groups validity, responsiveness analysis and responder definition analysis. RESULTS: Using data from this patient cohort (N = 53), confirmatory factor analysis demonstrated unidimensionality of the GPPGA total score (root mean square error of approximation <0.08), and GPPGA item-to-item and item-to-total correlations ranged from 0.58 to 0.90. The GPPGA total score, pustulation subscore and GPPASI total score all demonstrated good test-retest reliability (intraclass correlation coefficient: 0.70, 0.91 and 0.95 respectively), and good evidence of convergent validity. In anchor-based analyses, all three scores were able to detect changes in symptom and disease severity over time; reductions of -1.4, -2.2 and - 12.0 were suggested as clinically meaningful improvement thresholds for the GPPGA total score, GPPGA pustulation subscore and GPPASI total score respectively. Anchor-based analyses also supported the GPPASI 50 as a clinically meaningful threshold for improvement. CONCLUSIONS: Overall, our findings indicate that the GPPGA and GPPASI are valid, reliable and responsive measures for the assessment of GPP disease severity, and support their use in informing clinical endpoints in trials in GPP.

Pustular psoriasis: Molecular pathways and effects of spesolimab in generalized pustular psoriasis.

BACKGROUND: The IL-36 pathway plays a key role in the pathogenesis of generalized pustular psoriasis (GPP). In a proof-of-concept clinical trial, treatment with spesolimab, an anti-IL-36 receptor antibody, resulted in rapid skin and pustular clearance in patients presenting with GPP flares. OBJECTIVE: We sought to compare the molecular profiles of lesional and nonlesional skin from patients with GPP or palmoplantar pustulosis (PPP) with skin from healthy volunteers, and to investigate the molecular changes after spesolimab treatment in the skin and blood of patients with GPP flares. METHODS: Pre- and post-treatment skin and blood samples were collected from patients with GPP who participated in a single-arm, phase I study (n = 7). Skin biopsies from patients with PPP (n = 8) and healthy volunteers (n = 16) were obtained for comparison at baseline. Biomarkers were assessed by RNA-sequencing, histopathology, and immunohistochemistry. RESULTS: In GPP and PPP lesions, 1287 transcripts were commonly upregulated or downregulated. Selected transcripts from the IL-36 signaling pathway were upregulated in untreated GPP and PPP lesions. In patients with GPP, IL-36 pathway-related signatures, TH1/TH17 and innate inflammation signaling, neutrophilic mediators, and keratinocyte-driven inflammation pathways were downregulated by spesolimab as early as week 1. Spesolimab also decreased related serum biomarkers and cell populations in the skin lesions from patients with GPP, including CD3+ T, CD11c+, and IL-36γ+ cells and lipocalin-2-expressing cells. CONCLUSIONS: In patients with GPP, spesolimab showed rapid modulation of commonly dysregulated molecular pathways in GPP and PPP, which may be associated with improved clinical outcomes.

A Multicentre Randomised Controlled Study Evaluating the Effect of a Standardised Education Programme on Quality of Life, Disease Severity, and Disease Knowledge in Patients with Moderate-To-Severe Psoriasis: The EDUPSO Study.

BACKGROUND: Psoriasis is a chronic inflammatory skin disease that has a profound effect on health-related quality of life (HRQoL). Patient education programmes may help patients to gain life-long control over their chronic disease. OBJECTIVE: This multicentre randomised controlled study evaluated whether a standardised multidisciplinary education programme was beneficial to psoriasis patients. METHODS: Adults with moderate-to-severe psoriasis were randomly assigned (1:1) to an intervention group to receive an educational programme or to a control group to receive usual care. Randomization was stratified by previous treatment history. The primary outcome was HRQoL, assessed by scoring the Skindex-29 domains emotion, symptom, and functioning. Psoriasis severity was assessed using the psoriasis area severity index (PASI). Levels of perceived stress, patient knowledge about psoriasis, and patient satisfaction were also assessed. Follow-up evaluations were performed at 3, 6, and 12 months. RESULTS: A total 142 patients formed the intention-to-treat population: 70 in the control group and 72 in the intervention group. Skindex component scores and the PASI were significantly lower at 3, 6, and 12 months as compared to baseline in both groups, but no significant differences were found between the groups. Knowledge about psoriasis improved significantly during follow-up amongst patients from the intervention group compared to controls (68% of correct answers vs. 56%; p < 0.01). Patient satisfaction with psoriasis management and treatment was also better in the intervention group. CONCLUSIONS: The standardised education programme did not improve HRQoL and disease severity in psoriasis, but led to a significant improvement in patient knowledge about the disease and increased patient satisfaction.

Impact of Childhood Onset Psoriasis on Addictive Behaviours, Socioeconomic and Educational Data in Adulthood.

Paediatric psoriasis has been associated with school absenteeism, limitation of physical activities, psychiatric disorders and, in the longer term, with sexual dysfunction and addictions. This raises the hypothesis that childhood onset psoriasis may affect patients' educational development, and further social and professional outcomes. This study evaluated the relationship between childhood onset psoriasis and patients' educational and socioeconomic characteristics, and the development of addictions in adulthood. This cross-sectional ancillary study captured patients' characteristics at baseline in the French PSOBIOTEQ registry. Data in adulthood included: educational (baccalaureate) and socioeconomic (working activity) groups, smoking status (self-reporting of being a current smoker vs past smoker or non-smoker), alcohol consumption (defined as at least 1 glass of alcoholic beverage per day), and living conditions (alone/family/social institutions; child at home). A total of 1,960 patients were included, of whom 26.2% had childhood onset psoriasis. In multivariate analyses, childhood onset psoriasis was associated with smoker status (p = 0.02). No association was observed with educational level, working activity, living conditions, or alcohol consumption. This study provides reassuring data overall with regard to the impact of childhood onset psoriasis on major social outcomes. Evidence for some association with addictive behaviours paves the way for larger prospective studies assessing in depth the social and educational impact of this disease.

Evolution of Drug Survival with Biological Agents and Apremilast Between 2012 and 2018 in Patients with Psoriasis from the PsoBioTeq Cohort.

Drug survival reflects treatment effectiveness and safety in real life. There is limited data on the variation of drug survival with the availability of systemic treatments with additional biological disease-modifying antirheumatic drugs (bDMARDs) or synthetic disease-modifying antirheumatic drugs (sDMARDs). The aim of this study was to determine whether the increasing number of available systemic treatments for psoriasis affects drug survival over time. Patients were selected from the PsoBioTeq cohort, a French prospective observational cohort enrolling patients with moderate to severe psoriasis. All patients initiating a first bDMARD or sDMARD were included. The primary outcome was comparison of drug survival over time. A multivariate Cox proportional hazard ratio model was computed. A total of 1,866 patients were included; 739 females (39%), median age 47 years. In the multivariate Cox model, no association was found between the calendar year of initiation and drug survival (hazard ratio) overlapping from 0.80 (0.42-1.52) to 1.17 (0.64-2.17), p = 0.633). In conclusion, drug survival in psoriasis is not affected by the year of initiation.

Factors associated with adverse COVID-19 outcomes in patients with psoriasis-insights from a global registry-based study.

BACKGROUND: The multimorbid burden and use of systemic immunosuppressants in people with psoriasis may confer greater risk of adverse outcomes of coronavirus disease 2019 (COVID-19), but the data are limited. OBJECTIVE: Our aim was to characterize the course of COVID-19 in patients with psoriasis and identify factors associated with hospitalization. METHODS: Clinicians reported patients with psoriasis with confirmed/suspected COVID-19 via an international registry, Psoriasis Patient Registry for Outcomes, Therapy and Epidemiology of COVID-19 Infection. Multiple logistic regression was used to assess the association between clinical and/or demographic characteristics and hospitalization. A separate patient-facing registry characterized risk-mitigating behaviors. RESULTS: Of 374 clinician-reported patients from 25 countries, 71% were receiving a biologic, 18% were receiving a nonbiologic, and 10% were not receiving any systemic treatment for psoriasis. In all, 348 patients (93%) were fully recovered from COVID-19, 77 (21%) were hospitalized, and 9 (2%) died. Increased hospitalization risk was associated with older age (multivariable-adjusted odds ratio [OR] = 1.59 per 10 years; 95% CI = 1.19-2.13), male sex (OR = 2.51; 95% CI = 1.23-5.12), nonwhite ethnicity (OR = 3.15; 95% CI = 1.24-8.03), and comorbid chronic lung disease (OR = 3.87; 95% CI = 1.52-9.83). Hospitalization was more frequent in patients using nonbiologic systemic therapy than in those using biologics (OR = 2.84; 95% CI = 1.31-6.18). No significant differences were found between classes of biologics. Independent patient-reported data (n = 1626 across 48 countries) suggested lower levels of social isolation in individuals receiving nonbiologic systemic therapy than in those receiving biologics (OR = 0.68; 95% CI = 0.50-0.94). CONCLUSION: In this international case series of patients with moderate-to-severe psoriasis, biologic use was associated with lower risk of COVID-19-related hospitalization than with use of nonbiologic systemic therapies; however, further investigation is warranted on account of potential selection bias and unmeasured confounding. Established risk factors (being older, being male, being of nonwhite ethnicity, and having comorbidities) were associated with higher hospitalization rates.

Baseline Characteristics of a National French E-Cohort of Hidradenitis Suppurativa in ComPaRe and Comparison with Other Large Hidradenitis Suppurativa Cohorts.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition substantially impacting patients' quality of life; the pathogenesis remains unclear, and treatment is complex and not yet standardized. Observational data are increasingly being used to evaluate therapeutics in "real-life" interventions, and the development of e-cohorts is offering new tools for epidemiological studies at the population level. OBJECTIVE: The aim of this study was to describe the clinical characteristics and treatment history of HS participants in the Community of Patients for Research (ComPaRe) cohort and to compare these to other cohorts. METHODS: We performed a cross-sectional study of the baseline data of HS participants in ComPaRe, an e-cohort of patients with chronic diseases. Data were collected using patient-reported questionnaires about clinical-dem-ographic aspects, quality of life, and treatment history. RESULTS: A total of 396 participants (339 females, 57 males) were included (mean age 38 years); 83 (21%) had a family history of HS, 227 (57.3%) were current smokers, and 241 (60.9%) were overweight or obese. Most of the participants declared a Hurley stage II (n = 263, 66.4%) or III (n = 76, 20.3%). The breast was more frequently affected in women than men (37.5 vs. 5.3%, p < 0.0001), whereas the dorsal region was more frequently affected in men (39.5 vs. 10.9%, p < 0.0001). Increased disease stage was associated with obesity (25.9 vs. 33.8 vs. 51.3%, p = 0.02) and some HS localizations (genital [p < 0.005], pubis [p < 0.007], gluteal fold [p = 0.02], and groin [p < 0.0001]). The most frequently prescribed treatments were oral antibiotics (n = 362, 91.4%), especially amoxicillin-clavulanic acid and cyclins. Less than 10% of participants received biologics. Most of these results were consistent with previously published cohorts. CONCLUSION: Recruitment of participants by such a web platform can be a faster way to get relevant scientific data for a wide variety of patients that could be used for epidemiological studies and to evaluate therapeutics in "real-life" interventions.

First-Line Biologic Therapy and Obesity in Moderate-to-Severe Psoriasis: Results from the Prospective Multicenter Cohort Psobioteq.

BACKGROUND: Obesity is associated with an increased risk of psoriasis. OBJECTIVE: In this study, we examined whether body mass index (BMI) is taken into account when choosing first-line biologic therapy for psoriasis. METHODS: In this cohort study, we compared obese (BMI ≥30 kg/m2) and non-obese patients for the first-line biologic therapy prescribed, its survival, reasons for discontinuation, therapy optimization, co-prescription of methotrexate and factors associated with long drug survival. RESULTS: A total of 931 patients were included: 594 (64%) were male, median age was 46 years (interquartile range 36-56). The most-prescribed biologic agents as first-line treatment were adalimumab (ADA; 42.7%), ustekinumab (UST; 29.9%) and etanercept (ETA; 22.9%); only frequency of infliximab (IFX) prescription differed between groups. Drug survival was significantly shorter for obese than non-obese patients (p < 2.10-4) and was worse for obese than non-obese patients for UST (p = 0.009) and ETA (p = 0.02), with no difference for ADA (p = 0.11). The main reason for discontinuation was primary inefficacy (62%), which was more frequent in obese than non-obese patients. The cumulative incidence of optimization did not significantly differ between the groups, except for ADA (SHR 1.91, 95% CI [1.23-2.96], p = 0.005). On multivariate analysis, risk of discontinuation was associated with only ETA as first-line biologic therapy (HR 1.51, 95% CI 1.04-2.19). CONCLUSION: This study highlighted the lack of difference in prescription of first-line biologic treatment, except for IFX, between obese and non-obese patients presenting moderate-to-severe psoriasis. Drug survival in obese patients is shorter, mainly because of inefficacy, than in non-obese patients. This highlights the need for targeted pharmacological studies in obese individuals to find optimal administration schemes.

Pustular Psoriasis and Associated Musculoskeletal Disorders.

Pustular psoriasis (PsO) is an uncommon variant of PsO that may present in a generalized or localized fashion with or without musculoskeletal or systemic inflammatory involvement.Generalized pustular PsO (GPP) presents as a widespread acute or subacute pustular eruption that may be familial and is often associated with severe flares and systemic inflammation. The palmoplantar pustulosis variant is localized to palms and soles, whereas acrodermatitis continua of Hallopeau is localized to the nail apparatus. Patients with pustular PsO may have overlapping plaque PsO and may develop psoriatic arthritis (PsA). Pustulosis is also a feature of both synovitis, acne, pustulosis, hyperostosis, osteomyelitis (SAPHO) syndrome and chronic non-bacterial osteomyelitis. At the 2020 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting, members were given an overview of the cutaneous features of pustular PsO, SAPHO, and recent insights into the genetics of GPP, leading to new targeted drug therapies and the development of validated endpoints.

Long-term efficacy and safety of brodalumab in the treatment of psoriasis: 120-week results from the randomized, double-blind, placebo- and active comparator-controlled phase 3 AMAGINE-2 trial.

BACKGROUND: Randomized controlled trials have shown the efficacy and safety of brodalumab in patients with moderate to severe plaque psoriasis. OBJECTIVE: To evaluate the efficacy and safety of brodalumab through 120 weeks of treatment in the AMAGINE-2 trial. METHODS: Patients received ustekinumab through week 52 followed by brodalumab 210 mg every 2 weeks, continuous brodalumab 210 mg every 2 weeks, or any dose of brodalumab. Efficacy data were reported through 120 weeks by using observed data, last observation carried forward, and nonresponder imputation analyses. RESULTS: Of patients who received brodalumab 210 mg every 2 weeks, 84.4%, 75.6%, and 61.1% achieved 75%, 90%, and 100% improvement from baseline in Psoriasis Area and Severity Index at 120 weeks (observed data analysis), respectively. Patients who received brodalumab 210 mg every 2 weeks after receiving ustekinumab through 52 weeks achieved a similar skin clearance response as patients who received continuous brodalumab 210 mg every 2 weeks. Safety through 120 weeks was comparable to that of the blinded study periods. LIMITATIONS: A large number of discontinuations toward the end of the study (31% in the final 6 months) were due to early termination and led to differences between observed data and nonresponder imputation results. CONCLUSIONS: Brodalumab is well tolerated and showed robust efficacy for more than 2 years.

Efficacy and safety of risankizumab in moderate-to-severe plaque psoriasis (UltIMMa-1 and UltIMMa-2): results from two double-blind, randomised, placebo-controlled and ustekinumab-controlled phase 3 trials.

BACKGROUND: Risankizumab is a humanised IgG1 monoclonal antibody that binds to the p19 subunit of interleukin-23, inhibiting this key cytokine and its role in psoriatic inflammation. We aimed to assess the efficacy and safety of risankizumab compared with placebo or ustekinumab in patients with moderate-to-severe chronic plaque psoriasis. METHODS: UltIMMa-1 and UltIMMa-2 were replicate phase 3, randomised, double-blind, placebo-controlled and active comparator-controlled trials done at 139 sites in Australia, Austria, Belgium, Canada, Czech Republic, France, Germany, Japan, Mexico, Poland, Portugal, South Korea, Spain, and the USA. Eligible patients were 18 years or older, with moderate-to-severe chronic plaque psoriasis. In each study, patients were stratified by weight and previous exposure to tumour necrosis factor inhibitor and randomly assigned (3:1:1) by use of interactive response technology to receive 150 mg risankizumab, 45 mg or 90 mg ustekinumab (weight-based per label), or placebo. Following the 16-week double-blind treatment period (part A), patients initially assigned to placebo switched to 150 mg risankizumab at week 16; other patients continued their originally randomised treatment (part B, double-blind, weeks 16-52). Study drug was administered subcutaneously at weeks 0 and 4 during part A and at weeks 16, 28, and 40 during part B. Co-primary endpoints were proportions of patients achieving a 90% improvement in the Psoriasis Area Severity Index (PASI 90) and a static Physician's Global Assessment (sPGA) score of 0 or 1 at week 16 (non-responder imputation). All efficacy analyses were done in the intention-to-treat population. These trials are registered with ClinicalTrials.gov, numbers NCT02684370 (UltIMMa-1) and NCT02684357 (UltIMMa-2), and have been completed. FINDINGS: Between Feb 24, 2016, and Aug 31, 2016, 506 patients in UltIMMa-1 were randomly assigned to receive 150 mg risankizumab (n=304), 45 mg or 90 mg ustekinumab (n=100), or placebo (n=102). Between March 1, 2016, and Aug 30, 2016, 491 patients in UltIMMa-2 were randomly assigned to receive 150 mg risankizumab (n=294), 45 mg or 90 mg ustekinumab (n=99), or placebo (n=98). Co-primary endpoints were met for both studies. At week 16 of UltIMMa-1, PASI 90 was achieved by 229 (75·3%) patients receiving risankizumab versus five (4·9%) receiving placebo (placebo-adjusted difference 70·3% [95% CI 64·0-76·7]) and 42 (42·0%) receiving ustekinumab (ustekinumab-adjusted difference 33·5% [22·7-44·3]; p<0·0001 vs placebo and ustekinumab). At week 16 of UltIMMa-2, PASI 90 was achieved by 220 (74·8%) patients receiving risankizumab versus two (2·0%) receiving placebo (placebo-adjusted difference 72·5% [95% CI 66·8-78·2]) and 47 (47·5%) receiving ustekinumab (ustekinumab-adjusted difference 27·6% [16·7-38·5]; p<0·0001 vs placebo and ustekinumab). In UltIMMa-1, sPGA 0 or 1 at week 16 was achieved by 267 (87·8%) patients receiving risankizumab versus eight (7·8%) receiving placebo (placebo-adjusted difference 79·9% [95% CI 73·5-86·3]) and 63 (63·0%) receiving ustekinumab (ustekinumab-adjusted difference 25·1% [15·2-35·0]; p<0·0001 vs placebo and ustekinumab). In UltIMMa-2, 246 (83·7%) patients receiving risankizumab versus five (5·1%) receiving placebo (placebo-adjusted difference 78·5% [95% CI 72·4-84·5]) and 61 (61·6%) receiving ustekinumab achieved sPGA 0 or 1 at week 16 (ustekinumab-adjusted difference 22·3% [12·0-32·5]; p<0·0001 vs placebo and ustekinumab). The frequency of treatment-emergent adverse events in UltIMMa-1 and UltIMMa-2 was similar across risankizumab (part A: 151 [49·7%] of 304 and 134 [45·6%] of 294; part B: 182 [61·3%] of 297 and 162 [55·7%] of 291), placebo (part A: 52 [51·0%] of 102 and 45 [45·9%] of 98), ustekinumab (part A: 50 [50·0%] of 100 and 53 [53·5%] of 99; part B: 66 [66·7%] of 99 and 70 [74·5%] of 94), and placebo to risankizumab (part B: 65 [67·0%] of 97 and 61 [64·9%] of 94) treatment groups throughout the study duration. INTERPRETATION: Risankizumab showed superior efficacy to both placebo and ustekinumab in the treatment of moderate-to-severe plaque psoriasis. Treatment-emergent adverse event profiles were similar across treatment groups and there were no unexpected safety findings. FUNDING: AbbVie and Boehringer Ingelheim.

Mutation in IL36RN impairs the processing and regulatory function of the interleukin-36-receptor antagonist and is associated with DITRA syndrome.

The identification of loss-of-function mutations of the IL36RN gene encoding the interleukin-36 receptor antagonist (IL-36Ra) in generalized pustular psoriasis (GPP) emphasized the key role of this pathway in skin innate immunity and systemic inflammation. It has been previously shown in vitro that removal of the N-terminal amino acid IL36Ra (M1) is critical to its biological activity, but the in vivo contribution of this processing remains unknown. We report herein a new homozygous (c4G>T, pV2F) missense IL36RN mutation segregating in a family with three GPP-affected patients. The V2F mutation does not alter IL-36Ra protein expression but was devoid of any antagonist activity. Mass spectrometry showed that the V2F IL-36Ra mutant retains its first N-terminal methionine. These results provide the first in vivo demonstration that removal of N-terminal methionine of native IL-36Ra is a mandatory step to reach optimal antagonist activity and to prevent sustained skin and systemic inflammation in humans.