Efficacy and safety of delgocitinib cream in adults with moderate to severe chronic hand eczema (DELTA 1 and DELTA 2): results from multicentre, randomised, controlled, double-blind, phase 3 trials.

BACKGROUND: Chronic hand eczema is a fluctuating, inflammatory, pruritic, often painful disease of hands and wrists that strongly impacts quality of life and occupational capabilities of patients. The aim of phase 3 DELTA 1 and DELTA 2 was to assess the efficacy and safety of twice-daily applications of the topical pan-Janus kinase inhibitor delgocitinib cream 20 mg/g versus cream vehicle in adults with moderate to severe chronic hand eczema. METHODS: Both trials were randomised, double-blinded, and vehicle-controlled, with DELTA 1 being conducted at 53 trial centres in Canada, France, Germany, Italy, Poland, and the UK and DELTA 2 at 50 trial centres in Belgium, Canada, Denmark, Germany, the Netherlands, Poland, and Spain. Adults (aged ≥18 years) with moderate to severe chronic hand eczema were randomly assigned 2:1 to twice-daily delgocitinib cream 20 mg/g or cream vehicle for 16 weeks. The primary endpoint was Investigator's Global Assessment for Chronic Hand Eczema (IGA-CHE) treatment success at week 16, defined as IGA-CHE score of 0 (clear) or 1 (almost clear, defined as only barely perceptible erythema). Efficacy and safety were assessed in all patients who were exposed to trial treatment. These trials are registered with ClinicalTrials.gov, NCT04871711 and NCT04872101. FINDINGS: Between May 10, 2021, and Oct 31, 2022, 487 patients (181 male and 306 female) were enrolled in DELTA 1; between May 25, 2021, and Jan 6, 2023, 473 patients (161 male and 312 female) were enrolled in DELTA 2. 325 patients in DELTA 1 and 314 in DELTA 2 were assigned to delgocitinib cream; 162 patients in DELTA 1 and 159 in DELTA 2 were assigned to cream vehicle. At week 16, a greater proportion of delgocitinib-treated patients versus cream vehicle patients had IGA-CHE treatment success (64 [20%] of 325 vs 16 [10%] of 162 in DELTA 1 and 91 [29%] of 313 vs 11 [7%] of 159 in DELTA 2; both trials p≤0·0055). The proportion of patients who reported adverse events was similar with delgocitinib (147 [45%] of 325 in DELTA 1 and 143 [46%] of 313 in DELTA 2) and the cream vehicle (82 [51%] of 162 in DELTA 1 and 71 [45%] of 159 in DELTA 2). Most frequent adverse events occurring in at least 2% of patients were similar in both treatment groups and included COVID-19 and nasopharyngitis. INTERPRETATION: Overall, delgocitinib cream showed superior efficacy versus cream vehicle and was well tolerated over 16 weeks. These results support the clinical benefit of delgocitinib cream as a potential treatment option for patients with moderate to severe chronic hand eczema, who are unable to adequately control their disease with basic skin care practices and topical corticosteroids. FUNDING: LEO Pharma.

A genome-wide meta-analysis of palmoplantar pustulosis implicates TH2 responses and cigarette smoking in disease pathogenesis.

BACKGROUND: Palmoplantar pustulosis (PPP) is an inflammatory skin disorder that mostly affects smokers and manifests with painful pustular eruptions on the palms and soles. Although the disease can present with concurrent plaque psoriasis, TNF and IL-17/IL-23 inhibitors show limited efficacy. There is therefore a pressing need to uncover PPP disease drivers and therapeutic targets. OBJECTIVES: We sought to identify genetic determinants of PPP and investigate whether cigarette smoking contributes to disease pathogenesis. METHODS: We performed a genome-wide association meta-analysis of 3 North-European cohorts (n = 1,456 PPP cases and 402,050 controls). We then used the scGWAS program to investigate the cell-type specificity of the association signals. We also undertook genetic correlation analyses to examine the similarities between PPP and other immune-mediated diseases. Finally, we applied Mendelian randomization to analyze the causal relationship between cigarette smoking and PPP. RESULTS: We found that PPP is not associated with the main genetic determinants of plaque psoriasis. Conversely, we identified genome-wide significant associations with the FCGR3A/FCGR3B and CCHCR1 loci. We also observed 13 suggestive (P < 5 × 10-6) susceptibility regions, including the IL4/IL13 interval. Accordingly, we demonstrated a significant genetic correlation between PPP and TH2-mediated diseases such as atopic dermatitis and ulcerative colitis. We also found that genes mapping to PPP-associated intervals were preferentially expressed in dendritic cells and often implicated in T-cell activation pathways. Finally, we undertook a Mendelian randomization analysis, which supported a causal role of cigarette smoking in PPP. CONCLUSIONS: The first genome-wide association study of PPP points to a pathogenic role for deregulated TH2 responses and cigarette smoking.

Bimekizumab in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α inhibitors: a randomised, double-blind, placebo-controlled, phase 3 trial (BE COMPLETE).

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A. This study compared the efficacy and safety of bimekizumab with placebo over 16 weeks in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α (TNFα) inhibitors. METHODS: BE COMPLETE was a phase 3, multicentre, randomised, double-blind, placebo-controlled trial conducted across 92 sites (including hospitals, clinics, and research centres) in 11 countries (Australia, Canada, Czech Republic, Germany, Hungary, Italy, Japan, Poland, Russia, the UK, and the USA). Eligible patients were aged 18 years or older with adult-onset psoriatic arthritis (meeting the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening) with a history of inadequate response or intolerance to treatment with one or two TNFα inhibitors for either psoriatic arthritis or psoriasis. We stratified patients with active psoriatic arthritis by region and previous TNFα inhibitor use. Patients were randomly assigned (2:1) to receive subcutaneous bimekizumab 160 mg every 4 weeks or placebo by an interactive-voice and web-response system on the basis of a predetermined randomisation schedule. The primary endpoint was the proportion of patients with 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses were done in the randomised population. The safety analysis set comprised patients who received one or more doses of study treatment. This trial was registered at ClinicalTrials.gov, NCT03896581, and is completed. FINDINGS: Between March 28, 2019, and Feb 14, 2022, 556 patients were screened and 400 patients were randomly assigned to bimekizumab 160 mg every 4 weeks (n=267) or placebo (n=133). The primary and all hierarchical secondary endpoints were met at week 16. 116 (43%) of 267 patients receiving bimekizumab reached ACR50, compared with nine (7%) of 133 patients receiving placebo (adjusted odds ratio [OR] 11·1 [95% CI 5·4-23·0], p<0·0001). 121 (69%) of 176 patients with psoriasis affecting at least 3% body surface area at baseline who received bimekizumab reached 90% or greater improvement in the Psoriasis Area and Severity Index (PASI90), compared with six (7%) of 88 patients who received placebo (adjusted OR 30·2 [12·4-73·9], p<0·0001). Treatment-emergent adverse events up to week 16 were reported in 108 (40%) of 267 patients receiving bimekizumab and 44 (33%) of 132 patients receiving placebo. There were no new safety signals and no deaths. INTERPRETATION: Bimekizumab treatment led to superior improvements in joint and skin efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis and inadequate response or intolerance to TNFα inhibitors. The safety profile of bimekizumab was consistent with previous phase 3 studies in patients with plaque psoriasis, and studies of IL-17A inhibitors. FUNDING: UCB Pharma.

Bimekizumab in patients with psoriatic arthritis, naive to biologic treatment: a randomised, double-blind, placebo-controlled, phase 3 trial (BE OPTIMAL).

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17A and IL-17F. We assessed the efficacy and safety of bimekizumab in patients with active psoriatic arthritis who were naive to biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: BE OPTIMAL was a 52-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, active reference (adalimumab) trial done at 135 sites (hospitals, clinics, doctors' offices, and research centres) in 14 countries. Eligible patients were 18 years or older with a documented diagnosis of adult-onset psoriatic arthritis that met the Classification Criteria for Psoriatic Arthritis for at least 6 months before screening. Participants were randomly assigned with an interactive-voice and web-response system on the basis of a predetermined randomisation schedule (3:2:1, stratified by region and bone erosion number at baseline) to bimekizumab 160 mg every 4 weeks, placebo every 2 weeks, or the reference group (adalimumab 40 mg every 2 weeks), all administered subcutaneously. At week 16, patients randomly assigned to placebo switched to bimekizumab 160 mg every 4 weeks. The primary endpoint was the proportion of patients reaching 50% or greater improvement in American College of Rheumatology criteria (ACR50) at week 16 (non-responder imputation). Efficacy analyses included all patients who were randomly assigned (intention-to-treat population); the safety analysis set comprised patients who received one or more doses of treatment. Data are presented to week 24 (preplanned analysis). This trial is registered at ClinicalTrials.gov, NCT03895203. FINDINGS: Between April 3, 2019, and Oct 25, 2021, 1163 patients were screened and 852 were randomly assigned to bimekizumab (n=431), placebo (n=281), and reference (adalimumab; n=140) groups. At week 16, significantly more patients receiving bimekizumab (189 [44%] of 431) reached ACR50 response versus placebo (28 [10%] of 281; odds ratio 7·1 [95% CI 4·6-10·9], p<0·0001; adalimumab 64 [46%] of 140). All secondary hierarchical endpoints were met. Treatment-emergent adverse events up to week 16 were reported in 258 [60%] of 431 patients receiving bimekizumab, 139 [49%] of 281 patients receiving placebo, and 83 [59%] of 140 patients receiving adalimumab. No deaths occurred. INTERPRETATION: Bimekizumab treatment had superior improvements in joint, skin, and radiographic efficacy outcomes at week 16 compared with placebo in patients with psoriatic arthritis who were naive to biologic DMARDs. The safety profile of bimekizumab, including the occurrence of fungal infections, was consistent with previous phase 3 studies in patients with plaque psoriasis, and with IL-17A inhibitors. FUNDING: UCB Pharma.

Bimekizumab versus Adalimumab in Plaque Psoriasis.

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin-17A and interleukin-17F. The efficacy and safety of bimekizumab as compared with the tumor necrosis factor inhibitor adalimumab in patients with moderate-to-severe plaque psoriasis have not been extensively examined. METHODS: We randomly assigned patients with moderate-to-severe plaque psoriasis in a 1:1:1 ratio to receive subcutaneous bimekizumab at a dose of 320 mg every 4 weeks for 56 weeks; bimekizumab at a dose of 320 mg every 4 weeks for 16 weeks, then every 8 weeks for weeks 16 to 56; or subcutaneous adalimumab at a dose of 40 mg every 2 weeks for 24 weeks, followed by bimekizumab at a dose of 320 mg every 4 weeks to week 56. The primary end points were a 90% or greater reduction from baseline in the Psoriasis Area and Severity Index (PASI) score (PASI 90 response; PASI scores range from 0 to 72, with higher scores indicating worse disease) and an Investigator's Global Assessment (IGA) score of 0 or 1, signifying clear or almost clear skin (scores range from 0 [clear skin] to 4 [severe disease]), at week 16. The analysis of the primary end points tested noninferiority at a margin of -10 percentage points and then tested for superiority. RESULTS: A total of 614 patients were screened, and 478 were enrolled; 158 patients were assigned to receive bimekizumab every 4 weeks, 161 to receive bimekizumab every 4 weeks and then every 8 weeks, and 159 to receive adalimumab. The mean age of the patients was 44.9 years; the mean PASI score at baseline was 19.8. At week 16, a total of 275 of 319 patients (86.2%) who received bimekizumab (both dose groups combined) and 75 of 159 (47.2%) who received adalimumab had a PASI 90 response (adjusted risk difference, 39.3 percentage points; 95% confidence interval [CI], 30.9 to 47.7; P<0.001 for noninferiority and superiority). A total of 272 of 319 patients (85.3%) who received bimekizumab and 91 of 159 (57.2%) who received adalimumab had an IGA score of 0 or 1 (adjusted risk difference, 28.2 percentage points; 95% CI, 19.7 to 36.7; P<0.001 for noninferiority and superiority). The most common adverse events with bimekizumab were upper respiratory tract infections, oral candidiasis (predominantly mild or moderate as recorded by the investigator), hypertension, and diarrhea. CONCLUSIONS: In this 56-week trial, bimekizumab was noninferior and superior to adalimumab through 16 weeks in reducing symptoms and signs of plaque psoriasis but was associated with a higher frequency of oral candidiasis and diarrhea. Longer and larger trials are required to determine the efficacy and safety of bimekizumab as compared with other agents in the treatment of plaque psoriasis. (Funded by UCB Pharma; BE SURE ClinicalTrials.gov number, NCT03412747.).

Bimekizumab versus Secukinumab in Plaque Psoriasis.

BACKGROUND: Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits both interleukin-17A and interleukin-17F. The efficacy and safety of bimekizumab as compared with secukinumab, which selectively inhibits interleukin-17A alone, in patients with moderate-to-severe plaque psoriasis have not been extensively examined. METHODS: In this phase 3b trial, we randomly assigned patients with moderate-to-severe plaque psoriasis, in a 1:1 ratio, to receive bimekizumab subcutaneously at a dose of 320 mg every 4 weeks or secukinumab subcutaneously at a dose of 300 mg weekly to week 4, followed by every 4 weeks to week 48. At week 16, patients receiving bimekizumab underwent rerandomization, in a 1:2 ratio, to receive maintenance dosing every 4 weeks or every 8 weeks to week 48. The primary end point was 100% reduction from baseline in the Psoriasis Area and Severity Index (PASI) score at week 16. The primary analysis was first tested for the noninferiority of bimekizumab to secukinumab at a margin of -10 percentage points and then tested for superiority. RESULTS: A total of 1005 patients were screened and 743 were enrolled; 373 patients were assigned to receive bimekizumab and 370 to receive secukinumab. At week 16, a total of 230 patients (61.7%) in the bimekizumab group and 181 (48.9%) in the secukinumab group had a 100% reduction from baseline in the PASI score (PASI 100) (adjusted risk difference, 12.7 percentage points; 95% confidence interval [CI], 5.8 to 19.6); bimekizumab was shown to be noninferior and superior to secukinumab (P<0.001 for noninferiority and superiority). At week 48, a total of 250 patients (67.0%) treated with bimekizumab had a PASI 100 response, as compared with 171 patients (46.2%) treated with secukinumab (adjusted risk difference, 20.9 percentage points; 95% CI, 14.1 to 27.7; P<0.001). At the week 4 time point, 265 patients (71.0%) in the bimekizumab group had 75% or greater reduction from baseline in the PASI score, as compared with 175 patients (47.3%) in the secukinumab group (adjusted risk difference, 23.7; 95% CI, 17.0 to 30.4; P<0.001). Oral candidiasis occurred more often with bimekizumab (72 patients, 19.3%) than with secukinumab (11 patients, 3.0%). CONCLUSIONS: In patients with moderate-to-severe psoriasis, treatment with bimekizumab resulted in greater skin clearance than treatment with secukinumab over 16 and 48 weeks but was associated with oral candidiasis (predominantly mild or moderate as recorded by the investigator). Longer and larger trials are required to determine the comparative effect and risks of interleukin-17 inhibitors in psoriasis. (Funded by UCB Pharma; BE RADIANT ClinicalTrials.gov number, NCT03536884.).

IL23R mutations associated with decreased risk of psoriasis lead to the differential expression of genes implicated in the disease.

Psoriasis is an incurable immune-mediated skin disease, affecting around 1%-3% of the population. Various lines of evidence implicate IL23 as being pivotal in disease. Genetic variants within the IL23 receptor (IL23R) increase the risk of developing psoriasis, and biologic therapies specifically targeting IL23 demonstrated high efficacy in treating disease. IL23 acts via the IL23R, signalling through the STAT3 pathway, mediating the cascade of events that ultimately results in the clinical presentation of psoriasis. Given the essential role of IL23R in disease, it is important to understand the impact of genetic variants on receptor function with respect to downstream gene regulation. Here we developed model systems in CD4+ (Jurkat) and CD8+ (MyLa) T cells to express either the wild type risk or mutant (R381Q) protective form of IL23R. After confirmation that the model system expressed the genes/proteins and had a differential effect on the phosphorylation of STAT3, we used RNAseq to explore differential gene regulation, in particular for genes implicated with risk to psoriasis, at a single time point for both cell types, and in a time course experiment for Jurkat CD4+ T cells. These experiments discovered differentially regulated genes in the cells expressing wild type and mutant IL23R, including HLA-B, SOCS1, RUNX3, CCR5, CXCR3, CCR9, KLF3, CD28, IRF, SOCS6, TNFAIP and ICAM5, that have been implicated in both the IL23 pathway and psoriasis. These genes have the potential to define a IL23/psoriasis pathway in disease, advancing our understanding of the biology behind the disease.

Prevalence, incidence, mortality and healthcare resource use for generalized pustular psoriasis, palmoplantar pustulosis and plaque psoriasis in England: a population-based cohort study.

BACKGROUND: Generalized pustular psoriasis (GPP) and palmoplantar pustulosis (PPP) are chronic inflammatory skin conditions. Accumulating evidence shows that GPP and PPP have different characteristics to plaque psoriasis and are distinct clinical entities. OBJECTIVES: To assess the epidemiology, comorbidities, mortality and healthcare use for patients in England with GPP and PPP versus those with plaque psoriasis. METHODS: We carried out a cohort study involving analyses of longitudinal electronic health record data in the Clinical Practice Research Datalink Aurum database and linked hospital and mortality data between 2008 and 2019. The primary study outcome was the incidence and prevalence rates of GPP, PPP and plaque psoriasis in England. Secondary outcomes included survival rates and healthcare resource use (HCRU) by disease type. RESULTS: We identified 373 patients with GPP, 1828 with PPP and 224 223 with plaque psoriasis. Mean (SD) age was 55.9 (18.6) years for patients with GPP, 51.5 (16.4) years for those with PPP and 48.5 (19.1) years for those with plaque psoriasis; 62.5% and 65.9% of patients with GPP and PPP, respectively, were women, vs. 49.4% of those with plaque psoriasis. About half of patients were overweight or obese at baseline (GPP 48.6%, PPP 56.0%, plaque psoriasis 45.9%). The incidence rates for GPP, PPP and plaque psoriasis were 0.25 [95% confidence interval (CI) 0.21-0.28], 2.01 (95% CI 1.92-2.11) and 103.2 (95% CI 102.5-103.9) per 100 000 person-years, respectively. From 2008 to 2019, the prevalence rates per 100 000 persons ranged from 1.61 to 3.0 for GPP, from 1.1 to 18.7 for PPP and from 1771.0 to 1903.8 for plaque psoriasis. Survival rates were lower for patients with GPP, particularly those who were > 55 years of age and those with a history of one or more comorbidities in each cohort. HCRU was lower in the cohort with plaque psoriasis and highest in the cohort with GPP, particularly among those who had more than one GPP flare. CONCLUSIONS: Our results provide further evidence that, in England, GPP is a distinct disease with different epidemiology, lower survival and higher HCRU than plaque psoriasis.

There are several different forms of the inflammatory skin disease called psoriasis. Plaque psoriasis is characterized by flaky or scaly patches of skin. Generalized pustular psoriasis ('GPP') causes red skin and painful pustules. Palmoplantar pustulosis ('PPP') affects the palms and soles. In this study, we used electronic health record data from general practices that contribute to a database in England called the Clinical Practice Research Datalink (CPRD). We did this to find out how common plaque psoriasis, GPP and PPP are in England and understand how people use healthcare services. The number of patients with these conditions increased between 2008 and 2019. In 2019, the most frequent condition was plaque psoriasis, followed by PPP and GPP. Among people with GPP, 3 out of 5 were women, 7 out of 10 also had a diagnosis of plaque ­psoriasis and 7 out of 10 had other illnesses. Among people with PPP, about 2 out of 3 were women, 1 out of 3 also had a diagnosis of plaque psoriasis and 2 out of 3 had other illnesses. Overall survival was lowest for people with GPP, particularly those who were older than 55 years of age and those with other illnesses. We found that a higher proportion of patients with GPP were admitted to hospital and visited A&E than those with PPP or plaque psoriasis. These patients also had more outpatient and A&E visits every year. Our results suggest that GPP has a different epidemiology than plaque psoriasis, and patients with GPP use more healthcare services and have a higher mortality rate.

Epidermal growth factor receptor/mitogen-activated kinase inhibitor treatment induces a distinct inflammatory hair follicle response that includes collapse of immune privilege.

BACKGROUND: Inhibitors of epidermal growth factor receptor (EGFRi) or mitogen-activated kinase (MEKi) induce a folliculitis in 75-90% of patients, the pathobiology of which remains insufficiently understood. OBJECTIVES: To characterize changes in the skin immune status and global transcriptional profile of patients treated with EGFRi; to investigate whether EGFRi affects the hair follicle's (HF) immune privilege (IP); and to identify early proinflammatory signals induced by EGFRi/MEKi in human scalp HFs ex vivo. METHODS: Scalp biopsies were taken from patients exhibiting folliculitis treated long term with EGFRi ('chronic EGFRi' group, n = 9) vs. healthy scalp skin (n = 9) and patients prior to commencing EGFRi treatment and after 2 weeks of EGFRi therapy ('acute EGFRi' group, n = 5). Healthy organ-cultured scalp HFs were exposed to an EGFRi (erlotinib, n = 5) or a MEKi (cobimetinib, n = 5). Samples were assessed by quantitative immunohistomorphometry, RNA sequencing (RNAseq) and in situ hybridization. RESULTS: The 'chronic EGFRi' group showed CD8+ T-cell infiltration of the bulge alongside a partial collapse of the HF's IP, evidenced by upregulated major histocompatibility complex (MHC) class I, ß2-microglobulin (B2 M) and MHC class II, and decreased transforming growth factor-ß1 protein expression. Healthy HFs treated with EGFRi/MEKi ex vivo also showed partial HF IP collapse and increased transcription of human leucocyte antigen (HLA)-A, HLA-DR and B2 M transcripts. RNAseq analysis showed increased transcription of chemokines (CXCL1, CXCL13, CCL18, CCL3, CCL7) and interleukin (IL)-26 in biopsies from the 'chronic EGFRi' cohort, as well as increased IL-33 and decreased IL-37 expression in HF biopsies from the 'acute EGFRi' group and in organ-cultured HFs. CONCLUSIONS: The data show that EGFRi/MEKi compromise the physiological IP of human scalp HFs and suggest that future clinical management of EGFRi/MEKi-induced folliculitis requires HF IP protection and inhibition of IL-33.

About 75­90% of people with cancer who are treated with drugs called EGFR inhibitors (EGFRi) and MEK inhibitors (MEKi) will get a skin condition called folliculitis. This is where the hair follicles become inflamed. Despite this, the reasons why some patients develop this are not well understood. In this study, we had three goals. We wanted to understand how these medications alter the skin's immune response and genetic processes. We also wished to determine the impact of the medications on the immune protection of hair follicles. Finally, we wanted to find early signs of inflammation in hair follicles caused by the medications. We studied scalp samples from people who got folliculitis after long-term EGFRi treatment and compared them to samples of healthy scalp skin. We also examined patients before and after they began EGFRi treatment. In the lab, we exposed healthy hair follicles to an EGFRi called 'erlotinib' or a MEKi called 'cobimetinib'. We then carried out detailed imaging and genetic analyses. We found that long-term treatment with EGFRi increased certain immune cells (called CD8+ T cells) in the hair follicle area. This led to a breakdown in the immune protection around hair follicles. A similar breakdown was found in lab-treated healthy follicles. Genetic changes linked to inflammation were also found. Our findings suggest that EGFRi and MEKi treatments could affect the natural immune defence of hair follicles in the scalp and cause folliculitis. Protecting the immune system and controlling inflammation might be the key to treating people with these drug-related skin conditions.

The association of age at psoriasis onset and HLA-C*06:02 with biologic survival in patients with moderate-to-severe psoriasis: a cohort study from the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR).

BACKGROUND: Few studies have used real-world data to investigate the association between biologic therapy survival and age at psoriasis onset or HLA-C*06:02 status in patients with moderate-to-severe psoriasis. The robustness of these studies is limited by small sample size, short follow-up and diverse safety and effectiveness measures. OBJECTIVES: To describe biologic survival and explore whether the response to biologics is modified by age at psoriasis onset or HLA-C*06:02 status in patients with moderate-to-severe psoriasis. METHODS: Data from patients in the UK and the Republic of Ireland registered in the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR) from 2007 to 2022 on a first course of adalimumab, etanercept, secukinumab or ustekinumab with at least 6 months' follow-up and a subset of BADBIR patients with available HLA-C*06:02 information registered to Biomarkers and Stratification To Optimise outcomes in Psoriasis (BSTOP) were analysed. Patients aged ≥ 50 years at treatment initiation were classified into early-onset psoriasis (EOP) (presenting in patients ≤ 40 years of age) and late-onset psoriasis (LOP) (presenting in patients > 40 years of age). BADBIR patients with available information in BSTOP were categorized as HLA-C*06:02- or HLA-C*06:02 + . Biologic survival was defined as treatment discontinuation associated with ineffectiveness or occurrence of adverse events (AEs). Adjusted survival function and hazard ratio (aHR) with 95% confidence interval (CI) were estimated using a flexible parametric model to compare discontinuing therapy between age at psoriasis onset and HLA-C*06:02 groups. Each model included exposure (biologics), effect modifier (age at onset or HLA-C*06:02 status), interaction terms and several baseline demographic, clinical and disease severity covariates. RESULTS: Final analytical cohorts included 4250 patients in the age at psoriasis onset group [2929 EOP (69%) vs. 1321 LOP (31%)] and 3094 patients in the HLA-C*06:02 status group [1603 HLA-C*06:02+ (52%) vs. 1491 HLA-C*06:02- (48%)]. There was no significant difference between EOP and LOP in drug survival associated with ineffectiveness or AEs for any biologics. However, compared with patients who were HLA-C*06:02-, patients who were HLA-C*06:02 + were less likely to discontinue ustekinumab for reasons associated with ineffectiveness (aHR 0.56, 95% CI 0.42-0.75). CONCLUSIONS: HLA-C*06:02, but not age at psoriasis onset, is a predictive biomarker for biologic survival in patients with psoriasis. Findings from this large cohort provide further, important information to aid clinicians using biologic therapies to manage patients with psoriasis.

Bimekizumab safety in patients with moderate-to-severe plaque psoriasis: pooled data from up to 3†years of treatment in randomized phase III trials.

BACKGROUND: Patients with psoriasis require long-term management; therefore, understanding the long-term safety of new treatments, such as bimekizumab (BKZ), is crucial. OBJECTIVES: To evaluate BKZ's 3-year safety profile in patients with moderate-to-severe plaque psoriasis. METHODS: Three years of safety data were pooled from three phase III trials (BE VIVID, BE READY and BE SURE) and their ongoing open-label extension (BE BRIGHT). Treatment-emergent adverse events (TEAEs) are reported using exposure-adjusted incidence rates (EAIRs) per 100 patient-years (PY). RESULTS: In total, 1495 patients received at least one BKZ dose; total BKZ exposure was 3876.4 PY. The overall EAIR of TEAEs was 175.5/100 PY and decreased with longer exposure to BKZ. The most commonly reported TEAEs were nasopharyngitis, oral candidiasis and upper respiratory tract infection (EAIRs of 15.0/100 PY, 10.1/100 PY and 6.5/100 PY, respectively); 99.3% of oral candidiasis events were mild or moderate in severity, none were serious and few led to discontinuation. EAIRs of other TEAEs of interest were low, including serious infections (1.2/100 PY), adjudicated inflammatory bowel disease (0.2/100 PY) and laboratory elevations in aspartate aminotransferase or alanine aminotransferase (> 5 × upper limit of normal: 0.6/100 PY). CONCLUSIONS: In these analyses pooled across 3 years, no new safety signals were observed with longer exposure to BKZ. The vast majority of oral candidiasis events were mild or moderate in severity, as reported previously.

Deucravacitinib in plaque psoriasis: 2-year safety and efficacy results from the phase III POETYK trials.

BACKGROUND: In the phase III POETYK PSO-1 and PSO-2 trials, deucravacitinib, an oral selective allosteric tyrosine kinase 2 inhibitor, was well tolerated and efficacious over 1 year in patients with psoriasis. OBJECTIVE: To evaluate deucravacitinib safety and efficacy over 2 years in patients participating in the phase III trials. METHODS: In the POETYK long-term extension (LTE), an ongoing phase IIIb open-label trial, adults with moderate-to-severe plaque psoriasis who completed PSO-1 or PSO-2 receive deucravacitinib 6 mg once daily. Safety was assessed via adverse events (AEs) and laboratory parameter abnormalities. Efficacy endpoints, including ≥ 75% reduction from baseline Psoriasis Area and Severity Index score (PASI 75) and static Physician's Global Assessment (sPGA) score of 0/1 (clear/almost clear), were evaluated in patients originally randomized to deucravacitinib, patients who crossed over from placebo at week 16 and patients who achieved PASI 75 at week 24 (peak efficacy). RESULTS: At data cutoff (1 October 2021), 1519 patients had received at least one dose of deucravacitinib; 79.0% and 39.9% had ≥ 52 weeks and ≥ 104 weeks of total deucravacitinib exposure, respectively. Exposure-adjusted incidence rates (EAIRs) per 100 person-years were similar at 1 year and 2 years for any AEs (229.2 vs. 154.4, respectively), serious AEs (5.7 vs. 6.1), discontinuations (4.4 vs. 2.8), deaths (0.2 vs. 0.4), serious infections (1.7 vs. 2.6), herpes zoster (0.9 vs. 0.8), major adverse cardiovascular events (0.3 vs. 0.4), venous thromboembolic events (0.2 vs. 0.1) and malignancies (1.0 vs. 0.9). EAIRs for COVID-19 infections were higher at 2 years than at 1 year (5.1 vs. 0.5) owing to the peak of the global COVID-19 pandemic occurring during the LTE. No clinically meaningful changes from baseline or trends were observed over 2 years in haematological, chemistry or lipid parameters. Clinical responses were maintained in patients who received continuous deu-cravacitinib treatment from baseline [PASI 75: week 52, 72.4%; week 112, 79.7%; sPGA 0/1: week 52, 57.9%; week 112, 61.1% (as observed)]. Responses at week 52 were also maintained in placebo crossovers and in week-24 PASI-75 responders. CONCLUSIONS: Deucravacitinib maintained efficacy and demonstrated consistent safety with no new safety signals observed through 2 years.

Psoriasis is a chronic inflammatory skin condition. Many available treatments for psoriasis are injected, but can be inadequate in terms of effectiveness, and/or cause serious side-effects. Deucravacitinib is a recently approved oral medicine that interferes with an enzyme involved in inflammation called 'tyrosine kinase 2' (TYK2). Deucravacitinib has been shown to improve psoriatic patches and symptoms (such as itching) through 1 year in two global clinical trials in adults with moderate-to-severe plaque psoriasis (POETYK PSO-1 and PSO-2). This study was an analysis of the safety and efficacy of deu­cravacitinib for up to 2 years. To do this, the researchers used data from approximately 1500 people who completed both trials and continued into an ongoing, long-term extension trial (POETYK LTE). Overall, there were no new side-effects, and the number, type and severity of side-effects, as well as the number of patients who stopped treatment because of these side-effects, remained low. The most frequent side-effects included common cold symptoms and COVID-19. Rates of shingles and serious side-effects were comparable to rates reported in the real world. Improvements in psoriasis symptoms seen at 1 year were maintained for up to 2 years in patients receiving deucravacitinib treatment from the start of PSO-1 or PSO-2, or who crossed over from placebo to deucravacitinib at 4 months. Long-term treatment with deucravacitinib improved psoriasis symptoms and resulted in mostly mild side-effects. The study findings suggest that deucravacitinib could be a well-tolerated and effective treatment for people with psoriasis.

Discontinuation of anti-tumour necrosis factor alpha treatment owing to blood test abnormalities, and cost-effectiveness of alternate blood monitoring strategies.

BACKGROUND: There is no evidence base to support the use of 6-monthly monitoring blood tests for the early detection of liver, blood and renal toxicity during established anti-tumour necrosis factor alpha (TNFα) treatment. OBJECTIVES: To evaluate the incidence and risk factors of anti-TNFα treatment cessation owing to liver, blood and renal side-effects, and to estimate the cost-effectiveness of alternate intervals between monitoring blood tests. METHODS: A secondary care-based retrospective cohort study was performed. Data from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) were used. Patients with at least moderate psoriasis prescribed their first anti-TNFα treatment were included. Treatment discontinuation due to a monitoring blood test abnormality was the primary outcome. Patients were followed-up from start of treatment to the outcome of interest, drug discontinuation, death, 31 July 2021 or up to 5 years, whichever came first. The incidence rate (IR) and 95% confidence intervals (CIs) of anti-TNFα discontinuation with monitoring blood test abnormality was calculated. Multivariate Cox regression was used to examine the association between risk factors and outcome. A mathematical model evaluated costs and quality-adjusted life years (QALYs) associated with increasing the length of time between monitoring blood tests during anti-TNFα treatment. RESULTS: The cohort included 8819 participants [3710 (42.1%) female, mean (SD) age 44.76 (13.20) years] that contributed 25 058 person-years (PY) of follow-up and experienced 125 treatment discontinuations owing to a monitoring blood test abnormality at an IR of 5.85 (95% CI 4.91-6.97)/1000 PY. Of these, 64 and 61 discontinuations occurred within the first year and after the first year of treatment start, at IRs of 8.62 (95% CI 6.74-11.01) and 3.44 (95% CI 2.67-4.42)/1000 PY, respectively. Increasing age (in years), diabetes and liver disease were associated with anti-TNFα discontinuation after a monitoring blood test abnormality [adjusted hazard ratios of 1.02 (95% CI 1.01-1.04), 1.68 (95% CI 1.00-2.81) and 2.27 (95% CI 1.26-4.07), respectively]. Assuming a threshold of £20 000 per QALY gained, no monitoring was most cost-effective, but all extended periods were cost-effective vs. 3- or 6-monthly monitoring. CONCLUSIONS: Anti-TNFα drugs were uncommonly discontinued owing to abnormal monitoring blood tests after the first year of treatment. Extending the duration between monitoring blood tests was cost-effective. Our results produce evidence for specialist society guidance to reduce patient monitoring burden and healthcare costs.

A prospective observational cohort study comparing the treatment effectiveness and safety of ciclosporin, dupilumab and methotrexate in adult and paediatric patients with atopic dermatitis: results from the UK-Irish A-STAR register.

BACKGROUND: The main conventional systemic atopic dermatitis (AD) treatments are methotrexate (MTX) and ciclosporin (CyA). Dupilumab was the first novel systemic agent to enter routine clinical practice. There are no head-to-head randomised controlled trials or real-world studies comparing these agents directly. Network meta-analyses provide indirect comparative efficacy and safety data and have shown strong evidence for dupilumab and CyA. OBJECTIVES: The aim of this study was to compare the real-world clinical effectiveness and safety of CyA, dupilumab and MTX in AD. METHODS: We compared the effectiveness and safety of these systemic agents in a prospective observational cohort study of adult and paediatric patients recruited into the UK-Irish Atopic eczema Systemic TherApy Register (A-STAR). Treatment effectiveness measures included Eczema Area and Severity Index (EASI), Patient-Oriented Eczema Measure (POEM), Peak Pruritus Numerical Rating Scale (PP-NRS), Dermatology Life Quality Index (DLQI) and children's DLQI (cDLQI). Minimum duration of treatment was 28 days and follow-up was 12 months. Adjusted Cox-regression was used to compare the hazards of achieving EASI-50, EASI-75 and EASI-90 over time, and linear mixed-effects models were used to estimate changes in efficacy scores. Treatment safety was assessed by examining adverse events (AEs) at follow-up visits. RESULTS: 488 patients (n=311 adults and n=177 children/adolescents) on dupilumab (n=282), methotrexate (n=149), or CyA (n=57) were included. CyA and MTX were primarily used first line, while dupilumab was mainly a second line systemic as per UK National Institute of Clinical and Care Excellence (NICE) recommendations. EASI-50, EASI-75 and EASI-90 were achieved more rapidly in the dupilumab and CyA groups compared to MTX. After adjustment for previous severity, the reduction in EASI, POEM, PP-NRS and DLQI was greater for patients treated with dupilumab compared to MTX. In severe patients the reduction in EASI, POEM, and PP-NRS was even greater with CyA. The incidence of AEs was similar across groups (734, 654 and 594 per 10,000 person-month on CyA, dupilumab and MTX respectively). CONCLUSIONS: This real-world comparison of CyA, dupilumab and MTX in AD suggests that dupilumab is consistently more effective than MTX and that CyA is most effective in very severe disease within one follow-up year.

Orismilast in moderate-to-severe psoriasis: Efficacy and safety from a 16-week, randomized, double-blinded, placebo-controlled, dose-finding, and phase 2b trial (IASOS).

BACKGROUND: Orismilast is a novel oral phosphodiesterase-4 (PDE4) B/D inhibitor being investigated as a potential treatment for moderate-to-severe psoriasis. OBJECTIVE: To evaluate efficacy and safety of orismilast modified-release formulation in moderate-to-severe psoriasis. METHODS: This multicenter, randomized (1:1:1:1 to 20, 30, 40 mg orismilast or placebo, twice daily), double-blinded, placebo-controlled, parallel-group, phase 2b, 16-week, dose-ranging study evaluated orismilast in adults with moderate-to-severe plaque psoriasis (NCT05190419). Efficacy end points were analyzed using multiple imputation. RESULTS: Of 202 randomized patients, baseline characteristics were balanced across arms, except greater severe disease proportions for orismilast vs placebo. Orismilast showed significant improvements in the primary end point, percentage change in Psoriasis Area and Severity Index (PASI), from baseline to week 16 (orismilast -52.6% to -63.7% and placebo, -17.3%; all P <.001). Greater proportions receiving orismilast achieved PASI75 (39.5%-49.0%; P <.05) and PASI90 (22.0%-28.3%; P <.05 for 20 and 40 mg) vs placebo (PASI75, 16.5% and PASI90, 8.3%) at week 16. Safety findings were as expected with PDE4 inhibition; dose-dependent tolerability effects observed. LIMITATIONS: Small sample size, disease severity imbalance between groups, limited duration and diversity in study population. CONCLUSION: Orismilast demonstrated greater efficacy vs placebo and a safety profile in line with PDE4 inhibition.

Risk of Suicide and Suicidality in Patients with Moderate to Severe Psoriasis: results from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR).

BACKGROUND: Psoriasis is associated with poor mental health and reduced quality of life. Although the high risk for depression in patients with psoriasis is well-established, their suicidality risk is uncertain. Previous studies provide contrasting results and have not included patients with clinically-confirmed severe disease. OBJECTIVES: Our aim was to determine risk of suicide among patients with moderate to severe psoriasis compared with the general population, and investigate if psychiatric comorbidity or history of suicidality increases future suicidality risk in psoriasis. We further estimated the incidence of suicidal and self-injurious behaviours in patients. METHODS: Analysis was performed using the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR). As controls, general population mortality and suicide data were used. RESULTS: There were 9 suicides in BADBIR. The incidence rate of suicide was 12.5 per 100,000 person-years (95% CI 6.53, 24.11) in BADBIR versus 11.0 per 100,000 person-years (95% CI 10.7, 11.3) in the general population in England and Wales. Among patients, psychiatric comorbidity or past suicidality was associated with higher risk for suicidal ideation, suicide attempts and self-injurious behaviours. CONCLUSIONS: Suicide rates among patients with moderate to severe psoriasis were not significantly higher compared with the general population. Suicide is a rare event and our results are limited by the uncertainty in the estimate reliability. However, considering the high depression prevalence in psoriasis, our findings support the need for prompt assessment of patients for psychiatric comorbidities and suicidality history. Further research is required on suicidal behaviours and the role of psoriasis severity.

Deucravacitinib in moderate-to-severe plaque psoriasis: Pooled safety and tolerability over 52 weeks from two phase 3 trials (POETYK PSO-1 and PSO-2).

BACKGROUND: Two phase 3 trials, POETYK PSO-1 and PSO-2, previously established the efficacy and overall safety of deucravacitinib, an oral, selective, allosteric tyrosine kinase 2 (TYK2) inhibitor, in plaque psoriasis. OBJECTIVES: To further assess the safety of deucravacitinib over 52 weeks in the pooled population from these two trials. METHODS: Pooled safety data were evaluated from PSO-1 and PSO-2 in which patients with moderate-to-severe plaque psoriasis were randomized 1:2:1 to receive oral placebo, deucravacitinib or apremilast. RESULTS: A total of 1683 patients were included in the pooled analysis. Adverse event (AE) incidence rates were similar in each treatment group, serious AEs were low and balanced across groups, and discontinuation rates were lower with deucravacitinib versus placebo or apremilast. No new safety signals emerged with longer deucravacitinib treatment. Exposure-adjusted incidence rates of AEs of interest with placebo, deucravacitinib and apremilast, respectively, were as follows: serious infections (0.8/100 person-years [PY], 1.7/100 PY, and 1.8/100 PY), major adverse cardiovascular events (1.2/100 PY, 0.3/100 PY, and 0.9/100 PY), venous thromboembolic events (0, 0.2/100 PY, and 0), malignancies (0, 1.0/100 PY and 0.9/100 PY), herpes zoster (0.4/100 PY, 0.8/100 PY, and 0), acne (0.4/100 PY, 2.9/100 PY, and 0) and folliculitis (0, 2.8/100 PY, and 0.9/100 PY). No clinically meaningful changes from baseline in mean levels, or shifts from baseline to CTCAE grade ≥3 abnormalities, were reported in laboratory parameters with deucravacitinib. CONCLUSIONS: Deucravacitinib was well-tolerated with acceptable safety over 52 weeks in patients with psoriasis.

Integrated proteomics and genomics analysis of paradoxical eczema in psoriasis patients treated with biologics.

BACKGROUND: Few studies have explored the immunology and genetic risk of paradoxical eczema occurring as an adverse event of biologic therapy in patients with psoriasis. OBJECTIVES: We sought to describe the systemic inflammatory signature of paradoxical eczema using proteomics and explore whether this is genetically mediated. METHODS: This study used the Olink Target 96 Inflammation panel on 256 serum samples from 71 patients with psoriasis and paradoxical eczema, and 75 controls with psoriasis to identify differentially expressed proteins and enriched gene sets. Case samples from 1 or more time points (T1 prebiologic, T2 postbiologic, and T3 postparadoxical eczema) were matched 1:1 with control samples. Genes contributing to enriched gene sets were selected, and functional single nucleotide polymorphisms used to create polygenic risk scores in a genotyped cohort of 88 paradoxical eczema cases and 3124 psoriasis controls. RESULTS: STAMBP expression was lower in cases at T1 than in controls (log-fold change: -0.44; adjusted P = .022); no other proteins reached statistical significance at equivalent time points. Eleven gene sets including cytokine and chemokine pathways were enriched in cases at T2 and 10 at T3. Of the 39 proteins contributing to enriched gene sets, the majority are associated with the atopic dermatitis serum proteome. A polygenic risk score including 38 functional single nucleotide polymorphisms linked to enriched gene sets was associated with paradoxical eczema (adjusted P = .046). CONCLUSIONS: The paradoxical eczema systemic inflammatory proteome trends toward atopic dermatitis at a gene-set level and is detectable before onset of the phenotype. This signature could be genetically determined.

Loss-of-Function Myeloperoxidase Mutations Are Associated with Increased Neutrophil Counts and Pustular Skin Disease.

The identification of disease alleles underlying human autoinflammatory diseases can provide important insights into the mechanisms that maintain neutrophil homeostasis. Here, we focused our attention on generalized pustular psoriasis (GPP), a potentially life-threatening disorder presenting with cutaneous and systemic neutrophilia. Following the whole-exome sequencing of 19 unrelated affected individuals, we identified a subject harboring a homozygous splice-site mutation (c.2031-2A>C) in MPO. This encodes myeloperoxidase, an essential component of neutrophil azurophil granules. MPO screening in conditions phenotypically related to GPP uncovered further disease alleles in one subject with acral pustular psoriasis (c.2031-2A>C;c.2031-2A>C) and in two individuals with acute generalized exanthematous pustulosis (c.1705C>T;c.2031-2A>C and c.1552_1565del;c.1552_1565del). A subsequent analysis of UK Biobank data demonstrated that the c.2031-2A>C and c.1705C>T (p.Arg569Trp) disease alleles were also associated with increased neutrophil abundance in the general population (p = 5.1 × 10-6 and p = 3.6 × 10-5, respectively). The same applied to three further deleterious variants that had been genotyped in the cohort, with two alleles (c.995C>T [p.Ala332Val] and c.752T>C [p.Met251Thr]) yielding p values < 10-10. Finally, treatment of healthy neutrophils with an MPO inhibitor (4-Aminobenzoic acid hydrazide) increased cell viability and delayed apoptosis, highlighting a mechanism whereby MPO mutations affect granulocyte numbers. These findings identify MPO as a genetic determinant of pustular skin disease and neutrophil abundance. Given the recent interest in the development of MPO antagonists for the treatment of neurodegenerative disease, our results also suggest that the pro-inflammatory effects of these agents should be closely monitored.

Bimekizumab treatment in biologic DMARD-naïve patients with active psoriatic arthritis: 52-week efficacy and safety results from the phase III, randomised, placebo-controlled, active reference BE OPTIMAL study.

OBJECTIVES: Bimekizumab (BKZ) is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F in addition to IL-17A. BKZ treatment has demonstrated superior efficacy versus placebo (PBO) at Week 16 in biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with active psoriatic arthritis (PsA). Here, we report long-term efficacy and safety to Week 52. METHODS: BE OPTIMAL comprised a 16-week, double-blind, PBO-controlled period, then 36 weeks treatment-blind. Patients were randomised 3:2:1 to subcutaneous BKZ 160 mg every 4 weeks, PBO with switch to BKZ at Week 16, or reference arm (adalimumab (ADA) 40 mg every 2 weeks). Efficacy outcomes included the American College of Rheumatology (ACR) response criteria 20/50/70, Psoriasis Area and Severity Index (PASI) 75/90/100 in patients with baseline psoriasis affecting ≥3% body surface area and minimal disease activity (MDA); non-responder imputation. RESULTS: ACR20/50/70, PASI75/90/100 and MDA responses were sustained with BKZ to Week 52, consistent with results observed at Week 16. Patients who switched to BKZ at Week 16 demonstrated improvements in efficacy with similar results to BKZ-randomised patients by Week 52.To Week 52, 555/702 (79.1%) patients had ≥1 treatment-emergent adverse event (TEAE) during BKZ treatment; 113/140 (80.7%) on ADA. On BKZ, 46 (6.6%) patients had serious TEAEs. 54 (7.7%) Candida infections occurred during BKZ treatment and 1 (0.7%) during ADA; all cases were localised and non-serious. One death occurred in a BKZ-treated patient, unrelated to treatment. CONCLUSIONS: The efficacy of BKZ in bDMARD-naïve patients with PsA was sustained from Week 16 to Week 52. BKZ was well tolerated with no new safety signals observed. TRIAL REGISTRATION NUMBER: NCT03895203.