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In this 12-week, phase 2 trial, an anti–interleukin-17–receptor antibody was effective in treating moderate-to-severe psoriasis. Adverse events included neutropenia. Larger trials of longer duration are needed to assess the risk of infections. Psoriasis is a chronic T-cell–mediated autoimmune disease 1 that affects 2 to 3% of the U.S. population 2 , 3 and 0.6 to 6.5% of the European population. 4 Emerging data identify a subset of helper T cells, Th17, that preferentially produce interleukin-17 and play a major role in orchestrating inflammation in psoriasis. 5 – 7 Levels of interleukin-17 are elevated in the lesional skin and blood of patients with psoriasis 5 , 8 – 10 and correlate with disease severity. 11 The interleukin-17 cytokine family consists of six cytokines (interleukins 17A to 17F) and five receptors (interleukins 17RA to 17RE). 12 The interleukin 17A, 17F, and 17A/F heterodimer ligands share . . .

Although the histological changes seen in psoriasis have long been well characterized, the underlying cellular and molecular mechanisms have only begun to be elucidated over the past 20 years. Proinflammatory factors such as tumor necrosis factor (TNF)-α have a central role in psoriasis pathogenesis, and many T-helper 1 (Th1) cytokines and messenger RNAs are elevated in psoriatic lesions. IL-17A, IL-17F, and other Th17 cell–derived cytokines have been shown in murine models to induce features that mimic human psoriasis. This review focuses on the emerging biology of the IL-17 cytokine family in psoriasis, and on the molecular and genetic information gained from animal models and human clinical studies that confirm IL-17 as a crucial proinflammatory cytokine in psoriasis. Expression of IL-17A, IL-17C, and IL-17F is strikingly increased in psoriatic lesions, and successful therapy is associated with restoration of the expression of a wide range of genes (including effector molecules downstream of IL-17 such as cytokines, chemokines, and antimicrobial peptides) to near-normal levels. Therapeutic agents in development that target IL-17 are discussed, and an emerging model of the key role of IL-17 in the pathogenesis of psoriasis is presented.

Background Real-world studies assessing the comparative effectiveness of biologic or targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) as first-line targeted therapy are scarce. We analyzed the real-world persistence and effectiveness of etanercept (ETN), adalimumab (ADA), and Janus kinase inhibitors (JAKis) as first-line therapy in b/tsDMARD-naïve patients with rheumatoid arthritis (RA). Methods Adults (≥ 18 years) enrolled in the CorEvitas RA Registry and initiating ETN, ADA, or a JAKi (alone or in combination with csDMARDs) between November 2012 and June 2021 were included if they had 6 and/or 12 months’ follow-up. Treatment persistence and effectiveness outcomes including the change in Clinical Disease Activity Index (CDAI) and patient-reported outcomes (PROs) were evaluated at follow-up, adjusting for covariates using linear and logistic regression models. An exploratory analysis for patients on monotherapy was also conducted. Results Of 1059 ETN, 1327 ADA, and 581 JAKi initiators; 803 ETN, 984 ADA, and 361 JAKi initiators had 6 months’ follow-up. JAKi initiators were older and had a relatively longer disease duration than ETN or ADA initiators (mean age: 61.3 vs 54.5 and 55.5 years; mean duration of RA: 8.1 vs 5.7 and 5.6 years). Unadjusted mean improvements in CDAI and PROs were similar between the groups at 6 months, except the proportion achieving LDA, remission, and MCID in CDAI, which were numerically higher in the ETN and ADA groups vs JAKi group (LDA: 43.4% and 41.9% vs 32.5%; remission: 18.2% and 15.1% vs 11.5%; MCID: 46.5% and 47.8% vs 38.0%). Adjusted effectiveness results did not reveal statistically significant differences between treatment groups at 6 months, with an exception in MCID (odds ratio [95% CI] for JAKi vs ETN: 0.65 [0.43–0.98]). At 6 months, 68.2% of ETN, 68.5% of ADA, and 66.5% of JAKi initiators remained on therapy. The findings at 12 months’ follow-up and sensitivity analysis among monotherapy initiators also showed no differences in effectiveness outcomes between the groups. Conclusions This analysis of real-world data from the CorEvitas RA Registry did not show differences in clinical effectiveness and treatment persistence rates in b/tsDMARD-naïve patients initiating ETN, ADA, or JAKi as first-line targeted therapy either alone or in combination with csDMARDs.

Objective Real‐world studies assessing treatment response by psoriatic arthritis (PsA) domains are limited. This study aimed to describe the patient characteristics, frequency and combinations of disease domains, disease activity, and patient‐reported outcomes (PROs) by PsA domains in patients who initiated treatment with a tumor necrosis factor inhibitor (TNFi) or interleukin‐17 inhibitor (IL‐17i). Methods Adults with PsA who initiated treatment with a TNFi or an IL‐17i between January 2013 and January 2021 and had a 6 (±3)–month follow‐up were included. The prevalence of PsA domains, the most common domain combinations, treatment persistence, and unadjusted change in disease activity and PROs from baseline to 6 months for each PsA domain were summarized descriptively. Results Of the 1005 eligible patients, 63% were receiving TNFi and 37% were receiving IL‐17i. Forty percent of TNFi and 14% of IL‐17i initiators received these treatments as first‐line therapy. Peripheral arthritis and skin disease were the most common PsA domains identified in 86% and 82% of patients, respectively, and the triad of peripheral arthritis, skin disease, and nail psoriasis was the most common domain combination observed in 14% of patients. More than two thirds (68%) of patients remained on therapy at 6 months’ follow‐up. Improvements in disease activity and PROs were observed across all PsA domains in those receiving TNFi or IL‐17i. Conclusion This real‐world analysis highlights the heterogeneity in domain presentation; therefore, assessing all PsA domains is important for optimal disease management. Improvements in outcomes across all PsA domains demonstrate the effectiveness of TNFi and IL‐17i in diverse patient groups exhibiting different phenotypes of PsA.

ObjectiveWe used the Study of Etanercept And Methotrexate in Combination or as Monotherapy in Subjects with Psoriatic Arthritis (SEAM-PsA) data set to examine the impact of presence of enthesitis, dactylitis, nail disease and/or psoriasis on treatment response in patients with early psoriatic arthritis (PsA).MethodsThis post hoc analysis evaluated the effect of baseline Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index (EI), Leeds Enthesitis Index (LEI), Leeds Dactylitis Index (LDI), modified Nail Psoriasis Severity Index (mNAPSI) scores and body surface area (BSA) on composite outcomes of minimal disease activity (MDA) responses, Psoriatic Arthritis Disease Activity Score (PASDAS) low disease activity (LDA), PASDAS changes and Good Responses and Disease Activity Index for Psoriatic Arthritis (DAPSA) scores at Week 24.ResultsOverall, 851 patients completed the SEAM-PsA trial and were included in the analysis. Baseline enthesitis (SPARCC EI>0 vs SPARCC EI=0 or LEI>0 vs LEI=0) was not associated with improved outcomes. Baseline dactylitis (LDI>0 vs LDI=0) was positively associated with improved MDA (OR: 1.4, p=0.0457), PASDAS LDA (OR: 1.8, p=0.0014) and Good Responses (OR: 1.6, p=0.0101) and greater reductions in PASDAS (estimate: –0.9, p<0.0001) and DAPSA scores (estimate: –3.8, p=0.0155) at Week 24. Similarly, baseline nail disease (mNAPSI >1 vs mNAPSI≤1) was positively associated with improved MDA (OR: 1.8, p=0.0233) and PASDAS LDA (OR: 1.8, p=0.0168) responses and greater reduction in PASDAS (estimate: –0.7, p=0.0005) at Week 24.ConclusionsResults from our analysis suggest that presence of dactylitis and nail disease, but not enthesitis, are associated with improved outcomes in patients with early PsA who were treated with methotrexate and/or etanercept.

ObjectivesWe examined patient-reported outcomes (PROs) in The Study of Etanercept And Methotrexate in Patients with Psoriatic Arthritis (PsA); a 48-week, phase 3, randomised controlled trial that compared outcomes with methotrexate (MTX) monotherapy, etanercept monotherapy, and MTX+ etanercept in patients with PsA.MethodsEfficacy endpoints included: mean changes from baseline and proportion of patients who reported improvements≥minimal clinically important difference (MCID) at week 24 in treatment groups for Health Assessment Questionnaire-Disability Index, Patient Global Assessment (PtGA), Patient Global Assessment of Joint Pain (PtGAJP) and Medical Outcomes Study Short Form-36 Questionnaire (SF-36) Physical Component Summary (PCS), and Mental Component Summary, and eight domain scores. PROs were analysed as reported (observed), without multiplicity adjustment; therefore, p values are descriptive.ResultsAt week 24, patients receiving etanercept monotherapy or MTX+ etanercept combination reported greater improvements (p≤0.05) in PtGA, PtGAJP and SF-36 PCS scores compared with those receiving MTX monotherapy. Compared with MTX monotherapy, higher proportions of patients receiving etanercept monotherapy and combination therapy reported improvements≥MCID in PtGA (etanercept vs MTX, p=0.005) and PtGAJP (MTX +etanercept vs MTX, p=0.038). Across PROs, proportions of patients reporting scores≥age and gender-matched normative values at week 24 ranged from 20.8% to 51.0% with MTX monotherapy, 30.9% to 48.8% with etanercept monotherapy, and 30.6% to 52.3% with MTX+ etanercept combination.ConclusionsPatients receiving etanercept monotherapy or MTX+ etanercept reported greater improvements from baseline in several PROs compared with those receiving MTX monotherapy. PROs should be incorporated in discussions between patients and clinicians regarding their treatment choices as they can help determine which treatments are more beneficial in patients with PsA.

IntroductionThe magnitude and frequency of temporally related methotrexate (MTX)-associated side effects in rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients are difficult to quantify using traditional research methods. As proof of concept designed in part to implement digital data collection for remote patient monitoring, we conducted a study implementing self-controlled case series analytic methods to understand MTX-related symptoms in RA or PsA.MethodsIn study phase 1, adults with RA or PsA from the ArthritisPower® Registry (past or current oral MTX users) participated in a cross-sectional survey. In phase 2, current MTX users participated in a longitudinal study and completed the Patient-Reported Outcomes Measurement Information System (PROMIS®) 1-day nausea/vomiting and fatigue measure. Within-person change in PROMIS scores between risk (6–36 h post-dose) and control (96–144 h post-dose) windows were compared using mixed models.ResultsThe baseline survey was completed by 671 participants (mean age: 54 years, 88% female, 92% white, 79% with RA). Among current MTX users (353/671 [53%]), most reported MTX-associated side effects (216/353 [61%]), most frequently fatigue (161/353 [46%]). Among phase 2 participants with (n = 39) and without (n = 84) baseline nausea, mean increase in PROMIS nausea was 5.1 units (P < 0.0001) and 0.7 units (P = 0.135), respectively; among those with (n = 51) and without (n = 72) baseline fatigue, mean increase in PROMIS fatigue was 3.9 units (P = 0.0003) and 0.4 units (P = 0.554), respectively.ConclusionsDigital remote patient monitoring presents an opportunity to detect and address medication tolerability in real time. Using a novel study design to control for between-person confounding, the magnitude of nausea and fatigue experienced by participants with RA and PsA temporally related to weekly MTX use was substantial.

Although the histologic changes seen in psoriasis have long been well characterized, the underlying cellular and molecular mechanisms have only begun to be elucidated over the past 20 years. Proinflammatory factors such as tumor necrosis factor (TNF)-α have a central role in psoriasis pathogenesis, and many T helper 1 (Th1) cytokines and messenger RNAs are elevated in psoriatic lesions. Interleukin-17A (IL-17A), IL-17F, and other Th17 cell–derived cytokines have been shown in murine models to induce features that mimic human psoriasis. This review focuses on the emerging biology of the IL-17 cytokine family in psoriasis, and on the molecular and genetic information gained from animal models and human clinical studies that confirm IL-17 as a crucial proinflammatory cytokine in psoriasis. Expression of IL-17A, IL-17C, and IL-17F is strikingly increased in psoriatic lesions, and successful therapy is associated with restoration of the expression of a wide range of genes (including effector molecules downstream of IL-17 such as cytokines, chemokines, and antimicrobial peptides) to near normal levels. Therapeutic agents in development that target IL-17 are discussed, and an emerging model of the key role of IL-17 in the pathogenesis of psoriasis is presented.