Unpublished clinical trials of common rheumatic diseases.

OBJECTIVES: Randomized controlled trials (RCTs) provide high-quality evidence for treatment efficacy, but many RCTs remain unpublished. The objective of this study was to describe the proportion of unpublished RCTs in five rheumatic diseases and to identify factors associated with publication. METHODS: Registered RCTs for five rheumatic diseases (SLE, vasculitis, spondyloarthritis, SS and PsA) with over 30 months since study completion were identified using ClinicalTrials.gov. Index publications were identified by NCT ID numbers and structured text searches of publication databases. The results of unpublished studies were identified in abstracts and press releases; reasons for non-publication were assessed by surveying corresponding authors. RESULTS: Out of 203 studies that met eligibility criteria, 17.2% remained unpublished, representing data from 4281 trial participants. Higher proportions of published trials were phase 3 RCTs (57.1% vs 28.6% unpublished, P < 0.05) or had a positive primary outcome measure (64.9% vs 25.7% unpublished, P < 0.001). In a multivariable Cox proportional hazards model, a positive outcome was independently associated with publication (hazard ratio 1.55; 95% CI: 1.09, 2.22). Corresponding authors of 10 unpublished trials cited ongoing preparation of the manuscript (50.0%), sponsor/funder issues (40.0%) and unimportant/negative result (20.0%) as reasons for lack of publication. CONCLUSIONS: Nearly one in five RCTs in rheumatology remain unpublished 2 years after trial completion, and publication is associated with positive primary outcome measures. Efforts to encourage universal publication of rheumatology RCTs and reanalysis of previously unpublished trials should be undertaken.

Sequencing of Targeted Therapy in Psoriasis: Does it Matter?

With the continued development of biologics for the treatment of psoriasis, some patients have achieved optimal control, but a recommended biologic sequence if a biologic fails to initially improve the skin, termed primary nonresponse, or loses efficacy after initial improvement, termed secondary nonresponse, is still lacking. Primary and secondary nonresponse can occur with any class of biologics, and the type of nonresponse can drive the choice of whether to switch within a biologic class or to a different biologic class. The choice of biologic can also be challenging when managing psoriasis and concomitant psoriatic arthritis, as treatment differs on the basis of the severity of both diseases and further classification of axial and peripheral joint involvement. When choosing a biologic, each patient's comorbidities and preferences are also taken into account to provide the optimal therapy. With this lack of an established biologic sequence after biologic failure, the objective of our review is to define a therapy sequence for the tumor necrosis factor (TNF), interleukin-17 (IL-17), and interleukin-23 (IL-23) inhibitor classes in the treatment of psoriasis and psoriatic arthritis. Our proposed biologic sequence was derived through an analysis of the efficacy of each biologic class, primary and secondary nonresponse rates from clinical trials, and clinical experience with expert opinion.

Difficult-to-treat psoriatic arthritis (D2T PsA): a scoping literature review informing a GRAPPA research project.

BACKGROUND: Psoriatic arthritis (PsA) is a multifaceted condition with a broad spectrum of manifestations and a range of associated comorbidities. A notable segment of patients with PsA remains resistant to even advanced therapeutic interventions. This resistance stems from myriad causes, including inflammatory and non-inflammatory factors. OBJECTIVES: To collate and critically assess the various definitions and criteria of difficult-to-treat (D2T PsA present in the literature. METHODS: Using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) guidelines, we conducted a scoping review in July 2023, searching PubMed, American College of Rheumatology Convergence 2022, European Alliance of Associations for Rheumatology Congress 2023, Google Scholar and cited articles. Selection was made by two independent authors using Rayyan software, and conflicts were adjudicated by a third author. Eligibility criteria for PubMed focused on all article designs that were written in English, with full-text available, from the past decade, excluding only those not defining D2T PsA or targeting other populations. RESULTS: From the 565 references sourced, 15 studies were analysed, revealing considerable variations in defining both 'active disease' and 'resistant PsA', which was most often termed 'D2T' PsA. CONCLUSION: The definitions and criteria for D2T PsA and for 'active disease' are notably heterogeneous, with considerable variation across sources. The ongoing Group for Research and Assessment of Psoriasis and Psoriatic Arthritis initiative stands to bridge these definitional gaps and aims to provide guidance for clinicians and illuminate a path for pharmaceuticals and regulatory agencies to follow.

Deciphering difficult-to-treat psoriatic arthritis (D2T-PsA): a GRAPPA perspective from an international survey of healthcare professionals.

Objectives: This study contributes to the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA)'s effort to define 'difficult-to-treat' PsA (D2T-PsA), leveraging insights of healthcare professionals who are GRAPPA members. The primary objective is to inform GRAPPA's D2T PsA project, ensuring the consensus definition reflects clinical experience and expertise. Methods: An online survey was conducted among GRAPPA's healthcare professionals managing PsA patients. The survey covered demographic details, structured questions, and open-ended queries to gather comprehensive insights into the experts' viewpoints. Results: About 223 physicians completed the survey, comprising 179 (80.2%) rheumatologists and 40 (17.9%) dermatologists. The majority, 184 (82.5%), favoured establishing distinct definitions for D2T-PsA and complex-to-manage PsA (C2M-PsA). Furthermore, 202 (90.5%) supported a definition that includes objective inflammation signs (clinical, laboratory, imaging, among others). However, opinions varied on the criteria for prior treatment failures, with most (93, 41.7%) favouring a definition that includes at least one conventional synthetic disease-modifying anti-rheumatic drug and two or more biological- or targeted-synthetic-DMARDs with different mechanisms of action. Conclusion: The survey reveals a majority opinion among GRAPPA experts favouring the differentiation between D2T-PsA and C2M-PsA, and the inclusion of objective inflammatory markers in these definitions. However, there is less than 50% agreement on the specific treatment failure criteria, particularly regarding the number of therapies needed to classify PsA as D2T. These findings suggest a need for continued discussion to reach a more unified approach in defining D2T-PsA, reflecting the complexity of the condition.

Association between biological immunotherapy for psoriasis and time to incident inflammatory arthritis: a retrospective cohort study.

BACKGROUND: Targeted biological immunotherapies have been highly effective in controlling skin disease in patients with psoriasis, but whether therapy delays progression to inflammatory arthritis is unclear. The aim of this study was to compare the time to incident inflammatory arthritis among patients newly receiving biological therapies for psoriasis. METHODS: In this retrospective cohort study, we obtained data on a national sample of patients in the USA from the electronic health records database of the US-based TriNetX network. We included adult patients (aged ≥18 years) with two diagnostic codes for psoriasis (>30 days apart; International Classification of Diseases [ICD] codes) who had been newly prescribed a biologic (inhibitors of tumour necrosis factor [TNF], interleukin [IL]-17, IL-23, or IL-12/23, first prescribed on or after the date of receiving a first psoriasis diagnosis code). The time to incident inflammatory arthritis, defined by first occurrence of a diagnostic code for psoriatic arthritis or other inflammatory arthritis after initiation of biological therapy, was graphed with use of the Kaplan-Meier estimate. Time-dependent risk for inflammatory arthritis was calculated with weighted Cox proportional hazards regression with anti-TNF exposure as the reference, adjusted for demographic and clinical covariables. Sensitivity analyses were used to evaluate incident cases of psoriasis, increased exclusion periods for prevalent cases of inflammatory arthritis, drug switching, and more stringent disease and outcome definitions. FINDINGS: Between Jan 1, 2014, and June 1, 2022, we identified 15 501 patients with psoriasis (mean age 50·2 years [SD 15·0]; 8399 [54·2%] women and 7102 [45·8%] men; 11 175 [72·1%] White). 976 (6·3%) of the 15 501 patients developed inflammatory arthritis, with a cumulative incidence of 2·6 cases per 100 person-years. In multivariable regression analyses, the risk of developing inflammatory arthritis was significantly lower in patients prescribed IL-12/23 inhibitors (adjusted HR 0·58, 95% CI 0·43-0·76) or IL-23 inhibitors (0·41, 0·17-0·95) than in patients prescribed TNF inhibitors. We found no significant difference for IL-17 inhibitors (0·86, 0·54-1·38) compared with TNF inhibitors. For IL-12/23 inhibitors, the results persisted in all sensitivity analyses. For IL-23 inhibitors, the results persisted in three of six sensitivity analyses, when a higher diagnostic threshold for incident arthritis was used and when excluding patients who developed arthritis within 3 or 6 months after first biologic prescription. INTERPRETATION: In this large cohort study of patients with psoriasis, treatment with IL-12/23 inhibitors or IL-23 inhibitors was associated with reduced risk of progression to inflammatory arthritis compared with TNF inhibitors. Prospective observational cohorts with disease activity measures and pooled analyses of previous randomised trials are required to confirm these findings. FUNDING: None.

Novel PSTPIP1 gene mutation in a patient with pyogenic arthritis, pyoderma gangrenosum and acne (PAPA) syndrome.

INTRODUCTION: Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome is a rare autosomal dominant disease that usually presents in childhood with recurrent sterile arthritis. As the child ages into puberty, cutaneous features develop and arthritis subsides. We report the case of a now 25-year-old male patient with PAPA syndrome with the E250K mutation in PSTPIP1. We also present a systematic literature review of other PAPA cases. METHOD: We conducted a literature search of PubMed using the following search terms: E250K mutation, PSTPIP1, and PAPA. RESULTS: PAPA syndrome is caused by mutations on chromosome 15q affecting the proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1) gene, also known as CD2-binding protein 1 (CD2BP1). The reported cases of PAPA syndrome currently in the literature involve mutations in A230T and E250Q. One case of a novel E250K mutation has been reported, which presented with a different phenotype to previously described cases of PAPA syndrome. CONCLUSION: With variation present between disease presentations from case to case, it is possible that the spectrum of PAPA syndrome is wider than currently thought. Further research is needed which may uncover an as-yet undiscovered genetic abnormality linking these interrelated diseases together.