Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: final 3-year results from the PsABio real-world study.

OBJECTIVES: To evaluate real-world persistence and effectiveness of the IL-12/23 inhibitor, ustekinumab or a tumour necrosis factor inhibitor (TNFi) for psoriatic arthritis over 3 years. METHODS: PsABio (NCT02627768), a prospective, observational study, followed patients with PsA prescribed first-line to third-line ustekinumab or a TNFi. Persistence and effectiveness (achievement of clinical Disease Activity for PSA (cDAPSA) low disease activity (LDA)/remission and minimal disease activity/very LDA (MDA/VLDA)) were assessed every 6 months. Safety data were collected over 3 years. Analyses to compare the modes of action were adjusted on baseline differences by propensity scores (PS). RESULTS: In 895 patients (mean age 49.8 years, 44.7% males), at 3 years, the proportion of patients still on their initial treatments was similar with ustekinumab (49.9%) and TNFi (47.8%). No difference was seen in the risk of stopping/switching; PS-adjusted hazard ratio (95% CI) for stopping/switching ustekinumab versus TNFi was 0.87 (0.68 to 1.11). In the overall population, cDAPSA LDA/remission was achieved in 58.6%/31.4% ustekinumab-treated and 69.8%/45.0% TNFi-treated patients; PS-adjusted ORs (95% CI) were 0.89 (0.63 to 1.26) for cDAPSA LDA; 0.72 (0.50 to 1.05) for remission. MDA/VLDA was achieved in 41.4%/19.2% of ustekinumab-treated and 54.2%/26.9% of TNFi-treated patients with overlapping PS-adjusted ORs. A greater percentage of TNFi-treated patients achieved effectiveness outcomes. Both treatments exhibited good long-term safety profiles, although ustekinumab-treated patients had a lower rate of adverse events (AEs) versus TNFi. CONCLUSION: At 3 years, there was generally comparable persistence after ustekinumab or TNFi treatment, but AE rates were lower with ustekinumab.

Persistence and effectiveness of the IL-12/23 pathway inhibitor ustekinumab or tumour necrosis factor inhibitor treatment in patients with psoriatic arthritis: 1-year results from the real-world PsABio Study.

OBJECTIVE: We evaluated real-world treatment persistence and effectiveness at 1 year following initiation of IL-12/23 inhibitor ustekinumab or a tumour necrosis factor inhibitor (TNFi) for psoriatic arthritis (PsA). METHODS: PsABio (NCT02627768), a prospective, observational study, followed patients with PsA prescribed first-line to third-line ustekinumab or TNFi. Drug persistence, effectiveness (achievement of clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) low disease activity (LDA)/remission and minimal disease activity/very low disease activity (MDA/VLDA)), and safety were assessed every 6 months. In addition to descriptive statistics, propensity score (PS)-adjusted comparisons across cohorts were performed. RESULTS: At 1 year, overall persistence was similar in the ustekinumab (n=317/438, 72.4%) and TNFi (n=321/455, 70.5%) groups. PS-adjusted HR (95% CI) for stopping/switching ustekinumab versus TNFi was 0.82 (0.60; 1.13). cDAPSA LDA (including remission)/remission was achieved in 55.9%/22.1% of ustekinumab-treated and 67.1%/31.7% of TNFi-treated patients; PS-adjusted ORs (95% CI) were 0.80 (0.57; 1.10) for cDAPSA LDA and 0.73 (0.49; 1.07) for remission. MDA/VLDA was achieved in 34.2%/11.9% of ustekinumab-treated and 43.1%/12.6% of TNFi-treated patients; PS-adjusted ORs (95% CI) were 0.89 (0.63; 1.26) for MDA and 0.90 (0.54; 1.49) for VLDA. The safety profiles were similar in both groups. CONCLUSION: In the real-world PsABio Study, after 1 year of treatment, although unadjusted persistence was numerically slightly higher for ustekinumab versus TNFi and unadjusted effectiveness was numerically slightly higher for TNFi versus ustekinumab, the PS-adjusted comparisons demonstrated comparable overall persistence, effectiveness and safety for both modes of action in PsA.

Secukinumab versus adalimumab for treatment of active psoriatic arthritis (EXCEED): a double-blind, parallel-group, randomised, active-controlled, phase 3b trial.

BACKGROUND: Head-to-head trials in psoriatic arthritis are helpful in guiding clinical decision making. The EXCEED study evaluated the efficacy and safety of secukinumab versus adalimumab as first-line biological monotherapy for 52 weeks in patients with active psoriatic arthritis, with a musculoskeletal primary endpoint of American College of Rheumatology (ACR) 20 response. METHODS: This parallel-group, double-blind, active-controlled, phase-3b, multicentre (168 sites in 26 countries) trial enrolled patients aged at least 18 years with active psoriatic arthritis. Eligible patients were randomly assigned (1:1) by means of interactive response technology to receive secukinumab or adalimumab. Patients, investigators, site personnel, and those doing the assessments (except independent study drug administrators) were masked to study assignment. 300 mg secukinumab was administered subcutaneously at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks until week 48 as a pre-filled syringe. Adalimumab was administered every 2 weeks from baseline until week 50 as 40 mg per 0·4 mL citrate free subcutaneous injection. The primary outcome was the proportion of patients with at least 20% improvement in the ACR response criteria (ACR20) at week 52. Patients were analysed according to the treatment to which they were randomly assigned. Safety analyses included all safety data reported up to and including the week 52 visit for each patient who received at least one dose of study drug. The trial is registered at ClinicalTrials.gov, NCT02745080. FINDINGS: Between April 3, 2017 and Aug 23, 2018, we randomly assigned 853 patients to receive secukinumab (n=426) or adalimumab (n=427). 709 (83%) of 853 patients completed week 52 of the study, of whom 691 (81%) received the last study treatment at week 50. 61 (14%) of 426 patients in the secukinumab group discontinued treatment by week 52 versus 101 (24%) of 427 patients in the adalimumab group. The primary endpoint of superiority of secukinumab versus adalimumab for ACR20 response at week 52 was not met. 67% of patients in the secukinumab group achieved an ACR20 response at week 52 versus 62% of patients in the adalimumab group (OR 1·30, 95% CI 0·98-1·72; p=0·0719). The safety profiles of secukinumab and adalimumab were consistent with previous reports. Seven (2%) of 426 patients in the secukinumab group and six (1%) of 427 patients in the adalimumab group had serious infections. One death was reported in the secukinumab group due to colon cancer and was assessed as not related to the study drug by the investigator. INTERPRETATION: Secukinumab did not meet statistical significance for superiority versus adalimumab in the primary endpoint of ACR20 response at week 52. However, secukinumab was associated with a higher treatment retention rate than adalimumab. This study provides comparative data on two biological agents with different mechanisms of action, which could help guide clinical decision making in the management of patients with psoriatic arthritis. FUNDING: Novartis Pharma.

Effectiveness of IL-12/23 inhibition (ustekinumab) versus tumour necrosis factor inhibition in psoriatic arthritis: observational PsABio study results.

OBJECTIVES: To evaluate 6-month effectiveness of ustekinumab versus tumour necrosis factor inhibitor (TNFi), analysing predictors of low disease activity (LDA)/remission. METHODS: PsABio is a prospective, observational cohort study of patients with psoriatic arthritis (PsA) at 92 sites in eight European countries, who received first-line to third-line ustekinumab or a TNFi. Comparative achievement at 6 months of clinical Disease Activity Index for Psoriatic Arthritis (cDAPSA) LDA/remission, and minimal disease activity (MDA)/very LDA using propensity score (PS)-adjusted multivariate logistic regression was assessed. RESULTS: In the final analysis set of 868 participants with 6-month follow-up data (ustekinumab, n=426; TNFi, n=442), with long-standing disease and a high mean cDAPSA score (31.0 vs 29.8, respectively), proportions of patients in ustekinumab/TNFi treatment groups achieving cDAPSA LDA at 6 months were 45.7%/50.7%. cDAPSA remission was achieved in 14.9%/19.2%, and MDA in 26.4%/30.8% of patients. PS-adjusted odds ratios (OR; 95% confidence interval (CI)) of reaching cDAPSA LDA and MDA were 0.73 (0.46 to 1.15) and 0.87 (0.61 to 1.25) with ustekinumab versus TNFi, indicating no significant difference. High baseline body mass index or high cDAPSA were associated with a lower chance (OR (95% CI)) of reaching cDAPSA LDA with TNFi (0.94 (0.89 to 0.99) and 0.64 (0.52 to 0.79), respectively). Predictive factors were similar to previously published evidence, with cDAPSA and 12-item Psoriatic Arthritis Impact of Disease scores and chronic widespread pain at baseline appearing as new risk factors for unfavourable outcome. Safety data were similar between groups. CONCLUSION: Treatment targets were reached similarly after 6 months of treatment with ustekinumab and TNFi.

Improvement in patient-reported outcomes and work productivity following 3-year ustekinumab or tumour necrosis factor inhibitor treatment in patients with psoriatic arthritis: results from the PsABio real-world study.

BACKGROUND: To evaluate the real-world effect of the IL-12/23 inhibitor ustekinumab or of a tumour necrosis factor inhibitor (TNFi) on patient-reported outcomes (PRO) and their association with effectiveness endpoints in psoriatic arthritis (PsA) patients over 3 years. METHODS: In PsABio (NCT02627768), a prospective, observational study, patients with PsA that were prescribed first- to third-line ustekinumab or a TNFi, and remained on that drug for 3 years, were analysed for change in baseline in PROs (EuroQol-5 dimensions health state VAS [EQ-5D VAS], 12-item Psoriatic Arthritis Impact of Disease questionnaire [PsAID-12; range 0-10], Work Productivity and Activity Impairment for Psoriatic Arthritis questionnaire [WPAI; results expressed as a percentage for each domain]), and the association between PROs and WPAI with effectiveness endpoints, clinical disease activity index for psoriatic arthritis (cDAPSA), low disease activity (LDA)/remission, minimal disease activity (MDA) and very low disease activity (VLDA). RESULTS: In 437 patients (mean age 49.1 years, 47.8% female), at 3 years, ustekinumab and TNFi treatment led to comparable improvements in EQ-5D VAS; mean change from baseline (95% confidence intervals [CI]) was 11.0 (6.5; 15.4) and 18.9 (14.0; 23.9), respectively. Both groups improved PsAID-12 after 3 years; mean change from baseline (95% CI) was -2.9 (-3.2; -2.5) and -3.5 (-3.9; -3.2), respectively. At baseline, due to their PsA, TNFi-treated patients had lower work productivity compared to ustekinumab-treated patients; mean productivity reduction (95% CI) was 58.8 [52.4; 65.2] and 43.3 [35.6; 51.1]. Over 3 years, TNFi-treated patients had a greater improvement in work productivity compared to ustekinumab-treated patients, ultimately leaving work productivity to be comparable between groups; mean improvement (95% CI) was 44.5% (38.4; 50.6) and 24.9% (15.8; 34.0), respectively. A similar trend was observed in activity impairment. Patients in both treatment groups who achieved effectiveness endpoints, cDAPSA LDA/remission, MDA, and VLDA had greater improvement in PROs and WPAI than patients who did not achieve these endpoints. CONCLUSIONS: At 3 years, improvements in PROs following ustekinumab or TNFi treatment were generally comparable; however, TNFi-treated patients achieved a greater improvement in work productivity, although this group started from a lower baseline. Achievement of effectiveness endpoints, independent of treatment group, also improved PROs. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02627768. Registered on 11 December 2015.

Management of Peripheral Arthritis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: We aimed to compile evidence for the efficacy and safety of therapeutic options for the peripheral arthritis domain of psoriatic arthritis (PsA) for the revised 2021 Group in Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations. METHODS: A working group consisting of clinicians and patient research partners was convened. We reviewed the evidence from new randomized controlled trials (RCTs) for PsA treatment from February 19, 2013, to August 28, 2020. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-informed approach to derive evidence for the classes of therapeutic options for 3 patient groups: (1) naïve to treatment, (2) inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and (3) inadequate response to biologic DMARDs (bDMARDs). Recommendations were derived through consensus meetings. RESULTS: The evidence review included 69 RCTs. We derived GRADE evidence for each class of therapeutic options and achieved consensus for the recommendations. For patients naïve to treatment, the working group strongly recommends csDMARDs (methotrexate, sulfasalazine, leflunomide) and phosphodiesterase 4 inhibitors, and emphasizes regular assessment and early escalation to achieve treatment target. bDMARDs (tumor necrosis factor inhibitors [TNFi], interleukin 17 inhibitors [IL-17i], IL-12/23i, IL-23i) and Janus kinase inhibitors (JAKi) are also strongly recommended. For patients with inadequate response to csDMARDs, we strongly recommend TNFi, IL-17i, IL-12/23i, IL-23i, and JAKi. For those who had prior experience with bDMARDs, we strongly recommend a second TNFi, IL-17i, IL-23i, and JAKi. The evidence supporting nonpharmacological interventions was very low. An expert panel conditionally recommends adequate physical activity, smoking cessation, and diet to control weight gain. CONCLUSION: Evidence supporting optimal therapy for the peripheral arthritis domain of PsA was compiled for the revised 2021 GRAPPA treatment recommendations.

TCR repertoire profiling revealed antigen-driven CD8+ T cell clonal groups shared in synovial fluid of patients with spondyloarthritis.

Spondyloarthritis (SpA) comprises a number of inflammatory rheumatic diseases with overlapping clinical manifestations. Strong association with several HLA-I alleles and T cell infiltration into an inflamed joint suggest involvement of T cells in SpA pathogenesis. In this study, we performed high-throughput T cell repertoire profiling of synovial fluid (SF) and peripheral blood (PB) samples collected from a large cohort of SpA patients. We showed that synovial fluid is enriched with expanded T cell clones that are shared between patients with similar HLA genotypes and persist during recurrent synovitis. Using an algorithm for identification of TCRs involved in immune response we discovered several antigen-driven CD8+ clonal groups associated with risk HLA-B*27 or HLA-B*38 alleles. We further show that these clonal groups were enriched in SF and had higher frequency in PB of SpA patients vs healthy donors, implying their relevance to SpA pathogenesis. Several of the groups were shared among patients with different SpAs that suggests a common immunopathological mechanism of the diseases. In summary, our results provide evidence for the role of specific CD8+ T cell clones in pathogenesis of SpA.

The Phenotype of Axial Spondyloarthritis: Is It Dependent on HLA-B27 Status?

OBJECTIVE: To describe the radiographic phenotype of axial spondyloarthritis (SpA) according to the presence of HLA-B27. METHODS: An international collaboration compared the radiographic phenotype of axial SpA according to HLA-B27 status. Patients with ankylosing spondylitis (AS) and axial psoriatic arthritis (PsA) were collected. Radiographs were read centrally, blinded to clinical details. The symmetry of the sacroiliac joints and lumbar syndesmophytes and the morphology of syndesmophytes (typical marginal versus atypical chunky), together with the modified Stoke Ankylosing Spondylitis Spine Score and the Psoriatic Arthritis Spondylitis Radiographic Index, were recorded. RESULTS: A total of 244 patients with PsA and 198 patients with AS were included. In PsA, 60 patients (25%) were HLA-B27 positive while in AS, 148 patients (75%) were HLA-B27 positive. Patients with HLA-B27 were younger and more often male and had a longer duration of disease. In multivariable logistic regression, HLA-B27 was significantly associated with syndesmophyte symmetry (odds ratio [OR] 3.02 [95% confidence interval (95% CI) 1.38, 6.61]) and marginal syndesmophytes (OR 1.97 [95% CI 1.16, 3.36]) but not with sacroiliac symmetry. Mean radiographic scores were higher for patients with HLA-B27. CONCLUSION: Patients with axial SpA who are positive for HLA-B27 have more severe radiographic damage, more marginal syndesmophytes, and more frequent syndesmophyte symmetry compared to patients who are negative for HLA-B27.

Effect of the Pitot Tube on Measurements in Supersonic Axisymmetric Underexpanded Microjets.

This paper describes the results of methodical investigations of the effect of the Pitot tube on measurements of gas-dynamic parameters of supersonic axisymmetric underexpanded real and model microjets. Particular attention is paid to distortions of Pitot pressure variations on the jet axis associated with the wave structure of the jet and to distortions of the supersonic core length. In experiments with model jets escaping from nozzles with diameters ranging from 0.52 to 1.06 mm into the low-pressure chamber, the measurements are performed by the Pitot tubes 0.05 to 2 mm in diameter. The results are analyzed together with the earlier obtained data for real microjets escaping from nozzles with diameters ranging from 10 to 340 µm where the parameters of real microjets were determined by the Pitot microtube 12 µm in diameter. Interaction of the Pitot tube with an unsteady jet in the laminar-turbulent transition region is investigated; the influence of this interaction on Pitot pressure measurements is determined, and a physical interpretation of this phenomenon is provided.

Minimal Disease Activity as a Treatment Target in Psoriatic Arthritis: A Review of the Literature.

As in other inflammatory rheumatic diseases, the objective of psoriatic arthritis (PsA) treatment is the achievement of a defined target. Recent recommendations propose aiming for remission or low disease activity; however, a consensual definition of remission is lacking. A state of minimal disease activity (MDA) has been established and is defined by low activity assessed by tender/swollen joint counts, tender entheseal points, Psoriasis Area and Severity Index or body surface area, patient pain and global activity visual analog scale, and functional evaluation by Health Assessment Questionnaire. Since its development, MDA has been used increasingly in studies and clinical trials. In this article, the potential use of MDA as a treatment target in PsA is reviewed. The frequencies of MDA achievement with biologic disease-modifying antirheumatic drugs are summarized based on data from registries, observational studies, and clinical trials. Predictors and the prognostic effect of attaining MDA are also evaluated.