Enthesitis in patients with psoriatic arthritis treated with secukinumab or adalimumab: a post hoc analysis of the EXCEED study.

OBJECTIVES: To evaluate enthesitis treatment response, including time to resolution and data from multiple enthesitis instruments, in patients with PsA treated with secukinumab or adalimumab for 52 weeks. METHODS: In this post hoc analysis of the EXCEED study, patients receiving secukinumab 300 mg or adalimumab 40 mg per the label were grouped by presence or absence of baseline enthesitis based on the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC). Efficacy was assessed according to several enthesitis-related instruments using non-responder imputation for the achievement of enthesitis resolution (LEI/SPARCC = 0), Kaplan-Meier analysis for time to resolution, and as-observed data for other outcomes. RESULTS: Enthesitis was present at baseline in 498 of 851 patients (58.5%) as assessed by LEI and in 632 of 853 patients (74.1%) as assessed by SPARCC. Patients with baseline enthesitis generally presented with greater disease activity. Similar proportions of patients receiving secukinumab or adalimumab achieved resolution of LEI and SPARCC at weeks 24 (secukinumab: LEI/SPARCC, 49.6%/45.8%; adalimumab: LEI/SPARCC, 43.6%/43.5%) and 52 (secukinumab: LEI/SPARCC, 60.7%/53.2%; adalimumab: LEI/SPARCC, 55.3%/51.4%), with comparable mean time to enthesitis resolution. Improvements were similar for both drugs at individual enthesitis sites. Resolution of enthesitis with secukinumab or adalimumab was associated with improvements in quality of life at week 52. CONCLUSION: Secukinumab and adalimumab showed similar efficacy, including time to resolution, with respect to resolution of enthesitis. Inhibition of IL-17 with secukinumab reduced clinical enthesitis similarly to TNF-α inhibition. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02745080.

Comparative Efficacy of Advanced Therapies in the Treatment of Radiographic Axial Spondyloarthritis or Ankylosing Spondylitis as Evaluated by the ASDAS Low Disease Activity Criteria.

INTRODUCTION: With an increasing number of biologic/targeted synthetic disease-modifying antirheumatic drug options available for the treatment of active ankylosing spondylitis (AS), also known as radiographic axial spondyloarthritis, it is of clinical interest to determine the comparative efficacy of these advanced therapies among populations with differing prior advanced therapy exposure. This study aimed to assess the comparative efficacy of approved advanced therapies for AS in tumor necrosis factor inhibitor (TNFi)-naïve and, separately, in TNFi inadequate responder/intolerant (-IR) populations. METHODS: A systematic literature review was conducted to identify randomized clinical trials for TNFis, interleukin-17A inhibitors, and Janus kinase inhibitors used as advanced therapies for active AS. Clinical efficacy was considered by the Ankylosing Spondylitis Disease Activity Score low disease activity (ASDAS LDA) criteria, defined as ASDAS score less than 2.1, among approved therapies. Comparative efficacy in the TNFi-naïve population was assessed utilizing network meta-analysis, while comparative efficacy in the TNFi-IR population was assessed utilizing matching-adjusted indirect comparison. Odds ratios were calculated, from which absolute rates and numbers needed to treat were calculated. Safety in the form of trial-reported and placebo-adjusted rates of discontinuation due to adverse events (AEs) was reviewed. RESULTS: Among the TNFi-naïve population, the estimated ASDAS LDA rate between week 12 and 16 was highest for patients treated with upadacitinib (52.8%) and lowest for patients treated with placebo (11.6%). Among the TNFi-IR population, the estimated ASDAS LDA rate was 41.3% for patients treated with upadacitinib and 17.5% for patients treated with ixekizumab. The trial-reported and placebo-adjusted rates of discontinuation due to AEs were generally low across included advanced therapies. CONCLUSIONS: Relative to other assessed therapies, upadacitinib demonstrated greater clinical efficacy per ASDAS LDA in the treatment of active AS in both TNFi-naïve and TNFi-IR populations. Head-to-head and real-world data comparisons are warranted to both validate these findings and aid medical decision makers.

Pain in axial spondyloarthritis: role of the JAK/STAT pathway.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that is characterized by new bone formation in the axial musculoskeletal system, with X-ray discriminating between radiographic and non-radiographic forms. Current therapeutic options include non-steroidal anti-inflammatory drugs in addition to biological disease-modifying anti-rheumatic drugs that specifically target tumor necrosis factor-alpha (TNFα) or interleukin (IL)-17. Pain is the most critical symptom for axSpA patients, significantly contributing to the burden of disease and impacting daily life. While the inflammatory process exerts a major role in determining pain in the early phases of the disease, the symptom may also result from mechanical and neuromuscular causes that require complex, multi-faceted pharmacologic and non-pharmacologic treatment, especially in the later phases. In clinical practice, pain often persists and does not respond further despite the absence of inflammatory disease activity. Cytokines involved in axSpA pathogenesis interact directly/indirectly with the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling cascade, a fundamental component in the origin and development of spondyloarthropathies. The JAK/STAT pathway also plays an important role in nociception, and new-generation JAK inhibitors have demonstrated rapid pain relief. We provide a comprehensive review of the different pain types observed in axSpA and the potential role of JAK/STAT signaling in this context, with specific focus on data from preclinical studies and data from clinical trials with JAK inhibitors.

Inhibition of Interleukin-17 in Patients with Oligoarticular Psoriatic Arthritis.

INTRODUCTION: This study evaluated the efficacy of the interleukin-17A inhibitor secukinumab in patients with oligoarticular psoriatic arthritis (PsA). METHODS: A total of 84 patients with oligoarticular PsA, defined as 1-4 tender joints and 1-4 swollen joints, were pooled from the FUTURE 2-5 and MAXIMISE trials (NCT01752634, NCT01989468, NCT02294227, NCT02404350, and NCT02721966). Patients were grouped by treatment received at week 12 (secukinumab 300 mg, secukinumab 150 mg, or placebo) and week 52 (any secukinumab 300 mg or any secukinumab 150 mg). Efficacy was assessed by the proportion of patients achieving selected clinical outcomes. The predictors of Disease Activity index for Psoriatic Arthritis (DAPSA) responses at weeks 12 and 52 were identified by logistic regression analysis. RESULTS: Secukinumab treatment resulted in greater achievement of DAPSA-based low disease activity (LDA), DAPSA-based remission (REM), DAPSA50, and DAPSA75 than placebo at week 12, with improvements sustained or further increased through week 52. LDA or REM was achieved at week 52 by more than 90% of patients who received either secukinumab dose, although secukinumab 300 mg resulted in the highest achievement of the stringent DAPSA75 and DAPSA REM outcomes. At week 12, younger age was associated with DAPSA LDA or REM and DAPSA50, while lower baseline swollen joint count was associated with DAPSA REM. No predictors were identified at week 52. The safety profile was consistent with the full study populations. CONCLUSION: Secukinumab demonstrated efficacy vs placebo across several outcome measures in patients with oligoarticular PsA at week 12, with sustained or improved responses through week 52.

The effect of secukinumab on patient-reported outcomes in patients with active psoriatic arthritis in a randomised phase 3 trial.

BACKGROUND: The phase 3 FUTURE 5 trial (NCT02404350) showed the clinical and radiographical efficacy of secukinumab in patients with psoriatic arthritis. This analysis aimed to assess the effect of secukinumab on patient-reported outcomes (PROs). METHODS: FUTURE 5 was a phase 3, multicentre, parallel-group randomised trial in which patients who were 18 years old or older, met the classification criteria for psoriatic arthritis at screening, and had symptoms of moderate-to-severe psoriatic arthritis for at least 6 months were randomly assigned to receive secukinumab 300 mg, 150 mg, 150 mg no loading dose (NL), or placebo weekly from baseline to week 4 and every 4 weeks thereafter. The prespecified PROs of the FUTURE 5 trial were assessed first in the overall population. We report mean changes from baseline and the proportion of patients reporting improvements equal to or more than the minimum clinically important differences (MCIDs) and scores equal to or more than the normative values for patient global assessments (PtGA) of disease activity; psoriasis and arthritis visual analogue scale (VAS) scores; pain VAS; Health Assessment Questionnaire Disability Index (HAQ-DI); 36-item Short Form Health Survey (SF-36); Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F); and quality of life questionnaires. Patients were then stratified and assessed according to their tumour necrosis factor (TNF) inhibitor status (TNF-naive and TNF-inadequate responder [TNF-IR] populations) as a post-hoc analysis. FINDINGS: Patients in all secukinumab groups reported significant least-squares mean changes from placebo at week 16 in all PROs except SF-36 mental component summary (MCS), irrespective of TNF inhibitor use. These included PtGA (300 mg difference vs placebo -12·2 [95% CI -16·3 to -8·1], 150 mg -8·22 [-12·4 to -4·1], 150 mg NL -8·3 [-12·5 to -4·2]; all p<0·0001), pain VAS (300 mg -14·3 [-18·3 to -10·2], 150 mg -11·5 [-15·6 to -7·5], 150 mg NL -11·3 [-15·3 to -7·2]; all p<0·0001), HAQ-DI (300 mg -0·33 [-0·42 to -0·24], 150 mg -0·23 [-0·32 to -0·14], 150 mg NL -0·24 [-0·33 to -0·15]; all p<0·0001), and FACIT-F (300 mg 4·8 [3·2 to 6·4], 150 mg 4·2 [2·6 to 5·8], 150 mg NL 3·5 [1·9 to 5·1]; all p<0·0001). Similarly, the proportion of patients with improvements equal to or better than MCID at week 16 was higher in the secukinumab group compared with the placebo group for most PROs except SF-36 (MCS), regardless of TNF inhibitor use. INTERPRETATION: Secukinumab resulted in early, statistically significant, clinically meaningful, sustained improvements in PROs across all doses compared with placebo in patients with active psoriatic arthritis. These improvements were seen irrespective of previous TNF inhibitor use, in a post-hoc analysis. These results indicate that secukinumab provides comprehensive improvement for patients with psoriatic arthritis, regardless of previous therapy. FUNDING: Novartis.