4-Year Results from the RAPID-PsA Phase 3 Randomised Placebo-Controlled Trial of Certolizumab Pegol in Psoriatic Arthritis

Objective: To report the efficacy, patient-reported, radiographic and safety outcomes of 4 years\u27 certolizumab pegol (CZP) treatment in patients with psoriatic arthritis (PsA). Methods: RAPID-PsA (NCT01087788) was double-blind and placebo-controlled to Week 24, dose-blind to Week 48 and open-label (OL) to Week 216. Patients were randomised 1:1:1 to either placebo or CZP 200 mg every 2 weeks (Q2W) or 400 mg every 4 weeks (Q4W) (following 400 mg at Weeks 0/2/4). Patients randomised to CZP continued their assigned dose in the OL period. Patients randomised to placebo were re-randomised to CZP 200 mg Q2W or 400 mg Q4W (post-loading dose) at Week 16 (early escape) or after the double-blind phase. We present observed and imputed data; missing values were imputed using non-responder imputation (NRI) for categorical and last observation carried forward (LOCF) for continuous measures. Results: 409 patients were randomised; 20% (54/273) of Week 0 patients randomised to CZP had prior anti-tumour necrosis factor (TNF) exposure; 67% (183/273) completed 216 weeks. By Week 48, 60.4% of patients achieved Disease Activity Index for Psoriatic Arthritis low disease activity or remission, which was maintained; 66.3% achieved these outcomes at Week 216 (NRI). At Weeks 48 and 216, 39.2% of patients achieved minimal disease activity (NRI). 75% reduction in Psoriasis Area and Severity Index responses were 65% and 52% at Weeks 48 and 216 (NRI). Total resolution rates for enthesitis, dactylitis and nail psoriasis, at 4 years, were 71%, 81% and 65%, respectively (LOCF). Structural damage progression was low over 4 years\u27 treatment. No new safety signals were identified after Week 96. Conclusions: CZP efficacy in treating PsA was maintained over 4 years, in patients both with and without prior anti-TNF exposure, with no new safety signals identified

results of the randomized, placebo-controlled GO-RAISE study

Background In the present study, we evaluated relationships between serum biomarkers and clinical/magnetic resonance imaging (MRI) findings in golimumab-treated patients with ankylosing spondylitis. Methods In the GO- RAISE study, 356 patients with ankylosing spondylitis randomly received either placebo (n = 78) or golimumab 50 mg or 100 mg (n = 278) injections every 4 weeks through week 24 (placebo-controlled); patients continuing GO-RAISE received golimumab through week 252. Up to 139/125 patients had sera collected for biomarkers/serial spine MRI scans (sagittal plane, 1.5-T scanner). Two blinded readers employed modified ankylosing spondylitis spine magnetic resonance imaging score for activity (ASspiMRI-a) and ankylosing spondylitis spine magnetic resonance imaging score for chronicity. Spearman correlations (r s) were assessed between serum biomarkers (n = 73) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), C-reactive-protein (CRP)-based Ankylosing Spondylitis Disease Activity Score (ASDAS), modified Stokes Ankylosing Spondylitis Spine Score (mSASSS), and ASspiMRI scores. Serum biomarkers predicting postbaseline spinal fatty lesion development and inflammation were analyzed by logistic regression. Results Significant, moderately strong correlations were observed between baseline inflammatory markers interleukin (IL)-6, intracellular adhesion molecule-1, complement component 3 (C3), CRP, haptoglobin, and serum amyloid-P and baseline ASDAS (r s = 0.39–0.66, p ≤ 0.01). Only baseline leptin significantly correlated with ASDAS improvement at week 104 (r s = 0.55, p = 0.040), and only baseline IL-6 significantly predicted mSASSS week 104 change (β = 0.236, SE = 0.073, p = 0.002, model R 2 = 0.093). By logistic regression, baseline leptin, C3, and tissue inhibitor of metalloproteinase (TIMP)-1 correlated with new fatty lesions per spinal MRI at week 14 and week 104 (both p < 0.01). Changes in serum C3 levels at week 4 (r s = 0.55, p = 0.001) and week 14 (r s = 0.49, p = 0.040) significantly correlated with BASDAI improvement at week 14. Baseline IL-6 and TIMP-1 (r s = −0.63, −0.67; p < 0.05) and reductions at week 4 in IL-6 (r s = 0.61, p < 0.05) and C3 (r s = 0.72; p < 0.05) significantly correlated with week 14 ASspiMRI-a improvement. Conclusions Extensive serum biomarker multiparametric analyses in golimumab-treated patients with ankylosing spondylitis demonstrated few correlations with disease activity or MRI changes; IL-6 weakly correlated with radiographic progression

Infliximab treatment reduces depressive symptoms in patients with ankylosing spondylitis: an ancillary study to a randomized controlled trial (ASSERT)

Background: Patients with ankylosing spondylitis (AS) are at increased risk of depression. This increased risk has been hypothesized to be solely secondary due to AS-related symptoms, or additionally due to a common inflammatory pathway. From a clinical perspective, it is important to know whether treatment with tumor necrosis factor alpha inhibitors reduces depressive symptoms, while from a pathophysiological point of view, it would be insightful to understand whether such an effect would be a direct result of reduced inflammation, the result of reduced AS-related symptoms, or both. The objective of this study was to evaluate the effect of infliximab on depressive symptoms in patients with AS in a randomized-controlled trial setting. Methods: Data were retrieved from a subgroup of patients from the AS Study for the Evaluation of Recombinant Infliximab Therapy (ASSERT). Patients were randomly allocated to infliximab (n = 16) or placebo (n = 7) until week 24, after which all received infliximab until week 54. Associations between treatment group and depressive sy

Employment and the role of personal factors among patients with ankylosing spondylitis: A Dutch cross-sectional case-control study

Objectives To update the knowledge on employment and the role of mastery, a personal factor reflecting the level of control over life and disease, among Dutch patients with ankylosing spondylitis (AS) compared to general population subjects. Methods Data of persons ≤65 years participating in a Dutch cross-sectional multicentre study on social participation in AS were used. Being employed was the main outcome. Standardised employment ratios (SERs) were calculated using indirect standardisation after adjusting for age, gender and education and repeated after stratification by symptom duration tertiles. Modified Poisson regressions were performed to understand the role of mastery (Pearlin's scale) independent of sociodemographic and health-related factors. Results 214 patients and 470 controls (127 (59.3%) and 323 (68.7%) males; mean age 48.3 (SD 10.4) and 39.3 (SD 12.7) years, respectively) completed an online questionnaire. SER (95%CI) in patients was 0.83 (0.69-0.98); 0.84 (0.67-1.04) in males; 0.83 (0.59-1.07) in females. Adjusted absolute employment of patients compared to controls was 69% versus 84%; 73% versus 86% for males; 62% versus 78% for females. In multivariable analyses stratified for patients and controls, mastery was associated with being employed in patients, but only in those with low education. In controls, not mastery but higher education was associated with being employed. Conclusion Our study reveals that patients suffering from AS compared to population controls are less likely to be employed. Mastery is an important personal factor associated with employment in patients but not in controls. Interventions aimed at improving employment of patients with AS should likely account for mastery

A Fifty-Two-Week, Randomized, Placebo-Controlled Trial of Certolizumab Pegol in Nonradiographic Axial Spondyloarthritis

OBJECTIVE: The natural history of nonradiographic axial spondyloarthritis (SpA) is incompletely characterized, and there are concerns that nonsteroidal antiinflammatory drugs provide inadequate disease control in patients with active disease. This study was undertaken to investigate the effects of certolizumab pegol (CZP), an anti-tumor necrosis factor treatment, in patients with nonradiographic axial SpA with objective signs of inflammation. METHODS: In this ongoing parallel-group double-blind study, adults with active disease were recruited from 80 centers in Australia, Europe, North America, and Taiwan, and were randomized 1:1 to receive placebo or CZP (400 mg at weeks 0, 2, and 4, followed by 200 mg every 2 weeks) in addition to nonbiologic background medication (NBBM). Switching to open-label CZP (or other biologic) or making background medication changes was permitted at any point during the trial, although changes before week 12 were discouraged. The primary end point was the proportion of patients achieving major improvement (MI) (i.e., a \u3e /=2.0-point decrease in the score from baseline or achievement of the lowest possible score [0.6]) in the Ankylosing Spondylitis Disease Activity Score (ASDAS) at week 52. RESULTS: A total of 317 patients were randomized to receive placebo plus NBBM (n = 158) or CZP plus NBBM (n = 159). ASDAS-MI at week 52 was achieved in 47.2% (75 of 159) of CZP plus NBBM patients, which was significantly greater (P \u3c 0.0001) than the 7.0% (11 of 158) of placebo plus NBBM patients in whom ASDAS-MI was achieved. Of the placebo plus NBBM patients, 60.8% (96 of 158) switched to open-label treatment before week 52 compared to 12.6% (20 of 159) of the CZP plus NBBM patients. CONCLUSION: Adding CZP to background medication is superior to adding placebo in patients with active nonradiographic axial SpA. These results indicate that remission in nonradiographic axial SpA treated without biologics occurs infrequently, demonstrating the need for treatment beyond nonbiologic therapy. Inc. on behalf of American College of Rheumatology

Social role participation questionnaire for patients with ankylosing spondylitis: Translation into Dutch, reliability and construct validity

Objective: The Social Role Participation Questionnaire (SRPQ) assesses the influence of health on participation in 11 specific and one general participation role across 4 participation dimensions: 'importance', 'satisfaction with time', 'satisfaction with performance' and 'physical difficulty'. This study aimed to translate the SRPQ into Dutch, and assess the clinimetric properties and aspects of its validity among patients with ankylosing spondylitis (AS). Methods: Translation was performed using the dual panel approach. For each participation dimension, internal consistency, test-retest reliability (n=31), and construct validity were assessed in 246 patients with AS. Results: The translation required only minor adaptations. Cronbach αs were α≥0.7. A strong correlation was present between satisfaction with 'time' and 'performance'(r=0.85). Test-retest reliability was satisfactory (κ=0.79-0.95). Correlations with participation domains of the Short- Form Health Survey 36 (SF-36), the WHO Disease Assessment Score II, and generic as well as disease-specific health outcomes (Physical and Mental component scale of the SF-36, Satisfaction With Life Scale, Bath Ankylosing Spondy

MRI lesions of the spine in patients with axial spondyloarthritis: an update of lesion definitions and validation by the ASAS MRI working group

OBJECTIVES: Spinal MRI is used to visualise lesions associated with axial spondyloarthritis (axSpA). The ASAS MRI working group (WG) updated and validated the definitions for inflammatory and structural spinal lesions in the context of axSpA. METHODS: After review of the existing literature on all possible types of spinal MRI pathologies in axSpA, the group (12 rheumatologists and two radiologists) consented on the required revisions of lesion definitions compared with the existing nomenclature of 2012. In a second step, using 62 MRI scans from the ASAS classification cohort, the proposed definitions were validated in a multireader campaign by global (absent/present) and detailed (inflammation and structural) lesion assessment at the vertebral corner (VC), vertebral endplate, facet joints, transverse processes, lateral and posterior elements. Intraclass correlation coefficient (ICC) was used for analysis. RESULTS: Revisions were made for both inflammatory (bone marrow oedema, BMO) and structural (fat, erosion, bone spur and ankylosis) lesions, including localisation (central vs lateral), extension (VC vs vertebral endplate) and extent (minimum number of slices needed), while new definitions were suggested for the type of lesion based on lesion maturity (VC monomorphic vs dimorphic). The most reliably assessed lesions were VC fat lesion and VC monomorphic BMO (ICC (mean of all 36 reader pairs/overall 9 readers): 0.91/0.92; 0.70/0.67, respectively. CONCLUSIONS: The lesion definitions for spinal MRI lesions compatible with SpA were updated by consensus and validated by a group of experienced readers. The lesions with the highest frequency and best reliability were fat and monomorphic inflammatory lesions at the VC

Uncovering the heterogeneity of disease impact in axial spondyloarthritis:bivariate trajectories of disease activity and quality of life

Objective The goal of managing axial spondyloarthritis (axSpA) is to improve and maintain patients' health-related quality of life (HRQoL), mainly through targeting towards low disease activity. Here, we aim to gain insight into the joint evolution of HRQoL and disease activity by identifying and characterising latent subgroups of patients with longstanding disease displaying similar trajectories throughout 8 years of follow-up. Methods Data from Outcome in Ankylosing Spondylitis (AS) International Study (n=161) and Groningen Leeuwarden AS cohort (n=264) were used. Biennially, HRQoL was assessed by AS Quality of Life (ASQoL) and disease activity by AS Disease Activity Score-C reactive protein (ASDAS-CRP). Bivariate trajectories of these outcomes were estimated by group-based trajectory modelling. Next, trajectories were profiled by comparing the latent groups with respect to baseline factors using analysis of variance and chi(2) test. Results Five bivariate trajectories were distinguished, in which ASQoL and ASDAS-CRP were tightly linked: (t1) low impact of disease; (t2) moderate impact; (t3) high impact with major improvement; (t4) high impact with some improvement; (t5) very high impact. Profiling revealed, for example, that (t1) was characterised by male gender and Human Leucocyte Antigen B27 positivity; (t3) by younger age, shorter symptom duration and biological intake and (t5) by the highest proportion of females. Conclusions We identified five bivariate trajectories of HRQoL and disease activity demonstrating a clear mutual relationship. The profiles revealed that both individual-related and disease-related features define the type of disease course in respect to HRQoL and disease activity in axSpA. This may provide clinicians insight into the differences among patients and help in the management of the disease

Efficacy and safety of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, in patients with moderate-to-severe psoriatic arthritis: a 24-week, randomised, double-blind, placebo-controlled, phase II proof-of-concept trial

Objective: To evaluate the efficacy and safety of secukinumab, a fully human, anti-interleukin (IL)-17A monoclonal antibody, in patients with psoriatic arthritis (PsA). Methods: 42 patients with active PsA fulfilling ClASsification for Psoriatic ARthritis (CASPAR) criteria were randomly assigned (2:1) to receive two intravenous secukinumab doses (10 mg/kg; n=28) or placebo (n=14) 3 weeks apart. The primary endpoint was the proportion of American College of Rheumatology (ACR) 20 responses at week 6 for secukinumab versus placebo (one-sided p<0.1). Results: Primary endpoint: ACR20 responses at week 6 were 39% (9/23) for secukinumab versus 23% (3/13) for placebo (p=0.27). ACR20 responses were greater with secukinumab versus placebo at week 12 (39% (9/23) vs 15% (2/13), p=0.13) and week 24 (43% (10/23) vs 18% (2/11), p= 0.14). At week 6, ‘good’ European League Against Rheumatism response was seen in 21.7% (5/23) secukinumab versus 9.1% (1/11) placebo patients. Compared with placebo at week 6, significant reductions were observed among secukinumab recipients for C reactive protein (p=0.039), erythrocyte sedimentation rate (p=0.038), Health Assessment Questionnaire Disability Index (p=0.002) and Short Form Health Survey (SF-36; p=0.030) scores. The overall adverse event (AE) frequency was comparable between secukinumab (26 (93%)) and placebo (11 (79%)) recipients. Six serious AEs (SAEs) were reported in four secukinumab patients and one SAE in one placebo patient. Conclusions: Although the primary endpoint was not met, clinical responses, acute-phase reactant and quality of life improvements were greater with secukinumab versus placebo, suggesting some clinical benefit. Secukinumab exhibited satisfactory safety. Larger clinical trials of secukinumab in PsA are warranted

Secukinumab inhibition of interleukin-17A in patients with psoriatic arthritis

BACKGROUND In a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis. We sought to evaluate the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in such patients. METHODS In this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1:1:1 ratio to receive intravenous secukinumab (at a dose of 10 mg per kilogram) at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo. Patients in the placebo group were switched to subcutaneous secukinumab at a dose of 150 mg or 75 mg at week 16 or 24, depending on clinical response. The primary end point was the proportion of patients with an American College of Rheumatology 20 (ACR20) response at week 24, defined as a 20% improvement from baseline in the number of tender and swollen joints and at least three other important domains. RESULTS ACR20 response rates at week 24 were significantly higher in the group receiving secukinumab at doses of 150 mg (50.0%) and 75 mg (50.5%) than in those receiving placebo (17.3%) (