A randomized, double-blind, placebo-controlled 12-week trial of infliximab in patients with juvenile-onset spondyloarthritis.

OBJECTIVE: To assess the efficacy and safety of infliximab versus placebo in the treatment of patients with juvenile-onset spondyloarthritis (JoSpA). METHODS: Phase III, randomized, double-blind, placebo-controlled trial of 12 weeks that included patients ≤ 18 years old with JoSpA not responding to nonsteroidal anti-inflammatory drugs, sulfasalazine, or methotrexate. Patients were randomly assigned 1:1 to the infusion of infliximab 5mg/kg or placebo; completers entered then an open-label extension (OLE) period of 42 weeks. The primary endpoint was the number of active joints. Secondary outcomes included the assessment of disease activity, tender entheses, spinal mobility, serum C-reactive protein (CRP), the Bath Ankylosing Spondylitis Disease Activity and Functional Index, and the Childhood Health Assessment Questionnaire (CHAQ). RESULTS: We randomized 12 patients to infliximab and 14 to placebo. No significant differences were found between groups at baseline. At week 12, the mean number of active joints was 1.4 (SD 2.4) in the infliximab group and 4.1 (SD 3.0) in the placebo group (p = 0.0002). A repeated-measures mixed model analysis that included all endpoints in the study demonstrated sustained favourable outcomes of infliximab for active joints, tender joints, swollen joints, and tender enthesis counts, as well as for CHAQ and CRP (p < 0.01). Adverse events were more frequent in the infliximab group, including infections and infusion reactions, but none of them was serious. CONCLUSION: Infliximab is efficacious for patients with JoSpA with an inadequate response to conventional treatment. No serious adverse events with the use of infliximab were observed.

Ixekizumab for patients with non-radiographic axial spondyloarthritis (COAST-X): a randomised, placebo-controlled trial.

BACKGROUND: Ixekizumab, a high-affinity interleukin-17A (IL-17A) monoclonal antibody, has previously shown efficacy in radiographic axial spondyloarthritis (also known as ankylosing spondylitis). We aimed to evaluate the efficacy and safety of ixekizumab, an IL-17 inhibitor, in non-radiographic axial spondyloarthritis. Here, we report the primary results of COAST-X. METHODS: COAST-X was a 52-week, randomised, double-blind, placebo-controlled, parallel-group study done at 107 sites in 15 countries in Europe, Asia, North America, and South America. Eligible participants were adults (aged ≥18 years) with active axial spondyloarthritis without definite radiographic sacroiliitis (non-radiographic axial spondyloarthritis), objective signs of inflammation (via MRI or C-reactive protein), and an inadequate response or intolerance to non-steroidal anti-inflammatory drugs (NSAIDs). Patients were randomly assigned (1:1:1) to receive subcutaneous 80 mg ixekizumab every 4 weeks (Q4W) or every 2 weeks (Q2W), or placebo. Changing background medications or switching to open-label ixekizumab Q2W, or both, was allowed after week 16 at investigator discretion. Primary endpoints were Assessment of SpondyloArthritis international Society-40 (ASAS40) response (defined as an improvement of 40% or more and an absolute improvement from baseline of 2 units or more [range 0-10] in at least three of the four domains [patient global, spinal pain, function, and inflammation] without any worsening in the remaining one domain) at weeks 16 and 52. Patients who switched to open-label ixekizumab were imputed as non-responders in logistic regression analysis. This trial is registered with ClinicalTrials.gov, number NCT02757352. FINDINGS: Between Aug 2, 2016, and Jan 29, 2018, 303 patients were enrolled (105 to placebo, 96 to ixekizumab Q4W, and 102 to ixekizumab Q2W). Both primary endpoints were met: ASAS40 at week 16 (ixekizumab Q4W: 34 [35%] of 96, p=0·0094 vs placebo; ixekizumab Q2W: 41 [40%] of 102, p=0·0016; placebo: 20 [19%] of 105) and ASAS40 at week 52 (ixekizumab Q4W: 29 [30%] of 96, p=0·0045; ixekizumab Q2W: 32 [31%] of 102, p=0·0037; placebo: 14 [13%] of 105). 60 (57%) of 104 patients in the placebo group, 63 (66%) of 96 in the ixekizumab Q4W group, and 79 (77%) of 102 in the ixekizumab Q2W group had at least one treatment-emergent adverse event. The most common treatment-emergent adverse events in the ixekizumab groups were nasopharyngitis and injection site reaction. Of the treatment-emergent adverse events of special interest, there was one case of serious infection in the ixekizumab Q4W group. The frequency of serious adverse events was low (four [1%] of 302) and similar across the three groups. There were no malignancies or deaths. No new safety signals were identified. INTERPRETATION: Ixekizumab was superior to placebo for improving signs and symptoms in patients with non-radiographic axial spondyloarthritis at weeks 16 and 52. Reports of adverse events were similar to those of previous ixekizumab studies. Ixekizumab offers a potential therapeutic option for patients with non-radiographic axial spondyloarthritis who had an inadequate response or were intolerant to NSAID therapy. FUNDING: Eli Lilly and Company.

Validation and reliability of translation of the ASAS Health Index in a Colombian Spanish-speaking population with spondyloarthritis.

To validate a Spanish language translation of the ASAS Heath-Index (ASAS-HI) testing, its reliability, construct validity, and responsiveness in Colombian patients with spondyloarthritis. Translation was done following a forward-backward procedure. Patients fulfilling the Assessment of Spondyloarthritis international Society (ASAS) criteria for either axial or peripheral spondyloarthritis (SpA) participated. Test-retest reliability was assessed by intra-class correlation coefficient (ICC) in patients without treatment changes. In patients who required a therapeutic intervention, responsiveness was assessed using the standardized response mean (SRM). Construct validity was evaluated by Spearman correlation. Internal consistency (Cronbach's α) and discriminative ability of the ASAS-HI were assessed. Fifty patients were included: 54% male, mean (SD) age 44.8 (13.1), symptom duration 15.8 (9.7) years, Bath Ankylosing Spondylitis Disease Index (BASDAI) 4.6 (2.2), Bath Ankylosing Spondylitis Functioning Index (BASFI) 4.7 (2.5), Ankylosing Spondylitis Disease Activity Score with C-Reactive Protein (ASDAS-CRP) 2.2 (1.0). Axial SpA was established in 44 patients (ankylosing spondylitis (AS) = 30, non-radiographic axial SpA (nr-axSpA) = 14) and peripheral SpA in 6 patients. The score of the ASAS-HI was 8.2 (5.1). The test-retest reliability was good with an ICC of 0.84. SRM was 2.58 (1.75-3.37) in 10 patients with any intervention and 2.94 (2.13-4.24) for 7 patients starting TNF blockers. Construct validity showed a good correlation between ASAS-HI and pain, BASDAI, BASFI, and Ankylosing Spondylitis Disease Activity Score (ASDAS) (r ≥ 0.60). A high internal consistency was found with a Cronbach's α of 0.91. ASAS-HI discriminated well between patients with different stages of disease activity (BASDAI and ASDAS). Those with higher disease activity had higher ASAS-HI scores. The Spanish language translation of the ASAS-HI has proven to be psychometrically valid for Colombian patients with SpA. This version is available to evaluate the state of health and functioning in these patients and can be used in clinical practice.

Genetic diagnostic profiling in axial spondyloarthritis: a real world study.

OBJECTIVES: Spondyloarthritis (SpA) is often diagnosed late in the course of the disease and improved methods for early diagnosis are required. We have tested the ability of genetic profiling to diagnose axial SpA (axSpA) as a whole group, or ankylosing spondylitis (AS) alone, in a cohort of chronic back pain patients. METHODS: 282 patients were recruited from centres in the United Kingdom, Germany, Taiwan, Canada, Columbia and Turkey as part of the ASAS classification criteria for axSpA study (ASAS cohort). Subjects were classified according to the ASAS axSpA criteria, and the modified New York Criteria for AS. Patients were genotyped for ~200,000 immune-mediated disease SNPs using the Illumina Immunochip. RESULTS: We first established the predictive accuracy of genetic data comparing 9,638 healthy controls and 4,428 AS cases from the homogenous International Genetics of AS (IGAS) Consortium Immunochip study which showed excellent predictive power (AUC=0.91). Genetic risk scores had lower predictive power (AUC=0.83) comparing ASAS cohort axSpA cases meeting the ASAS imaging criteria with IGAS controls. Comparing genetic risk scores showed moderate discriminatory capacity between IGAS AS and ASAS imaging positive cases (AUC 0.67±0.05), indicating that significant differences in genetic makeup exist between the cohorts. CONCLUSIONS: In a clinical setting of referred back pain patients suspected to have axial SpA we were unable to use genetic data to construct a predictive model better than that based on existing clinical data. Potential confounding factors include significant heterogeneity in the ASAS cohort, possibly reflecting the disease heterogeneity of axSpA, or differences between centres in ascertainment or classification performance.

Factors associated with the decision of the rheumatologist to order sacroiliac joints magnetic resonance imaging (SI-MRI) or HLA-B27 testing in the diagnostic work-up of patients with spondyloarthritis in clinical practice.

OBJECTIVES: To evaluate the patients' characteristics associated with the clinical decision to request SI-MRI and/or HLA-B27 in patients with SpA in daily practice. METHODS: Patients referred to a rheumatology outpatient-clinic in a national referral-centre were selected. Patients with a clinical diagnosis of SpA according to the rheumatologist were included. SI-MRI and HLA-B27 was available for patients in whom the rheumatologists had ordered these tests. Characteristics associated with ordering SI-MRI or HLA-B27 were identified with univariable analyses. Variables with p-value <0.05 and >80% completeness were selected for further analysis. A multivariable logistic regression analysis was used to evaluate the determinants related with the decision to perform SI-MRI and/or HLA-B27 and odds ratios with 95% confidence intervals were calculated. RESULTS: In total, 581 patients with SpA were included in the cohort, 72% were men, mean age 34.6±12.1 and disease duration 7.3±9.7 years. Of these patients, 24% (n=137) had SI-MRI and 77% (n=441) had HLA-B27 tests ordered. Independently predictive factors for ordering a SI-MRI were the presence of IBP (OR=1.81), enthesitis (OR=1.57) and the number of initial-symptoms at presentation (OR=1.27 per additional symptom present). Independently predictive factors of HLA-B27 testing were the number of initial-symptoms (OR=1.45 per symptom) and uveitis (OR=3.19). CONCLUSIONS: This study strongly suggests that rheumatologists use certain clinical clues to decide if they order expensive and scarce tests in the diagnostic work-up of SpA patients. These manifestations may increase the efficiency of these tests in clinical practice and suggest that clinical reasoning follows principles of Bayesian theory.

Analysis and performance of various classification criteria sets in a Colombian cohort of patients with spondyloarthritis.

The objective of this study was to investigate the performance of classification criteria sets (Assessment of SpondyloArthritis international Society (ASAS), European Spondylarthropathy Study Group (ESSG), and Amor) for spondyloarthritis (SpA) in a clinical practice cohort in Colombia and provide insight into how rheumatologists follow the diagnostic path in patients suspected of SpA. Patients with a rheumatologist's diagnosis of SpA were retrospectively classified according to three criteria sets. Classification rate was defined as the proportion of patients fulfilling a particular criterion. Characteristics of patients fulfilling and not fulfilling each criterion were compared. The ASAS criteria classified 81 % of all patients (n = 581) as having either axial SpA (44 %) or peripheral SpA (37 %), whereas a lower proportion met ESSG criteria (74 %) and Amor criteria (53 %). There was a high degree of overlap among the different criteria, and 42 % of the patients met all three criteria. Patients fulfilling all three criteria sets were older (36 vs. 30 years), had more SpA features (3 vs. 1 features), and more frequently had a current or past history of back pain (77 vs. 43 %), inflammatory back pain (47 vs. 13 %), enthesitis (67 vs. 26 %), and buttock pain (37 vs. 13 %) vs. those not fulfilling any criteria. HLA-B27, radiographs, and MRI-SI were performed in 77, 59, and 24 % of the patients, respectively. The ASAS criteria classified more patients as having SpA in this Colombian cohort when the rheumatologist's diagnosis is used as an external standard. Although physicians do not perform HLA-B27 or imaging in all patients, they do require these tests if the clinical symptoms fall short of confirming SpA and suspicion remains.

Comparison of recommendations for the use of anti-tumour necrosis factor therapy in ankylosing spondylitis in 23 countries worldwide.

OBJECTIVE: To give an overview of the recommendations for the use of anti-TNF-α therapy in AS in 23 countries worldwide. METHODS: The recommendations were collected, translated and a summary was checked by Assessment of SpondyloArthritis International Society (ASAS) members from the respective countries. The recommendations were compared with the ASAS recommendations (2006) on three aspects: patient selection for initiation of treatment (diagnosis, disease activity, previous treatment and contraindications), assessment of disease and assessment of response. RESULTS: The majority of the recommendations are similar to the ASAS recommendation with regard to patient selection, assessment of disease and treatment response. Additional objective assessments of disease activity are required in eight countries, leading to a more strict indication to start anti-TNF-α therapy. CONCLUSION; Most national recommendations follow the international ASAS recommendations, suggesting that the latter are widely implemented. This might contribute to comparable access with anti-TNF-α treatment across countries. This article shows that general consensus exists about the use of anti-TNF-α therapy in AS across the world, although some countries require additional objective signs of inflammation and/or more pre-treatment, which limits access.