[The role of HLA-B27 in the pathogenesis and diagnosis of axial spondyloarthritis : 50 years after discovery of the strong genetic association]. / Zur Rolle von HLA-B27 in der Pathogenese und Diagnostik der axialen Spondyloarthritis : 50 Jahre nach Entdeckung der starken genetischen Assoziation.

BACKGROUND: The association of the human lymphocyte antigen B27 (HLA-B27) with ankylosing spondylitis (AS), also now called axial spondylarthritis (axSpA), was first described 50 years ago. OBJECTIVE: This article gives an overview of the available knowledge on the topic. MATERIAL AND METHODS: This is a narrative review based on the experience of the authors. RESULTS: The HLA-B27 is a member of the HLA class I family of genes of the major histocompatibility complex (MHC). The prevalence of HLA-B27 in the central European population is approximately 8 %, i.e., the vast majority of carriers of HLA-B27+ remain healthy. The frequency of HLA-B27 shows a decline from north to south. The HLA-B27 explains only 30 % of the genetic burden of axSpA. The prevalence of the disease correlates with the frequency of HLA-B27 in the population, i.e., there are geographic differences. Approximately 60-90 % of patients with axSpA worldwide are HLA-B27+. Some 200 subtypes of HLA-B27 can be differentiated using the polymerase chain reaction (PCR). In Thailand and Sardinia two subtypes were found that are not associated with axSpA. The physiological function of HLA class I molecules is the defence of the organism against microbes. Microbial peptides are presented to the immune system, which can be specifically attacked by CD8+ T­cells. Genetic polymorphisms of the enzyme endoplasmic reticulum aminopeptidase 1 (ERAP1), which breaks down peptides in the endoplasmic reticulum, are associated only with HLA-B27+ diseases. DISCUSSION: The pathogenesis of axSpA is unclear but a major hypothesis is that of the arthritogenic peptides. In this it is assumed that potentially pathogenic foreign or autologous peptides can be presented by HLA-B27. If nothing else, HLA-B27 plays an important role in the diagnosis, classification and determination of the severity of axSpA.

Case report: Cerebral amyloid angiopathy-related inflammation in a patient with granulomatosis with polyangiitis.

Background: Cerebral amyloid angiopathy-related inflammation (CAA-ri) defines a subacute autoimmune encephalopathy, which is presumably caused by increased CSF concentrations of anti-Aß autoantibodies. This autoinflammatory reaction is temporally and regionally associated with microglial activation, inflammation and radiological presence of vasogenic edema. Clinical characteristics include progressive demential development as well as headache and epileptic seizures. In the absence of histopathologic confirmation, the criteria defined by Auriel et al. allow diagnosis of probable resp. possible CAA-ri. CAA-ri shows responsiveness to immunosuppressive therapies and a possible coexistence with other autoinflammatory diseases. Methods: We present a case report and literature review on the diagnosis of CAA-ri in a patient with known granulomatosis with polyangiitis (GPA). Results: Initially, the presented patient showed neuropsychiatric abnormalities and latent arm paresis. Due to slight increase in CSF cell count, an initial antiviral therapy was started. MR tomography showed a pronounced frontotemporal edema as well as cerebral microhemorrhages, leading to the diagnosis of CAA-ri. Subsequent high-dose steroid treatment followed by six intravenous cyclophosphamide pulses resulted in decreased CSF cell count and regression of cerebral MRI findings. Conclusion: The symptoms observed in the patient are consistent with previous case reports on CAA-ri. Due to previously known GPA, we considered a cerebral manifestation of this disease as a differential diagnosis. However, absence of pachymeningitis as well as granulomatous infiltrations on imaging made cerebral GPA less likely. An increased risk for Aß-associated pathologies in systemic rheumatic diseases is discussed variously.

ASAS-EULAR recommendations for the management of axial spondyloarthritis: 2022 update.

OBJECTIVES: To update the Assessment of SpondyloArthritis international Society (ASAS)-EULAR recommendations for the management of axial spondyloarthritis (axSpA). METHODS: Following the EULAR Standardised Operating Procedures, two systematic literature reviews were conducted on non-pharmacological and pharmacological treatment of axSpA. In a task force meeting, the evidence was presented, discussed, and overarching principles and recommendations were updated, followed by voting. RESULTS: Five overarching principles and 15 recommendations with a focus on personalised medicine were agreed: eight remained unchanged from the previous recommendations; three with minor edits on nomenclature; two with relevant updates (#9, 12); two newly formulated (#10, 11). The first five recommendations focus on treatment target and monitoring, non-pharmacological management and non-steroidal anti-inflammatory drugs (NSAIDs) as first-choice pharmacological treatment. Recommendations 6-8 deal with analgesics and discourage long-term glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for pure axial involvement. Recommendation 9 describes the indication of biological DMARDs (bDMARDs, that is, tumour necrosis factor inhibitors (TNFi), interleukin-17 inhibitors (IL-17i)) and targeted synthetic DMARDs (tsDMARDs, ie, Janus kinase inhibitors) for patients who have Ankylosing Spondylitis Disease Activity Score ≥2.1 and failed ≥2 NSAIDs and also have either elevated C reactive protein, MRI inflammation of sacroiliac joints or radiographic sacroiliitis. Current practice is to start a TNFi or IL-17i. Recommendation 10 addresses extramusculoskeletal manifestations with TNF monoclonal antibodies preferred for recurrent uveitis or inflammatory bowel disease, and IL-17i for significant psoriasis. Treatment failure should prompt re-evaluation of the diagnosis and consideration of the presence of comorbidities (#11). If active axSpA is confirmed, switching to another b/tsDMARD is recommended (#12). Tapering, rather than immediate discontinuation of a bDMARD, can be considered in patients in sustained remission (#13). The last recommendations (#14, 15) deal with surgery and spinal fractures. CONCLUSIONS: The 2022 ASAS-EULAR recommendations provide up-to-date guidance on the management of patients with axSpA.

Treatment with tumour necrosis factor inhibitors is associated with a time-shifted retardation of radiographic spinal progression in patients with axial spondyloarthritis.

OBJECTIVE: The objective of the current study was to analyse the association between treatment with tumour necrosis factor inhibitors (TNFi) and radiographic spinal progression in patients with axial spondyloarthritis (axSpA) from a long-term inception cohort. METHODS: A total of 243 patients with axSpA from the German Spondyloarthritis Inception Cohort with at least two sets of spinal radiographs obtained at least 2 years apart during a 10-year follow-up were included. Spinal radiographs were evaluated by three trained and calibrated readers according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The association between the current TNFi, previous TNFi and radiographic spinal progression defined as the absolute mSASSS change score over 2 years was analysed using longitudinal generalised estimating equations analysis. RESULTS: TNFi treatment in the current 2-year interval was not associated with retardation of radiographic spinal progression (ß=-0.02 (95% CI -0.37 to 0.34) and -0.17 (95% CI -0.54 to 0.20) for any and ≥12 months treatment duration, respectively, adjusted for sex, the Ankylosing Spondylitis Disease Activity Score, smoking, presence of definite radiographic sacroiliitis, mSASSS at baseline and non-steroidal anti-inflammatory drug intake). TNFi treatment in the previous 2-year interval, was, however, significantly associated with reduction of mSASSS progression, which was especially evident in patients who received TNFi in the previous and in the current intervals: ß=-0.58 (95% CI -1.02 to -0.13), adjusted for the same variables. CONCLUSION: TNFi treatment was associated with a time-shifted effect on radiographic spinal progression in axSpA that became evident between years 2 and 4 after treatment initiation.

Certolizumab Pegol Efficacy in Patients With Non-Radiographic Axial Spondyloarthritis Stratified by Baseline MRI and C-Reactive Protein Status: An Analysis From the C-axSpAnd Study.

OBJECTIVE: Tumor necrosis factor inhibitors (TNFi) are an effective treatment for non-radiographic axial spondyloarthritis (nr-axSpA). To be eligible, however, many authorities require patients with nr-axSpA to show active sacroiliitis on magnetic resonance imaging (MRI) and/or an elevated C-reactive protein (CRP) level, possibly resulting in a perception that patients with nr-axSpA without both factors have only low responses to TNFi treatment. We evaluated clinical responses to certolizumab pegol (CZP) in patients with nr-axSpA stratified by baseline MRI/CRP status. METHODS: C-axSpAnd was a phase 3, multicenter study on CZP in adult patients with active nr-axSpA and objective signs of inflammation. This analysis assessed efficacy of CZP over the 52-week randomized, double-blind, placebo-controlled period in patients stratified into subgroups based on the presence of active sacroiliitis on MRI and CRP level at baseline. RESULTS: CZP-treated patients across all MRI/CRP subgroups achieved clinical responses greater than placebo. Across outcome measures, CZP-treated MRI+/CRP+ patients demonstrated the greatest clinical responses, but substantial improvements were also observed in CZP-treated MRI+/CRP- and MRI-/CRP+ patients. Ankylosing Spondylitis Disease Activity Score Major Improvement response rates at week 52 among CZP-treated patients (75.6% MRI+/CRP+; 47.5% MRI-/CRP+; and 29.7% MRI+/CRP-) were higher than rates in placebo groups (range: 3.9%-12.5%). Assessment of SpondyloArthritis international Society 40% response, Bath Ankylosing Spondylitis Disease Activity Index, and Bath Ankylosing Spondyloarthritis Functional Index had similar response patterns, although differences between the CZP-treated MRI/CRP subgroups were smaller. Clinical responses among CZP-treated patients were also observed in additional subgroups, including those with low Spondyloarthritis Research Consortium of Canada MRI sacroiliac joint inflammation scores and those with normal baseline CRP levels. CONCLUSION: Our findings indicate that CZP treatment benefits patients with nr-axSpA across MRI+/CRP+, MRI-/CRP+, and MRI+/CRP- subgroups.

Treatment With Tumor Necrosis Factor Inhibitors Is Associated With a Time-Shifted Retardation of Radiographic Sacroiliitis Progression in Patients With Axial Spondyloarthritis: 10-Year Results From the German Spondyloarthritis Inception Cohort.

OBJECTIVE: To investigate the longitudinal association between radiographic sacroiliitis progression and treatment with tumor necrosis factor inhibitors (TNFi) in patients with early axial spondyloarthritis (SpA) in a long-term inception cohort. METHODS: We included patients from the German Spondyloarthritis Inception Cohort who underwent radiographic assessment of the sacroiliac joints at baseline and at least once more during the 10-year follow-up. Two central readers scored the radiographs according to the modified New York criteria for ankylosing spondylitis. The sacroiliac sum score was calculated as a mean of the scores determined by both readers. TNFi use was assessed according to exposure in the current and/or previous 2-year radiographic interval. The association between TNFi use and radiographic sacroiliitis progression was examined by longitudinal generalized estimating equation analysis with adjustment for potential confounders. RESULTS: In this long-term inception cohort, 10-year follow-up data on 737 radiographic intervals assessed in 301 patients with axial SpA (166 patients with nonradiographic axial SpA and 135 patients with radiographic axial SpA) were obtained. Having received ≥12 months of treatment with TNFi in the previous 2-year radiographic interval was associated with a significant decrease in the sacroiliitis sum score (ß = -0.09 [95% confidence interval (95% CI) -0.18, -0.003]; analyses adjusted for age, sex, symptom duration, HLA-B27 status, Bath Ankylosing Spondylitis Disease Activity Index score, C-reactive protein, and nonsteroidal antiinflammatory drug intake). In contrast, among patients receiving TNFi in the current radiographic interval, there was no significant association with change in the sacroiliitis sum score (ß = 0.05 [95% CI -0.05, 0.14]). This effect of having received ≥12 months of treatment with TNFi in the previous 2-year radiographic interval was stronger in patients with nonradiographic axial SpA as compared to patients with radiographic axial SpA (ß = -0.16 [95% CI -0.28, -0.03] versus ß = -0.04 [95% CI -0.15, 0.07]). CONCLUSION: Treatment with TNFi was associated with the reduction in radiographic sacroiliitis progression in patients with axial SpA. This effect became evident between 2 and 4 years after treatment was initiated.

Long-term safety and clinical outcomes of certolizumab pegol treatment in patients with active non-radiographic axial spondyloarthritis: 3-year results from the phase 3 C-axSpAnd study.

BACKGROUND: 52-week results from C-axSpAnd demonstrated the safety and efficacy of certolizumab pegol (CZP) in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) and objective signs of inflammation (sacroiliitis on MRI and/or elevated C-reactive protein levels). Long-term safety and clinical outcomes, including MRI assessments, are evaluated up to 3 years for CZP-treated patients with nr-axSpA. METHODS: C-axSpAnd was a phase 3 study comprising a 1-year double-blind, placebo-controlled period and 2-year open-label safety follow-up extension (SFE). At baseline, 317 patients were randomised 1:1 to placebo or CZP 200 mg every 2 weeks. Patients completing the double-blind phase who enrolled into the SFE received open-label CZP for an additional 104 weeks. Long-term safety and clinical outcomes are reported to Week 156. Continuous outcomes are presented as observed case (OC) and dichotomous outcomes as OC and with non-responder imputation. RESULTS: 243/317 (76.7%) patients entered the SFE, during which 149 (61.3%) experienced ≥1 treatment-emergent adverse event (TEAE); 15 (3.3/100 patient-years) experienced serious TEAEs. Continuous outcome scores (including Ankylosing Spondylitis Disease Activity Score [ASDAS]: 1.8; Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]: 2.7) at Week 52 were maintained at Week 156 (ASDAS: 1.8; BASDAI: 2.6) for the initial CZP-randomised group. Mean SPARCC MRI sacroiliac joint inflammation scores for these patients decreased at Week 52 (baseline: 7.6; Week 52: 1.7), remaining low at Week 156 (2.4). CONCLUSIONS: CZP treatment was well tolerated up to 3 years, with no new safety signals versus previous reports. Clinical outcomes achieved after 1 year were sustained to 3 years. TRIAL REGISTRATION NUMBER: NCT02552212.

Data-driven definitions for active and structural MRI lesions in the sacroiliac joint in spondyloarthritis and their predictive utility.

OBJECTIVES: To determine quantitative SI joint MRI lesion cut-offs that optimally define a positive MRI for inflammatory and structural lesions typical of axial SpA (axSpA) and that predict clinical diagnosis. METHODS: The Assessment of SpondyloArthritis international Society (ASAS) MRI group assessed MRIs from the ASAS Classification Cohort in two reading exercises where (A) 169 cases and 7 central readers; (B) 107 cases and 8 central readers. We calculated sensitivity/specificity for the number of SI joint quadrants or slices with bone marrow oedema (BME), erosion, fat lesion, where a majority of central readers had high confidence there was a definite active or structural lesion. Cut-offs with ≥95% specificity were analysed for their predictive utility for follow-up rheumatologist diagnosis of axSpA by calculating positive/negative predictive values (PPVs/NPVs) and selecting cut-offs with PPV ≥ 95%. RESULTS: Active or structural lesions typical of axSpA on MRI had PPVs ≥ 95% for clinical diagnosis of axSpA. Cut-offs that best reflected a definite active lesion typical of axSpA were either ≥4 SI joint quadrants with BME at any location or at the same location in ≥3 consecutive slices. For definite structural lesion, the optimal cut-offs were any one of ≥3 SI joint quadrants with erosion or ≥5 with fat lesions, erosion at the same location for ≥2 consecutive slices, fat lesions at the same location for ≥3 consecutive slices, or presence of a deep (i.e. >1 cm depth) fat lesion. CONCLUSION: We propose cut-offs for definite active and structural lesions typical of axSpA that have high PPVs for a long-term clinical diagnosis of axSpA for application in disease classification and clinical research.

Relation of α2-Antiplasmin Genotype and Genetic Determinants of Fibrinogen Synthesis and Fibrin Clot Formation with Vascular Endothelial Growth Factor Level in Axial Spondyloarthritis.

OBJECTIVE: Coagulation and fibrinolysis are interrelated with the expression of vascular endothelial growth factor (VEGF), which frequently is increased in axial spondyloarthritis (axSpA). We tested whether (i) α2-antiplasmin (A2AP) Arg6Trp, (ii) fibrinogen, factor XIII A-subunit or B-subunit genotypes are associated with VEGF levels and assessed whether the known association between elevated VEGF and radiographic spinal progression in axSpA depends on genetic background. METHODS: One hundred and eighty-six axSpA patients from the German Spondyloarthritis Inception Cohort were genotyped, characterized for VEGF levels, and statistically analyzed. The association between VEGF and radiographic spinal progression was assessed in dependence on genetic background in stratified analyses. RESULTS: A2AP 6Trp carriage was associated with VEGF elevation (OR: 2.37, 95% CI: 1.06-5.29) and VEGF levels (6Trp, 455 ± 334 pg/mL; 6Arg/Arg, 373 ± 293 pg/mL; p < 0.008). Association between elevated VEGF and radiographic spinal progression in axSpA (OR: 3.11, 95% CI: 1.02-8.82) depended remarkably on the fibrinogen (FGA) genotype. When considering axSpA patients with elevated VEGF, in FGA rs6050A>G wild types, 42.1% of patients (8 of 19) progressed, while in G-allele carriers, no radiographic progression happened (0 of 13) (p < 0.04). CONCLUSIONS: The A2AP Arg6Trp genotype seems to influence VEGF levels in axSpA. The predictive value of VEGF elevations in respect of radiographic spinal progression in axSpA depends on FGA genotypes.

The impact of certolizumab pegol treatment on the incidence of anterior uveitis flares in patients with axial spondyloarthritis: 48-week interim results from C-VIEW.

BACKGROUND: Acute anterior uveitis (AAU) is the most common extra-articular manifestation in patients with axial spondyloarthritis (axSpA). C-VIEW investigates the impact of the Fc-free TNF inhibitor certolizumab pegol (CZP) on AAU flares in patients with active axSpA at high risk of recurrent AAU. METHODS: C-VIEW (NCT03020992) is a 96-week ongoing, multicentre, open-label, phase 4 study. Included patients had an axSpA diagnosis, a history of recurrent AAU (≥2 AAU flares, ≥1 flare in the year prior to study entry), HLA-B27 positivity, active disease, and failure of ≥2 non-steroidal anti-inflammatory drugs. Patients received CZP 400 mg at Weeks 0/2/4, then 200 mg every 2 weeks up to 96 weeks. This 48-week pre-planned interim analysis compares AAU flare incidence in the 48 weeks before and after initiation of CZP treatment, using Poisson regression to account for possible within-patient correlations. RESULTS: In total, 89 patients were included (male: 63%; radiographic/non-radiographic axSpA: 85%/15%; mean axSpA disease duration: 8.6 years). During 48 weeks' CZP treatment, 13 (15%) patients experienced 15 AAU flares, representing an 87% reduction in AAU incidence rate (146.6 per 100 patient-years (PY) in the 48 weeks pre-baseline to 18.7 per 100 PY during CZP treatment). Poisson regression analysis showed that the incidence rate of AAU per patient reduced from 1.5 to 0.2 (p<0.001). No new safety signals were identified. CONCLUSIONS: There was a significant reduction in the AAU flare rate during 48 weeks of CZP treatment, indicating that CZP is a suitable treatment option for patients with active axSpA and a history of recurrent AAU.

MRI lesions in the sacroiliac joints of patients with spondyloarthritis: an update of definitions and validation by the ASAS MRI working group.

OBJECTIVES: The Assessment of SpondyloArthritis international Society (ASAS) MRI working group (WG) was convened to generate a consensus update on standardised definitions for MRI lesions in the sacroiliac joint (SIJ) of patients with spondyloarthritis (SpA), and to conduct preliminary validation. METHODS: The literature pertaining to these MRI lesion definitions was discussed at three meetings of the group. 25 investigators (20 rheumatologists, 5 radiologists) determined which definitions should be retained or required revision, and which required a new definition. Lesion definitions were assessed in a multi-reader validation exercise using 278 MRI scans from the ASAS classification cohort by global assessment (lesion present/absent) and detailed scoring (inflammation and structural). Reliability of detection of lesions was analysed using kappa statistics and the intraclass correlation coefficient (ICC). RESULTS: No revisions were made to the current ASAS definition of a positive SIJ MRI or definitions for subchondral inflammation and sclerosis. The following definitions were revised: capsulitis, enthesitis, fat lesion and erosion. New definitions were developed for joint space enhancement, joint space fluid, fat metaplasia in an erosion cavity, ankylosis and bone bud. The most frequently detected structural lesion, erosion, was detected almost as reliably as subchondral inflammation (κappa/ICC:0.61/0.54 and 0.60/0.83) . Fat metaplasia in an erosion cavity and ankylosis were also reliably detected despite their low frequency (κappa/ICC:0.50/0.37 and 0.58/0.97). CONCLUSION: The ASAS-MRI WG concluded that several definitions required revision and some new definitions were necessary. Multi-reader validation demonstrated substantial reliability for the most frequently detected lesions and comparable reliability between active and structural lesions.

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 ≥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 < 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.

Added value of biomarkers compared with clinical parameters for the prediction of radiographic spinal progression in axial spondyloarthritis.

OBJECTIVES: The objective of this study was to examine whether adding biomarkers to routine clinical parameters improves prediction of radiographic spinal progression in axial spondyloarthritis. METHODS: One hundred and seventeen patients with ankylosing spondylitis who completed the Effects of NSAIDs on RAdiographic Damage in Ankylosing Spondylitis (ENRADAS) trial were included. Radiographic spinal progression was defined as worsening of the modified Stoke Ankylosing Spondylitis Spine Score by ⩾2 points after 2 years. A clinical prediction model was constructed out of baseline syndesmophytes, elevated CRP, cigarette smoking and male sex. The following serum biomarkers were measured at baseline by ELISA: MMP3, VEGF, calprotectin, leptin, high molecular weight adiponectin, osteoprotegerin, sclerostin, N-terminal telopeptide, procollagen type II N-terminal propeptide and serum amyloid A. RESULTS: Repeated cross-validation analyses revealed one biomarker combination with potential added predictive value in addition to the clinical model: leptin + high molecular weight adiponectin + VEGF. This biomarker combination showed an area under the curve (AUC)Biomarkers = 0.731 (95% CI: 0.614, 0.848), which was numerically superior to the clinical model [AUCClinical = 0.665 (95% CI: 0.553, 0.776)]. A combination of clinical parameters + biomarkers showed an improved predictive value compared with the clinical model reflected by AUCClinical+Biomarkers = 0.768 (95% CI: 0.666, 0.871), though not statistically significant (P = 0.051). However, by considering the part of the receiver operating characteristic curve with a specificity ⩾75% resulting in partial AUC (pAUC), the improvement becomes significant (pAUCClinical+Biomarkers = 0.119; pAUCClinical = 0.053; P = 0.01). CONCLUSION: Biomarkers show potential to improve the prediction of radiographic spinal progression in axial spondyloarthritis when used in addition to the clinical parameters, though the added value seems to be rather small.

Is active sacroiliitis on MRI associated with radiographic damage in axial spondyloarthritis? Real-life data from the ASAS and DESIR cohorts.

OBJECTIVE: To assess any association between bone marrow oedema on MRI of the sacroiliac joints (MRI-SIJ) according to local readings in daily practice and the development of structural damage on radiographs of the SIJ (X-SIJ) in axial spondyloarthritis (axSpA). METHODS: Patients with axSpA from the Assessment of the SpondyloArthritis international Society (ASAS) and DEvenir des Spondylarthopathies Indifférenciées Récentes (DESIR) multicentre cohorts were included. MRI-SIJ and X-SIJ were obtained at baseline, and X-SIJ at follow-up after a mean 4.6 years (ASAS) and 5.1 years (DESIR). All images were scored by local readers. Structural damage in the X-SIJ was defined according to the modified New York criteria. The percentage of structural net progression (number of 'progressors' minus the number of 'regressors' divided by the total number of patients) was assessed and the effect of bone marrow oedema on MRI-SIJ on X-SIJ damage evaluated by multivariable logistic regression. RESULTS: In total, 125 (ASAS-cohort) and 415 (DESIR-cohort) patients had baseline MRI-SIJ and complete X-SIJ data available. According to local readings, progression and 'improvement' in X-SIJ was seen in both the ASAS- and DESIR-cohort, yielding a net progression that was higher in the former than in the latter (19.2% and 6.3%). In multivariable analysis, baseline bone marrow oedema on MRI-SIJ was strongly associated with X-SIJ structural progression in both ASAS (odds ratio = 3.2 [95% CI: 1.3; 7.9]), and DESIR (odds ratio = 7.6 [95% CI: 4.3; 13.2]). CONCLUSION: Inflammation on MRI-SIJ is associated with future radiographic progression according to local readings despite an expected increased imprecision invoked by local readings.

Treating axial spondyloarthritis and peripheral spondyloarthritis, especially psoriatic arthritis, to target: 2017 update of recommendations by an international task force.

Therapeutic targets have been defined for axial and peripheral spondyloarthritis (SpA) in 2012, but the evidence for these recommendations was only of indirect nature. These recommendations were re-evaluated in light of new insights. Based on the results of a systematic literature review and expert opinion, a task force of rheumatologists, dermatologists, patients and a health professional developed an update of the 2012 recommendations. These underwent intensive discussions, on site voting and subsequent anonymous electronic voting on levels of agreement with each item. A set of 5 overarching principles and 11 recommendations were developed and voted on. Some items were present in the previous recommendations, while others were significantly changed or newly formulated. The 2017 task force arrived at a single set of recommendations for axial and peripheral SpA, including psoriatic arthritis (PsA). The most exhaustive discussions related to whether PsA should be assessed using unidimensional composite scores for its different domains or multidimensional scores that comprise multiple domains. This question was not resolved and constitutes an important research agenda. There was broad agreement, now better supported by data than in 2012, that remission/inactive disease and, alternatively, low/minimal disease activity are the principal targets for the treatment of PsA. As instruments to assess the patients on the path to the target, the Ankylosing Spondylitis Disease Activity Score (ASDAS) for axial SpA and the Disease Activity index for PSoriatic Arthritis (DAPSA) and Minimal Disease Activity (MDA) for PsA were recommended, although not supported by all. Shared decision-making between the clinician and the patient was seen as pivotal to the process. The task force defined the treatment target for SpA as remission or low disease activity and developed a large research agenda to further advance the field.

Serum levels of leptin and high molecular weight adiponectin are inversely associated with radiographic spinal progression in patients with ankylosing spondylitis: results from the ENRADAS trial.

BACKGROUND: Previous research indicates a role of adipokines in inflammation and osteogenesis. Hence adipokines might also have a pathophysiological role in inflammation and new bone formation in patients with ankylosing spondylitis (AS). The aim of this study was to investigate the role of adipokine serum levels as predictors of radiographic spinal progression in patients with AS. METHODS: A total of 120 patients with definite AS who completed a 2-year follow up in the ENRADAS trial were included in the current study. Radiographic spinal progression was defined as: (1) worsening of the modified Stoke Ankylosing Spondylitis spine (mSASSS) score by ≥2 points and/or (2) new syndesmophyte formation or progression of existing syndesmophytes after 2 years. Serum levels of adipokines (adiponectin (APN) and its high molecular weight form (HMW-APN), chemerin, leptin, lipocalin-2, omentin, resistin, visfatin) were measured using enzyme-linked immunosorbent assays. RESULTS: There was a significant association between radiographic spinal progression and both leptin and HMW-APN. Baseline serum levels of both adipokines were lower in patients who showed radiographic spinal progression after 2 years. This association was especially evident in men; they had generally lower leptin and HMW-APN serum levels as compared to women. The inverse association between adipokines and radiographic spinal progression was confirmed in the logistic regression analysis: the odds ratios (OR) for the outcome "no mSASSS progression ≥2 points" were 1.16 (95% CI 1.03 to 1.29) and 1.17 (95% CI 0.99 to 1.38), for leptin and HMW-APN, respectively; for "no syndesmophyte formation/progression" the respective OR were 1.29 (95% CI 1.11 to 1.50) and 1.18 (95% CI 0.98 to 1.42), adjusted for the presence of syndesmophytes at baseline, C-reactive protein at baseline, sex, body mass index (BMI), non-steroidal anti-inflammatory drugs intake score over 2 years, and smoking status at baseline. CONCLUSION: Serum leptin and HMW-APN predict protection from spinal radiographic progression in patients with AS. Women generally have higher leptin and HMW-APN serum levels that might explain why they have less structural damage in the spine as compared to male patients with AS. TRIAL REGISTRATION: EudraCT: 2007-007637-39. ClinicalTrials.gov, NCT00715091 . Registered on 14 July 2008.

Sustained efficacy, safety and patient-reported outcomes of certolizumab pegol in axial spondyloarthritis: 4-year outcomes from RAPID-axSpA.

Objective: The aim was to assess the long-term safety and efficacy of certolizumab pegol over 4 years of continuous treatment in patients with axial spondyloarthritis (axSpA), including both AS and non-radiographic (nr-) axSpA. Methods: RAPID-axSpA was a phase 3 randomized trial, double blind and placebo controlled to week 24, dose blind to week 48 and open label to week 204. Patients had a clinical diagnosis of axSpA, meeting Assessment of SpondyloArthritis international Society (ASAS) criteria, and had active disease. The assessed outcomes included ASAS20, ASAS40, AS DAS (ASDAS), BASDAI, BASFI and BASMI scores, along with selected measures of remission. Further patient-reported outcomes, peripheral arthritis, enthesitis, uveitis and quality-of-life measures are also reported. Results: Two hundred and eighteen of 325 patients randomized (AS: 121; nr-axSpA: 97) received certolizumab pegol from week 0. Of these, 65% remained in the study at week 204 (AS: 67%; nr-axSpA: 63%). Across all outcomes, for AS and nr-axSpA, sustained improvements were observed to week 204 [week 204 overall axSpA: ASAS20: 54.1% (non-responder imputation); 83.7% (observed case, OC); ASAS40: 44.0% (non-responder imputation); 68.1% (OC); ASDAS inactive disease: 32.1% (last observation carried forward); 31.4% (OC)]. In the safety set (n = 315), there were 292.8 adverse events and 10.4 serious adverse events per 100 patient-years. No deaths were reported. Conclusion: In the first study to evaluate the efficacy of an anti-TNF across both axSpA subpopulations, improvements in clinical and patient-reported outcomes at 24 and 96 weeks were sustained through 4 years of treatment, with no new safety signals. Trial registration: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01087762.

2016 update of the ASAS-EULAR management recommendations for axial spondyloarthritis.

To update and integrate the recommendations for ankylosing spondylitis and the recommendations for the use of tumour necrosis factor inhibitors (TNFi) in axial spondyloarthritis (axSpA) into one set applicable to the full spectrum of patients with axSpA. Following the latest version of the European League Against Rheumatism (EULAR) Standardised Operating Procedures, two systematic literature reviews first collected the evidence regarding all treatment options (pharmacological and non-pharmacological) that were published since 2009. After a discussion of the results in the steering group and presentation to the task force, overarching principles and recommendations were formulated, and consensus was obtained by informal voting. A total of 5 overarching principles and 13 recommendations were agreed on. The first three recommendations deal with personalised medicine including treatment target and monitoring. Recommendation 4 covers non-pharmacological management. Recommendation 5 describes the central role of non-steroidal anti-inflammatory drugs (NSAIDs) as first-choice drug treatment. Recommendations 6-8 define the rather modest role of analgesics, and disprove glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs) for axSpA patents with predominant axial involvement. Recommendation 9 refers to biological DMARDs (bDMARDs) including TNFi and IL-17 inhibitors (IL-17i) for patients with high disease activity despite the use (or intolerance/contraindication) of at least two NSAIDs. In addition, they should either have an elevated C reactive protein and/or definite inflammation on MRI and/or radiographic evidence of sacroiliitis. Current practice is to start with a TNFi. Switching to another TNFi or an IL-17i is recommended in case TNFi fails (recommendation 10). Tapering, but not stopping a bDMARD, can be considered in patients in sustained remission (recommendation 11). The final two recommendations (12, 13) deal with surgery and spinal fractures. The 2016 Assessment of SpondyloArthritis international Society-EULAR recommendations provide up-to-date guidance on the management of patients with axSpA.

Partial remission in ankylosing spondylitis and non-radiographic axial spondyloarthritis in treatment with infliximab plus naproxen or naproxen alone: associations between partial remission and baseline disease characteristics.

OBJECTIVES: To evaluate partial remission during treatment with infliximab (IFX) + naproxen (NPX) vs NPX alone in patients from the two subgroups of SpA and explore baseline predictors of partial remission. METHODS: Infliximab as First Line Therapy in Patients with Early Active Axial Spondyloarthritis Trial was a double-blind, randomised controlled trial of IFX in biologic-naïve patients with early, active axial SpA. Patients were randomised (2:1) to receive 28 weeks of treatment with i.v. IFX 5 mg/kg (weeks 0, 2, 6, 12, 18 and 24) + NPX 1000 mg/day or i.v. placebo (PBO) + NPX 1000 mg/day. The current post hoc analysis evaluated outcomes in patients who did or did not meet modified New York radiographic criteria for AS. RESULTS: The analysis included 94 patients who met AS criteria and 56 with non-radiographic axial SpA (nr-axSpA). At week 28, Assessment of SpondyloArthritis international Society (ASAS) partial remission was greater with IFX + NPX than PBO + NPX for both the AS group (70.5 vs 33.3%, respectively) and the nr-axSpA group (50.0 vs 37.5%, respectively). A similar pattern occurred with several efficacy measures. Larger treatment effects occurred in the AS group than the nr-axSpA group, possibly due to baseline differences in disease characteristics. Multivariable analyses identified the type of treatment, age and HLA-B27 status as predictors of ASAS partial remission in the total study population. MRI sacroiliac joint scores were associated with partial remission during IFX + NPX treatment. CONCLUSION: Patients with AS had greater partial remission with IFX + NSAID than NSAID therapy alone; patients with nr-axSpA had a smaller treatment effect. Baseline disease characteristics and age were associated with partial remission with IFX therapy.