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Axial spondyloarthritis (axSpA) encompasses both radiographic and non-radiographic axSpA. It is a chronic inflammatory disease with a predilection for involving the axial skeleton. The most common presenting symptoms are chronic back pain and spinal stiffness but peripheral and extra-musculoskeletal manifestations occur also frequently. The diagnosis of axSpA relies on the recognition of a clinical pattern of the disease, based on clinical, laboratory and imaging features. The Assessment in SpondyloArthritis international Society classification criteria for axSpA are valid and well implemented for research purposes. Sustained disease activity, measured by validated tools such as the Ankylosing Spondylitis Disease Activity Score, leads to irreversible structural damage and poor functioning and therefore should be abrogated. As part of the management algorithm, non-steroidal anti-inflammatory drugs remain as the first line of pharmacological treatment besides physiotherapy. As a second line, tumour necrosis factor inhibitor and interleukin-17 inhibitor are available but recently Janus kinase inhibitors have also shown efficacy in improving symptoms of the disease.

BackgroundA consensus definition for active sacroiliitis by MRI, mentioned in the Assessment of SpondyloArthritis International Society (ASAS) classification criteria for axial spondyloarthritis (axSpA), was published in 2009 and included a qualitative and quantitative MRI cut-off component. In 2021, updates to the quantitative component were preliminarily proposed. This post hoc analysis of part A of the phase 3 open-label C-OPTIMISE study (NCT02505542) explores the differences by applying the 2009 and preliminary 2021 inflammatory cut-offs on clinical outcomes of axSpA patients treated with certolizumab pegol.MethodsBaseline MRI scans were used to classify 657 patients as MRI+ or MRI– according to the quantitative components of the 2009 and preliminary 2021 MRI cut-offs for inflammatory lesions. Clinical outcomes, including ASAS ≥40% improvement (ASAS40), Ankylosing Spondylitis Disease Activity Score and Bath Ankylosing Spondylitis Disease Activity Index, were reported to week 48.ResultsAcross all analysed outcomes, 2009 MRI+ and preliminary 2021 MRI+ subgroups showed similar results. Notably, clinical outcomes for the discordant group (2009 MRI+but preliminary 2021 MRI– group; 53/657 [8.1%]) were close to those seen in MRI– patients according to either 2009 or preliminary 2021 inflammatory cut-offs, and notably different from the totality of MRI+ subgroups.ConclusionThis analysis suggests that the preliminary 2021 cut-offs for MRI inflammatory lesions may slightly increase the specificity of the quantitative part of the 2009 MRI inflammatory lesion definition. The effects of the updated MRI cut-offs need to be assessed on the basis of efficacy outcomes and with the inclusion of aspects of structural changes.Trial registration numberNCT02505542.

IntroductionThis post hoc analysis evaluated the relationship between objective measures of inflammation and clinical outcomes following 12 weeks of certolizumab pegol (CZP) treatment in patients with active axial spondyloarthritis (axSpA).MethodsWe report the proportion of patients achieving ≥50% and ≥75% improvements in clinical composite outcome measures of disease activity (Axial Spondyloarthritis Disease Activity Score [ASDAS], Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]) and objective measures of inflammation (C reactive protein [CRP], Ankylosing Spondylitis spine MRI score [ASspiMRI-a] Berlin score and Spondyloarthritis Research Consortium of Canada [SPARCC] MRI Sacroiliac Joints [SIJ] score) following 12 weeks of CZP treatment. Data from two independent readers over four MRI reading campaigns were pooled using a mixed model with repeated measures for each variable.Results136 patients (radiographic axSpA [r-axSpA]: 76; non-radiographic axSpA [nr-axSpA]: 60) were included. Following CZP treatment, CRP, ASspiMRI-a Berlin score and SPARCC SIJ score were reduced by ≥50% in most patients (CRP: 136/136 [100.0%]; Berlin: 73/136 [53.7%]; SPARCC SIJ: 71/136 [52.2%]), and often by ≥75%. Less than half of patients with r-axSpA and nr-axSpA showed ≥50% reduction in clinical responses (BASDAI: 64/136 [47.1%]; ASDAS: 66/136 [48.5%]). These results were also observed at the individual patient level; ≥50% improvements in MRI/CRP inflammatory measures did not translate into similar improvements in clinical responses for most patients.ConclusionThere is a potential disconnect between objective measures of inflammation and clinical outcome responses in patients with axSpA. The use of only clinical response measures as trial endpoints may underestimate anti-inflammatory treatment effects.Trial registration numberNCT01087762.

ObjectivesTo identify clusters of highly correlated genes enriched in biological functions and specific molecular pathways involved in the pathogenesis of radiographic damage in axial spondyloarthritis (axSpA) and to discover molecular biomarkers of radiographic progression and disease severity.MethodsA total of 144 patients with axSpA were included. First, RNA from peripheral blood mononuclear cells was sequenced in a cohort of 24 patients with axSpA. Hub genes were measured in a n=60 validation cohort through microfluidic PCR. A 5-year follow-up enabled the classification of the patients into fast/moderate or slow progressors. Machine learning approaches were applied to identify a predictive biomarker of progression by integrating gene expression data with clinical variables. An independent cohort of 60 patients with axSpA, with spine radiographs taken 5 years prior, underwent serum proteomic analysis using a Proximity Extension Assay.ResultsUnsupervised clustering analysis using transcriptomics revealed two distinct groups of patients with axSpA, differentiated by their clinical profiles. Weight gene correlation network analysis identified six gene modules differentially expressed between the two clusters. Patients in cluster 2 exhibited higher disease activity, greater functional impairment and more structural damage. Molecular alterations linked to structural damage revealed a specific circulating inflammatory proteome profile associated with disease severity. A predictive model composed of two genes and basal total modified Stoke Ankylosing Spondylitis Spinal Score emerged as a key biomarker for identifying moderate-to-fast radiographic progression.ConclusionsThis study identified molecular pathways involved in radiographic damage and discovered potential proteomic biomarkers of disease severity and transcriptomic predictors of radiographic progression in axSpA.

The study aims to evaluate the clinical efficacy, safety, pharmacokinetics, pharmacodynamics and immunogenicity of seniprutug (BCD-180) in patients with active radiographic axial spondyloarthritis (r-axSpA, or ankylosing spondylitis).Materials and methods.Two hundred sixty patients with active r-axSpA and inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs) were randomized into three groups to receive either seniprutug (BCD-180) 5 or 7 mg/kg, or placebo. BCD-180 was administered in the respective group dose using a 0–12–36 week regimen. The placebo group patients were switched to BCD-180 5 mg/kg at Week 24, with therapy continued at Week 36. The primary endpoint was the proportion of patients achieving 40% improvement in the Assessment in Spondyloarthritis International Society (ASAS40) score at Week 24.The secondary endpoints included the proportion of patients achieving an ASAS20/40 response, improvement in 5 of 6 ASAS criteria (ASAS5/6), partial remission according to ASAS, ASDAS-CRP clinically important improvement in (Ankylosing Spondylitis Disease Activity Score with C-reactive protein level, ASDAS-CII) and ASDAS-CRP major improvement (ASDAS-MI). An analysis of changes over time in the disease activity status according to ASDAS-CRP, BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and BASFI (Bath Ankylosing Spondylitis Functional Index) scores, as well as changes over time in laboratory markers (CRP and erythrocyte sedimentation rate (ESR)) was also conducted. Safety was assessed based on the frequency and profile of adverse events (AE) and adverse reactions (AR).Results.The proportion of patients who achieved an ASAS40 response at Week 24 on seniprutug (BCD-180) at doses of 7 and 5 mg/kg was 51.4 and 40.8%, respectively, compared with 24% in the Placebo group (p = 0.0012 and p = 0.0417, respectively). Analysis of secondary endpoints showed that the efficacy of BCD-180 at both study doses was statistically significantly superior to placebo in patients with r-axSpA at Week 24 in the following respects: reduction in the proportion of subjects with very high disease activity (ASDAS-CRP > 3.5), achieving ASDAS-CII, ASAS20, ASAS5/6 response. A statistically significant decrease in the ASDAS-CRP, BASDAI, BASFI score, as well as CRP and ESR levels was demonstrated. Tolerability of seniprutug therapy was assessed as acceptable. The most common AEs were infusion-related reactions, most of which were mild to moderate according to CTCAE 5.0 (Common Terminology Criteria for Adverse Events) and developed mainly during the first administration. The proportion of patients with detected binding antibodies was 5.1%. No neutralizing antibodies were detected.Conclusions.Seniprutug (BCD-180) as a therapy for r-axSpA has demonstrated superiority over placebo in the clinical efficacy, a good safety profile and low immunogenicity.

Objectives To estimate the prevalence of late-onset axial spondyloarthritis (lo-axSpA) and to identify clinical, laboratory, and imaging features associated with this phenotype. Methods This single-center, observational study included patients diagnosed with axSpA from the “Reuma-check” SpA program. Patients with a symptom onset ≥ 45 years were classified as lo-axSpA, as opposed to early-onset axSpA (eo-axSpA, onset < 45 years). The prevalence of lo-axSpA was calculated, and lo-axSpA and eo-axSpA were compared in terms of clinical, laboratory and imaging characteristics. Factors associated with lo-axSpA were analyzed with univariable followed by multivariable logistic regression. Results A total of 126 patients were included, 35 (28%) were lo-axSpA. Comparing lo-axSpA vs. eo-axSpA, significant differences were observed: higher female prevalence in lo-axSpA vs. eo-axSpA (51% vs. 29%), lower NSAID response (52% vs. 73%), increased skin psoriasis prevalence (42% vs. 17%,), and shorter diagnosis delay (40 vs. 93 months). In the multivariable analysis, male sex and diagnosis delay were independently and inversely associated with lo-axSpA (OR 0.2, 95% CI 0.06–0.8 and OR 0.9, 95% CI 0.96–0.99, respectively), while psoriasis was associated with a higher odds for lo-axSpA (OR 4.8, 95% CI 1.1–29). Conclusion lo-axSpA was present in more than a quarter of the patients. Although recall bias in the symptom duration cannot be excluded, the presentation with lo-axSpA seems to be associated with distinct features, being more frequent in females and more associated with psoriasis and with a shorter diagnostic delay. Key Points • Late-onset axSpA ( ≥  45Y) is observed in 28% in our cohort, a higher frequency than previously reported. • Female sex and psoriasis are associated with a higher likelihood for late-onset axSpA.

Background In axial spondyloarthritis (axSpA), 5–10% of patients have comorbid inflammatory bowel disease (IBD). Beyond that, 50–60% display histologic inflammation in ileum/colon biopsies, and fecal calprotectin (F-calprotectin) is elevated in relation to healthy controls. Prior studies have shown such, often subclinical, gut inflammation in axSpA to be associated with more active disease, as measured by clinical indices as well as magnetic resonance imaging – both known risk factors for structural spinal damage development. In light of this, in the current study we aimed to examine whether gut inflammation, assessed by F-calprotectin, is associated with more structural spinal damage in axSpA. Methods Patients with well-characterized non-radiographic or radiographic axSpA (nr-axSpA/r-axSpA; n  = 76/152), according to ASAS or modified New York criteria, enrolled in a population-based cohort study in southern Sweden, were assessed for structural spinal damage (modified Stoke ankylosing spondylitis spinal score [mSASSS]) and gut inflammation (F-calprotectin). mSASSS values were compared between patients with normal (< 50 mg/kg), moderately elevated (50–149 mg/kg) or distinctly elevated (≥ 150 mg/kg) F-calprotectin, reflecting no/some/evident gut inflammation, respectively (one-way ANOVA). Moreover, logistic regression was applied to explore if elevated F-calprotectin (≥ 50 mg/kg) was associated with mSASSS values above the median, adjusted for sex, symptom duration, HLA-B27 status, smoking, CRP, NSAID and anti-TNF therapy. Analyses limited to r-axSpA were also performed. Results In both axSpA patients overall and separately in r-axSpA, mSASSS distributions differed significantly between subjects with normal/moderately/distinctly elevated F-calprotectin, with more damage observed in those with higher F-calprotectin levels. Furthermore, elevated F-calprotectin (≥ 50 mg/kg) was associated with mSASSS values above the median, in both the entire axSpA group (adjusted odds ratio [OR] 2.2 [95%CI 1.1–4.2]); and in r-axSpA alone (adjusted OR 2.9 [1.2–7.1]). Conclusion In the current study, the presence of gut inflammation, assessed by F-calprotectin, was cross-sectionally associated with more structural damage in the spine in patients with axSpA, even after adjustments for known risk factors for spinal damage. Prospective studies are, however, needed to investigate whether gut inflammation may be a predictor of spinal radiographic progression in axSpA.

ObjectiveTo investigate complement system activation and complement protein levels in relation to radiographic progression in axial spondyloarthritis (axSpA) within a longitudinal randomised controlled trial (RCT) of radiographic axSpA patients initiating tumour necrosis factor inhibitor (TNFi) therapy.MethodsSerum samples from 96 patients with active radiographic axSpA in the multicentre RCT CONSUL were analysed by immunoassays for complement activation, that is, C3dg and complement proteins (MBL, CL-L1, M-, H- and L-ficolin; MASP-1,–2 and −3; and MAp44) before and after 108 weeks of TNF inhibitor therapy with golimumab.ResultsBaseline serum levels of total complement activation, that is, C3dg and lectin pathway activating protease MASP-1 were elevated in patients with new bone formation (new syndesmophytes and/or growth of existing syndesmophytes) after 2 years of follow-up, whereas baseline MASP-3 levels were decreased. Assessed by univariate logistic regression, baseline levels of MASP-1, MASP-3 and C3dg were associated with the development of new bone formation and remained significant in a corresponding multivariate logistic regression analysis. At follow-up, serum levels of C3dg and complement lectin pathway initiator L-ficolin were elevated in patients with new bone formation, and C3dg remained significant in a corresponding multivariate logistic regression analysis.ConclusionsComplement activation marker C3dg, MASP-1 and MASP-3 levels before TNFi therapy predicted new bone formation after 2 years of follow-up among axSpA patients with a high risk of radiographic progression. Furthermore, levels of L-ficolin and C3dg at follow-up were elevated in axSpA patients with new bone formation. Our findings support an association between activation of the complement system and radiographic spinal progression in patients with axSpA.

Background In SELECT-AXIS 2, upadacitinib improved the signs and symptoms of active non-radiographic axial spondyloarthritis (nr-axSpA) through 52 weeks versus placebo and was well tolerated. Here, we evaluated the efficacy and safety of upadacitinib through 2 years. Methods The study enrolled eligible adult patients with a clinical diagnosis of nr-axSpA who met the 2009 Assessment of SpondyloArthritis international Society (ASAS) classification criteria and had objective signs of active inflammation on magnetic resonance imaging (MRI) of sacroiliac joints and/or high-sensitivity C-reactive protein. Patients were randomized 1:1 to receive double-blinded treatment with upadacitinib 15 mg once daily (QD) or placebo for 52 weeks, after which all patients received open-label treatment with upadacitinib 15 mg QD. Efficacy results over 104 weeks were reported as observed (AO) and either AO with non-responder imputation (AO-NRI; binary endpoints) or AO with mixed-effect model for repeated measures (continuous endpoints). Treatment-emergent adverse events (TEAEs) were summarized through week 104. Results Of 313 patients randomized and treated, 224 (continuous upadacitinib n  = 117; placebo/upadacitinib n  = 107) completed 104 weeks of treatment. In patients who received continuous upadacitinib, sustained improvement was observed through 2 years of treatment across efficacy endpoints including disease activity, pain, function, enthesitis, quality of life, and MRI measures of inflammation. At week 104, 57.1%, 59.0%, and 31.4% of patients achieved ASAS40 response, and low disease activity and inactive disease (as defined by Axial Spondyloarthritis Disease Activity Score), respectively (AO-NRI); week 104 outcomes were generally similar in patients who initially received placebo and were switched to upadacitinib at week 52. In total, 286 patients were exposed to ≥ 1 dose of upadacitinib, comprising 378.3 patient-years (PY) of exposure. Upadacitinib was generally well tolerated, with exposure-adjusted event rates (EAERs) for TEAEs, serious adverse events (AEs), and AEs leading to study drug discontinuation of 207.5, 8.7, and 5.3 events/100 PY, respectively. EAERs of TEAEs of special interest were broadly consistent with those reported through week 52. Conclusions Treatment with upadacitinib demonstrated consistent improvement and maintenance of treatment effect across efficacy endpoints through 2 years; no new safety signals were identified with additional exposure. Trial registration NCT04169373.