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Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that predominantly affects the axial skeleton, although it can affect peripheral joints, and extra-musculoskeletal manifestations also occur. Historically, axSpA was thought to be a disease predominantly seen in men, although with the advent of magnetic resonance imaging techniques and advances in research, this dogma has been challenged and refuted. Sex and gender are different concepts, and both can have a role in disease. In axSpA, consideration of the influence of sex and gender on the disease phenotype is necessary to predict outcomes and to enable the development of therapeutic approaches that are best suited to individual patients.In this Review, the authors discuss the roles of sex and gender in relation to axial spondyloarthritis. Although evidence now suggests that the disease has equal prevalence in men and women, important differences occur in phenotypes, response to therapy and outcomes.

Background Secukinumab is an interleukin (IL)-17 inhibitor approved to treat patients with axial spondyloarthritis (axSpA), including radiographic (r)-axSpA and non-radiographic (nr)-axSpA. Treatment recommendations highlight the importance of individualized treatment of patients with axSpA according to symptoms, extra-musculoskeletal manifestations, and comorbidities. The objective of this post hoc analysis was to compare clinical responses to secukinumab treatment through Week 16 between younger and older patients with r-axSpA and nr-axSpA from six placebo-controlled phase 3 clinical studies. Methods This post hoc analysis evaluated data pooled from 1427 patients with axSpA from the MEASURE 1–5 trials (NCT01358175, NCT01649375, NCT02008916, NCT02159053, and NCT02896127) and the PREVENT trial (NCT02696031). All patients were randomized to secukinumab 150 mg, 300 mg, or placebo through Week 16. Patient subgroups were defined based on median age at baseline (18 to < 40 years vs. ≥ 40 years). Treatment effect (secukinumab 150/300 mg vs. placebo) within each age subgroup and the difference in treatment effect between younger vs. older age subgroups were assessed. Results Secukinumab treatment demonstrated clinical efficacy and improvements in patient-reported outcomes vs. placebo at Week 16 in patients with r-axSpA or nr-axSpA irrespective of age. No difference in treatment effect of ASAS20, ASAS40, or ASDAS response was observed between younger vs. older patients with r-axSpA or nr-axSpA (all P >.05). Among patients with r-axSpA, younger patients experienced a larger treatment effect of secukinumab on SF-36 than older patients (difference in least-squares mean [LSM]: 2.2; P  < .05). Among patients with nr-axSpA, younger patients experienced a larger treatment effect of secukinumab on the Berlin SIJ total edema score (difference in LSM: − 1.2; P  < .05) and Total ASspi-MRI-a score (LSM, − 0.4; P <.05). Conclusion Clinical efficacy of secukinumab vs. placebo at Week 16 was generally similar between older and younger patients with either r-axSpA or nr-axSpA.

Early diagnosis of psoriatic arthritis (PSA) is important for successful therapeutic intervention but currently remains challenging due, in part, to the scarcity of non-invasive biomarkers. In this study, we performed single cell profiling of transcriptome and cell surface protein expression to compare the peripheral blood immunocyte populations of individuals with PSA, individuals with cutaneous psoriasis (PSO) alone, and healthy individuals. We identified genes and proteins differentially expressed between PSA, PSO, and healthy subjects across 30 immune cell types and observed that some cell types, as well as specific phenotypic subsets of cells, differed in abundance between these cohorts. Cell type-specific gene and protein expression differences between PSA, PSO, and healthy groups, along with 200 previously published genetic risk factors for PSA, were further used to perform machine learning classification, with the best models achieving AUROC ≥ 0.87 when either classifying subjects among the three groups or specifically distinguishing PSA from PSO. Our findings thus expand the repertoire of gene, protein, and cellular biomarkers relevant to PSA and demonstrate the utility of machine learning-based diagnostics for this disease.

Background Bimekizumab, a monoclonal IgG1 antibody that selectively inhibits IL-17F in addition to IL-17A, showed efficacy to 2 years in patients with axial spondyloarthritis (axSpA). In this post hoc analysis, we compare the impact of shorter versus longer symptom duration on the efficacy of bimekizumab to Week 104. Methods Efficacy outcomes by symptom duration (≤ 2 [ASAS early axSpA definition] versus > 2 years; ≤ 5 versus > 5 years) were assessed across patients from BE MOBILE 1 and 2 (non-radiographic [NCT03928704]/radiographic axSpA [NCT03928743]) and the combined open-label extension (NCT04436640). (Relative) odds ratios and (relative) differences were calculated to compare 16-week bimekizumab versus placebo treatment effect and 104-week outcomes, and infer the significance of differences, between symptom duration subgroups. Analyses were neither powered for these comparisons nor multiplicity adjusted, and should be interpreted accordingly. Results Improved disease activity, physical function, fatigue, health-related quality of life and objective signs of inflammation were seen with bimekizumab versus placebo at Week 16 regardless of symptom duration. Outcomes were then sustained or improved with bimekizumab to Week 104 across all subgroups. 16-week bimekizumab versus placebo treatment effect was comparable between subgroups (e.g., ≤ 2-year versus > 2-year symptom duration relative odds ratio [95% CI] for ASDAS < 2.1 in BE MOBILE 1: 0.82 [0.22, 3.08]). Significant differences were observed for some 104-week outcomes between symptom duration subgroups across both studies (e.g., ≤ 5-year versus > 5-year symptom duration odds ratio [95% CI] for ASDAS < 2.1 in BE MOBILE 2: 1.94 [1.02, 3.68]), all favouring the shorter symptom duration subgroups. Conclusions Bimekizumab was efficacious to 2 years regardless of symptom duration, with comparable 16-week treatment effect but generally better 104-week outcomes in the shorter versus longer symptom duration subgroups. Trial registration Registered on ClinicalTrials.gov; NCT03928704 (BE MOBILE 1; 23rd April 2019), NCT03928743 (BE MOBILE 2; 23rd April 2019), NCT04436640 (BE MOVING; 15th June 2020).

Background To investigate the efficacy of secukinumab in patients with active non-radiographic axial spondyloarthritis (nr-axSpA) grouped by disease activity as assessed by C-reactive protein (CRP) levels and/or magnetic resonance imaging (MRI) scores, human leukocyte antigen (HLA)-B27 status, and sex. Methods The phase III PREVENT study randomized (1:1:1) 555 patients to receive subcutaneous secukinumab 150 mg with (LD) or without (NL) loading dose or placebo weekly, followed by every 4 weeks starting at week 4. Here, we report the results of a post hoc analysis reporting the efficacy outcomes (pooled secukinumab) to 16 weeks by CRP, MRI, HLA-B27, and sex. Results Efficacy differences between the secukinumab and the placebo groups were highest in the CRP+, MRI+, HLA-B27+, and male subgroups, particularly for Ankylosing Spondylitis Disease Activity Score-CRP inactive disease and Assessment of SpondyloArthritis international Society (ASAS) partial remission outcomes. ASAS40 response rates in the CRP+/MRI+ subgroup was 52.3% (secukinumab) versus 21.8% (placebo; P < 0.0001) at week 16. ASAS40 response rates (secukinumab versus placebo) were 43.9% versus 32.6% in HLA-B27+, 32.7% versus 16.4% in HLA-B27− subgroups, 51.2% versus 30.8% in male, and 31.7% versus 25.3% in female patients, respectively. Conclusions Secukinumab improved the signs and symptoms of nr-axSpA across patients grouped by CRP (+/−) and/or MRI (+/−) status, HLA-B27 (+/−) status, and sex. The highest treatment differences between secukinumab and placebo were observed in patients with both elevated CRP and evidence of sacroiliitis on MRI. Treatment difference was minimal between HLA-B27 (+) and (−) subgroups. Male patients had higher relative responses than female patients. Trial registration ClinicalTrials.gov , NCT02696031 . Registered on 02 March 2016

Background Axial spondyloarthritis including ankylosing spondylitis (AS) is characterized by chronic inflammation and new bone formation in the axial skeleton. On the other hand, bone loss, osteoporosis and an increased risk of vertebral fractures is known to frequently occur in AS. In the MEASURE 1 study, the clinically efficacious interleukin-17A inhibitor secukinumab was shown to have limited radiographic progression through 4 years in patients with active AS. Here we present a post hoc analysis to evaluate the effect of secukinumab on bone mineral density (BMD) and bone turnover biomarkers over 2 years in this study. Methods BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine, total hip, and femoral neck. Spinal radiographs performed at baseline and Week 104 were assessed by modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and analyzed in relation to BMD change, considering baseline syndesmophytes. Bone turnover biomarkers were assessed at baseline and at Weeks 52 or 104. Results Among 104 patients included in this analysis, 66% were male, with a mean (SD) age of 40.4 (12.3) years. In postmenopausal women and men ≥50 years of age (T-score), the proportion of patients having normal BMD at baseline and Week 104 were 54.5%/54.5% (lumbar spine), 31.6%/55.6% (total hip), and 42.1%/44.4% (femoral neck). Similarly, at baseline, the proportion of patients with osteopenia/osteoporosis was 31.8%/13.6% (lumbar spine), 57.9%/10.5% (total hip), 42.1%/15.8% (femoral neck), and 36.4%/9.1% (lumbar spine), 44.4%/0% (total hip) and 55.6%/0% (femoral neck) at Week 104, respectively. In premenopausal women and men < 50 years of age (Z-score), the proportion of patients having BMD below the expected range for age at baseline and Week 104 were 25.0%/21.2% (lumbar spine), 11.3%/17.8% (total hip), and 9.9%/8.9% (femoral neck). In relation to mSASSS change scores ≥2 over 2 years, the increase in lumbar spine BMD was not related to radiographic progression and syndesmophyte formation. No significant changes were observed in the bone turnover markers over time. Conclusion The high proportion of AS patients with diminished BMD was confirmed in this study. An increase of BMD in the lumbar spine after 2 years of secukinumab treatment in patients with AS was found that was probably unrelated to radiographic progression. No relevant effects of secukinumab on bone turnover biomarkers were documented. Trial registration MEASURE 1 (post hoc analysis) Clinicaltrials.gov, NCT01358175 ; Registered, 23 May 2011.

Ankylosing spondylitis (AS) is an immune-mediated inflammatory disorder that primarily affects the axial skeleton, especially the sacroiliac joints and spine. This results in chronic back pain and, in extreme cases, ankylosis of the spine. Despite its debilitating effects, the pathogenesis of AS remains to be further elucidated. This study used single cell CITE-seq technology to analyze peripheral blood mononuclear cells (PBMCs) in AS and in healthy controls. We identified a number of molecular features associated with AS. CD52 was found to be overexpressed in both RNA and surface protein expression across several cell types in patients with AS. CD16 + monocytes overexpressed TNFSF10 and IL-18Rα in AS, while CD8 + T EM cells and natural killer cells overexpressed genes linked with cytotoxicity, including GZMH, GZMB , and NKG7 . Tregs underexpressed CD39 in AS, suggesting reduced functionality. We identified an overrepresented NK cell subset in AS that overexpressed CD16, CD161, and CD38, as well as cytotoxic genes and pathways. Finally, we developed machine learning models derived from CITE-seq data for the classification of AS and achieved an Area Under the Receiver Operating Characteristic (AUROC) curve of > 0.95. In summary, CITE-seq identification of AS-associated genes and surface proteins in specific cell subsets informs our understanding of pathogenesis and potential new therapeutic targets, while providing new approaches for diagnosis via machine learning.

Background Radiographic progression and course of inflammation over 2 years in patients with non-radiographic axial spondyloarthritis (nr-axSpA) from the phase 3, randomized, PREVENT study are reported here. Methods In the PREVENT study, adult patients fulfilling the Assessment of SpondyloArthritis International Society classification criteria for nr-axSpA with elevated CRP and/or MRI inflammation received secukinumab 150 mg or placebo. All patients received open-label secukinumab from week 52 onward. Sacroiliac (SI) joint and spinal radiographs were scored using the modified New York (mNY) grading (total sacroiliitis score; range, 0–8) and modified Stoke Ankylosing Spondylitis Spine Score (mSASSS; range, 0–72), respectively. SI joint bone marrow edema (BME) was assessed using the Berlin Active Inflammatory Lesions Scoring (0–24) and spinal MRI using the Berlin modification of the AS spine MRI (ASspiMRI) scoring (0–69). Results Overall, 78.9% (438/555) of patients completed week 104 of the study. Over 2 years, minimal changes were observed in total radiographic SI joint scores (mean [SD] change, − 0.04 [0.49] and 0.04 [0.36]) and mSASSS scores (0.04 [0.47] and 0.07 [0.36]) in the secukinumab and placebo-secukinumab groups. Most of the patients showed no structural progression (increase ≤ smallest detectable change) in SI joint score (87.7% and 85.6%) and mSASSS score (97.5% and 97.1%) in the secukinumab and placebo-secukinumab groups. Only 3.3% ( n  = 7) and 2.9% ( n  = 3) of patients in the secukinumab and placebo-secukinumab groups, respectively, who were mNY-negative at baseline were scored as mNY-positive at week 104. Overall, 1.7% and 3.4% of patients with no syndesmophytes at baseline in the secukinumab and placebo-secukinumab group, respectively, developed ≥ 1 new syndesmophyte over 2 years. Reduction in SI joint BME observed at week 16 with secukinumab (mean [SD], − 1.23 [2.81] vs − 0.37 [1.90] with placebo) was sustained through week 104 (− 1.73 [3.49]). Spinal inflammation on MRI was low at baseline (mean score, 0.82 and 1.07 in the secukinumab and placebo groups, respectively) and remained low (mean score, 0.56 at week 104). Conclusion Structural damage was low at baseline and most patients showed no radiographic progression in SI joints and spine over 2 years in the secukinumab and placebo-secukinumab groups. Secukinumab reduced SI joint inflammation, which was sustained over 2 years. Trial registration ClinicalTrials.gov, NCT02696031.

Background: Involvement of the axial skeleton (sacroiliac joints and spine) is a relatively frequent manifestation associated with psoriatic skin disease, mostly along with involvement of peripheral musculoskeletal structures (peripheral arthritis, enthesitis, dactylitis), which are referred to as psoriatic arthritis (PsA). Data suggest that up to 30% of patients with psoriasis have PsA. Depending on the definition used, the prevalence of axial involvement varies from 25% to 70% of patients with PsA. However, there are currently no widely accepted criteria for axial involvement in PsA.Objective: The overarching aim of the Axial Involvement in Psoriatic Arthritis (AXIS) study is to systematically evaluate clinical and imaging manifestations indicative of axial involvement in patients with PsA and to develop classification criteria and a unified nomenclature for axial involvement in PsA that would allow defining a homogeneous subgroup of patients for research. Design: Prospective, multicenter, multinational, cross-sectional study. Methods and analyses: In this multicenter, multinational, cross-sectional study, eligible patients [adult patients diagnosed with PsA and fulfilling Classification Criteria for Psoriatic Arthritis (CASPAR) with musculoskeletal symptom duration of ⩽10 years not treated with biological or targeted synthetic disease-modifying anti-rheumatic drugs] will be recruited prospectively. They will undergo study-related clinical and imaging examinations. Imaging will include radiography and magnetic resonance imaging examinations of sacroiliac joints and spine. Local investigators will evaluate for the presence of axial involvement based on clinical and imaging information which will represent the primary outcome of the study. In addition, imaging will undergo evaluation by central review. Finally, the central clinical committee will determine the presence of axial involvement based on all available information. Ethics: The study will be performed according to the ethical principles of the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines. The study protocol will be approved by the individual Independent Ethics Committee / Institutional Review Board of participating centers. Written informed consent will be obtained from all included patients.Registration: ClinicalTrials.gov ID: NCT04434885.

We aimed to perform a structured literature review of spinal radiographic progression, as assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), in patients with ankylosing spondylitis (AS) or nonradiographic axial spondyloarthritis (nr-axSpA) treated with biologic therapy. Searches were limited to English language manuscripts published in the 11 years prior to 9 July 2019. Randomized controlled trials, open-label extensions (OLEs) and observational studies reporting mSASSS progression in patients with AS or nr-axSpA treated with biologics were eligible for inclusion. Bias was assessed using the methodological index for nonrandomized studies (MINORS) tool. Among the 322 studies identified in the literature search, 23 (11 OLEs and 12 cohort studies) met the eligibility criteria and were selected for inclusion. Most studies reported mSASSS progression in patients with AS receiving tumor necrosis factor inhibitor (TNFi) treatment. One study reported mSASSS progression in patients with AS treated with secukinumab, an interleukin-17A inhibitor. The mean (range) MINORS score was 11.3 (7–15) for the 15 noncomparative studies and 15 (12–22) for the 8 comparative studies. Although results of the individual studies were variable, mSASSS progression in patients with AS was generally minimal and slow with long-term TNFi therapy. Moreover, odds ratios for the likelihood of mSASSS progression with/without TNFi favoured TNFi therapy in several of the cohort studies. The rate of mSASSS progression following continuous secukinumab treatment was low and remained stable over 4 years. Of two studies reporting progression in patients with nr-axSpA treated with TNFis, one showed no mSASSS progression; however, the lack of control limited comparative conclusions.