Annals of the Rheumatic Diseases最新文献

Objectives: Enthesitis, a hallmark of psoriatic arthritis (PsA), reflects the interplay between mechanical stress and immune dysregulation at tendon-bone interfaces. This study investigates the cellular and molecular responses in entheseal tissues following interleukin (IL)-17A inhibition in patients with active PsA.

Methods: In this prospective, interventional phase 4 trial, we enrolled 10 patients with enthesitis of the lateral epicondyle, performed entheseal biopsies, and analysed tissues by imaging mass cytometry (IMC) and spatial transcriptomics before and after treatment.

Results: Following 24 weeks of IL-17A inhibition, 9/10 patients of the cohort clinically responded to treatment as assessed by Disease Activity in Psoriatic Arthritis (DAPSA), Spondyloarthritis research consortium of canada (SPARCC) score, and power Doppler sonography. IMC analysis showed significant reductions of enthesitis-related immune cell populations, in particular IL-17-producing CD4, CD8, CD4^neg/CD8^neg T cells, granulocytes, and innate lymphoid cells type 3. Spatial transcriptomics revealed that CD200+DKK3+ fibroblasts and innate lymphoid cells type 2 expanded and formed an anti-inflammatory niche upon treatment. Notably, IL-17A inhibition led to decreased osteoblast differentiation markers, suggesting a potential mechanism to inhibit pathological bone formation.

Conclusions: These findings underline the pivotal role of IL-17A in enthesitis, showing that IL-17A inhibition profoundly modulates the tissue microenvironment of entheses in PsA.

Objectives: In patients with dermatomyositis with anti-Mi2 autoantibodies, autoantibodies can enter muscle cells, leading to the aberrant expression of genes normally repressed by the Mi2/nucleosome remodelling and deacetylation (NuRD) complex. However, the mechanism by which autoantibodies interfere with Mi2/NuRD function remains unclear. This study aimed to identify additional autoantibodies in anti-Mi2-positive patients and the epitopes recognised by these autoantibodies.

Methods: Phage immunoprecipitation sequencing (PhIP-Seq) was used to screen sera from patients with anti-Mi2 autoantibody-positive myositis. Enzyme-linked immunosorbent assays (ELISAs) and luciferase immunoprecipitation system (LIPS) immunoassays were used to detect autoantibodies in sera from healthy controls, patients with myositis, and those with other autoimmune diseases.

Results: PhIP-Seq identified autoantibodies recognising the autoimmune regulator (AIRE) in sera from anti-Mi2 autoantibody-positive patients. Both anti-AIRE and anti-Mi2 autoantibodies predominantly recognised a homologous region containing the plant homeodomain zinc finger type I (PHD1), which is critical for AIRE and Mi2/NuRD function. ELISA and LIPS showed that anti-Mi2 autoantibody-positive patients were positive for anti-AIRE autoantibodies, whereas AIRE reactivity was largely absent in healthy comparators, anti-Mi2 autoantibody-negative myositis, and other autoimmune diseases. Affinity-purified anti-Mi2 autoantibodies recognised both Mi2 and AIRE by ELISA, whereas anti-Mi2-depleted fractions did not recognise either protein.

Conclusions: Autoantibodies targeting Mi2 recognise AIRE at a shared PHD1 epitope - a conserved motif found in numerous transcriptional regulators. These findings support a model in which anti-Mi2 autoantibodies disrupt the Mi2/NuRD complex, and potentially other PHD1-containing proteins, by interfering with chromatin binding, although further studies are needed to directly demonstrate this mechanism in vivo.

In this narrative review, the author, a privileged witness to exciting developments in the field of lupus nephritis over almost 4 decades, describes and comments on the new therapies that have recently become available, after years of trial failures. He stresses the use of combination therapy, now widely supported by expert recommendations to mitigate the risk of chronic kidney disease. He reviews the early days of cellular therapy and proposes some further lines of research.

Objectives: This study aims to study the framework describing the longitudinal association between disease activity and function (independent variables) and health-related quality of life (HRQoL, outcome) in axial spondyloarthritis (axSpA).

Methods: Patients with AxSpA (symptoms <3 years) from the Devenir des Spondylarthropathies Indifferénciées Récentes cohort were followed up for 10 years. The association of disease activity (ASDAS) and function (BASFI) with HRQoL (physical component summary [PCS] and mental component summary [MCS] of 36-item short-form health survey, ankylosing spondylitis quality of life [ASQoL]) was assessed. Multivariable generalised estimating equations models were built with PCS, MCS, or ASQoL as outcomes (higher PCS/MCS = better HRQoL, higher ASQoL = worse), and ASDAS and BASFI as main predictors. Standard and autoregressive (i.e., corrected for prior HRQoL) models were used. The impact of ASDAS vs BASFI on HRQoL was compared through standardised coefficients. Mediation analysis assessed whether the effect of ASDAS on HRQoL was mediated by BASFI. Confounders/effect modifiers (eg, contextual factors) were considered in all models.

Results: A total of 663 patients with axSpA (46% males, mean age 33.5 [8.6] years) were included. In standard and autoregressive multivariable models, significant associations for ASDAS and BASFI with HRQoL were found (beta coefficient [95% CI] for autoregressive models: PCS -2.93 [-3.28, -2.58]; -2.13 [-2.31, -1.96]), MCS (-2.38 [-2.91, -1.86]; -1.10 [-1.36, -0.84]), ASQoL (1.18 [1.02, 1.36]; 1.08 [0.99, 1.17]). A larger influence of BASFI, compared to ASDAS, on HRQoL was noted. Mediation analysis showed the ASDAS effect on HRQoL was mostly (∼75%) mediated by BASFI, but a direct effect (∼25%) also existed.

Conclusions: A validated longitudinal framework has been established for interpreting HRQoL: even correcting for contextual factors, disease activity consistently impacts HRQoL-primarily through functional impairment, but also directly. While HRQoL is an overarching outcome in axSpA, targeting low disease activity is crucial to optimise HRQoL.