Annals of the Rheumatic Diseases最新文献

Objectives: The aim of the study was to determine the frequency of adverse pregnancy outcomes in women with spondyloarthritis (SpA) in comparison to controls from the French general population, and to identify factors associated with these adverse pregnancy outcomes.

Methods: This French prospective multicentre cohort study included pregnant women with SpA (both axial and peripheral) according to their treating rheumatologist between December 2015 and June 2021. Maternal characteristics, disease activity, treatments, and pregnancy outcomes were analysed. Outcomes of pregnancies in women with SpA were compared to that of matched (1:4) general population women from the 2016 and 2021 French National Perinatal Surveys, including pregnancy, neonatal, and maternal outcomes. For adverse pregnancy outcomes that are significantly more frequent in patients with SpA, logistic regression analysis was performed to identify potential risk factors.

Results: A total of 135 SpA pregnancies in 124 women were analysed: they have a mean age of 32.1 years, a mean disease duration of 6.3 years, and 50.4% were nulliparous. Small for gestational age (SGA) was the most common adverse pregnancy outcome and occurred more frequently in women with SpA compared to controls (17.4% vs 9.8%, odds ratios = 1.94, 95% CI 1.09-3.39). Other adverse pregnancy outcomes rates, including preterm birth and caesarean delivery, were comparable to the general population. No predictor of SGA was identified in women with SpA.

Conclusions: In this contemporary cohort, compared to the general population, SpA was associated with a higher risk of SGA, but no other adverse pregnancy outcomes, providing reassurance for most pregnant women with SpA.

Objectives: This study aims to develop classification criteria for haemochromatosis arthropathy (HA).

Methods: A task force was convened per European Alliance of Associations for Rheumatology standardised operating procedures, including physicians experienced in genetic haemochromatosis and its arthropathy and patient research partners. Candidate classification criteria items were selected via systematic literature review, consensus, and Delphi process. Derivation cohorts of patients with C282Y homozygous HFE gene mutation, joint pain, and iron loading, along with disease mimics (primary generalised osteoarthritis or calcium pyrophosphate deposition disease), were recruited from routine care and assessed against candidate items. Group comparison and diagnostic performance analyses identified variables with the greatest discriminatory capacity. A subset of these variables, agreed upon by consensus (considering both statistical results and the HA disease construct), was modelled using multivariable logistic regression and receiver operating characteristic curve analysis to develop classification criteria models. The final model was agreed upon through discussion, voting, and consensus, taking both statistical performance and disease Gestalt (face validity) into account.

Results: A derivation cohort of 154 patients with HA and 120 patients with disease mimics was recruited. A point-based classification model was developed using 8 variables covering age of symptom onset, clinical, and radiographic features at the metacarpophalangeal, distal interphalangeal, and ankle joints, and surgery of hips or ankles. A score ≥5 out of 11 provides 93.3% specificity and 71.4% sensitivity for classifying HA.

Conclusions: An international multicentre task force has developed the first classification criteria for HA from a unique derivation cohort using rigorous methodology. Criteria should be used to include patients in research studies and await external validation in separate cohorts.

Objectives: This study aims to develop a modified Disease Activity index for PSoriatic Arthritis (DAPSA) score using the 44-joint count instead of the 66 swollen/68 tender joint counts (SJC/TJC) in patients with spondyloarthritis (SpA) (axial SpA [axSpA], peripheral SpA [pSpA], and psoriatic arthritis [PsA]) and evaluate its construct validity.

Methods: Patients with axSpA, pSpA, and PsA included in the Assessment of SpondyloArthritis international Society-PerSpA (PERipheral involvement in SpondyloArthritis) study were randomly allocated 1:2 stratified for diagnosis and country into a derivation and validation cohort. For all patients, the 66SJC/68TJC were available, from which the SJC44/TJC44 were extracted. The derivation cohort was used to calculate the conversion factors for SJC66/TJC68 into SJC44/TJC44 to obtain the DAPSA44 using mixed-effects linear regression models. The validation cohort assessed the DAPSA44 construct validity through the agreement between continuous original-DAPSA/DAPSA44 (intraclass correlation coefficient [ICC]) and DAPSA disease activity states (weighted-kappa), Bland-Altman plot, Spearman correlations between original-DAPSA/DAPSA44 and external constructs, and discrimination between known groups (standardised mean differences [SMDs]) after stratifying patients into active/inactive based on a combination of patient global assessment (≥5/<5) and SJC (≥1/0 or ≥2/<2).

Results: A total of 4121 patients (65% axSpA, 10% pSpA, and 25% PsA) were included. Conversion factors from the derivation cohort (n = 1364) for TJC and SJC were 1.30 and 1.34, respectively. The validation cohort (n = 2757) analyses showed almost-perfect agreement between original-DAPSA and DAPSA44 (ICC 0.98, kappa 0.95). Spearman correlation coefficients between DAPSA44 and external constructs fell within the predefined 0.3-wide range of corresponding original-DAPSA coefficients. DAPSA44 demonstrated excellent discriminatory ability (SMD > 0.8) across all scenarios of active/inactive disease.

Conclusions: These findings support the use of DAPSA44 as a comparable tool to the original DAPSA for assessing disease activity due to peripheral arthritis in SpA, especially in situations where only a reduced joint count is available.

Objectives: Anti-Jo1+ antisynthetase syndrome (ASyS) is characterised by autoantibodies targeting histidyl t-RNA synthetase (HisRS), association with HLA-DRB1*03:01 and a distinct clinical phenotype including interstitial lung disease, myositis, arthritis, and mechanic's hands. Previous studies of autoreactive HisRS-specific CD4⁺T cells point to yet undiscovered T cell epitopes. We aimed to identify new epitopes on HisRS to investigate the presence of autoreactive T cells and their corresponding T-cell receptor (TCR) repertoire from patients with ASyS.

Methods: Peptides from HisRS N-terminal region with appropriate major histocompatibility complex (MHC) anchor residues were selected for in vitro binding assays. The peptide (HisRS_41-55) with the highest HLA-DRB1*03:01 binding affinity was selected for studies with HLA-class II tetramers. Peripheral blood mononuclear cells (PBMCs) from patients with ASyS with HLA-DRB1*03:01 (n = 12) were stimulated in vitro with peptide and peptide-HLA-DRB1*03:01 tetramers were used to detect HisRS⁺CD4⁺T cells. Single TCR sequencing of captured T cells allowed analyses of the underlying TCR repertoire.

Results: We identified a new T cell epitope on HisRS with high affinity for HLA-DRB1*03:01. Autoreactive HisRS⁺CD4⁺T cells were detected in PBMCs of patients (n = 6/12). TCR repertoire analysis of HisRS⁺CD4⁺T cells revealed shared gene V-alpha and beta usages. Moreover, HisRS⁺CD4⁺T cells persisted after treatment in 2 patients (P2 and P4) and 2 identical T cell clones were detected between the initial and follow-up time points in 1 patient (P2).

Conclusions: Autoreactive T-cells targeting a new HisRS epitope were identified indicating T cell reactivity to diverse epitopes of the HisRS protein in patients with anti-Jo1 autoantibodies. Furthermore, we demonstrated the TCR repertoire of autoreactive HisRS+CD4+T cells in patients. Persistence of these T-cells and specific clones may be contributing to disease.

Objectives: To establish the long-term impact of cytokine-directed therapies on glucocorticoid use and clinical outcomes in Vacuoles, E1-enzyme, X-linked, Autoinflammatory, Somatic (VEXAS).

Methods: Patients with VEXAS were prospectively followed for events of transfusion dependence, haematopoietic stem cell transplantation or death. Laboratory results, glucocorticoid exposure and clinical measures were retrospectively assessed in relationship to treatment initiation with interleukin-6-directed therapies (anti-IL6R) or Janus kinase inhibitors (JAKi). Patients were stratified by UBA1 variants and presence of typical clonal haematopoiesis with variant allele fraction ≥ 10% (CH^VAF≥10%).

Results: In 71 VEXAS patients (81.7% with anti-IL6R or JAKi exposure), event-free survival differed by genotype and presence of concomitant CH^VAF≥10%: p.M41V (HR [95% confidence interval (CI)]: 5.7 [1.5-20.4]) or p.M41L/T with CH^VAF≥10% (hazard ratio [HR]: 5.7 [1.6-20.8]) compared to p.M41L. No association between event rates and exposure to anti-IL6R or JAKi was observed. The p.M41V genotype had the highest risk of anaemia, elevated C-reactive protein (CRP) levels, and monocytopenia. Over a median follow-up of 4.8 (interquartile range [IQR] 3.0, 8.1) years, the patients' mean glucocorticoid dose was >15 mg/day prednisone regardless of variant or disease duration. At prospective visits, clinical remission on ≤10 mg/day prednisone was observed in only 2.7% of visits. Treatment with anti-IL6R or JAKi showed no clinically meaningful reduction (<5 mg/day difference) in steroid exposure at 1 year post-treatment. No attenuation in the progression of anaemia was observed in response to anti-IL6R and JAKi.

Conclusions: Cytokine-directed therapies alone do not alter the risk of haematologic disease progression or significantly reduce glucocorticoid exposure in VEXAS. These data provide benchmarks for future interventional studies.

Objectives: The aims of this 5-year study were to explore the maintenance of low serum uric acid (sUA) during treat-to-target urate-lowering therapy (T2T-ULT) and whether long-term low sUA results in continuous decrease of ultrasound-detected crystal depositions, complete dissolution of depositions, and reduction of flares.

Methods: Patients with a recent gout flare were included, initiated T2T-ULT, and were followed for 5 years (outpatient clinic year 1, general practitioner years 2-5) with visits at baseline, 1, 2, and 5 years. Each visit included assessment of sUA, ultrasound examination for crystal depositions (double contour, tophi, and aggregates) in bilateral hands, elbows, knees, ankles, feet, and number of flares the previous year. Calculations included independent or paired samples t-tests, analysis of variance (ANOVA), and linear regression analyses.

Results: Of the 209 patients included at baseline (mean age 56.4 years, disease duration 7.9 years), 163 patients were examined at 5 years. At the 5-year visit, sUA was reduced from 500 (baseline) to 337 μmol/L (P < .001), 71.2% had sUA <360 μmol/L, all ultrasound depositions were reduced (P < .001), full dissolution of double contour (83.4%) and tophi (63.2%) (where examining only first metatarsophalangeal joints identified most of these patients), and only 16% had flares the previous year all of whom had higher sUA and depositions (P = .035-.006).

Conclusions: Five years of T2T-ULT resulted in most patients achieving sUA target, reduction of crystal depositions, and dissolution of double contour and tophi in most patients. Only a few patients experienced flares, and they had higher levels of sUA and crystal depositions, supporting the importance of keeping sUA low.