Annals of the Rheumatic Diseases最新文献

Objectives: Proteasome-associated autoinflammatory syndromes (PRAAS) include a group of autoinflammatory interferonopathies caused by 20S proteasome dysfunction. We characterised pathomechanisms and treatment responses of patients with a de novo, dominant-negative (DN)-proteasome subunit beta type-8 (PSMB8) variant.

Methods: Patients with the DN-PSMB8 p.G209R variant encoding a mutant β5i subunit of the 20S immunoproteasome were evaluated. Interferon biomarkers, proteasome activity, structural modelling, and proteotoxic stress responses were assessed. Patients' T cells underwent integrated transcriptomic and proteomic profiling to characterise immune dysregulation, proteotoxic stress responses, mitochondrial function, and type I interferon (IFN-I) associated stress signalling.

Results: Patients with DN-PRAAS presented with early-onset systemic inflammation, panniculitis, cytopenias, infections, and porto-sinusoidal vascular liver disease (PSVD), indicating broader immune dysfunction that partially responds to Janus kinase inhibition and/or interferon-α/β receptor blockade (anifrolumab). Mechanistically, the PSMB8 p.G209R variant caused steric hindrance that impaired β5i propeptide processing and final 20S proteasome formation, resulting in intracellular protein aggregation, impaired mitochondrial metabolism, and altered neutral lipid processing. The IFN-I signature of patients' T cells was reduced by blockade of 2 integrated stress response (ISR)-regulating kinases, protein kinase R (PKR) and general control nonderepressible 2 (GCN2), and by Janus kinase signalling.

Conclusions: The DN-PSMB8 p.G209R variant broadens the clinical and mechanistic PRAAS spectrum by causing 20S proteasome maturation arrest and uncovering a convergence between mitochondrial dysfunction and the ISR. Our findings implicate cytopenia in a pattern of vascular pathology, including PSVD of the liver. We further identify PKR and GCN2 as key mediators of maladaptive IFN-I responses and potential therapeutic targets.

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 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.

Objectives: We assessed the association between 25-hydroxyvitamin D (25(OH)D) levels and rates of mortality and cardiovascular events (stroke, myocardial infarction, angina/bypass) in patients with systemic lupus erythematosus (SLE).

Methods: The Hopkins Lupus Cohort began measuring 25(OH)D quarterly in 2009. We examined associations between 25(OH)D levels-baseline, mean in the last year, and most recent values-and both mortality and cardiovascular events (stroke, myocardial infarction, angina/bypass). Two analyses were conducted: (i) a prospective analysis of events occurring after the first 25(OH)D measurement, and (ii) a lifetime analysis including events before cohort entry. All models adjusted for age, sex (female or male), race, and body mass index.

Results: The prospective analysis included 11,302 person-years from 1768 patients. Patients with 25(OH)D <20 ng/mL had the highest mortality and cardiovascular event rates. Compared to those with levels of 30-39 ng/mL, those with levels <20 ng/mL at cohort entry had significantly increased risk of death (hazard ratio [HR] 2.05, 95% CI: 1.19-3.54, P = .0095) and cardiovascular events (HR 2.98, 95% CI: 1.30-6.85, P = .010). Risk of myocardial infarction alone was not statistically significant (HR 1.90, P = .30), but risk of angina/bypass was elevated (HR 3.53, 95% CI: 1.13-11.0, P = .030). The lifetime analysis suggested these associations, with a U-shaped pattern for myocardial infarction risk.

Conclusions: An initial 25(OH)D level <20 ng/mL was associated with increased mortality and cardiovascular events (but not stroke) in SLE. The U-shaped curve for myocardial infarction mirrors our previous work in adverse pregnancy outcomes. Lack of association with mean or recent 25(OH)D levels questions the impact of supplementation on risk modification.

Objectives: Glucocorticoids effectively treat many diseases, but toxicity limits their utility. We aimed to learn whether, by reducing active intracellular glucocorticoid exposures, the 11β-hydroxysteroid dehydrogenase type 1 inhibitor clofutriben could selectively reduce glucocorticoid efficacy but reduce toxicity more strongly. We hypothesised that by increasing the prednisolone dose, it might be possible to restore efficacy back to the original level, thereby improving the benefit-risk profile.

Methods: In sequential cohorts, adults with polymyalgia rheumatica received (single blind) prednisolone 10 mg/d with placebo for 2 weeks, then clofutriben with either prednisolone 10, 15, 20, or 30 mg/d for 2 weeks.

Results: Forty-nine and 47 participants completed each trial period with evaluable data. Five who received prednisolone 10 mg/d with clofutriben experienced clinical relapse. No clinical relapses occurred during other treatments. Participants reported more severe symptoms and physical disability when prednisolone 10 mg/d or 15 mg/d, but not 20 mg/d or 30 mg/d, was given with clofutriben. Inflammatory biomarkers followed a similar pattern. Across all prednisolone doses, clofutriben coadministration mitigated glucocorticoid-related adverse effects on biomarkers of bone turnover, lipid metabolism, hypercoagulability, and cardiovascular and adrenal function.

Conclusions: Further trials to assess clofutriben's potential to improve the benefit-risk profile of prednisolone are warranted.

Objectives: Front-line treatment for psoriatic arthritis (PsA) often involves the use of tumour necrosis factor alpha (TNFα) blocking medications (tumour necrosis factor alpha inhibition [TNFi]). However, more than 40% of patients exhibit inadequate responses, and there is no predictive clinical test available. Our goal is to investigate whether the response to TNFi treatment is associated with TNFα receptor 2 (TNFR2) rs1061622 polymorphic variants, TNFR2-M or TNFR2-R, in PsA. Furthermore, to elucidate the underlying mechanisms, differences in cell signalling and gene expression conferred by TNFR2-M vs TNFR2-R were examined.

Methods: TNFR2 rs1061622 polymorphism status of 164 patients was assessed using restriction fragment length polymorphisms analysis. Discontinuation of the TNFi agents <12 months due to inadequate efficacy determined by chart review was the primary outcome. Human endothelial cells expressing endogenous or recombinant TNFR2-M or TNFR2-R and Jurkat T cells expressing recombinant TNFR2-M or TNFR2-R were utilised to investigate differences in cell signalling and gene expression.

Results: Patients with PsA with TNFR2-R variant had a ∼5-fold increased likelihood of discontinuing TNFi therapy <12 months, vs TNFR2-M carriers (95% CI 1.98-12.78). The cells with TNFR2-R alleles showed higher levels of proinflammatory gene expression in the absence of TNFa stimulation (P < .01). This activity of TNFR2-R was unaffected by a TNFα-neutralising antibody, whereas blocked by a Rho kinase (ROCK)-specific inhibitor.

Conclusions: TNFR2 rs1061622 polymorphism significantly influences TNFi therapy responsiveness in PsA. The TNFα-independent, but ROCK activity-dependent gain-of-function activity conferred by TNFR2-R variant potentially serves as a mechanism underlying inadequate responses to TNFi in a subset of patients with PsA.