Annals of the Rheumatic Diseases最新文献

Objectives: Disease activity control in patients with systemic lupus erythematosus (SLE) with corticosteroid and immunosuppressant withdrawal is a treatment goal. We evaluated whether this could be attained with sequential subcutaneous belimumab (BEL) and one cycle of rituximab (RTX).

Methods: In this phase 3, double-blind BLISS-BELIEVE trial (GSK Study 205646), patients with active SLE initiating subcutaneous BEL 200 mg/week for 52 weeks were randomised to intravenous placebo (BEL/PBO) or intravenous RTX 1000 mg (BEL/RTX) at weeks 4 and 6 while stopping concomitant immunosuppressants/tapering corticosteroids; standard therapy for 104 weeks (BEL/ST; reference arm) was included.

Primary endpoint: proportion of patients achieving disease control (SLE Disease Activity Index-2000 (SLEDAI-2K) ≤2; without immunosuppressants; prednisone equivalent ≤5 mg/day) at week 52 with BEL/RTX versus BEL/PBO. Major (alpha-controlled) secondary endpoints: proportion of patients with clinical remission (week 64; clinical SLEDAI-2K=0, without immunosuppressants/corticosteroids); proportion of patients with disease control (week 104). Other assessments: disease control duration, anti-dsDNA antibody, C3/C4 and B cells/B-cell subsets.

Results: The modified intention-to-treat population included 263 patients. Overall, 16.7% (12/72) of BEL/PBO and 19.4% (28/144) of BEL/RTX patients achieved disease control (OR (95% CI) 1.27 (0.60 to 2.71); p=0.5342) at week 52. For major secondary endpoints, differences between BEL/RTX and BEL/PBO were not statistically significant. Anti-dsDNA antibodies and most assessed B cells/B-cell subsets were lower with BEL/RTX versus BEL/PBO. Mean disease control duration through 52 weeks was significantly greater with BEL/RTX versus BEL/PBO.

Conclusions: BEL/RTX showed no superiority over BEL/PBO for most endpoints analysed; however, it led to significant improvements in disease activity markers compared with BEL/PBO. Further investigation of combination treatment is warranted.

Trial registration number: NCT03312907.

Objectives: To investigate the frequency and factors associated with disease flare following vaccination against SARS-CoV-2 in people with inflammatory/autoimmune rheumatic and musculoskeletal diseases (I-RMDs).

Methods: Data from the European Alliance of Associations for Rheumatology Coronavirus Vaccine physician-reported registry were used. Factors associated with flare in patients with I-RMDs were investigated using multivariable logistic regression adjusted for demographic and clinical factors.

Results: The study included 7336 patients with I-RMD, with 272 of 7336 (3.7%) experiencing flares and 121 of 7336 (1.6%) experiencing flares requiring starting a new medication or increasing the dosage of an existing medication. Factors independently associated with increased odds of flare were: female sex (OR=1.40, 95% CI=1.05 to 1.87), active disease at the time of vaccination (low disease activity (LDA), OR=1.45, 95% CI=1.08 to 1.94; moderate/high disease activity (M/HDA), OR=1.37, 95% CI=0.97 to 1.95; vs remission), and cessation/reduction of antirheumatic medication before or after vaccination (OR=4.76, 95% CI=3.44 to 6.58); factors associated with decreased odds of flare were: higher age (OR=0.90, 95% CI=0.83 to 0.98), non-Pfizer/AstraZeneca/Moderna vaccines (OR=0.10, 95% CI=0.01 to 0.74; vs Pfizer), and exposure to methotrexate (OR=0.57, 95% CI=0.37 to 0.90), tumour necrosis factor inhibitors (OR=0.55, 95% CI=0.36 to 0.85) or rituximab (OR=0.27, 95% CI=0.11 to 0.66), versus no antirheumatic treatment. In a multivariable model using new medication or dosage increase due to flare as the dependent variable, only the following independent associations were observed: active disease (LDA, OR=1.47, 95% CI=0.94 to 2.29; M/HDA, OR=3.08, 95% CI=1.91 to 4.97; vs remission), cessation/reduction of antirheumatic medication before or after vaccination (OR=2.24, 95% CI=1.33 to 3.78), and exposure to methotrexate (OR=0.48, 95% CI=0.26 to 0.89) or rituximab (OR=0.10, 95% CI=0.01 to 0.77), versus no antirheumatic treatment.

Conclusion: I-RMD flares following SARS-CoV-2 vaccination were uncommon. Factors associated with flares were identified, namely higher disease activity and cessation/reduction of antirheumatic medications before or after vaccination.

Objectives: We report the safety, tolerability and efficacy of tofacitinib in patients with juvenile idiopathic arthritis (JIA) in an ongoing long-term extension (LTE) study.

Methods: Patients (2-<18 years) with JIA who completed phase 1/3 index studies or discontinued for reasons excluding treatment-related serious adverse events (AEs) entered the LTE study and received tofacitinib 5 mg two times per day or equivalent weight-based doses. Safety outcomes included AEs, serious AEs and AEs of special interest. Efficacy outcomes included improvement since tofacitinib initiation per the JIA-American College of Rheumatology (ACR)70/90 criteria, JIA flare rate and disease activity measured by Juvenile Arthritis Disease Activity Score (JADAS)27, with inactive disease corresponding to JADAS ≤1.0.

Results: Of 225 patients with JIA (median (range) duration of treatment, 41.6 (1-103) months), 201 (89.3%) had AEs; 34 (15.1%) had serious AEs. 10 patients developed serious infections; three had herpes zoster. Two patients newly developed uveitis. Among patients with polyarticular course JIA, JIA-ACR70/90 response rates were 60.0% (78 of 130) and 33.6% (47 of 140), respectively, at month 1, and generally improved over time. JIA flare events generally occurred in <5% of patients through to month 48. Observed mean (SE) JADAS27 was 22.0 (0.6) at baseline, 6.2 (0.7) at month 1 and 2.8 (0.5) at month 48, with inactive disease in 28.8% (36 of 125) of patients at month 1 and 46.8% (29 of 82) at month 48.

Conclusions: In this interim analysis of LTE study data in patients with JIA, safety findings were consistent with the known profile of tofacitinib, and efficacy was maintained up to month 48.

Trial registration number: NCT01500551.

Objectives: Bone remodelling is a highly dynamic process dependent on the precise coordination of osteoblasts and haematopoietic-cell derived osteoclasts. Changes in core metabolic pathways during osteoclastogenesis, however, are largely unexplored and it is unknown whether and how these processes are involved in bone homeostasis.

Methods: We metabolically and transcriptionally profiled cells during osteoclast and osteoblast generation. Individual gene expression was characterised by quantitative PCR and western blot. Osteoblast function was assessed by Alizarin red staining. immunoresponsive gene 1 (Irg1)-deficient mice were used in various inflammatory or non-inflammatory models of bone loss. Tissue gene expression was analysed by RNA in situ hybridisation.

Results: We show that during differentiation preosteoclasts rearrange their tricarboxylic acid cycle, a process crucially depending on both glucose and glutamine. This rearrangement is characterised by the induction of Irg1 and production of itaconate, which accumulates intracellularly and extracellularly. While the IRG1-itaconate axis is dispensable for osteoclast generation in vitro and in vivo, we demonstrate that itaconate stimulates osteoblasts by accelerating osteogenic differentiation in both human and murine cells. This enhanced osteogenic differentiation is accompanied by reduced proliferation and altered metabolism. Additionally, supplementation of itaconate increases bone formation by boosting osteoblast activity in mice. Conversely, Irg1-deficient mice exhibit decreased bone mass and have reduced osteoproliferative lesions in experimental arthritis.

Conclusion: In summary, we identify itaconate, generated as a result of the metabolic rewiring during osteoclast differentiation, as a previously unrecognised regulator of osteoblasts.

Objectives: The objective of this study was to evaluate efficacy, safety and tolerability of the first-in-class, anti-CCL17 monoclonal antibody, GSK3858279, in treating knee osteoarthritis (OA) pain.

Methods: This was a phase I, randomised, placebo-controlled, two-part, proof-of-mechanism and proof-of-concept study. In part A, healthy participants were randomised 3:1 to receive GSK3858279 as either single intravenous (0.1-10 mg/kg) doses, a subcutaneous (3 mg/kg up to 240 mg maximum) dose, or placebo, to evaluate safety and tolerability. In part B, participants with knee OA pain were randomised 1:1 to receive weekly subcutaneous 240 mg GSK3858279, or placebo, for 8 weeks, to assess safety and change from baseline (CFB) in average and worst knee pain intensity. Exploratory endpoints included CFB in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, function and stiffness scores.

Results: GSK3858279 demonstrated greater median CFB (95% credible interval (CrI)) in average and worst knee pain intensity versus placebo (average, -1.18 (-2.15, -0.20); worst, -1.09 (-2.29, 0.12)) at week 8. Median CFB (95% CrI) for GSK3858279 versus placebo in WOMAC pain and function scores were -1.41 (-2.35, -0.46) and -1.29 (-2.28, -0.29), respectively, at week 8. Overall, 72% (26/36; part A) and 88% (21/24; part B) of participants receiving GSK3858279 experienced adverse events (AEs); with nasopharyngitis being the most common in part A and injection site reactions in part B. No serious AEs or deaths were observed.GSK3858279 improved pain intensity and WOMAC pain and function scores in adults with knee OA pain and demonstrated favourable safety and tolerability in both healthy participants and adults with knee OA pain.

The increasing prevalence of autoimmune and immune-mediated diseases (AIMDs) underscores the need to understand environmental factors that contribute to their pathogenesis, with the microbiome emerging as a key player. Despite significant advancements in understanding how the microbiome influences physiological and inflammatory responses, translating these findings into clinical practice remains challenging. This viewpoint reviews the progress and obstacles in microbiome research related to AIMDs, examining molecular techniques that enhance our understanding of microbial contributions to disease. We discuss significant discoveries linking specific taxa and metabolites to diseases such as rheumatoid arthritis, systemic lupus erythematosus and spondyloarthritis, highlighting the role of gut dysbiosis and host-microbiome interactions. Furthermore, we explore the potential of microbiome-based therapeutics, including faecal microbiota transplantation and pharmacomicrobiomics, while addressing the challenges of identifying robust microbial targets. We advocate for integrative, transdisease studies and emphasise the need for diverse cohort research to generalise findings across populations. Understanding the microbiome's role in AIMDs will pave the way for personalised medicine and innovative therapeutic strategies.

Introduction: Evidence from randomised controlled trials on anti-tumour necrosis factor (TNF) agents in patients with Behçet's syndrome (BS) is low.

Method: We conducted a phase 3, multicentre, prospective, randomised, active-controlled, parallel-group study to evaluate the efficacy and safety of either infliximab (IFX) or adalimumab (ADA) in patients with BS. Adults patients with BS presenting with active mucocutaneous manifestations, occurring while on therapy with either azathioprine or cyclosporine for at least 3 months prior to study entry, were eligible. Participants were randomly assigned (1:1) to receive IFX or ADA for 6 months. The primary study outcome was the time to response of manifestations over 6-month anti-TNF alpha agents' treatment.

Results: 42 patients underwent screening visits, of whom 40 were randomly assigned to the IFX group (n=22) or to the ADA group (n=18). All patients at the time of randomisation had active mucocutaneous manifestations and a smaller proportion had concomitant vital organ involvement (ie, six and three patients with ocular and neurological involvement, respectively). A total of 14 (64%) responders in the IFX group and 17 (94%) in the ADA group were observed. Retention on treatment was 95% and 94% in the IFX and in the ADA group, respectively. Quality of life resulted to be significantly improved in both groups from baseline, as well as Behçet's Disease Current Activity Form assessment. We registered two adverse events (one serious) in the ADA group and three non-serious adverse events in the IFX group.

Discussion: The overall results of this study confirm the effectiveness of both IFX and ADA in achieving remission in patients with BS affected by mucocutaneous involvement.