Annals of the Rheumatic Diseases最新文献

Objectives: Osteoarthritis (OA) is linked to disrupted lipid metabolism. We aimed to profile the lipid composition of human articular cartilage, investigate OA-associated lipidome changes, and explore biological effects.

Methods: Lipidomic profiling and computational analyses were performed on human articular chondrocytes (hACs) from non-OA (n = 13) and OA (n = 14) hips. Lipid changes were confirmed in the destabilisation of the medial meniscus (DMM) mouse model. The effect of specific lipids was evaluated by in vitro supplementation and gene silencing.

Results: We identified 573 lipid species covering 11 lipid classes in hACs. OA and non-OA hACs showed distinct lipid profiles. Most ceramides and dihydroceramides were increased, while cholesteryl esters, diacylglycerols, triacylglycerols, sphingomyelins, hexosylceramides, and lactosylceramides were predominantly decreased in OA chondrocytes. Most upregulated lipids in OA contained C18:1, C20:4, or C22:4 side chains. Many downregulated lipids contained C18:2 or odd-chain C17:0. Lipid profiling of articular cartilage from the DMM mouse model paralleled changes in OA hACs, including odd-chain C17:0 reduction. Further analysis showed that deficiency in enzyme 2-hydroxyacyl-CoA lyase 1 (HACL1), responsible for odd-chain fatty acid synthesis, leads to accumulation of 2-hydroxy C18:0, precursor of C17:0, which results in a shift in hACs from an anabolic to a catabolic state.

Conclusions: Our study maps the hAC lipid composition and highlights changes in lipid profiles associated with OA. Dysregulation of certain lipids, especially odd-chain fatty acids, linked to a deficiency in the enzyme HACL1, leads to pathological changes. This understanding opens potential avenues for therapies aimed at targeting lipid imbalances to slow down or treat OA.

Objectives: Tocilizumab (TCZ), rituximab (RTX), mycophenolate mofetil (MMF), and cyclophosphamide (CYC) are the immunosuppressants (IS) most frequently used for systemic sclerosis-associated interstitial lung disease (SSc-ILD). This post hoc study aimed to compare their effectiveness in patients with SSc-ILD from the European Scleroderma Trials and Research (EUSTAR) database.

Methods: We included radiologically confirmed SSc-ILD patients with treatment records for TCZ, RTX, MMF, or CYC. The primary endpoint was the change in forced vital capacity (FVC) percent predicted from baseline to follow-up. Analyses were adjusted for clinical and demographic characteristics, cotreatments, and follow-up duration using propensity score-based inverse probability of treatment weighting (IPTW).

Results: Nine hundred fifty-five patients with 997 treatment observations were included in the study. The median follow-up time was 11 months (IQR, 8-14 months). After IPTW, the changes in FVC percent predicted were not significantly different in the multigroup comparison (P = .101). Paired comparisons showed no significant difference. CYC was associated with stable FVC in logistic regression. For subgroup analysis, the treatment differences in change of FVC percent predicted among the 4 groups were not significant in patients with combination IS or previous exposure to TCZ, RTX, or conventional IS, as well as in current smokers or nonsmokers, and regardless of whether observations started either at the initiating or noninitiating stage of the treatment.

Conclusions: In this first large real-world study, the effectiveness of TCZ, RTX, MMF, and CYC on FVC change in SSc-ILD patients was not statistically different.

Objectives: Anifrolumab is approved for the treatment of systemic lupus erythematosus (SLE). We aimed to determine if anifrolumab plus standard of care (SOC) was associated with reduced organ damage accumulation in adult patients with moderately to severely active SLE compared to real-world (RW) external controls from the University of Toronto Lupus Clinic (UTLC) cohort who received SOC only.

Methods: Patients who initiated 300 mg anifrolumab in the TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) trials were included in the anifrolumab arm; key eligibility criteria were applied to the UTLC to create the RW SOC arm. Propensity score and censoring weighting were used to account for baseline confounding and loss to follow-up. The primary endpoint was change in Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score from baseline to week 208, and the secondary endpoint was time to first SDI score increase.

Results: 354 patients were included in the anifrolumab arm, and 561 patients were included in the RW SOC arm. Following weighting, mean change in SDI was 0.416 points lower (95% CI: -0.582, -0.249; P < .001) in the anifrolumab arm than in the RW SOC arm. Patients in the anifrolumab arm were 59.9% less likely (hazard ratio: 0.401; 95% CI: 0.213, 0.753, P = .005) to experience an increase in SDI within 208 weeks.

Conclusions: Patients who received anifrolumab accumulated significantly less organ damage after 208 weeks than patients who received RW SOC. The addition of anifrolumab to SOC is effective at preventing and/or delaying organ damage in patients with moderately to severely active SLE.

Background: There is considerable practice variation in labelling, diagnosis and treatment of adults with sterile bone inflammation. We developed a expert consensus recommendations on the disease definition, diagnosis and treatment of this rare condition.

Methods: Systematic literature review and Grading of Recommendations, Assessment, Development and Evaluations-based appraisal of evidence, two Delphi surveys and three digital and in-person consensus meetings with a multidisciplinary expert panel and patient representatives.

Results: A consensus disease definition was developed and the term 'chronic non-bacterial osteitis' (CNO) is proposed to describe adults with sterile bone inflammation. For initial imaging evaluation of adults with suspected CNO, the panel recommends MRI or otherwise CT combined with nuclear imaging. Whole-body imaging at initial evaluation can be considered for diagnostic and prognostic purposes. Suggested first-line treatment in adults with active CNO includes nonsteroidal anti-inflammatory drugs/cyclooxygenase 2-inhibitors. Second-line treatment preferably consists of intravenous bisphosphonates, and otherwise tumour necrosis factor-α inhibitors. Choice between them should be individualised, considering the presence of additional inflammatory features. The panel further discusses outcome measures, follow-up and management of adverse events and complications.

Conclusions and future perspectives: These expert consensus recommendations are intended to support healthcare professionals worldwide in their care for adults with CNO. They also lay the groundwork for establishing international patient registries, translational research lines and multicentre trials, all of which are urgently required.

Background: Anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR)-positive immune-mediated necrotising myopathy (IMNM) is characterised by the presence of IgG autoantibodies against HMGCR and a strong association with specific HLA-DR alleles. Although these findings implicate HMGCR-specific CD4⁺T-cells in the disease's pathogenesis, no such cells have been described. In this study, we aimed to identify and characterise HMGCR-reactive CD4⁺T-cells and assess their presence in affected muscle tissue from patients with anti-HMGCR+IMNM.

Methods: Peripheral blood mononuclear cells from patients with anti-HMGCR+IMNM (n=10) and dermatomyositis (DM; n=10) were stimulated with HMGCR protein and peptides identified using a natural antigen processing assay (NAPA; n=6). CD4⁺T-cell activation was assessed by CD154 upregulation via flow cytometry. T-cell receptor β(TCR) sequencing was performed on paired HMGCR-reactive T-cells and muscle biopsy tissue (n=5).

Results: CD4⁺T-cell responses to HMGCR protein were higher in patients with anti-HMGCR+IMNM compared with DM (median 0.06 vs 0.00, p=0.0059). These responses were enriched in Th1-Th17 cells, and when present, they positively correlated with anti-HMGCR antibody levels (r²=0.89, p=0.0012). NAPA revealed convergent presentation of seven HMGCR core peptides, with substantial overlap in the peptide repertoires between patients. These HMGCR peptides elicited robust CD4⁺T-cell responses, with 9/10 anti-HMGCR+IMNM patients responding to at least one peptide, compared with 1/10 DM (p=0.0003). Analysis of HMGCR-reactive TCRs β yielded antigen-reactive motifs that were enriched in muscle biopsies (projection score 0.03 vs 0.63, p=0.007).

Conclusion: HMGCR-antigen-reactive CD4⁺T-cells are present in the circulation and target tissue of patients with anti-HMGCR+IMNM, suggesting an active role for these cells in the pathogenesis of anti-HMGCR+IMNM.

Objectives: This study aimed to investigate the efficacy of mitochondrial transplantation as a therapeutic intervention for idiopathic inflammatory myopathy (IIM). This study used a comprehensive approach, incorporating both in vitro and in vivo IIM models, and conducted a first-in-human clinical trial to assess the effectiveness and safety of mitochondria isolated from human umbilical cord mesenchymal stem cells (PN-101).

Methods: Mitochondria isolated from umbilical cord mesenchymal stem cells were designated as PN-101. The efficacy of PN-101 was assessed using myoblasts derived from patients with IIM and C2C12 mouse perforin/granzyme B-treated myoblasts as an in vitro IIM model. PN-101's effect on IIM was examined using C protein-induced myositis (CIM) mice as an in vivo model. The efficacy and safety of PN-101 were evaluated in a phase 1/2a clinical trial involving 9 adult patients with refractory polymyositis or dermatomyositis.

Results: The myoblasts derived from patients with IIM exhibited defects in mitochondrial function and myogenesis. PN-101 transplantation enhances muscle differentiation and mitochondrial function in IIM myoblasts. PN-101 also enhanced intracellular adenosine triphosphate content, cell viability, and myogenesis in C2C12 perforin/granzyme B-treated myoblasts. In an in vivo model, PN-101 reduced myositis severity by exhibiting anti-inflammatory effects and restoring the CIM-induced metabolic shift. In a phase 1/2a prospective clinical trial involving adult patients with refractory IIM, PN-101 demonstrated no severe adverse drug reactions and showed at least minimal improvement in the International Myositis Assessment and Clinical Studies Group (IMACS)-Total Improvement Scores (TISs) compared with baseline.

Conclusions: PN-101 transplantation could serve as a novel treatment for IIM by enhancing mitochondrial repair and reducing inflammation in muscle tissues.

Background: Targeted therapies have been associated with potential risk of malignancy, which is a common concern in daily rheumatology practice in patients with inflammatory arthritis (IA) and a history of cancer.

Objectives: To perform a systematic literature review to inform a Task Force formulating EULAR points to consider on the initiation of targeted therapies in patients with IA and a history of cancer.

Methods: Specific research questions were defined within the Task Force before formulating the exact research queries with a librarian. We included studies reporting a relative risk measure of patients with a history of cancer initiating a targeted therapy or a conventional synthetic disease-modifying antirheumatic drug (csDMARD), regardless of the time since diagnosis of cancer. All relevant studies included in PubMed or Embase up to 15 July 2022 were included. Two reviewers independently performed standardised article selection, data extraction, synthesis and risk of bias assessment.

Results: 14 published articles and one ACR abstract fulfilled the inclusion criteria. All studies were high-quality observational studies, representing a median follow-up from treatment initiation of 4.52 years among 4428 patients and 15 062 patient-years of follow-up for new or recurrent cancer. All patients had a history of cancer, most frequently solid cancer, most frequently receiving treatment for rheumatoid arthritis and most frequently treated with tumour necrosis factor-alpha inhibitors. Across these studies, the overall HR of new incident cancer or cancer recurrence was 0.90 (95% CI 0.74 to 1.10) for patients receiving a targeted therapy versus a csDMARD.

Conclusion: Overall, the targeted therapies and clinical contexts covered by the included studies were not associated with an increased risk of new incident cancer or cancer recurrence as compared with csDMARDs.