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Objective: Mitochondria are found in the extracellular space in rheumatoid arthritis (RA). However, whether mitochondria are a source of autoantigens in RA has not been carefully addressed. Thus, we undertook this study to investigate the presence and significance of antimitochondrial antibodies (AMAs) in patients with RA. Methods: AMAs were measured in serum samples from 3 cross‐sectional cohorts of RA patients (n = 95, n = 192, and n = 117) and healthy individuals (n = 38, n = 72, and n = 50) using a flow cytometry–based assay. Further, AMAs were detected using an anti–mitofusin‐1 (anti–MFN‐1) IgG enzyme‐linked immunosorbent assay and Western blot analysis. A longitudinal inception cohort, followed up for a median of 8 years, was used to study disease progression. Results: AMA levels were elevated in RA patients from all 3 cohorts as compared to healthy individuals (P < 0.001, P < 0.05, and P < 0.01), with a range of 14–26% positivity. Levels of anti–MFN‐1 antibodies correlated with AMA levels (r = 0.31, P = 0.006) and were elevated in RA patients as compared to healthy individuals (P < 0.001). The presence of AMAs was associated with erosive disease (P < 0.05) and interstitial lung disease (P < 0.01). Further, AMA levels were found to predict erosive disease (odds ratio [OR] 4.59, P = 0.006) and joint space narrowing (OR 3.08, P = 0.02) independent of anti–citrullinated protein antibodies. Finally, anti–MFN‐1 antibodies identified seronegative patients developing erosive disease (OR 9.33; P = 0.02). Conclusion: Our findings demonstrate the presence of novel autoantibodies targeting mitochondria in the setting of RA. AMAs were used to stratify patients based on disease phenotype and to predict development of erosive disease, including in patients with seronegative disease. Our results highlight the essential role of mitochondria in the pathogenesis of RA and suggest a possible benefit of therapies targeting mitochondrial‐mediated inflammation and clearance in these patients. [ABSTRACT FROM AUTHOR]

Objective: Exaggerated neutrophil activation and formation of neutrophil extracellular traps (NETs) are linked to inflammation and autoimmunity, including rheumatoid arthritis (RA). However, whether NETs are present in the circulation of RA patients and contribute to inflammation and disease progression has not been carefully addressed. We undertook this study to assess markers of neutrophil activation and NET formation in plasma samples, investigating whether they add clinical value in improving the determination of prognosis and monitoring in RA patients. Methods: Markers of neutrophil activation (calprotectin) and cell death (NETs) were analyzed, using enzyme‐linked immunosorbent assay, in serum and plasma obtained from patients in 3 cross‐sectional RA cohorts and sex‐matched healthy controls. A longitudinal inception cohort (n = 247), seen for a median follow‐up of 8 years, was used for predictive analyses. Results: Markers of neutrophil activation and cell death were increased in RA patients compared to healthy individuals (P < 0.0001). Calprotectin levels correlated with the Clinical Disease Activity Index (r = 0.53, P < 0.0001) and could be used to distinguish between patients with disease in remission and those with active disease, an observation not seen when examining C‐reactive protein levels. A biomarker panel consisting of anti–citrullinated protein antibody and calprotectin could predict erosive disease (odds ratio [OR] 7.5, P < 0.0001) and joint space narrowing (OR 4.9, P = 0.001). NET levels were associated with markers of inflammation (P = 0.0002). Furthermore, NETs and a "neutrophil activation signature" biomarker panel had good predictive value in identifying patients who were developing extraarticular nodules (OR 5.6, P = 0.006). Conclusion: Neutrophils undergo marked activation and cell death in RA. Neutrophil biomarkers can provide added clinical value in the monitoring and prognosis of RA patients and may allow for early preventive treatment intervention. [ABSTRACT FROM AUTHOR]

Objective: Juvenile idiopathic arthritis (JIA) comprises 7 heterogeneous categories of chronic childhood arthritides. Approximately 5% of children with JIA have rheumatoid factor (RF)–positive arthritis, which phenotypically resembles adult rheumatoid arthritis (RA). Our objective was to compare and contrast the genetics of RF‐positive polyarticular JIA with those of RA and selected other JIA categories, to more fully understand the pathophysiologic relationships of inflammatory arthropathies. Methods: Patients with RF‐positive polyarticular JIA (n = 340) and controls (n = 14,412) were genotyped using the Immunochip array. Single‐nucleotide polymorphisms were tested for association using a logistic regression model adjusting for admixture proportions. We calculated weighted genetic risk scores (wGRS) of reported RA and JIA risk loci, and we compared the ability of these wGRS to predict RF‐positive polyarticular JIA. Results: As expected, the HLA region was strongly associated with RF‐positive polyarticular JIA (P = 5.51 × 10−31). Nineteen of 44 RA risk loci and 6 of 27 oligoarticular/RF‐negative polyarticular JIA risk loci were associated with RF‐positive polyarticular JIA (P < 0.05). The RA wGRS predicted RF‐positive polyarticular JIA (area under the curve [AUC] 0.71) better than did the oligoarticular/RF‐negative polyarticular JIA wGRS (AUC 0.59). The genetic profile of patients with RF‐positive polyarticular JIA was more similar to that of RA patients with age at onset 16–29 years than to that of RA patients with age at onset ≥70 years. Conclusion: RF‐positive polyarticular JIA is genetically more similar to adult RA than to the most common JIA categories and thus appears to be a childhood‐onset presentation of autoantibody‐positive RA. These findings suggest common disease mechanisms, which could lead to novel therapeutic targets and shared treatment strategies. [ABSTRACT FROM AUTHOR]