Objective Protein citrullination is an important posttranslational modification recognized by rheumatoid arthritis (RA)–specific autoantibodies. One of the citrullinating enzymes, peptidyl arginine deiminase type 4 (PAD‐4), is genetically associated with development of RA in some populations, although the mechanism(s) mediating this effect are not yet clear. There have been descriptions of anti–PAD‐4 autoantibodies in different rheumatic diseases. This study was undertaken to investigate whether anti–PAD‐4 antibodies are specific to RA, are associated with disease phenotype or severity, and whether PAD‐4 polymorphisms influence the anti–PAD‐4 autoantibody response. Methods Sera from patients with established RA, patients with other rheumatic diseases, and healthy adults were assayed for anti–PAD‐4 autoantibodies by immunoprecipitation of in vitro–translated PAD‐4. The epitope(s) recognized by PAD‐4 autoantibodies were mapped using various PAD‐4 truncations. PAD‐4 genotyping was performed on RA patients with the TaqMan assay. Joint erosions were scored from hand and foot radiographs using the Sharp/van der Heijde method. Results PAD‐4 autoantibodies were found in 36–42% of RA patients, and were very infrequent in controls. Recognition by anti–PAD‐4 autoantibodies required the 119 N‐terminal amino acids, which encompass the 3 nonsynonymous polymorphisms associated with disease susceptibility. Strikingly, the anti–PAD‐4 immune response was associated with the RA susceptibility haplotype of PADI4. Anti–PAD‐4 antibodies were associated with more severe joint destruction in RA. Conclusion Our findings indicate that anti–PAD‐4 antibodies are specific markers of RA, independently associated with more severe disease, suggesting that an anti–PAD‐4 immune response may be involved in pathways of joint damage in this disease. Polymorphisms in the PADI4 gene influence the immune response to the PAD‐4 protein, potentially contributing to disease propagation.

Objective. Arthritis in the K/BxN mouse model results from pathogenic immunoglobulins that recognize glucose-6-phosphate isomerase (GPI), a glycolytic enzyme residing in the cytoplasm of all cells. Antibodies directed against GPI can, alone, transfer arthritis to healthy recipients. Previous experiments have revealed significant titers of anti-GPI antibodies in the serum of many patients with rheumatoid arthritis (RA). We evaluated the generality of these observations in cohorts of patients with 12 different arthritic and chronic autoimmune diseases and in population-matched healthy control subjects.Methods. Anti-GPI antibodies were assayed in 811 individual serum samples by enzyme-linked immunosorbent assay with 2 forms of GPI, recombinant and native. Results were confirmed by immunoblotting.Results. Several patients had significantly elevated anti-GPI antibody titers, but without the prevalence or the specificity reported previously. Only 15% of RA patients had anti-GPI antibodies (range 12-29% in different cohorts), with a higher prevalence in patients with active disease. Psoriatic arthritis, undifferentiated arthritis, and spondylarthropathy patients also displayed anti-GPI antibodies at similar frequencies (12-25%). Similar titers were detected in a proportion (5-10%) of control subjects or patients with Crohn's disease or sarcoidosis. Very high titers were found in rare cases of RA and systemic lupus erythematosus.Conclusion. No disease-specific pattern of antibody positivity to GPI was apparent. While the antibody-mediated mechanism at play in the mouse model may exemplify a generic mechanism for some forms of arthritis in humans, GPI itself does not appear to be a target common to the majority of RA patients.

Objective To determine the incidence of inflammatory arthritis and autoantibody prevalence in Indigenous North American people. Methods Unaffected relatives of Indigenous North Americans with rheumatoid arthritis (RA) from central Canada and Alaska were systematically monitored from 2005 to 2017. Rheumatoid factor (RF) and anti–citrullinated protein antibodies (ACPAs) were tested at every visit, and a subset was tested for ACPA fine specificity using a custom multiplex assay. Multistate models based on all available study visits were developed to determine the likelihood of transitioning between autoantibody states, or to inflammatory arthritis. Results Eighteen of 374 relatives (4.8%) developed inflammatory arthritis during follow‐up (after a mean ± SD of 4.7 ± 2.4 years), yielding a transition rate of 9.2 cases/1,000 person‐years. Thirty percent of those who developed inflammatory arthritis were seronegative at baseline, but all were seropositive at inflammatory arthritis onset. Although 30% of ACPA/RF double‐seropositive individuals developed inflammatory arthritis (after 3.2 ± 2.2 years), the majority of these individuals did not develop inflammatory arthritis. Multistate modeling indicated a 71% and 68% likelihood of ACPA and RF seropositive states, respectively, reverting to a seronegative state after 5 years, and a 39% likelihood of an ACPA/RF double‐seropositive state becoming seronegative. Fine specificity testing demonstrated an expansion of the ACPA repertoire prior to the development of inflammatory arthritis. Conclusion Despite a high incidence of inflammatory arthritis in this cohort of at‐risk relatives of Indigenous North Americans with RA, a large proportion of autoantibody‐positive individuals do not develop inflammatory arthritis and revert back to an autoantibody‐negative state.

Objective Anti–citrullinated protein antibodies (ACPAs) are disease‐specific biomarkers in rheumatoid arthritis (RA). More than 90% of IgG ACPAs harbor N‐linked glycans in the antibody variable (V) domain. The corresponding N‐glycosylation sites in ACPA V‐region sequences result from somatic hypermutation, a T cell–dependent process. As ample evidence indicates that T cells drive the maturation of the ACPA response prior to arthritis onset, we undertook this study to investigate whether the presence of glycans in IgG ACPA V domains predicts the transition from predisease autoimmunity to overt RA. Methods We analyzed 2 independent sets of serum samples obtained from 126 ACPA‐positive first‐degree relatives (FDRs) of RA patients. Both sets originated from an Indigenous North American population and comprised cross‐sectional and longitudinal samples of individuals who did or did not develop inflammatory arthritis. Serum IgG ACPAs were affinity‐purified and subjected to ultra high‐performance liquid chromatography–based glycan analysis. Results In both data sets, FDR‐derived IgG ACPA displayed markedly lower levels of V domain glycans (<50%) compared to IgG ACPA from RA patients. Notably, FDRs who later developed RA showed extensive V‐domain glycosylation before the onset of arthritis. Moreover, IgG ACPA V‐domain glycosylation was strongly associated with future development of RA (hazard ratio 6.07 [95% confidence interval 1.46–25.2]; P = 0.013). Conclusion Extensive glycosylation of the IgG ACPA V domain is present in a subset of predisposed FDRs of Indigenous North American RA patients. The presence of this feature substantially increases the risk of RA development. Based on these findings, we propose that glycosylation of the IgG ACPA V domain represents a predictive marker for RA development in ACPA‐positive individuals and may serve to better target prevention measures.

The QRISK2, EULAR multiplier and ERS-RA algorithms did not predict CVD risk more accurately in patients with RA than CVD risk calculators developed for the general population.

Formation of autoantibodies to carbamylated proteins (anti-CarP) is considered detrimental in the prognosis of erosive rheumatoid arthritis (RA). The source of carbamylated antigens and the mechanisms by which anti-CarP antibodies promote bone erosion in RA remain unknown. Here, we find that neutrophil extracellular traps (NETs) externalize carbamylated proteins and that RA subjects develop autoantibodies against carbamylated NET (cNET) antigens that, in turn, correlate with levels of anti-CarP. Transgenic mice expressing the human RA shared epitope (HLADRB1* 04:01) immunized with cNETs develop antibodies to citrullinated and carbamylated proteins. Furthermore, anti–carbamylated histone antibodies correlate with radiographic bone erosion in RA subjects. Moreover, anti–carbamylated histone–immunoglobulin G immune complexes promote osteoclast differentiation and potentiate osteoclast-mediated matrix resorption. These results demonstrate that carbamylated proteins present in NETs enhance pathogenic immune responses and bone destruction, which may explain the association between anti-CarP and erosive arthritis in RA.

Objective. To determine how HLA alleles are associated with the clinical disease patterns of patients with synovitis of recent onset. Methods. The HLA alleles A, B, C, DR1, and DQ1 were determined in a cohort of 211 patients (mean age 42 years, 64% female, 79% white) with recent-onset synovitis in 1 or more peripheral joints. At a mean disease duration of 33 weeks, 98 patients (46%) met the American College of Rheumatology (ACR) criteria for rheumatoid arthritis (RA), 38 (18%) met the European Spondylarthropathy Study Group criteria for spondylarthropathy (SpA), and 75 (36%) were classified as having undifferentiated arthropathy (UA). Controls were racially matched healthy individuals (n 244). Results. Shared epitope (SE) alleles were significantly more common in rheumatoid factor-positive (RF) patients fulfilling the ACR RA criteria than in other patients with early arthritis (65% versus 35%; P < 0.001). In addition, the RA patients had by far the highest frequency of radiographic erosions (52% and 39% in RF and RF RA, respectively, versus 3% and 9% in SpA and UA patients, respectively; P < 0.0001). The presence of SE alleles was a particularly strong predictor of early erosions in the RF RA patients (odds ratio [OR] 6.8, 95% confidence interval [95% CI] 1.2-45). The presence of 2 SE alleles or an associated DQ1*0301 (DQ7) or DQ1*0302 (DQ8) allele appeared to modestly increase the risk of early erosions, although these DQ alleles were in strong linkage disequili-brium with DR1*0401, both in the patient and in the control populations. B27 was linked with the presence of SE alleles in the patients, including those patients fulfilling the RA criteria, but not in the controls (12% versus 3%; P < 0.001). Enthesitis was present in 23 (11%) of 211 patients, was highly associated with B27 (OR 4.2, 95% CI 1.5-11.5), and surprisingly, was not a feature specific only to the SpA group. The B8-DR3 haplotype was significantly increased in the patient subgroups compared with controls (17% versus 7%; P < 0.01), although the clinical significance of this association is unclear. Conclusion. This study of HLA associations in a diverse cohort of early synovitis patients emphasizes the complex degree of genetic interaction between alleles at several major histocompatibility complex loci, which regulates clinical phenotypes. In particular, SE and B27, while predisposing patients to characteristic clinical syndromes, had an unexpected degree of association in this cohort, perhaps explaining the overlap in clinical features in many patients. Synovitis in 1 or more peripheral joints is the presenting feature of several chronic inflammatory ar-thropathies. The clinical spectrum of rheumatoid arthritis (RA) and the seronegative spondylarthropathies (SpA), which are disorders presumably having distinct pathogenetic mechanisms, can be difficult to differentiate early in the disease course. Moreover, a large proportion of patients with synovitis of recent onset lack specific diagnostic features and are classified as having undifferentiated ...

The estimated prevalence of RA, AS, and PsD was higher in the First Nations population, while crystal-related arthritis was less prevalent compared to the non-First Nations population. First Nations people were more likely to see primary care physicians and were less likely to see specialists for inflammatory arthritis care.