Objective: We investigated the rheumatoid arthritis (RA) diagnostic performances of anti‐cyclic citrullinated peptide antibody (anti‐CCP) and antifilaggrin antibody (AFA) in comparison with RF and matrix metalloproteinase‐3 (MMP‐3). Methods: We used a second generation enzyme‐linked immunosorbent assay (ELISA) kit for the detection of anti‐CCP. We constructed recombinant human filaggrin, which was citrullinated in vitro by human peptidylarginine deiminase, and subsequently used it as the coating antigen for AFA‐ELISA. A total of 549 RA patients and 208 other rheumatic disease patients were included in the study. Results: The specificities of anti‐CCP (88.9%) and AFA (94.7%) were superior to those of RF (81.7%) and MMP‐3 (49.5%). The sensitivity of anti‐CCP (87.6%) was superior to all others. However, the sensitivity of AFA (68.7%) was inferior to those of RF (69.8%) and MMP‐3 (75.7%). Furthermore, receiver operating characteristic curves of anti‐CCP and AFA passed closer to the upper left corner than those of RF and MMP‐3, and the areas under the curves (AUC) of AFA and anti‐CCP were significantly larger. In addition, the AUC of anti‐CCP was significantly larger than that of AFA. Conclusion: ELISA detection of antibodies to citrullinated antigens, especially a second generation anti‐CCP, showed higher discriminative ability than other assays, including RF, and would be useful to aid the diagnosis of RA in clinical practice.

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease that develops in genetically susceptible individuals in response to environmental factors. SLE and primary immunodeficiency disease (PID) share some clinical manifestations in that certain PIDs present with autoimmune phenomena. Patients with SLE become susceptible to infection via three pathways. First, SLE and PID share some genetic factors, such as complement and mannose-binding lectin genes, which predispose patients to infection. Second, patients with SLE have an inherently high risk of infection because of their intrinsic immunological abnormalities induced by SLE. Third, patients with SLE receiving immunosuppressive treatment are at high risk of infection. Further studies delineating the abnormalities related to both autoimmunity and immunodeficiency would be warranted to identify a new potential drug target for SLE.

Introduction: Anti-citrullinated protein/peptide antibodies (ACPAs) are highly specific to rheumatoid arthritis (RA) patients and are thought to have a close relationship with the pathogenesis of arthritis. Several proteins, including fibrinogen, vimentin, and alpha-enolase, were reported as ACPA-target antigens, and their importance in RA pathogenesis was widely proposed. We identified citrullinated immunoglobulin binding protein (citBiP) as another ACPA target in RA patients and examined its pro-inflammatory role in arthritis. Methods: We measured the levels of anti-citBiP, anti-BiP, and anti-cyclic citrullinated peptide (CCP) antibodies in the serum of RA patients (n = 100), systemic lupus erythematosus (SLE) patients (n = 60), and healthy controls (n = 30) using ELISA and immunoblotting. Epitope mapping was performed using 27 citBiP-derived peptides. In the mouse study, after DBA/1J mice were immunized with BiP or citBiP, serum titers of ACPAs were measured by ELISA and immunohistochemistry. The development of collagen-induced arthritis (CIA) was observed in BiP- or citBiP-pre-immunized mice. Results: The serum levels of anti-BiP and anti-citBiP antibodies were significantly increased in RA patients, although only anti-BiP antibodies were slightly increased in SLE patients. Interestingly, anti-citBiP antibody levels were higher than anti-BiP antibody levels in 72% of RA patients, whereas no significant increase in anti-citBiP antibody levels was detected in SLE patients and healthy controls. The serum levels of anti-CCP antibodies were correlated with those of anti-citBiP antibodies in RA patients (R² = 0.41). Several citrulline residues of citBiP were determined to be major epitopes of anti-citBiP antibodies, one of which showed cross-reactivity with CCP. Immunization of DBA/1J mice with citBiP induced several kinds of ACPAs, including anti-CCP and anti-citrullinated fibrinogen antibodies. Pre-immunization with citBiP exacerbated CIA, and anti-CCP antibody levels were increased in citBiP-pre-immunized CIA mice. Conclusions: CitBiP is a newly described ACPA target that may play a pro-inflammatory role in arthritis.

Introduction: The objective of this study was to directly compare the safety of tocilizumab (TCZ) and TNF inhibitors (TNFIs) in rheumatoid arthritis (RA) patients in clinical practice. Methods: This prospective cohort study included RA patients starting TCZ [TCZ group, n = 302, 224.68 patient-years (PY)] or TNFIs [TNFI group, n = 304, 231.01 PY] from 2008 to 2011 in the registry of Japanese RA patients on biologics for long-term safety registry. We assessed types and incidence rates (IRs) of serious adverse events (SAEs) and serious infections (SIs) during the first year of treatment. Risks of the biologics for SAEs or SIs were calculated using the Cox regression hazard analysis. Results: Patients in the TCZ group had longer disease duration (P <0.001), higher disease activity (P = 0.019) and more frequently used concomitant corticosteroids (P <0.001) than those in the TNFI group. The crude IR (/100 PY) of SIs [TCZ 10.68 vs. TNFI 3.03; IR ratio (95% confidence interval [CI]), 3.53 (1.52 to 8.18)], but not SAEs [21.36 vs. 14.72; 1.45 (0.94 to 2.25)], was significantly higher in the TCZ group compared with the TNFI group. However, after adjusting for covariates using the Cox regression hazard analysis, treatment with TCZ was not associated with higher risk for SAEs [hazard ratio (HR) 1.28, 95% CI 0.75 to 2.19] or SIs (HR 2.23, 95% CI 0.93 to 5.37). Conclusions: The adjusted risks for SAEs and SIs were not significantly different between TCZ and TNFIs, indicating an influence of clinical characteristics of the patients on the safety profile of the biologics in clinical practice.

Objective To determine the frequencies at which either a valine or leucine occurs at position 247 in the β₂‐glycoprotein I (β₂GPI) gene of normal individuals of the Caucasian, African American, and Asian ethnic groups and to compare these data with those in patients with the antiphospholipid syndrome (APS), with and without anti‐β₂GPI antibodies. Methods The DNA segment containing the position‐247 polymorphism was amplified by seminested polymerase chain reaction, and the polymorphism was detected by restriction endonuclease digestion. DNA samples from 370 healthy controls of different racial backgrounds were analyzed, and the results were compared with those from 149 APS patients (66 primary; 83 secondary). Allele and genotype frequencies were compared using Fisher's exact test. When significant differences were detected, pairwise comparisons were made using Fisher's exact test with a Bonferroni adjustment. Results Allele and genotype expression was significantly different (P < 0.0001 for both) among the 3 races, with the V allele and the VV genotype occurring most often among Caucasians, less among African Americans, and least among Asians. Conversely, the V allele and the VV genotype were found more frequently among Asian APS patients than among controls (P = 0.0028 and P = 0.0023, respectively). No significant differences in allele or genotype frequencies were seen in comparisons of the Caucasian or the African American patients with appropriate controls. The differences in allele and genotype frequencies seen in the Asian APS patients were restricted to the anti‐β₂GPI–positive patients (P = 0.0018 and P = 0.0005, respectively). Conclusion In Asian patients with APS, expression of a V at position 247, especially in the homozygous state, is significantly associated with the presence of anti‐β₂GPI antibodies and, therefore, can be viewed as a major risk factor in this ethnic group (odds ratio 9.19 and 16.33, respectively).