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Objectives: There is a lack of indicators to distinguish between interleukin-6 inhibitors responders and tumor necrosis factor inhibitors responders in the treatment of rheumatoid arthritis. Osteoporosis is a complication of rheumatoid arthritis and is closely related to inflammatory pathology. The purpose of this study was to evaluate whether bone mineral density can distinguish interleukin-6 inhibitors responders from tumor necrosis factor inhibitors responders in rheumatoid arthritis. Methods: Either interleukin-6 inhibitors or tumor necrosis factor inhibitors was introduced as the first biologics to patients naïve to both corticosteroid and osteoporosis treatment. Correlations between baseline bone mineral density and Clinical Disease Activity Index after 3 months were analyzed. Results: The subjects were 26 rheumatoid arthritis patients with a median age of 60 years old, disease duration of 1.4 years, Clinical Disease Activity Index of 13.7, and C-reactive protein of 1.69 mg/dL. The subjects were divided into two groups (high (H) and low (L)) according to their femoral bone mineral density with a cutoff of young adult mean of 80%. Six in group H and 11 in group L received interleukin-6 inhibitors, and nine in group H received tumor necrosis factor inhibitors. Clinical Disease Activity Index remission rate by interleukin-6 inhibitors was significantly greater in group L (8/11 (72.7%)) than in group H (1/6 (16.7%); p

Background: Rheumatoid arthritis (RA) is occasionally complicated with interstitial lung disease (ILD). A recent genome-wide association study of ILD in RA reported an association with the polymorphism rs12702634 in RPA3-UMAD1 . We conducted an association study of this variant with ILD in Japanese RA patients to replicate this association. Methods: Genotyping of rs12702634 was performed in 175 RA with ILD and 411 RA without chronic lung disease. Results: No association was detected for rs12702634 with ILD in RA ( P = .6369, odds ratio [OR] 1.13, 95% confidence interval [CI] 0.72-1.78). Meta-analysis of these data combined with the data from the recent report showed no significant association ( P = .0996, OR 1.52, 95% CI 0.92–2.49). Conclusions: The present study demonstrated no association of RPA3-UMAD1 rs12702634 with ILD in RA, suggesting the heterogeneity of the disease.

Objectives: The severe acute respiratory syndrome coronavirus 2 causes coronavirus disease 2019. A serological test is conducted to determine prior infection by severe acute respiratory syndrome coronavirus 2. We investigated whether the results of anti-severe acute respiratory syndrome coronavirus 2 antibody tests are modified in patients with rheumatoid arthritis. Methods: Patients in Japan with rheumatoid arthritis were recruited at Sagamihara Hospital from July 2014 to October 2015 ( n = 38; 2014 cohort) and at Tokyo Hospital from June to October 2020 ( n = 93; 2020 cohort). Anti-severe acute respiratory syndrome coronavirus 2 antibodies were measured by electrochemiluminescence immunoassay or immunochromatographic assay. Results: Anti-severe acute respiratory syndrome coronavirus 2 antibodies were not detected in any of the samples from rheumatoid arthritis patients tested by electrochemiluminescence immunoassay. Anti-severe acute respiratory syndrome coronavirus 2 antibodies were detected by immunochromatographic assay in the 3 (7.9%) serum samples in the 2014 cohort and 15 (16.1%) serum samples in the 2020 cohort. The IgM rheumatoid factor levels were increased in rheumatoid arthritis patients with IgM anti-severe acute respiratory syndrome coronavirus 2 antibodies detected by immunochromatographic assay (mean ± standard deviation (IU/ml), 1223.0 ± 1308.7 versus 503.6 ± 1947.2; P = 0.0101). The levels of IgG rheumatoid factor were also upregulated in rheumatoid arthritis patients with IgM anti-severe acute respiratory syndrome coronavirus 2 antibodies detected by immunochromatographic assay (4.0 ± 0.7 versus 2.4 ± 0.9; P = 0.0013). Conclusion: The results of IgM anti-severe acute respiratory syndrome coronavirus 2 antibody testing by immunochromatographic assay are modified by IgM or IgG rheumatoid factors in rheumatoid arthritis patients.

Interstitial lung disease (ILD) is frequently a complication of rheumatoid arthritis (RA) as an extra-articular manifestation which has a poor prognosis. Acute-onset diffuse ILD (AoDILD) occasionally occurs in RA and includes acute exacerbation of ILD, drug-induced ILD, and Pneumocystis pneumonia. AoDILD also confers a poor prognosis in RA. Previously-established biomarkers for ILD include Krebs von den lungen-6 and surfactant protein-D originally defined in patients with idiopathic pulmonary fibrosis; the sensitivity of these markers for RA-associated ILD (RA-ILD) is low. Although many studies on ILD markers have been performed in idiopathic pulmonary fibrosis, only a few validation studies in RA-ILD or AoDILD have been reported. Biomarkers for RA-ILD and AoDILD are thus still required. Recently, genomic, cytokine, antibody, and metabolomic profiles of RA-ILD or AoDILD have been investigated with the aim of improving biomarkers. In this review, we summarize current preliminary data on these potential biomarkers for RA-ILD or AoDILD. The development of biomarkers on RA-ILD has only just begun. When validated, such candidate biomarkers will provide valuable information on pathogenesis, prognosis, and drug responses in RA-ILD in future.

Objective: Acute-onset diffuse interstitial lung disease (AoDILD) includes acute exacerbation of interstitial lung disease (ILD), drug-induced ILD, and Pneumocystis pneumonia, and frequently occurs in patients with rheumatoid arthritis (RA). Since AoDILD causes a poor prognosis in RA, biomarkers for AoDILD were eagerly desired. Metabolomic analyses were extensively performed in cancer patients and successfully generated better diagnostic biomarkers. In the present study, serum metabolomic profiles of AoDILD in RA were investigated to generate better potential metabolomic biomarkers. Methods: Serum samples of 10 RA patients with AoDILD were collected on admission and in a stable state, more than 3 months before the admission. Serum metabolomic analyses were conducted on the samples from these RA patients with AoDILD. Results: Apparently distinct serum metabolomic profiles in AoDILD were not observed in univariate or hierarchical cluster analyses. Partial least squares-discriminant analysis (PLS-DA) was performed to select candidate metabolites based on variable importance in projection (VIP) scores. The PLS-DA model generated from the four metabolites with VIP scores more than 2.25 (mannosamine, alliin, kynurenine, and 2-hydroxybutyric acid) could successfully discriminate AoDILD from the stable condition (area under the curve: 0.962, 95% confidence interval: 0.778–1.000). Conclusion: It was demonstrated that metabolomic profiling was useful to generate better biomarkers in AoDILD.

Objective: Acute-onset diffuse interstitial lung disease (AoDILD) includes acute exacerbation of interstitial lung disease (ILD), drug-induced ILD, and Pneumocystis pneumonia in collagen diseases patients. As AoDILD causes a poor prognosis in collagen disease patients, the pathogenesis of AoDILD should be investigated. Exome sequencing studies revealed that rare variants were detected to be causative in some diseases. Recently reported upregulated genes in acute exacerbation of idiopathic pulmonary fibrosis could provide candidate genes for restricted exome analysis of AoDILD in collagen disease. Here, we investigated rare variants in the coding and boundary regions of these candidate genes in AoDILD. Methods: Deleterious rare variants in the coding and boundary regions of the candidate genes were analyzed by exome sequencing and the deleterious rare allele frequencies in AoDILD were compared with those of controls. Results: A significant association was detected for deleterious rare alleles in NPL ( P = .0044, P c = .0399, odds ratio [OR] = 10.05, 95% confidence interval [CI] = 3.01-33.55). A deleterious rare allele frequency in the 9 candidate genes ( P = .0011, OR = 7.17, 95% CI = 2.80-18.33) was also increased in AoDILD in multigene panel analysis. The Krebs von den Lungen–6 (KL-6) levels in AoDILD patients with deleterious rare alleles were tended to be lower than those without ( P = .0168, P c = .1509). Conclusions: The deleterious rare alleles in NPL were associated with AoDILD. In addition, the deleterious rare allele frequency in the 9 candidate genes was also increased in AoDILD. The deleterious rare alleles might contribute to the pathogenesis of AoDILD.

Interstitial lung disease (ILD) is frequently associated with collagen disease. It is then designated as collagen vascular disease-associated ILD (CVD-ILD), and influences patients’ prognosis. The prognosis of acute-onset diffuse ILD (AoDILD) occurring in patients with collagen disease is quite poor. Here, we report our investigation of auto-antibody (Ab) profiles to determine whether they maybe useful in diagnosing CVD-ILD or AoDILD in collagen disease. Auto-Ab profiles were analyzed using the Lambda Array Beads Multi-Analyte System, granulocyte immunofluorescence test, ProtoArray Human Protein Microarray, AlphaScreen assay, and glutathione S-transferase capture enzyme-linked immunosorbent assay in 34 patients with rheumatoid arthritis (RA) with or without CVD-ILD and in 15 patients with collagen disease with AoDILD. The average anti-major histocompatibility complex class I-related chain A (MICA) Ab levels were higher in RA patients with CVD-ILD than in those without (P = 0.0013). The ratio of the average anti-MICA Ab level to the average anti-human leukocyte antigen class I Ab level (ie, MICA/Class I) was significantly higher in RA patients with CVD-ILD compared with those without (P = 4.47 × 10 –5 ). To the best of our knowledge, this is the first report of auto-Ab profiles in CVD-ILD. The MICA/ Class I ratio could be a better marker for diagnosing CVD-ILD than KL-6 (Krebs von den lungen-6).

Interstitial lung disease (ILD) is a chronic, progressive fibrotic lung disease with a dismal prognosis. ILD of unknown etiology is referred to as idiopathic interstitial pneumonia (IIP), which is sporadic in the majority of cases. ILD is frequently accompanied by rheumatoid arthritis (RA), systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM), and other autoimmune diseases, and is referred to as collagen vascular disease-associated ILD (CVD-ILD). Susceptibility to ILD is influenced by genetic and environmental factors. Recent advances in radiographic imaging techniques such as high-resolution computed tomography (CT) scanning as well as high-throughput genomic analyses have provided insights into the genetics of ILD. These studies have repeatedly revealed an association between IIP (sporadic and familial) and a single nucleotide polymorphism (SNP) in the promoter region of the mucin 5B ( MUC5B ). HLA-DRB1*11 alleles have been reported to correlate with ILD in European patients with SSc, whereas in Japanese patients with RA, the HLA-DR2 serological group was identified. The aim of this review is to describe the genetic background of sporadic IIP, CVD-ILD, drug-induced-ILD (DI-ILD), pneumoconiosis, and hypersensitivity pneumonitis. The genetics of ILD is still in progress. However, this information will enhance the understanding of the pathogenesis of ILD and aid the identification of novel therapeutic targets for personalized medicine in future.

Background Drug-induced proteinuria can occur in rheumatoid arthritis (RA) patients treated with d-penicillamine, gold salts, or bucillamine (Buc), and represents a drug hypersensitivity reaction. Striking associations of human leukocyte antigen (HLA) alleles with adverse reactions have recently been reported for many drugs. Methods We investigated the association of HLA class II with Buc-induced proteinuria (BI-Pro) in 485 Japanese RA patients treated with Buc, of whom 25 had developed BI-Pro. Results and Conclusion This preliminary study showed a highly significant association of DRB1*08:02 with BI-Pro ( P = 1.09 × 10 −6 , corrected P [ Pc ] = 1.96 × 10 −5 , odds ratio [OR] 25.17, 95% confidence interval [CI] 7.98-79.38). DQB1*04:02 was also significantly associated with increased risk of BI-Pro ( P = 2.44 × 10 −5 , Pc = 2.69 × 10 −4 , OR 10.35, 95%CI 3.99–26.83). These findings provide useful information for promoting personalized medicine for RA.