Objective: To estimate the disease activity score (DAS)28-Creactive protein (CRP) threshold values that correspond to DAS28-erythrocyte sedimentation rate (ESR) values for remission, low disease activity and high disease activity in patients with rheumatoid arthritis. Methods: DAS28 data were analysed using a large observational study (Institute of Rheumatology Rheumatoid Arthritis) database of 6729 patients with rheumatoid arthritis. Firstly, the relationship between the DAS28-ESR and the DAS28-CRP values was analysed. Secondly, the best DAS28-CRP trade-off values for each threshold were calculated using receiver operating characteristic (ROC) curves. Results: The correlation coefficient of ESR versus CRP was 0.686, whereas that of DAS28-ESR versus DAS28-CRP was 0.946, showing the strong linear relationship between DAS28-ESR and DAS28-CRP values. DAS28-CRP threshold values corresponding to remission, low disease activity and high disease activity were 2.3, 2.7 and 4.1, respectively. The sensitivity and specificity from the ROC curves were gradually reduced as DAS28 values became lower. Conclusions: This study showed that DAS28-CRP and DAS28-ESR were well correlated, but the threshold values should be reconsidered. As the results were derived from only Japanese patients, it is essential to compare DAS28-CRP threshold values in people of other ethnic groups.

Expression and immunological significance of IFN-γ, a pivotal cytokine in murine lupus, have not been clearly demonstrated in human systemic lupus erythematosus (SLE). In the present study we investigated the expression of IFN-γ in peripheral blood T cells from patients with SLE and its role in the production of the soluble B lymphocyte stimulator (sBLyS). Peripheral blood T cells from patients with SLE expressed significantly larger amounts of IFN-γ in response to stimulation with anti-CD3 mAb plus anti-CD28 mAb than those from normal controls as shown by three analytical methods, including ELISA, flow cytometry, and quantitative RT-PCR. The ratio of IFN-γ-producing T cells to effector memory T cells in CD3+CD4+ and CD3+CD8+ populations in patients with SLE was significantly higher than that of normal controls. The T-box expressed in T cells (T-bet) mRNA/GATA-binding protein-3 (GATA-3) mRNA ratio was significantly higher in patients with SLE than in normal controls. T cell culture supernatants from patients with SLE contained significantly higher sBLyS-inducing activity than normal controls; this was almost completely inhibited by the addition of anti-human IFN-γ mAb. Percentages of BLyS-expressing peripheral blood monocytes in patients with SLE were significantly higher than those of normal controls. Monocytes from patients with SLE produced significantly larger amounts of sBLyS in response to IFN-γ than those from normal controls. Taken together, these data strongly indicate that the overexpression of IFN-γ in peripheral blood T cells contributes to the immunopathogenesis of SLE via the induction of sBLyS by monocytes/macrophages, which would promote B cell activation and maturation.

No abstract

Objective. STAT4 encodes a transcriptional factor that transmits signals induced by several key cytokines, and it might be a key molecule in the development of autoimmune diseases. Recently, a STAT4 haplotype was reported to be associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) in Caucasian populations. This was replicated in a Korean RA population. Interestingly, the degree of risk of RA susceptibility with the STAT4 haplotype was similar in the Caucasian and Korean populations. The present study was undertaken to investigate the effect of STAT4 on susceptibility to RA and SLE in the Japanese.Methods. We performed an association study using 3 independent Japanese RA case-control populations (total 3,567 cases and 2,199 controls) and 3 independent Japanese SLE populations (total 591 cases). All samples were genotyped using the TaqMan fluorogenic 5 nuclease assay for single-nucleotide polymorphism (SNP) rs7574865, which tags the susceptibility haplotype. The association of the SNP with disease susceptibility in each case-control study was calculated using Fisher's exact test, and the results were combined, using the Mantel-Haenszel method, to obtain combined odds ratios (ORs).Results. We observed a significant association of the STAT4 polymorphism with susceptibility to both RA and SLE. The combined ORs for RA and SLE, respectively, were 1.27 (P ‫؍‬ 8.4 ؋ 10 ؊9 ) and 1.61 (P ‫؍‬ 2.1 ؋ 10 ؊11 ) for allele frequency distribution; these ORs were quite similar to those previously observed in the Caucasian population.Conclusion. We conclude that STAT4 is associated with RA and SLE in the Japanese. Our results indicate that STAT4 is a common genetic risk factor for autoimmune diseases, with similar strength across major racial groups.

Serum ferritin can be useful as a predictor of the occurrence of A/SIP and correlates with the prognosis of A/SIP in DM. The intensive treatment using combination therapy with various immunosuppressant agents should be chosen for patients with ILD with DM showing hyperferritinaemia, especially levels >1500 ng/ml.

Objective. To develop and validate a self-administered instrument for measuring functional status in Japanese-speaking rheumatoid arthritis patients. Methods. We translated the Stanford Health Assessment Questionnaire (HAQ) into Japanese (original HAQ), and then made a tentative Japanese version of the HAQ (J-HAQ) with culturally appropriate modifications of the arising, eating, and reach category questions. The questionnaire was then administered to 3,763 RA patients (82.6% female; mean age 58.0 years; mean onset age 47.4 years; mean disease duration 10.5 years). Results. This instrument showed excellent internal reliability (Cronbach

Objective. The peptidylarginine deiminase type 4 gene (PADI4) was recently reported to be associated with rheumatoid arthritis (RA) in a Japanese population. The presence of a single-nucleotide polymorphism (SNP) located in intron 3 of PADI4 provided the strongest evidence of this association. Moreover, functional haplotypes that affect stability of transcripts were identified. However, subsequent research failed to confirm the observed association in a UK population. The present study was undertaken to further investigate the association of PADI4 with RA, using a series of population-based samples from subjects with the same ethnic background as the subjects in the original study.Methods. DNA samples were obtained from 1,230 Japanese RA patients and 948 ethnically matched controls. Genotyping was performed using 5 allele discrimination assays. All samples were genotyped for 3 SNPs on PADI4 (padi4_94, padi4_104, and padi4_102), which comprised the reported haplotypes. Chi-square testing was performed for a case-control study and the PENHAPLO program was used for haplotype estimation.Results. All tested SNPs were found to show significant differences in frequency between cases and controls (P ‫؍‬ 0.010-0.0008), which confirmed the association observed in the original study. Odds ratios calculated for allele frequencies were 1.23, 1.21, and 1.36 in padi4_94, padi4_104, and padi4_102 respectively.Conclusion. Replication of association in individual samples strongly suggests that PADI4 is a true susceptibility gene for RA.

In polymyositis (PM)/dermatomyositis (DM), T cells infiltrate the muscle tissues and interact with muscle cells via cell surface molecules. Recently, myoblasts have been reported to express CD40, but little is known about the role of CD40 in myoblasts. In the present study we examined the expression and involvement of CD40 and CD40 ligand (CD40L) in the interaction between muscle cells and T cells in PM/DM. Immunohistochemical staining revealed that CD40 was expressed on muscle cells in five of five PM and four of five DM patients, and that infiltrating mononuclear cells (MNCs) expressed CD40L in all cases of PM/DM. These CD40L-expressing MNCs were primarily CD4+ T cells. IFN-γ, which is known to induce CD40 expression on various types of cells, was also expressed on the MNCs in four of the PM and four of the DM patients. Although cultured human myoblasts (SkMC 2859) did not express CD40 constitutively, IFN-γ induced CD40 expression in a dose-dependent manner. To clarify the functional roles of CD40-mediated signals, the effects of a trimeric form of recombinant human CD40L on cytokine production were studied in SkMC 2859 that were prestimulated with IFN-γ to express CD40. Recombinant human CD40L markedly increased the production of IL-6, IL-8, IL-15, and monocyte chemoattractant protein-1 of SkMC 2859. The expression of these humoral factors in muscle cells of PM and DM was demonstrated by immunohistochemistry. These results suggest that interaction between T cells and muscle cells via the CD40-CD40L system contributes to the immunopathogenesis of PM/DM by augmenting inflammation via cytokine production by the muscle cells.