The homozygous c.14576G>A variant in RNF213 could be a good DNA biomarker for predicting the severe type of MMD, for which early medical/surgical intervention is recommended, and may provide a better monitoring and prevention strategy.

Rheumatoid arthritis (RA) is characterized by proliferation of synoviocytes that produce inflammatory cytokines and chemokines. The expressed chemokines are thought to be involved in the migration of inflammatory cells into the synovium. In this study we show that CCL2/monocyte chemotactic protein-1, CCL5/RANTES, and CXCL12/stromal cell-derived factor-1 enhanced IL-6 and IL-8 production by fibroblast-like synoviocytes (FLS) from patients with RA, and their corresponding receptors, CCR2, CCR5, and CXCR4, respectively, were expressed by RA FLS. The chemokines stimulated RA FLS more effectively than skin fibroblasts. Culture with CCL2 enhanced phosphorylation of extracellular signal-related kinase 1 (ERK1) and ERK2, but not phosphorylation of p38 or Src. Moreover, activation of ERK1/2 was inhibited by pertussis toxin, a Gi-coupled protein inhibitor, and RS-504393, CCR2 antagonist, suggesting that ERK1/2 was activated by CCL2 via CCR2 and Gi-coupled protein. On the other hand, CCL2, CCL5, and CXCL12 were expressed on RA FLS, and their production was regulated by TNF-α, IL-1β, and TGF-β1. Our results indicate that the chemokines not only play a role in inflammatory cell migration, but are also involved in the activation of FLS in RA synovium, possibly in an autocrine or paracrine manner.

Objective. Rheumatoid arthritis (RA) is characterized by chronic inflammation of multiple joints. Large numbers of T cells, which produce type 1 cytokines, infiltrate into RA synovium. Chemokines and chemokine receptors are considered to contribute to the T cell infiltration. In this study, we examined the role of CX3CL1/fractalkine and its receptor CX3C chemokine receptor 1 (CX3CR1) in the T cell migration into RA synovium.Methods. Using flow cytometry, immunohistochemistry, and reverse transcription-polymerase chain reaction, we analyzed CX3CR1 expression by peripheral blood and synovial T cells, and CX3CL1 expression in synovium from patients with RA. Cytokine and cytotoxic molecule expression by CX3CR1-positive T cells was analyzed by flow cytometry.Results. CX3CR1 expression by peripheral CD4؉ and CD8؉ T cells was up-regulated in RA patients. The peripheral CD4؉ and CD8؉ T cells expressing CX3CR1 predominantly produced interferon-␥ and tumor necrosis factor ␣, and expressed cytotoxic molecules such as granzyme A and perforin. Furthermore, CX3CR1؉,CD3؉ T cells infiltrated into RA synovium. CX3CL1, the unique ligand of CX3CR1, was expressed by endothelial cells and synoviocytes in RA synovium, but not in osteoarthritis synovium.Conclusion. Our findings suggest that the interactions of CX3CL1 and CX3CR1 might contribute to the accumulation of CX3CR1؉ T cells expressing type 1 cytokines and possessing cytotoxic granules in RA synovium.

Interstitial lung disease (ILD) is a common complication of polymyositis (PM) and dermatomyositis (DM), and accounts for a significant proportion of their morbidity and mortality because of the resistance to therapeutic agents including corticosteroids. Its pathogenic mechanism is not known, but several studies have provided findings implicating that T-cells, especially activated CD8+ cells, may play essential roles, and thus could be therapeutic targets in this disease. To test this hypothesis, we began clinical investigation of the efficacy of T-cell-specific immunosuppressants, cyclosporine (CsA) and FK506, in PM/DM patients with ILD. In our retrospective nationwide multi-center study compiling a total of 53 patients, a combination of CsA and corticosteroids resulted in favorable early and long-term outcome in the majority of patients except for DM patients with acute ILD. In this subset, those who received the combination as an initial therapy had better survival than those who initially received corticosteroids alone. FK506 has a similar mode of action but is up to 100-fold more potent than CsA in vitro, and has been used in more refractory ILD cases. We next reviewed 5 PM/DM patients with ILD who failed on various immunosuppressants including CsA and were subsequently treated with FK506 in our hospital, and found that 3 improved promptly, 1 gradually and steadily, and another case responded slowly after prednisolone dose was increased. None developed adverse effects. In summary, these T-cell targeted therapies have a potential to be the cornerstone of the treatment for ILD in PM/DM patients. The combination therapy with CsA and corticosteroids may be efficacious especially when used early. FK506 may be advantageous even in refractory cases to CsA. These findings indicate that further investigation is warranted. Currently, prospective investigation of FK506 is underway.

We performed a retrospective analysis to establish a statistical model for the prediction of Pneumocystis pneumonia (PCP) in patients with connective tissue diseases (CTD) undergoing medium- or high-dose corticosteroid therapy, to identify independent risk factors for PCP and to evaluate the efficacy of the prophylactic use of trimethoprim-sulfamethoxazole (TMP/SMX) against PCP. One hundred and twenty-four patients who were receiving the equivalent of or more than 30 mg/day of prednisol-one (PSL) were classified into two groups according to the presence (prophylaxis group, n = 46) or absence (nonprophylaxis group, n = 78) of prophylactic TMP/SMX. We developed a statistical model that was suitable for predicting the development of PCP using a logistic regression analysis. The initial steroid dosage, decreased peripheral blood lymphocyte counts at 2 weeks (<500/microl), and usage of immunosuppressant during 2 weeks after the institution of PSL (>or=30 mg/day) were found to independently contribute to the development of PCP. Finally, in the patient group with a defined risk for PCP, a significant prophylactic effect of TMP/SMX was demonstrated. We recommend the prophylactic use of TMP/SMX for patients with CTD undergoing medium- or high-dose corticosteroid therapy who are determined to have a high risk of developing PCP.