Kenji Nagasaka

Chemokines regulate IL-6 and IL-8 production by fibroblast-like synoviocytes from patients with rheumatoid arthritis.

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.

Polymyositis/dermatomyositis and interstitial lung disease: A new therapeutic approach with T-cell-specific immunosuppressants

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.

Time‐dependent increased risk for serious infection from continuous use of tumor necrosis factor antagonists over three years in patients with rheumatoid arthritis

To investigate associations between continuous treatments with tumor necrosis factor (TNF) antagonists and risk for developing serious infections (SIs) over 3 years in Japanese patients with rheumatoid arthritis (RA) enrolled in the Registry of Japanese RA Patients for Long‐Term Safety (REAL) database.

Gene Transfer of a Cell Cycle Modulator Exerts Anti-Inflammatory Effects in the Treatment of Arthritis

Forced expression of a cyclin-dependent kinase inhibitor gene, p21Cip1 in the synovial tissues was effective in treating animal models of rheumatoid arthritis. Synovial hyperplasia in the treated joints was suppressed, reflecting the inhibitory effect of p21Cip1 on cell cycle progression. Additionally, lymphocyte infiltration, expression of inflammatory cytokines, and destruction of the bone and cartilage were inhibited. To determine why the cell cycle regulator gene exerted such anti-inflammatory effects, we investigated gene expression by rheumatoid synovial fibroblasts with or without the p21Cip1 gene transferred. We have found that p21Cip1 gene transfer down-regulates expression of various inflammatory mediators and tissue-degrading proteinases that are critically involved in the pathology of rheumatoid arthritis. These molecules included IL-6, -8, type I IL-1R (IL-1R1), monocyte chemoattractant protein-1, macrophage inflammatory protein-3α, cathepsins B and K, and matrix metalloproteinases-1 and -3. Down-regulation of IL-1R1 by p21Cip1 resulted in attenuated responsiveness to IL-1. Inhibition of the inflammatory gene expression by p21Cip1 was seen even when IL-1 is absent. This IL-1R1-independent suppression was accompanied by reduced activity of c-Jun N-terminal kinase, which was associated with p21Cip1, and inactivation of NF-κB and AP-1. These multiple regulatory effects should work in concert with the primary effect of inhibiting cell cycle in ameliorating the arthritis, and suggest a heretofore unexplored relationship between cyclin-dependent kinase inhibitor gene and inflammatory molecules.

Prediction of and prophylaxis against Pneumocystis pneumonia in patients with connective tissue diseases undergoing medium- or high-dose corticosteroid therapy.

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/µl), and usage of immunosuppressant during 2 weeks after the institution of PSL (≥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.

Efficacy of combination treatment with cyclosporin A and corticosteroids for acute interstitial pneumonitis associated with dermatomyositis

Abstract Interstitial pneumonitis (IP) associated with polymyositis and dermatomyositis (PM/DM) is a serious complication that affects prognosis. We therefore undertook a retrospective multicenter study to examine the efficacy of a combination treatment with cyclosporin A (CsA) and corticosteroids. Fifty-three IP patients with PM/DM (9 PM, 44 DM) were analyzed. Thirty-two patients treated with CsA plus corticosteroids (9 PM, 23 DM) were included in the study. Four parameters, i.e., subjective symptoms, ausculatory sound, chest radiographs, and respiratory index, were serially evaluated. A general evaluation was performed 4 weeks after the start of the combination treatment. All patients with PM and chronic IP with DM, and 52% of those with acute IP with DM were graded as better than “partially effective” in the general evaluation. In contrast, all patients graded as “progressive” in the general evaluation had acute IP with DM. It is of note that in acute IP with DM, the survival rate of the group primarily treated with CsA and corticosteroids from the early stage of their disease was significantly higher than that of the group initially treated with corticosteroids alone (P = 0.049). In conclusion, a combination treatment of CsA and corticosteroids from the early stage of disease may be advantageous for patients with IP with PM/DM, especially acute IP with DM.

Exacerbation of chronic active Epstein–Barr virus infection in a patient with rheumatoid arthritis receiving humanised anti-interleukin-6 receptor monoclonal antibody

We describe deterioration of chronic active Epstein–Barr virus (CAEBV) infection in a patient with rheumatoid arthritis who received a single infusion of humanised anti-IL6 receptor monoclonal antibody (tocilizumab). A 60-year-old woman with rheumatoid arthritis who had been treated with methotrexate developed lymphadenopathy in October 1999, which was ameliorated in 2 months by cessation of methotrexate. Re-institution of methotrexate in September 2000 led to recurrence of lymphadenopathy, which was diagnosed as necrotising lymphadenitis by histological examination, with high titres of anti-Epstein–Barr virus (EBV) antibodies (antiviral capsid antigens IgG 1:1280, anti-early antigens IgG 1:640) and EBV DNA in plasma (3100 copies/ml). The lymphadenopathy gradually disappeared after cessation of methotrexate at the expense of active arthritis. In July 2001, the patient was …

Suppression of elevations in serum C reactive protein levels by anti-IL-6 autoantibodies in two patients with severe bacterial infections

Serum C reactive protein (CRP) is generally elevated by infection. We encountered two patients with severe bacterial infections without increases in CRP. Patient 1: A 67-year-old man developed thoracic empyema by Escherichia coli and Streptococcus intermedius . His body temperature was 36.6°C, his leukocyte count was elevated (9960/μl) and he was negative for CRP (0.01 mg/dl). Despite antibiotic treatment, he died of respiratory failure. Patient 2: A 56-year-old woman developed multiple subcutaneous abscesses by Staphylococcus aureus . She had rheumatoid arthritis (RA) for 30 years and was treated with sodium aurothiomalate. Her body temperature was 37.4°C, and leukocyte count (5600/μl) and CRP (0.05 mg/dl) were not elevated. She recovered with antibiotics. Neither patient had a past history of severe bacterial infection. Since serum CRP is mainly controlled by interleukin (IL)-6,1 the lack of IL-6 function was suggested. Serum IL-6 was not detected by ELISA in either patient, although it is known to increase with severe infection.2 ,3 However, IL-6 production from peripheral blood monocytes with/without lipopolysaccharide stimulation was similar between Patient 1 and healthy controls (data not shown). Soluble IL-6 receptor (IL-6R) and IL-6 signal transducer (IL-6ST) serum levels were also …

Two cases of acute respiratory distress syndrome resulting from adult-onset Still's disease

Abstract Adult-onset Stills disease (AOSD) is a systemic inflammatory disorder of unknown origin. Acute respiratory distress syndrome (ARDS) is a rare complication of AOSD, with only nine cases having been reported in the literature. Here, we describe two cases of AOSD complicated with ARDS that were successfully treated with immunosuppressive therapy, including corticosteroids. Although ARDS is a life-threatening complication in AOSD, early commencement of high-dose corticosteroids and mechanical ventilation improve the prognosis.

妊娠中に発症し，タクロリムス，シクロホスファミド追加併用療法が有用であった，縦隔気腫を合併した多発性筋炎に伴う間質性肺炎の1例

A 30-year-old pregnant woman experienced mild dyspnea in April 2009. She complained of mild myalgia and was subsequently admitted to our hospital in June 2009 because of worsening dyspnea. Physical examination revealed fine crackles in the lower lung field, but no eruptions externally. Laboratory findings revealed elevated serum levels of myogenic enzymes (aldolase, 17.6 IU/l and myoglobin, 247.2 ng/ml) and positive titers for the anti-Jo-1 antibody and hypoxia (PaO(2), 79.4 Torr). The chest radiograph revealed a ground-glass opacity. The patient was diagnosed as interstitial pneumonia (IP) associated with polymyositis (PM) at 20 weeks of gestation. On July 9, we commenced the initial treatment-steroid pulse therapy with 60 mg/day of prednisolone and 3 mg/day of tacrolimus. We also induced abortion. The treatment of corticosteroids and tacrolimus was, however, ineffective even after increasing the tacrolimus dose to 6 mg/day. On July 30, she suddenly experienced chest pain along with severe dyspnea. Computed tomography revealed the presence of pneumomediastinum and deterioration of the IP. We added cyclophosphamide pulse therapy to the existing regimen ; this improved the disease course, reduced hypoxia, and improved radiographic findings. We believe that this is a rare case of IP with PM during pregnancy.