Published papers

Objective Acute-onset diffuse interstitial lung disease (AoDILD) in patients with rheumatoid arthritis (RA) has been a serious concern, especially for those under treatment with biological agents which may affect the presentation and outcome of AoDILD, including Pneumocystis pneumonia (PCP). Therefore, we conducted a retrospective, multi-center study of AoDILD in RA patients receiving biological agents. Methods Patients who developed AoDILD while receiving biological agents (infliximab, etanercept, adalimumab and tocilizumab) were enrolled in the study. Definite PCP was defined as patients who showed either P. jirovecii organisms in their respiratory samples by microscopic examination, or positive tests for both P. jirovicii DNA-PCR with respiratory samples and an elevated serum 1,3-β-D-glucan level above the cut-off value. Probable PCP was defined as either a positive test for P. jirovicii PCR or an elevated serum β-D-glucan level. Chest HRCT findings were evaluated and scored by two board-certified radiologists. Results The final diagnoses for 26 patients examined were definite PCP for 13 patients, probable PCP for 11, and methotrexate-associated pneumonitis in 2 patients. Definite and probable PCP cases were clinically indistinguishable. Generalized, diffuse ground-glass opacity (GGO) is the characteristic HRCT finding in patients with definite or probable PCP, which was different from our previous findings in RA patients, mostly without biologics, showing GGO distributed in a panlobular or multilobular manner. The clinical outcome was favorable by treatment with trimethoprim-sulfamethoxazole and glucocorticoids. Conclusion The possibility of PCP should be intensively investigated in RA patients developing AoDILD while receiving biological agents. © 2011 The Japanese Society of Internal Medicine.

Objective: An interim analysis of an all-patient postmarketing surveillance programme in Japan to investigate the safety of tocilizumab for the treatment of rheumatoid arthritis (RA) in the real world. Methods: This analysis included 3881 patients. Patients received 8 mg/kg of tocilizumab every 4 weeks, and were observed for 28 weeks. Data on baseline characteristics and adverse events (AE) were collected. Results: Total and serious AE were reported as 167 and 27 events/100 patient-years, respectively. The most frequent AE and serious AE were infections. Logistic regression analysis identified the following risk factors for the development of serious infection: concurrent or medical history of respiratory disorders; prednisolone dose at baseline ≥5 mg/day; and age ≥65 years. Twenty-five patients died, and the standardised mortality ratio, with the Japanese general population in 2008 as reference, was 1.66, similar to the results from the Japanese cohort study for RA patients. Conclusions: Tocilizumab is acceptably safe in the real clinical setting. Tocilizumab needs to be used with consideration of the benefit-risk balance to avoid serious infections in elderly patients and those on high doses of corticosteroids or with a concurrent or medical history of respiratory disorders.

Objectives: To evaluate the safety and efficacy of retreatment with tocilizumab (TCZ) in patients who had participated in the DREAM study (Drug free remission/low disease activity after cessation of tocilizumab [Actemar] monotherapy study) and had experienced loss of efficacy. Methods: Patients were retreated with TCZ or other disease modifying antirheumatic drugs (DMARDs). Disease activity was measured using the 28-joint disease activity score (DAS28) for 12 weeks. Results: A total of 164 eligible patients, including 161 who experienced loss of efficacy within 52 weeks of the DREAM study, resumed treatment: 157 with TCZ and 7 with DMARDs and/or infliximab. Of TCZ-treated patients, 88.5 % (139 patients) achieved DAS28 <2.6 within 12 weeks, whereas among patients treated with DMARDs and/or infliximab only 14.3 % (1 patient) achieved DAS28 <2.6. Adverse events were observed in 70 TCZ-treated patients (44.0 %), but no serious infusion reactions were observed. Conclusions: Retreatment with TCZ was well-tolerated and effective in patients who had responded to the preceding TCZ monotherapy but had experienced loss of efficacy after cessation of TCZ. © 2013 Japan College of Rheumatology.

Objectives: A post-marketing surveillance (PMS) program was implemented to assess the safety and effectiveness of tacrolimus (TAC) in Japanese rheumatoid arthritis (RA) patients and to identify risk factors related to adverse drug reactions (ADRs). Methods: Patients were registered centrally and monitored for all adverse events (AEs) for 24 weeks. Effectiveness was evaluated using the Disease Activity Score 28-CRP (DAS28-CRP). Results: Data from 3,172 patients (mean age 62.2 years) were evaluated in the safety analysis. Of the safety population, 78.5 %were female and 25.9 % were in Steinbrocker's functional class 3 or 4. TAC was prescribed as monotherapy in 52.5 % and the most common concomitant disease modifying antirheumatic drug (DMARD) was methotrexate, used in 28.9 % of the patients. The incidence of AEs, serious AEs (SAEs), ADRs and serious ADRs were 41.2, 6.4, 36.0, and 4.9 %, respectively. The most frequent serious ADR category was infections and infestations. Age ≥65 years, concurrent renal dysfunction, and concurrent diabetes mellitus were identified as significant risk factors for ADR. Based on EULAR response criteria, 65.4 % of the patients showed moderate or good response. Conclusions: The results demonstrate that TAC is well tolerated by Japanese patients with active RA, including those receiving concomitant methotrexate, in the real world. © 2013 Japan College of Rheumatology.

Objectives: To investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration. Methods: Disease activity was monitored for 56 weeks. The rate of continued efficacy was estimated by Kaplan-Meier curves. Results: A total of 187 patients were eligible. At baseline of this study, median disease duration was 7.8 years, preceding TCZ treatment period was 4.0 years and DAS28 was 1.5. The rate of continued LDA at 52 weeks was 13.4 % according to the Kaplan-Meier estimate. 19 patients (10 %) were completely drug-free and 17 patients (9.1 %) fulfilled DAS28 remission at 52 weeks. Multivariate Cox regression analysis identified low serum IL-6 and normalisation of MMP-3 levels at cessation of TCZ as independent predictive markers for longer duration of LDA. In patients with low serum IL-6 (<12.9 pg/mL) and normal MMP-3 levels, the rate of continued LDA reached 38.0 % at 52 weeks. Conclusions: TCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare. © 2013 Japan College of Rheumatology.

Objectives To investigate the duration of remission and low disease activity (LDA) after cessation of tocilizumab (TCZ) treatment in rheumatoid arthritis patients who showed remission or LDA as assessed by DAS28 in response to preceding TCZ monotherapy, and to explore the factors contributing to prolonged efficacy duration. Methods Disease activity was monitored for 56 weeks. The rate of continued efficacy was estimated by Kaplan-Meier curves. Results A total of 187 patients were eligible. At baseline of this study, median disease duration was 7.8 years, preceding TCZ treatment period was 4.0 years and DAS28 was 1.5. The rate of continued LDA at 52 weeks was 13.4 % according to the Kaplan-Meier estimate. 19 patients (10 %) were completely drug-free and 17 patients (9.1 %) fulfilled DAS28 remission at 52 weeks. Multivariate Cox regression analysis identified low serum IL-6 and normalisation of MMP-3 levels at cessation of TCZ as independent predictive markers for longer duration of LDA. In patients with low serum IL-6 (<12.9 pg/mL) and normal MMP-3 levels, the rate of continued LDA reached 38.0 % at 52 weeks. Conclusions TCZ monotherapy may induce biologics-free remission or LDA without concomitant use of synthetic DMARDs. Serum levels of IL-6 and MMP-3 are useful markers for identifying patients who could discontinue TCZ without acute disease flare. © 2013 Japan College of Rheumatology.

Objectives To evaluate the safety and efficacy of retreatment with tocilizumab (TCZ) in patients who had participated in the DREAM study (Drug free remission/low disease activity after cessation of tocilizumab [Actemar] monotherapy study) and had experienced loss of efficacy. Methods Patients were retreated with TCZ or other disease modifying antirheumatic drugs (DMARDs). Disease activity was measured using the 28-joint disease activity score (DAS28) for 12 weeks. Results A total of 164 eligible patients, including 161 who experienced loss of efficacy within 52 weeks of the DREAM study, resumed treatment: 157 with TCZ and 7 with DMARDs and/or infliximab. Of TCZ-treated patients, 88.5 % (139 patients) achieved DAS28 <2.6 within 12 weeks, whereas among patients treated with DMARDs and/or infliximab only 14.3 % (1 patient) achieved DAS28 <2.6. Adverse events were observed in 70 TCZ-treated patients (44.0 %), but no serious infusion reactions were observed. Conclusions Retreatment with TCZ was well-tolerated and effective in patients who had responded to the preceding TCZ monotherapy but had experienced loss of efficacy after cessation of TCZ. © 2013 Japan College of Rheumatology.

Objectives A post-marketing surveillance (PMS) program was implemented to assess the safety and effectiveness of tacrolimus (TAC) in Japanese rheumatoid arthritis (RA) patients and to identify risk factors related to adverse drug reactions (ADRs). Methods Patients were registered centrally and monitored for all adverse events (AEs) for 24 weeks. Effectiveness was evaluated using the Disease Activity Score 28-CRP (DAS28-CRP). Results Data from 3,172 patients (mean age 62.2 years) were evaluated in the safety analysis. Of the safety population, 78.5 %were female and 25.9 % were in Steinbrocker's functional class 3 or 4. TAC was prescribed as monotherapy in 52.5 % and the most common concomitant disease modifying antirheumatic drug (DMARD) was methotrexate, used in 28.9 % of the patients. The incidence of AEs, serious AEs (SAEs), ADRs and serious ADRs were 41.2, 6.4, 36.0, and 4.9 %, respectively. The most frequent serious ADR category was infections and infestations. Age ≥ 65 years, concurrent renal dysfunction, and concurrent diabetes mellitus were identified as significant risk factors for ADR. Based on EULAR response criteria, 65.4 % of the patients showed moderate or good response. Conclusions The results demonstrate that TAC is well tolerated by Japanese patients with active RA, including those receiving concomitant methotrexate, in the real world. © 2013 Japan College of Rheumatology.

Lupus nephritis (LN) is a common and important manifestation of systemic lupus erythematosus (SLE). Evidence suggests higher rates of lupus renal involvement in Asian populations, and maybe more severe nephritis, compared with other racial or ethnic groups. The management of LN has evolved considerably over the past three decades, based on observations from clinical studies that investigated different immunosuppressive agents including corticosteroids, cyclophosphamide, azathioprine, mycophenolic acid, calcineurin inhibitors and novel biologic therapies. This is accompanied by improvements in both the short-term treatment response rate and long-term renal function preservation. Treatment guidelines for LN have recently been issued by rheumatology and nephrology communities in U.S.A. and Europe. In view of the racial difference in disease manifestation and response to therapy, and the substantial disease burden in Asia, a panel of 15 nephrologists and rheumatologists from different Asian regions with extensive experience in lupus nephritis - the Steering Group for the Asian Lupus Nephritis Network (ALNN) - met and discussed the management of lupus nephritis in Asian patients. The group has also reviewed and deliberated on the recently published recommendations from other parts of the world. This manuscript summarizes the discussions by the group and presents consensus views on the clinical management and treatment of adult Asian patients with LN, taking into account both the available evidence and expert opinion in areas where evidence remains to be sought. © 2013 The Authors. Nephrology © 2013 Asian Pacific Society of Nephrology.

PURPOSE. To characterize lacrimal gland function and lymphocyte infiltration in patients with Mikulicz's disease (MD) and Sjogren's syndrome (SS). METHODS. Four patients with MD and 5 with SS were recruited, on whom were performed Schirmer test I (Schirmer test without anesthesia), Schirmer test with nasal stimulation, and vital staining of the ocular surface. The lacrimal gland was then biopsied and the tissues stained with CD3, CD4, CD8, B220, APO2.7, Fas, and Fas ligand (Fas-L) antibodies. RESULTS. Although regular Schirmer test results in the MD group were less than 10 mm, those with nasal stimulation, 38.1 ± 3.4 mm, were significantly greater than the SS group. There were minimal ocular surface changes in MD. Morphologic staining with hematoxylin and eosin was identical in both groups, but the acinar cells were stained with APO2.7 only in the SS group. There was strong Fas and Fas-L staining in SS patients but not in those with MD. CONCLUSIONS. Lacrimal gland acinar cells in those with MD maintained their function and were not programmed for cell death. The sicca syndrome was not observed in MD patients. Although the pathology is similar for MD and SS, the difference in acinar cell apoptosis and function can explain clinical differences.

Objective. Acute/subacute interstitial pneumonia (A/SIP) in patients with polymyositis/dermatomyositis (PM/DM) is frequently fatal within months despite high dose prednisolone (PSL) therapy. Our objective was to improve the survival rate of patients with A/SIP associated with PM/DM; and to characterize patients with PM/DM who are at high risk of developing A/SIP. Methods. We conducted a pilot trial of combined immunosuppressive therapy with high dose PSL, 10-30 mg/kg of intravenous pulse cyclophosphamide (IVCYC) every 3-4 weeks, and 2-4 mg/kg/day of cyclosporin A (CSA) for patients with A/SIP. A/SIP was diagnosed based on a history of rapidly worsening respiratory symptoms, progressive radiological findings or hypoxemia, and compatible findings in high resolution computed tomography images. Results. Before December 2000, 12 patients with DM among 83 PM/DM patients developed A/SIP, and 9 patients died despite treatment using high dose PSL with or without a choice of CSA, cyclophosphamide, or azathioprine. Thereafter, 10 patients with DM among 27 PM/DM patients developed A/SIP, and they were given combination therapy with PSL, CSA, and IVCYC. Five patients survived and are doing well for more than 2 years, although the remaining 5 patients died of respiratory failure within 3 months. DM patients with A/SIP showed the following characteristic features: mild myositis, palmar papule, fever, and negative or low titer of antinuclear antibody. Conclusion. Immediate institution of intensified immunosuppressive therapy should be considered for patients with A/SIP complicating DM. However, even early recognition of A/SIP and immediate commencement of a regimen including CSA and IVCYC in addition to high dose PSL may not be sufficient for some of those patients.

The integrin αEβ7 is expressed on intestinal intraepithelial T lymphocytes and CD8+ T lymphocytes in inflammatory lesions near epithelial cells. Adhesion between αEβ7 + T and epithelial cells is mediated by the adhesive interaction of αEβ7 and E-cadherin; this interaction plays a key role in the damage of target epithelia. To explore the structure-function relationship of the heterophilic adhesive interaction between E-cadherin and αEβ 7, we performed cell aggregation assays using L cells transfected with an extracellular domain-deletion mutant of E-cadherin. In homophilic adhesion assays, L cells transfected with wild-type or a domain 5-deficient mutant formed aggregates, whereas transfectants with domain 1-, 2-, 3-, or 4-deficient mutants did not. These results indicate that not only domain 1, but domains 2, 3, and 4 are involved in homophilic adhesion. When αEβ7 + K562 cells were incubated with L cells expressing the wild type, 23% of the resulting cell aggregates consisted of αEβ7 + K562 cells. In contrast, the binding of αEβ7 + K562 cells to L cells expressing a domain 5-deficient mutant was significantly decreased, with αEβ7 + K562 cells accounting for only 4% of the cell aggregates, while homophilic adhesion was completely preserved. These results suggest that domain 5 is involved in heterophilic adhesion with αEβ7, but not in homophilic adhesion, leading to the hypothesis that the fifth domain of E-cadherin may play a critical role in the regulation of heterophilic adhesion to αEβ7 and may be a potential target for treatments altering the adhesion of αEβ7 + T cells to epithelial cells in inflammatory epithelial diseases. Copyright © 2005 by The American Association of Immunologists, Inc.

The reduction or absence of TCR ζ-chain (ζ) expression in patients with systemic lupus erythematosus (SLE) is thought to be a factor in the pathogenesis of SLE. We previously reported a splice variant of ζ mRNA that lacks the 36-bp exon 7 (ζ mRNA/exon 7(-)) and is accompanied by the down-regulation of ζ protein in T cells from SLE patients. In this study, we show that EX7-mutants (MA5.8 cells deficient in ζ protein that have been transfected with ζ mRNA/exon 7(-)) exhibit a reduction in the expression of TCR/CD3 complex and ζ protein on their cell surface as well as a reduction in the production of IL-2 after stimulation with anti-CD3 Ab, compared with that in wild-type (WT) mutants (MA5.8 cells transfected with the WT ζ mRNA). Furthermore, real-time PCR analyses demonstrated that ζ mRNA/exon 7(-) in EX7- mutants was easily degraded compared with ζ mRNA by the WT mutants. Pulse-chase experiment showed ζ protein produced by this EX7- mutants was more rapidly decreased compared with the WT mutants. Thus, the lower stability of ζ mRNA/exon 7(-) might also be responsible for the reduced expression of the TCR/CD3 complex, including ζ protein, in SLE T cells. Copyright © 2005 by The American Association of Immunologists, Inc.

Differences in ethnic backgrounds as well as in medical and socioeconomic status often affect both the efficacy and adverse effects of medications. Recent data suggest an increased risk of opportunistic infections, especially tuberculosis (TB), among rheumatoid arthritis (RA) patients receiving infliximab, a chimeric monoclonal anti-tumor necrosis factor α (TNF-α) antibody. In this regard, the annual incidence of TB is approximately five times higher in Japan than in the United States. Furthermore, since Bacillus Calmette-Guérin vaccination is mandatory in childhood when the skin test for purified protein derivative (PPD) is negative, a high incidence of false-positive PPD skin tests is observed among the Japanese population. In addition, the upper limit of methotrexate dosage to be used for RA is lower in Japan. We have therefore established official guidelines for the proper use of infliximab in Japanese RA patients. In this review, an algorithm for the diagnosis and management of TB in RA is presented in an evidenced-based form. © Japan College of Rheumatology and Springer-Verlag Tokyo 2005.

Methotrexate (MTX) is the most commonly used disease-modifying antirheumatic drug (DMARD) throughout the world. In Japan, MTX is recommended by the Japanese Ministry of Health, Labour, and Welfare to be given as the second or third DMARD and at a dosage of no more than 8 mg/week. We analyzed the efficacy of MTX in Japanese patients with RA in order to determine whether it is comparable to that in Western countries, where 15-20 mg/week of MTX is used, as well as to elucidate the factors associated with the favorable response to MTX. Around 8 mg/week of MTX was effective in half of the RA patients in the current study, and male sex was the only factor associated with a good response to MTX from a multivariate regression model analysis. Some of the patients who had a poor response to MTX showed an improvement with the addition of bucillamine or prednisolone. For the remaining patients, an increase in the MTX dosage to more than 8 mg/week or the use of biologics such as the anti-tumor necrosis factor (TNF)-α monoclonal antibody may be required. © Japan College of Rheumatology and Springer-Verlag Tokyo 2004.

Objective. To evaluate the incidence and effect of cytomegalovirus (CMV) reactivation in patients with inflammatory connective tissue diseases (CTD) undergoing immunosuppressive therapy. Methods. A total of 18 consecutive CMV seropositive patients undergoing immunosuppressive therapy for inflammatory CTD were enrolled. CMV reactivation was determined by detection of CMV-DNA in peripheral blood leukocytes (PBL) or plasma using quantitative real-time polymerase chain reaction. Results. CMV reactivation was detected in PBL in 7 of 17 evaluable patients (41%), and in plasma in 5 of 17 patients (29%). Patients with detectable CMV-DNA in plasma were exclusively positive for CMV-DNA in PBL. Conclusion. Patients with inflammatory CTD under immunosuppressive therapy are at high risk for CMV reactivation. The clinical significance of such an event and indications for antiviral therapy should be examined further.

Objective. Interleukin-6 (IL-6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL-6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL-6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti-IL-6 receptor antibody, MRA, in patients with RA. Methods. In a multicenter, double-blind, placebo-controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria. Results. Treatment with MRA reduced disease activity in a dose-dependent manner. At 3 months, 78% of patients in the 8-mg group, 57% in the 4-mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8-mg group versus placebo). Forty percent of patients in the 8-mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4-mg, and 8-mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti-DNA antibodies. Anti-MRA antibodies were detected in 2 patients. Conclusion. Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.