Hideto Kameda

Incidence and Risk Factors for Serious Infection in Patients with Rheumatoid Arthritis Treated with Tumor Necrosis Factor Inhibitors: A Report from the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety

Objective. To compare tumor necrosis factor-α (TNF-α) inhibitors to nonbiological disease-modifying antirheumatic drugs (DMARD) for the risk of serious infection in Japanese patients with rheumatoid arthritis (RA). Methods. Serious infections occurring within the first year of the observation period were examined using the records for patients recruited to the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety (REAL), a hospital-based prospective cohort of patients with RA. The analysis included 1144 patients, 646 of whom were treated with either infliximab or etanercept [exposed group: 592.4 patient-years (PY)]. The remaining 498 patients received nonbiological DMARD with no biologics (unexposed group: 454.7 PY). Results. In the unexposed group, the incidence rate for all serious adverse events (SAE) was 9.02/100 PY and for serious infections, 2.64/100 PY. In the exposed group, SAE occurred in 16.04/100 PY and serious infections in 6.42/100 PY. The crude incidence rate ratio comparing serious infections in the exposed group with the unexposed group was 2.43 (95% CI 1.27–4.65), a significant increase. A multivariate analysis revealed that the use of TNF inhibitors is a significant independent risk factor for serious infection (relative risk 2.37, 95% CI 1.11–5.05, p = 0.026). Conclusion. Our study has provided the first epidemiological data on Japanese patients with RA for the safety of TNF inhibitors compared to nonbiological DMARD for up to 1 year of treatment. Anti-TNF therapy was associated with a significantly increased risk for serious infections, compared to treatment with nonbiological DMARD.

The Japanese experience with biologic therapies for rheumatoid arthritis

The unique genetic, environmental and medical backgrounds of people in Japan might influence the effectiveness and safety of biologic agents in patients with rheumatoid arthritis (RA). Indeed, clinical trials revealed higher response rates to some biologic agents (including infliximab, etanercept and tocilizumab) in patients with RA in Japan than patients treated with the same agents in Western countries, although response rates to adalimumab were comparable in both populations. The reasons why response rates to some biologic agents differ in Japanese individuals is currently under investigation. Post-marketing surveillance data have been collected for all patients with RA who were treated with biologic agents in Japan to monitor drug safety. These data clearly demonstrated that only ∼5% of these patients experienced adverse drug reactions to biologic agents, which were well tolerated. Pneumonia, tuberculosis, Pneumocystis jirovecii pneumonia and interstitial pneumonitis are considered important severe adverse reactions and risk factors for these adverse effects have been identified. Adverse drug reactions could exaggerate the risks associated with biologic therapy in Japanese patients with RA. Attempts have, therefore, been made to predict clinical response and adverse effects to enable personalized therapy with biologic agents and to optimize the outcomes of these patients.

Consensus statement for the diagnosis and treatment of drug-induced lung injuries.

Keishi Kubo, Arata Azuma, Minoru Kanazawa, Hideto Kameda, Masahiko Kusumoto, Akihiko Genma, Yasuo Saijo, Fumikazu Sakai, Yukihiko Sugiyama, Koichiro Tatsumi, Makoto Dohi, Hitoshi Tokuda, Shu Hashimoto, Noboru Hattori, Masayuki Hanaoka, Yuh Fukuda, the Japanese Respiratory Society Committee for formulation of Consensus statement for the diagnosis and treatment of drug-induced lung injuries Nagano Prefectural Hospital Organization, Japan Division of Pulmonary Medicine, Infections Diseases, and Oncology, Department of Internal Medicine, Nippon Medical School, Japan Department of Respiratory Medicine, Saitama Medical University, Japan Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Japan Department of Diagnostic Radiology, National Cancer Center Hospital, Japan Department of Medical Oncology, Niigata University Graduate School of Medical and Dental Sciences, Japan Department of Diagnostic Radiology, Saitama International Medical Center, Saitama Medical University, Japan Division of Pulmonary Medicine, Department of Internal Medicine, Jichi Medical University, Japan Department of Respirology, Chiba University Graduate School of Medicine, Japan Department of Allergy and Rheumatology, Tokyo University Graduate School of Medicine, Japan Department of Respiratory Medicine, Social Insurance Central General Hospital, Japan Division of Respiratory Medicine, Department of Internal Medicine, Nihon University School of Medicine, Japan Department of Molecular and Internal Medicine, Hiroshima University Graduate School of Biomedical & Health Sciences, Japan Department of Analytic Human Pathology, Graduate School of Medicine, Nippon Medical School, Japan

Sensitivity and specificity of 2010 rheumatoid arthritis classification criteria

OBJECTIVE To validate the sensitivity and specificity of the 2010 RA classification criteria. METHODS A total of 313 undiagnosed subjects, who first visited Keio University Hospital with joint symptoms, including arthralgia, joint swelling and morning stiffness, without any previous treatment except for NSAIDs, were included in the present study. A clinical diagnosis of RA was made by rheumatologists, and the gold standard diagnosis of RA was defined as an indication for instituting DMARDs for RA. RESULTS Seventy-six subjects were diagnosed as gold standard RA. Among these, 8 did not have any swollen joints, 50 were classified as definite RA under the 2010 criteria and the other 18 as not having RA. Eighty-two subjects were eligible for the 2010 criteria, and the sensitivity and specificity under the 2010 criteria were 73.5 and 71.4%, respectively, compared with 47.1 and 92.9% under the 1987 criteria. But the sensitivity of the 2010 criteria decreased to 15.8% when both RF and anti-CCP were negative. According to the result of a receiver-operated characteristic (ROC) curve of the scoring system, if swollen joints and differential diagnosis are not accurately detected, it would be better to use a score of 5 as the cut-off level to detect RA. CONCLUSION The 2010 classification criteria have a high sensitivity and have been verified to be useful for distinguishing RA at an early stage.

Re-expression of functional P-selectin molecules on the endothelial cell surface by repeated stimulation with thrombin

P‐selectin (GMP‐140, PADGEM, CD62P) is a cell adhesion receptor which is believed to play an important role in inflammatory diseases by supporting leucocyte rolling. P‐selectin is located on the granule membrane of Weibel‐Palade bodies in resting endothelial cells and is expressed on the cell surface during cellular activation with various stimulators such as thrombin. Thereafter, P‐selectin is internalized and sorted to the Golgi region and Weibel‐Palade bodies again. However, whether P‐selectin is re‐expressed upon subsequent cellular stimulation has, to date, been unclear.  To address this question, we measured the cellular content and surface expression of P‐selectin, using indirect immunofluorescence and confocal laser cytometry. Surface expression of P‐selectin reached a maximum < 2 min after thrombin stimulation and declined to basal levels after 180 min. Rechallenge with thrombin induced rapid surface re‐expression of P‐selectin, which was independent of de novo protein synthesis, since cycloheximide did not inhibit re‐expression. Moreover, re‐expressed P‐selectin supported the adherence of HL60 promyelocytic cells.  These results clearly demonstrated that functional P‐selectin molecule was recycled after repeated stimulation with thrombin, raising the possibility that P‐selectin is involved in chronic inflammation.

Regulatory mechanisms for the production of BAFF and IL-6 are impaired in monocytes of patients of primary Sjögren's syndrome.

IntroductionIn this study, we investigated possible aberrations of monocytes from patients with primary Sjögrens syndrome (pSS). We focused on B-cell-activating factor of the TNF family (BAFF) and IL-6 because they are both produced by monocytes and are known to be involved in the pathogenesis of pSS.MethodsPeripheral monocytes were prepared from both pSS patients and normal individuals. The cells were stimulated in vitro with IFN-γ, and the amounts of IL-6 and soluble BAFF (sBAFF) produced by the cells were quantitated. The effect of sBAFF itself on the production of IL-6 was also studied. To investigate the response of pSS monocytes to these stimuli, the expression levels of the genes encoding BAFF receptors and IL-6-regulating transcription factors were quantitated.ResultsPeripheral pSS monocytes produced significantly higher amounts of sBAFF and IL-6 than normal monocytes did, even in the absence of stimulation. The production of these cytokines was significantly increased upon stimulation with IFN-γ. The elevated production of IL-6 was significantly suppressed by an anti-BAFF antibody. In addition, stimulation of pSS monocytes with sBAFF induced a significant increase in IL-6 production. Moreover, the expression levels of a BAFF receptor and transcription factors regulating IL-6 were significantly elevated in pSS monocytes compared to normal monocytes.ConclusionsThe results of the present study suggest that the mechanisms underlying the production of sBAFF and IL-6 are impaired in pSS monocytes. Our research implies that this impairment is due to abnormally overexpressed IL-6-regulating transcription factors and a BAFF receptor. These abnormalities may cause the development of pSS.

Clinicopathological analyses in patients with other iatrogenic immunodeficiency-associated lymphoproliferative diseases and rheumatoid arthritis

Abstract Despite numerous attempts to uncover the mechanism of other iatrogenic immunodeficiency-associated lymphoproliferative diseases (OIIA-LPDs), this mechanism remains poorly understood, especially in rheumatoid arthritis (RA) patients. We analyzed the data on 23 patients with LPDs and RA. Patients were categorized into three groups according to whether they had methotrexate (MTX); MTX-regressive LPDs, MTX-persistent LPDs or other drugs-mediated LPDs. The LPDs seen in OIIA-LPDs-RA might have a unique behavior to think about several rare phenotypes. The overall survival of all patients was 74% at 5 years, and those of the three groups were 100%, 64% and 60%, respectively. Among the 6 patients who died, 4 had LPDs that were detected late, and thus adequate treatment was not given. In addition, several patients with diffuse large B cell lymphoma with a complex karyotype achieved complete remission (CR). Only one among the 17 patients who achieved CR relapsed. OIIA-LPDs-RA appeared to have a better prognosis than other more common types of lymphomas. Regarding RA treatment, various anti-RA drugs were given to the patients after developing LPDs, including MTX, but no recurrent patients were documented.

Baseline levels of soluble interleukin-6 receptor predict clinical remission in patients with rheumatoid arthritis treated with tocilizumab: implications for molecular targeted therapy

Interleukin-6 (IL-6) is a monomeric protein that binds to either soluble or membrane-bound IL-6 receptors (IL-6R)1 ,2 Tocilizumab, a humanised anti-IL-6R monoclonal antibody, binds to soluble IL-6R (sIL-6R) and membrane-bound IL-6R, blocking signal transduction pathways through competitive inhibition of IL-6 binding.3 We have previously demonstrated that baseline plasma tumour necrosis factor (TNF) levels are associated with the clinical response to infliximab, anti-TNF monoclonal antibody binding to soluble and membrane-bound TNF.4 Therefore, it is tempting to speculate that baseline serum levels of sIL-6R, rather than those of IL-6, are associated with clinical response to tocilizumab in patients with rheumatoid arthritis (RA). To test this hypothesis, we analysed serum levels of IL-6 and sIL-6R before tocilizumab treatment in our institution and evaluated their association with clinical remission. Consecutive patients with RA in our institution who commenced 8 mg/kg tocilizumab treatment every 4 weeks as the first biologic agent between March 2010 and April 2012 were included. At baseline, serum levels of IL-6 and sIL-6R were measured by electrochemiluminescence assay with the Ultra-Sensitive Kit (Meso Scale …

Effect of interleukin-6 receptor inhibitor, tocilizumab, in preventing joint destruction in patients with rheumatoid arthritis showing inadequate response to TNF inhibitors

Abstract Objectives. To examine the effectiveness of tocilizumab (TCZ) in preventing joint destruction in patients with inadequate response to tumor necrosis factor inhibitors (TNF-IR) by assessing X-rays. Methods. RA patients were extracted from the Retrospective actemra investigation for optimal needs of RA patients (REACTION) study. Parameters and components of disease activity were evaluated during anti-TNF treatment and during TCZ treatment. X-ray images of hands and feet at the beginning of this study during anti-TNF treatment (Pre), at the start point of TCZ treatment (Baseline) and after TCZ treatment (Post) were collected for assessing joint destruction. Results. Forty-five patients from the REACTION study fulfilled the criteria of clinical TNF-IR. During anti-TNF treatment, mean DAS28-ESR rose from 5.35 to 5.87 (mean observation duration, 16 months) but improved significantly to 2.94 (P < 0.0001) at 52 weeks after switching to TCZ. Mean change in van der Heijde-modified Sharp score (TSS) during anti-TNF treatment was 3.17 in this TNF-IR population. After switching to TCZ, mean change in TSS was 1.20 (P < 0.05). Rate of radiographic non-progression improved to 66.7% during TCZ treatment from 40.0% during anti-TNF treatment. The predictive factor for no radiographic progression after switching to TCZ was a HAQ disability index (HAQ-DI) score of ≤ 1.88 at switching to TCZ. Conclusion. TCZ was a good treatment option for improving signs and symptoms and inhibiting progression of joint damage in patients with clinical and structural TNF-IR.

The effect of tocilizumab on preventing relapses in adult-onset Still's disease: A retrospective, single-center study.

Abstract Objectives. To investigate the clinical effectiveness of tocilizumab (TCZ), a monoclonal antibody against the interleukin-6 receptor, in preventing relapse in patients with adult-onset Stills disease (AOSD). Methods. This retrospective study included clinical data from 40 patients who underwent regular follow-up at our institution in June 2013. Among these patients, 10 received TCZ. The relapse-free rate was analyzed by the Kaplan–Meier method. Results. The age at disease onset (median, interquartile range [IQR]) was 39 (29–52) years. The duration of disease in June 2013 (median, IQR) was 86 (41–193) months. A total of 87 relapses were documented in 27 patients. Ten patients with refractory or relapsing disease received 8 mg/kg of TCZ every 2–4 weeks. After 6 months of TCZ treatment, the median levels of C-reactive protein significantly decreased from 6.3 to 0.01 mg/dl (p < 0.01). Among these 10 patients, 11 relapses were observed before TCZ treatment, and none were observed after the treatment. The relapse-free rate of the 10 patients after starting TCZ was significantly higher than that of all 40 patients after the initial treatments (100% and 67% at 12 months, respectively; p = 0.03). Conclusions. TCZ effectively prevented relapses of AOSD, and it resolved the disease activity.