Rheumatoid Arthritis: Miyasaka N

Koike R, Takeuchi T, Eguchi K, Miyasaka N, Anonymous00064. · Department of Pharmacovigilance, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. · Mod Rheumatol. · Pubmed #18084695 No free full text.

Abstract: Application of biological agents targeting tumor necrosis factor-alpha (TNF-alpha) caused a paradigm shift in the treatment of rheumatoid arthritis (RA). The introduction of infliximab in 2003 and etanercept in 2005 in Japan had a significant impact on both Japanese rheumatologists and RA patients, although serious adverse effects such as bacterial pneumonia, tuberculosis and Pneumocystis jiroveci pneumonia are significant concerns. Based on the data from post-marketing surveillance in Japan and accumulating evidence worldwide, the Internal Medicine Rheumatology Study Group of the Ministry of Health, Labor and Welfare (MHLW), Japan, has updated the guidelines for the use of anti-TNF-alpha agents for RA, which were subsequently approved by the Board of Japan College of Rheumatology (JCR). In the present revised guidelines, we combined the guidelines for use of each of infliximab and etanercept together with some modifications and precautions, paying special attention to serious adverse reactions. Although it is still controversial whether the use of TNF-alpha blocking agents per se increases the risk of infection or not, bacterial pneumonia, regardless of the pathogens, is the most frequent complications in RA. The risk factors associated with pneumonia identified in the post-marketing surveillance of infliximab in Japan are presented in this guideline. The diagnostic algorithm is also designed for early diagnosis and treatment of pulmonary lesions seen during the treatment of biological agents. Preventive measures and precautions against tuberculosis, another frequent and significant complication in Japan, are also described. Furthermore, risk factors for developing Pneumocystis pneumonia, which uniquely occurs at 30- to 50-fold frequency under TNF-alpha blockade therapy in Japan, are described here and its preventive measures are discussed. It is stressed that secondary-care rheumatologists should be better familiarized with the proper use of TNF-alpha blocking agents and be alert to any adverse events for a better management of RA patients.

Miyasaka N. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #19149033 No free full text.

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Nakasato M, Nonomura Y, Miyasaka N, Kohsaka H. · Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #18311039 links to  free full text

Abstract: A gene therapy of synovial tissue is potentially a novel therapeutic method in rheumatoid arthritis (RA). The method induces expression of anti-arthritic molecules in target cells, and is also useful for the investigation of novel therapeutic targets in vitro. Previous studies showed that viral vectors, which can infect non-proliferative cells well, i.e. adenovirus-based vector, were effective in gene transfer to synovial tissue. In this review, we discuss the properties and effectiveness of these methods and our investigations in forcing expression in synovial tissue or cells. The methods of gene transfer are classified into two categories : virus vectors and virus-free vectors. The virus vectors seem to be more applicable to clinical approaches since clinical trials of adeno-associated virus mediated gene therapy were performed in 2007. At the same time, many effective novel virus-free vectors have been developed. Although these gene transfer technologies still have to be improved more to warrant their safety, the gene therapy is an ideal technique in performing "Bench to Clinic and Clinic to Bench" research studies. We hope that it will be applied to RA therapy in near future.

Miyasaka N, Koike R. · Department of Medicine and Rheumatology, Tokyo Medical and Dental University. · Nippon Rinsho. · Pubmed #17642228 No free full text.

Abstract: Application of biological agents targeting tumor necrosis factor alpha (TNFalpha) dramatically caused the paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-TNFalpha monoclonal antibody, has initially been introduced to Japan in 2003 and shown to be dramatically effective in alleviating arthritis refractory to conventional treatment. However, serious adverse events such as bacterial pneumonia, tuberculosis and Pneumocystis jiroveci pneumonia were reported to be in relatively high incidence. Etanercept, a recombinant chimeric protein consisting of p75 TNFalpha receptor and human IgG, was subsequently introduced to Japan in 2005. The guidelines were initially designed by principle investigators (N.M, T.T, K.E) of RA study groups of the Ministry of Health, Labor and Welfare (MHLW), Japan, and approved by the Japan College of Rheumatology (JCR). We introduce the revised guidelines for the use of biologics in Japanese RA patients in this article.

Miyasaka N, Takeuchi T, Eguchi K. · Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8519, Japan. · Mod Rheumatol. · Pubmed #16633923 No free full text.

Abstract: Application of biological agents targeting inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) dramatically caused a paradigm shift in the treatment of rheumatoid arthritis (RA). Infliximab, a chimeric anti-TNF-alpha monoclonal antibody, has initially been introduced to Japan in 2003 and shown to be dramatically effective in alleviating arthritis refractory to conventional treatment. However, serious adverse events such as bacterial pneumonia, tuberculosis, and Pneumocystis jiroveci pneumonia were reported to be in relatively high incidence; i.e., 2%, 0.3%, and 0.4%, respectively, in a strict postmarketing surveillance of an initial 4000 cases in Japan. Etancercept, a recombinant chimeric protein consisting of p75 TNF-alpha receptor and human IgG, was subsequently introduced to Japan in March of 2005. We therefore drew up treatment guidelines for the use of etanercept to avoid potential serous adverse events, since only approximately 150 cases have been included in the clinical study of etanercept in Japan. The guidelines were initially designed by the principal investigators (N.M, T.T., K.E.) of rheumatoid arthritis study groups of the Ministry of Health, Labor and Welfare (MHLW), Japan, and finally approved by the board of directors of the Japan College of Rheumatology. The MHLW assigned a duty to the pharmaceutical companies to perform a complete postmarketing surveillance of an initial 3000 cases to explore any adverse events, and this was performed according to the treatment guidelines shown in this article.

Miyasaka N. · Department of Medicine & Rheumatology, Tokyo Medical & Dental University. · Nippon Rinsho. · Pubmed #15954440 No free full text.

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Miyasaka N. · Department of Medicine & Rheumatology, Graduate School, Tokyo Medical & Dental University. · Nippon Rinsho. · Pubmed #15799411 No free full text.

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Hagiyama H, Kubota T, Komano Y, Kurosaki M, Watanabe M, Miyasaka N. · No affiliation provided · Clin Exp Rheumatol. · Pubmed #15144137 No free full text.

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Miyasaka N. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #11681068 No free full text.

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Miyasaka N. · Division of Rheumatology, Tokyo Medical & Dental University. · Arerugi. · Pubmed #11517512 No free full text.

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Miyasaka N. · No affiliation provided · Nippon Naika Gakkai Zasshi. · Pubmed #11307541 No free full text.

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Miyasaka N. · Department of Regulatory Medicine and Rheumatology, Tokyo Medical and Dental University. · Ryoikibetsu Shokogun Shirizu. · Pubmed #11269128 No free full text.

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Iizuka H, Miyasaka N. · Center for Rheumatic Disease, Metropolitan Bokuto Hospital. · Ryoikibetsu Shokogun Shirizu. · Pubmed #11269111 No free full text.

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Kohsaka H, Taniguchi K, Nonomura Y, Nagasaka K, Inoue N, Nasu K, Miyasaka N. · First Department of Internal Medicine, School of Medicine, Tokyo Medical and Dental University. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #10726472 No free full text.

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Miyasaka N, Anonymous00003. · Department of Medicine and Rheumatology, Graduate School of Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan · Mod Rheumatol. · Pubmed #18330677 links to  free full text

Abstract: This multicenter, double-blind study evaluated the effects of three doses of adalimumab in Japanese patients with rheumatoid arthritis (RA). Patients were randomized to placebo (n = 87) or adalimumab 20 mg (n = 87), 40 mg (n = 91), or 80 mg (n = 87) every other week for 24 weeks. The primary efficacy endpoint was the American College of Rheumatology criteria for 20% improvement (ACR20) at Week 24. At Week 24, all adalimumab treatment groups achieved statistically significantly better ACR20 response rates (20 mg: 28.7%, P < 0.05; 40 mg: 44.0%, P < 0.001; and 80 mg: 50.6%, P < 0.001) versus placebo (13.8%), as well as statistically significantly greater ACR50 and ACR70 responses for the two higher adalimumab doses versus placebo. Rates of adverse events were comparable between the adalimumab groups and the placebo group, except for injection-site reactions, which occurred in more adalimumab-treated patients. Adalimumab 20, 40, and 80 mg were safe and effective in Japanese patients; however, the greatest responses occurred with the 40 and 80 mg doses. These results and comparable ACR20 responses in Western patients support adalimumab 40 mg every other week as the appropriate dosage to treat RA in Japanese patients.

Nishimoto N, Yoshizaki K, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Hashimoto J, Azuma J, Kishimoto T. · Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Suita-City, Osaka, Japan. · Arthritis Rheum. · Pubmed #15188351 links to  free full text

Abstract: 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.

Murakami Y, Akahoshi T, Aoki N, Toyomoto M, Miyasaka N, Kohsaka H. · Tokyo Medical and Dental University, Department of Medicine and Rheumatology, Graduate School, Tokyo, Japan. · Arthritis Rheum. · Pubmed #19479878 No free full text.

Abstract: OBJECTIVE: Triggering receptor expressed on myeloid cells 1 (TREM-1) is inducible on monocyte/macrophages and neutrophils and accelerates tissue destruction by propagating inflammatory responses in disease related to bacterial infections. Its blockade rescues the hosts in murine models of sepsis, to clear the bacteria without impairing the host defense. The aim of this study was to investigate the involvement of TREM-1 in an autoimmune, noninfectious disease. METHODS: Synovial tissue specimens from the joints of patients with rheumatoid arthritis (RA) and the joints of mice with collagen-induced arthritis (CIA) were examined for TREM-1 expression, using flow cytometric analysis. Expression of TREM-1 on macrophages was induced by lipopolysaccharide, with or without a cyclooxygenase inhibitor. Rheumatoid synovial cells were stimulated with agonistic anti-TREM-1 antibodies. Recombinant adenovirus encoding the extracellular domain of TREM-1 fused with IgG-Fc (AxCATREM-1 Ig) or synthetic TREM-1 antagonistic peptides were injected to treat CIA, and the clinical manifestations of the antigen-specific T cell and B cell responses were evaluated. RESULTS: TREM-1 was expressed on CD14+ cells in rheumatoid synovial tissue and synovial macrophages from mice with CIA. Unlike murine macrophages, human monocyte/macrophages did not depend on prostaglandin E2 for up-regulation of TREM-1. Agonistic anti-TREM-1 antibodies promoted tumor necrosis factor alpha production from rheumatoid synovial cells. Blockade of TREM-1 using AxCATREM-1 Ig and antagonistic peptides ameliorated CIA without affecting the serum levels of anti-type II collagen antibodies or the proliferative responses of splenocytes to type II collagen. CONCLUSION: TREM-1 ligation contributes to the pathology of autoimmune arthritis. The results of this study implied that blockade of TREM-1 could be a new approach to rheumatic diseases that is safer than the presently available immunosuppressive treatments.

Hashimoto J, Garnero P, van der Heijde D, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Yoshikawa H, Nishimoto N. · Osaka University Graduate School of Medicine, Osaka, Japan. · Mod Rheumatol. · Pubmed #19452245 No free full text.

Abstract: The aim of this study was to evaluate the predictive value of biological, radiological and clinical parameters for the progression of radiographic joint damage in rheumatoid arthritis (RA) patients treated with conventional disease-modifying anti-rheumatic drugs (DMARDs). We analyzed the 145 patients with active RA for less than 5 years who were participating in the prospective 1-year randomized controlled trial of tocilizumab (SAMURAI trial) as a control arm treated with conventional DMARDs. Progression of joint damage was assessed by sequential radiographs read by two independent blinded X-ray readers and scored for bone erosion and joint space narrowing (JSN) using the van der Heijde-modified Sharp method. Multivariate analysis revealed that increased urinary levels of C-terminal crosslinked telopeptide of type II collagen (U-CTX-II), an increased urinary total pyridinoline/total deoxypyridinoline (U-PYD/DPD) ratio and low body mass index (BMI) at baseline were independently associated with a higher risk for progression of bone erosion. In addition to these three variables, the JSN score at baseline was also significantly associated with an increased risk of progression of the JSN score and total Sharp score. High baseline U-CTX-II levels, U-PYD/DPD ratio and JSN score and a low BMI are independent predictive markers for the radiographically evident joint damage in patients with RA treated with conventional DMARDs.

Takahashi N, Matsumoto K, Saito H, Nanki T, Miyasaka N, Kobata T, Azuma M, Lee SK, Mizutani S, Morio T. · Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. · J Immunol. · Pubmed #19380800 No free full text.

Abstract: Interaction of ICOS with its ligand is essential for germinal center formation, T cell immune responses, and development of autoimmune diseases. Human ICOS deficiency has been identified worldwide in nine patients with identical ICOS mutations. In vitro studies of the patients to date have shown only mild T cell defect. In this study, we report an in-depth analysis of T cell function in two siblings with novel ICOS deficiency. The brother displayed mild skin infections and impaired Ig class switching, whereas the sister had more severe symptoms, including immunodeficiency, rheumatoid arthritis, inflammatory bowel disease, interstitial pneumonitis, and psoriasis. Despite normal CD3/CD28-induced proliferation and IL-2 production in vitro, peripheral blood T cells in both patients showed a decreased percentage of CD4 central and effector memory T cells and impaired production of Th1, Th2, and Th17 cytokines upon CD3/CD28 costimulation or PMA/ionophore stimulation. The defective polarization into effector cells was associated with impaired induction of T-bet, GATA3, MAF, and retinoic acid-related orphan nuclear hormone receptor (RORC). Reduced CTLA-4(+)CD45RO(+)FoxP3(+) regulatory T cells and diminished induction of inhibitory cell surface molecules, including CTLA-4, were also observed in the patients. T cell defect was not restricted to CD4 T cells because reduced memory T cells and impaired IFN-gamma production were also noted in CD8 T cells. Further analysis of the patients demonstrated increased induction of receptor activator of NF-kappaB ligand (RANKL), lack of IFN-gamma response, and loss of Itch expression upon activation in the female patient, who had autoimmunity. Our study suggests that extensive T cell dysfunction, decreased memory T cell compartment, and imbalance between effector and regulatory cells in ICOS-deficient patients may underlie their immunodeficiency and/or autoimmunity.

Komano Y, Harigai M, Koike R, Sugiyama H, Ogawa J, Saito K, Sekiguchi N, Inoo M, Onishi I, Ohashi H, Amamoto F, Miyata M, Ohtsubo H, Hiramatsu K, Iwamoto M, Minota S, Matsuoka N, Kageyama G, Imaizumi K, Tokuda H, Okochi Y, Kudo K, Tanaka Y, Takeuchi T, Miyasaka N. · Tokyo Medical and Dental University, Tokyo, Japan. · Arthritis Rheum. · Pubmed #19248121 No free full text.

Abstract: OBJECTIVE: To establish proper management of Pneumocystis jiroveci pneumonia (PCP) in rheumatoid arthritis (RA) patients treated with infliximab. PCP has been observed in 0.4% of patients with RA treated with infliximab in Japan. METHODS: Data from patients with RA (n = 21) who were diagnosed with PCP during infliximab treatment and from 102 patients with RA who did not develop PCP during infliximab therapy were collected from 14 rheumatology referral centers in Japan. A retrospective review of these patients and a case-control study to compare patients with and without PCP were performed. RESULTS: The median length of time from the first infliximab infusion to the development of PCP was 8.5 weeks. At the onset of PCP, the median dosages of prednisolone and methotrexate were 7.5 mg/day and 8 mg/week, respectively. Pneumocystis jiroveci was microscopically identified in only 2 patients, although the polymerase chain reaction test for the organism was positive in 20 patients. The patients with PCP had significantly lower serum albumin levels (P < 0.001) and lower serum IgG levels (P < 0.001) than the patients without PCP. Computed tomography of the chest in all patients with PCP revealed ground-glass opacity either with sharp demarcation by interlobular septa or without interlobular septal boundaries. Sixteen of the 21 patients with PCP developed acute respiratory failure, but all survived. CONCLUSION: PCP is a serious complication that may occur early in the course of infliximab therapy in patients with RA. For the proper clinical management of this infectious disease, physicians need to be aware of the possibility of PCP developing during infliximab therapy.

Nonomura Y, Mizoguchi F, Suzuki A, Nanki T, Kato H, Miyasaka N, Kohsaka H. · Department of Medicine and Rheumatology, Graduate School, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, 113-8519, Tokyo, Japan. · J Rheumatol. · Pubmed #19228663 No free full text.

Abstract: OBJECTIVE: Uncontrolled proliferation of synovial fibroblasts is characteristic of the pathology of rheumatoid arthritis (RA). Since synovial tissues in the rheumatoid joints are hypoxic, we investigated how hypoxia affects RA synovial fibroblast (RASF) proliferation. METHODS: RASF were cultured at 2000 cells (low density culture) or at 5000 cells (high density, growth-inhibitory confluent culture) per microtiter well under hypoxic (10%, 3%, or 1% O2) or normoxic (21% O2) conditions. Some RASF were treated with recombinant human interleukin 1 receptor antagonist (IL-1ra), anti-tumor necrosis factor-alpha (TNF-alpha)-neutralizing antibodies, anti-N-cadherin-blocking antibodies, or MG132. 3H-labeled thymidine incorporation was quantified to assess their proliferation. Total RNA and cell lysates were prepared for real-time polymerase chain reaction and Western blot analyses. RESULTS: Hypoxia exerted no effect on proliferation of RASF cultured at low density. At high density, it abrogated contact-dependent growth inhibition of RASF, but not of human dermal fibroblasts. Addition of anti-TNF-alpha antibodies or IL-1ra did not affect the results. Upregulated expression of cyclin-dependent kinase inhibitor p27Kip1 was observed in the cells cultured at high density under normoxic conditions, but not under hypoxic conditions. Hypoxia decreased N-cadherin expression on RASF. Addition of anti-N-cadherin-blocking antibodies mimicked the effects of hypoxic culture; it promoted proliferation of RASF cultured at high density under normoxic conditions. This antibody treatment also downmodulated p27Kip1 expression. CONCLUSION: Hypoxia downregulates N-cadherin expression on RASF, and thus prevents p27Kip1 upregulation for their contact inhibition. It is likely that hypoxia in rheumatoid synovial tissues contributes to rheumatoid pathology by augmenting proliferation of synovial fibroblasts.

Nishimoto N, Miyasaka N, Yamamoto K, Kawai S, Takeuchi T, Azuma J, Kishimoto T. · Laboratory of Immune Regulation, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan. · Mod Rheumatol. · Pubmed #18979150 links to  free full text

Abstract: We investigated the clinical efficacy and safety of tocilizumab (a humanized anti-IL-6 receptor antibody) monotherapy in active rheumatoid arthritis (RA) patients with an inadequate response to low dose methotrexate (MTX). In a multicenter, double-blind, randomized, controlled trial, 125 patients were allocated to receive either tocilizumab 8 mg/kg every 4 weeks plus MTX placebo (tocilizumab group) or tocilizumab placebo plus MTX 8 mg/week (control group) for 24 weeks. The clinical responses were measured using the American College of Rheumatology (ACR) criteria and the Disease Activity Score in 28 joints. Serum vascular endothelial growth factor (VEGF) levels were also monitored. At week 24, 25.0% in the control group and 80.3% in the tocilizumab group achieved ACR20 response. The tocilizumab group showed superior ACR response criteria over control at all time points. Additionally, serum VEGF levels were significantly decreased by tocilizumab treatment. The overall incidences of adverse events (AEs) were 72 and 92% (serious AEs: 4.7 and 6.6%; serious infections: 1.6 and 3.3%) in the control and the tocilizumab groups, respectively. All serious adverse events improved by adequate treatment. Tocilizumab monotherapy was well tolerated and provided an excellent clinical benefit in active RA patients with an inadequate response to low dose MTX.

Ogasawara H, Hayashi K, Toi H, Hagihara M, Tohda S, Miyasaka N, Tojo N. · Department of Clinical Laboratory, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo. · Rinsho Byori. · Pubmed #18709990 No free full text.

Abstract: In many patients taking bucillamine, an anti-rheumatic drug, urinary examinations show false-positive findings for ketone on urine dipsticks, because of the SH radicals in bucillamine. Our group examined the frequency of false-positive ketone testing and the causative factors in 179 outpatients being treated by the Department of Rheumatology in our hospital. The samples that remained purple even after boiling were determined to be false-positives, because boiling volatilizes urinary ketones while leaving bucillamine unchanged. Forty-six of 49 patients taking bucillamine tested false-positive for ketone, whereas there were no false-positive reactions among patients not receiving bucillamine. The patients showing false-positive reactions had significantly lower serum albumin levels, higher specific gravity of urine and more acidic urine. Moreover, we could predict whether the reaction was true-positive or bucillamine-induced false-positive by observing differences between the colors and levels of discoloration of the urine test paper. In the evaluation of ketone findings on urinary dipstick, the physician must ascertain whether the patient is taking bucillamine.

Ochi S, Kubota T, Sugihara T, Ogawa J, Komano Y, Nonomura Y, Miyasaka N. · Department of Medicine and Rheumatology, Tokyo Medical and Dental University. · Nihon Rinsho Meneki Gakkai Kaishi. · Pubmed #18311044 links to  free full text

Abstract: A 64-year-old woman had been treated with prednisolone (PSL) for interstitial pneumonia (IP) of unknown origin since 1988. The IP progressed gradually, however, and home oxygen therapy was instituted in 1993. In 2002, persistent arthritis of the hands appeared and diagnosis of rheumatoid arthritis (RA) was finally established based on radiological and pathological findings. Salazosulfapyridine was given with only partial effect. On October 2002, she was hospitalized because of back pain followed by dyspnea. Chest X-ray revealed multiple giant bullae on bilateral upper lung fields, accompanied by deterioration of IP. Methyl-prednisolone pulse therapy followed by 30 mg/day of PSL was instituted and the bullae were diminished with gradual improvement of IP and synovitis. On the 55th hospital day, she complained of chest oppression, and chest X-ray revealed a complication of pneumomediastinum. Since IP was still active and serum KL-6 remained high, 3 mg/day of tacrolimus was added to control IP further and to reduce the dosage of PSL which was recognized as one of the aggravation factors of pneumomediastinum. As a result, pneumomediastinum disappeared gradually along with amelioration of IP. PSL was successfully tapered to 15 mg/day by the 87th hospital day and the patient was discharged. Although the efficacy of tacrolimus on IP complicated with polymyositis / dermatomyositis and other autoimmune diseases has been reported, this case first suggests its efficacy on IP associated with RA.

Sekine C, Sugihara T, Miyake S, Hirai H, Yoshida M, Miyasaka N, Kohsaka H. · Clinical Immunology, RIKEN Research Center of Allergy and Immunology, Yokohama, Japan. · J Immunol. · Pubmed #18209094 links to  free full text

Abstract: Intraarticular gene transfer of cyclin-dependent kinase (CDK) inhibitors to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis. Endogenous CDK inhibitors also modulate immune function via a CDK-independent pathway. Accordingly, systemic administration of small molecules that inhibit CDK may or may not ameliorate arthritis. To address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and a newly synthesized CDK4/6-selective inhibitor were tested for antiarthritic effects. In vitro, they inhibited proliferation of human and mouse synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis mice with alvocidib suppressed synovial hyperplasia and joint destruction, whereas serum concentrations of anti-collagen type II (CII) Abs and proliferative responses to CII were maintained. Treatment was effective even when therapeutically administered. Treated mice developed arthritis after termination of treatment. Thus, immune responses to CII were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed collagen-induced arthritis. Both small-molecule CDK inhibitors were effective in treating animal models of rheumatoid arthritis not by suppressing lymphocyte function. Thus, the two small-molecule CDK inhibitors ameliorated arthritis models in a distinctive way, compared with other immunosuppressive drugs.