tacrolimus and Rheumatic-Diseases

The introduction of biologic DMARDs into rheumatology has resulted in a substantial reduction of the burden of many rheumatic diseases. In the slipstream of the success achieved with these biologic DMARDs, some conventional immunosuppressive drugs have also found use in new indications. Notably, mycophenolate mofetil, azathioprine and tacrolimus have made their way from solid organ transplantation drugs to become useful assets in rheumatology practice. Mycophenolate mofetil and azathioprine inhibit the purine pathway and subsequently diminish cell proliferation. Both drugs have a pivotal role in the treatment of various rheumatic diseases, including lupus nephritis. Tacrolimus inhibits lymphocyte activation by inhibiting the calcineurin pathway. Mycophenolate mofetil and tacrolimus are, among other indications, increasingly being recognized as useful drugs in the treatment of interstitial lung disease in systemic rheumatic diseases and skin fibrosis in systemic sclerosis. A broad array of trials with mycophenolate mofetil, azathioprine and/or tacrolimus are ongoing within the field of rheumatology that might provide further novel avenues for the use of these drugs. In this Review, we discuss the historical perspective, pharmacodynamics, clinical indications and novel avenues for mycophenolate mofetil, azathioprine and tacrolimus in rheumatology.

Topics: Antirheumatic Agents; Azathioprine; Drug Therapy, Combination; Enzyme Inhibitors; Humans; Immunosuppressive Agents; Mycophenolic Acid; Rheumatic Diseases; Rheumatology; Tacrolimus

In recent years, novel immunosuppressive drugs applies to various autoimmune diseases and the evidences increase. Since immunosuppressive drugs inhibit nonselectively the whole immune system, there are possibilities that infection may be induced by decreasing the immunity against pathological agents and malignancy may develop by suppressing immune surveillance. In order to use the immunosuppressants safely and effectively, we should obey the indication and dosage, and be familiar with the side effects. It is also important to take informed consent from patients after explaining the benefit and risk. Therefore, the doctors who are going to use immunosuppressive drugs must know well about the indication, the side effects, the metabolism and the action mechanisms of those drugs.

Topics: Azathioprine; Calcineurin Inhibitors; Collagen Diseases; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Methotrexate; Rheumatic Diseases; Ribonucleosides; Risk Assessment; Tacrolimus

This article examines immunosuppressant transplant agents used to treat the various rheumatic diseases. The older drugs of this type have been used in this dual role for decades. There is a new generation of immunosuppressant drugs with established use in the arena of transplantation medicine. Only recently have the potential rheumatologic applications for these agents been investigated. The authors review in depth the published experience with the newer agents. The authors also discuss novel rheumatologic uses for the older agents that have been described within the past year.

Topics: Autoimmune Diseases; Azathioprine; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Male; Mycophenolic Acid; Rheumatic Diseases; Severity of Illness Index; Sirolimus; Tacrolimus; Transplants; Treatment Outcome

Immunologic manipulations under current investigation include various biologic agents and pheresis procedures. Second-generation monoclonal antibodies have been "humanized" to circumvent human anti-mouse antibody production or to carry toxin amplification. At present these studies focus on refractory rheumatoid arthritis and lupus nephritis. Interferons, prostacyclin, and tolerance-inducing or blocking peptides are filling difficult therapeutic niches. Of particular importance are remarkable results for interferon alfa-2b in mastocytosis, and iloprost in Raynaud's disease with digital ulcerations. Enhanced pheresis procedures with photochemotherapy involving psoralens and extracorporeal removal of specific autoantibodies may broaden the spectrum of pheresis applications. Dietary manipulations of fatty-acid intake and caloric restriction have also received attention.

Topics: Antibodies, Monoclonal; Blood Component Removal; Cyclosporine; Humans; Iloprost; Immunotherapy; Interferons; Peptides; Rheumatic Diseases; Tacrolimus

Calcineurin inhibitors (CNI), including oral cyclosporin A and tacrolimus, are intensive immunosuppressants that are extensively used in the treatment of rheumatic and immunologic diseases in China. CNI selectively inhibit the activation and proliferation of T lymphocytes and the transcription of cytokines [such as tumor necrosis factor-α, interleukin (IL)-6, and IL-17] through inhibiting the activation of calcineurin in cells and reducing the release of IL-2. To standardize the use of CNI in the field of rheumatic and immunologic diseases, this consensus statement was developed by the National Clinical Research Center for Dermatologic and Immunologic Diseases (Peking Union Medical College Hospital), in conjunction with the Chinese Association of Rheumatology and Immunology Physicians, the Chinese Research Hospital Association, the Rheumatology and Immunology Professional Committee, and the Chinese Association of Rehabilitation Medicine. The 2011 Oxford Centre for Evidence-Based Medicine Levels of Evidence was used to rate the quality of the evidence and the strength of the recommendations, and the RIGHT (Reporting Items for practice Guidelines in HealThcare) checklist was followed to report the consensus. The consensus offers recommendations addressing nine clinical challenges to Chinese clinicians. The primary objective of this consensus is to deliver scientific and detailed guidance on CNI for Chinese clinicians, and to improve the quality of patient-centered medical services.. 钙调磷酸酶抑制剂（CNI）类药物属强效免疫抑制剂，我国风湿免疫性疾病领域主要应用的该类药物为口服环孢素A和他克莫司，其可通过抑制细胞内钙调磷酸酶活性，减少白细胞介素（IL）-2释放，从而选择性抑制T淋巴细胞活化增殖及肿瘤坏死因子-α、IL-6、IL-17等细胞因子转录。为规范口服CNI类药物在风湿免疫性疾病领域的应用，由国家皮肤与免疫疾病临床医学研究中心（北京协和医院）发起，中国医师协会风湿免疫科医师分会、中国研究型医院学会风湿免疫专业委员会、中国康复医学会风湿免疫康复专业委员会参与制订，采用2011年牛津循证医学中心分级系统和国际实践指南报告标准（RIGHT），对我国临床医生关注的9个临床问题，给出了较为详细的循证推荐意见，旨在为相关医疗卫生人员提供科学、具体的CNI类药物用药参考和指导，提高以患者为中心的医疗服务质量。.

Topics: Calcineurin Inhibitors; Humans; Immune System Diseases; Immunosuppressive Agents; Rheumatic Diseases; T-Lymphocytes; Tacrolimus

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA-LPDs, including 36 with diffuse large B-cell lymphoma (DLBCL)-type and 19 with Hodgkin lymphoma (HL)-type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein-Barr virus positivity in DLBCL-type (P = 0·013). The 2-year overall survival and progression-free survival (PFS) at a median follow-up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2-year PFS was seen between patients with DLBCL-type and HL-type OIIA-LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour-derived DNA from 20 DLBCL-type OIIA-LPD samples, histone-lysine N-methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha-induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL-type OIIA-LPD. Cases with DLBCL-type OIIA-LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA-LPDs, especially DLBCL-types, showed favourable prognoses.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Histone-Lysine N-Methyltransferase; Hodgkin Disease; Humans; Iatrogenic Disease; Immunologic Deficiency Syndromes; Immunosuppressive Agents; Kaplan-Meier Estimate; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Male; Methotrexate; Middle Aged; Myeloid-Lymphoid Leukemia Protein; Prognosis; Progression-Free Survival; Proportional Hazards Models; Receptors, Tumor Necrosis Factor, Member 14; Retrospective Studies; Rheumatic Diseases; Tacrolimus; Tumor Necrosis Factor alpha-Induced Protein 3

We aimed to evaluate the obstetric complications and the risk factors for these events in pregnant women with rheumatic diseases (RDs).. A single-center retrospective study of women with RDs at Hokkaido University Hospital between 2007 and 2016 was conducted. Clinical features and maternal and fetal outcomes were retrospectively collected. The rate of pregnancy complications was compared with the general obstetric population (GOP) in Japan.. Overall, 132 pregnancies in 95 women with RDs were recorded. Underlying RDs were systemic erythematosus (SLE) (. Pregnancies with RDs were at increased risk of having both maternal complications and adverse neonatal outcomes, indicating these pregnancies should be closely monitored.

Topics: Adult; Antibodies, Antinuclear; Antibodies, Antiphospholipid; Antiphospholipid Syndrome; Arthritis, Rheumatoid; Cesarean Section; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infant, Newborn; Japan; Lupus Erythematosus, Systemic; Perinatal Mortality; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Retrospective Studies; Rheumatic Diseases; Risk Factors; Tacrolimus

To evaluate the in vitro effects of 4 antiinflammatory and 5 immunosuppressive agents on the release of preformed and de novo-synthesized mediators from human synovial mast cells (HSyMC) activated by immunologic and nonimmunologic stimuli.. The effects of antiinflammatory and immunosuppressive agents were evaluated on the in vitro release of histamine and tryptase and the de novo synthesis of prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) by HSyMC challenged with anti-IgE and substance P.. Nimesulide, a sulfonanilide nonsteroidal antiinflammatory drug (NSAID) chemically unrelated to other acidic NSAIDs (such as acetylsalicylic acid [ASA], diclofenac, and piroxicam) inhibited in a concentration-dependent manner the release of preformed (histamine and tryptase) mediators from HSyMC challenged with anti-IgE. In contrast, diclofenac and piroxicam had little or no effect on HSyMC activated by anti-IgE. ASA, diclofenac, piroxicam, and nimesulide caused a concentration-dependent inhibition of IgE-mediated PGD2 release from HSyMC. Nimesulide, but not diclofenac or piroxicam, also inhibited the de novo synthesis of LTC4 by HSyMC challenged with anti-IgE. Nimesulide, diclofenac, and piroxicam had no effect on HSyMC activated by substance P. Cyclosporin A (CSA) inhibited histamine release from HSyMC challenged with anti-IgE, whereas cyclosporin H (CSH) had no effect. FK-506 also inhibited histamine release from HSyMC activated by anti-IgE, whereas rapamycin had no effect. Neither CSA, CSH, FK-506, nor rapamycin inhibited the release of histamine from HSyMC induced by substance P. Methotrexate had no effect on the release of mediators from these cells, whereas adenosine (R-phenylisopropyl adenosine and 5'-N-ethylcarboxamide adenosine) enhanced histamine release from immunologically activated HSyMC in a concentration-dependent manner.. Mast cells isolated from human synovia display 4 levels of pharmacologic heterogeneity with regard to 1) the inhibitory effects of 4 antiinflammatory drugs; 2) the capacity of different immunosuppressive drugs to exert antiinflammatory activity; 3) the inhibition of the release of different mediators; and 4) the capacity of antiinflammatory and immunosuppressive drugs to modulate HSyMC activated by different stimuli. This complexity of pharmacologic modulation of HSyMC in vitro might help explain the different activity of the compounds used to treat various pathophysiologic aspects of the inflammatory arthritides.

Topics: Adenosine; Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Chymases; Cyclosporine; Diclofenac; Histamine Release; Humans; Immunoglobulin E; Immunosuppressive Agents; Leukotriene C4; Mast Cells; Methotrexate; Middle Aged; Polyenes; Prostaglandins D; Rheumatic Diseases; Serine Endopeptidases; Sirolimus; Substance P; Sulfonamides; Synovial Membrane; Tacrolimus; Tryptases