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Drugs Treating Rheumatism

Drugs Treating Rheumatism. 1. Definitions. 风湿病（ rheumatism, rheumatic diseases ）是一组侵犯关节、骨骼、肌肉、血管及有关软组织或结缔组织为主的疾病，其中多数为自身免疫性疾病。发病多较隐蔽而缓慢，病程较长，且大多具有遗传倾向。包括： 1. 弥漫性结缔组织病 : 类风湿关节炎 (rheumatoid arthritis, RA) 、系统红斑狼疮 (systemic lupus erythematosus, SLE ) 、硬皮病、多肌炎、重叠综合征、血管炎

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Drugs Treating Rheumatism

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  1. Drugs Treating Rheumatism

  2. 1. Definitions • 风湿病（rheumatism, rheumatic diseases）是一组侵犯关节、骨骼、肌肉、血管及有关软组织或结缔组织为主的疾病，其中多数为自身免疫性疾病。发病多较隐蔽而缓慢，病程较长，且大多具有遗传倾向。包括： • 1. 弥漫性结缔组织病:类风湿关节炎(rheumatoid arthritis, RA)、系统红斑狼疮(systemic lupus erythematosus, SLE )、硬皮病、多肌炎、重叠综合征、血管炎 • 2. 脊柱关节病:强制性脊柱炎、Reiter综合征、银屑病关节炎、未分化脊柱关节病等

  3. 3. 退行性变:骨关节炎（osteoarthritis, OS） • 4. 与代谢和内分泌相关的风湿病:痛风、假性痛风、马方综合征、免疫缺陷病等 • 5. 和感染相关的风湿病:反应性关节炎、风湿热（rheumatic fever, RF）等 • 6. 肿瘤相关性风湿病:原发性(滑膜瘤、滑膜肉瘤等)；继发性(多发性骨髓瘤、转移瘤等) • 7. 神经血管疾病:神经性关节病、压迫性神经病变(周围神经受压、神经根受压等)、雷诺病等 • 8. 骨与软骨病变:骨质疏松、骨软化、肥大性骨关节病、弥漫性原发性骨肥厚、骨炎等 • 9. 非关节性风湿病:关节周围病变、椎间盘病变、特发性腰痛、其他痛综合征(如精神性风湿病)等 • 10. 其他有关节症状的疾病:周期性风湿热、间歇性关节积液、药物相关的风湿综合征、慢性活动性肝炎等

  4. 2. Drugs treating rheumatism • 1. Non-steroidal anti-inflammatory drugs(NSAIDs,非甾体抗炎药）antipyretic, analgesic and anti-inflammatory drugs(解热镇痛抗炎药) • 2. Glucocorticosteroids(糖皮质激素) steroidal anti-inflammatory drugs (甾体抗炎药) • 3. Disease-modifying anti-rheumatic drugs(DMARDs,改善病情的抗风湿药）mainly immunosuppressants • 4. Other adjuvant drugs • Analgesic drugs（镇痛药） • Bone metabolism-regulating drugs（骨代谢调节药） • Antibacterial drugs（抗菌药） • Gout suppressants （痛风治疗药）

  5. DMARDs • 1.Glucocorticoids(糖皮质激素类)： • prednisolone (泼尼松龙) , methylprednisolone (甲泼尼松龙) • 2. Calcineurin inhibitors (钙调磷酸酶抑制剂)： • cyclosporine (CsA, 环孢素),tacrolimus(FK506, 他克莫司) • 3. Antiproliferative and antimetabolic drugs (抗增殖/抗代谢类)： • rapamycin (雷帕霉素, sirolimus 西罗莫司), mycophenolate mofetil (MMF, 霉酚酸酯), azathioprine (Aza, 硫唑嘌呤) , cyclophosphamide (CTX, 环磷酰胺) • methotrexate(氨甲喋呤, MTX), chloroquine (氯喹),hydroxychloroquine(羟氯喹） sulfasalazine (柳氮磺吡啶), leflunomide (来氟米特) • 4. Antibodies and other biological agents (抗体及其他生物制剂)： • Active TCM components (中药有效成分, 尚未进入国际药物分类)： • tripterygium glycosides(雷公藤总苷)

  6. Analgesic drugs • Opioid analgesics (centrally acting) • opiates • synthetic agents • Antipyretic, analgesic, and anti-inflammatory drugs (peripherally acting) • aspirin, indomethacin • Other drugs (for special types of pain) • carbamazepine, atropine, nitroglycerin, etc.

  7. Bone metabolism-regulating drugs • Hormones（激素类） • estrogens（雌激素类）：diethylstilbestrol（己烯雌酚） • androgens（雄激素类）：Testosterone（睾酮） • parathyroid hormone（甲状旁腺激素，PTH） and teriparatide（特立帕肽）, calcitonin（降钙素） • Diphosphonates（双膦酸盐类药物 ） • alendronate sodium（阿仑膦酸钠 ） • Calcium and Vitamin D3（钙及维生素D3） • Others • Glucosamine（氨基葡萄糖）, chondroitin sulfate（硫酸软骨素）, fluorides（氟化物）

  8. Calcium and phosphate metabolism in the body and the regulation parathyroid hormone (PTH), Calcitonin (CT)，1,25(OH)2 D3 (D), fibroblast growth factor 23 (FGF23)

  9. Antibacterial drugs • Agents against streptococcal（链球菌）infections • Penicillins （青霉素类）：penicillin G(benzylpenicillin,苄青霉素) • Cepharosporins（头孢菌素类） • Macrolides（大环内酯类）：erythromycin (红霉素) • Lincomycins（林可霉素类） • Quinolones (喹诺酮类) • Sulfonamides (磺胺类)

  10. Gout suppressants • Colchicine(秋水仙碱): • relieving the pain and inflammation of gouty arthritis • Indomethacin (吲哚美辛) and other NSAIDs (except aspirin, salicylates and tolmetin): • inhibiting urate crystal phagocytosis(尿酸结晶体吞噬) • Probenecid (丙磺舒) and sulfinpyrazone (磺吡酮): • decreasing reabsorption of uric acid in the proximal tubule, thereby accelerating uric acid excretion (uricosuric drugs, 尿酸促排剂) • Allopurinol (别嘌醇) and febuxostat: • Inhibiting xanthine oxidase, thereby reducing uric acid synthesis

  11. 3. Drug treatment of rheumatic diseases • (1) Rheumatoid arthritis (RA, 类风湿关节炎) • (2) Systemic lupus erythematosus (SLE,系统红斑狼疮) • (3) Osteoarthritis (OS, 骨关节炎) • (4) Rheumatic fever(RF,风湿热)

  12. 3. Drug treatment of rheumatic diseases • (1) Rheumatoid arthritis (RA)

  13. Key pathological changes in the synovium in rheumatoid arthritis

  14. (1) Rheumatoid arthritis (RA) • Treatment of symptoms • Analgesics reduce pain • Non-steroidal antiinflammatory drugs (NSAIDs) lessen pain and stiffness • NSAIDs have lost their historical role as first-line treatment because of concerns about their limited effectiveness, inability to modify the long-term course of disease, and gastrointestinal and cardiac toxic effects. These agents should be given with proton-pump inhibitors for gastroprotection, with short-acting drugs administered for short periods to minimise risks.

  15. (1) Rheumatoid arthritis (RA) • Disease-modifying antirheumatic drugs (DMARDs) • A heterogeneous collection of agents grouped together by use and convention. • They are the mainstay of treatment for rheumatoid arthritis. Their diverse mechanisms of action are incompletely understood. • They reduce joint swelling and pain, decrease acute-phase markers, limit progressive joint damage, and improve function.

  16. (1) Rheumatoid arthritis (RA) • Methotrexate (MTX)is the dominant DMARD. • Sulfasalazine (柳氮磺吡啶) and leflunomide (来氟米特) are also widely used. Their efficacy has been established in placebo-controlled trials. • Hydroxychloroquine (羟氯喹) and chloroquine (氯喹) have DMARD-like properties. • Gold (sodium aurothiomalate) and cyclosporin are additional DMARDs • Their use is limited by toxic effects.

  17. Evolution of RA drug treatment

  18. (1) Rheumatoid arthritis (RA)

  19. (1) Rheumatoid arthritis (RA) • Biological agents • TNF inhibitors [etanercept(依那西普),infliximab(英夫利西单抗),adalimumab(阿达木单抗) ] were the first licensed biological agents, followed byabatacept(阿巴西普, CTLA-Ig),rituximab(利妥昔单抗), and tocilizumab: they are highly effective. • Effects of biological agents can be especially striking in the subset of inadequately treated or non-responsive patients selected for trials.

  20. (1) Rheumatoid arthritis (RA) trials of individual drugs meta-analysis ACR50 responses in trials of DMARDs and biological agents ACR50=50% improvements in five of the seven measures of American College of Rheumatology criteria. Error bars=95% CIs.

  21. (1) Rheumatoid arthritis (RA) • Glucocorticoids (GCs) • Short-term GCs reduce synovitis • Long term GCs decrease joint damage • GCS can be especially useful in two settings: • Short-term useduring flare-ups in disease can lead to rapid improvement and allow other treatments—such as DMARDs, which have a slower onset of action—to be adjusted. Use of GCs in this way is low risk. • Intra-articular GCsare a highly effective local treatment for individual active joints.

  22. Dosage of GCs in the treatment of RA

  23. (2) Systemic lupus erythematosus (SLE)

  24. (2) Systemic lupus erythematosus (SLE) Pharmacological management The main advances in the past decade in the conventional management of SLE have included studies showing efficacy for mycophenolate as an induction agent for lupus nephritis and the equivalent efficacy of low-dose cyclophosphamide given every 2 weeks in comparison with the preceding National Institutes of Health protocol. Many other immunosuppressives, such as methotrexate, cyclosporin, and leflunomide, are used as steroid-sparing agents to treat SLE and the other autoimmune rheumatic diseases.

  25. (2) Systemic lupus erythematosus (SLE) • Glucocorticoids • Changes gene expression, decreases pro-inflammatory cytokines and adhesion molecules, and induces anti-infl ammatory cytokines • Rapid onset of action, dose dependent on degree of organ involvement (typically 5–60 mg daily) • Substantial long-term side-effects including osteoporosis, diabetes, and hypertension; major predictor of damage accrual in systemic lupus erythematosus at 15 year follow-up.

  26. (2) Systemic lupus erythematosus (SLE) • Hydroxychloroquine • Changes lysosomal pH and has immunomodulative action through changing activation of toll-like receptor. • Effective for control of articular, cutaneous, and constitutional symptoms (eg, fatigue), usual dose 200–400 mg per day • Findings from a recent systematic review showed improved disease activity, reduced mortality, and a modest effect on thrombotic risk and damage accrual, potential beneficial effect on lipid profile and cardiovascular disease, safe for use in pregnancy

  27. (2) Systemic lupus erythematosus (SLE) • Azathioprine • Purine analogue, inhibits synthesis of xanthylic and adenylic acids • Used for active systemic disease including maintenance treatment of lupus nephritis, selective use as induction treatment for lupus nephritis, usual dose 1–3 mg/kg per day. • Data from trial suggest similar efficacy to mycophenolate as maintenance treatment for lupus nephritis after induction with low-dose cyclophosphamide

  28. (2) Systemic lupus erythematosus (SLE) • Mycophenolate • Inhibits monophosphate dehydrogenase and blocks synthesis of guanosine nucleotides and proliferation of T cells and B cells • Used for induction and maintenance treatment of lupus nephritis, also useful agent for other systemic features of systemic lupus erythematosus, usual dose 0.5–3 g per day • Findings from ALMS (370 patients) study showed no significant difference between cyclophosphamide and mycophenolate as induction agents for lupus nephritis.

  29. (2) Systemic lupus erythematosus (SLE) • Cyclophosphamide • Forms active alkylating metabolites in liver and other tissues and prevents cell division by crosslinking DNA and suppressing DNA synthesis • Used as induction treatment of lupus nephritis (orally or intravenously); Euro-lupus project showed equivalent efficacy of low-dose intravenous cyclophosphamide (six fortnightly pulses of 500 mg) to the National Institutes of Health protocol (750 mg/m2 monthly intravenous cyclophosphamide for 6 months followed by quarterly infusions for 2 years) • Also used for other organ or life-threatening manifestations

  30. (2) Systemic lupus erythematosus (SLE) Biological treatments Improved understanding of the immune response and abnormalities in apoptosis have allowed the recognition of cells and molecules that are crucial to the development of SLE and other autoimmune rheumatic diseases. Increased recognition of the multifaceted role that B cells have in the pathophysiology of SLE has led to the development of several novel treatments, notably rituximab and belimumab.

  31. (2) Systemic lupus erythematosus (SLE) Targeted biological agents available and in present or previous clinical trials of systemic lupus erythematosus (SLE) pDC=plasmacytoid dendritic cell. BLys=B-lymphocyte stimulator. TNF = tumour necrosis factor . APC=antigen-presenting cell.

  32. (3) Osteoarthritis (OS)

  33. (3) Osteoarthritis (OS) • Treatment of symptoms • NSAIDs; opioids • Injections • intra-arthritic GCs or hyaluronic acid (透明质酸) • intramuscular NSAIDs • Localapplications • NSAIDs; capsaicin • Disease-modifyingosteoarthritisdrugs(DMOADs, 缓解病情的骨关节炎药) and protective drugs of cartilage(软骨)

  34. (3) Osteoarthritis (OS) • Disease-modifyingosteoarthritisdrugs(DMOADs) and protective drugs of cartilage • Glucosamine（氨基葡萄糖）, • Chondroitinsulfate（硫酸软骨素） • Diacerein(双醋瑞因): IL-1inhibitor • Doxycycline(多西环素):inhibitor of MMPs • Diphosphonates（双膦酸盐类药物 ）alendronate sodium（阿仑膦酸钠) • Vitamins: A, D, C, E

  35. (4) Rheumatic fever (RF)

  36. (4) Rheumatic fever (RF) Anti-rheumatic treatment Aspirin or other NSAIDs GCs Preventive treatment Penicillin G and other antibacterial drugs

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