Drugs Treating Rheumatism

Drugs Treating Drugs Treating RheumatismRheumatism

1. Definitions1. Definitions

• 风湿病（风湿病（ rheumatism, rheumatic diseasesrheumatism, rheumatic diseases ）是一组侵）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：慢，病程较长，且大多具有遗传倾向。包括：

• 1. 1. 弥漫性结缔组织病弥漫性结缔组织病 :: 类风湿关节炎类风湿关节炎 (rheumatoid arthritis, R(rheumatoid arthritis, RA)A) 、系统红斑狼疮、系统红斑狼疮 (systemic lupus erythematosus, SLE )(systemic lupus erythematosus, SLE ) 、硬皮、硬皮病、多肌炎、重叠综合征、血管炎病、多肌炎、重叠综合征、血管炎

• 2. 2. 脊柱关节病脊柱关节病 :: 强制性脊柱炎、强制性脊柱炎、 ReiterReiter 综合征、银屑病关节炎、综合征、银屑病关节炎、未分化脊柱关节病等未分化脊柱关节病等

• 3. 3. 退行性变退行性变 :: 骨关节炎骨关节炎（ osteoarthritis, OS ）• 4. 4. 与代谢和内分泌相关的风湿病与代谢和内分泌相关的风湿病 :: 痛风、假性痛风、马方综痛风、假性痛风、马方综

合征、免疫缺陷病等合征、免疫缺陷病等• 5. 5. 和感染相关的风湿病和感染相关的风湿病 :: 反应性关节炎、反应性关节炎、风湿热（风湿热（ rheumatic rheumatic

fever, RFfever, RF ））等等• 6. 6. 肿瘤相关性风湿病肿瘤相关性风湿病 :: 原发性原发性 (( 滑膜瘤、滑膜肉瘤等滑膜瘤、滑膜肉瘤等 )) ；继发；继发

性性 (( 多发性骨髓瘤、转移瘤等多发性骨髓瘤、转移瘤等 ))

• 7. 7. 神经血管疾病神经血管疾病 :: 神经性关节病、压迫性神经病变神经性关节病、压迫性神经病变 (( 周围神经周围神经受压、神经根受压等受压、神经根受压等 )) 、雷诺病等、雷诺病等

• 8. 8. 骨与软骨病变骨与软骨病变 :: 骨质疏松、骨软化、肥大性骨关节病、弥漫骨质疏松、骨软化、肥大性骨关节病、弥漫性原发性骨肥厚、骨炎等性原发性骨肥厚、骨炎等

• 9. 9. 非关节性风湿病非关节性风湿病 :: 关节周围病变、椎间盘病变、特发性腰痛、关节周围病变、椎间盘病变、特发性腰痛、其他痛综合征其他痛综合征 (( 如精神性风湿病如精神性风湿病 )) 等等

• 10. 10. 其他有关节症状的疾病其他有关节症状的疾病 :: 周期性风湿热、间歇性关节积液、周期性风湿热、间歇性关节积液、药物相关的风湿综合征、慢性活动性肝炎等药物相关的风湿综合征、慢性活动性肝炎等

• 2. Drugs treating rheumatism2. Drugs treating rheumatism• 1. Non-steroidal anti-inflammatory drugs1. Non-steroidal anti-inflammatory drugs (NSAIDs,(NSAIDs,

非甾体抗炎药非甾体抗炎药）） antipyretic, analgesic and anti-inflammatory druantipyretic, analgesic and anti-inflammatory drugsgs (( 解热镇痛抗炎药解热镇痛抗炎药 ))

• 2. Glucocorticosteroids2. Glucocorticosteroids (( 糖皮质激素糖皮质激素 )) steroidal anti-inflamm steroidal anti-inflammatory drugs atory drugs (( 甾体抗炎药甾体抗炎药 ))

• 3. 3. Disease-modifying anti-rheumatic drugsDisease-modifying anti-rheumatic drugs (DM(DM

ARDs,ARDs, 改善病情的抗风湿药改善病情的抗风湿药）） mainly immunosuppressantsmainly immunosuppressants

• 4. Other adjuvant drugs4. Other adjuvant drugs• Analgesic drugsAnalgesic drugs （（镇痛药镇痛药））• Bone metabolism-regulating drugsBone metabolism-regulating drugs （（骨代谢调节药骨代谢调节药））• Antibacterial drugsAntibacterial drugs （（抗菌药抗菌药））• Gout suppressants Gout suppressants （（痛风治疗药痛风治疗药））

DMARDsDMARDs

• 1.1. GlucocorticoidsGlucocorticoids (( 糖皮质激素类糖皮质激素类 ))：：• prednisolone prednisolone (( 泼尼松龙泼尼松龙 )) , , methylprednisolone methylprednisolone (( 甲泼尼松龙甲泼尼松龙 ))

• 2. Calcineurin inhibitors 2. Calcineurin inhibitors (( 钙调磷酸酶抑制剂钙调磷酸酶抑制剂 )) ：：• cyclosporine cyclosporine (CsA, (CsA, 环孢素环孢素 ),), tacrolimustacrolimus (FK506, (FK506, 他克莫司他克莫司 ))

• 3. Antiproliferative and antimetabolic drugs 3. Antiproliferative and antimetabolic drugs (( 抗增殖抗增殖 // 抗代谢类抗代谢类 ))：：• rapamycin rapamycin (( 雷帕霉素雷帕霉素 , sirolimus , sirolimus 西罗莫司西罗莫司 ), ), mycophenolate mofetil mycophenolate mofetil (MMF, (MMF, 霉酚酸霉酚酸

酯酯 ), ), azathioprine azathioprine (Aza, (Aza, 硫唑嘌呤硫唑嘌呤 ) ,) , cyclophosphamide cyclophosphamide (CTX, (CTX, 环磷酰胺环磷酰胺 ))

• methotrexatemethotrexate (( 氨甲喋呤氨甲喋呤 , , MTXMTX),), chloroquine chloroquine (( 氯喹氯喹 ),), hhydroxychloroquineydroxychloroquine(( 羟氯喹）羟氯喹） sulfasulfasalazine (salazine ( 柳氮磺吡啶柳氮磺吡啶 ), ), leflunomide leflunomide (( 来氟米特来氟米特 ))

• 4. Antibodies and other biological agents 4. Antibodies and other biological agents (( 抗体及其他生物制剂抗体及其他生物制剂 ))：：• Active TCM components Active TCM components (( 中药有效成分中药有效成分 , , 尚未进入国际药物分类尚未进入国际药物分类 ))：：• tripterygium tripterygium glycosides (( 雷公藤总苷雷公藤总苷 ))

Analgesic drugsAnalgesic drugs

• Opioid analgesics Opioid analgesics (centrally acting)(centrally acting)• opiatesopiates• synthetic agentssynthetic agents• Antipyretic, analgesic, and anti-inflammatory dAntipyretic, analgesic, and anti-inflammatory d

rugs rugs (peripherally acting)(peripherally acting)• aspirin, indomethacinaspirin, indomethacin• Other drugs Other drugs (for special types of pain)(for special types of pain)• carbamazepine, atropine, nitroglycerin, carbamazepine, atropine, nitroglycerin, etc.etc.

Bone metabolism-regulating drugs Bone metabolism-regulating drugs

• HormonesHormones （激素类）（激素类） • eestrogensstrogens （雌激素类）（雌激素类）：： diethylstilbestroldiethylstilbestrol （己烯雌酚）（己烯雌酚）• androgensandrogens （雄激素类）（雄激素类）：： TestosteroneTestosterone （睾酮）（睾酮）• parathyroid hormoneparathyroid hormone （甲状旁腺激素，（甲状旁腺激素， PTHPTH ）） and teriparatideand teriparatide（（特立帕肽特立帕肽）） , calcitonin, calcitonin （降钙素）（降钙素）

• DiphosphonatesDiphosphonates （双膦酸盐类药物）（双膦酸盐类药物）• alendronate sodiumalendronate sodium （阿仑膦酸钠）（阿仑膦酸钠）

• Calcium and Vitamin DCalcium and Vitamin D33 （钙及维生素（钙及维生素 DD33 ））

• OthersOthers• GlucosamineGlucosamine （氨基葡萄糖）（氨基葡萄糖） , , chondroitin sulfatechondroitin sulfate （硫酸软骨素）（硫酸软骨素） , , ff

luoridesluorides （氟化物）（氟化物）

Calcium and phosphate metabolism in the body and the regulationCalcium and phosphate metabolism in the body and the regulation

parathyroid hormone (PTH), Calcitonin (CT)parathyroid hormone (PTH), Calcitonin (CT) ，， 1,25(OH)1,25(OH)2 2 DD33 (D), fibroblast growth fact (D), fibroblast growth fact

or 23 (FGF23)or 23 (FGF23)

Antibacterial drugs Antibacterial drugs

• Agents against streptococcalAgents against streptococcal （链球菌）（链球菌） infectioninfectionss

• Penicillins Penicillins （青霉素类）（青霉素类）：： penicillin Gpenicillin G (benzylpenicillin,benzylpenicillin, 苄青霉素苄青霉素 ))

• CepharosporinsCepharosporins （头孢菌素类）（头孢菌素类）

• MacrolidesMacrolides （大环内酯类）（大环内酯类）：： erythromycin erythromycin (( 红霉素红霉素 ))

• LincomycinsLincomycins （林可霉素类）（林可霉素类）

• Quinolones Quinolones (( 喹诺酮类喹诺酮类 ))

• Sulfonamides Sulfonamides (( 磺胺类磺胺类 ))

Gout suppressantsGout suppressants

• ColchicineColchicine (( 秋水仙碱秋水仙碱 )):: • relievrelievinging the pain and inflammation of gouty arthritis the pain and inflammation of gouty arthritis

• Indomethacin Indomethacin (( 吲哚美辛吲哚美辛 )) and other NSAIDs and other NSAIDs (except a(except a

spirin, salicylates and tolmetin)spirin, salicylates and tolmetin) :: • inhibiting urate crystal phagocytosisinhibiting urate crystal phagocytosis ((尿酸结晶体吞噬尿酸结晶体吞噬 ))

• Probenecid Probenecid ((丙磺舒丙磺舒 )) and sulfinpyrazone and sulfinpyrazone (( 磺吡酮磺吡酮 )) :: • decreasing reabsorption of uric acid in the proximal tubule, theredecreasing reabsorption of uric acid in the proximal tubule, there

by accelerating uric acid excretionby accelerating uric acid excretion ( (uricosuric drugs, 尿酸促排剂尿酸促排剂 ))

• Allopurinol Allopurinol ((别嘌醇别嘌醇 )) and febuxostat: and febuxostat: • Inhibiting xanthine oxidase, thereby reducing uric acid synthesisInhibiting xanthine oxidase, thereby reducing uric acid synthesis

3. Drug treatment of rheumatic 3. Drug treatment of rheumatic diseasesdiseases

• (1) Rheumatoid arthritis (RA, (1) Rheumatoid arthritis (RA, 类风湿关节炎类风湿关节炎 ) )

• (2) Systemic lupus erythematosus (SLE,(2) Systemic lupus erythematosus (SLE,系统红斑狼疮系统红斑狼疮 ))

• (3) Osteoarthritis (OS, (3) Osteoarthritis (OS, 骨关节炎骨关节炎 ))

• (4) Rheumatic fever(4) Rheumatic fever (RF,(RF, 风湿热风湿热 ))

3. Drug treatment of rheumatic 3. Drug treatment of rheumatic diseasesdiseases

• (1) Rheumatoid arthritis (RA) (1) Rheumatoid arthritis (RA)

Key pathological changes in the synovium in rheumatoid arthritisKey pathological changes in the synovium in rheumatoid arthritis

• Treatment of symptomsTreatment of symptoms

• Analgesics reduce pain

• Non-steroidal antiinflammatory drugs (NSAIDNon-steroidal antiinflammatory drugs (NSAIDs) lessen pain and stiffnesss) lessen pain and stiffness

• NSAIDs have lost their historical role as first-line treatment beNSAIDs have lost their historical role as first-line treatment because of concerns about their limited effectiveness, inability to cause of concerns about their limited effectiveness, inability to modify the long-term course of disease, and gastrointestinal anmodify the long-term course of disease, and gastrointestinal and cardiac toxic effects. These agents should be given with protd cardiac toxic effects. These agents should be given with proton-pump inhibitors for gastroprotection, with short-acting drugon-pump inhibitors for gastroprotection, with short-acting drugs administered for short periods to minimise risks.s administered for short periods to minimise risks.



• Disease-modifying antirheumatic drugs Disease-modifying antirheumatic drugs (DMARDs) (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.

• Methotrexate (MTX)Methotrexate (MTX) is the dominant DMARDis the dominant DMARD. .

• Sulfasalazine (Sulfasalazine ( 柳氮磺吡啶柳氮磺吡啶 ) and leflunomide () and leflunomide ( 来氟来氟米特米特 ) ) are also widely used. Their efficacy has been eare also widely used. Their efficacy has been e

stablished in placebo-controlled trials.stablished in placebo-controlled trials.

• Hydroxychloroquine (Hydroxychloroquine ( 羟氯喹羟氯喹 ) and chloroquine ) and chloroquine (( 氯喹氯喹 ) ) have DMARD-like propertieshave DMARD-like properties. .

• Gold (sodium aurothiomalate) and cyclosporiGold (sodium aurothiomalate) and cyclosporin n are additional DMARDsare additional DMARDs

• Their use is limited by toxic effects.Their use is limited by toxic effects.


Evolution of RA drug treatmentEvolution of RA drug treatment


• Biological agentsBiological agents• TNF TNF inhibitorsinhibitors [ [etanerceptetanercept ((依那西普依那西普 ),), infliximabinfliximab ((英夫英夫利西单抗利西单抗 ),), adalimumabadalimumab (( 阿达木单抗阿达木单抗 )) ] ] were the first licenswere the first licensed biological agents, followed byed biological agents, followed by abataceptabatacept (( 阿巴西普阿巴西普 , , CTLA-Ig),CTLA-Ig), rituximabrituximab ((利妥昔单抗利妥昔单抗 ),), and and tocilizumabtocilizumab: : they arthey are highly effective.e highly effective.

• Effects of biological agents can be especially striking in tEffects of biological agents can be especially striking in the subset of inadequately treated or non-responsive patihe subset of inadequately treated or non-responsive patients selected for trials. ents selected for trials.



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.

trials of individual drugstrials of individual drugs meta-analysismeta-analysis

• GlucocorticoidsGlucocorticoids (GCs) (GCs)

• Short-term GCs reduce synovitis• Long term GCs decrease joint damage

• GCS can be especially useful in two settings: GCS can be especially useful in two settings: • Short-term useShort-term use during flare-ups in disease can lead to raduring flare-ups in disease can lead to ra

pid improvement and allow other treatments—such as DMApid improvement and allow other treatments—such as DMARDs, which have a slower onset of action—to be adjusted. URDs, which have a slower onset of action—to be adjusted. Use of GCs in this way is low risk.se of GCs in this way is low risk.

• Intra-articular GCsIntra-articular GCs are a highly effective local treatment fare a highly effective local treatment for individual active jointsor individual active joints..


Dosage of GCs in the treatment of RADosage of GCs in the treatment of RA

• (2) Systemic lupus erythematosus (SLE) (2) Systemic lupus erythematosus (SLE)


Pharmacological managementPharmacological management The main advances in the past decade in the conventional management The main advances in the past decade in the conventional management of SLE have included studies showing efficacy for of SLE have included studies showing efficacy for mycophenolate mycophenolate as an as an induction agent for lupus nephritis and the equivalent efficacy of low-doinduction agent for lupus nephritis and the equivalent efficacy of low-dose se cyclophosphamidecyclophosphamide given every 2 weeks in comparison with the prece given every 2 weeks in comparison with the preceding National Institutes of Health protocol. ding National Institutes of Health protocol.

Many other immunosuppressives, such as Many other immunosuppressives, such as methotrexate, cyclosporin, methotrexate, cyclosporin, aandnd leflunomide, leflunomide, are used as steroid-sparing agents to treat SLE and the are used as steroid-sparing agents to treat SLE and the other autoimmune rheumatic diseases.other autoimmune rheumatic diseases.

• Glucocorticoids Glucocorticoids

• Changes gene expression, decreases pro-inflammatory cytokinChanges gene expression, decreases pro-inflammatory cytokines and adhesion molecules, and induces anti-infl ammatory cytes and adhesion molecules, and induces anti-infl ammatory cytokinesokines

• Rapid onset of action, dose dependent on degree of organ invoRapid onset of action, dose dependent on degree of organ involvement (typically 5–60 mg daily) lvement (typically 5–60 mg daily)

• Substantial long-term side-effects including osteoporosis, diabSubstantial long-term side-effects including osteoporosis, diabetes, and hypertension; major predictor of damage accrual in setes, and hypertension; major predictor of damage accrual in systemic lupus erythematosus at 15 year follow-up.ystemic lupus erythematosus at 15 year follow-up.


• HydroxychloroquineHydroxychloroquine

• Changes lysosomal pH and has immunomodulative action throChanges lysosomal pH and has immunomodulative action through changing activation of toll-like receptor.ugh changing activation of toll-like receptor.

• Effective for control of articular, cutaneous, and constitutional Effective for control of articular, cutaneous, and constitutional symptoms (eg, fatigue), usual dose 200–400 mg per daysymptoms (eg, fatigue), usual dose 200–400 mg per day

• Findings from a recent systematic review showed improved disFindings from a recent systematic review showed improved disease activity, reduced mortality, and a modest effect on thrombease activity, reduced mortality, and a modest effect on thrombotic risk and damage accrual, potential beneficial effect on lipid otic risk and damage accrual, potential beneficial effect on lipid profile and cardiovascular disease, safe for use in pregnancyprofile and cardiovascular disease, safe for use in pregnancy


• Azathioprine

• Purine analogue, inhibits synthesis of xanthylic and adenylic aPurine analogue, inhibits synthesis of xanthylic and adenylic acids cids

• Used for active systemic disease including maintenance treatmUsed for active systemic disease including maintenance treatment of lupus nephritis, selective use as induction treatment for lent of lupus nephritis, selective use as induction treatment for lupus nephritis, usual dose 1–3 mg/kg per day. upus nephritis, usual dose 1–3 mg/kg per day.

• Data from trial suggest similar efficacy to mycophenolate as mData from trial suggest similar efficacy to mycophenolate as maintenance treatment for lupus nephritis after induction with loaintenance treatment for lupus nephritis after induction with low-dose cyclophosphamidew-dose cyclophosphamide


• Mycophenolate 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.


• Cyclophosphamide Cyclophosphamide

• Forms active alkylating metabolites in liver and other tissues aForms active alkylating metabolites in liver and other tissues and prevents cell division by crosslinking DNA and suppressing nd prevents cell division by crosslinking DNA and suppressing DNA synthesisDNA synthesis

• Used as induction treatment of lupus nephritis (orally or intraveUsed as induction treatment of lupus nephritis (orally or intravenously); Euro-lupus project showed equivalent efficacy of low-nously); Euro-lupus project showed equivalent efficacy of low-dose intravenous cyclophosphamide (six fortnightly pulses of dose intravenous cyclophosphamide (six fortnightly pulses of 500 mg) to the National Institutes of Health protocol (750 mg/m500 mg) to the National Institutes of Health protocol (750 mg/m22 monthly intravenous cyclophosphamide for 6 months followed monthly intravenous cyclophosphamide for 6 months followed by quarterly infusions for 2 years)by quarterly infusions for 2 years)

• Also used for other organ or life-threatening manifestationsAlso used for other organ or life-threatening manifestations



Biological treatmentsBiological treatments

Improved understanding of the immune response and abnormalities iImproved understanding of the immune response and abnormalities in apoptosis have allowed the recognition of cells and molecules that an apoptosis have allowed the recognition of cells and molecules that are crucial to the development of SLE and other autoimmune rheumatire crucial to the development of SLE and other autoimmune rheumatic diseases. c diseases.

Increased recognition of the multifaceted role that B cells have in the Increased recognition of the multifaceted role that B cells have in the pathophysiology of SLE has led to the development of several novel trpathophysiology of SLE has led to the development of several novel treatments, notably rituximab and belimumab. eatments, notably rituximab and belimumab.


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.

• (3) Osteoarthritis (OS)(3) Osteoarthritis (OS)

• Treatment of symptomsTreatment of symptoms• NSAIDs; opioidsNSAIDs; opioids

• InjectionsInjections• intra-arthritic GCs or hyaluronic acid intra-arthritic GCs or hyaluronic acid ((透明质酸透明质酸 )) • intramuscular NSAIDsintramuscular NSAIDs

• LocalLocal applicationsapplications• NSAIDs; capsaicinNSAIDs; capsaicin

• Disease-modifyingDisease-modifying osteoarthritisosteoarthritis drugsdrugs ((DMOADDMOAD

s, s, 缓解病情的骨关节炎药缓解病情的骨关节炎药 ) and protective drugs of carti) and protective drugs of cartilagelage ( 软骨软骨 ))


• Disease-modifyingDisease-modifying osteoarthritisosteoarthritis drugsdrugs ((DMODMOADsADs) and protective drugs of cartilage) and protective drugs of cartilage

• GlucosamineGlucosamine （氨基葡萄糖）（氨基葡萄糖） , ,

• ChondroitinChondroitin sulfatesulfate （硫酸软骨素）（硫酸软骨素）

• DiacereinDiacerein (( 双醋瑞因双醋瑞因 )): : IL-1IL-1 inhibitorinhibitor

• DoxycyclineDoxycycline (( 多西环素多西环素 ):): inhibitor of MMPsinhibitor of MMPs

• DiphosphonatesDiphosphonates （双膦酸盐类药物）（双膦酸盐类药物） alendronate sodiumalendronate sodium（阿仑膦酸钠（阿仑膦酸钠 ))

• Vitamins: A, D, C, EVitamins: A, D, C, E


(4) Rheumatic fever (RF)(4) Rheumatic fever (RF)

Anti-rheumatic treatmentAnti-rheumatic treatment Aspirin or other NSAIDsAspirin or other NSAIDs GCsGCs

Preventive treatmentPreventive treatment Penicillin G and other antibacterial drugsPenicillin G and other antibacterial drugs

(4) Rheumatic fever (RF)(4) Rheumatic fever (RF)

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Drugs Treating Rheumatism