1. Balqis Mohamad Zin (F0155) 15 th June 2012 RHEUMATOID ARTHRITIS

2. What is Rheumatoid arthritis (RA)? It is an autoimmune disorder The deregulated immune system starts to attack the joints Chronic systemic inflammatory disorders Which the synovial (lines and lubricates the joints) becomes inflamed According to Arthritis Foundation Malaysia, RA affects about 5 in 1000 people in Malaysia. Prevalence estimated to be 1% worldwide

3. Pathophysiology Begins with inflammation of the synovial lining. The thin membrane proliferates, and become transformed into the synovial pannus. The pannus, a highly erosive enzyme-laden inflammatory exudate  invades articular cartilage,  erodes bone  destroys periarticular structures resulting in joint deformities

4. Diagnosis American Rheumatism Association Criteria (ACR) CriteriaDefinition Morning stiffnessMorning stiffness in and around the joints at least 1 hour before maximal improvement Arthritis of three or more joints areas At least three joint areas simultaneously have soft tissue swelling or fluid (not bony overgrowth alone) observed by a physician. The 14 possible joints areas are (R/L):PIP, MCP, wrist, elbow, knee, ankle and MTP joints Arthritis of hand jointsAt least one joint area swollen as above in wrist, MCP or PIP joints Symmetric arthritisSimultaneous involvement of the same joint areas(as in 2) on both sides of the body Rheumatoid nodulesSubcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions, observed by a physician Serum rheumatoid factorDemonstartion of abnormal amounts of serum rheumatoid factor by any method that has been positive in less than 5% of normal control subjects Radiographic changesRadiographical changes typical of RA on posteroanterior hand and wrist x-rays, which must include erosions or unequivocal bony decalcification localized to or most marked adjacent to the involved joint Patient is said to have RA if she/he satisfied at least 4 of these 7 criteria

5. Aim To minimize joint damage to reduce joint swelling, stiffness and pain Improve quality of life

6. TreatmentPain Relief NSAIDs / COX- 2 inhibitors Modification of the disease DMARDs Biological modifiers Pharmacological treatment

7. NSAIDS/ COX-2 Inhibitors As adjunct therapy to DMARDs Primarily by inhibiting the prostaglandin synthesis. Reduce stiffness BUT do not slow disease progression or prevent joint deformity Aspirin Celecoxib Diclofenac Indomethacin Meloxicam Naproxen

8. Corticosteroids Only given in a short period of time Helps to reduce the progression rate of disease Given not more than a year Low dosages of Oral corticosteroid 10mg of prednisolone or less Injected corticosteroid useful when flares involves only a few joints should not be given more than once every 3 months

9. Disease-Modifying Antirheumatic Drugs (DMARDs) Initial therapy once patient diagnosed Should not be delayed beyond 3 months Proven to slow down RA activity May not be effective in up to 20% patients

10. Before DMARD treatmentAfter DMARD treatment

11. Methotrexate MOAMOA in treatment of RA is unknown but may affect immune functions Side effectsArachnoiditis, reddening of skin, ulcerative stomatitis, alopecia DoseInitial: 5-7.5mg / week, not exceed 20 mg/week Special cautionsHazardous agent – use appropriate precautions for handling and disposal Folic acid supplement (5mg/week) will be given as combination to reduce side effects.  MTX is a folate antagonist Should not be given on the same day as MTX is administered May reduce the effect of MTX Compete for dihydrofolate reductase enzyme Folic acid should be taken on the next day after MTX is taken.

12. Hydrochloroquine MOAImpairs complement-dependant antigen-antibody reactions Side effectsalopecia, angioedema, abdominal cramping, myopathy, bronchospasm, nausea & vomiting DoseInitial: 310mg-465mg / day taken with food or milk. Dose may increase to achieve optimum response. After 4-6 weeks, dose should be reduced by ½ to a maintenance dose of 155-310mg/day Special cautionsMay cause opthalmic adverse effect/neomyopathy

13. Cyclosporin MOAInhibition of production and release of interleukin-II and inhibits interlukin II-induced activation of resting T-lymphocytes Side effectsHypertension, edema, hirsutism, nausea DoseInitial dose: 2.5mg/kg/day divided twice daily, may be increased by 0.5-0.75 mg/kg/day: additional dosage increases may made again at 12 weeks. Max: 4mg/kg/day Special cautionsMonitor renal function closely. Use with cautions with other potentially nephrotoxic drugs CostRM 3.30 per tablet

14. Sulphasalazine MOAAct locally in the colon to decrease the inflammatory response and systematically interferes with secretion by inhibiting prostaglandin synthesis Side effectsHeadache, photosensitivity, anorexia, nausea, vomiting, diarrhea DoseInitial: 0.5-1g/day; increase weekly to maintenance dose of 2g/day in 2 divided doses, max: 3 g/day Special cautionsUse caution in patients with renal impairment, severe allergies or asthma or G6PD deficiency: may cause folate deficiency( supplement folate should be consider)

15. Penicillamine MOADepresses circulating IgM rheumatoid factor, depresses T cell but not B-cell activity Side EffectCommon: nausea, anorexia, taste loss, blood disorders including thrombocytopenia, aplastic anemia DoseInitially: 125-250mg daily before food for 1 month and increased by similar amount at intervals of not less than 4 weeks to usual maintenance of 500-750mg daily in divided doses. Max: 1.5 g daily Special CautionsToxicity may be dose related. Patient should be warned to report promptly any symptoms suggesting toxicity (fever, sore throat, chills, bleeding or bruising)

16. Azathioprine MOAInhibit synthesis of DNA, RNA and proteins. Side effectsfever, malaise, thrombocytopenia, nausea & vomiting DoseInitial: 1mg/kg/day given once daily or divided twice daily for 6- 8 weeks; increase by 0.5mg/kg every 4 weeks until response or up to 2.5mg/kg/day Maintenance: reduce dose by 0.5mg/kg every 4 weeks until lowest effective dose is reached Special cautionsHas mutagenic potential to both men and women. Hepatotoxicity may occur

17. Biological Modifiers Mimic the biological substances in human body Suppressed excessive macrophage- produced cytokines (TNF-α, IL-1, IL-6, IL-8) which are abundant in rheumatoid synovial tissues and fluids

18. Rituximab MOAA monoclonal antibody directed against the CD20 antigen on B- lymphocytes. (imp. Role in development of RA) Side EffectsFever, chills, nausea, dizziness, weakness Doseas 2 infusions of 1000 mg with a 2-wk interval. Repeat according to patient’s response Special precautionsHydrate patient well, Stabilise uric acid levels before treatment, Antihistamine should be given to prevent allergic reactions, Painkiller and steroid to be given before each infusion CostRM 5300/vial

19. Etanercept MOABinds tumor necrosis factor(TNF) and blocks its interaction with cell surface receptors Side effectsHeadache, abdominal pain, respiratory tract infection Dose50mg once a week 25mg twice a week (should separated by 72-96 hours) Special cautionsSerious and potentially fatal infections have been reported including bacterial sepsis and tuberculosis CostRM 1000 per injection

20. Infliximab MOABinds to TNF alpha, interfering with endogenous TNFα activity Side effectsHeadache, nausea, diarrhea, ALT increased (concomitant with MTX), infections DoseIn combination with MTX: 3mg/kg at 0, 2, and 6 weeks, then every 8 weeks thereafter. Special cautionsOpportunistic infections and/or reactivation of latent infections have been associated with infliximab therapy CostRm 2250 per injection

21. Source: 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis

23. Monitoring ESR/CRP LFT WBC Platelet Creatinine

24. Non-pharmacological treatment Occupational therapy Tai Chi Passive exercise should prescribed

25. Joint Protection Principles Source: http://www.afm.org.my/info/li ving.htm

26. Treatment available in UMMC DoseCriteria Methotrexate5-7.5mg / weekStandard formulary. Folic Acid5mg ODStandard formulary. Prednisolone5-10mg ODStandard formulary. Hydrochloroquine155-310mg/dayStandard formulary Cyclosporin2.5mg/kg/day divided twice daily Restricted formulary. Sulphasalazineof 2g/day in 2 divided dosesNormal formulary. Penicillamine500-750mg dailyNormal formulary. Rituximabas 2 infusions of 1000 mg with a 2-wk interval Special formulary, to buy from Pharm UMMC Etenarcept50mg once a weekSpecial formulary, to buy from Pharm UMMC Infliximab3mg/kg at 0, 2, and 6 weeks, then every 8 weeks thereafter. Special formulary, to buy from Pharm UMMC

27. Summary To minimize the pain and joint damage, proper treatment should be given. Early treatment !!…. Reversible Counseling is important Side effect Administration

28. References BNF Drug information Handbook. 18 th Edition B.G.Wells, J.T. DiPiro,T.L Schwinghammer, C.V DiPiro. Pharmacotherapy handbook, 7 th edition, Mc Graw Hill M.A Koda-Kimble, L.Y Young, B.K.Alldredge, R.L Corelli, et al,. Applied therapeutics, 9 th edition, Lippincott Williams & Wilkins J.A Singh, D.E Furst, et al. 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis, Arthritis & Care Research, Vol 64 No.5, May 2012. NICE guideline: The management of Rheumatoid Arthritis in adult, February 2009. “Stop it Before it Stops You”, by Dr Chow Sook Khuan, Consultant Rheumatologist, Sunway Medical Centre, Keep Smiling, Volume 8/2008 http://www.afm.org.my/info/ra.htm RHEUMATOID ARTHRITIS, National clinical guideline for management and treatment in adults, Royal College of Physicians http://www.livestrong.com/article/420615-why-cant-i-take-folic-acid-the-same- day-as-methotrexate/