Balqis Mohamad Zin (F0155)15th June 2012

RHEUMATOID ARTHRITIS

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

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

DiagnosisAmerican Rheumatism Association Criteria (ACR)Criteria DefinitionMorning stiffness Morning 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 joints At least one joint area swollen as above in wrist, MCP or PIP joints

Symmetric arthritis Simultaneous involvement of the same joint areas(as in 2) on both sides of the body

Rheumatoid nodules Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxtaarticular regions, observed by a physician

Serum rheumatoid factor Demonstartion of abnormal amounts of serum rheumatoid factor by any method that has been positive in less than 5% of normal control subjects

Radiographic changes Radiographical 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

Aim

• To minimize joint damage• to reduce joint swelling, stiffness and pain• Improve quality of life

Treatment

Pain ReliefNSAIDs /

COX-2 inhibitors

Modification of the

disease

DMARDs

Biological modifiers

Pharmacological treatment

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

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

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

Before DMARD treatment After DMARD treatment

Methotrexate

MOA MOA in treatment of RA is unknown but may affect immune functions

Side effects Arachnoiditis, reddening of skin, ulcerative stomatitis, alopecia

Dose Initial: 5-7.5mg / week, not exceed 20 mg/week

Special cautions

Hazardous 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.

Hydrochloroquine

MOA Impairs complement-dependant antigen-antibody reactions

Side effects alopecia, angioedema, abdominal cramping, myopathy, bronchospasm, nausea & vomiting

Dose Initial: 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 cautions

May cause opthalmic adverse effect/neomyopathy

Cyclosporin

MOA Inhibition of production and release of interleukin-II and inhibits interlukin II-induced activation of resting T-lymphocytes

Side effects Hypertension, edema, hirsutism, nausea

Dose Initial 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 cautions

Monitor renal function closely. Use with cautions with other potentially nephrotoxic drugs

Cost RM 3.30 per tablet

Sulphasalazine

MOA Act locally in the colon to decrease the inflammatory response and systematically interferes with secretion by inhibiting prostaglandin synthesis

Side effects Headache, photosensitivity, anorexia, nausea, vomiting, diarrhea

Dose Initial: 0.5-1g/day; increase weekly to maintenance dose of 2g/day in 2 divided doses, max: 3 g/day

Special cautions

Use caution in patients with renal impairment, severe allergies or asthma or G6PD deficiency: may cause folate deficiency( supplement folate should be consider)

Penicillamine

MOA Depresses circulating IgM rheumatoid factor, depresses T cell but not B-cell activity

Side Effect Common: nausea, anorexia, taste loss, blood disorders including thrombocytopenia, aplastic anemia

Dose Initially: 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 Cautions

Toxicity may be dose related. Patient should be warned to report promptly any symptoms suggesting toxicity (fever, sore throat, chills, bleeding or bruising)

Azathioprine

MOA Inhibit synthesis of DNA, RNA and proteins.

Side effects fever, malaise, thrombocytopenia , nausea & vomiting

Dose Initial: 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/dayMaintenance: reduce dose by 0.5mg/kg every 4 weeks until lowest effective dose is reached

Special cautions

Has mutagenic potential to both men and women. Hepatotoxicity may occur

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

Rituximab

MOA A monoclonal antibody directed against the CD20 antigen on B-lymphocytes. (imp. Role in development of RA)

Side Effects Fever, chills, nausea, dizziness, weakness

Dose as 2 infusions of 1000 mg with a 2-wk interval. Repeat according to patient’s response

Special precautions

Hydrate 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

Cost RM 5300/vial

Etanercept

MOA Binds tumor necrosis factor(TNF) and blocks its interaction with cell surface receptors

Side effects Headache, abdominal pain, respiratory tract infection

Dose 50mg once a week25mg twice a week (should separated by 72-96 hours)

Special cautions

Serious and potentially fatal infections have been reported including bacterial sepsis and tuberculosis

Cost RM 1000 per injection

Infliximab

MOA Binds to TNF alpha, interfering with endogenous TNFα activity

Side effects Headache, nausea, diarrhea, ALT increased (concomitant with MTX), infections

Dose In combination with MTX: 3mg/kg at 0, 2, and 6 weeks, then every 8 weeks thereafter.

Special cautions

Opportunistic infections and/or reactivation of latent infections have been associated with infliximab therapy

Cost Rm 2250 per injection

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

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

Monitoring

• ESR/CRP• LFT•WBC• Platelet• Creatinine

Non-pharmacological treatment

• Occupational therapy• Tai Chi• Passive exercise should prescribed

Joint Protection Principles

Source: http://www.afm.org.my/info/living.htm

Treatment available in UMMCDose Criteria

Methotrexate 5-7.5mg / week Standard formulary.

Folic Acid 5mg OD Standard formulary.

Prednisolone 5-10mg OD Standard formulary.

Hydrochloroquine

155-310mg/day Standard formulary

Cyclosporin 2.5mg/kg/day divided twice daily

Restricted formulary.

Sulphasalazine of 2g/day in 2 divided doses

Normal formulary.

Penicillamine 500-750mg daily Normal formulary.

Rituximab as 2 infusions of 1000 mg with a 2-wk interval

Special formulary, to buy from Pharm UMMC

Etenarcept 50mg once a week Special formulary, to buy from Pharm UMMC

Infliximab 3mg/kg at 0, 2, and 6 weeks, then every 8 weeks thereafter.

Special formulary, to buy from Pharm UMMC

Summary

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

References• BNF• Drug information Handbook. 18th Edition• B.G.Wells, J.T. DiPiro,T.L Schwinghammer, C.V DiPiro. Pharmacotherapy

handbook, 7th edition, Mc Graw Hill• M.A Koda-Kimble, L.Y Young, B.K.Alldredge, R.L Corelli, et al,. Applied

therapeutics, 9th 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/