Approach to the Treatment of RA Try to figure out ‘what type’ of Rheumatoid Arthritis the patient has This is not a uniform disease Young, Sero-positive patient vs. Older Sero-negative patient. Abrupt vs gradual onset Mild DMARDS vs Immunosuprssives

Treatment of early RA *Nonsteroidal Anti-Inflammatory Drugs- do not alter the course of the arthritis and its outcome *Glucocorticoids- *Disease-Modifying Antirheumatic Drugs *Methotrexate- favorable risk–benefit ratio, is (as in established RA) regarded to be the drug of first choice. *hydroxychloroquine or sulfasalazine

Antiproliferative agents More aggressive doses of methotrexate Leflunomide Biologics Infliximab/ Etanercept/Humira (TNF-  ) Kineret (IL-1ra) Orencia (abatacept) Rituxan (B-cell depletion) MRA (IL-6 receptor) Small Modular Immunopharmaceutical (SIMP) Combination therapy—sooner than ever before

Specific drugs: Methotrexate  Anti folic acid-  Anti folic acid- inhibition of proliferation of cells responsible for synovial inflammation   Decreases markers of inflammation, including the erythrocyte sedimentation rate and c-reactive protein (CRP)   Adverse Effects-low-dose weekly-7.5 to 10 mg   anorexia, nausea, vomiting, and diarrhea(10%)   Hematologic-leukopenia (3%)   ? cirrhosis and liver failure (1/1000)   acute interstitial pneumonitis

“MTX is currently considered a first-line agent in the treatment of RA, and the “anchor drug” for combination therapy with other DMARDs and biologic agents. It has become the standard of care and the most widely used drug in the treatment of RA.”

-Try to induce remission with i.m. depot methylprednisolone mg if synovitis persists beyond 6 weeks.

-If synovitis recurs, start with disease modifying anti-rheumatic drugs (DMARDs) like sulfasalazine or methotrexate. Give a second dose of i.m. depot methylprednisolone

Slow acting anti rheumatic drugs** There are increasing number of drugs that like steroids nonspecifically suppress chronic inflammatory disease. In contrast to steroids, these drugs have delayed action & must be taken for weeks or months before full therapeutic action appears..

There précised mode of action is unclear, however, these drugs can reduce the clinical signs of inflammation,improve parameters of acute phase response & may reduce target tissue damage, hence they called Disease Modifying Anti- Rheumatic Drugs(DMARD).

Examples of DMARDs used in treatment of RA 1-sulfasalazine:500mg daily PO. SE: nausea, skin rash, mouth ulcer, neutropenia, abnormal LFT 2- methotrexate:2.5-25mg weekly PO or S.C SE: nausea, mouth ulcer, abnormal LFT, renal impairment, lung fibrosis 3-leflunomide 100mg daily then 20mg daily PO

4-TNF-alpha blockers: a- Etanercept(alone or with methotrexate):25mg weekly S.C b- Adalimumab(with methotrexate):40mg alternate weeks S.C c- Infliximab(with methotrexate):3- 10mg/kg every 4-8weeks I.V SE: injection site reactions, infection, HF, autoimmune syndromes, reversible lupus like syndromes.

5- Other biological agents(used with methotrexate): a- Anakinra: 1mg/kg S.C daily SE: injection site reaction, serious reactions b- Rituximab: IV mg SE: hypo or hypertension, skin rash, nausea, back pain

. 6- Hydroxychloroquine: mg /day SE- corneal deposits 7- D-pencillamine: mg/ day SE- protein urea, thrombocytopenia 8- Gold: 50 mg/ month IM injection SE- myelosuppresion 9- Azathioprine: mg/ day SE- hepatitis, myelosuppresion 10- Chlorambucil: 4-8 mg/ day SE- bone marrow suppression, azospermia 11- Ciclosporin : mg/ day SE- renal impairment, hypertension. SE: alopecia, HT, neutropenia, diarrhea

-If there is no significant improvement in 6-12 weeks as measured by less pain, less morning stiffness and reduced acute-phase response, use a combination of methotrexate and sulfasalazine.

-If no better,used an alternative agent, such as gold, D- pencillamine, leflunomide or anti- TNF alpha therapy

DMARDs --Traditional DMARDs, which mainly act through cytokine inhibitors,reduce inflammation, with a reduction of joints swelling, a fall in the plasma acute-phase reactants and slowing of the development of joints erosion and irreversible damage..

Their beneficial effect is not immediate(hence slow acting agents) and may be partial or transient

--DMARDs often only have a partial effect, achieving between 20-50% improvement by ACR(American College of Rheumatology) criteria for disease remission (morning stiffness more than 15 min, no fatigue, joint pain, joint tenderness or soft tissue swelling; an ESR of more than 30 in women and more than 20 in men)..

TNF-alpha blocking agents and rituximab achieve almost 70% improvement in around 20% of patients and they also act more rapidly

--Sulphasalazin, methotrexate, leflunomide, TNF-alpha blockers, ciclosporin and rituximab have all been shown to reduce the rate of progressive joint damage in early and late disease.

A second choice DMARD to be used after methotrexate has a long half-life (2 wks) dose:20 mg daily leflunomide, sulfasalazine, and methotrexate reduced radiologic progression Leflunomide

Generally DMARDs are used after symptomatic treatment. However, patients positive for RF and anti-CCP with persistent joint swelling have a poor prognosis and they should be treated early with DMARDs- preferably before the appearance of erosion on X-rays of the hands and feet.

Studies of early RA suggest that intervention with DMARDs at 6 weeks to 6months improves the outcome.

The use of combination of 3-4 drugs(steroids, methotrexate, sulfasalazine & hydroxychloroquine) in early RA, reducing the number of agents once remission has been achieved, is more controversial & its long term efficacy is yet to be proven.

Effective treatment with DMARDs reduces the increased cardiovascular risk seen in patient with RA.

1- persistent synovitis > 6 weeks 2- sever extra articular disorders ( vasculitis, scleritis, renal involvement 3- steroid- sparing effect (e.g. Polymyalgia rheumatica resistant to low dose steroids)

4- inflammatory myositis The use of such drugs should be monitored because of side effects & they are contraindicated in pregnancy especially in the first trimester.

They can be used as monotherapy or in combination & can be used as adjuvant to other drugs such as painkillers& analgesics(NSAIDs).

CORTICOSTEROIDS : Should be used sparingly, in low doses & for short time. They are used for brief exacerbations of the disease & used in patients taking DMARDs, since the later drugs need time to work

SURGERY synovectomy, osteotomy, arthrosis or arthroplasty play a major rule in patient rehabilitation.

PROGNOSIS average life span is reduced by 8-15 years & 5 years survival for patients with severe RA is only 50%. A poor prognosis is indicated by:- - a clinical picture of an insidious rather than explosive onset of RA.

summary Early aggressive therapy especially in young seropositive patients— DMARDS within 3 months of diagnosis. Best chance for remission Methotrexate first—But in partial responders rapidly move to TNF-  blockers. The data suggest the they should be ADDED to Methotrexate. Biologics to induce early remissions for those with erosions at diagnosis.

Try more than one TNF-  blocker (70% respond to a switch) Orencia/Rituxan in TNF-  Failures ?Low dose prednisone (5-10 mg) combined with osteoporosis protection—Many need it for symptoms NSAIDS/COX-2 as bridge therapy in mild Rheumatoid Arthritis (essentially worthless)