BY Doaa waseem Nada Assistant lecturer of physical medicine , Rheumatology and Rehabilitation.

1. Treatment of RA BY Doaa waseem Nada Assistant lecturer of physical medicine , Rheumatology and Rehabilitation. Faculty of Medicine Tanta University

2. eatment of a patient with active disease ( Fig. 67-1 ).

3. Ra: Traditional Treatment Paradigm • Pyramid of therapy • Start conservatively • Gradually ascend the pyramid in order of potency and toxicity of therapy • Only the most severely affected patients receive immuno-supressive, DMARDs • DMARD therapy begun only after period of significant delay

4. Re-Thinking the RA Treatment Pyramid • Emphasizes earlier diagnosis and initiation of therapy with disease modifying anti-rheumatic drugs

5. ACR RA Practice Guidelines 2002 • Most patients with Rheumatoid Arthritis should be evaluated • Treatment with DMARD instituted within 3 months of diagnosis • Goals are to prevent or control joint damage, prevent loss of function, and decrease pain

6. The Current Pyramid Paradigm • Early initiation and titration of DMARD • If incomplete response to DMARD alone, after reasonable titration, addition of biologic recommended ? 2nd Line Biologic MTX + Biologic Methotrexate

7. Non-Pharmacologic: Referral to PT/OT Evaluate ADLs Assistive devices/splints Weight loss Smoking cessation Pharmacologic: Anti-inflammatory Interrupt progression Development of erosions Joint space narrowing Therapy

8. The choice of drugsis highly individualized and typically changes often during the course of the disease. • Factors that are considered in treatment decisions include: • the type and severity of RA. • the person's response to treatment • risks of drug side effects.

9. The principal drugs used in management of RA: • NSAIDS and analgesics and corticosteroid • DMARDS Cytotoxic, or immunosuppressive, drugs - methotrexate - sulfasalazine - hydroxychloroquine - leflunomide • Biologics - TNF inhibition: infliximab, etanercept, adalimumab - Inhibitor T cell activation: abatacept - B cell inhibition: rituximab - IL 1 inhibition: anakinra IL6 inhibition:Actemra

10. 1-Non-Steroidal Anti-inflammatory Drugs • NSAIDs are particularly helpful at any time during the course of the disease because they provide partial relief of pain and stiffness. • NSAIDs suppress inflammation but do not slow the progression of the disease

13. Mechanism of action: -NSAIDs interfere with the metabolism of arachidonic acid released from cellular membrane phospholipids in response to inflammatory stimuli. -They prevent the formation of proinflammatory prostaglandins and other lipid mediators that are important in the initial phase of the inflammatory reaction.

14. The main toxicities of NSAIDs • -due to inhibition of prostaglandin production in the gastric mucosa and kidney, tissues where prostaglandins play important physiologic roles. • gastrointestinal ulcer, perforation hemorrhage, • arterial hypertension.

16. Risk factors for use of NSAIDs (including aspirin) have been identified and include the following: • Advanced age    • History of peptic ulcer (with or without a known infection with Helicobacter pylori)    • Concomitant use of glucocorticoids or anticoagulants    • Thrombocytopenia or platelet dysfunction    • Pregnancy    • Moderate or severe congestive heart failure, cirrhosis, or renal insufficiency    • Aspirin intolerance, asthma, and nasal polyposis

17. 1-The selective COX-2 inhibitors. • The fundamental difference between COX-1 and COX-2 is that COX-1 is an enzyme synthesized at a constant rate by the tissues that produce it, whereas COX-2 is induced in monocytes or macrophages, endothelial cells, chondrocytes, synovial cells, and osteoblasts by cytokines and other products generated during inflammation. • The selective COX-2 inhibitors seem to be more effective in the treatment of arthritis and as effective as moderate doses of standard nonselective NSAIDs. The utility of the selective agents comes from potential safety advantages, including a lower risk of the development of gastrointestinal bleeding. The selective agents also have no significant effects on platelets. • selective COX-2 inhibition may increase risks for cardiovascular events, hypertension and renal insufficiency .

18. Acetaminophen is a very useful drug and can prove a useful adjunct in the treatment of arthritis. In patients without evidence of liver disease, acetaminophen can be taken in doses of 3 g or more per day without generating significant side effects. • Their use alone in polyarthritis for more than 6 weeks (i.e., the minimum period for acceptably classifying a polyarthritis as RA) should be discouraged and reserved only for patients who have severe and persistent disease despite all attempts to bring the disease under better control through the use of DMARDs and other adjuncts.

19. 1-it inhibit PG less than NSAIDS with low risk of GIT symptoms 2-it doesn't impair platelet function 3-dose:150-200 mg / dl

20. 3-Corticosteroids • are potent suppressors of the inflammatory response in RA but their dose-dependent side effects are major and familiar to all clinicians. • There still is controversy about if, when, and how these compounds should be used to treat RA. • Data from recent and older trials have clearly established that corticosteroids decrease the progression of RA as detected radiographically

22. Mechanism of action. • The anti-inflammatory effects of corticosteroids are mediated through their action on nearly all components of the immune and inflammatory systems, as well as many cellular targets of the immune system. • Corticosteroids inhibit the production of proinflammatory cytokines, such as TNF- a ,IL-1, IL-2 by monocytes/macrophages and lymphocytes. • They interfere with the signal transduction pathway of interferons and induce apoptosis of lymphocytes. • They inhibit lymphocyte proliferation and delayed-type hypersensitivity by interfering with antigen presentation. • Corticosteroids inhibit phospholipase A2 and block the production of proinflammatory prostaglandins, leukotrienes, and reactive oxygen intermediates.

23. Corticosteroids in low doses (e.g., <10 mg of prednisone/daily) are used to treat 30% to 60% of the patients, either in short courses or in the long term. • In moderate to severe disease, intramuscular methylprednisolone (Depo-Medrol) 120 mg or short 4-day courses of daily prednisone beginning at 20 mg will reset the inflammatory process and allow other drugs to work faster and better. • This is particularly useful in the window period that is normally required before a favorable therapeutic effect of DMARD therapy is achieved (i.e., weeks to months).

24. Minipulses of intravenous methylprednisolone (Solu-Medrol) (250 mg to 1,000 mg intravenously daily for 1 to 3 days) can be used for severe disease that is refractory to more conventional treatment or in patients with visceral involvement or RA vasculitis. • Intra-articular corticosteroid injections [e.g., methylprednisolone (Depo-Medrol) 10 to 80 mg] are often helpful in suppressing the inflammation in single joint that is resistant to systemic treatment. • The possibility of infection should always be considered and excluded before the intra-articular corticosteroid injection.

25. side effects of corticosteroids • thinning of the skin, • cataract formation, • osteoporosis, • hypertension, and hyperlipidemia. • The last three conditions may be preventable with aggressive management of osteoporosis and cardiovascular risk factors. • Other side effects include infection, diabetes, mood changes, myopathy, and osteonecrosis.

26. Guidelines for the Use of Glucocorticoids in the Treatment of Rheumatoid Arthritis • Prednisone >10 mg daily is rarely indicated for articular disease. • Avoid using glucocorticoids without DMARDs • Use glucocorticoids as a "bridge" to effective DMARD therapy. • Minimize duration and dose by slowly tapering to the lowest dose that controls arthritis. • Always consider prophylaxis to minimize osteoporosis.

28. All patients taking corticosteroids should receive supplemental calcium (1 to 1.5 g/day) and vitamin D3 (800 IU/day). • Bisphosphonates are very effective in reducing vertebral fractures in patients taking corticosteroids and should be prescribed for patients who have low bone density.

31. Methotrexate (Rheumatrex) Hydroxychloroquine (Plaquenil) Sulfasalazine (Azulfidine) D-penicillamine Leflunomide (Arava) Azathioprine (Imuran) Gold (Solganol, Ridaura) Cyclosporine (Neoral) Minocycline (Minocin) Traditional DMARD’s

32. Disease ModifyingAnti-Rheumatic Drugs • Must change course of RA over 1 year evidenced by sustained improvement in • physical function • decreased inflammation • slowing or prevention of structural joint damage • ACR 20 50 70

33. Antimalarial drugs • antimalarial drugs(chloroquine – hydroxychloroquine) are most commonly used as part of combination DMARD therapy mainly with methotrexate. Its mechanism of action: -Is related to accumulation of the drug in the acid vesicular lysosomal system of mononuclear cells, granulocytes, and fibroblasts. -inhibit antigen presentation and IL-1 release.

34. Inhibit cytokine production IL1,TNF a, Decrease autoantibody production. Inhibit NK cell activity. Inhibit immune complex formation. Increase apoptosis. The initial dose is 200 mg/day and the recommended maintenance dose is 200 mg twice daily. 6 weeks to 6 months of therapy may be required before a therapeutic effect is evident.

35. Side effects: • -Nausea,abdominal cramps, • -rash,alopecia,leukopenia,aplastic anaemia • -skin hyperpigmentation, • -retinopathy (Yearly ophthalmologic exam).

36. METHOTREXATE • MTX inhibits(DHFR), needed for DNA synthesis. . • its therapeutic action thought to be due to suppression of lymphocyte proliferation. -MTX is converted inside cells to a polyglutamated form that inhibits 5- aminoimidazole-4-carboxamidoribonucleotide transformylase. (AICAR) -This enzymatic block leads to extracellular adenosine release. • Adenosine binds to specific receptors on the surface of lymphocytes, monocytes, and neutrophils, and downregulates inflammatory pathways.

37. MTX also inhibits: • -neovascularization, • -neutrophil activity and chemotaxis, - interleukin (IL) 1 activity and IL-8 production by stimulated peripheral mononuclear cells, • - TNF production by stimulated peripheral T cells. • -S-adenosyl methionine formation. • -decrease metalloprotinase ,P G E2,super oxide production.

38. Methotrexate can be taken orally , SC or IM injection. the oral form of MTX is initiated for convenience, but may be switched to SC route to improve GIT tolerability as well as bioavailability. Initial doses of MTX range from 7.5 to 15 mg weekly and may be increased every 4-8 weeks to a maximum dose of 25-30 mg weekly to yield maximal disease control. Concomitant administration of folic acid (1-3 mg/day) decreases the frequency of toxicities without interfering with efficacy.

39. Predisposing factors for MTX toxicity: • Folate deficiency, • Advanced age, • Renal insuficiency, • Use of anti folate as NSAIDs. Discontinue ttt-------before pregnancy pre operative grade IIIB, IV liver biopsy

40. risk factors for liver toxicity in pt receiving MTX: • Alcohol, • Morbid obesity, • Chronic hepatitis, • Diabetes, • Reduced alpha 1 antitrypsin.

41. Methotrexate Adverse Events • GI - Mucositis, diarrhea, abdominal pain • Hematologic - Cytopenias, macrocytosis • Hepatic- Transaminitis, fibrosis, and cirrhosis • Pulmonary - Hypersensitivity pneumonitis, pulmonary fibrosis • Infections • Neoplasia - reversible lymphoproliferative disorder, lymphoma, and leukemia • Accelerated nodulosis and vascultitis • Reproductive – abortifacient and teratogenic • Must use birth control and d/c drug 2-6 months before planned pregnancy

42. Dihydrofolate reductase inhibitor Well tolerated, Mono/Combo Onset: 6-12 weeks Metabolism: Liver Clearance: Kidneys Monitoring: Baseline:CXR,, HBV/HCV CBC, LFTs(AST,ALT, Albumin) Q4-8 weeks Liver biopsy. Nausea Mucosal ulcerations Fatigue & Flu-like symptoms BM Toxicity Hepatotoxicity CNS,musculosk.,reproductive. Neoplasia nodulosis Treat with Folic acid, 1 mg/d Methotrexate

43. Leflunomide (Arava) • a pyrimidine antagonist,(A77 17 26) its active metabolite, is a new conventional DMARD approved for use in RA. • It has a very long half-life and is given daily in a dose of 10–20 mg. • When leflunomide was first introduced, a loading dose of 100 mg daily for 3 days was routinely used because of the long half-life, but most experts no longer use a loading dose because of increased side effects.

44. Mechanism of action: • Inhibits (DHOD)------ Inhibits pyrimidine synthesis.(low dose) • Inhibits tyrosine kinase (T,B cell signal) in high dose • Inhibits IL 1, TNF alpha • Suppress nuclear factor kappa B . • Reduce glycosylation of adhesion molecules.

45. Toxicity: • The most common toxicity with leflunomide is diarrhea, which may respond to dose reduction. • Leflunomide is teratogenic. • Because of its long half-life, women who have previously received leflunomide should have blood levels <0.02g/ml if they wish to become pregnant. • If toxicity occurs or if pregnancy is being considered, cholestyramine can rapidly eliminate leflunomide.(8g tid for 11 days)

46. Inhibits dihydrooratate dehydrogenase Dec. activated T-cells Onset: rapid Efficacy: ≤6 weeks Monitoring: CBC, LFTs Derm - rash, alopecia Diarrhea BM toxicity Hepatotoxicity hypertension Leflunomide

47. Sulfasalazine (Asulfadine) was the first DMARD that was developed specifically to treat RA and has an efficacy similar to that of methotrexate. Sulfasalazine is the most commonly used initial DMARD in Europe and in the United States as part of a combination DMARD therapy. The mechanism of action: • inhibition of prostaglandin production, ability to modify proreactive oxygen species released from activated macrophages, • reduction of activated circulatory lymphocytes, • effects on the metabolism of folic acid and adenosine.

48. The initial dose of sulfasalazine is 500 mg/day given with breakfast. The dose is then raised by 500 mg/week after a complete blood count and LFTs are checked and record normal results. The optimal dose range is between 2 and 3 g/day, usually taken as 1,000 to 1,500 mg with breakfast and dinner. Sulfasalazine is usually given as part of a combination treatment with methotrexate or with methotrexate and hydroxychloroquine.

49. The most common side effectsare • - Gastrointestinal, mainly nausea and vomiting. This problem is usually avoided with the use of enteric-coated tablets of sulfasalazine, and administration of the drug with meals. • -leukopenia and granulocytopenia . • the initial monitoring for dosing: • complete blood counts and differential counts are repeated at the end of the first month and then every 6 to 8 weeks along with estimation of serum levels of (AST) and (ALT).

50. Azathioprine: 1-3 mg/kg/day. M.D dose: 1-2 mg/kg/day. • Adverse side effects Bone marrow suppression (<5 %). Leukopenia (15 %). Infections (herps zoster) (40-70 %). Malignancies (<5 %). infertility (15 %). Nausea (15 %).