RHEUMATOID ARTHRITIS.

Rheumatoid arthritis (RA) is a chronic, progressive inflammatory disorder of unknown etiology characterized by polyarticular symmetric joint involvement and systemic manifestations.

1. RHEUMATOID ARTHRITIS PRESENTed BY: D r. SHAISTA SUMAYYA PharmD SULTAN UL ULOOM COLLEGE OF PHARMACY, HYDERABAD

2. DEFINITION Rheumatoid arthritis (RA) is a chronic, progressive inflammatory disorder of unknown etiology characterized by polyarticular symmetric joint involvement and systemic manifestations.

3. PATHOPHYSIOLOGY

4. CLINICAL PRESENTATION: EARLY FEATURE : Most commonly affects MCPJ and PIPJ, wrist, tendon sheaths around the joints (wrist – feet – knee – shoulder ) Bilateral symmetrical polysynovitis Pain, fusiform swelling, stiffness, loss of mobility Constitutional symptom: - malaise, low-grade fever - tenosynovitis

5. LATE FEATURE (DESTRUCTIVE) Spread to other joint Morning stiffness(more than 30mins) – improve with activity MORE LATER (DEFORMITY) Pain, deformity, instability, decreased ROM Thumb – Z-deformity Fingers – swan neck deformity, boutonniere’s deformities, ulnar deviation Wrist – radial and volar displacement Elbow – limited extension Shoulder – limited abduction Knees – swollen Toes – clawed

6. RISK FACTORS Factors that may increase your risk of rheumatoid arthritis include: Gender .  Women are more likely than men to develop rheumatoid arthritis. Age .  Rheumatoid arthritis can occur at any age, but it most commonly begins in middle age. Family history .  If a member of your family has rheumatoid arthritis, you may have an increased risk of the disease. Smoking .  Cigarette smoking increases your risk of developing rheumatoid arthritis, particularly if you have a genetic predisposition for developing the disease. Smoking also appears to be associated with greater disease severity. Environmental exposures .  Although poorly understood, some exposures such as asbestos or silica may increase the risk of developing rheumatoid arthritis. Obesity .  People — especially women age 55 and younger — who are overweight or obese appear to be at a higher risk of developing rheumatoid arthritis.

7. EULAR RA CLASSIFICATION CRITERIA

8. DIAGNOSIS Laboratory tests Rheumatoid factor (RF) detectable in 60% to 70 %. Anticyclic citrullinated peptide (anti-CCP) antibodies have similar sensitivity to RF but are more specific and are present earlier in the disease . Elevated erythrocyte sedimentation rate and C-reactive protein are markers for inflammation. Normocytic normochromic anaemia is common as is thrombocytosis. Other diagnostic tests Joint fluid aspiration may show increased white blood cell counts without infection, crystals. Joint radiographs may show periarticular osteoporosis, joint space narrowing, or erosions.

9. RADIOGRAPHIC EXAMINATION

10. TREATMENT NON PHARMACOLOGICAL : Diet Exercise Stress reduction E motional support SURGERY : Synovectomy Arthroscopic surgery Osteotomy Arthroplasty Arthrodesis

11. PHARMACOLOGIC THERAPY

12. MEDICATIONS

13. ALGORITHM FOR TREATMENT OF RA

14. Management: Before start of therapy : CBC Serum creatinine – should be normal LFT – SGOT, SGPT should be normal Viral markers Chest x ray – ask history of TB Rheumatoid factor ESR/CRP After start of therapy : Monitor CBC, serum creatinine, LFT, ESR every 3 months

15. DMARDS should be started within the first 3 months of symptom onset DMARDs commonly used include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide . Methotrexate is first line agent

16. DRUG OF CHOICE FOR RA METHOTREXATE DOSE : 7.5mg/week – 25mg/week Start with 10mg/week MTX shows response after 6-12 weeks Patient needs to report after 2-4 weeks with LFT If patient has tolerated the dose then increase dose @5mg/week up to 25mg/week FORM OF THERAPY: Below 15mg/wk. – oral Above 15mg/wk. – SC/IM Intrathecal for single joint involvement – usually given in cancer HOW LONG TO GIVE THE THERAPY? 3-5 yrs. minimum duration of therapy Patients with response to MTX cures with more frequency

17. MOA: Methotrexate inhibits cytokine production, inhibits purine biosynthesis, and may stimulate release of adenosine, all of which may lead to its anti inflammatory properties. ADR OF MTX : GI (stomatitis, nausea/vomiting, diarrhoea), myelosuppression (thrombocytopenia, leukopenia), hepatic (elevated enzymes, rarely cirrhosis), pulmonary (fibrosis, pneumonitis), rash Contraindications: chronic liver disease Immunodeficiency pleural or peritoneal effusions leukopenia, thrombocytopenia, preexisting blood disorders creatinine clearance of less than 40 mL/min .

18. LEFLUNOMIDE Used as Alternative to MTX Leflunomide is a DMARD that inhibits pyrimidine synthesis, leading to a decrease in lymphocyte proliferation and modulation of inflammation. Leflunomide has efficacy similar to methotrexate for treating rheumatoid arthritis. DOSE: loading dose – 100mg daily for 3 days maintenance dose – 20mg daily Lower doses - if patients have gastrointestinal intolerance, complain of hair loss, or have other signs of dose-related toxicity. contraindicated in patients with preexisting liver disease . The drug is teratogenic , Because leflunomide undergoes enterohepatic circulation, the drug takes many months to drop to a plasma concentration considered safe during pregnancy. Hence should be given to patients who are above 40yrs. Cholestyramine may be used to rapidly clear the drug from plasma

19. HYDROXYCHLOROQUINE The main advantage of hydroxychloroquine is the lack of myelosuppressive, hepatic, and renal toxicities that may be seen with other DMARDs, which simplifies monitoring Dose: Oral : 200–300 mg bid, after 1–2 months may ↓ to 200 mg bid or daily OTHER DMARDS : Sulfasalazine, Gold salts, azathioprine, D-penicillamine, cyclosporine, cyclophosphamide, and minocycline have all been used to treat rheumatoid arthritis.

20. BIOLOGICAL DMARDS - BIOLOGICS E ffective for patients who fail treatment with other DMARDs .

21. IMPORTANT POINTS REGARDING BIOLOGICS Given when response to DMARD’s alone is poor Biologics always given in combination with MTX in RA Increase the risk of infections Screen for latent TB and hepatitis B before therapy There should be no infections before, while or after starting the therapy Patient should be asked to report slightest infection Vaccinate for influenza If patient already has an infection, treat the infection before starting therapy Tuberculin skin testing is recommended prior to treatment with these drugs . If patient develop infections while on biologic agents temporarily discontinue them until the infection is cured. Given for a short course of 3-9 months High cost

22. INFLIXIMAB DOSE : IV infusion of 3 mg/kg at 0, 2, and 6 weeks and then every 8 weeks. Infliximab should be given in combination with methotrexate to prevent development of antibodies that may reduce drug efficacy or induce allergic reactions . combination of methotrexate plus infliximab halted progression of joint damage in patients and was superior to methotrexate monotherapy

23. CORTICOSTEROIDS They are valuable in controlling symptoms before the onset of action of DMARDs. This is referred to as a “bridge therapy” A burst of corticosteroids can be used in acute flares. Continuous low doses may be adjuncts when DMARDs do not provide adequate disease control. may be injected into joints and soft tissues to control local inflammation Prednisone is the most often used steroid in RA treatment . ADR : Hypertension , hyperglycaemia, osteoporosis

24. USE OF STEROIDS IN RA Lowest dose – prednisone ≤ 7.5mg/day Lowest duration - ≤ 3 months Used as initial therapy with MTX INTRAMUSCULAR ROUTE : preferred in patients with compliance problems. Ex: triamcinolone acetonide, triamcinolone hexacetonide, and methylprednisolone acetate. provides the patient with 2 to 6 weeks of symptomatic control. INTRAARTICULAR STEROIDS : preferred due to lesser side effects Given if small number of joints are affected one joint should not be injected more than 2-3 times /year because of the risk of accelerated joint destruction and atrophy of tendons. . Daily supplements of calcium (800–1,000 mg) and vitamin D (400–800 units) are recommended along with steroids.

25. NSAIDS A djuncts to DMARD treatment . R educe stiffness and pain associated with rheumatoid arthritis. Few examples of NSAIDS: Aspirin 2.6–5.2 g ---Four times daily Celecoxib 200–400 mg — Daily to twice daily Diclofenac 150–200 mg — Three times per day to four times daily ADR : GI ulceration and bleeding, renal damage Aspirin - contraindicated in children

26. COMBINATION THERAPY Given when there is active disease even when MTX is ≥15mg/wk. for 8-12 weeks TRIPLE THERAPY : MTX+ sulfasalazine(1-2g/day)- start with 500mg/day + hydroxychloroquine(200-400mg/day) Given to patients who didn’t respond to MTX alone OR Leflunomide (100mg daily for 3 days then 10-20mg daily )+ sulfasalazine + hydroxychloroquine Methotrexate + sulfasalazine +prednisone infliximab + methotrexate

27. JUVENILE IDIOPATHIC ARTHRITIS Clinical presentation : The morning stiffness and joint pain may manifest as increased irritability, guarding of involved joints, or refusal to walk. Fatigue, low-grade fever, anorexia, weight loss , failure to grow Treatment: NSAID: NSAID therapy is the treatment of choice for treating the joint manifestations as well as the febrile episodes in systemic-onset JIA Ex: Naproxen 10 to 15 mg/kg/day (maximum, 750 mg) in two daily divided doses DMARD: For patients with polyarticular disease MTX is given 5 to 15 mg/m2 (0.15–0.5 mg/kg) orally or subcutaneously each week BIOLOGIC DMARD: Etanercept (Enbrel), the only FDA-approved biological agent for the treatment of JIA I ndicated for patients 4 years of age and older whose conditions have failed to respond to one or more DMARDs Dose : 0.4 mg/kg (maximum, 25 mg) subcutaneously twice weekly.

28. ANEMIA IN RA RA can cause anemia of chronic disease If MTX is given, give folic acid to manage anemia If MTX is causing Hb drop >1-2g/dl – discontinue MTX HEPATITIS IN RA : Hydroxychloroquine+ sulfasalazine Do not give biologics RENAL DYSFUNCTION : If sr. creatinine is >30ml/min low dose MTX is given If sr. creatinine is <30ml/min, sulfasalazine+ low dose hydroxychloroquine

29. HIV+ RA : Antiviral drugs+low dose hydroxychloroquine+sulfasalazine/low dose MTX Avoid biologics

30. VITAMIN SUPPLEMENTS Folic acid - Because MTX is a folic acid antagonist, it can induce a folic acid deficiency. This deficiency is thought to be partly responsible for methotrexate toxicity, and supplementation with folic acid does alleviate some adverse effects. Dose : 5mg weekly/5mg daily other than the day of MTX administration Vitamin D - given as weekly therapy for 8-10 weeks, then given as monthly therapy Calcium - initially 1g/day, later 500mg/day Vitamin B12

31. MANAGEMENT OF RA DURING PREGNANCY BEFORE PREGNANCY : Discontinue MTX at least 3 months before pregnancy - teratogenic If pregnancy is confirmed – discontinue MTX Controlled disease for at least 6 months Avoid MTX, leflunomide and biologics during pregnancy DURING PREGNANCY : 1 st trimester – hydroxychloroquine ±sulfasalazine 2 nd trimester – hydroxychloroquine + sulfasalazine 3 rd trimester – hydroxychloroquine + steroids SOS POST DELIVERY : Hydroxychloroquine

32. COMPLICATIONS OF RA Rheumatoid arthritis increases your risk of developing: Osteoporosis .  Rheumatoid arthritis itself, along with some medications used for treating rheumatoid arthritis, can increase your risk of osteoporosis — a condition that weakens your bones and makes them more prone to fracture. Rheumatoid nodules .  These firm bumps of tissue most commonly form around pressure points, such as the elbows. However, these nodules can form anywhere in the body, including the lungs. Sjogren's syndrome People who have rheumatoid arthritis are much more likely to experience Sjogren's syndrome, a disorder that decreases the amount of moisture in your eyes and mouth . Felty’s Syndrome: Rheumatoid arthritis in association with splenomegaly and neutropenia is known as Felty’s syndrome. Thrombocytopenia also may be a manifestation of the syndrome Abnormal body composition .  The proportion of fat to lean mass is often higher in people who have rheumatoid arthritis, even in people who have a normal body mass index (BMI )..

33. Carpal tunnel syndrome .  If rheumatoid arthritis affects your wrists, the inflammation can compress the nerve that serves most of your hand and fingers. Heart problems .  Rheumatoid arthritis can increase your risk of hardened and blocked arteries, as well as inflammation of the sac that encloses your heart(pericarditis) Lung disease .  People with rheumatoid arthritis have an increased risk of inflammation and scarring of the lung tissues, which can lead to progressive shortness of breath. Lymphoma .  Rheumatoid arthritis increases the risk of lymphoma, a group of blood cancers that develop in the lymph system

34. How to differentiate between RA and Ankylosing spondylitis Rheumatoid arthritis Most common in females (35-50yrs) Pain in knuckles, hands, small joints – deformity occurs if therapy is not given CSR, CRP elevated Positive rheumatoid factor Positive anti citrullinated antibody Ankylosing spondylitis Young males(20-40yrs) Patient complaints of backache in the morning Sacro- ileac joint inflammation Buttock pain Bamboo spine Pain at rest – goes away on exercising HLA B27 positive

35. OSTEOARTHRITIS AND RA

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