Management of rheumatoid arthritis .by Dr.Harmanjit Singh,GMC, Patiala

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Management of rheumatoid arthritis .by Dr.Harmanjit Singh,GMC, Patiala

  1. 1. MANAGEMENT OF RHEUMATOID ARTHRITIS Dr.Harmanjit Singh Department of Pharmacology Govt Medical College,Patiala.
  2. 2. INTRODUCTION <ul><li>RA is chronic multisystem disease of unknown cause. </li></ul><ul><li>Characteristic feature is persistent inflammatory synovitis. </li></ul><ul><li>Usually involve peripheral joints in symmetric distribution. </li></ul><ul><li>Joint changes probably represent autoimmune reaction. </li></ul>
  3. 3. <ul><li>Etiology: </li></ul><ul><li>Cause is unknown . </li></ul><ul><li>Family studies indicate genetic predisposition. </li></ul><ul><li>HLA DR4, Dw16, DR10, DR9, DR3 associated with rheumatoid arthritis. </li></ul><ul><li>HLADR5, DR7, DR2 may protect against rheumatoid arthritis ( Frequency less). </li></ul><ul><li>. May be manifestation of response to infection by mycoplasma, EBV, CMV, Parvovirus & rubella virus. </li></ul><ul><li>.Cigarette smoking – triggering factor. </li></ul>
  4. 4. <ul><li>Pathology : </li></ul><ul><li>Hyperplasia & hypertrophy of synovial cells. </li></ul><ul><li>Infiltration with mononuclear cells, macrophages. </li></ul><ul><li>Production of IL-1, IL-6 TNF alpha, PGE2, Leukotriene B4. </li></ul><ul><li>TNF alpha : proliferation of inflammatory cells </li></ul><ul><li>IL-1 : cartilage proteoglycan resorption, bone erosion,destructive aspect of RA </li></ul><ul><li>IL-6 : mediates IL-1 & TNF alpha actions </li></ul><ul><li>stimulates B cells </li></ul>
  5. 6. Diagnosis of rheumatoid arthritis Morning stiffness  1h Three or more joints involved Arthritis of hand joints Symmetric arthritis Rheumatoid nodules ( over bony prominence , extensor surfaces) Rheumatoid factor (positive < 5% normal subjects) Radiographic changes (must show erosion/decalcification) Present for  6wk Any 4 of the following must be present to allow diagnosis of RA ( Patients with 2 or more clinical diagnoses are not excluded )
  6. 7. RA- joint involvement <ul><li>Extraarticular manifestations </li></ul><ul><li>Pericarditis </li></ul><ul><li>Interstitial lung disease </li></ul><ul><li>Felty’s syndrome </li></ul><ul><li>Vasculitis </li></ul><ul><li>Neuropathy </li></ul>
  7. 8. <ul><li>INVESTIGATIONS </li></ul><ul><li>Rheumatoid Factor .   : +ve In about 80% of cases </li></ul><ul><li>- Also present in about 5% of normal individuals </li></ul><ul><li>- when it appears in patients with arthritic pain on both sides of the body, it is a strong indicator of RA. </li></ul><ul><li>ESR.   The higher the ESR the greater the inflammation., help determine how active the condition is. </li></ul><ul><li>C-Reactive Protein .  High levels of C-reactive protein (CRP) are also indicators of active inflammation.. </li></ul><ul><li>Anti-CCP Antibody Test .  The presence of antibodies to cyclic citrullinated peptides (CCP) can identify RA years before symptoms develop. </li></ul><ul><li>Tests for Anemia .   normocytic normochromic </li></ul>
  8. 9. <ul><li>IMAGING TECHNIQES </li></ul><ul><li>X-Rays, Dexa Scans . Ultrasound.  Special ultrasound techniques called power Doppler ultrasonography (PDUS) or quantitative ultrasound (QUS) may be helpful in RA. </li></ul><ul><li>Magnetic Resonance Imaging .  Specially designed magnetic resonance imaging (MRI) equipment called extremity MRI may be able detect bone erosions in the hands of RA patients where x-rays cannot. </li></ul><ul><li>Above lab findings plus clinical features are important to make the diagnosis </li></ul>
  9. 10. <ul><li>Monitoring progression </li></ul><ul><li>  Disease Activity Score of 28 joints  (DAS28). It is widely used as an indicator of RA disease activity and response to treatment The joints included in DAS28 are PIP , MCP joints, wrists ,  elbows  ,  shoulders  and  knees   </li></ul><ul><li>When looking at these joints, both the number of joints with tenderness upon touching ( TEN28 ) and swelling ( SW28 ) are counted. </li></ul><ul><li>In addition, the   ESR is measured. </li></ul><ul><li>Score less than 3.2 means pt is inactive </li></ul><ul><li>3.2-5.1 means moderately active patient </li></ul><ul><li>more than 5.1 means pt is active </li></ul>
  10. 11. Goals of therapy Alleviate pain Preservation of function Control disease activity Maximize quality of life Slow progression/rate of joint damage
  11. 12. MANAGEMENT <ul><li>Physical Therapies </li></ul><ul><li>Diet </li></ul><ul><li>Pharmacologic Therapies </li></ul><ul><li>NSAIDS </li></ul><ul><li>Glucocorticoids </li></ul><ul><li>DMARDS </li></ul><ul><li>Biologics </li></ul><ul><li>Surgical treatment </li></ul><ul><li>Future trends </li></ul>
  12. 13. MANAGEMENT <ul><li>Physical therapies </li></ul><ul><li>Splinting: prevents unwanted joint movement </li></ul><ul><li>Exercise: directed to maintain muscle strength & joint mobility </li></ul><ul><li>Diet   </li></ul><ul><li>.Some studies suggest that omega-3 fatty acids may reduce rheumatoid arthritis inflammation. </li></ul><ul><li>Some Herbal remedies also found to be useful </li></ul>
  13. 14. <ul><li>Pharmacologic measures: </li></ul><ul><li>NSAIDS </li></ul><ul><li>First line drugs in mild/early cases </li></ul><ul><li>Afford symptomatic relief in pain , swelling , morning stiffness </li></ul><ul><li>Do not arrest disease process </li></ul><ul><li>Non selective Cox inhibitors : </li></ul><ul><li>Naproxen - 500 mg bd. </li></ul><ul><li>Piroxicam -20 mg qid </li></ul><ul><li>Nabumetone 1000mg od </li></ul><ul><li>Aceclofenac , Etodolac upto 1000 mg/day </li></ul><ul><li>Indomethacin reserve dg when other NSAIDs don’t provide relief </li></ul><ul><li>Aspirin is rarely used now </li></ul><ul><li>Adverse effects :G I bleeding, ulcers, hepatoxicity, rash. </li></ul>
  14. 15. <ul><li>Selective cox-2 inhibitors : </li></ul><ul><li>Celecoxib100-200mg bd </li></ul><ul><li>Etoricoxib 90 mg od has highest selectivity ratio for inhibition of cox 2. & has superior efficacy compared with 500 mg naproxen bd over 12 weeks </li></ul><ul><li>Rafecoxib valdecoxib are obsolete now because of their cardiotoxicity </li></ul>
  15. 16. NSAID Therapy <ul><li>Disadvantages </li></ul><ul><li>Does not affect disease progression </li></ul><ul><li>GI toxicity common </li></ul><ul><li>Renal complications (eg, irreversible renal insufficiency, papillary necrosis) </li></ul><ul><li>Hepatic dysfunction </li></ul><ul><li> </li></ul><ul><li>Advantages </li></ul><ul><li>Effective control of inflammation and pain </li></ul><ul><li>Effective reduction in swelling </li></ul><ul><li>Improves mobility, flexibility, range of motion </li></ul><ul><li>Improve quality of life </li></ul><ul><li>Relatively low-cost </li></ul>
  16. 17. GLUCOCORTICOIDS <ul><li>Second line agents </li></ul><ul><li>Mostly combined with NSAIDS </li></ul><ul><li>Pharmacological actions </li></ul><ul><ul><li>Antiinflammatory & immunosuppressant action </li></ul></ul><ul><ul><li>Suppress signs & symptoms </li></ul></ul><ul><ul><li>Slow appearance of new bone erosions </li></ul></ul>
  17. 18. GLUCOCORTICOIDS <ul><li>PKs </li></ul><ul><li>Route: </li></ul><ul><ul><li>Oral </li></ul></ul><ul><ul><li>Intraarticular- transient symptomatic therapy when systemic therapy fails, don’t repeat before 4-6 months </li></ul></ul><ul><li>Dose </li></ul><ul><ul><li>Prednisolone- 7.5 mg/d, or equivalent </li></ul></ul><ul><ul><li>Reduce dose gradually </li></ul></ul>
  18. 19. GLUCOCORTICOIDS: ADRs <ul><li>Cushing’s habitus </li></ul><ul><li>Infections </li></ul><ul><li>Delayed healing </li></ul><ul><li>Peptic ulcers </li></ul><ul><li>Cataract </li></ul><ul><li>Glaucoma </li></ul><ul><li>Growth retardation </li></ul><ul><li>Muscle weakness </li></ul><ul><li>Mood changes </li></ul><ul><li>Osteoporosis </li></ul><ul><li>Hyperglycemia </li></ul>
  19. 20. Corticosteroid Therapy <ul><li>Disadvantages </li></ul><ul><li>Does not conclusively affect disease progression </li></ul><ul><li>Tapering and discontinuation of use often unsuccessful </li></ul><ul><li>Low doses result in skin thinning, ecchymoses, and Cushingoid appearance </li></ul><ul><li>Significant cause of steroid-induced osteopenia </li></ul><ul><li>Advantages </li></ul><ul><li>Anti-inflammatory and immunosuppressive effects </li></ul><ul><li>Can be used to bridge gap between initiation of DMARD therapy and onset of action. </li></ul><ul><li>Intra-articular injections can be used for individual joint flares </li></ul>
  20. 21. <ul><li>Disease modifying anti rheumatic dgs (DMARDs): </li></ul><ul><li>- Current recommendation is to add DMARDs as soon as the diagnosis is confirmed </li></ul><ul><li>-Slow acting, take 6wks to 6 months to show the effects. </li></ul><ul><li>-They modify/ alter disease progression </li></ul><ul><li>Commonly used DMARDs are -: </li></ul><ul><li>- Mehotrexate </li></ul><ul><li>- Sulphasalazine </li></ul><ul><li>- Chloroquine & Hydroxychloroquine </li></ul><ul><li>- Leflunomide </li></ul><ul><li>- cyclosporine </li></ul><ul><li>- Azathioprine </li></ul>
  21. 22. Advantages of DMARDs <ul><li>Slow disease progression </li></ul><ul><li>Improve functional disability </li></ul><ul><li>Decrease pain </li></ul><ul><li>Interfere with inflammatory processes </li></ul><ul><li>Retard development of joint erosions </li></ul>
  22. 23. Combination DMARD therapy <ul><li>MTX + SSZ </li></ul><ul><li>MTX + Hydroxychloroquine </li></ul><ul><li>MTX + cyclosporine </li></ul><ul><li>MTX + Leflunomide </li></ul><ul><li>Excellent safety & improved efficacy over MTX alone </li></ul>
  23. 24. Who should be put on combination of DMARDs? <ul><li>Failure to respond to > one DMARD / partial response </li></ul><ul><li>When to change? </li></ul><ul><li>- If response is not adequate / toxicity develops </li></ul>
  24. 25. How to combine two drugs? <ul><li>'step-up' approach : (easier to control ADR, may use only one drug in those who respond) </li></ul><ul><li>consisting of starting the patient on a first DMARD followed by the addition of a second if there is no adequate response </li></ul><ul><li>'step-down' approach : (better control in early RA) </li></ul><ul><li>in which initial combination therapy is followed by a reduction of the dose or the abandonment of one or more of the DMARDs. </li></ul>
  25. 26. <ul><li>Methotrexate: </li></ul><ul><li>Considered first choice to treat RA </li></ul><ul><li>MOA: it probably relates to inhibition of aminoimidazolecarboxamide ribonucleotide (AICAR) transformylase & thymidylate synthetase </li></ul><ul><li>It has secondary effects on PMN cells chemotaxis. </li></ul><ul><li>It has direct inhibitory effects on proliferation and stimulates apoptosis in immune - inflammatory cells </li></ul><ul><li>Orally 70% absorption </li></ul><ul><li>Dose 15-25 mg weekly, starting with 7.5 mg </li></ul>
  26. 27. <ul><li>Adverse effects of Methotrexate: </li></ul><ul><li>Nausea, mucosal ulcers. </li></ul><ul><li>Dose related hepatotoxicity. </li></ul><ul><li>Leucovorin used to reduce side effects. </li></ul><ul><li>Contraindicated in pregnancy. </li></ul>
  27. 28. <ul><li>Sulfasalazine: </li></ul><ul><li>It is metabolised to sulfapyridine & 5- aminosalicylic acid. </li></ul><ul><li>In treated arthritis patients, IgA & IgM rheumatoid factor production are decreased. </li></ul><ul><li>Suppression of T cell responses to concanavalin (glycoprotein that play role in cell cell interaction in inflammatory cell). </li></ul><ul><li>Inhibition of in vitro B cell proliferation. </li></ul><ul><li>Reduces radiologic disease progression. </li></ul>
  28. 29. <ul><li>Ad effects : N, V </li></ul><ul><li>headache </li></ul><ul><li>rash </li></ul><ul><li>Hemolytic anaemia </li></ul><ul><li>methemoglobinemia </li></ul><ul><li>Neutropenia </li></ul><ul><li>Pulmonary toxicity </li></ul><ul><li>Reversible infertility only in men. </li></ul><ul><li>Dose : 40 m g/kg/day </li></ul>
  29. 30. <ul><li>Chloroquine & Hydroxychloroquine </li></ul><ul><li>Proposed mech : </li></ul><ul><li>Suppresion of T lymphocytes response to mitogen </li></ul><ul><li>Decrease chemotaxis </li></ul><ul><li>Stablization of lysosomal enzymes </li></ul><ul><li>A/E: - N/V, abdominal pain, Rash </li></ul><ul><li>Retinitis : More with Chloroquine </li></ul><ul><li>CNS: convulsions </li></ul><ul><li>Cardiac depression </li></ul><ul><li>Dose :Chloroquine : 200 mg/day </li></ul><ul><li>Hydroxychloroquine : upto 6.4 mg/kg/day </li></ul>
  30. 31. <ul><li>Leflunomide: </li></ul><ul><li>MOA: its active metabolite ( A77-1726) inhibits dihydroorotate dehydrogenase and causes arrest of dividing T cells and inhibition of production of autoantibodies by B cells </li></ul><ul><li>in RA it is as effective as MTX </li></ul><ul><li>Inhibits bony damage </li></ul><ul><li>A/e diarrhoea, Hepatitis (FDA boxed warning), alopecia, wt gain, HTN </li></ul><ul><li>C/I : pregnancy </li></ul><ul><li>DOSE : 20mg/day </li></ul>
  31. 32. GOLD COMPOUNDS <ul><li>MOA: </li></ul><ul><li>Alters morphology & functional capabilities of macrophages </li></ul><ul><li>Inhibiting monocyte chemotactic factor-1, IL-8, 1 β & VEGF </li></ul><ul><li>Additionally </li></ul><ul><li>Alter lysosomal enzyme activity </li></ul><ul><li>Reduce histamine release from mast cells </li></ul><ul><li>Formulations- </li></ul><ul><li>Oral: auranofin (29% elemental gold) </li></ul><ul><li>I/M: aurothiomalate, aurothioglucose (50% elemental gold) </li></ul>
  32. 33. GOLD COMPOUNDS <ul><li>Dose : IM gold: Test dose of 5-25 mg & then 50 mg wkly for 20 wks </li></ul><ul><li>Oral gold: 6 mg daily in 1 or 2 doses </li></ul><ul><li>ADRs :-Pruritic skin rash, eosinophilia,Stomatitis & metallic taste,Aplastic anemia- rare, but fatal </li></ul><ul><li>Proteinuria (8-10% pts), nephrotic syndrome </li></ul><ul><li>Corneal gold deposition </li></ul><ul><li>Nitritoid rxns- sweating, flushing & headache, sp. with gold thiomalate </li></ul><ul><li>Rarely used now because of Questnable efficacy and high Toxicity </li></ul>
  33. 34. D-PENICILLAMINE <ul><li>A copper chelating agents </li></ul><ul><li>Gold like action in RA </li></ul><ul><li>Dose: Start with 125-250 mg OD, then 250 mg BD </li></ul><ul><li>ADRs : Same as gold </li></ul><ul><li>Other: loss of taste, SLE & Myasthenia gravis </li></ul><ul><li>Rarely used because of toxicity </li></ul><ul><li>OTHER drugs approved are Chlorambucil, Cyclophosphamide , Cyclosporine, Azathioprine </li></ul>
  34. 35. <ul><li>Biologic therapies, or biologics </li></ul><ul><li>Newer drugs that reduce RA inflammation in a more highly targeted manner than the DMARDs. These are used when there is inadequate response with the DMARDS </li></ul><ul><li>Biologics are made through biotechnology and target very specific proteins or cells that are involved in the inflammatory process. </li></ul><ul><li>Biologics have also been shown to help reduce the progression of joint damage in RA. </li></ul><ul><li>The currently available biologic therapies for RA must either be injected under the skin [etanercept, adalimumab, anakinra] or infused [infliximab, abatacept, and rituxumab]). </li></ul>
  35. 36. <ul><li>TNF α inhibitors </li></ul><ul><li>Etanercept: </li></ul><ul><li>MOA: it is recombinant fusion protein consisting of two soluble TNF p75 receptor moieties linked to Fc portion of human IgG1, it binds TNF α molecule </li></ul><ul><li>It decreases rate of formation of new erosion </li></ul><ul><li>DOSE: 25 mg twice weekly given s.c. </li></ul><ul><li>A/E </li></ul><ul><li>- Opportunistic infections, Activation of latent TB </li></ul>
  36. 37. <ul><li>Adalimumab </li></ul><ul><li>MOA: it is fully human IgG1 anti TNF monoclonal antibody complexes with soluble TNF α and prevents its interaction with cell surface receptors causing down regulation of macrophages and Tcell function </li></ul><ul><li>DOSE: 40 mg given every 2 weely given s.c. </li></ul><ul><li>Respiratory infection is a common a/e </li></ul><ul><li>Comb with MTX to improve response </li></ul>
  37. 38. <ul><li>Infliximab </li></ul><ul><li>MOA: it is chimeral IgG1 monoclonal antibody that binds with TNF α </li></ul><ul><li>DOSE: 3-10 mg/kg as an i.v. infusion every 8 weekly </li></ul><ul><li>Comb with MTX improves response and decreases rate of formtion of new erosions more than MTX alone </li></ul><ul><li>A/E: URTI, nausea, headache, sinusitis, rash, activation of latent TB </li></ul><ul><li>C/I: multiple sclerosis as demyelinating syndromes have been reported </li></ul>
  38. 39. TNf-  blocking agents More effective in combination with methotrexate Drug Primary action ROA Usual dose Half life Infliximab Chimeric anti TNF- Ab I/V inj. 3 mg/kg at 0,2,6 wks, then 8 wkly. Gradual ↑ to 10 mg/kg if incomplete response 9 days Etanercept Soluble TNF fusion protein, Binds TNF- α & β S/C inj. 25 mg twice/wk or 50 mg once/wk 4 days Adalimumab Human anti- TNF- α Ab S/C inj. 40 mg every 2 nd wk 2 wks
  39. 40. <ul><li>IL-1 ANTAGONIST </li></ul><ul><li>Anakinra - It is recombinant human IL-1 receptor antagonist. </li></ul><ul><li>Used in cases who have failed on others drugs. </li></ul><ul><li>A/e local reaction on s/c inj. & chest infection </li></ul><ul><li>Do not use in combination with TNF-alpha antagonists </li></ul>
  40. 41. IL-1R antagonists: ANAKINRA
  41. 42. IL-6 BLOCKING AGENT : TOCILIZUMAB <ul><li>IL-6 activation leads to systemic inflammatory manifestations and abnormal lab findings in patients with RA. </li></ul><ul><li>Tocilizumab is a Humanized anti IL-6 monoclonal Ab that specifically inhibits the action of 1L-6 </li></ul><ul><li>It is reserved for Resistant RA </li></ul>
  42. 43. <ul><li>Abatacept: </li></ul><ul><li>It is recombinant fusion protein. </li></ul><ul><li>MOA: inhibits activation of T cell </li></ul><ul><li>DOSE: depends on body wt it is given as i.v inj. </li></ul><ul><li><60 kg: 500mg </li></ul><ul><li>60-100 kg: 750 mg </li></ul><ul><li>>100kg: 1000mg. </li></ul>
  43. 44. <ul><li>Used when there is inadequate response to DMARDS </li></ul><ul><li>A/e : </li></ul><ul><li>Risk of infections </li></ul><ul><li>Hypersensitivity reaction </li></ul><ul><li>Unfortunately not all patients respond sufficiently to TNF blockade and some of the patients become unresponsive to TNF-blocking agents. </li></ul>
  44. 45. B CELL DEPLETION THERAPY <ul><li>Targeting B-lymphocytes in these patients has opened a new therapeutic window </li></ul><ul><li>Rituximab </li></ul><ul><li>Chimeric monoclonal Ab, targets CD20 B cells </li></ul><ul><li>Used in resistant RA . Benefit in treatment of RA refractory to antiTNF agents </li></ul><ul><li>Combination therapy with methotrexate </li></ul><ul><li>Dose: 2 IV infusions 2 wks apart </li></ul><ul><li>ADRs: Mild infusion reactions (infrequent) </li></ul>
  45. 46. BIOLOGICS : FUNCTION AT A GLANCE
  46. 47. Adverse Effects of Biologics <ul><li>Infusion related : dyspnoea , chest pain , rash, hypotension </li></ul><ul><li>Serious Infections </li></ul><ul><ul><li>TB : Activation of latent TB </li></ul></ul><ul><ul><li>Skin and soft tissue </li></ul></ul><ul><li>Malignancy ? Lymphoma,? Solid Tumors </li></ul><ul><li>OTHERS </li></ul><ul><li>Optic neuritis, demyelination , Cytopenias, Increase LFT, ILD, Vasculitis; </li></ul><ul><li>Pregnancy: stop before 3 months </li></ul><ul><li>No live vaccines should be given </li></ul>
  47. 48. SURGICAL TREATMENT <ul><li>Reserved for pts with severely damaged joints </li></ul><ul><li>Includes </li></ul><ul><li>Arthroplasty/Total joint replacement </li></ul><ul><li>Open/arthroscopic synovectomy </li></ul><ul><li>Reconstructive hand surgery </li></ul>
  48. 49. FUTURE PROSPECTIVES compound MOA Development phase USA EU TNF inhibitors CDP-870 Anti-TNF Ab fragment III III Pegsunercept Pegylated soluble TNF R type 1 II ISIS-104838 TNF-  antisense inhibitors II AGIX4207 TNF inhibitor (oral) II II IL based therapies Atlizumab Humanized anti-IL6 R monoclonal Ab II I HuMAX-IL-15/AMG-714 Anti-IL-15 monoclonal Ab II II ABT-874/J-695 Anti-IL-12 monoclonal Ab II II
  49. 50. FUTURE PROSPECTIVES Compound MOA Development phase USA EU Cell adhesion molecule inhibitors Natalizumab Humanized monoclonal Ab II II Co-stimulation inhs CTLA4-Ig CD27/B7 pathway inhibitor III Alefacept CD2 antagonist II
  50. 51. FUTURE PROSPECTIVES Immunoadsorption Apheresis – new technique used in pts who are not responding to drug therepy Compound MOA Development phase USA EU Other therapies CCI-779/ Temsirolimus Cell cycle inhibitor II Belimumab Ab against B cell stimulator protein II AT-001/dnaJp1 Heat shock derived protein II
  51. 52. <ul><li>FDA Adds Boxed Warning To Leflunomide For Severe Liver Injury </li></ul><ul><li>July 13, 2010 — The rheumatoid arthritis drug leflunomide has received a boxed warning about the risk for severe liver injury. </li></ul><ul><li>The FDA identified 49 cases of severe liver injury associated with the drug, including 14 cases of fatal liver failure. </li></ul>
  52. 54. <ul><li>Summary </li></ul><ul><li>Rheumatoid arthritis is a common autoimmune disease that can lead to serious functional limitations, joint destruction, extra-articular disease, poor quality of life, and premature death </li></ul><ul><li>Early recognition of arthritis and speedy referral to a rheumatologist are essential </li></ul><ul><li>Treatment should start early and aggressively to prevent functional limitations and structural damage </li></ul><ul><li>Innovations in treatment and monitoring have resulted in patients achieving early and sustained clinical and radiographic remission </li></ul><ul><li>Methotrexate is the first line drug, but in high risk patients early combination of methotrexate with prednisone or a tumour necrosis factor inhibitor improves outcomes </li></ul>
  53. 55. <ul><li>Thanks…… </li></ul>

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