Rheumatoid arthritis

rheumatoid arthritis

1. Pharmacotherapy of Rheumatoid Arthritis(RA) Dr Shinde Viraj Ashok Junior Resident -2 Dept. of Pharmacology GMC Nagpur

2. Overview

3. Definition Is a autoimmune disease in which there is joint inflammation , synovial proliferation and destruction of articular cartilage

4. Pathogenesis Immune complexes composed of IgM activate complement and release cytokines – chemotactic to neutrophils Inflammatory cells secrete lysosomal enzymes which damage cartilage and erode bone while prostaglandins cause vasodilatation and pain Chronic progressive , crippling disorder with a waxing and waning course

5. Pathogenesis of rheumatoid arthritis. The figure summarises some of the cytokines and cellular interactions believed to be important in RA. The molecular targets for biologic agents currently used in the treatment of RA are shown. It is thought that TNF plays a particularly important role by orchestrating production of other cytokines. (IL = interleukins; MMP = matrix metalloproteinases ; PGE = prostaglandin E; TCR = T-cell receptor; TNF = tumour necrosis factor; VEGF = vascular endothelial growth factor)

6. Role of Non Steroidal Anti Inflammatory Drugs(NSAIDs) First line drugs afford symptomatic relief in pain , swelling , morning stiffness , immobility Relatively rapid improvement compared with Disease modifying antirheumatic drugs (DMARDs), which may take weeks to months before benefit is seen No impact on disease progression

7. Pharmacotherapy Goals of Treatment : To induce complete remission or low disease activity To control Disease activity & joint pain Maintain ability to function in daily activities Slow destructive joint changes & Delay disability

8. Classification Disease modifying antirheumatic drugs (DMARDs) Non biological drugs Immunosuppressants – Methotrexate , Azathioprine , Cyclosporine Sulfasalazine Chloroquine or Hydroxychloroquine Leflunomide Biological agents TNF α inhibitors : Etanercept , Infliximab , Adalimumab IL- 1 antagonist : Anakinra Adjuvant drugs Corticosteroids : Prednisolone and others

9. PHARMACOLOGIC THERAPY General Approach After disease onset - Start disease modifying antirheumatic drugs (DMARDs) - Early treatment results in more favourable outcomes - Slow RA disease progression MTX - Long-term data suggest superior outcomes compared with other DMARDs and lower cost than biologic agents

10. Nonbiologic DMARD Methotrexate Dihydrofolate reductase inhibitor Inhibits Cytokine production Purine biosynthesis Stimulate adenosine release DMARD of first choice

11. Methotrexate Oral low dose (7.5 – 15mg) weekly – improved acceptability of this drug Onset - early as 4 to 6 weeks Contraindicated Pregnant and nursing women Chronic liver disease Creatinine clearance of less than 40 ml/min

12. Methotrexate Oral bioavailability – variable & affected by food Probenecid & aspirin increases its levels and toxicity Adverse events – oral ulceration and gastrointestinal upset

13. Azathioprine 6-Thioguanine – major metabolite - Suppresses inosinic acid synthesis , B-cell and T-cell function, immunoglobulin production and interleukin-2 secretion Adverse effects - Bone marrow suppression, GI disturbances , & some increase in infection risk Dose – 50 - 150mg/day Primarily used - Steroid sparing effect

14. Leflunomide Immunomodulator – inhibits proliferation of stimulated lymphocytes Rapidly converted to active metabolite – inhibits dihydroorotate dehydrogenase & pyrimidine synthesis in actively dividing cells Arthritic symptoms are suppressed and radiological disease progression is retarded Efficacy rated comparable to methotrexate

15. Leflunomide Onset of action – 4 weeks Active metabolite has long t 1/2 Loading dose 100mg daily for 3 days followed by 20mg OD Contraindicated Preexisting liver disease Pregnancy

16. Chloroquine & Hydroxychloroquine Induce remission in 50% patients of rheumatoid arthritis Used in mild RA or Especially when one or few joints are involved or Adjuvant in combination DMARD therapy

17. Chloroquine & Hydroxychloroquine Onset delayed for up to 6weeks Therapeutic failure – 6 months of therapy with no response Hydroxychloroquine preferred over chloroquine Periodic ophthalmologic examination - early detection of reversible retinal toxicity Dose – Chloroquine 150mg/day Hydroxychloroquine 400mg /day for 4 -6 weeks fb 200mg for maintenance

18. Sulfasalazine Antirheumatic effects - Seen within 2 months Efficacy in RA is modest Side effetcs are unpleasant – neutropenia thrombocytopenia in 10 % patients and hepatitis Used as second line drug for milder cases or is combined with methotrexate Dose – 1 – 3 gm /day

19. Tofacitinib Nonbiologic JAK inhibitor Moderate to severe RA - Failed or have intolerance to MTX Labeling includes black-box warnings Serious infections Lymphomas Live vaccinations – should not be given

20. Gold – auranofin d – Penicillamine No longer used drugs Due to Higher toxicity Replacement by better drugs

21. Biologic agents

22. Tumour Necrosis Factor (TNF) Potent inflammatory cytokine Produced mainly by macrophages and monocytes Major contributor to the inflammatory and destructive changes that occur in RA Blockade of TNF results in a reduction in a number of other pro-inflammatory cytokines (IL-1, IL-6, & IL-8)

23. Macrophage Any Cell Trans-Membrane Bound TNF TNF Receptor Soluble TNF How Does TNF Exert Its Effect?

24. Trans-Membrane Bound TNF Soluble TNF Strategies for Reducing Effects of TNF Macrophage Monoclonal Antibody

25. Biologic DMARDs Used when non biologic DMARDs fail Considerably more expensive TNF- α inhibitors First biologic DMARDs used Combination biologic DMARD - Not recommended ↑ sed infection risk (tuberculosis and pneumocystis pneumonia) Congestive heart failure (HF)- Relative contraindication

26. Mechanism of action Suppress macrophage and T cell function Regression of Inflammatory changes in joint & new erosions are slowed

27. Etanercept Recombinant fusion protein of TNF receptor and Fc portion of human Ig G Slows erosive disease progression more than oral MTX Patients with inadequate response to MTX monotherapy Dose – subcutaneous injection of 50mg weekly

28. Infliximab ( Remicade ) Chimeric anti-TNF antibody fused to a human constant - region IgG Combination of infliximab and MTX - Halt progression of joint damage - Superior to MTX monotherapy -Improves response and decreases antibody formation against infliximab Acute infusion reaction Autoantibodies and lupus-like syndrome have also been reported Dose – 3-5mg /kg iv every 4-8weeks

29. Adalimumab Recombinant monoclonal anti TNF antibody Subcutaneous 40mg every 2weeks Combination with Mtx improves response and decreases antibody formation

30. Certolizumab Recombinant humanised antibody Fab fragment conjugated to a polyethylene glycol (PEG) with specificity for human TNF α Half life of 14 days Methotrexate ↓ appearance of anticertolizumab antibodies Used in moderate to severe rheumatoid arthritis

31. Golimumab Human monoclonal antibody with high affinity for soluble and membrane bound TNF α Half life – 14 days Concomittant use with methotrexate ↑ its serum levels & ↓anti golimumab antibodies Dose – subcutaneous 40mg every 4 weeks Used alongwith methotrexate in modertate to severe rheumatoid arthritis

32. IL -1 antagonist

33. Anakinra IL-1 receptor antagonist Clinically less effective than TNF inhibitors - used in cases – failed on one or more DMARDs Dose – 100mg subcutaneously Main adverse effects Local reaction Chest infections

34. Abatacept Binds to CD80/CD86 receptors on antigen-presenting cells Inhibits interactions between antigen-presenting cells and T cells Used in refractory RA

35. Rituximab Monoclonal chimeric antibody Binding of rituximab to B cells - Nearly complete depletion of peripheral B cells Useful in patients failing MTX or TNF inhibitors Methylprednisolone 100 mg 30 minutes prior to rituximab to reduce incidence and severity of infusion reactions

36. Tocilizumab Attaches to IL-6 receptors Preventing cytokine from interacting with IL-6 receptors Moderately to severely active RA who have failed to respond to one or more anti-TNF biologic agents Monotherapy or in combination with MTX or another DMARD

37. Corticosteroids

38. Corticosteroids Anti-inflammatory and immunosuppressive properties Long term use carries serious disadvantages. Therefore either Low doses (5 -10mg) used to supplement NSAIDS Higher doses are employed for shorter periods in cases severe systemic manifestation while patient awaits response from remission inducing drug

39. Intramuscular route – Preferable in nonadherent patients Depot forms (triamcinolone acetonide , triamcinolone hexacetonide , and methylprednisolone acetate) Provide 2 to 6 weeks of symptomatic control Onset of effect may be delayed for several days

40. Intra-articular injections Depot forms useful - Only a few joints are involved Do not inject any one joint more than two or three times per year

41. Standard treatment protocol Methotrexate - DMARD of first choice - Initial treatment of moderate-to-severe RA Failure to achieve adequate improvement with methotrexate therapy - Consideration for an effective combination regimen Effective combinations include : Methotrexate, sulfasalazine, and hydroxychloroquine (triple therapy) Methotrexate and leflunomide Methotrexate plus a biological

42. Combination of methotrexate and an anti-TNF agent Randomized, controlled trials to be superior to methotrexate alone Reducing signs and symptoms of disease For retarding progression of structural joint damage.

43. Some patients may not respond to an anti-TNF drug or be intolerant of its side effects. Initial responders to an anti-TNF agent that later worsen may benefit from switching to another anti-TNF agent. Other biologicals - abatacept and rituximab, may also be considered for treatment - disease refractory to anti-TNF therapy. Addition of abatacept or rituximab to background methotrexate therapy – In well-designed clinical trials Effective for reducing signs and symptoms of joint inflammation and slowing radiographic progression of disease.

44. OTHER MANAGEMENT CONSIDERATIONS Pregnancy Up to 75% of female RA patients - overall improvement in symptoms - during pregnancy Will often flare post-delivery Flares during pregnancy - Low doses of prednisone ; hydroxychloroquine and sulfasalazine (probably safest DMARDs to use during pregnancy) Methotrexate and leflunomide - Contraindicated during pregnancy (due to their teratogenicity in animals and humans) Experience with biologic agents - Insufficient to make specific recommendations for their use during pregnancy.

45. Elderly Patients RA - Up to one-third of patients after age of 60 Recognized that older individuals - Receive less aggressive treatment due to concerns about increased risks of drug toxicity Studies suggest - Conventional DMARDs as well as biologic agents - Equally effective and safe in younger and older patients

46. Due to comorbidities - ↑ risk of infection Aging – ↓ in renal function may raise risk for side effects from NSAIDs and some DMARDS, such as methotrexate Methotrexate - not prescribed for patients with a serum creatinine greater than 2 mg/dl

47. NON PHARMACOLOGIC THERAPY Adequate rest Weight reduction - if obese Occupational therapy Physical therapy Use of assistive devices may improve symptoms and help maintain joint function Patients with severe disease may benefit from surgical procedures such as Teno synovectomy Tendon repair Joint replacements Patient education about disease and benefits and limitations of drug therapy is important

48. Summary NSAIDS – Provide symtomatic relief Used in mild or early cases DMARDs Retard disease progression To be started as soon as diagnosis RA confirmed In early or mild cases of RA benefits should be weighed agaist adverse effects Corticosteroids Low doses – to supplement NSAIDs High doses – for systemic manifestation

49. References Goodman & Gilman’s The Pharmacological Basis of Therapeutics 12 th edition Katzung Basic and Clinical Pharmacology 12 th edition Harrison's Principles of Internal Medicine, 18e

50. Algorithm for treatment of rheumatoid arthritis in early disease.

51. DMARDs - less frequently used include Anakinra (IL-1 receptor antagonist) Azathioprine Penicillamine Gold salts (including auranofin ) Minocycline Cyclosporine Cyclophosphamide Less efficacy or higher toxicity, or both

52. Algorithm for treatment of rheumatoid arthritis in established disease (>6 months).

53. Biologic DMARDs include Anti-TNF agents Etanercept Infliximab Adalimumab Certolizumab Golimumab Costimulation modulator - Abatacept IL-6 receptor antagonist Tocilizumab Rituximab Biologic DMARDs - Proven effective for patients failing treatment with non biologic DMARDs