A presentation on Rheumatoid arthritis and management

A presentation on Rheumatoid arthritis.

1. Lecture- 21 Lecture Title Rheumatoid Arthritis Lecture speaker Mr. Subeesh K Viswam

2. Objectives At the end of this lecture, student will be able to: Explain different treatment options for rheumatoid arthritis Identify suitable lifestyle modification required for rheumatoid arthritis

3. Treatment goals The ultimate goal is to achieve complete disease remission, although this goal is hardly ever achieved Additional goals include Controlling disease activity and joint pain Maintaining the ability to function in daily activities or work Improving the quality of life Slowing destructive joint changes

4. Includes pharmacologic and nonpharmacologic therapies. Nonpharmacologic therapy Rest (relieves stress on inflamed joints) Occupational therapy (skills and exercises) Physical therapy Use of assistive devices Weight reduction Surgery Treatment

5. Pharmacologic Therapy A disease-modifying antirheumatic drug (DMARD) should be started within the first 3 months of onset of symptoms of rheumatoid arthritis provides more favorable outcome NSAIDs and/or corticosteroids may be used for symptomatic relief if needed They provide relatively rapid improvement in symptoms compared with DMARDs DMARDs may take weeks to months for any benefit NSAIDs have no impact on disease progression, and corticosteroid use carries a long-term risk of complications

6. Treatment Commonly used DMARDs include methotrexate, hydroxychloroquine , sulfasalazine, and leflunomide The biologic agents that have also been demonstrated to have disease-modifying activity include The anti-TNF drugs The interleukin-1–receptor antagonist, anakinra Less frequently used are azathioprine, d-penicillamine, gold (including auranofin), minocycline, cyclosporine, and cyclophosphamide This is due to either less efficacy, high toxicity, or both

7. Treatment Leflunomide appears to have similar long-term efficacy as that of methotrexate The biologic agents have proven effective for patients who fail treatment with other DMARDs Infliximab should be given in combination with methotrexate to prevent development of antibodies that may reduce drug efficacy or induce allergic reactions Combination therapy with two or more DMARDs may be effective when single-DMARD treatment is unsuccessful

8. Treatment NSAIDs and/or corticosteroids may be used for symptomatic relief if needed They provide relatively rapid improvement in symptoms compared with DMARDs It may take weeks to months before benefit is seen NSAIDs have no impact on disease progression and the long-term complication risk of corticosteroids make them less desirable Early treatment with DMARDs can reduce mortality Patients with RA have increased mortality compared to people without the disease

9. Treatment DMARDs including biologic agents should be used in all patients except those with limited disease DMARDs commonly used include methotrexate, hydroxychloroquine , sulfasalazine, and leflunomide The biologic agents that have disease-modifying activity include the anti-TNF drugs ( etanercept , infliximab, adalimumab , certolizumab , golimumab ), the costimulation modulator abatacept , and rituximab, which depletes peripheral B cells

10. Treatment Less frequently used are the IL-1 receptor antagonist anakinra, azathioprine, d -penicillamine, gold (including auranofin), minocycline, cyclosporine, and cyclophosphamide This is due to either less efficacy, high toxicity, or both The order in which the first-line agents are used is not clearly defined, although methotrexate is often chosen because long-term data suggests superior outcomes with methotrexate than with other DMARDs and a lower cost than biologic agents

11. Treatment Leflunomide appears to have similar long-term efficacy as that of methotrexate The biologics have proven effective for patients who fail treatment with other DMARDs Infliximab should be given in combination with methotrexate to prevent development of antibodies that may reduce drug efficacy or induce allergic reactions Methotrexate during combination with other biologics is more effective than biologic monotherapy and the combination is frequently used

12. Treatment Combination therapy with two or more DMARDs may be effective when single-DMARD treatment is unsuccessful One study suggests that the initial combination therapy with either methotrexate, sulfasalazine plus prednisone infliximab plus methotrexate were superior to more conventional sequential monotherapy or step-up combinations of DMARDs in early rheumatoid arthritis

13. Treatment For patients with moderate to high disease activity Nonbiologic and biologic dmards are dual DMARD combinations of methotrexate plus hydroxychloroquine Methotrexate plus leflunomide, or methotrexate plus sulfasalazine Also recommend the triple combination of sulfasalazine, hydroxychloroquine, and methotrexate

14. Treatment Corticosteroids can be used in various ways They are valuable in controlling symptoms before the onset of action of DMARDs A burst of corticosteroids can be used in acute flares Continuous low doses may be adjuncts when DMARDs do not provide adequate disease control Corticosteroids may be injected into joints and soft tissues to control local inflammation Corticosteroids seldom should be used as monotherapy

15. Treatment There are data to suggest they have disease-modifying activity It is preferable to avoid chronic use when possible to avoid long-term complications NSAIDs and DMARDs have steroid-sparing properties that permit reductions of corticosteroid doses As immunosuppression may reduce the ability to mount an antibody response, the need for immunizations should be assessed, and these should be administered if needed before nonbiologic or biologic DMARDs are started

16. Treatment Post vaccination antibody titters seem to be only minimally affected by conventional DMARDs and TNF antagonists Rituximab and abatacept seem to reduce the ability to develop antibodies after vaccination Live vaccines are not recommended for patients taking biologic DMARDs Postvaccination antibody titers seem to be only minimally affected by conventional DMARDs and TNF antagonists Rituximab and abatacept seem to reduce the ability to develop antibodies after vaccination

17. Treatment Nonsteroidal Antiinflammatory Drugs NSAIDs should seldom be used as monotherapy for rheumatoid arthritis because they do not alter the course of the disease; instead, they should be viewed as adjuncts to DMARD treatment NSAIDs possess both analgesic and antiinflammatory properties and reduce stiffness associated with RA NSAIDs mainly inhibit prostaglandin synthesis, which is only a small portion of the inflammatory cascade

18. Treatment Methotrexate Methotrexate is now considered the nonbiologic DMARD of choice by many rheumatologists for treating RA In psoriatic arthritis it not only treats the joint symptoms but also improves the skin disease for most patients Methotrexate is contraindicated in pregnant and nursing women

19. Treatment It is also contraindicated in patients with Chronic liver disease Immunodeficiency Pleural or peritoneal effusions Leukopenia Thrombocytopenia Preexisting blood disorders A creatinine clearance of less than 40 ml/min Absorption of methotrexate is variable and averages approximately 70% of an oral dose

20. Treatment Methotrexate is extensively metabolized intracellularly to polyglutamated derivatives It is excreted by the kidney, 80% unchanged, by glomerular filtration and active transport Some methotrexate may be reabsorbed, but this transport process may be saturated even with low doses, resulting in increased renal clearance Methotrexate inhibits cytokine production, inhibits purine biosynthesis, and may stimulate release of adenosine, all of which may lead to its antiinflammatory properties

21. Treatment The drug has a fairly rapid onset of action; results may be seen as early as 2 to 3 weeks after starting therapy Some 45% to 67% of patients remain on methotrexate therapy in studies ranging from 5 to 7 years Methotrexate may be given intramuscularly, subcutaneously, or orally Doses greater than 15 mg per week generally are given parenterally because of decreased oral bioavailability of larger doses

22. Treatment The toxicities of methotrexate therapy are mainly gastrointestinal, hematologic, pulmonary, and hepatic Stomatitis occurs in 3% to 10% of patients and may be painful or painless. Diarrhea , nausea, and vomiting may occur in up to 10% of patients The most common hematologic toxicity is thrombocytopenia in 1% to 3% of patients Leukopenia also may occur, but in a smaller number of patients Pulmonary fibrosis and pneumonitis can be severe adverse effects, they are rare

23. Treatment Elevated liver enzymes may occur in up to 15% of patients; cirrhosis is rare Liver function tests, aspartate aminotransferase or alanine aminotransferase, should be performed periodically Methotrexate should be discontinued if these test values show sustained results greater than twice the upper limits of normal

24. Treatment Biopsies during methotrexate therapy are recommended only for patients who develop consistently abnormal liver function tests Because the drug is teratogenic, patients should use contraception to avoid pregnancy and discontinue the drug if conception is planned Because it is a folic acid antagonist, methotrexate 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

25. Treatment Leflunomide Leflunomide is a DMARD that inhibits pyrimidine synthesis, leading to a decrease in lymphocyte proliferation and modulation of inflammation It is given as a loading dose of 100 mg daily for 3 days, followed by a maintenance dose of 20 mg daily Lower doses may be used if patients have gastrointestinal intolerance, complain of hair loss, or have other signs of dose-related toxicity

26. Treatment The loading dose allows the patient to achieve a more rapid therapeutic response, usually within the first month The long elimination half-life of the drug (14–16 days) would require the patient to take the drug for several months to achieve steady state without a loading dose Some rheumatologists prefer to begin with maintenance dosing as the loading dose may put the patient at increased risk for toxicity

27. Treatment Leflunomide has efficacy similar to methotrexate for treating RA The drug may cause liver toxicity and is contraindicated in patients with preexisting liver disease Patients taking the drug should have alanine aminotransferase monitored monthly initially and periodically thereafter as long as they continue treatment Leflunomide may cause bone marrow toxicity and complete blood count with platelets is recommended monthly for 6 months and then every 6 to 8 weeks thereafter

28. Treatment The drug is teratogenic, and appropriate contraceptive measures are recommended to avoid pregnancy for all sexually active male and female patients who are taking leflunomide If conception is desired, leflunomide must be discontinued Leflunomide undergoes enterohepatic circulation, the drug takes many months to drop to a plasma concentration considered safe during pregnancy (<0.02 μ g/mL [<0.02 mg/L; 74 nmol/L])

29. Treatment Cholestyramine may be used to rapidly clear the drug from plasma In addition to pregnancy, cholestyramine use may be warranted to rapidly clear the drug in the event of severe toxicity Hydroxychloroquine The pharmacokinetics of hydroxychloroquine are poorly understood It is well absorbed orally and widely distributed to body tissues Hydroxychloroquine is partially metabolized in the liver and is excreted by the kidney

30. Treatment The onset of action of hydroxychloroquine may be delayed up to 6 weeks But the drug is considered a therapeutic failure only when 6 months of therapy without a response has elapsed The main advantage of hydroxychloroquine is the lack of myelosuppressive, hepatic, and renal toxicities that may be seen with other DMARDs, which simplifies monitoring Short-term toxicities of hydroxychloroquine include gastrointestinal effects such as nausea, vomiting, and diarrhea , which can be managed by taking doses with food

31. Treatment Ocular toxicity includes Accommodation defects Benign corneal deposits Blurred vision Scotomas (small areas of decreased or absent vision in the visual field) Night blindness Although the risk of true retinopathy with hydroxychloroquine approaches zero, preretinopathy may occur in 2.7% of patients

32. Treatment Sulfasalazine Sulfasalazine, a prodrug, is cleaved by bacteria in the colon into sulfapyridine and 5-aminosalicylic acid Sulfapyridine moiety is responsible for the agent’s antirheumatic properties, although the exact mechanism of action is unknown Once the colonic bacteria have cleaved sulfasalazine, sulfapyridine and 5-aminosalicylic acid are absorbed rapidly from the gastrointestinal tract

33. Treatment Sulfapyridine distributes rapidly throughout the body, but higher concentrations are found in certain tissues such as serous fluid, liver, and intestines Both sulfasalazine and its metabolites are excreted in the urine Antirheumatic effects should be seen in 2 months Use of sulfasalazine is often limited by its adverse effects Gastrointestinal adverse effects such as nausea, vomiting, diarrhea,and anorexia are the most common

34. Treatment These can be minimized by initiating therapy with low doses and titrating gradually to higher doses, dividing the dose more evenly throughout the day, or using enteric-coated preparations Rash, urticaria , and serum sicknesslike reactions can be managed with antihistamines and, if indicated, corticosteroids If a hypersensitivity reaction occurs, therapy should be stopped immediately and another DMARD substituted

35. Treatment Sulfasalazine is associated with leukopenia, alopecia, stomatitis, and elevated hepatic enzymes It also may cause the patient’s urine and skin to turn a yellow-orange color , which is of no clinical consequence however; patients should be educated about this to avoid premature discontinuance Sulfasalazine’s absorption can be decreased when antibiotics are used that destroy the colonic bacteria Sulfasalazine also binds iron supplements in the gastrointestinal tract that can lead to a decreased absorption of sulfasalazine

36. Treatment The administration of these two agents should be separated temporally to avoid this interaction Sulfasalazine can potentiate warfarin’s effects by displacing it from protein-binding sites Close monitoring of the patient’s international normalized ratio is indicated Minocycline The tetracycline derivative minocycline has been suggested as a treatment alternative for patients with RA who have low disease activity and without features of poor prognosis

37. Other Disease-Modifying Antirheumatic Drugs Biologic Agents TNF- α Inhibitors Congestive heart failure (CHF) is a relative contraindication for anti-TNF agents Increased cardiac mortality has been seen in patients treated with infliximab and etanercept -associated heart failure exacerbations have been documented Patients with a history of uncompensated CHF or recent hospital admissions for CHF should not use anti–TNF- α therapy

38. Treatment Patients whose CHF worsens while taking anti–TNF- α therapy should discontinue the drug Anti–TNF- α therapy has been reported to induce a multiple sclerosis- like illness or exacerbate multiple sclerosis in patients with the disease Patients with neurologic symptoms suggestive of multiple sclerosis should discontinue therapy TNF inhibitors may predispose patients to increased cancer risk, especially lymphoproliferative cancer, as TNF plays a role in ridding the body of cancer cells

39. Treatment Etanercept Etanercept is a fusion protein consisting of two p75- soluble TNF receptors linked to an Fc fragment of human IgG 1 The drug binds to TNF, making it biologically inactive and preventing it from interacting with the cell-surface TNF receptors that would lead to cell activation The drug is given by subcutaneous injection, 50 mg once weekly or 25 mg twice weekly, usually through self-injections or administration by a caregiver

40. Treatment Aside from local injection-site reactions, adverse effects are rare There are case reports of pancytopenia and neurologic demyelinating syndromes like multiple sclerosis associated with use of etanercept , but these are rare. No laboratory monitoring is required Infliximab Infliximab is a chimeric antibody combining portions of mouse and human IgG 1 An anti-TNF antibody was created by exposing mice to human TNF

41. Treatment The binding portion of that antibody was fused to a human constant-region IgG 1 to reduce the antigenicity of the foreign protein This antibody, when injected in humans, binds to TNF and prevents its interaction with TNF receptors on inflammatory cells Infliximab is given by intravenous infusion at a dose of 3 mg/kg at 0, 2, and 6 weeks and then every 8 weeks

42. Treatment To prevent the formation of antibodies to this foreign protein, methotrexate should be given orally in doses typically used to treat RA for as long as the patient continues on infliximab Antibodies develop in 7% to 15% of patients, which leads to a greater risk of infusion reactions and also may reduce the efficacy of the drug Loss of response may be seen in patients with RA who have good initial response requiring increased doses or shorter intervals between doses to maintain response

43. Treatment Infusion reactions may occur in any patient treated with the drug. Both acute (within 24 hours of infusion) and delayed (24 hours to 14 days) reactions following infusion have been identified An acute infusion reaction with symptoms including fever, chills, pruritus, and rash may occur during infusion or within 1 to 2 hours after giving the drug Treatment includes slowing infusion rates and administering acetaminophen, diphenhydramine, or corticosteroids, depending on the severity of symptoms

44. Treatment Fortunately these reactions are rarely severe or anaphylactic in nature. The drug may increase risk of infection Adalimumab Adalimumab is a human IgG 1 antibody to TNF Because it has no foreign protein components, it is less antigenic than infliximab The drug is provided as either premixed syringes or injection pens containing 40 mg, which is administered by subcutaneous injection every 14 days

45. Treatment It has similar response rates to those seen with the other TNF inhibitors Local injection-site reactions were the most common adverse reactions noted in clinical trials It has the same precautions regarding tuberculosis and other infections as the other biologics

46. Treatment Golimumab Golimumab is a human antibody to TNF- α In addition to RA, this agent is also indicated for treatment of psoriatic arthritis and ankylosing spondylitis The drug is available as an injection pen, through which doses of 50 mg is given monthly by subcutaneous injection Precautions are similar to other TNF- α inhibitors

47. Treatment Certolizumab Certolizumab is a humanized antibody specific for human TNF- α For RA, dosing recommendations are for 400 mg (2 doses of 200 mg) given by subcutaneous injection at weeks 0, 2, and 4 followed by 200 mg every 2 weeks Precautions and side effects are similar to other TNF- α inhibitors

48. Treatment Abatacept Abatacept is a costimulation modulator approved for the treatment of RA in patients with moderate to severe disease who fail to achieve an adequate response from one or more DMARDs

49. Treatment The adverse effects include Headache Nasopharyngitis Dizziness Cough Back pain Hypertension Dyspepsia Urinary tract infection Rash, and extremity pain reported more frequently than placebo in clinical trials

50. Treatment In patients who failed to achieve adequate responses with TNF- α inhibitors, half had a clinical response to abatacept Live vaccines should not be given to patients during and for 3 months after the completion of abatacept therapy Rituximab Rituximab is a monoclonal chimeric antibody consisting of mostly human protein with the antigen-binding region

51. Treatment The binding of rituximab to B cells results in nearly complete depletion of peripheral B cells, with a gradual recovery over several months The prolonged effect on B cells results in a duration of action that allows for intermittent therapy which varies based on reactivation of arthritis symptoms Rituximab is useful in patients who failed methotrexate or TNF inhibitors

52. Treatment Acetaminophen and antihistamines may also be of benefit in patients who have a history of reactions Methotrexate should be given concurrently in the usual doses used for RA, as the combination has proved to provide the best therapeutic outcomes Duration of benefit is variable after a course of rituximab and patients will need retreatment with reactivation of their disease The drug is currently FDA approved for TNF inhibitor treatment failures

53. Treatment Live vaccines should not be given to patients given rituximab Tocilizumab IL-6 is a major cytokine believed to have a role in promoting inflammation in RA Tocilizumab attaches to IL-6 receptors, which prevents the cytokine from interacting with cells. In clinical trials, 4 to 8 mg/kg was given intravenously every 4 weeks It has been used as monotherapy or in combination with methotrexate

54. Treatment Infusion reactions and increased infection risk have been reported Additionally, increased plasma lipids have been reported in tocilizumab -treated patients Anakinra Anakinra is a naturally occurring IL-1 receptor antagonist Results of clinical trials suggest it to be less effective than other biologic DMARDs

55. Treatment Treatment Strategies for Patients with Suboptimal Response to Biologics TNF- α antagonists are generally the first biologic agents chosen for use in patients with RA Approximately 30% of patients discontinue treatment with these drugs because of lack of efficacy or adverse effects In such situations, addition of a nonbiologic DMARD may be beneficial if the patient is not already taking one

56. Treatment Dose escalation or decreased interval between infusions may be useful for those patients taking infliximab Higher doses of other TNF- α inhibitors have not been demonstrated to be effective Choosing an alternative TNF- α inhibitor may be beneficial for some patients Treatment with rituximab or abatacept may also prove to be effective in TNF- α treatment failures Combination biologic DMARD therapy is not recommended because of the increased risk for infection

57. Summary There is no cure for RA, but treatments can improve symptoms and slow the progress of the disease. Disease-modifying treatment has the best results when it is started early and aggressively The goals of treatment are to minimize symptoms such as pain and swelling, to prevent bone deformity (for example, bone erosions visible in X-rays), and to maintain day-to-day functioning This can often be achieved using two main classes of medications: analgesics such as NSAIDs, and disease-modifying antirheumatic drugs (DMARDs)

58. Summary RA should generally be treated with at least one specific anti-rheumatic medication The use of benzodiazepines (such as diazepam) to treat the pain is not recommended as it does not appear to help and is associated with risks Analgesics, other than NSAIDs, offer lesser, but some benefit with respect to pain whilst not causing the same level of gastrointestinal irritation