Rheumatoid arthritis and management

RA

1. RHEUMATOID ARTHRITIS AND MANAGEMENT

2. RHEUMATOID ARTHRITIS

3. RHEUMATOID ARTHRITIS Rheumatoid arthritis (RA) is a complex condition that is well characterised by chronic inflammation in the synovial membrane of affected joints, often with systemic manifestations . It affects approximately 1 % of the adult population. It is characterized by chronic inflammation in the synovial membrane of affected joints that ultimately leads to loss of daily function due to chronic pain and fatigue. The majority of patients also have deterioration of cartilage and bone in the affected joints, which may eventually lead to permanent disability. Rheumatoid arthritis is associated with increased morbidity and mortality.

4. INDIAN SCENARIO RA is widely prevalent throughout the world. The overall worldwide prevalence is 0.8-1% and steadily increases to 5% in women over the age of 70. RA is two to three times more common in women compared to men. In India the prevalence has been estimated to be 0.5%- 0.75%.

5. ONSET Although Rheumatoid arthritis may present at any age, patients most commonly are first affected in the third to sixth decades. Female : male 3:1 Initial pattern of joint involvement could be :- 1 ) Polyarticular : most common 2 ) Oligoarticular 3 ) Monoarticular Morning joint stiffness > 1 hour and easing with physical activity is characteristic. Small joints of hand and feet are typically involved

6. RELATIVE INCIDENCE OF JOINT INVOLVEMENT IN RA MCP and PIP joints of hands & MTP of feet 90% Knees , ankles & wrists- 80% Shoulders- 60% Elbows- 50% TM , Acromio - clavicular & SC joints- 30%

7. LABORATORY INVESTIGATION CBC ( TLC, DLC, Hb ) Acute phase reactants ( ESR, CRP ) Rheumatoid Factor (RF ). Anti- CCP antibodies (most specific )

8. RHEUMATOID FACTOR (RF) Antibodies that recognize Fc portion of IgG . Can be IgM , IgG , IgA 85 % of patients with RA over the first 2 years become RF positive . A negative RF may be repeated 4-6 monthly for the first two year of disease, since some patients may take 18-24 months to become seropositive. PROGNISTIC VALUE - Patients with high titres of RF, in general, tend to have POOR PROGNOSIS, MORE EXTRA ARTICULAR MANIFESTATION

9. SERUM ANTI-CCP ANTIBODIES The presence of serum anti-CCP antibodies has about the same sensitivity as serum RF for the diagnosis of RA. However, its specificity approaches 95 %. A positive test for anti-CCP antibodies in the setting of an early inflammatory arthritis is useful for distinguishing RA from other forms of arthritis. There is some incremental value in testing for the presence of both RF and anti-CCP, as some patients with RA are positive for RF but negative for anti-CCP and visa versa. The presence of RF or anti-CCP antibodies also has prognostic significance, with anti-CCP antibodies showing the most value for predicting worse outcomes.

10. OTHER LAB ABNORMALITIES Elevated APRs( ESR, CRP ) Thrombocytosis Leukocytosis ANA - 30-40% Inflammatory synovial fluid Hypoalbuminemia

11. OTHER LAB ABNORMALITIES Radiographic Features Peri -articular osteopenia Uniform symmetric joint space narrowing Marginal subchondral erosions Joint Subluxations Joint destruction Collapse Ultrasound detects early soft tissue lesions. MRI has greatest sensitivity to detect synovitis and marrow changes

12. DIAGNOSTIC CRITERIA

13. DIFFERNETIATING FEATURES WITH OSTEOARTHRITIS

14. GOALS OF MANAGEMENT Focused on relieving pain Preventing damage/disability Patient education about the disease Physical Therapy for stretching and range of motion exercises Occupational Therapy for splints and adaptive devices Treatment should be started early and should be individualised . EARLY AGGRESSIVE TREATEMNT

15. TREATMENT OPTIONS The treatment of RA optimally involves a combination of non-pharmacological intervention (patient education, rest and exercise, and joint protection), a pharmacological intervention (such as medications nonsteroidal anti-inflammatory drugs [NSAIDs], disease-modifying antirheumatic drugs [DMARDs], tumor necrosis factor [TNF]- alpha inhibitors, immunosuppressant , and steroids) and occasionally surgery . Treatment options in RA 1. Antiinflammatory drugs: Non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids 2. Analgesics 3.Conventional disease modifying antirheumatoid drugs (DMARDs) 4. Biologicals DMARDs

16. NSAIDS Non-Steroidal anti-inflammatory drugs (NSAIDS ) for symptom control : Reduce pain and swelling by inhibiting COX Do not alter course of the disease. Chronic use should be minimised. Most common side effect related to GI tract.

17. CORTICOSTEROIDS Corticosteroids, both systemic and intra-articular are important adjuncts in management of RA. Indications for systemic steroids are :- For treatment of rheumatoid flares. For extra-articular RA like rheumatoid vasculitis and interstitial lung disease. As bridge therapy for 6-8 weeks before the action of DMARDs begin. Maintainence dose of 10mg or less of predinisolone daily in patients with active RA. Sometimes in pregnancy when other DMARDs cannot be used

18. DISEASE MODIFYING ANTI-RHEUMATIC AGENTS Drugs that actually alter the disease course . Should be used as soon as diagnosis is made. Appearance of benefit delayed for weeks to months. NSAIDS must be continued with them until true remission is achieved . Induction of true remission is unusual .

19. DMARDS Most commonly used Methotrexate Leflunomide Sulfasalazine Hydroxychloroquine Less commonly used Chloroquine Gold Cyclosporine A D- penicillamine Azathioprine Cyclophosphamide

20. WHEN TO START DMARDS DMARDs are indicated in all patients with RA who continue to have active disease even after 3 months of NSAIDS use. The period of 3 months is arbitary & has been chosen since a small percentage of patients may go in spontaneous remission. The vast majority , however , need DMARDs and many rheumatologists start DMARDs from Day 1.

21. SELECTION OF DMARDs There are no strict guidelines about which DMARDs to start first in an individual. Methotrexate has rapid onset of action than other DMARD. Taking in account patient tolerance, cost considerations and ease of once weekly oral administration METHOTREXATE is the DMARD of choice, most widely prescribed in the world

22. DMARDs - ALONE OR IN COMBINATION? Since single DMARD therapy (in conjunction with NSAIDS) is often only modestly effective , combination therapy has an inherent approach . DMARD combination is specially effective if they include methotrexate as an anchor drug. Combination of methotrexate with leflunamide are synergestic since there mode of action is different.

23. LIMITATIONS OF CONVENTIONAL DMARDS The onset of action takes several months. The remission induced in many cases is partial. There may be substantial toxicity which requires careful monitoring. DMARDs have a tendency to lose effectiveness with time-(slip out ). These drawbacks have made researchers look for alternative treatment strategies for RA- The Biologic Response Modifiers.

24. BIOLOGICAL AGENTS Biological agents are produced in a living system like a microorganism , plant or an animal cell by harnessing rDNA . The end product is a protein directed against a specific gene or another protein which is highly specific for its function and target antigen . The introduction of biological such as erythropoietin, insulin, growth hormones and anti-cytokine therapies brought a new era in modern medicine and transformed the treatment of many chronic diseases . The first biologic approved was humulin in 1982 by USFDA.

25. DEFINITIONS BIOLOGICAL PRODUCT : Medical products are made from a variety of natural sources using biotechnology methods and other cutting edge technologies and are intended to prevent or treat diseases and medical conditions. BIOSIMILAR(EMA ) : A biosimilar is biological medicinal product that contains a version of the active substance of an already authorized original biological medicinal product. It demonstrates similarity to the reference product in terms of quality characteristics, biological activity, safety and efficacy . BIOSIMILAR(INDIA ) : A biological product/drug produced by genetic engineering techniques and claimed to be similar in terms of safety, efficacy, and quality to a reference biological .

26. HOW ARE BIOLOGICAL DRUGS MANUFACTURED?

27. WORLDWIDE SCENARIO Biologics are one of the top selling drugs worldwide but the major drawback of this drug has been its exorbitant cost , which makes it unaffordable and inaccessible to many patients, especially in developing countries where a large number of people are poor and the concept of health insurance is at its nascent stage. But the silver lining is that once the innovator company loses their intellectual property right and patent protection after a stipulated period, it opens the window of opportunities for companies evince an interest in manufacturing similar products, which cost less, and at that time, it is known as biosimilar or similar biologic

28. GENERICS BIOSIMILARS They have active ingredients whose chemical and therapeutic characteristics are identical to the reference products in terms of dosage, strength, route of administration, quality, safety, efficacy and intended use. The same standards of generic drugs cannot be applied to biosimilars as there are many differences Regulatory agencies generally approve applications of generic drug manufacturers requiring only demonstration of bioequivelance to reference products in terms of pharmacokinetics parameters and bioavailability. Biosimilar cannot be made an exact replica of reference biological due to: 1- Complex structure. 2- Complex manufacturing process and heterogenecity . 3- Characterisation. 4-Effect of external conditions

29. BIOSIMILARS VS BIOLOGICS DEVELOPMENTAL PATHWAY

30. HOW BIOSIMILARS DIFFER FROM ORIGINAL OR INNOVATOR BIOLOGICS

31. DIFFERENCE BETWEEN BIOLOGIC AND BIOSIMILAR

32. DIFFERENCE BETWEEN BIOLOGIC AND BIOSIMILAR

33. ADVANTAGES Biologics have benefitted the patients with rheumatologic diseases, inflammatory bowel disease, malignant conditions, dermatological conditions, and other connective tissue disorders by halting the disease progression , alleviating the symptoms, and improving the quality of life.

34. SAFETY AND IMMUNOGENICITY Immunogenecity is an important safety concern for biosimilars . Immune reactions may lead to inactivation of drugs and thus limiting its efficacy and affecting its safety leading to adverse effects. Factors affecting immunogenicity include: 1- Product-Related factors 2- Route of administration 3- Patient Factors 4- Eprex episode.

35. BIOSIMILARS APPROVED IN INDIA

36. BIOLOGICS IN RHEUMATOLOGY

37. ROLE IN RA Biologics are typically reserved for people whose arthritis has not responded adequately to traditional disease-modifying anti rheumatic drugs ( DMARDs) Biologics are usually given by Injection or IV Biologics require a strict follow-up schedule All biologics increase risk of infection. Patients should be screened for tuberculosis and other infections before starting a biologic .

38. HOW DO BIOLOGICS TREAT RHEUMATOID ARTHRITIS They inhibit specific components of the immune system that play pivotal roles in inflammation. Biologics are used to treat moderate to severe rheumatoid arthritis that has not responded adequately to other treatments . Slow down the progression of rheumatoid arthritis when 1st line drugs have failed. Aggressive treatment is known to help prevent long-term disability from RA.

39. Anti-TNF agents Biologics, and specifically the anti-TNF biologics, can have a very rapid onset of action : same day. Radiographic efficacy of the anti-TNF agents exceeded expectations. Anti-TNF agents, and biologics in general, are surprisingly well tolerated and relatively safe. Biologics have a well-defined and specific mechanism Of action

40. ROLE OF B CELL IN PATHOGENESIS OF RA B cells may function as antigen presenting cells and provide important co-stimulatory signals required for CD4+ T cell clonal expansion and effector functions. B cells in RA synovial membrane may also secrete pro-inflammatory cytokines such as TNF α and chemokines. Rheumatoid synovial membrane contains an abundance of B cells that produce the rheumatoid factor (RF) antibody .

41. ROLE OF B CELL IN PATHOGENESIS OF RA RF may also be a self-perpetuating stimulus for B cells, potentially leading to activation and antigen presentation to Th cells, which may be mechanistically responsible for further RF production. Thus, RF immune complex mediated complement activation, in conjunction with binding of the Fcg receptor, collectively contribute to the propagation of the inflammatory cascade. T cell activation is considered to be a key component of the pathogenesis of RA. Recent evidence indicates that this activation is critically dependent on the presence of B cells.

42. ROLE OF RITUXIMAB IN RA It is uncertain which of these mechanisms is most important in the depletion of B cells in patients with RA, although some data suggest that Fc receptor mediated antibody-dependent cytotoxicity and antibody-dependent phagocytosis are the principal mechanisms. Intravenous rituximab in RA patients results in almost complete depletion of peripheral B cells and variable depletion of B cells in synovium and other sites such as lymphoid tissue and bone marrow. Rheumatoid factor levels are reduced by a greater proportion than are serum immunoglobulin (Ig) levels by rituximab treatment. The advantage of rituximab therapy is that there is no increased risk for TB.

43. DOSAGE AND ADMINISTRATION Rituximab has been approved by the US Food and Drug Administration and the European Medicines Agency in Europe for the treatment of RA in patients with an incomplete response or intolerance to tumor necrosis inhibitors ( TNFi ). Administer Rituximab as two 1000-mg intravenous infusions separated by 2 weeks.

44. DOSAGE AND ADMINISTRATION INFUSION RATE ON DAY 1 Time mg/hour ml/hour 1 st 30 minutes 50 mg/hour 25 ml/hour 2 nd 30 minutes 100 mg/hour 50 ml/hour Thereafter the rate can be increased by 50mg/hour (25mls/hour) every 30 minutes to a maximum rate of 400mg/hour (200mls/hour) providing no adverse reactions occur

45. DOSAGE AND ADMINISTRATION INFUSION RATE ON DAY 15 Time Mgs/hour Mls/hour 1 st 30 minutes 100 mg/hour 50 mls/hour 2 nd 30 minutes 200 mg/hour 100 mls/hour Thereafter the rate can be increased by 100mg/hour (50 mls /hour) every 30 minutes to a maximum rate of 400mg/hour (200mls/hour) providing no adverse reactions occur

46. BIOSIMILAR AGENTS USED IN RHEUMATOLOGY IN INDIA

47. ADVERSE EFFECTS Infusion related reactions : Dyspnoea , chest pain , headache , high blood pressure, dizziness, rash, flushing , hypotension or a “tickle in the throat .” Serious Infections: Tuberculosis and sepsis Malignancy : Lymphoma, Solid Tumors OTHERS : Optic neuritis, Increase LFT, Severe allergic reaction, Numbness and Tingling Pregnancy : stop before 3 months No live vaccines should be given

48. TOXICITY

49. SURGICAL APPROACHES Synovectomy is ordinarily not recommended for patients with rheumatoid arthritis, primarily because relief is only transient. However , an exception is synovectomy of the wrist, which is recommended if intense synovitis is persistent despite medical treatment over 6 to 12 months . Total joint arthroplasties , particularly of the knee, hip, wrist , and elbow, are highly successful. Other operations include release of nerve entrapments (e.g., carpal tunnel syndrome ), arthroscopic procedures, and, occasionally, removal of a symptomatic rheumatoid nodule.

50. RA IN PREGNANCY Most patients with RA go into remission during pregnancy. Methotrexate and leflunomide should be discontinued for at least 3 months before trying to conceive. Paracetamol is the oral analgesic of choice during pregnancy. Corticosteroids may be used to control disease flares DMARDs that may be used: sulfasalazine, hydroxychloroquine, azathioprine or ciclosporin if required to control inflammation. DMARDs that must be avoided: methotrexate, leflunomide,cyclophosphamide , gold and penicillamine . Biological therapies: safety during pregnancy is currently unclear.

51. References Edwards JW et al Efficacy of B-Cell–Targeted Therapy with Rituximab in Patients with Rheumatoid Arthritis N Engl J Med 2004;350:2572-81 Indian Rheumatology Association consensus statement on the management of adults with rheumatoid arthritis Indian Journal of Rheumatology 2008 :3(3);( Suppl ); pp. S1–S16