Rheumatoid Arthritis

1. Rheumatoid Arthritis Carole Callaghan Principal Pharmacist NHS Lothian

2. Aim • To update pharmacists on the current • management of rheumatoid arthritis and • explore ways to implement • pharmaceutical care for this patient group • as part of normal working practice.

3. Objectives • Describe the common signs and symptoms associated with rheumatoid arthritis. • Define the current therapeutic management for both the alleviation of symptoms and for modifying disease progression in rheumatoid arthritis. • Identify pharmaceutical care issues and appropriate management solutions when responding to symptoms in patient scenarios. • Explore how to implement the principles of a pharmaceutical care needs assessment tool in practice.

4. Rheumatoid Arthritis • A chronic systemic inflammatory disease, characterised by potentially deforming symmetrical polyarthritis and extra-articular features.

5. Epidemiology • prevalence approx. 1% in UK • 3:1 ratio of females:males affected • peak onset 40 and 50 years of age • genetic, environmental and infective factors involved in disease development

6. Pathogenesis • cause remains unknown • toxic substances found in synovium • destruction of joints • immunological disturbances identified • RA is an autoimmune disease

7. Pathology • disease of the synovium • inflammation due to infiltration of lymphocytes, macrophages etc • proliferation of cells results in ”pannus” formation

8. Pathology

9. Pathology

10. Symptoms • joint pain (usually worse on waking) • morning stiffness (can vary in duration) • general symptoms e.g. fatigue, malaise, bone ‘ache’

11. Signs • swelling • tenderness • reduced range of movement • deformities (if untreated over long-term) • extra-articular features e.g. nodules, anaemia of chronic disease, pleural effusion

12. Signs

13. Joint involvement • hands/wrists • elbows/shoulders • cervical spine • knees • ankles/feet • unpredictable pattern

14. Investigation • Imaging e.g. x-ray, ultrasound, MRI • FBC and ESR • Other tests e.g RhF, anti-CCP (antibodies)

15. Management (1st stage) • lifestyle – maintain where possible • multidisciplinary e.g. • physiotherapy • occupational therapy • podiatry

16. Management (2nd stage) • relief of symptoms

17. NSAIDs • more effective than simple analgesics • variation in response • balance efficacy • and toxicity

18. NSAID toxicity • related to dose and duration of therapy • GI • renal and cardiovascular • elderly more at risk

19. GI toxicity • well documented in literature • identifiable risk factors e.g. age, previous history, other medication (steroids, warfarin), alcohol • improved use secondary to identifying those at risk and using gastroprotection

20. NSAID summary • use lowest dose compatible with symptom relief • use gastroprotection in “at risk” patient • reduce and, if possible, withdraw when good response from DMARD

21. COX-2 Inhibitors • selectively block COX-2 isoenzyme • provide pain relief (as efficacious as NSAIDs) • less GI bleeding than NSAIDs (less significant GI symptoms remain e.g. dyspepsia) • CV risk??

22. Management (3rd stage) • long-term suppressive drug therapy with disease modifying anti-rheumatic drugs (DMARDs)

23. Early DMARD • stabilise joint function as early as possible = better outcome • greater awareness of NSAID toxicity • DMARDs slow disease progression

24. DMARDs • efficacy .vs. toxicity • methotrexate and sulfasalazine have the best efficacy:toxicity ratio in meta-analyses • Increased use of combination therapy – TICORA, COBRA, BeST. • better than sequential monotherapy

25. DMARDs (cont) • DAS28 (Disease Activity Score) • -swollen joints • -tender joints • -ESR • -patient’s general health score • Monitoring • -FBC • -LFTs • -U&Es • -BP • -urinalysis

26. Systemic corticosteroids • not recommended for routine use • if necessary, use lowest dose, shortest time • monitor due to side effect profile

27. Intra-articular corticosteroids • “target” joint i.e. one or two large joints affected, can avoid systemic steroid • maximum number per joint/time – but no evidence for this theory • evidence lacking for this practice, • but patients report benefit

28. Activated Macrophage Target Cell sTNFR Signal TNF TNF a -Mode of Action

29. Activated Macrophage Activated Target Target Cell Cell TNFR TNFR Signal Signal sTNFR sTNFR TNF TNF Anti-TNF Biologics - Mode of Action

30. TNF a • Three agents currently licensed in UK and • SMC approved: • infliximab (human antichimeric antibody) • etanercept (fusion protein) • adalimumab (fully humanised monocloncal antibody)

31. Effects of Blocking TNFa • Immunology •  RF, T cell function restored • Inflammation •  Cytokine production in joints (IL1, IL6, TNF) • Angiogenesis •  levels of angiogenesis • Joint destruction •  damage to bone and cartilage • Haematology •  platelets, fibrinogen, restoration of Hb

32. B Cell Involvement in the Pathogenesis of RA

33. Biologic Pathways

34. Nomenclature • -ximab Chimeric antibody • -zumab Humanised antibody • -umab Human antibody • -cept Fusion protein

35. Immunogenecity

36. Eligibility Criteria for Biologic Therapy (BSR) • DAS28 >5.1 • At least 2 previous DMARDs • Adequate response at 3 months • 3-monthly monitoring

37. Infection • Do not initiate in presence of serious • active infection or in patients at high risk • Discontinue in presence of serious • infection

38. Tuberculosis • Screen for TB • Active TB needs to adequately treated • Prophylactic anti-TB therapy for potential latent • disease • Monitor during/after biologic; treat if required

39. Other Infections • Listeria/salmonella • Varicella • HBV/HCV • HIV

40. Vaccination • Data limited • Influenza and pnuemococcal • recommended (many also on MTX) • Hep B

41. Malignancy • No increased risk of solid tumours or • lymphoproliferative disease • Investigate/stop therapy • Caution in pre-malignant conditions • Preventative skin care/ongoing surveillance

42. Rituximab • With MTX only (SMC restricted use) • Inadequate response or intolerant of other • DMARDs, including at least one anti-TNF • By specialists in accordance with criteria

43. Safety with Rituximab • Delay post-anti-TNF • Check immunoglobulins • Re-treat on clinical signs • Active infection, severe immunocompromised • Screen for hepatitis (B & C)

44. Abatacept

45. Abatacept (contd) • Selective T cell co-stimulation modulator – • blocks the co-stimulatory signal required for full • T cell activation • Not recommended by SMC and reserved for • refractory disease • Increase in efficacy after first year of treatment

46. Tocilizumab

47. Tocilizumab (contd) • Recommended by SMC for combination • therapy only i.e. with MTX • ADRs e.g. liver enzymes, neutropenia, • lipids etc . . . • Place in therapy?

48. Certolizumab • Nanomolecule comprising a humanised • antibody fragment against TNF alpha with • a polyethylene glycol tail - designed • to increase bioavailability • RCTs show rapid improvement in disease • activity (ACR20) compared with placebo • and methotrexate • SMC outcome due May 2010

49. Summary • RA = inflammatory & destructive • symptomatic relief • early disease modification