Prof. Dr. Sarma. R.V.S.N M.D.(Med), M.Sc.(Canada), RCGP, FCGP, FIMSA Consultant Physician and

1. Website: www.drsarma.in You Tube: drsarmaji channel Rheumatoid Arthritis Prof. Dr. Sarma. R.V.S.N M.D.(Med), M.Sc.(Canada), RCGP, FCGP, FIMSA Consultant Physician and Cardio-Metabolic Specialist National Professor of Medicine Visiting Faculty – Frontier Life Line Visiting Professor of Medicine – SBMC

2. Rheumatoid Arthritis (RA): Definition • Progressive, systemic, Autoimmune inflammation • Often aggressive, devastating consequences • Unknown etiology (auto immune, ?infection, smoking) • Characterized by Symmetric synovitis – Chronic Polyarthritis Joint erosions, cartilage and bone destruction Multisystem - extra-articular manifestations Onset usually slow & insidious over months In 15 to 20% may have rapid or acute Aggressive management leads to good control

3. Rheumatoid Arthritis (RA): Epidemiology • Prevalence of - 0.8% to 2.1% of the population • Gender predilection ratio – Women: Men – 3:1 • Prevalence increases with age – Juvenile RA • About 40-60% have severe disease – 3 fold  mortality • Median life expectancy is shortened by 3 to 7 years • Onset mostly between ages of 35 – 60 years • Genetic – HLA-DR1(1*0101, 0401) – Class II HCA • Exact etiology is not known

4. Cost of RA versus CAD Costs per patient in $ per year RA CAD Direct costs 3790 7929 Indirect costs 2735 1051 Total costs 6525 8980

5. Immunology

7. Rheumatoid Factors, anti-CCP Immune complexes B cell T cell IFN- & HLA Neutrophil -DR other cytokines Antigen- presenting cells Macrophage Mast cell B cell or macrophage Synoviocytes Chondrocytes TNF IL-1 Pannus Articular cartilage Production of collagenase and other neutral proteases Rheumatoid Arthritis: Pathogenesis Current Treatment Targets Complement Osteoclast Bone Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15

8. Immunology of RA

9. Imbalance in Mediators – Chronic Inflammation

10. The Mediators of Joint Destruction

11. The Natural Course of RA

12. Time Line of Function Loss in RA Moderate loss of function Severe loss of function Very severe loss of function 0 2 5 10 Years from onset of symptoms 25% require surgical Rx. Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306.

13. Rheumatoid Arthritis: Diagnosis - ACR Criteria • Four or more of the following criteria must be present: • Morning stiffness > 1 hour • Arthritis of > 3 joint areas of the possible 28 joints • Arthritis of hand joints (MCPs, PIPs, wrists) • Symmetric swelling (arthritis) – same joints on both sides • Serum rheumatoid factor – RA Factor (antibody to IgG) • Rheumatoid nodules • Radiographic changes • First four criteria must be present for 6 weeks or more

14. Rheumatoid Arthritis: Typical Involvement • Wrist joints and MCP joints - very commonly involved • Index and middle Metacarpophalangeal joints • Proximal interphalangeal joints (PIP) • Metacarpophalangeal joints (MCP) • Metatarsophalangeal joints (MTP) • Elbows, Shoulders • Knees, Ankles, Hips. Lumbosacral area is not involved • Spine: only Atlanto-axial joint (C1– C2), subluxation • Terminal interphalangeal (TIPS) joints are not involved

15. The Joints Involved in RA

16. DAS28 (Disease Activity Scoring) for RA - EULAR • Calculated using a formula that includes • Counts for tender and swollen joints – (28 joints) • General health by the patient (on a scale of 0 to 100) • A measurement of ESR or CRP • Score > 5.1 – High disease activity, • Score 5.1 to 3.2 – Moderate disease activity • Score < 3.2 – Low disease activity • Score < 2.6 – Being in Remission • Response to Rx. –  of ≥ 1.2 – Good and < 0.6 – Poor European League Against Rheumatism (EULAR)

17. Rheumatoid Arthritis – ACR Functional Classes

18. Extra Articular Manifestations of RA

21. Swan-Neck and Boutonniere Deformities in RA http://images.rheumatology.org – Album of American College of Rheumatology

24. Radiological Changes in Rheumatoid Arthritis

25. Erosion of the Odontoid process Atlanto-Axial subluxation

26. Blood Parameters in RA • Acute Phase Reactants (APR ) • C-Reactive Protein (CRP) - > 4 mg% - • It is the single most useful marker • ESR is raised > 30 mm – other confounders • Ceruloplasmin • Haptoglobin (Hp) • Leukocytosis, Nutrophilia • Normocytic normochromic anemia • Thrombocytosis

27. Synovial Fluid in RA • No need in general for joint aspiration • Required to exclude other causes of arthritis • Inflammatory arthritis picture • Turbid fluid with reduced viscosity • Increased protein content • Decreased glucose content • WBC count from 2,000 to 50,000/l • PMNLs predominate • Total compliment, C3 and C4 are markedly 

28. Rheumatoid Factor (RA Factor) • Developed by Eric Waller in 1937 – Rose Waller Test • Agglutinating Abs - Latex particle agglutination assay • Isotype specific enzyme immunoassays – New technique • Antibodies to Fc portion of our own IgG - These Abs are IgM • Positive in 5% of normal persons and in only 70-80% of RA • Low specificity (false +ves) & low sensitivity (false –ves.) • It is not a screening or Dx. tool – More a prognostic tool • It is negative in 30% cases of RA – Sero negative RA • RF are commonly seen other disease – see next slide

29. Positive Rheumatoid Factor is seen in:

30. Anti-CCP Antibody Test in RA (ACPA) • Antibodies to Cyclic Citrullinated Peptides (anti-CCP) • Similar sensitivity for RA (70%) • Specificity for RA (>95%) better than RA Factor • In early polyarthritis anti-CCP are useful for Dx. • Anti-CCP are associated with more severe disease • They spell a poorprognosis and rapid progression • They may be positive in asymptomatic patients years before the onset of symptoms

31. Serology in Rheumatoid Arthritis Test RA Factor is IgM Antibody to the Fc portion of the IgG Anti CCP: Antibodies to Cyclic Citrullinated Peptides

32. Differential Diagnosis of RA • Connective tissue diseases - Scleroderma and SLE • Fibromyalgia, Palindromic Rheumatism • Infectious endocarditis, Acute Rheumatic Fever • Poly articular gout • Polymyalgia Rheumatica • Sarcoidosis, Hemochromatosis • Sero negative spondylo arthropathies • Reactive arthritis - evaluate for psoriasis, Reiter’s, IBD • Still’s disease, Thyroid disease, Viral arthritis

33. Rheumatoid Arthritis v/s Osteoarthritis

34. Early Progression of Bone Erosions in RA

35. Rheumatoid Arthritis: Predictors of Prognosis • Presence of > 20 inflamed joints • Markedly elevated ESR • Radiographic evidence of bone erosions • Presence of rheumatoid nodules • High titers of RA Factor and anti CCP • Higher class of functional disability • Persistent inflammation; comorbidities • Advanced age of onset • Low socio-economic status, low education level • HLA-DR*0401 or DR*0404 40%-85% of RA pts unable to work in 8-10 years

36. Rheumatoid Arthritis: Complications • Carpal tunnel syndrome, • Baker’s cyst, Subcutaneous nodules, • Systemic Vasculitis, • Sjögren’s syndrome, • Peripheral neuropathy, • Cardiac and pulmonary involvement, • Felty’s syndrome, and anemia • Risk of lymphomas three times greater • Risk of infection due to disease and treatment

37. Goals of Therapy • Relief of pain • Reduction of inflammation • Protection of articular structures • Maintenance of functional activity • Control of systemic involvement • Slow the progression of disease • Increase the over all quality of life

38. Non Pharmacological Management • Rest • Exercise • Flexibility/stretching • Muscle conditioning • Cardiovascular/aerobic • Diet • Weight management • Physical and occupational therapy

39. Therapeutic Window of Opportunity • Erosive changes occur early in disease • Even a brief delay of therapy can have a significant impact on disease parameters years later • Early DMARD treatment to arrest progression • MTX is the sheet anchor – Combination of DMARDs • Bridge the gap initially with NSAID and GC • Biologics only for refractory case – with caution; cost • Surgical treatment options in selected patients • O’Dell JR. Arthritis Rheum. 2002;46:283-285. • Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.

40. Therapeutic Window of Opportunity • Erosive changes occur early in disease • Even a brief delay of therapy can have a significant impact on disease parameters years later • Early DMARD treatment to arrest progression • MTX is the sheet anchor – Combination of DMARDs • Bridge the gap initially with NSAID and GC • Biologics only for refractory case – with caution; cost • Surgical treatment options in selected patients Surgical Treatment will be mandated in 25% • O’Dell JR. Arthritis Rheum. 2002;46:283-285. • Van der Heijde DM. Br J Rheum. 1995;34 (suppl 2):74-78.

41. Medical Management – Drug Classes

42. NSAIDS in RA • Selective COX 2 Inhibitors • Improved GI tolerability • Reduced effects on RBF • No effect on platelets • Called as COXIBs • May have adverse effect on heart • Celecoxib • Etoricoxib • Meloxicam Inducible pathway Inflammation Constituent pathway Renal and GI homeostasis

43. NSAID Class of Drugs Non Selective • Ibuprofen • Ketoprofen • Diclofenac • Aceclofenac • Piroxicam • Lornaxicam • Naproxen • Indomethacin NSAIDs used as analgesics • Ketorolac • Aspirin (NSAID) Selective COX-2 • Celecoxib, Etoricoxib • Meloxicam Analgesics • Tramadol • Paracetamol

44. Pros and Cons of NSAID Therapy PROS • Effective control of inflammation and pain • Effective reduction in swelling • Improves mobility, flexibility, range of motion • Improve quality of life • Relatively low-cost CONS • Does not affect disease progression • GI toxicity common • Renal complications (eg. Irreversible renal insufficiency, papillary necrosis) • Hepatic dysfunction • CNS toxicity

45. Pros and Cons of Corticosteroid Therapy PROS • Anti-inflammatory and immunosuppressive effects • Can be used to bridge gap between initiation of DMARD therapy and onset of action • Intra-articular steroid (IAS) injections can be used for individual joint flares CONS • Does not conclusively affect disease progression • Tapering and discontinuation of use often unsuccessful • Low doses result in skin thinning, ecchymoses, and Cushingoid appearance • Significant cause of steroid-induced osteopenia

46. Methotrexate (MTX) • MTX is given 10 to 30 mg orally, IM, or SC per week • It is DHF reductase inhibitor – Supplemental folic acid • The clinical improvement takes one to two months • Nausea, diarrhea; mouth ulcers; rash, alopecia; Abnormal LFT • Rare: low WBC & platelets; pneumonitis; sepsis; liver disease; EBV related lymphoma; • CBC, creatinine, and LFTs monthly for six months, then every one to two months; repeat AST or ALT in two to four weeks if initially elevated, and adjust dose as needed; • Rapid onset (six to 10 weeks); tends to produce more sustained results over time than other DMARDs and lowers all-cause mortality; • Can be used when cause of polyarthritis uncertain; • Often combined with other DMARDs like Leflunomide, SSZ, HCQ

47. Changing Paradigm of Treatment Current Treatment Traditional DMARDs

50. New Treatment Paradigm for RA Higher dose steroids for flares or extraarticular disease Orthopedic surgery Occupationaltherapy Intraarticularsteroids Physicaltherapy Simple analgesic Patient education Weaver AL, 2008.