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Website: www.drsarma.in You Tube: drsarmaji channel 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 BioEd Online 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 2 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 3 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 4 Immunology 5 6 Rheumatoid Arthritis: Pathogenesis Current Treatment Targets Rheumatoid Factors, anti-CCP B cell Immune complexes Complement T cell IFN- & Neutrophil other cytokines Antigenpresenting cells B cell or macrophage Synoviocytes Pannus Macrophage Mast cell TNF Chondrocytes IL-1 Osteoclast Articular cartilage Production of collagenase and other neutral proteases Bone 7 Adapted from Arend WP, Dayer JM. Arthritis Rheum. 1990;33:305–15 Immunology of RA 8 Imbalance in Mediators – Chronic Inflammation 9 The Mediators of Joint Destruction Chemokines IL-1, IL-6 Cytokines MMP TNF VEGF Immune destruction 10 The Natural Course of RA Severe RA with Deformities Early RA – Mild Disease Undifferentiated Polyarthritis 11 Time Line of Function Loss in RA Moderate loss of function 0 2 Severe loss of function Very severe loss of function 5 10 Years from onset of symptoms 25% require surgical Rx. Wolfe F, Cathey MA. J Rheumatol. 1991;18:1298-1306. 12 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 13 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 14 The Joints Involved in RA 15 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) 16 Rheumatoid Arthritis – ACR Functional Classes Classification Specifications of activity levels Class I Complete ability to perform daily activities self-care, vocational and avocational Class II Ability to perform usual self-care and vocational activities; limited avocational activities Class III Ability to perform usual self-care activities; limited vocational or avocational activities Class IV Limited ability to perform usual self-care or vocational or avocational activities 17 Extra Articular Manifestations of RA Systemic involvement Special Features Musculoskeletal wasting Episcleritis, Scleromalacia Tenosynovitis, Bursitis Pleural effusion, Nodules Osteoporosis, Rh nodules Cervical cord compression Vasculitis, Arteritis Mononeutitis, carpel tunnel Pericarditis, Myocarditis Felty’s syndrome, Caplan’s 18 19 20 Swan-Neck and Boutonniere Deformities in RA http://images.rheumatology.org – Album of American College of Rheumatology 21 22 23 Radiological Changes in Rheumatoid Arthritis 24 Erosion of the Odontoid process Atlanto-Axial subluxation 25 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 26 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 27 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 28 Positive Rheumatoid Factor is seen in: Disease Frequency Advanced Rheumatoid Arthritis 100% Rheumatoid Arthritis (over all) 70% Sjögren's syndrome 90% Systemic Lupus Erythematosis (SLE) 30% Sub acute bacterial endocarditis (SABE) 40% Tuberculosis 15% Old Age 20% Normal healthy individuals 5% 29 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 poor prognosis and rapid progression They may be positive in asymptomatic patients years before the onset of symptoms 30 Serology in Rheumatoid Arthritis Test RA Factor is IgM Antibody to the Fc portion of the IgG Anti CCP: Antibodies to Cyclic Citrullinated Peptides 31 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 32 Rheumatoid Arthritis v/s Osteoarthritis Feature Rheumatoid Arthritis Osteoarthritis Pathology Autoimmune Degenerative Age Any age – usually 35+ Increases with age Joints involved Small joints MCP, PIP Large joints, TIP Spine (Axial) C1-C2 - Subluxation Lumbosacral Extra articular Many systemic effects Few systemic effects Course Rapidly progressive Slowly progressive Disability Highly disabling Mild to moderate 33 Early Progression of Bone Erosions in RA 34 Rheumatoid Arthritis: Predictors of Prognosis Presence of > 20 inflamed joints Markedly elevated ESR Radiographic evidence of bone erosions 40%-85% of RA pts unable to work in 8Presence of rheumatoid nodules High titers of RA Factor10 andyears 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 35 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 36 Goals of Therapy 1. Relief of pain 2. Reduction of inflammation 3. Protection of articular structures 4. Maintenance of functional activity 5. Control of systemic involvement 6. Slow the progression of disease 7. Increase the over all quality of life 37 Non Pharmacological Management Rest Exercise Flexibility/stretching Muscle conditioning Cardiovascular/aerobic Diet Weight management Physical and occupational therapy 38 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. 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 Surgical Treatment will be mandated in Early DMARD treatment to arrest progression 25% 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. Medical Management – Drug Classes Classes NSAIDs – Cox-1 & Cox-2 inhibitors Glucocorticoids – Prednisolone, MP IAS – Intra articular steroids DMARDs – MTX, SSZ, HCQ, CQ Immunosuppressive Rx.– AZT, Leflunomide, CS Cytotoxic agents – Cyclophosphamide Biologics – TNF- antibodies, IL-1 R antagonist Old drugs – Gold salts, D-Penicillamine 41 NSAIDS in RA NSAIDs COX 1 Constituent pathway Renal and GI homeostasis COX2 Inducible pathway Inflammation 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 42 NSAID Class of Drugs Non Selective NSAIDs used as analgesics Ibuprofen Ketorolac Ketoprofen Aspirin (NSAID) Diclofenac Selective COX-2 Aceclofenac Celecoxib, Etoricoxib Piroxicam Meloxicam Lornaxicam Analgesics Naproxen Tramadol Indomethacin Paracetamol 43 Pros and Cons of NSAID Therapy PROS Effective control of inflammation and pain Effective reduction in swelling CONS Improves mobility, flexibility, range of motion Improve quality of life Relatively low-cost Does not affect disease progression GI toxicity common Renal complications (eg. Irreversible renal insufficiency, papillary necrosis) Hepatic dysfunction CNS toxicity 44 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 steroidinduced osteopenia 45 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 46 Changing Paradigm of Treatment Evolving paradigm Current Treatment Traditional DMARDs • Early Aggressive Rx. • Biological • Combination treatment 47 48 49 New Treatment Paradigm for RA Orthopedic surgery Occupational therapy Higher dose steroids for flares or extraarticular disease Intraarticular steroids Physical therapy Patient education Simple analgesic Weaver AL, 2008. 50 Biological Agents in RA TNFα antagonists Adalimumab (Humira) Etanercept (Enbrel) Infliximab (Remicade) Interleukin-1 antagonist Suppressors of T-Cell activation Anakinra (Kineret) Abatacept (Orencia) Anti B-Cell monoclonal antibody Rituximab (Rituxan) 51 Characteristics of Biologicals used in RA Etanercept Enbrel Infliximab Remicade Adalimumab Humira Anakinra Kineret Abatacept Orencia Rituximab Rituxan Target TNF TNF TNF IL-1 Receptor T-Cell Activation B-Cell Half Life 3-5 Days 8-10 Days 10-20 Days 4-6 Hrs 13-16 Days 19 Days Construct Human Chimeric Human Human Human Chimeric Dosing Once Biweeklyweekly Once every 4-8 weeks Once every 1-2 weeks Once Daily Once Monthly Twice every 6-12 months Route Sub-Cut I.V. Sub-Cut Sub-Cut I.V. I.V. 52 Biologics: Relative Contraindications Active Hepatitis B Infection Multiple sclerosis, optic neuritis Active serious infections Chronic or recurrent infections Current neoplasia History of TB or evidence of Koch’s Congestive heart failure (Class III or IV) 53 Safety Considerations of Biologicals Serious Infections Opportunistic infections (TB) Malignancies/lymphoma Demyelination Hematologic abnormalities Administration reactions Congestive heart failure Hepatic Autoantibodies and drug induced lupus Vaccination 54 www.drsarma.in BioEd Online