Rheumatoid Arthritis DOM MR Week of 9/8/2008 Rozina

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>Rheumatoid Arthritis DOM MR Week of 9/8/2008 Rozina Mithani Rheumatoid Arthritis DOM MR Week of 9/8/2008 Rozina Mithani

>Joint Pain most common symptom Pain (arthralgia) vs. Inflammation (arthritis) Inflammation:  heat, redness, Joint Pain most common symptom Pain (arthralgia) vs. Inflammation (arthritis) Inflammation: heat, redness, pain, swelling, loss of function inflammatory arthritis (RA, SLE) vs. pain syndrome (fibromyalgia)

>Number of Joints Affected  Inflammatory vs. Non-Inflammatory Number of Joints Affected Inflammatory vs. Non-Inflammatory

>Number of Joints Affected Monoarticular Crystal-induced Infection Reactive Arthritis Hemarthrosis OA: joint effusions Autoimmune Number of Joints Affected Monoarticular Crystal-induced Infection Reactive Arthritis Hemarthrosis OA: joint effusions Autoimmune disease Psoriasis, IBD, AS, Behçet's Oligo/Polyarticular Monoarticular causes RA SLE Viral infection B19 Acute Serum Sickness Untreated Crystal-induced Vasculidities

>Inflammatory vs. Non-Inflammatory Inflammatory: i.e. RA Generalized AM stiffness > 30 min Resolves with Inflammatory vs. Non-Inflammatory Inflammatory: i.e. RA Generalized AM stiffness > 30 min Resolves with movement Classic signs of inflammation Non-Inflammatory: i.e. Osteoarthritis Localized AM stiffness < 30 min

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>Arthrocentesis Confirm diagnoses Differentiate between inflammatory & noninflammatory Therapeutic/Adjunct to Antibiotics   Labs: Arthrocentesis Confirm diagnoses Differentiate between inflammatory & noninflammatory Therapeutic/Adjunct to Antibiotics Labs: cell count w/diff crystal analysis Gram stain & Culture WBC >2000/µL indicates inflammatory arthritis Arthroscopy Evaluate ligamentous & cartilaginous integrity Biopsy Infectioun: aspirate thick or loculated fluid

>Rheumatoid Arthritis Rheumatoid Arthritis

>RA Systemic inflammatory autoimmune disorder ~1% of population Onset: 52 years 40-70 years of RA Systemic inflammatory autoimmune disorder ~1% of population Onset: 52 years 40-70 years of age <60 - 3-5:1 female predominance

>Genetics Increased incidence among Pima & Chippewa Native American tribes (5%) Genetic & Environmental Genetics Increased incidence among Pima & Chippewa Native American tribes (5%) Genetic & Environmental HLA-DRB1*0401 & HLA-DRB1*0404 Increased risk Increased joint damage Increased joint surgery

>Pathophysiology Pathophysiology

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>Immunology Macrophages: Produce cytokines Cytokines (TNF-α) cause systemic features Release chemokines  recruit PMNs Immunology Macrophages: Produce cytokines Cytokines (TNF-α) cause systemic features Release chemokines  recruit PMNs into synovial fluid/membrane TNF-α & IL-1: Proliferation of T cells Activation of B cells Initiates proinflammatory/joint-damaging processes TH-1 cells: Mediate disease processes Activate B cells B cells: Release cytokines Plasma cells that produce Ab Osteoclasts: Bone erosion Juxta-articular & Systemic osteoporosis

>Pathophysiology Swelling of Synovial lining Angiogenesis  Rapid division/growth of cells = Pannus Synovial Pathophysiology Swelling of Synovial lining Angiogenesis Rapid division/growth of cells = Pannus Synovial thickening/hyperplasia Inflammatory vascularized tissue Generation of Metalloproteinases Cytokine release Infiltration of leukocytes Change in cell-surface adhesion molecules & cytokines Destruction of bone & cartilage

>Bottom Line Proliferation Destruction of joints Disability Bottom Line Proliferation Destruction of joints Disability

>Disease Trigger Subclinical vs. Viral trigger Lab manifestations up to 10 yrs before clinical Disease Trigger Subclinical vs. Viral trigger Lab manifestations up to 10 yrs before clinical RF & anti-CCP (anti–cyclic citrullinated peptide) Ab Increased CRP subclinical inflammatory disease ADLs: > 50% of pts stop working w/i 5-10 years of disease onset ~ 80% disabled to some degree > 20 years Life expectancy: decreased by 3-18 years

>Clinical Presentation Gradual onset Stiffness & Swelling Intermittent or Migratory involvement Extraarticular manifestations Myalgia, Clinical Presentation Gradual onset Stiffness & Swelling Intermittent or Migratory involvement Extraarticular manifestations Myalgia, fatigue, low-grade fever, wt loss, depression

>Stiffness & Swelling Pain with pressure to joint Pain with movement of joint Swelling Stiffness & Swelling Pain with pressure to joint Pain with movement of joint Swelling due to hypertrophy Effusion Heat Redness

>Physical Exam Decreased grip strength Boxing glove edema Carpal tunnel Ulnar deviation Boutonniere/Swan neck Physical Exam Decreased grip strength Boxing glove edema Carpal tunnel Ulnar deviation Boutonniere/Swan neck deformities Extensor tendon rupture

>Extraarticular Involvement Anemia Rheumatoid nodules Pleuropericarditis Neuropathy Episcleritis, Scleritis Splenomegaly Sjogren’s Vasculitis Extraarticular Involvement Anemia Rheumatoid nodules Pleuropericarditis Neuropathy Episcleritis, Scleritis Splenomegaly Sjogren’s Vasculitis

>Differential Seronegative polyarthritis Psoriatic arthritis Crystal-induced Tophaceous gout Pseudogout  Erosive inflammatory OA Reiter’s Differential Seronegative polyarthritis Psoriatic arthritis Crystal-induced Tophaceous gout Pseudogout Erosive inflammatory OA Reiter’s Enteropathic arthritis SLE Paraneoplastic syndrome

>Diagnostic Criteria Diagnostic Criteria

>Diagnostic Criteria Symmetric peripheral polyarthritis AM Stiffness >1 hour Rheumatoid nodules Laboratory features Radiographic Diagnostic Criteria Symmetric peripheral polyarthritis AM Stiffness >1 hour Rheumatoid nodules Laboratory features Radiographic bone erosions

>Symmetric Peripheral Polyarthritis 3 or more Joints for >6 weeks  Small Joints Hands Symmetric Peripheral Polyarthritis 3 or more Joints for >6 weeks Small Joints Hands & Feet Peripheral to Proximal MCP and PIP Joints SPARES DIP MTP & Plantar subluxation Leads to Deformity & Destruction of Joints Erosion of cartilage and bone

>Stiffness AM or after Prolonged Inactivity Bilateral In/Around Joints > 1 hours Reflects severe Stiffness AM or after Prolonged Inactivity Bilateral In/Around Joints > 1 hours Reflects severe joint inflammation Better with movement Present >6 weeks

>Rheumatoid Nodules Extensor surfaces elbows Very Specific Only occur in ~30% Late in Disease Rheumatoid Nodules Extensor surfaces elbows Very Specific Only occur in ~30% Late in Disease

>Laboratory Features RF 70-80% of pts Overlap with HCV/Cryoglobulinemia  Anti-Cyclic Citrulline Peptide (anti-CCP) Laboratory Features RF 70-80% of pts Overlap with HCV/Cryoglobulinemia Anti-Cyclic Citrulline Peptide (anti-CCP) Rare overlap with HCV Acute Phase reactants ESR, CRP  monitoring disease activity

>Rheumatoid Factor IgM against IgG IgM+ pts: more severe disease & poorer outcome Non-specific Rheumatoid Factor IgM against IgG IgM+ pts: more severe disease & poorer outcome Non-specific SLE, Sjögren's, Sarcoidosis, Chronic infections

>Anti-CCP IgG against synovial membrane peptides damaged via inflammation Value in IgM-RF negative Anti-CCP IgG against synovial membrane peptides damaged via inflammation Value in IgM-RF negative Sensitivity (65%) & Specificity (95%) Predictive of Erosive Disease Disease severity Radiologic progression Poor functional outcomes

>Other Lab Abnormalities AOCD Thrombocytosis Leukocytosis ANA 30-40% Inflammatory synovial fluid Hypoalbuminemia Other Lab Abnormalities AOCD Thrombocytosis Leukocytosis ANA 30-40% Inflammatory synovial fluid Hypoalbuminemia

>Radiology Evaluate disease activity & joint damage Bony decalcification Baseline AP views Initiation of Radiology Evaluate disease activity & joint damage Bony decalcification Baseline AP views Initiation of DMARDs

>Radiological Studies Plain Films Bilateral hands & feet Only 25% of lesions Less expensive Radiological Studies Plain Films Bilateral hands & feet Only 25% of lesions Less expensive Through bone cortex around joint margins Color Doppler U/S & MRI Early signs of damage i.e. Erosions Bone Edema - even with normal findings on radiography

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>Disease Severity Disease Severity

>Arthralgias >3 inflamed joints Mild functional limitation Minimally elevated ESR & CRP No erosions/cartilage Arthralgias >3 inflamed joints Mild functional limitation Minimally elevated ESR & CRP No erosions/cartilage loss No extraarticular disease i.e. anemia Mild Disease

>Moderate Disease 6-20 Inflamed joints Moderate functional limitation Elevated ESR/CRP Radiographic evidence of inflammation Moderate Disease 6-20 Inflamed joints Moderate functional limitation Elevated ESR/CRP Radiographic evidence of inflammation No extraarticular disease

>Severe Disease >20 persistently inflamed joints Rapid decline in functional capacity Radiographic evidence of Severe Disease >20 persistently inflamed joints Rapid decline in functional capacity Radiographic evidence of rapid progession of bony erosions & loss of cartilage Extraarticular disease: AOCD, Hypoalbuminemia

>Prognostic Features RF & Anti-CCP antibodies Early development of multiple inflamed joints and joint Prognostic Features RF & Anti-CCP antibodies Early development of multiple inflamed joints and joint erosions Severe functional limitation Female HLA epitope presence Lower socioeconomic status & Less education Persistent joint inflammation for >12 weeks

>CV Disease Leading cause of death ~50%  2x more likely to develop MI CV Disease Leading cause of death ~50% 2x more likely to develop MI chronic, inflammatory vascular burden  premature atherosclerosis MTX: elevated homocysteine levels Control inflammatory process = Decreased atherosclerosis/morbidity Lipid screening & treatment Control of obesity, Hyperhomocystinemia, DM, HTN ASA

>Other diseases 70% more likely to have a stroke  70% higher risk for Other diseases 70% more likely to have a stroke 70% higher risk for developing infection 44x more likely to develop NHL

>Staging Early <3 months  Established/Persistent 6-12 months  End-stage Significant joint destruction Functional Staging Early <3 months Established/Persistent 6-12 months End-stage Significant joint destruction Functional disability

>Management Early and aggressive disease control  Rheumatologist Referral  Early/Undiagnosed: NSAIDs, short course Management Early and aggressive disease control Rheumatologist Referral Early/Undiagnosed: NSAIDs, short course Corticosteroids Late/Uncontrolled: DMARD therapy depends on the presence or absence of joint damage, functional limitation, presence of predictive factors for poorer prognosis Goals achieve NED & inflammation no treatment to resolve erosions once they occur

>Treatment Strategies Treatment Strategies

>Therapy Non-Pharmacologic: Referral to PT/OT Evaluate ADLs Assistive devices/splints Weight loss Smoking cessation Pharmacologic: Therapy Non-Pharmacologic: Referral to PT/OT Evaluate ADLs Assistive devices/splints Weight loss Smoking cessation Pharmacologic: Anti-inflammatory Interrupt progression Development of erosions Joint space narrowing

>Pharmacologic Therapy Analgesics NSAIDs Glucocorticoids SAARD/DMARD Anticytokine therapy Pharmacologic Therapy Analgesics NSAIDs Glucocorticoids SAARD/DMARD Anticytokine therapy

>Analgesics Topical Capsaicin Diclofenac Oral Tylenol Opiods Analgesics Topical Capsaicin Diclofenac Oral Tylenol Opiods

>NSAIDs  Analgesic, Antipyretic, Anti-inflammatory   Don’t alter disease progression Ineffective in Erosive NSAIDs Analgesic, Antipyretic, Anti-inflammatory Don’t alter disease progression Ineffective in Erosive disease GI/Ulcers Hepatotoxicity Nephrotoxicity AIN Bleeding – antiplatelet Rash Aseptic meningitis

>Corticosteroids Decrease cytokines  Slow Joint Inflammation  Insomnia Emotional lability Fluid retention Weight Corticosteroids Decrease cytokines Slow Joint Inflammation Insomnia Emotional lability Fluid retention Weight gain HTN Hyperglycemia Osteoporosis Bisphosphonates: >5mg/d for >3months Cataracts Avascular necrosis Myopathy Psychosis

>Disease modification SAARD – slow acting antirheumatic drugs  DMARD – disease modifying antirheumatic Disease modification SAARD – slow acting antirheumatic drugs DMARD – disease modifying antirheumatic drugs

>Methotrexate Dihydrofolate reductase inhibitor Well tolerated, Mono/Combo Onset: 6-12 weeks  Metabolism: Liver Methotrexate Dihydrofolate reductase inhibitor Well tolerated, Mono/Combo Onset: 6-12 weeks Metabolism: Liver Clearance: Kidneys Monitoring: Baseline:CXR, PFTs, HIV, HBV/HCV CBC, LFTs Q4-8 weeks Caution with CRI Nausea Mucosal ulcerations Fatigue & Flu-like symptoms BM Toxicity Hepatotoxicity Treat with Folic acid, 1 mg/d

>Leflunomide Inhibits dihydrooratate dehydrogenase Dec. activated T-cells  Onset: rapid  Efficacy: ≤6 weeks Leflunomide Inhibits dihydrooratate dehydrogenase Dec. activated T-cells Onset: rapid Efficacy: ≤6 weeks Monitoring: CBC, LFTs Derm - rash, alopecia Diarrhea BM toxicity Hepatotoxicity

>Azathioprine Corticosteroid-sparing  Monitoring: CBC Q1-2 months AST/ALT Infection  BM Toxicity Hepatitis Malignancy Azathioprine Corticosteroid-sparing Monitoring: CBC Q1-2 months AST/ALT Infection BM Toxicity Hepatitis Malignancy

>Cyclophosphamide Alkylating agent  Monitoring: CBC, UA monthly Yearly UA +/- Cytology  Alopecia Cyclophosphamide Alkylating agent Monitoring: CBC, UA monthly Yearly UA +/- Cytology Alopecia Nausea Infection BM suppression  pancytopenia Infertility – pretreat women with Leuprolide Renal: hemorrhagic cystitis, bladder malignancy – treat with acrolein Oral more toxic than IV

>Anticytokine therapy Anti-TNF alpha agents Etanercept Infliximab Adalimumab IL-1 receptor antagonist (Anakinra) Anticytokine therapy Anti-TNF alpha agents Etanercept Infliximab Adalimumab IL-1 receptor antagonist (Anakinra)

>TNF-a Inhibitors Anti-inflammatory Block TNF-α (proinflammatory cytokine) Etanercept, Adalimumab (SQ), Infliximab (IV) Very expensive: TNF-a Inhibitors Anti-inflammatory Block TNF-α (proinflammatory cytokine) Etanercept, Adalimumab (SQ), Infliximab (IV) Very expensive: > $15,000/patient Combo therapy with MTX Injection site reaction Infection Reactivated TB Infliximab infusion reaction Pancytopenia Autoantibody/SLE-like Exacerbate CHF Malignancy – lymphoma

>More aggressive approach Combo therapy Adjunctive therapy: TNF-α antagonist More aggressive approach Combo therapy Adjunctive therapy: TNF-α antagonist

>Disease Course Long Remission 10%  Intermittent Disease 15-30%  Progressive Disease Disease Course Long Remission 10% Intermittent Disease 15-30% Progressive Disease

>Summary Approach to Arthritis Number of Joints Affected Inflammatory vs. Non-Inflammatory  Rheumatoid Arthritis Summary Approach to Arthritis Number of Joints Affected Inflammatory vs. Non-Inflammatory Rheumatoid Arthritis Diagnostic Criteria Pathophysiology Therapeutic Approach Disease Severity and Course

>Questions? Questions?