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Rheumatoid Arthritis
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Goals General Approach to Arthritis Rheumatoid Arthritis
Diagnostic Criteria Pathophysiology Therapeutic Approach Disease Severity and Course
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Approach to Arthritis
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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)
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Number of Joints Affected
Inflammatory vs. Non-Inflammatory
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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
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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: 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
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Rheumatoid Arthritis
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RA Systemic inflammatory autoimmune disorder ~1% of population
Onset: 52 years 40-70 years of age < :1 female predominance
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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
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Pathophysiology
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Immunology Macrophages: TNF-α & IL-1: TH-1 cells: B cells:
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
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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
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Bottom Line Proliferation Destruction of joints Disability
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Disease Trigger Subclinical vs. Viral trigger ADLs:
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
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Clinical Presentation
Gradual onset Stiffness & Swelling Intermittent or Migratory involvement Extraarticular manifestations Myalgia, fatigue, low-grade fever, wt loss, depression
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Stiffness & Swelling Pain with pressure to joint
Pain with movement of joint Swelling due to hypertrophy Effusion Heat Redness
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Physical Exam Decreased grip strength Boxing glove edema Carpal tunnel
Ulnar deviation Boutonniere/Swan neck deformities Extensor tendon rupture
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Extraarticular Involvement
Anemia Rheumatoid nodules Pleuropericarditis Neuropathy Episcleritis, Scleritis Splenomegaly Sjogren’s Vasculitis
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Differential Seronegative polyarthritis Psoriatic arthritis
Crystal-induced Tophaceous gout Pseudogout Erosive inflammatory OA Reiter’s Enteropathic arthritis SLE Paraneoplastic syndrome
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Diagnostic Criteria
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Diagnostic Criteria Symmetric peripheral polyarthritis
AM Stiffness >1 hour Rheumatoid nodules Laboratory features Radiographic bone erosions
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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
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Stiffness AM or after Prolonged Inactivity Bilateral In/Around Joints
> 1 hours Reflects severe joint inflammation Better with movement Present >6 weeks
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Rheumatoid Nodules Extensor surfaces Very Specific Only occur in ~30%
elbows Very Specific Only occur in ~30% Late in Disease
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Laboratory Features RF Anti-Cyclic Citrulline Peptide (anti-CCP)
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
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Rheumatoid Factor IgM against IgG
IgM+ pts: more severe disease & poorer outcome Non-specific SLE, Sjögren's, Sarcoidosis, Chronic infections
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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
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Other Lab Abnormalities
AOCD Thrombocytosis Leukocytosis ANA 30-40% Inflammatory synovial fluid Hypoalbuminemia
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Radiology Evaluate disease activity & joint damage
Bony decalcification Baseline AP views Initiation of DMARDs
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Radiological Studies Plain Films Color Doppler U/S & MRI
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
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Mild Disease Arthralgias >3 inflamed joints
Mild functional limitation Minimally elevated ESR & CRP No erosions/cartilage loss No extraarticular disease i.e. anemia
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Moderate Disease 6-20 Inflamed joints Moderate functional limitation
Elevated ESR/CRP Radiographic evidence of inflammation No extraarticular disease
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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
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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
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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
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Other diseases 70% more likely to have a stroke
70% higher risk for developing infection Likely 2/2 treatment 44x more likely to develop NHL
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Staging Early Established/Persistent End-stage <3 months
Significant joint destruction Functional disability
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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
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Treatment Strategies
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Therapy Non-Pharmacologic: 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
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Pharmacologic Therapy
Analgesics NSAIDs Glucocorticoids SAARD/DMARD Anticytokine therapy
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Analgesics Topical Capsaicin Diclofenac Oral Tylenol Opiods
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NSAIDs Pros: Cons: GI/Ulcers Analgesic, Antipyretic, Anti-inflammatory
Don’t alter disease progression Ineffective in Erosive disease GI/Ulcers Hepatotoxicity Nephrotoxicity AIN Bleeding – antiplatelet Rash Aseptic meningitis
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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
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Disease modification SAARD – slow acting antirheumatic drugs
DMARD – disease modifying antirheumatic drugs
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Methotrexate Dihydrofolate reductase inhibitor Metabolism: Liver
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
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Leflunomide Monitoring: Inhibits dihydrooratate dehydrogenase
Dec. activated T-cells Onset: rapid Efficacy: ≤6 weeks Monitoring: CBC, LFTs Derm - rash, alopecia Diarrhea BM toxicity Hepatotoxicity
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Azathioprine Corticosteroid-sparing Monitoring: Infection BM Toxicity
CBC Q1-2 months AST/ALT Infection BM Toxicity Hepatitis Malignancy
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Cyclophosphamide Alkylating agent Alopecia Nausea Infection
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
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Anticytokine therapy Anti-TNF alpha agents Etanercept Infliximab
Adalimumab IL-1 receptor antagonist (Anakinra)
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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
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More aggressive approach
Combo therapy Adjunctive therapy: TNF-α antagonist
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Disease Course Long Remission Intermittent Disease Progressive Disease
10% Intermittent Disease 15-30% Progressive Disease
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Summary Approach to Arthritis Rheumatoid Arthritis
Number of Joints Affected Inflammatory vs. Non-Inflammatory Rheumatoid Arthritis Diagnostic Criteria Pathophysiology Therapeutic Approach Disease Severity and Course
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