03.rheumatoid arthritis

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    Introduction

    Clinical features

    Laboratory features

    Extra-articular features

    Management considerations and paradigmsPrognosis

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    RA - Definition

    Chronic systemic inflammatory disorder

    Unknown etiology

    Symmetrical joints

    Synovium affected

    Bone, cartilage, ligamentsDeformity

    Extra-articular manifestations

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    RA - Definition

    Clinical diagnosis

    Cymmetric polyarthritis of small jointssubacute

    acute

    Rheumatoid factor positivityErosive disease

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    RA - Epidemiology

    Worldwide distribution

    All races

    Female > male 3:1

    Usual age of onset 20-40 years though individuals

    of any age group may be affected

    Genetic associationsHLA-DR4, DR1

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    Rheumatoid factor

    series of antibodies that recognize the Fc portion

    of an IgG molecule

    any serotype

    most IgM

    many conditions associated with RF positivity -

    chronic inflammation

    70% RA positive at onset, overall 85% in first twoyears

    associated with more severe disease, extra-

    articular manifestations, mortality

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    Etiology

    Probable background genetic susceptibility(multiple genes/risk factors involved)

    Concordance rates 15-30% identical twins

    2.5-3.0 times more prevalent inWomen>Men

    Family history

    Female Sex

    Specific genes: HLA-DR4

    Specific region in HLA DRB1 gene

    confers increased risk of RA and severity

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    Case Presentation:

    55 YOF complains of months of bilateral handpain. She describes progressive morningstiffness lasting 3 hours with wrist, MCP, andPIP pain and swelling. She has also noted some

    discomfort and perhaps swelling in her wrists,shoulders, knees, and toes.

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    Rheumatoid Arthritis

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    Rheumatoid nodule

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    Case Presentation:

    Physical exam is notable for swelling,

    tenderness, and warmth in the elbows,

    wrists, MCPs, PIPs, knees, and MTPs withnon-tender soft tissue nodules over the

    olecronon.

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    Laboratory abnormalities

    anemia of chronic disease

    thrombocytosis in active disease

    ESR

    CRP

    X rays of joints

    Rheumatoid factor

    ACPA

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    RA: Erosion Progression

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    Rheumatoid arthritis- late stage

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    Extra-articular manifestations

    General

    fever, lymphadenopathy, weight loss, fatigue

    Dermatologic

    palmar erythema, nodules, vasculitis

    Ocular

    episcleritis/scleritis, scleromalacia perforans,

    choroid and retinal nodules

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    Extra-articular manifestations

    Cardiac

    pericarditis, myocarditis, coronary vasculitis,

    nodules on valves

    Neuromuscular

    entrapment neuropathy, peripheral neuropathy,

    mononeuritis multiplex, cervical cord

    compression

    Hematologic

    Feltys syndrome, large granular lymphocyte

    syndrome, lymphomas

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    Extra-articular manifestations

    Pulmonary

    pleuritis, nodules, interstitial lung disease,

    bronchiolitis obliterans, arteritis, effusions

    Others

    Sjogrens syndrome, amyloidosis

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    Feltys syndrome

    classic triad

    RA, splenomegaly, leukopenia

    generally a neutropenia (

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    D.Dx of a positive RF

    normal - 1-4%, 10-25% over age 70

    systemic autoimmune diseases

    infections

    malignancy

    chronic liver diseasepulmonary diseases

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    ANA in RA

    25% RA are positive for ANA

    other serologies usually negative

    ? more severe disease (RA) with worse

    prognosis

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    Anti-Citrullinated Peptide

    Antibodies (ACPA)Rheumatoid factor (RF) has low specificity

    for RA

    ACPA more specific than RF for RA

    CCP is commercially available test

    Sensitivity similar to RF (~60-80%)More specific for RA (~96%)

    Predicts poor prognosis

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    RA - differential diagnosis

    Common diseases

    Spondyloarthropathies

    rheumatic fever

    CTDs

    viral infections

    fibromyalgia

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    RA - differential diagnosis

    Uncommon

    hypothyroidism

    SBE

    sarcoidosis

    lyme disease

    amyloidHIV

    malignancies/paraneoplastic syndromes

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    Problems with old ACR Criteria

    Work best in longstanding RA

    But DMARDs work best in early RA and the goal is

    to prevent development of damage

    Need criteria addressing earlier diagnosis given thebenefits of early treatment

    Need to include ACPA (CCP)

    Balance with need for use in low resource settingswhere CCP not available

    Goal of new criteria: predict who should be treated

    with DMARDs

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    New ACR/EULAR Proposed Criteria

    Initial screen: 1+ swollen joints (if no, not RA)

    Better explained by other dz? (if yes, not RA) Typical RA erosion on X-ray? (if yes, RA)

    Next step:

    Pattern of joint involvement (more points for more joints

    and small joints)

    Serology (RF and/or CCP, negative, low, high)

    Duration (

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    ACR Guidelines for Management

    Summarize evidence for DMARDs and

    biologics in different settings

    Incorporate the following in treatmentdecisions

    Disease duration (24 mo)

    Disease activity (low, moderate, high) Features of poor prognosis

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    Measurement of Disease Activity: DAS28 as

    Example

    DAS28 = 0.56 * sqrt(tender28) + 0.28 *

    sqrt(swollen28) + 0.70 * ln(ESR) + 0.014

    * GHIncludes:

    Tender joint count

    Swollen joint count

    ESR (or CRP in different version)

    GH: Patient global disease activity assessment

    Categorized as low, moderate, or high

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    Poor Prognostic Factors in

    RA

    Presence of RF and/or CCP antibodiesRadiographic erosions

    Functional limitation

    Extraarticular disease

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    RA - Management

    Non-pharmacologic

    rest

    fatigue, splinting

    pain relief

    heat, cold, ultrasound, paraffin, massage

    physical therapyoccupational therapy

    Patient education

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    RA - Management

    Pharmacologic

    analgesics

    NSAIDs - full dose

    corticosteroids

    prednisone at low dose - bridge, burst

    intra-articular steroids

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    Disease modifying agents

    every patient should be considered for at

    least one modifying agent

    limitations

    may not prevent damage

    may not have lasting effect

    may not be tolerated due to toxicity

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    DMARDs

    hydroxychloroquine

    mild non-erosive disease

    combinations

    200 mg bid

    eye exams

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    DMARDs

    Sulfasalazine

    1 gm bid - tid

    CBC, LFTs

    onset 1 - 2 months

    Methotrexate

    most commonly used drug

    fast acting (4-6 weeks)

    po, SQ - weekly

    FBC, LFTs

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    DMARDs

    IM Gold

    slow onset (3-6 months)

    weekly then monthly injections

    CBC, UA before each injection

    Oral Gold

    less effective

    slow acting (4-6 months)

    daily

    CBC, UA

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    DMARDs

    Azathioprine

    100-200 mg daily

    CBC, LFTs

    ?malignancy potential

    onset 2 - 3 months

    D-Penicillamine

    daily

    slow onset (3-6 months)

    CBC, UA

    autoimmune phenomenon

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    DMARDs

    CyclosporinA

    daily

    BP, UA

    Cyclophosphamide

    refractory cases

    CBC

    Chlorambucil

    CBC

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    New Therapies for RA

    Enbrel

    Soluble tumor necrosis factor fusion protein

    Arava

    Leflunomide

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    Chimeric A2 (cA2) Monoclonal Antibody

    Mouse(binding site for TNF-a)

    Human (IgG1)

    Chimeric (mouse/human) IgG1

    monoclonal antibody

    Binds to TNF-a with high

    affinity and specificity

    Knight, et al.Mol Immunol. 1993.

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    Response to therapy

    AM stiffness, total number swollen, tender

    joints, (S1T2W+)

    perception of pain

    perception of overall response

    health assessment measurement

    ESR, CRP levels

    physicians assessment

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    Criteria for Remission (ACR)

    no fatigue

    morning stiffness for 15 minutes or less

    no joint pain

    no joint tenderness or pain on motion

    no soft tissue swelling in joints or tendon sheath

    ESR

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    RA - long term prognosis

    RA shortens survival and produces disability

    1/3 leave work force in five years

    aggressive DMARD TX can reduce disability by30% in 10-20 years