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RHEUMATOID ARTHRITIS
INTRODUCTION
 Epidemiology/genetics
 Pathogenesis
 Clinical Features
 Laboratory Manifestations
 Diagnosis
 Management considerations and therapy
RHEUMATOID ARTHRITIS
 Chronic, systemic inflammatory disease
 Unknown etiology
 Persistent inflammatory synovitis
 Synovial inflammation (pannus) cartilage destruction,
bone erosion with subsequent deformity
 Peripheral joints in symmetric fashion
 Extra-articular manifestations also occur
EPIDEMIOLOGY
 2.5 million Americans (~1%), 165 million worldwide
 Females > males 3:1; all races
 Peak age onset: 4 th -5 th decade
 80% develop between ages 35-50yrs
 Prevalence increases with age
GENETICS
 Strongly associated with HLA -DR4
 DRB1*0401/0404  severe and erosive disease
 “Shared epitope” on 3 rd hypervariable region of HLA DRB1
 + HLA-DR4 seen in 20-30% of general population
 Other factors involved for disease to develop
GENETICS
 T lymphocytes recognizing antigens in synovial tissue
 T cells, macrophages + fibroblasts produce proinflammatory cytokines
 Play a key role in synovitis and tissue destruction
 Pro-inflammatory cytokines: TNF alpha, IL-1 and IL-6
Pathophysiological Role of Cytokines + Other Mediators and Inhibitors in RA
Scott D and Kingsley G. N Engl J Med 2006;355:704-712.
RISK FACTORS FOR AGGRESSIVE RA
 HLA-DR4, High titer RF and + CCP ab
 Early radiographic erosions
 Constitutional symptoms
 Insidious onset
 Early appearance of rheumatoid nodules
DISEASE ONSET
 Insidious: Most common presentation
 Small peripheral joints: MCPs, PIPs, wrists
 Abrupt:
 Acute polyarthritis  Intense pain, swelling + limitation
 Slow monoarticular:
 Knees/shoulders  progresses to small joints
OVERVIEW: JOINT INVOLVEMENT
TMJ: 20-30%
C-spine: 40-50%
Hips: 40-50%
Shoulder: 50-60%
Knees: 60-80%
SC Joints : ?
Ankles: 50-80%
Elbow: 40-50%
Foot :
MTP 50-90%
PIP 65-90%
Wrist: 80-90%
Hand:
MCP 90-95%
PIP 65-90%
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CLINICAL FEATURES
 Symmetric inflammatory synovitis (palpable
swelling) of small peripheral joints
 Tenderness to palpation and ROM
 Symptoms last > 6 weeks
 Useful indicator of disease activity
 Morning stiffness > 1˚  improves with activity
CLINICAL FEATURES
 Symmetric polyarticular joint involvement (>3 joints)
 Small joint arthropathy: MCPs, PIPs, wrists, MTPs
 Knees, ankles and shoulders
 Typically spares: thoracolumbar spine + DIP joints
 Entrapment syndromes also commonly occur
 Carpal tunnel and tarsal tunnel
BOUTONNIERE DEFORMIT Y
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SWAN NECK DEFORMIT Y
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FOOT ABNORMALITIES
TENOSYNOVITIS
BAKER’S CYST
 Swelling posterior knee
 Ruptured popliteal
cyst swelling of calf
(pseudo-phlebitis)
 Mimics DV T
 “Crescent sign”
AXIAL DISEASE
AXIAL DISEASE
 Anterior alantoaxial subluxation of C1-2 common
 ≥ 3 mm separation between odontoid and atlas
 Recurrent HA, tingling in UE, unexplained dizziness
 Susceptible to trauma with endotracheal intubation
 Must get pre-op X-rays of neck (lateral flexion/extension)
 Symptomatic cervical myelopathy  spinal fusion
C SPINE X-RAY
EXTRA-ARTICULAR MANIFESTATIONS
 40% of patients
 Increased frequency:
 +RF, +CCP ab, HLA-DR1 +DR4
 Environmental factors such as smoking
 Life expectancy loss of 18 yrs
 5x mortality risk
Organ System
Systemic Extra-Articular Manifestations
General
Fever, LAD, weight loss and fatigue
Bone
Osteopenia and osteoporosis
Cardiovascular
CAD, MI, pericarditis, myocarditis, coronary vasculitis,
nodules on the valves
Dermatologic
Palmar erythema, subcutaneous nodules, vasculitis
Hematologic
Anemia, thrombocytosis, Felty’s syndrome, LGL, NHL
Neuromuscular
Entrapment neuropathy, peripheral neuropathy,
mononeuritis multiplex
Ocular
Keratoconjunctivits sicca, scleritis, episcleritis, peripheral
ulcerative keratitis
Other
Sjogrens syndrome, amyloidosis, vasculitis
Pulmonary
Pleural Effusion, pleuritis, nodules, ILD, bronchiolitis
obliterans,
RHEUMATOID NODULES
 20-40%of SPRA patients
 Reflects level of RA disease activity
 Develops on pressure areas
 Risk factors: +RF, subchondral cysts, Methotrexate(MTX)
RHEUMATOID NODULES
 Single/multiple nodules
 Interfere with
function/ulcerate
 Regress with DMARDS
 MTX may result in ↑
nodulosis
RHEUMATOID NODULES
 May involve internal organs
 Sites of movement:
 Pulmonary parenchyma/pleura
 Pericardium/myocardium
 Heart valves
 Vocal cords
CAPLAN’S SYNDROME
 Pulmonary nodulosis + pneumoconiosis
 Exposure to inorganic dusts (coal, asbestos, silca)
 Similar to simple rheumatoid nodules
 Modified tissue response to inhaled dusts
 May lead to progressive massive fibrosis (PMF)
INTERSTITIAL LUNG DISEASE
 Most common lung manifestation
 ↑ mesenchymal reactivity  fibrosis
 PE: fine, diffuse dry rales; low DLCO
 CXR:
 Reticular/reticulonodular pattern  honeycombing
INTERSTITIAL LUNG DISEASE
 Wide spectrum of findings on lung biopsy
 Histologic finding  idiopathic interstitial pneumonia (IIP)
 Tx: “ground-glass” on HRCT  good response to tx
 High dose steroids, imuran and cytoxan
PLEURISY/PLEURAL DISEASE
 Inflamed pleura  thicken, calcify + forming adhesions
 Pleural fluid reveals:
 Low glucose (< 30mg/dl)
 High protein (>4 g/dl) and LDH
 Low complement (CH 50 )
 Cellular infiltrates (mononuclear)
 Improves with treatment of RA
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HEMATOLOGIC INVOLVEMENT
 Mild hypochromic normocytic anemia
 Thrombocytosis
 Lymphadenopathy
 Felty’s syndrome
 Large granular lymphocyte syndrome
 “Pseudo-Felty Syndrome
FELT Y’S SYNDROME
 Classic triad: RA, neutropenia, splenomegaly
 Risk factors: RF+, nodular RA and +HLADR4
 Manifestations:
 Non-healing leg ulcers
 Infections
 PMNs < 1000/mm3
 Common cause of death
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FELT Y’S SYNDROME
 Treatment:
 DMARDs  Methotrexate
 Splenectomy
 TNFi  no studies in actual treatment of Felty’s
 Steroids improve neutropenia but ↑ risk of infection
LARGE GRANULAR LYMPHOCY TE
SYNDROME
 Variant of Felty’s
 Peripheral blood or bone
marrow  LGL cells
 Circulating LGLs,
neutropenia, frequent
infections, splenomegaly
 3-14%  leukemia unlike
Felty’s. No splenectomy!
OCULAR INVOLVEMENT
 Keratoconjunctivitis sicca
 Episcleritis
 Local or diffuse
 Scleritis
 Local or diffuse
 Scleromalacia perforans
 Choroid and retinal nodules
RHEUMATOID VASCULITIS
 < 1% of RA pts
 Risk factors:
 High titer RF & long standing, severe disease (> 10yrs )
 Male gender
 Smoking
 Prior DMARD use
 Hypocomplemetemia
 Circulating cryoglobins
RHEUMATOID VASCULITIS
 Clinical presentations:
 Cutaneous ulcerations
 Mononeuritis multiplex
 Foot/wrist drop
 Palpable purpura
 Distal arteritis
 Visceral arteritis:
 Heart, lungs, bowel, spleen, kidneys
COURSE OF RA
 Intermittent (15-20%)
 Long clinical remission (10%)
 Progressive disease (65-70%)
RISK FACTORS FOR INCREASED
MORBIDIT Y/MORTALIT Y
Social factors:
Physical factors:
 Early age at diagnosis
 Extra-articular features
 ↓ socioeconomic status
 Erosions on x-ray
 Psychosocial stress
 ↑RF + ↑ESR/CRP
 Low HAQ scores
 Duration of disease
 Disability at diagnosis
 > 20 swollen joints
MORBIDIT Y/MORTALIT Y IN RA
 Median life expectancy decreased by 3 -18 yrs
 Mortality rates higher with extra-articular manifestions
and women
 ~50% stop working within 5-10ys of diagnosis
 ~80% disabled to some degree after 20 yrs
MORBIDIT Y/MORTALIT Y IN RA
 Infection: 70% more likely to have infection
 Don’t forget septic arthritis in RA patients  arthocentesis
 NH lymphoma: 2-5 fold increased risk
 CAD: 3x the risk of sudden death/MI
 Cerebrovascular diseases:
 70% more likely to have a stroke
LABORATORY MANIFESTATIONS
 No lab test is specific for RA
 RF +
 Anti-CCP + (anti-cyclic citrullinated peptide antibody)
 Increased ESR/CRP
 ANA + (25% of patients)
 Anemia +thrombocytosis
RHEUMATOID FACTOR
 Usually IgM Ab recognizes Fc portion of IgG molecule
 70% RF+ at onset, 85% overall in first 2 years
 High titer  severe disease, extra-articular
manifestations, increased mortality
 Normal 1-4%, 10-25% + over age 70
MNEMONIC FOR +RF
 CHronic:
 CH: Chronic diseases  liver/pulmonary/sarcoidosis
 R: Rheumatoid arthritis
 O: Other CTDS (SLE, SS, MCTD)
 N: Neoplasms (XRT, chemotherapy)
 I: Infections (SBE, HIV, Hepatitis B+C, TB, Parvovirus B19)
 C: Cryoglobinemia
ANTI-CCP
 Autoantibody directed at cyclic citrullinated peptide
 Sensitivity 65-70%, specificity (95%)
 RF and CCP ab combination  specificity 99.5%
 Detectable in early RA
 May antedate onset of inflammatory disease
 Predictor of aggressive + erosive disease
1987 ACR CLASSIFICATION CRITERIA
FOR RA
Must have 4 of 7 criteria:
 Morning stiffness at least 1 ˚
 Swelling in 3 or more joints
 Swelling of MCP, PIP or wrist joints
At least 6
weeks
 Symmetric joint swelling
 Radiographic erosions or periarticular osteopenia
 SQ rheumatoid nodules
 Positive RF
Differential Diagnosis for RA
Comments
Connective tissue diseases
SLE, Systemic sclerosis, Sjogren’s
Hemochromatosis
2nd /3rd MCP joints, distinctly asymmetric
Check iron studies and skin changes
Infectious endocarditis
R/o murmurs, high fever and IVDA
Polyarticular gout
Joints often erythematous, rarely coexists with
RA
PMR
Unlike PMR, RA rarely presents with proximal
extremity pain
Sarcoidosis
Granulomas likely, as are hypercalcemia and
chest X-ray findings common
Seronegative spondyloarthopathy
Tends to be more asymmteric than RA and
typically involves the spine.
Still’s disease
Fever, leukocytosis, sore throat, liver
dysfunction and salmon colored rash
Viral arthritis
Parvovirus B19, hepatitis B and C
PARVOVIRUS B19
 Symmetrical polyarthritis of peripheral small joints
 May resemble RA as well as SLE
 More common in adults (60%) > children (5-10%)
 Daycare worker or mother of small children
 Check B19 IgM antibodies or viral B19 DNA
 Self limited  but may require further treatment
WORK-UP FOR AN INFLAMMATORY
ARTHRITIS
 CBC, CMP, UA, RF/CCP, ESR/CRP
 Uric acid, HIV, chronic hepatitis, Parvovirus B19 IgM,
TSH, ANA, PPD
 X-rays: bilateral hands/feet + chest X -ray
 Arthrocentesis:
 Inflammatory  WBC 5,000-50,000 (N 60-80%)
IMPORTANCE OF EARLY DIAGNOSIS
 RA is progressive
 Structural damage occurs within first 2-3 years of disease
 70% have radiographic damage with in first 3 years
 MRI reveals erosions earlier in disease
 Early aggressive treatment  slows progression
+disability
RADIOGRAPHS
RADIOGRAPHIC FEATURES
 A: abnormal alignment
 B: bones
 C: cartilage
 D: deformity
 E: erosions
 S: soft tissue swelling
JOINT SPACE NARROWING, PERIARTICULAR
OSTEOPENIA AND EROSIONS
MARGINAL EROSIONS
RA TREATMENT
 Step up or step down approach  achieve remission
 Treat early disease aggressively and alleviate pain
 Maintain function for essential daily activities
 Maximize quality of life
 Slow progression/rate of joint damage
OVERVIEW OF RA TREATMENT
 Patient education
 Modify CAD RF and Stop smoking !!!
 NSAIDs + low dose corticosteroids
 Disease modifying agents (DMARDs)
 Biologics
 Physical/occupational therapy
 Surgery for structural joint damage
Keys to Optimizing the Outcome of Treatment
O'Dell J. N Engl J Med 2004;350:2591-2602
NSAID THERAPY
Pros
Cons
 Controls inflammation
 Does not modify
 ↓ pain/swelling
disease progression
 Improves mobility, ROM
 GI toxicity
 Improve quality of life
 Renal complications
 Low cost
 CNS toxicity
CORTICOSTEROID THERAPY
Pros
Cons
 Anti-inflammatory +
 Disease progression?
immunosuppressive
effects
 Bridge to initiation of
DMARD therapy
 Dose of < 10 mg/day
 CSI used for joint flares
 Tapering + discontinuation
difficult
 Skin thinning, Cushingoid
appearance, cataracts
 Steroid induced
osteopenia/osteoporosis
DISEASE MODIFYING ANTI-RHEUMATIC
DRUGS
 Slows disease progression
 Decreases radiographic progression
 Improves functional disability
 Decreases pain + interferes with inflammatory
processes
METHOTREXATE
Pros
Cons
 Gold standard DMARD
 Labs q 2 months
 Improves survival
 Bone marrow suppression
 Proven ef ficacy and
 Alopecia, stomatitis
durability in moderate to
severe RA
 Used in combination with
other DMARDs
 Lung + liver toxicity
 Contraindicated: pregnancy,
pre-existing renal + liver
disease (hepatitis)
LEFLUNOMIDE (ARAVA)
Pros
Cons
 Early onset of action (~4
 Black box warning:
weeks)
 Targets autoimmune
lymphocytes  antiinflammatory
 Effective for
moderate/severe RA
Hepatotoxicity
 HTN, alopecia
 GI side effects 
diarrhea, weight loss
 Contraindicated: severe
liver disease, pregnancy
OTHER DMARDS
 Hydroxycloroquine (HCQ) aka plaquenil
 Ocular toxicity (eye examination every year)
 Sulfasalazine (SSZ)
 Reversible oligospermia
 Minocycline
 Cyclosporine
 Gold
COMBINATION THERAPY
 Does not increase toxicity significantly
 Long term outcome more favorable
 Superior efficacy to monotherapy
 Combinations:
 MTX/SSZ/HCQ
 MTX and biologics
Biologic Therapies
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ANTI-TUMOR NECROSIS FACTOR THERAPY
 FDA approved:
 Infliximab (Remicaide)  IV infusion
 Given with MTX to reduce human anti-chimeric ab (HACAs)
 Adalimumab (Humira)
 Etanercept (Enbrel)
 Certoluzimab pegol (Cimzia)
 Golimumab (Simponi)
ANTI-TNF SUMMARY
 Rapid onset of action with improvement in symptoms
 Disability and quality of life
 Inhibition of radiographic progression
 Sustained efficacy of at least 5 years
 Class effect
 1 st line therapy with MTX for high disease activity
SAFET Y DATA FOR TNF
 Serious infections (opportunistic fungal, TB)
 Infusion, injection reactions
 Malignancy potential
 Neurologic/demyelinating disease
 Autoab (ANA + DS DNA) and lupus like syndrome
 CHF worsening, new onset
OTHER BIOLOGICS
 Anakinra (Kineret)
 IL-1 receptor antagonist
 Rituximab (Rituxan)
 Chimeric monoclonal
IgG1 anti-CD20
antibody
 B lymphocyte depletion
 Abatacept (Orencia)
 CTLA-4Ig
 Support or abrogate
activation of T-cells
 Tocilizumab (Actemra)
 Humanized
monoclonal antibody
against IL-6 receptor
INITIATING BIOLOGIC THERAPY
 Basic labs: CBC, CMP
 PPD (TB screen) or quantiferon gold
 Chronic hepatitis panel and HIV
 Routine health screening and vaccinations:
 Flu and PNA
 No live vaccines after initiation of therapy
 Ensure routine cancer screening UTD
CONCLUSIONS
 Recognize and treat RA early
 RA is progressive  disability
 Newer agents and aggressive therapy offers great
hope for the future of most patients
ANY QUESTIONS???
BIBLIOGRAPHY
 Feldmann M. Development of anti -TNF therapy for rheumatoid
arthritis. Nature Review. 2002;
2:364-371.
 Turesson C, et al. Extra-articular disease manifestations in
rheumatoid arthritis: incidence of trends and risk factors over
46 years. Ann Rheum Dis 2003; 62: 722-727.
 Turesson C, et al. Rheumatoid factor and antibodies to cyclic
citullinated peptides are associated with severe extra articular manifestations in rheumatoid arthritis. Ann Rheum
Dis 2007; 66:59-64.
 Turesson C, Matteson E. Vasculitis in Rheaumatoid Arthritis.
Current Opinion in Rheumatology. Feb 2009.
 Levesque M. Systemic Extra -articular manifestations of
rheumatoid arthritis. Medscape 2008.
BIBLIOGRAPHY
 Scott et al. Tumor Necrosis Factor Inhibitors for Rheumatoid
arthritis. N Engl J Med 2006; 355: 704-12.
 Olson et al. New Drugs for Rheumatoid Arthritis. N Engl J
Med 2004; 350:2167-79.
 Odell, J. Therapeutic Strategies for Rheumatoid Arthritis. N
Engl J Med 2004; 350: 2591-602.
 Harris E, et al. Overview of the systemic and nonarticular
manifestations of rheumatoid arthritis. Uptodate June 09.
 Odell JR et al. Treatment of rheumatoid arthritis with
methotrexate alone, sulfasalazine and hydroxychloroquine, or
a combination of all three medications. N Engl J Med 1996;
334: 1287-91.
Feldmen M. Nature Reviews 2002; 2:364-371.
Inflammation in the Rheumatoid Joint
Olsen N and Stein C. N Engl J Med 2004;350:2167-2179.