RHEUMATOID ARTHRITIS

Epidemiology/genetics

Pathogenesis

Clinical Features

Laboratory Manifestations

Diagnosis

Management considerations and therapy

INTRODUCTION

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

RHEUMATOID ARTHRITIS

2.5 million Americans (~1%), 165 million

worldwide

Females > males 3:1; all races

Peak age onset: 4th-5th decade

80% develop between ages 35-50yrs

Prevalence increases with age

EPIDEMIOLOGY

Strongly associated with HLA-DR4

DRB1*0401/0404 severe and erosive

disease

“Shared epitope” on 3rd 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 pro-

inflammatory cytokines

Play a key role in synovitis and tissue destruction

Pro-inflammatory cytokines: TNF alpha, IL-1

and IL-6

GENETICS

Scott D and Kingsley G. N Engl J Med 2006;355:704-712.

Pathophysiological Role of Cytokines + Other Mediators and Inhibitors in RA

HLA-DR4, High titer RF and + CCP ab

Early radiographic erosions

Constitutional symptoms

Insidious onset

Early appearance of rheumatoid nodules

RISK FACTORS FOR AGGRESSIVE RA

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

DISEASE ONSET

OVERVIEW: JOINT INVOLVEMENT

TMJ: 20-30%

C-spine: 40-50%

Shoulder: 50-60%

SC Joints : ?

Elbow: 40-50%

Wrist: 80-90%

Hand:MCP 90-95%PIP 65-90%

Hips: 40-50%

Knees: 60-80%

Ankles: 50-80%

Foot : MTP 50-90% PIP 65-90%

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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

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 DEFORMITY

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SWAN NECK DEFORMITY

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FOOT ABNORMALITIES

TENOSYNOVITIS

Swelling posterior knee

Ruptured popliteal

cyst swelling of calf

(pseudo-phlebitis)

Mimics DVT

“Crescent sign”

BAKER’S CYST

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

AXIAL DISEASE

C SPINE X-RAY

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

EXTRA-ARTICULAR MANIFESTATIONS

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,

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

RHEUMATOID NODULES

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)

CAPLAN’S SYNDROME

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

INTERSTITIAL LUNG DISEASE

Inflamed pleura thicken, calcify + forming adhesions

Pleural fluid reveals:

Low glucose (< 30mg/dl)

High protein (>4 g/dl) and LDH

Low complement (CH50 )

Cellular infiltrates (mononuclear)

Improves with treatment of RA

PLEURISY/PLEURAL DISEASE

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Mild hypochromic normocytic anemia

Thrombocytosis

Lymphadenopathy

Felty’s syndrome

Large granular lymphocyte syndrome

“Pseudo-Felty Syndrome

HEMATOLOGIC INVOLVEMENT

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

FELTY’S SYNDROME

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Treatment:

DMARDs Methotrexate

Splenectomy

TNFi no studies in actual treatment of Felty’s

Steroids improve neutropenia but ↑ risk of infection

FELTY’S 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!

LARGE GRANULAR LYMPHOCYTE SYNDROME

Keratoconjunctivitis sicca

Episcleritis

Local or diffuse

Scleritis

Local or diffuse

Scleromalacia perforans

Choroid and retinal nodules

OCULAR INVOLVEMENT

< 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

RHEUMATOID VASCULITIS

Intermittent (15-20%)

Long clinical remission (10%)

Progressive disease (65-70%)

COURSE OF RA

Social factors:

Early age at diagnosis

↓ socioeconomic

status

Psychosocial stress

Low HAQ scores

Physical factors:

Extra-articular

features

Erosions on x-ray

↑RF + ↑ESR/CRP

Duration of disease

Disability at diagnosis

> 20 swollen joints

RISK FACTORS FOR INCREASED MORBIDITY/MORTALITY

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

MORBIDITY/MORTALITY 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

MORBIDITY/MORTALITY IN RA

No lab test is specific for RA

RF +

Anti-CCP + (anti-cyclic citrullinated peptide

antibody)

Increased ESR/CRP

ANA + (25% of patients)

Anemia +thrombocytosis

LABORATORY MANIFESTATIONS

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

RHEUMATOID FACTOR

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

MNEMONIC FOR +RF

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

ANTI-CCP

Must have 4 of 7 criteria:

Morning stiffness at least 1 ˚

Swelling in 3 or more joints

Swelling of MCP, PIP or wrist joints

Symmetric joint swelling

Radiographic erosions or periarticular osteopenia

SQ rheumatoid nodules

Positive RF

1987 ACR CLASSIFICATION CRITERIA FOR RA

At least 6 weeks

Differential Diagnosis for RA

Comments

Connective tissue diseases

SLE, Systemic sclerosis, Sjogren’s

Hemochromatosis 2nd /3rd MCP joints, distinctly asymmetricCheck 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%)

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

IMPORTANCE OF EARLY DIAGNOSIS

RADIOGRAPHS

A: abnormal alignment

B: bones

C: cartilage

D: deformity

E: erosions

S: soft tissue swelling

RADIOGRAPHIC FEATURES

JOINT SPACE NARROWING, PERIARTICULAR OSTEOPENIA AND EROSIONS

MARGINAL EROSIONS

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

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

OVERVIEW OF RA TREATMENT

O'Dell J. N Engl J Med 2004;350:2591-2602

Keys to Optimizing the Outcome of Treatment

Pros

Controls

inflammation

↓ pain/swelling

Improves mobility, ROM

Improve quality of life

Low cost

Cons

Does not modify

disease progression

GI toxicity

Renal complications

CNS toxicity

NSAID THERAPY

Pros

Anti-inflammatory +

immunosuppressive

effects

Bridge to initiation of

DMARD therapy

Dose of < 10 mg/day

CSI used for joint flares

Cons

Disease progression?

Tapering +

discontinuation difficult

Skin thinning, Cushingoid

appearance, cataracts

Steroid induced

osteopenia/osteoporosis

CORTICOSTEROID THERAPY

Slows disease progression

Decreases radiographic progression

Improves functional disability

Decreases pain + interferes with inflammatory

processes

DISEASE MODIFYING ANTI-RHEUMATIC DRUGS

Pros

Gold standard DMARD

Improves survival

Proven efficacy and

durability in moderate

to severe RA

Used in combination with

other DMARDs

Cons

Labs q 2 months

Bone marrow suppression

Alopecia, stomatitis

Lung + liver toxicity

Contraindicated:

pregnancy, pre-existing

renal + liver disease

(hepatitis)

METHOTREXATE

Pros

Early onset of action (~4

weeks)

Targets autoimmune

lymphocytes anti-

inflammatory

Effective for

moderate/severe RA

Cons

Black box warning:

Hepatotoxicity

HTN, alopecia

GI side effects

diarrhea, weight loss

Contraindicated: severe

liver disease, pregnancy

LEFLUNOMIDE (ARAVA)

Hydroxycloroquine (HCQ) aka plaquenil

Ocular toxicity (eye examination every year)

Sulfasalazine (SSZ)

Reversible oligospermia

Minocycline

Cyclosporine

Gold

OTHER DMARDS

Does not increase toxicity significantly

Long term outcome more favorable

Superior efficacy to monotherapy

Combinations:

MTX/SSZ/HCQ

MTX and biologics

COMBINATION THERAPY

                                                                                                                           

Biologic Therapies

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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-TUMOR NECROSIS FACTOR THERAPY

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

1st line therapy with MTX for high disease activity

ANTI-TNF SUMMARY

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

SAFETY DATA FOR TNF

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-cellsTocilizumab

(Actemra)Humanized monoclonal antibody against IL-6 receptor

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

INITIATING BIOLOGIC THERAPY

Recognize and treat RA early

RA is progressive disability

Newer agents and aggressive therapy offers great

hope for the future of most patients

CONCLUSIONS

ANY QUESTIONS???

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.

BIBLIOGRAPHY

Feldmen M. Nature Reviews 2002;

2:364-371.

Olsen N and Stein C. N Engl J Med 2004;350:2167-2179.

Inflammation in the Rheumatoid Joint