RHEUMATOID ARTHRITIS

Introduction
Clinical

features Laboratory features Extra-articular features Management considerations and paradigms Prognosis

RA - Definition
Chronic

systemic inflammatory disorder Unknown etiology Symmetrical joints Synovium affected Bone, cartilage, ligaments Deformity Extra-articular manifestations

RA - Definition
Clinical

diagnosis Cymmetric polyarthritis of small joints

subacute acute

Rheumatoid

factor positivity Erosive disease

RA - Epidemiology
Worldwide All

distribution

races Female > male 3:1 Usual age of onset 20-40 years though individuals of any age group may be affected Genetic associations
HLA-DR4,

DR1

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 two years
associated

with more severe disease, extraarticular manifestations, mortality

Etiology
Probable

background genetic susceptibility (multiple genes/risk factors involved) Concordance rates 15-30% identical twins 2.5-3.0 times more prevalent in Women>Men Family history Female Sex Specific genes: HLA-DR4 Specific region in HLA DRB1 gene confers increased risk of RA and severity

Case Presentation:
55 YOF complains of months of bilateral hand pain. She describes progressive morning stiffness lasting 3 hours with wrist, MCP, and PIP pain and swelling. She has also noted some discomfort and perhaps swelling in her wrists, shoulders, knees, and toes.

Rheumatoid Arthritis

Rheumatoid nodule

Case Presentation:
Physical

exam is notable for swelling, tenderness, and warmth in the elbows, wrists, MCPs, PIPs, knees, and MTPs with non-tender soft tissue nodules over the olecronon.

Laboratory abnormalities
anemia

of chronic disease thrombocytosis in active disease

ESR CRP

rays of joints Rheumatoid factor ACPA

RA: Erosion Progression

Rheumatoid arthritis- late stage

Extra-articular manifestations
General
fever,

lymphadenopathy, weight loss, fatigue erythema, nodules, vasculitis

Dermatologic
palmar

Ocular
episcleritis/scleritis,

scleromalacia perforans, choroid and retinal nodules

Extra-articular manifestations
Cardiac
pericarditis,

myocarditis, coronary vasculitis, nodules on valves neuropathy, peripheral neuropathy, mononeuritis multiplex, cervical cord compression syndrome, large granular lymphocyte syndrome, lymphomas

Neuromuscular
entrapment

Hematologic
Feltys

Extra-articular manifestations
Pulmonary
pleuritis,

nodules, interstitial lung disease, bronchiolitis obliterans, arteritis, effusions syndrome, amyloidosis

Others
Sjogrens

Feltys syndrome
classic
RA,

triad

splenomegaly, leukopenia

a neutropenia (<2000/mm3) thrombocytopenia may occur complications

generally
infections,

non-healing leg ulcers

most

require no additional treatment for cytopenias splenectomy?

D.Dx of a positive RF
normal

- 1-4%, 10-25% over age 70 systemic autoimmune diseases infections malignancy chronic liver disease pulmonary diseases

ANA in RA
25%

RA are positive for ANA other serologies usually negative ? more severe disease (RA) with worse prognosis

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

RA - differential diagnosis
Common

diseases
fever

Spondyloarthropathies rheumatic CTDs viral

infections fibromyalgia

RA - differential diagnosis
Uncommon
hypothyroidism SBE sarcoidosis lyme

disease amyloid HIV malignancies/paraneoplastic syndromes

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 the benefits of early treatment Need to include ACPA (CCP) Balance with need for use in low resource settings where CCP not available Goal of new criteria: predict who should be treated with DMARDs

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 (<6 wk, 6+ wk) ESR and/or CRP (both normal vs. one abnormal)

ACR Guidelines for Management

Summarize

evidence for DMARDs and biologics in different settings Incorporate the following in treatment decisions

Disease duration (<6mo, 6-24, >24 mo) Disease activity (low, moderate, high) Features of poor prognosis

Measurement of Disease Activity: DAS28 as Example

DAS28

= 0.56 * sqrt(tender28) + 0.28 * sqrt(swollen28) + 0.70 * ln(ESR) + 0.014 * GH Includes:

Tender joint count Swollen joint count ESR (or CRP in different version) GH: Patient global disease activity assessment Categorized as low, moderate, or high

Poor Prognostic Factors in RA

Presence

of RF and/or CCP antibodies Radiographic erosions Functional limitation Extraarticular disease

RA - Management
Non-pharmacologic
rest
fatigue,

splinting

pain

relief
cold, ultrasound, paraffin, massage

heat,

physical

therapy occupational therapy Patient education

RA - Management
Pharmacologic
analgesics NSAIDs

- full dose corticosteroids

at low dose - bridge, burst intra-articular steroids
prednisone

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

DMARDs
hydroxychloroquine
mild

non-erosive disease combinations 200 mg bid eye exams

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

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

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

DMARDs
Cyclosporin
daily BP,

UA cases

Cyclophosphamide
refractory CBC

Chlorambucil
CBC

New Therapies for RA

Enbrel
Soluble

tumor necrosis factor fusion protein

Arava
Leflunomide

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.

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

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 <30 mm/hr (women) or 20 mm/hr (men)

5 of 6 present for 2 months no vasculitis, pericarditis, pleuritis, myositis, weight loss, fever

RA - long term prognosis

RA

shortens survival and produces disability 1/3 leave work force in five years aggressive DMARD TX can reduce disability by 30% in 10-20 years