Rheumatoid arthritis

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Rheumatoid Arthritis - Comprehensive Overview

Definition

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory autoimmune disease of unknown etiology, characterized by symmetric inflammatory polyarthritis that primarily targets the synovium. Without treatment, the disease course is progressive, leading to joint destruction, disability, and significant comorbidities including premature cardiovascular disease. Extra-articular manifestations affect up to 40% of patients, particularly those who are seropositive.

Goldman-Cecil Medicine, p. 2790
Washington Manual of Medical Therapeutics, p. 944

Epidemiology

Prevalence: 1-2% of adults; rises to ~10% in those over 65 years
Women : Men ratio = 3:1
Peak incidence: 20-50 years of age
70% have an insidious onset
Higher concordance in monozygotic twins than dizygotic twins, reflecting a genetic basis through MHC class II gene products (HLA-DR)
Textbook of Family Medicine 9e, p. 1603

Pathophysiology

RA involves a complex interaction of genetic predisposition and an unidentified inciting trigger (possibly infectious). The central mechanism:

HLA-DR alleles (part of MHC class II) predispose to disease through triggering by various stimuli
Synovial lining cells and subsynovial vessels proliferate, forming a pannus - an invasive fibrovascular tissue
Leukocytes invade, releasing proteases and cytokines (especially TNF-alpha, IL-1, IL-6)
Rheumatoid factor (RF): autoantibody directed against the Fc fragment of IgG - influenced by HLA-DR polymorphism and associated with more severe, extra-articular disease
Anti-cyclic citrullinated peptide (anti-CCP) antibodies are more specific than RF and appear early in disease
The inflammatory cascade leads to cartilage destruction, bony erosions, and tendon damage

Patients with active, polyarticular, RF-positive RA have >70% chance of developing joint damage within 2 years without treatment.

Textbook of Family Medicine 9e, p. 1605

Clinical Features

Articular Manifestations

The hallmark is symmetric synovitis with morning stiffness lasting >1 hour.

Joints most commonly affected (small joints first):

Metacarpophalangeal (MCP) joints
Proximal interphalangeal (PIP) joints
Wrists, ankles, knees, shoulders

Classic deformities (late disease):

Deformity	Description
Ulnar deviation	MCPs deviated toward ulnar side
Swan neck	MCP flexion, PIP hyperextension, DIP flexion
Boutonniere	PIP flexion, DIP hyperextension
Cock-up toes	Forefoot deformities

Cervical spine - C1-C2 articulation can be involved, causing subluxation that may lead to myelopathy or even death.

Other joints: temporomandibular, cricoarytenoid (hoarseness, rarely acute airway compromise), and sternoclavicular.

Rheumatoid nodules along the extensor surface of the forearm

Rheumatoid nodules - a classic extra-articular manifestation, seen on the extensor surface of the forearm and olecranon bursa (Goldman-Cecil Medicine)

Extra-Articular Manifestations

All extra-articular features are more common in seropositive patients (RF+ or anti-CCP+).

System	Manifestation
Skin	Subcutaneous nodules (~20% of patients, almost exclusively seropositive), vasculitis, pyoderma gangrenosum
Cardiovascular	Pericarditis (50% by echo, usually asymptomatic), premature atherosclerosis, valve disease, increased VTE risk
Pulmonary	Pleural effusions, interstitial lung disease (up to 45%, may be clinically silent), rheumatoid nodules, bronchiolitis obliterans, Caplan syndrome (with dust exposure)
Eyes	Keratoconjunctivitis sicca (secondary Sjögren's, most common), scleritis, episcleritis, scleromalacia perforans
Neurologic	Entrapment neuropathy (carpal tunnel most common), cervical myelopathy, mononeuritis multiplex
Hematologic	Anemia (chronic disease), thrombocytosis, lymphadenopathy, Felty syndrome (splenomegaly + neutropenia), large granular lymphocyte syndrome
Renal	Amyloidosis, vasculitis
Bone	Osteopenia/osteoporosis

Constitutional symptoms (fatigue, weight loss, low-grade fever) are common.

Goldman-Cecil Medicine, p. 2790; Washington Manual, p. 944

Diagnosis

RA is primarily a clinical diagnosis, confirmed by labs and imaging in context.

2010 ACR/EULAR Classification Criteria

(Score-based; a total score ≥6/10 classifies RA in patients with active synovitis)

Domain	Score
Joint involvement	1 large joint = 0; 2-10 large joints = 1; 1-3 small joints = 2; 4-10 small joints = 3; >10 joints (at least 1 small) = 5
Serology	Negative RF and anti-CCP = 0; Low-positive = 2; High-positive = 3
Acute-phase reactants	Normal CRP and ESR = 0; Abnormal = 1
Duration of symptoms	<6 weeks = 0; ≥6 weeks = 1

(The 1987 ACR criteria require 4 of 7 features and ≥6 weeks of symptoms)

Laboratory Tests

Test	Finding in RA
Rheumatoid Factor (RF)	Positive in ~80%; not specific (also positive in hepatitis C, SBE, lymphoma, SLE, Sjögren's, TB - mnemonic CHRONIC)
Anti-CCP antibodies	Positive in 50-60% with early RA; >90% specific for RA; appear before symptoms
ESR / CRP	Elevated (reflect disease activity)
CBC	Normocytic anemia, thrombocytosis
Synovial fluid	WBC >2,000/mm³, no crystals
ANA	Low-titer positive in ~30%

Imaging

Plain radiographs (hands/wrists): periarticular osteopenia, joint space narrowing, bony erosions (appear months to 1 year after onset - late finding)
MRI and ultrasound: more sensitive than X-rays; detect subclinical synovitis and erosions earlier
Washington Manual, p. 944; Textbook of Family Medicine 9e, p. 1610

Treatment

Treatment Goals (Treat-to-Target Strategy)

The target is remission or low disease activity. When treated early, remission is achievable in >50% and low disease activity in at least another 35%.

Treatment pillars:

Pain control
Suppression of inflammation
Prevention of progressive joint destruction
Maintenance of function

Step 1 - NSAIDs

Provide symptomatic relief only - do NOT alter the underlying disease or prevent erosions
Should never be used without a concomitant DMARD
COX-2 inhibitors (e.g., celecoxib) preferred if GI risk; monitor cardiovascular risk
Add PPI for GI protection in all RA patients on NSAIDs

Step 2 - Glucocorticoids

Rapid, dramatic symptom improvement + reduce radiographic progression
Used as "bridge therapy" while waiting for DMARDs to take effect (2-6 months)
Prednisone: rarely exceed 10 mg/day; slow taper to lowest effective dose
Always use with concomitant DMARD - never as monotherapy long-term
Monitor for: infection risk (25% increased at 5 mg/day; doubled at 5-10 mg/day), osteoporosis (prescribe bisphosphonate prophylaxis)
Intra-articular injections useful for refractory joint flares

Step 3 - DMARDs (cornerstone of therapy)

DMARDs are initiated as soon as RA is diagnosed - they modify the disease course by halting erosion and synovial destruction.

Conventional (csDMARDs)

Drug	Dose / Notes	Monitoring
Methotrexate (MTX)	First-line anchor DMARD for most patients; economical; makes all other DMARDs work better; contraindicated in pregnancy	CBC + AST/ALT every 8-12 weeks; supplement with folic acid
Hydroxychloroquine	200 mg PO once or twice daily; least toxic csDMARD; use for mild RA	Eye exam at 6 months; yearly after 5 years of therapy; keep dose <5 mg/kg/day
Sulfasalazine	2-3 g/day in divided doses; used alone if no poor prognostic factors	CBC for neutropenia (monthly x1 month, then every 4-6 weeks); check sulfa allergy
Leflunomide	Alternative to MTX; long half-life (cholestyramine washout needed); contraindicated in pregnancy	CBC + AST/ALT every 4-8 weeks

Note: Hydroxychloroquine < Sulfasalazine < Methotrexate - in order of increasing toxicity

Poor prognostic factors favoring early aggressive DMARD use:

Functional limitation
Extra-articular disease
RF+ or anti-CCP+
Bony erosions on imaging

Biologic DMARDs (bDMARDs)

Used when conventional DMARDs are inadequate. Usually added to MTX.

Class	Examples	Target
TNF inhibitors	Etanercept, adalimumab, infliximab, certolizumab, golimumab	TNF-alpha
IL-6 receptor inhibitors	Tocilizumab, sarilumab	IL-6 receptor
B-cell depletion	Rituximab	CD20 on B cells
T-cell co-stimulation blocker	Abatacept	CD80/CD86 on APCs
IL-1 inhibitor	Anakinra	IL-1 receptor

Caution with biologics: Stop if fevers/infection symptoms appear; risk of reactivating latent TB (screen before starting TNF inhibitors); may precipitate CHF, demyelinating disease, or lupus-like syndromes.

Targeted Synthetic DMARDs (tsDMARDs) - JAK inhibitors

Drug	Notes
Baricitinib	Effective after inadequate DMARD response; superior to adalimumab in MTX-inadequate responders
Tofacitinib, upadacitinib	JAK1/2 or JAK1-selective inhibitors

Goldman-Cecil Medicine, p. 2795-2796

Monitoring Disease Activity

Common validated tools:

DAS28 (Disease Activity Score using 28 joint count)
CDAI (Clinical Disease Activity Index)
SDAI (Simplified Disease Activity Index)

Regular monitoring of:

CBC, liver enzymes, renal function (per DMARD used)
ESR/CRP
Joint counts and functional status
Annual ophthalmology if on hydroxychloroquine (after 5 years)
Bone density (with glucocorticoids)
Cardiovascular risk factors

Complications & Comorbidities

Cardiovascular disease: RA patients have significantly increased morbidity/mortality from CAD and heart failure. Chronic inflammation accelerates atherosclerosis beyond conventional risk factors
Infection: Increased susceptibility, worsened by immunosuppressive therapy
Osteoporosis: From disease-related inflammation + glucocorticoid use
Malignancy: Slightly increased risk of lymphoma (especially with high disease activity)
Felty syndrome: RA + splenomegaly + profound neutropenia (rare, ~1%)
Cervical myelopathy: From C1-C2 subluxation

Key Takeaways

RA is a systemic autoimmune disease, not just a joint disease
Early diagnosis and early aggressive DMARD therapy are the most important interventions
Methotrexate is the anchor first-line DMARD
NSAIDs and glucocorticoids are adjuncts only - never monotherapy substitutes for DMARDs
Anti-CCP antibodies are more specific than RF for diagnosis
Seropositive patients (RF+/anti-CCP+) have worse prognosis and more extra-articular disease
Treat-to-target (remission or low disease activity) is the modern standard of care

Sources: Goldman-Cecil Medicine (International Edition), Textbook of Family Medicine 9e, Washington Manual of Medical Therapeutics

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