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Rheumatoid Arthritis (RA)

Source: Goldman-Cecil Medicine, 26th ed. | Firestein & Kelley's Textbook of Rheumatology

Definition

Rheumatoid arthritis is a chronic systemic inflammatory disease of unknown etiology that primarily targets synovial tissues. While the joint is the primary target, systemic inflammation drives important comorbidities including cardiovascular disease, osteoporosis, cognitive dysfunction, and cancer.

Epidemiology

Global prevalence: 0.5-1% of adults
Women are affected ~3x more than men (before menopause)
Incidence: ~40/100,000 per year in women; ~20/100,000 in men
Can occur at any age; prevalence rises with each decade
Heritability ~60%; monozygotic twin concordance 12-15%

Clinical Features

Articular (Joint) Manifestations

Early disease:

Typically begins in the small joints of the hands (PIP and MCP joints) and toes (MTP joints)
Importantly, DIP joints are characteristically spared (unlike OA and psoriatic arthritis)
Morning stiffness lasting >1 hour is characteristic
Joints are warm, swollen, and tender - symmetrical involvement

Later disease:

Larger joints become involved: wrists, knees, elbows, ankles, hips, and shoulders
Cervical spine (C1-C2 articulation) - uniquely involved among the axial skeleton; can cause atlantoaxial subluxation, cervical myelopathy, and even death
Temporomandibular, cricoarytenoid (hoarseness, respiratory distress), and sternoclavicular joints can be affected

Characteristic deformities (advanced disease):

Severe advanced RA of the hands showing ulnar deviation of MCPs, swan-neck deformity, and dorsal wrist swelling

Severe advanced RA - ulnar deviation of MCP joints, swan-neck deformity, massive dorsal wrist tendon swelling, and severe muscle wasting

Deformity	Description
Ulnar deviation	MCPs deviate toward the ulnar side
Swan-neck deformity	PIP hyperextension + DIP flexion
Boutonniere deformity	PIP flexion + DIP hyperextension
Z-deformity of thumb	IP hyperextension + MCP flexion
Volar subluxation	MCPs and wrists

Extra-Articular Manifestations

Systemic features (fatigue, weight loss, low-grade fever) are common. All other extra-articular features are more common in seropositive (RF+ or ACPA+) patients.

Skin:

Rheumatoid nodules - in ~20% of patients, almost exclusively seropositive; firm, non-tender; extensor surfaces (forearms), over joints and pressure points; can also appear in lungs, heart, and eye
Rheumatoid vasculitis - small brown infarcts of palms/fingers

Pulmonary:

Pleural effusion (most common pulmonary manifestation)
Interstitial lung disease (ILD) - NSIP and UIP patterns
Pulmonary nodules, bronchiectasis
Caplan syndrome (pneumoconiosis + RA)

Cardiac:

Pericarditis (most common cardiac manifestation)
Accelerated atherosclerosis/coronary artery disease (major cause of excess mortality)
Myocarditis, conduction defects

Neurologic:

Carpal tunnel syndrome (median nerve entrapment) - common
Tarsal tunnel syndrome
Mononeuritis multiplex (from vasculitis)
C1-C2 subluxation causing cervical myelopathy

Ocular:

Keratoconjunctivitis sicca (secondary Sjögren's) - most common
Episcleritis, scleritis, scleromalacia perforans

Hematologic:

Anemia of chronic disease (most common)
Felty syndrome - triad of RA + splenomegaly + neutropenia; seen in severe RF/ACPA-positive disease

Diagnosis

RA has no single pathognomonic finding. Diagnosis requires a combination of history, physical exam, labs, and imaging.

2010 ACR/EULAR Classification Criteria

(Score ≥6/10 = classifiable as RA)

Domain	Criteria	Points
Joint involvement	1 large joint	0
	2-10 large joints	1
	1-3 small joints (±large)	2
	4-10 small joints (±large)	3
	>10 joints (at least 1 small)	5
Serology	Negative RF and ACPA	0
	Low-positive RF or ACPA	2
	High-positive RF or ACPA (>3x ULN)	3
Acute-phase reactants	Normal CRP and ESR	0
	Abnormal CRP or ESR	1
Duration	<6 weeks	0
	≥6 weeks	1

Laboratory Findings

Test	Findings
Rheumatoid Factor (RF)	Positive in ~70-80%; non-specific (also positive in SLE, Sjögren's, infections, healthy elderly)
Anti-CCP (ACPA)	More specific (~95%) than RF; high-titer ACPA predicts more aggressive disease
CRP / ESR	Elevated - correlate with disease activity
CBC	Normocytic anemia; thrombocytosis; neutropenia in Felty's
Synovial fluid	Inflammatory (WBC 5,000-50,000; predominantly neutrophils)

Imaging

X-ray - periarticular osteopenia and soft tissue swelling (early); bony erosions and joint space narrowing (later)
Ultrasound - detects synovitis and erosions in early disease before X-ray changes
MRI - most sensitive for early synovitis, bone marrow edema, and erosions

Differential Diagnosis

Conditions that must be excluded include:

Systemic lupus erythematosus (oral ulcers, rash, renal disease)
Psoriatic arthritis (DIP involvement, nail changes, rash)
Reactive arthritis (urethritis, history of infection)
Crystal arthropathies (gout, CPPD)
Viral polyarthritis (self-limiting ~2-3 weeks)
Polymyalgia rheumatica (elderly, shoulder/hip girdle, high ESR)

Treatment

The guiding principle is "treat-to-target" - aiming for clinical remission (DAS28 <2.6) or at minimum low disease activity. Early aggressive therapy with DMARDs prevents irreversible joint damage.

Treatment Algorithm

Phase I - Conventional Synthetic DMARDs (csDMARDs)

Methotrexate (MTX) - anchor drug and first-line therapy

Oral or SC; usually 15-25 mg/week
Folic acid supplementation required to reduce side effects (mucositis, cytopenias)
Monitor: LFTs, CBC, creatinine
Contraindicated in pregnancy, hepatic disease, significant renal impairment

Leflunomide - alternative to MTX

Prodrug converted to teriflunomide; inhibits pyrimidine synthesis
10-20 mg/day; teratogenic (very long half-life - requires cholestyramine washout)
Monitor LFTs

Hydroxychloroquine (antimalarial)

200-400 mg/day (max 5 mg/kg)
Least toxicity of all DMARDs; no blood test monitoring needed
Annual ophthalmology review after 5 years (retinal toxicity - rare)
Decreases cholesterol and reduces incidence of diabetes

Sulfasalazine

1-3 g/day
Monitor CBC (especially WBC) in first 6 months

Triple therapy (MTX + sulfasalazine + hydroxychloroquine) has efficacy similar to TNF inhibitor + MTX, and is more economical.

Glucocorticoids - bridge therapy during DMARD initiation; short-term only; avoid long-term use

Phase II - Biologic DMARDs (bDMARDs) or JAK Inhibitors

Used when csDMARDs fail, especially if poor prognostic factors are present (high-titer RF/ACPA, high disease activity, early joint damage, failure of ≥2 csDMARDs).

Drug Class	Examples	Notes
TNF inhibitors	Etanercept, infliximab, adalimumab, golimumab, certolizumab	Most widely used; always screen for latent TB before starting
IL-6 receptor blockers	Tocilizumab, sarilumab	Tocilizumab superior to rituximab; effective as monotherapy
T-cell costimulation blocker	Abatacept (anti-CTLA4-Ig)	Blocks CD80/86-CD28 interaction
B-cell depletion	Rituximab (anti-CD20)	Useful in patients with prior malignancy; requires premedication
IL-1 inhibitor	Anakinra	Rarely used in RA
JAK inhibitors (tsDMARDs)	Tofacitinib, baricitinib, upadacitinib	Oral; comparable to biologics; caution re: thromboembolism, cardiac events

All biologic therapies require infection monitoring - risk of atypical and opportunistic infections. Screen for latent TB and hepatitis B before initiation.

Phase III - Refractory Disease

Switch to a bDMARD or JAK inhibitor from a different class (or same class, different agent). Continue reassessing at 3 months; target at 6 months. Dose reduction is possible in sustained remission.

Non-Pharmacologic Measures

Occupational therapy and joint protection strategies
Physiotherapy to maintain range of motion and muscle strength
Orthotics/splints (especially wrist and hand)
Surgical intervention for severely damaged joints (synovectomy, joint replacement)
Cardiovascular risk factor management (RA independently doubles CV risk)
Osteoporosis prophylaxis (calcium, vitamin D; bisphosphonates if on glucocorticoids)
Smoking cessation (smoking is a major modifiable risk factor for RA and worsens disease)

Key takeaway: RA is a treat-to-target disease. Start MTX early, assess at 3 months, and escalate to bDMARDs/JAK inhibitors if targets are not met - particularly when poor prognostic markers are present.

Sources: Goldman-Cecil Medicine 26e (pp. 2784-2800) | Firestein & Kelley's Textbook of Rheumatology, 11e

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