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Rheumatoid Arthritis¶

Chapter 370 | Part 11: Immune-Mediated, Inflammatory, and Rheumatologic Disorders · Part 11 – Rheumatology & Immunology · Chapter 370

Key Clinical Points¶

RA is a chronic inflammatory disease characterized by symmetric, erosive polyarthritis.
Morning joint stiffness lasting >1 h that eases with physical activity is a hallmark symptom.
Early involvement typically affects small joints of the hands and feet (MCP, PIP, wrists).
Subcutaneous nodules occur in 30–40% of patients; they are firm, nontender, and adherent to periosteum/tendons.
Secondary Sjögren’s syndrome is defined by keratoconjunctivitis sicca and xerostomia in association with RA.
Interstitial lung disease (ILD) prevalence in RA can reach 12%, primarily presenting as UIP or NSIP patterns.
Cardiovascular disease is the most common cause of death in RA patients.
HLA-DRB1 shared epitope (SE) alleles increase risk 4-fold (single allele) to 8-fold (two alleles).
Smoking combined with SE alleles increases RA risk by 20- to 40-fold.
Felty’s syndrome is defined by the triad of neutropenia, splenomegaly, and nodular RA.

DEFINITION & CLASSIFICATION¶

• Definition (Harrison's 22e): chronic inflammatory disease characterized by a symmetric, erosive polyarthritis. • Clinical Nature: ◦ Most common form of chronic inflammatory arthritis. ◦ Persistent activity leads to articular cartilage/bone destruction and functional disability. ◦ Systemic disease: includes fatigue, subcutaneous nodules, lung involvement, pericarditis, peripheral neuropathy, vasculitis, and hematologic abnormalities. • Incidence: ◦ Increases between 25 and 55 years of age. ◦ Plateaus until age 75, then decreases.

EPIDEMIOLOGY¶

• Prevalence & Incidence: ◦ Affects ~0.5–1% of the adult population worldwide. ◦ Prevalence remains stable while incidence has decreased in recent decades due to increased longevity. ◦ Gendered distribution: 2–3:1 ratio (females to males); some regions show up to 6–8:1. • Genetic Factors: ◦ Heritability estimated at 40–60% (higher in ACPA-positive patients). ◦ HLA-DRB1 shared epitope (SE) alleles are the primary genetic risk factors. ◦ Risk of RA: → Single SE allele = 4x higher risk → Two SE alleles = 8x higher risk ◦ Specific alleles: 0401 (high risk), 0101, 0404, 1001, 0901 (moderate risk). ◦ Protective alleles: 1301 and 1302 (protect against ACPA-positive RA). • Environmental Factors: ◦ Smoking: → 1.5–3.5x increased risk generally. → 20–40x increased risk when combined with SE alleles. → Risk persists even 15 years after cessation; primarily affects RF and ACPA-positive disease. ◦ Other factors: Inhalant-related occupations, silica inhalants, and potential microbial dysbiosis (e.g., Porphyromonas gingivalis* in the oral cavity).

ETIOLOGY & PATHOPHYSIOLOGY¶

• Pathologic Hallmarks: ◦ Synovial inflammation and proliferation. ◦ Formation of pannus (thickened cellular membrane of fibroblast-like synoviocytes and granulation-reactive fibrovascular tissue). ◦ Focal bone erosions and thinning of articular cartilage. • Cellular Components: ◦ T cells (30–100% of infiltrate). ◦ B cells, plasma cells, dendritic cells, mast cells, and granulocytes. • Bone Destruction Mechanism: ◦ Osteoclasts: Multinucleated giant cells forming resorption lacunae at the pannus-bone interface. ◦ RANKL/RANK Pathway: → RANKL (from stromal cells, synoviocytes, T cells) binds to RANK on pre-osteoclasts. → Required for osteoclast differentiation; Osteoprotegerin (OPG) acts as a decoy receptor to inhibit this process. ◦ Wnt Pathway Inhibition: → TNF-α upregulates Dickkopf-1 (DKK-1). → DKK-1 inhibits Wnt receptors on osteoblast precursors, inhibiting bone formation. • Immune Activation: ◦ T-cell activation: CD4+ T cells are central to orchestrating the response via MHC class II interaction. ◦ Differentiation: CD4+ T cells differentiate into Th1 (IFN-γ, TNF-α) and Th17 (IL-17A, IL-17F, IL-6, GM-CSF). ◦ B-cell role: Produce RF and anti-CCP antibodies. ◦ TLR Activation: TLR2, 3, and 4 are expressed by synovial fibroblasts; binding of ligands leads to pro-inflammatory cytokine production.

Synovial Membrane Anatomy¶

• Structure: ◦ Type A synoviocytes (macrophage-derived). ◦ Type B synoviocytes (fibroblast-derived; produce collagen, fibronectin, laminin). • Lubrication: ◦ Synovial fluid contains hyaluronan and lubricin to facilitate joint movement.

CLINICAL FEATURES¶

• Joint Involvement: ◦ Early symptoms: Inflammation of joints, tendons, and bursae. ◦ Morning stiffness: Lasts >1 h; eases with activity. ◦ Common sites: Wrists, MCP, and PIP joints. ◦ Deformities: → Ulnar deviation (from MCP subluxation). → Swan-neck deformity (hyperextension of PIP, flexion of DIP). → Boutonnière deformity (flexion of PIP, hyperextension of DIP). → Z-line deformity (subluxation of 1st MCP with hyperextension of 1st IP). ◦ Tendon issues: Flexor tendon tenosynovitis; potential for rupture (e.g., flexor pollicis longus). • Extraarticular Manifestations: ◦ Occur in up to 40% of patients. ◦ Risk factors: Smoking, early onset disability, RF/ACPA positivity. ◦ Specific conditions: → Ocular: Keratoconjunctivitis sicca, episcleritis, scleritis. → Pulmonary: Pleural effusions, nodules, ILD (up to 12%), pulmonary vasculitis. → Cardiac: Pericarditis, ischemic heart disease, myocarditis, cardiomyopathy. ● Table 370-1 (Extraarticular Manifestations): Includes systemic impacts such as Rheumatoid nodules, purpura, pyoderma gangrenosum, and secondary amyloidosis.

DIFFERENTIAL DIAGNOSIS¶

• Undifferentiated Inflammatory Arthritis: ◦ Patients with too few joints for RA diagnosis. ◦ High risk of later RA diagnosis if: → Higher number of tender/swollen joints. → Positive RF or ACPA. → Higher scores for physical disability.

DIAGNOSTIC APPROACH¶

Clinical Assessment:
Evaluate joint count (Table 370-1) and duration of symptoms.
Identify specific features: → Joint involvement ≥6 weeks = 1 point. → Presence of morning stiffness and symmetric distribution.
Serological Testing:
Rheumatoid Factor (RF).
Anti-cyclic citrullinated peptide (ACPA) antibodies.
Note: High-positive results (>3x ULN) contribute to classification score.
Acute Phase Reactants:
C-reactive protein (CRP).
Erythrocyte Sedimentation Rate (ESR).
Imaging Studies:
Ultrasound: Identify joint effusion and synovial thickening (Figure 4, Figure 6).
X-ray: Assess for erosions, subluxation, and periarticular osteopenia (Figure 5).

MANAGEMENT & TREATMENT¶

Initial Evaluation:
Baseline labs: CBC, LFTs, ESR/CRP.
Specific screenings: Tuberculosis screening for all TNF-inhibitors; G6PD level if starting Hydroxychloroquine (if risk of hemolysis).
Pharmacologic Therapy (DMARDs):
Hydroxychloroquine: → Dose: 200–400 mg/d orally (≤5 mg/kg) or 500 mg twice daily (initial). → Monitoring: Eye exam if >40 years old; OCT and visual field testing every 12 months.
Methotrexate: → Dose: 10–25 mg/week orally or SQ; 10–20 mg/d for other uses. → Co-therapy: Folic acid 1 mg/d to reduce toxicities. → Monitoring: CBC, LFTs, creatinine every 2–3 months.
TNF-α Inhibitors: → Infliximab: 3 mg/kg IV (weeks 0, 2, 6; then every 8 weeks). → Etanercept: 50 mg SQ weekly or 25 mg SQ biweekly. → Adalimumab: 40 mg SQ every other week. → Golimumab: 50 mg SQ monthly. → Certolizumab: 400 mg SQ (weeks 0, 2, 4) then 200 mg every other week.
Anakinra: → Dose: 100 mg SQ daily. → Alternative: 1000 mg IV imes 2 (days 0 and 14).
IL-6 Inhibitors: → Tocilizumab: 4–8 mg/kg IV monthly or 162 mg SQ every other week. → Sarilumab: 200 mg SQ every other week.
Non-Pharmacologic & Surgical:
Management of joint deformities and physical therapy for range of motion.

COMPLICATIONS & PROGNOSIS¶

• Cardiovascular Disease: Most common cause of death; higher incidence than general population. • Osteoporosis: Resulting from systemic inflammation and local bone loss (periarticular osteopenia). • Lymphoma: Associated with long-standing RA and certain medications. • Remission Criteria (Table 370-3): - Patient must satisfy: → Tender joint count ≤1. → Swollen joint count ≤1. → CRP ≤1 mg/dL. → Patient global assessment ≤1 (on 0–10 scale). - OR: Simplified Disease Activity Index (SDAI) score of ≤3.3.

SPECIAL POPULATIONS¶

• Pregnancy: - Methotrexate is categorized as Pregnancy category X. - Other DMARDs require careful consideration due to potential risks (e.g., infection, myelosuppression).

KEY PEARLS & HIGH-YIELD POINTS¶

• Symmetry: RA is typically a symmetric polyarthritis. • Early Detection: ACPA and RF can be present years before clinical symptoms. • Smoking Synergy: Smoking risk for RA is exponentially higher in the presence of HLA-DRB1 shared epitope. • Bone Loss Triad: 1. Periarticular osteopenia (early). 2. Bone erosions (at pannus interface). 3. Generalized osteoporosis.

Reference Tables¶

TABLE 370-1 Classification Criteria for Rheumatoid Arthritis Joint involvement¶

Harrison's 22e, p.2847

		SCORE
Joint involvement	1 large joint (shoulder, elbow, hip, knee, ankle) 2–10 large joints 1–3 small joints (MCP, PIP, thumb IP, MTP, wrists) 4–10 small joints >10 joints (at least 1 small joint)	0 1 2 3 5
	Negative RF and negative ACPA Low-positive RF or low-positive anti-CCP antibodies (≤3 times ULN) High-positive RF or high-positive anti-CCP antibodies (>3 times ULN)
Acute-phase reactants	Normal CRP and normal ESR Abnormal CRP or abnormal ESR	0 1
	<6 weeks ≥6 weeks

TABLE 370-2 DMARDs Used for the Treatment of Rheumatoid Arthritis DRUG Hydroxychloroquine¶

Harrison's 22e, p.2850

DRUG	DOSAGE	SERIOUS TOXICITIES	OTHER COMMON SIDE EFFECTS	INITIAL EVALUATION	MONITORING
Hydroxychloroquine	200–400 mg/d orally (≤5 mg/kg)	Irreversible retinal damage Cardiotoxicity Blood dyscrasia	Nausea Diarrhea Headache Rash	Eye examination if >40 years old or prior ocular disease	Optical coherence tomography and visual field testing every 12 months
	Initial: 500 mg orally twice daily Maintenance: 1000–1500 mg twice daily	Granulocytopenia Hemolytic anemia (with G6PD deficiency)	Nausea Diarrhea Headache	CBC, LFTs G6PD level
Methotrexate	10–25 mg/week orally or SQ Folic acid 1 mg/d to reduce toxicities	Hepatotoxicity Myelosuppression Infection Interstitial pneumonitis Pregnancy category X	Nausea Diarrhea Stomatitis/mouth ulcers Alopecia Fatigue	CBC, LFTs Viral hepatitis panela Chest x-ray	CBC, creatinine, LFTs every 2–3 months
	10–20 mg/d	Hepatotoxicity Myelosuppression Infection Pregnancy category X	Alopecia Diarrhea	CBC, LFTs Viral hepatitis panela
TNF-α inhibitors	Infliximab: 3 mg/kg IV at weeks 0, 2, 6, then every 8 weeks. May increase dose up to 10 mg/kg every 4 weeks	↑ Risk bacterial, fungal infections Reactivation of latent tuberculosis ↑ Lymphoma risk (controversial) Drug-induced lupus Neurologic deficits	Infusion reaction ↑ LFTs	Tuberculosis screeningb	LFTs periodically
	Etanercept: 50 mg SQ weekly, or 25 mg SQ biweekly	As above	Injection site reaction	Tuberculosis screening	Monitor for injection site reactions
	Adalimumab: 40 mg SQ every other week	As above	Injection site reaction	Tuberculosis screening	Monitor for injection site reactions
	Golimumab: 50 mg SQ monthly	As above	Injection site reaction	Tuberculosis screening	Monitor for injection site reactions
	Certolizumab: 400 mg SQ weeks 0, 2, 4, then 200 mg every other week	As above	Injection site reaction	Tuberculosis screening	Monitor for injection site reactions
	Weight based: <60 kg: 500 mg 60–100 kg: 750 mg >100 kg: 1000 mg IV dose at weeks 0, 2, and 4, and then every 4 weeks OR 125 mg SQ weekly	↑ Risk bacterial, viral infections	Headache Nausea	Tuberculosis screening
Anakinra	100 mg SQ daily	↑ Risk bacterial, viral infections Reactivation of latent tuberculosis Neutropenia	Injection site reaction Headache	Tuberculosis screening CBC with differential	CBC every month for 3 months, then every 4 months for 1 year Monitor for injection site reactions
	1000 mg IV × 2, days 0 and 14 May repeat course every 24 weeks or more Premedicate with methylprednisolone 100 mg to decrease infusion reaction	↑ Risk bacterial, viral infections Infusion reaction Cytopenia Hepatitis B reactivation	Rash Fever	CBC Viral hepatitis panela
Interleukin-6 inhibitors	Tocilizumab: 4–8 mg/kg IV monthly OR 162 mg SQ every other week (<100 kg weight) 162 mg SQ every week (≥100 kg weight) Sarilumab: 200 mg SQ every other week	Risk of infection Infusion reaction LFT elevation Dyslipidemia Cytopenias		Tuberculosis screening	CBC and LFTs at regular intervals

TABLE 370-3 ACR/EULAR Provisional Definition of Remission in Rheumatoid Arthritis At any time point, patient must…¶

Harrison's 22e, p.2852

At any time point, patient must satisfy all of the following:
Tender joint count ≤1
Swollen joint count ≤1
C-reactive protein ≤1 mg/dL
Patient global assessment ≤1 (on a 0–10 scale)
OR
At any time point, patient must have a Simplified Disease Activity Index score of
≤3.3