Epidemiology

Etiology

Idiopathic inflammatory autoimmune disorder of unknown etiology
Risk factors include:
- Genetic disposition: associated with HLA-DR4 and HLA-DR1
- Environmental factors (e.g., smoking)
- Hormonal factors (premenopausal women are at the highest risk, suggesting a predisposing role of female sex hormones)

Core Concept: A systemic autoimmune disease triggered by an environmental factor in a genetically susceptible host, leading to chronic synovial inflammation and joint destruction.
Initiation
- Genetics: HLA-DR4 is the key association.
- Triggers: Smoking is the most significant environmental risk factor.
- Mechanism: Triggers cause citrullination of self-antigens, creating neoantigens targeted by the immune system.
Key Immune Components
- T_H cells (CD4⁺): The central drivers. They activate B-cells and macrophages.
- B-cells: Produce autoantibodies:
  - Rheumatoid Factor (RF): IgM antibody against the Fc portion of IgG. Low specificity.
  - Anti-CCP: Highly specific antibody targeting citrullinated peptides.
- Macrophages: Release key pro-inflammatory cytokines.
The “Big 3” Cytokines
- TNF-α, IL-1, and IL-6 are the primary mediators of inflammation and joint destruction. (High-yield for pharmacology).
Joint Destruction Cascade
1. Synovitis: Synovial lining becomes inflamed and hypertrophied.
2. Pannus Formation: The inflamed synovium transforms into an aggressive a pannus (a mass of synovium, inflammatory cells, and granulation tissue).
3. Erosion: The pannus invades and destroys adjacent cartilage (via MMPs) and bone (via RANKL-mediated osteoclast activation).

Articular (Joints):
- Symmetric polyarthritis: Hallmark feature.
- Joints involved: Typically affects small joints of the hands and feet, such as the metacarpophalangeal (MCP), proximal interphalangeal (PIP), and metatarsophalangeal (MTP) joints, as well as the wrists.
- Morning stiffness: Lasts >1 hour and improves with activity (unlike osteoarthritis).
- Spared joints: The distal interphalangeal (DIP) joints are typically spared.
- Deformities (late-stage): Ulnar deviation of fingers, swan-neck deformity (PIP hyperextension, DIP flexion), and Boutonnière deformity (PIP flexion, DIP hyperextension).
Extra-articular Manifestations:
- Constitutional: Fever, fatigue, weight loss, and malaise are common.
- Rheumatoid Nodules: Most common extra-articular finding; firm, subcutaneous nodules over extensor surfaces or pressure points.
- Pulmonary: Interstitial lung disease, pleuritis, and pulmonary nodules.
- Cardiovascular: Increased risk of premature atherosclerosis and coronary artery disease; pericarditis.
- Hematologic: Anemia of chronic disease, thrombocytosis.
- Ocular: Scleritis, episcleritis, and secondary Sjögren’s syndrome.

Definition: a potentially life-threatening complication caused by the inflammatory destruction of the ligaments affecting the atlantoaxial joint and the intervertebral joints
Clinical features
- Pain and stiffness of the neck (typically early-morning neck pain at rest)
- Head tilt
- Neurological deficits
  - Cervical radiculopathy with peripheral paresthesias of the upper limb
  - In some cases, symptoms of high spinal cord compression
    - Slowly progressive spastic quadriparesis
    - Hyperreflexia or positive Babinski reflex
    - Respiratory insufficiency
Diagnostics
- Extension and flexion x-rays of the cervical spine
- MRI

Warning

Endotracheal intubation can acutely worsen the subluxation and cause compression of the spinal cord and/or vertebral arteries.

Anticitrullinated peptide antibodies (ACPA), e.g., anticyclic citrullinated peptide (anti-CCP)
- Tissue inflammation causes arginine residues in proteins such as vimentin to be enzymatically converted into citrulline through a process called citrullination. This alters the shape of the proteins, which can then serve as neoantigens that generate an immune response.
Rheumatoid factor (RF): IgM autoantibodies against the Fc region of IgG antibodies

Parvovirus B19 will presents with similar symptoms, except for rash, normal ESR, and acute onset
See Differential diagnosis

Characteristic	Osteoarthritis (OA)	Rheumatoid Arthritis (RA)
Age of onset	>50 years	30-50 years
Cause	”Wear and tear” or trauma causing cartilage deterioration	Autoimmune inflammatory reaction against synovium
Primary joints affected	Weight-bearing joints (hips, knees), DIP, CMC of thumb	PIP, MCP, ankle, elbow, wrist; spares DIP Atlantoaxial subluxation
Joint characteristics	Hard and bony	Soft, warm, and tender
Pain pattern	Worse during or after activity	Worse in the morning or with inactivity
Stiffness	<30 minutes in morning, worse with activity	>30 minutes in morning, worse with inactivity
Joint symmetry	Often asymmetric, reflecting use patterns	Typically symmetric, diffuse involvement
Lab findings	Normal rheumatoid factor, normal anti-CCP antibody, normal ESR and CRP	Positive rheumatoid factor, positive anti-CCP antibody, elevated ESR and CRP
Associated signs	Heberden’s nodes (DIP), Bouchard’s nodes (PIP)	Ulnar deviation, boutonniere deformity, swan-neck deformity
Systemic involvement	None	Potential pulmonary and cardiac disease
Gender predilection	None	2x more common in females
X-ray findings	Osteophytes, subchondral sclerosis, asymmetric joint space narrowing	Symmetric joint space loss, osteopenia, “apple coring” bone erosion
Exam findings	Effusion, tenderness	Effusion, tenderness, redness, warmth, synovitis

Glucocorticoids
- Systemic prednisone
  - Longer-term therapy: Only use in patients with highly active RA
NSAIDs and selective COX-2 inhibitors: relieve symptoms, but do not improve the prognosis

Methotrexate (MTX): first-line treatment in patients with moderate to high disease activity
- To minimize adverse effects, administer folic acid.
Hydroxychloroquine: Consider in patients with low disease activity.
- Decreases complement-dependent antigen-antibody reactions

Indication: persistent moderate or severe disease activity after 3 months of conventional DMARD therapy
Agents
- TNF-α inhibitors: e.g., adalimumab, infliximab, etanercept
  - See Etanercept