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Rheumatoid Arthritis

Rheumatoid Arthritis

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Clinical Presentation
Typically presents with:
Symmetric joint pain
  • Symmetric joint pain (especially of the hands (MCPs, PIPs, wrists), stiffness, and swelling over at least 6 weeks (remember that OA is classically asymmetric)
Fatigue
  • Prominent fatigue and low-grade fever
Morning stiffness
  • Morning stiffness usually > 60 minutes
    • Remember that morning stiffness in OA was limited to less than 30 minutes.
Pathogenesis
Autoimmune response to citrullinated proteins. Pannus formation.
  • Its pathophysiology involves an autoimmune response to citrullinated proteins (a loss of self-tolerance to citrulline-containing self-proteins), that leads to joint destruction via synovitis and pannus formation and resultant cartilage and bone break-down, as well as systemic inflammation.
Systemic complications
  • Systemic inflammation produces extra-articular manifestations (disease outside of the joint), which can involve wide-spread organ systems, including cardiac, pulmonary, vascular, neuromuscular, dermatologic, ocular, and hematologic systems.
Knee findings
Cartilage thinning and ankylosis
  • Cartilage thinning and joint space narrowing (like in OA) but also bone fusion (called ankylosis), which is not found in OA.
  • There is prominent osteopenia and bony erosion, especially at the joint margins; whereas, in OA bone spurs and sclerosis are prominent.
Pannus formation
  • Prominent synovitis and pannus formation and star this finding, which is the major differentiator of RA vs OA.
    • Pannus refers to invasive inflammatory synovial tissue – a hyperplastic (thickened, edematous, vascularized) synovial membrane, which comprises inflammatory mediators and neovasculature that invades the joint and destroys bone (via osteoclasts) and cartilage (via synoviocytes (most notably), as well as via other destructive cells such as neutrophils and chondrocytes).
Osteoarthritis vs Rheumatoid Arthritis
  • Most notably, prominent inflammation invades the joint in RA, which does not occur in OA – in OA, there is mild inflammation, at most.
  • In OA, there is prominent formation of bone spurs and sclerosis whereas this these features are negligible in RA.
  • In RA, there is prominent osteopenia and bony erosions, which are negligible in OA.
  • In both conditions, there is prominent joint narrowing via cartilage break-down but in RA, ankylosis – bone fusion – can also occur (which does not occur in OA).
Predisposing factors
Female sex
  • It occurs in women (most commonly in their mid-thirties) roughly 3 times more than men (most commonly in their mid-fifties) (remember that OA tends to occur much later in life).
  • The following can upregulate protein arginine deiminases (PADs), which citrullinate proteins:
    • Smoking, which upregulates PAD enzymes in the lungs and confers a ~ 12-fold increase risk of RA.
    • Chronic periodontitis, which changes the oral and gut bacterial microbiome and as a result upregulates PAD enzymes. Remember that citrullinated proteins are thought to be a key trigger for the immune cascade of RA.
  • The HLA-DRB1 allele (and the corresponding HLA-DR4 serotype antigen) confers the greatest known genetic risk for developing RA.
Labwork
Inflammatory synovial fluid
  • In regards to labwork, synovial fluid will have high inflammatory cell counts – greater than 5,000 WBC per cubic millimeter (compare this to OA in which the count is less than 2,000) up to 50,000, with the predominance of being polymorphonuclear cells (PMNs).
    • Note that the synovial fluid does NOT contain crystals and is culture negative (this is important in differentiating it from other inflammatory conditions).
RF vs ACPAs
  • Despite its name, rheumatoid factor (RF) is only 85% specific whereas anti-citrullinated protein antigens (ACPAs) are 95% specific.
    • Note that ACPAs replaced anti-cyclic citrullinated peptide antibodies (anti-CCPs) because ACPA is able to detect non-cyclic citrullinated peptides.
Affected Joints
Symmetric
  • RA affects the joints symmetrically (vs OA which is asymmetric).
Early: Wrists, MCPs, MTPs
  • The most commonly affected joints: those of the hands.
  • Early on in the disease, the wrists and MCP joints are affected, as well as the PIP joints (which are also affected in OA).
  • The metatarsophalangeal joints (MTPs) of the feet are also involved.
Later: Large joints
  • Later in the disease, indicate the ankles, elbows, and shoulders are involved.
  • The cervical spine, hips, and knees are also affected (as they can be in OA).
Hand Deformities
  • There can be ulnar deviation of the fingers at the MCPs, which are typically swollen and enlarged, and also swan neck deformities of the fingers (flexion at the DIP joints and hyperextension at the PIP joints secondary to MCP flexion contraction).
  • Other findings include:
    • Fusiform swelling of the PIP joints from PIP synovitis
    • Boutonniere deformity (which is the opposite of swan neck deformity – there is DIP hyperextension and PIP flexion)
    • Hitchhiker thumb (hyperextension of the IP joint with MCP flexion)
    • And piano key ulnar head (with a floating ulnar styloid due to ulnar collateral ligament destruction).
Atlantoaxial (C1-C2) subluxation
  • We must be mindful of the potential for atlantoaxial (C1-C2) subluxation, especially when we are intubating RA patients.
    • Atlantoaxial subluxation involves anterior subluxation due to synovial proliferation at the site of the odontoid process articulation with the anterior arch of C1.
    • Ultimately, stretching and rupture of the transverse and alar ligaments can occur and can cause spinal cord compression.
  • Additional cervical spine disease include C1-C2 impaction and stair-stepping at subaxial levels (C2-C3 and/or C3-C4).
Extra-articular (systemic) manifestations
  • Inflammation produces numerous extra-articular manifestations and that elevated ESR and CRP levels are a nonspecific marker of inflammation seen in RA.
Those manifestations include but are not limited to (by system):
  • General: fatigue, fever, weight loss
  • Cardiac: pericarditis, myocarditis, valvular nodules, coronary vasculitis
  • Dermatologic: palmar erythema, subcutaneous nodules (central fibrinoid necrosis with palisades of elongated histiocytes)
  • Hematologic: Felty's syndrome (RA, splenomegaly, and neutropenia), lymphadenopathy, lymphoma
  • Neuromuscular: peripheral neuropathy, entrapment neuropathies, mononeuritis multiplex
  • Ocular: episcleritis, scleritis, choroid and retinal nodules, sicca symptoms (dry eyes with coexistent Sjogren's syndrome)
  • Pulmonary: pleuritis (pleurisy and pleural effusions), pulmonary nodules, interstitial lung disease, bronchiolitis obliterans
  • Rheumatologic: Sjogren's syndrome
  • Skeletal: osteoporosis
  • Vascular: vasculitis, amyloidosis, atherosclerosis
Hypersensitivity Type IV
  • Affects the synovial joints of the hands and feet.
Key Inflammatory Mediators
  • Helper T cells release interferon gamma and IL-17
  • Interferon gamma activates macrophages, and IL-17 recruits inflammatory neutrophils and monocytes.
  • Macrophages release tumor necrosis factor and IL-1, which trigger the release of degradative proteases.
  • Activated T cells express RANKL, which promotes bone resorption.

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