What is the pathophysiology of ankylosing spondylitis?

Pathophysiology of Ankylosing Spondylitis

Ankylosing spondylitis (AS) is a chronic inflammatory arthropathy characterized by sacroiliitis, enthesitis, and a marked propensity for sacroiliac joint and spinal fusion, driven primarily by genetic factors (especially HLA-B27), inflammatory processes involving TNF-α and IL-17 pathways, and gut microbiome interactions that lead to bone erosion, sclerosis, and eventual ankylosis. 1

Genetic Factors

• HLA-B27 association: Present in 74-89% of AS patients, making it the strongest genetic risk factor 1
• Multiple other susceptibility genes have been identified, creating a complex genetic predisposition 2
• Genetic factors explain the familial clustering of AS, with prevalence estimated between 0.9-1.4% in the US adult population 1

Inflammatory Processes

The pathogenesis involves three key processes at the entheses (where ligaments, tendons, and capsules attach to bone):

1. Inflammation:

   • Characterized by enthesitis, synovitis, and osteitis 1
   • Involves immune-mediated mechanisms with inflammatory cellular infiltrates 3
   • Type 17 immune responses are particularly important in driving disease 4

2. Bone Erosion:

   • Inflammatory processes lead to bone destruction at sites of involvement 1
   • This process is distinct from the mechanisms driving syndesmophyte formation 2

3. New Bone Formation (Syndesmophytes):

   • Abnormal bone formation and remodeling leads to syndesmophytes 2
   • Eventually results in spinal ankylosis and fusion 1

Key Cytokines and Immune Pathways

• TNF-α (Tumor Necrosis Factor alpha):

  • Critical mediator of inflammatory processes 2
  • Targeted by first-line biologic therapies 1
  • Less involved in bone erosion and syndesmophyte formation 2

• IL-17 Pathway:

  • Emerging evidence shows importance of IL-17 and Type 17 immune responses 4
  • Targeted by newer biologics like secukinumab and ixekizumab 1

Anatomical Distribution and Progression

• Initial Involvement:

  • Classically begins with sacroiliac joints 1
  • Bilateral sacroiliitis is typical in AS, while other spondyloarthritides may present with unilateral involvement 1

• Spinal Involvement:

  • Progresses to involve the spine, particularly the thoracic spine and thoracolumbar junction 1
  • A minority of patients may have isolated spinal involvement without sacroiliitis 1

• Disease Progression:

  • Leads to ligamentous ossification, vertebral joint fusion, osteoporosis, and kyphosis 5
  • Results in a weakened vertebral column with increased susceptibility to fractures 5

Role of Gut Microbiome

• Recent studies have strongly implicated the gut microbiome in AS pathogenesis 4
• Approximately 30-50% of AS patients have associated peripheral arthritis or enthesitis 1
• Association with inflammatory bowel disease highlights gut-joint axis importance 1

Clinical Manifestations Related to Pathophysiology

• Inflammatory Back Pain: Present in 70-80% of patients, characterized by:

  • Insidious onset
  • Improvement with exercise
  • No improvement with rest
  • Nocturnal pain
  • Age of onset <40 years 1

• Extra-articular Manifestations:

  • Acute anterior uveitis (up to 40% of patients) 1
  • Aortic root and valve involvement (up to 80% of patients) 1
  • Psoriasis and inflammatory bowel disease 1

Structural Consequences

• Progressive spinal fusion leads to:
  • Limited spinal mobility
  • Kyphotic deformity
  • Increased risk of vertebral fractures and spinal cord injury 5
  • Decreased quality of life and work disability 3

Pathophysiological Differences from Other Arthritides

• Unlike rheumatoid arthritis, AS is seronegative (no rheumatoid factor) 2
• Distinguished from other spondyloarthritides by universal sacroiliac joint involvement and more prevalent spinal ankylosis 1
• Local metabolic environment of the joint may play a key role specific to AS pathogenesis 4

Understanding the complex pathophysiology of AS has led to targeted therapies that address specific inflammatory pathways, though complete disease modification remains challenging as the mechanisms of bone formation are not fully inhibited by current treatments.