I-32. Autoimmune joint diseases: rheumatoid arthritis & ankylosing spondylitis

自己免疫性関節疾患：関節リウマチと強直性脈椎炎

Rheumatoid Arthritis (RA)

Systemic, chronic inflammatory disease; affects small joints → progresses to larger (non-suppurative proliferative synovitis; destroys cartilage + bone → disabling arthritis).
Genetic: HLA-DR4. Suspected triggers: EBV, Borrelia, Mycoplasma, parvovirus.

Pathomechanism

CD4⁺ T-cells react with unknown arthritogenic antigens.
Activate B-cells + macrophages.
Cytokines/autoantibodies → synovial inflammation: TNF-α (leukocyte recruitment, macrophage activation), IL-1 (synovial/fibroblast proliferation), RANKL (osteoclast differentiation).

Autoantibodies

Rheumatoid factor (RF): low specificity.
Anti-CCP (citrullinated peptide): more specific/sensitive (>90%), predicts joint destruction; anti-MCV diagnostic in RF-negative. Combined point-of-care test >99% specificity → early diagnosis prevents joint destruction.

Clinical (remitting-relapsing)

Symmetric arthritis (small joints).
Chronic synovitis (neutrophils/fibrin; ↑osteoclast → bone erosion).
Pannus (proliferating synovium, granulation tissue, frond-like).
Ankylosis (fibrosis/calcification → permanent stiffness, tendon/ligament destruction, deformities).
Rheumatoid nodules (subcutaneous, lung, spleen, heart, aorta).
Raynaud phenomenon → chronic leg ulcers.

Progression: synovitis → pannus → ankylosis.

Ankylosing Spondylitis (Bechterew)

Severe spinal joint inflammation (starts sacroiliac); most carry HLA-B27.
Symptoms: waist/neck pain, onset <40, pain relieved by movement not rest, overnight pain, ↓spinal mobility, hyperkyphosis within 10 yrs, enthesitis → ankylosis.
Extra-articular: acute (usually unilateral) uveitis, IBD, ↑cardiovascular risk.
Complications: osteoporosis within 10 yrs, vertebral fractures, spinal cord/nerve compression.
ER stress: misfolded peptide accumulation → ER stress → pro-inflammatory cytokines.
Diagnosis: ↑CRP, synovial fluid, imaging (especially MR).

Gout

Inflammatory arthritis with recurrent attacks of a red, hot, swollen joint (usually >60 yrs). Most common cause: hyperuricemia (>400 µmol/L).
↑Uric acid production: primary (HGPRT lack, rare), secondary (cytostatic treatment in malignancy → purine release).
↓Excretion: primary (only at high urate), secondary (renal insufficiency, hypertension, alcohol).
Uric acid: liver end-product of purine degradation (80% endogenous); low = anti-inflammatory, high = atherogenic; renally excreted.
Acute attack: urate crystals deposit (insoluble) → phagocytosed by PMNs → crystal damages cell → ruptures → releases inflammatory mediators. Sudden, painful asymmetric mono-/oligoarthritis (big toe), fever.
Diagnosis: crystals in joint aspirate smear (DDx infective arthritis). Enhancing factors: obesity, alcohol, purine-rich diet (liver, red meat).

一問一答

▶What genetic and suspected infectious triggers are linked to RA?

Genetic: HLA-DR4. Suspected triggers: EBV, Borrelia, Mycoplasma, and parvovirus.

▶Compare rheumatoid factor and anti-CCP in RA.

RF has low specificity; anti-CCP (citrullinated peptide) is more specific/sensitive (>90%), predicts joint destruction, and anti-MCV helps diagnose RF-negative cases.

▶What is the pathomechanism of RA?

CD4⁺ T cells react to unknown arthritogenic antigens → activate B cells and macrophages → cytokines/autoantibodies drive synovial inflammation.

▶What is rheumatoid arthritis?

A systemic, chronic inflammatory disease causing non-suppurative proliferative synovitis that affects small joints first and progresses to larger ones, destroying cartilage and bone → disabling arthritis.

▶What are the roles of TNF-α, IL-1, and RANKL in RA?

TNF-α: leukocyte recruitment + macrophage activation; IL-1: synovial/fibroblast proliferation; RANKL: osteoclast differentiation (bone erosion).

▶What is the typical joint pattern in RA?

Symmetric arthritis of small joints, with a remitting-relapsing course.

▶What is the progression of joint destruction in RA?

Synovitis → pannus (proliferating synovium/granulation tissue) → ankylosis (fibrosis/calcification → permanent stiffness and deformity).

▶What is a pannus in RA?

Proliferating synovium with granulation tissue forming a frond-like mass that erodes cartilage and bone.

▶What are the extra-articular features of RA?

Rheumatoid nodules (subcutaneous, lung, spleen, heart, aorta) and Raynaud phenomenon (→ chronic leg ulcers).

▶What is ankylosing spondylitis and its key genetic association?

Severe inflammation of spinal joints starting at the sacroiliac joints; most patients carry HLA-B27.

▶What are the characteristic symptoms of ankylosing spondylitis?

Waist/neck pain with onset <40, pain relieved by movement (not rest), overnight pain, reduced spinal mobility, hyperkyphosis within 10 years, and enthesitis → ankylosis.

▶What are the extra-articular features and complications of ankylosing spondylitis?

Acute (usually unilateral) uveitis, IBD, and increased cardiovascular risk; complications include osteoporosis, vertebral fractures, and spinal cord/nerve compression.

▶How does ER stress contribute to ankylosing spondylitis?

Accumulation of misfolded peptides causes ER stress, which triggers release of pro-inflammatory cytokines.

▶What is gout and its most common cause?

An inflammatory arthritis with recurrent attacks of a red, hot, swollen joint, most commonly caused by hyperuricemia (>400 µmol/L).

▶What causes increased uric acid production vs decreased excretion in gout?

↑Production: primary (HGPRT deficiency, rare) or secondary (cytostatic therapy releasing purines). ↓Excretion: primary (only at high urate) or secondary (renal insufficiency, hypertension, alcohol).

▶What is the mechanism of an acute gout attack?

Insoluble urate crystals deposit in the joint, are phagocytosed by PMNs, damage and rupture the cells → release of inflammatory mediators → sudden painful asymmetric mono-/oligoarthritis (often the big toe) with fever.

▶How is gout diagnosed and what factors enhance it?

Diagnosis: identifying urate crystals in joint aspirate (DDx infective arthritis). Enhancing factors: obesity, alcohol, and a purine-rich diet (liver, red meat).

▶What is uric acid and what are its systemic effects?

The liver end-product of purine degradation (80% endogenous), renally excreted; low levels are anti-inflammatory while high levels are atherogenic.

▶How is ankylosing spondylitis diagnosed?

By elevated CRP, synovial fluid analysis, and imaging (especially MRI).

▶Why is early diagnosis with anti-CCP testing valuable in RA?

A combined point-of-care test reaches >99% specificity, and early diagnosis allows treatment that prevents joint destruction.