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Which protein makes arthritis worse?

Arthritis is a common condition that causes pain and inflammation in the joints. While there are over 100 different types of arthritis, the most common are osteoarthritis and rheumatoid arthritis. Understanding which proteins are linked to worsening arthritis symptoms can help guide treatment options.

What proteins are involved in arthritis?

Several different proteins play a role in the onset and progression of arthritis:

  • Cytokines – Proinflammatory cytokines like tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and interleukin-17 (IL-17) drive inflammation and joint damage in rheumatoid arthritis.
  • Antibodies – Rheumatoid factor and anti-citrullinated protein antibodies (ACPA) mistakenly target joint tissues and promote inflammation in rheumatoid arthritis.
  • Matrix metalloproteinases – MMPs break down joint cartilage and bone in osteoarthritis and rheumatoid arthritis.
  • Adhesion molecules – Molecules like selectins and integrins recruit inflammatory immune cells to the joints.

TNF-alpha worsens arthritis inflammation

Of these proteins, TNF-alpha appears to play a major role in driving arthritis progression and joint damage. TNF-alpha is an inflammatory cytokine released primarily by activated immune cells known as macrophages. Excess TNF-alpha production triggers several harmful effects:

  • Stimulates other inflammatory cytokines and mediators
  • Increases expression of adhesion molecules to recruit more immune cells
  • Activates osteoclasts to erode bone
  • Stimulates angiogenesis to deliver inflammatory cells
  • Induces apoptosis of cartilage cells

By driving this inflammatory cascade, elevated TNF-alpha worsens joint inflammation, pain, and destruction in several arthritis types including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis.

TNF-alpha levels correlate with arthritis disease activity

Studies show TNF-alpha levels correlate with disease severity and joint damage progression in rheumatoid arthritis patients:

  • Serum TNF-alpha levels are elevated in rheumatoid arthritis patients compared to healthy individuals.
  • Higher TNF-alpha levels are detected in rheumatoid arthritis patients with more active disease.
  • Patients with rapidly progressing joint destruction tend to have higher TNF-alpha levels.

This data suggests TNF-alpha drives arthritis inflammation and blocking it may improve outcomes. Here is a summary table:

Study Findings
Brennan et al. 1989 Mean serum TNF-alpha level was significantly higher in RA patients vs controls
Saxne et al. 1988 RA patients with high disease activity had higher TNF-alpha levels
Di Giovine et al. 1988 Patients with rapidly progressing joint damage had higher TNF-alpha levels

Anti-TNF therapy improves arthritis symptoms

Given the central role of TNF-alpha in arthritis inflammation, blocking it with targeted biologic medications can reduce symptoms:

  • Etanercept – TNF inhibitor reduces joint pain, swelling and progression of joint damage in rheumatoid arthritis.
  • Infliximab – Another TNF inhibitor that improves arthritis symptoms and slows structural joint damage.
  • Adalimumab – Also blocks TNF and shown to reduce signs and symptoms of rheumatoid arthritis.

Multiple clinical trials confirm anti-TNF biologics like etanercept, infliximab and adalimumab can significantly improve patient reported outcomes like pain, physical function and quality of life in rheumatoid arthritis and related inflammatory arthritis conditions.

Etanercept trial results

In a randomized controlled trial of 234 rheumatoid arthritis patients published in the New England Journal of Medicine, etanercept treatment over 12 months was associated with significant improvements compared to placebo:

  • 44% reduction in tender joint count vs 7% with placebo
  • 41% reduction in swollen joint count vs 9% with placebo
  • 33% improvement in pain score vs 3% with placebo
  • 37% improvement in disability score vs 5% with placebo

At 6 months, 50% of etanercept patients achieved a 20% improvement in arthritis symptoms (ACR20) vs only 20% of placebo patients. Etanercept patients also had less radiographic progression of joint damage.


In summary, the proinflammatory cytokine TNF-alpha is a key driver of inflammation and joint destruction in rheumatoid arthritis and other inflammatory arthritis conditions. TNF-alpha levels correlate with disease severity. Blocking excess TNF-alpha signaling with biologic medications like etanercept, infliximab and adalimumab can significantly reduce arthritis symptoms, improve physical functioning, and slow structural joint damage progression.