What is the recommended treatment for refractory Rheumatoid Arthritis (RA)?

Treatment for Refractory Rheumatoid Arthritis

For refractory rheumatoid arthritis, patients should receive another TNF inhibitor, abatacept, rituximab, or tocilizumab after failure of a first TNF inhibitor, with rituximab plus methotrexate being particularly effective for patients who have failed multiple prior therapies. 1, 2

Treatment Algorithm for Refractory RA

Step 1: Define Refractory Status

• Refractory RA is defined as disease that has failed to respond adequately to:
  • Methotrexate (MTX) at optimal dosing (20-25 mg/week)
  • At least one TNF inhibitor (adalimumab, certolizumab, etanercept, golimumab, infliximab)
  • Possibly other conventional synthetic DMARDs

Step 2: Evaluate Poor Prognostic Factors

• High RF/ACPA levels
• High disease activity
• Early joint damage
• Failure of 2 or more csDMARDs

Step 3: Select Appropriate Next-Line Therapy

For patients who failed one TNF inhibitor:

1. Switch to a different TNF inhibitor 1

   • Particularly if the patient had initial response to first TNF inhibitor
   • Examples: adalimumab, certolizumab, etanercept, golimumab, infliximab

2. Switch to a different mechanism of action 1, 2

   • Rituximab (1000mg IV q14d for 2 doses, then q6 months)
     • Particularly effective for seropositive RA patients who failed multiple therapies
     • Preferred in patients with lung disease
   • Abatacept (T-cell co-stimulation modulator)
   • Tocilizumab (IL-6 receptor inhibitor)
   • JAK inhibitors (tofacitinib, baricitinib, etc.)

For severe refractory RA with contraindications to biologics:

• Consider alternative synthetic DMARDs: 1
  • Azathioprine
  • Ciclosporin A
  • Cyclophosphamide (in exceptional cases)

Monitoring and Follow-up

1. Frequent monitoring is essential:

   • Assess disease activity every 1-3 months 1, 2
   • If no improvement after 3 months, adjust therapy
   • If target not reached by 6 months, change treatment approach

2. Treatment targets:

   • Remission (SDAI ≤3.3, CDAI ≤2.8) or
   • Low disease activity (SDAI ≤11, CDAI ≤10) 2

3. Safety monitoring:

   • Screen for tuberculosis, hepatitis B before starting biologics
   • Monitor immunoglobulin levels before and during rituximab treatment
   • Avoid combining different biologics due to increased infection risk 2

Important Considerations

• Combination therapy: Biologic DMARDs should typically be combined with MTX for optimal efficacy 1, 2
• Route of administration: For patients on MTX, consider switching to subcutaneous administration if oral route is ineffective 2, 3
• Glucocorticoids: Can be added at low to moderately high doses for short-term benefit but should be tapered as rapidly as clinically feasible (within 6 months) 1, 2

Common Pitfalls to Avoid

1. Inadequate dosing: Ensure MTX is dosed appropriately (20-25 mg/week) before declaring treatment failure 2, 3
2. Premature switching: Allow sufficient time (3-6 months) to evaluate response before changing therapy 1, 2
3. Ignoring comorbidities: Consider patient-specific factors (lung disease, infection risk) when selecting therapy 2
4. Neglecting monitoring: Regular assessment of disease activity and treatment response is crucial 1, 2
5. Discontinuing all DMARDs: Even when adding biologics, continuing MTX often improves outcomes 1, 2

The European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) both emphasize a treat-to-target approach with regular monitoring and treatment adjustments to achieve remission or low disease activity, which has been shown to improve long-term outcomes including physical function, quality of life, and reduction of comorbidity risks 2, 4.