What is the definition of refractory Rheumatoid Arthritis (RA)?

Definition of Refractory Rheumatoid Arthritis

Refractory rheumatoid arthritis is defined as disease that has failed treatment with ≥2 biological or targeted synthetic DMARDs with different mechanisms of action after failing conventional synthetic DMARD therapy, with persistent signs of active/progressive disease despite optimal treatment. 1

Core Components of Refractory RA Definition

The European League Against Rheumatism (EULAR) has established specific criteria for what they term "difficult-to-treat RA" (D2T RA), which represents the most current and comprehensive definition of refractory RA. All three of the following criteria must be present:

1. Treatment failure history:

   • Failure of ≥2 b/tsDMARDs with different mechanisms of action after failing csDMARD therapy
   • Example: Failing both a TNF inhibitor and an IL-6 inhibitor after initial methotrexate failure

2. Signs of active/progressive disease:

   • At least one of the following:
     • Moderate to high disease activity (DAS28-ESR >3.2 or CDAI >10)
     • Signs/symptoms of active disease (joint-related or other)
     • Inability to taper glucocorticoids below 7.5 mg/day prednisone
     • Rapid radiographic progression
     • Well-controlled disease but with RA symptoms reducing quality of life

3. Clinical impact:

   • Management of signs/symptoms is perceived as problematic by both the rheumatologist and patient

Prevalence and Risk Factors

Refractory RA affects approximately 6-21% of patients with RA, depending on the definition used and study population 2, 3. Several factors increase the risk of developing refractory disease:

• Female gender
• Younger age at diagnosis
• Shorter disease duration at time of treatment initiation
• Higher baseline disease activity
• Worse functional status (higher HAQ scores)
• Current smoking
• Obesity
• Greater social deprivation
• Treatment delay 2, 3

Clinical Implications and Management Challenges

The concept of refractory RA has evolved over time as treatment options have expanded. Registry studies show that patients are cycling through b/tsDMARDs more rapidly in recent years, leading to earlier classification as refractory 3.

Key challenges in managing refractory RA include:

• Distinguishing true inflammatory disease activity from non-inflammatory comorbid conditions
• Addressing factors beyond disease activity scores, such as fatigue
• Limited evidence for optimal sequencing of therapies after multiple failures
• Lack of validated biomarkers to predict response to specific therapies

Research Needs

The 2020 EULAR recommendations for RA management specifically highlight refractory RA as an area requiring further research, asking: "How can refractory RA be best defined, and what is the optimal treatment approach?" 1

Current evidence gaps include:

• Optimal treatment strategies after failure of multiple b/tsDMARDs
• Safety and efficacy of combining JAK inhibitors with biologics
• Efficacy of switching between drugs within the same class (e.g., between IL-6 inhibitors or between JAK inhibitors)
• Identification of biomarkers to guide therapy selection

Practical Approach to Suspected Refractory RA

When evaluating a patient with suspected refractory RA:

1. Confirm the diagnosis - Ensure the patient truly has RA and not an alternative diagnosis
2. Evaluate for non-inflammatory causes of persistent symptoms (e.g., fibromyalgia, osteoarthritis)
3. Assess treatment adherence - Non-adherence can mimic refractory disease
4. Review prior therapies - Ensure adequate dosing and duration of previous treatments
5. Consider comorbidities that may impact treatment response
6. Evaluate for secondary loss of efficacy due to immunogenicity (anti-drug antibodies)

By applying this structured approach to defining and managing refractory RA, clinicians can better identify patients who truly have treatment-resistant disease and develop appropriate therapeutic strategies to improve outcomes.