Definitions for improvement in RA treatment trials

What are the definitions for improvement in RA treatment trials? What radiographic scoring system is most often used to measure radiographic progression in RA trials?

An American College of Rheumatology (ACR) study group determined that improvement for clinical trial patients with RA should be defined as:

Required: ≥20% improvement in tender joint count

and

≥20% improvement in swollen joint count.

Plus: ≥20% improvement in three of the following five:

  • • Patient pain assessment.
  • • Patient global assessment.
  • • Physician global assessment.
  • • Patient self-assessed disability (health assessment questionnaire [HAQ]).
  • • Acute-phase reactant (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]).

Patients who improve as defined earlier are said to have met criteria for ACR 20. If improved 50% or 70%, they have met criteria for ACR 50 or ACR 70. Achieving an ACR 20/50/70 is more difficult than just improving the patient’s joint count by 20%, 50%, or 70%.

The European League Against Rheumatism developed the disease activity score 28 (DAS28) to measure disease activity and improvement in clinical trials and practice. This takes into account: (1) number of tender joints out of 28 examined; (2) number of swollen joints out of 28 examined; (3) the measured ESR; and (4) patient’s subjective assessment of disease activity (patient global) over preceding 7 days (scale 0–100). These parameters are put into a formula (DAS calculator; www.das-score.nl ) and a disease activity score is calculated (scale 0.49–9.07). Using the DAS28-ESR the cutoff values are:

  • • >5.1, high disease activity.
  • • >3.2 to ≤ 5.1, moderate disease activity.
  • • ≤3.2, low disease activity.
  • • ≤2.6, remission.

Change from baseline DAS28-ESR must exceed 0.6 to be clinically meaningful. Some investigators use CRP instead of ESR and a slightly different formula that reportedly has the same cutoff values. Several reports have suggested that the DAS28-CRP underestimates the disease activity compared with the DAS28-ESR. In addition, clinical trials using biologics that block IL-6 will affect CRP measurements and thus the DAS28-CRP cannot be used in those trials.

The most commonly used radiographic scoring system in RA trials is the van der Heijde modification of the Sharp scoring system . In brief, this method scores the presence of erosions in 16 joints of hands and wrists (graded from 0–5) and in 6 joints of the feet (graded from 0–5), and the presence of joint space narrowing in 15 joints of the hands and wrists (graded from 0–4), and in 6 joints of the feet (graded from 0–4). The maximal range is 280 units for erosion and 168 units for joint space narrowing, summing up to a maximum of 448 units for the total Sharp score. Studies have shown that an increase of 5 to 6 units in total Sharp score was equivalent to destroying one small joint and correlated with a physician’s desire to change therapy. An increase of 25 units of total Sharp score correlates with a 0.22 to 0.25 increase in the HAQ-disability index (DI) score, which is the minimally important difference that can be detected clinically. A total Sharp score of over 50 to 100 units correlates with a HAQ-DI of 1.0 (0.0–3.0 total scale), which correlates with moderate functional impairment.

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