The interpretation of clinical trial data has advanced due to expert consensus on clinical response criteria in patients with rheumatoid arthritis (RA). Two main examples are American College of Rheumatology (ACR) criteria and Disease Activity Score (DAS). 

With the DAS index, the number of swollen/tender joints is conflated with measures of general health and acute phase reactants.

 

Two types of DAS

 

Scores on the DAS28 range from 0.0-9.4 and include 28 swollen or tender joints. Therapeutic interventions can be based on DAS28 levels, with scores <3.2 defined as the threshold for a low disease activity state and <2.6 as the threshold for remission. Taken together, the European League Against Rheumatism (EULAR) response criteria plus the DAS28 score at the time of evaluation, as well as the change in DAS28 score between two time points, can help determine improvement or response to treatment. 

In clinical trials, the DAS28 score based on erythrocyte-sedimentation rate, or DAS28-ESR in combination with EULAR response criteria, have been extensively validated, as noted by the authors of a retrospective study published in ACR Open Rheumatology.

Greenmyer JR, Stacy JM, Sahmoun AE, et al. DAS28-CRP Cutoffs for High Disease Activity and Remission Are Lower Than DAS28-ESR in Rheumatoid Arthritis. ACR Open Rheumatol. 2020 Sep;2(9):507-511. doi: 10.1002/acr2.11171. Epub 2020 Aug 29.

 

DAS can also be assessed using CRP or DAS-CRP. Radiographic progression and physical function measures have been used to validate DAS28-CRP, and indicate that similar to DAS28-ESR, it is clinically meaningful in RA. 

It should be noted that DAS28 is rarely—if ever—used outside of clinical trials. DAS28 also has limitations, including a subjective portion; variability in joint assessment; limited joint coverage (ie, doesn't include feet); lack of imaging data; and IL 6 blockade—all of which may impact the results of the ESR/CRP.

 

DAS in action

 

Building on a previous analysis of the Veterans Affairs Rheumatoid Arthritis, which demonstrated that greater than half of RA patients were not prescribed a major therapeutic change (MTC) despite having moderate or severe disease activity, researchers publishing in Arthritis Research & Therapy examined disease thresholds that motivated rheumatologists and nurse practitioners to start an MTC in RA patients.

Sauer BC, Chen W, Xu Y, et al. Empirical evidence of disease activity thresholds used to indicate need for major therapeutic change in US veterans with rheumatoid arthritis. Arthritis Res Ther. 2020 Oct 22;22(1):253. doi: 10.1186/s13075-020-02346-1.

They also looked at the effect of the MTC on RA disease activity. The three disease activity measures (DAMs) they examined were DAS28, Clinical Disease Activity Index, and Routine Assessment of Patient Index Data 3.

 

The investigators found that MTC predicted clinical improvement in all DAMs. The greatest effects were observed in patients with RA disease activity above the study’s Youden threshold. 

 

The Youden Index is typically used to identify optimal cut points for diagnostic tests. In the study, however, the authors used it to determine the DAM value that maximized the correct classification of MTC, with equal weight for sensitivity and specificity.

The following is a breakdown for the DAS28 scores: 

1. Remission and low disease activity for DAS28 (< 3.2)

2. Low-moderate for DAS28 (3.20–4.02)

3. High-moderate (DAS28 (4.03–5.10)

4. High disease activity for DAS28 (> 5.1)

Study results published in The New England Journal of Medicine provided a second example of DAS being used as a trial outcome.

Rubbert-Roth A, Enejosa J, Pangan AL, et al. Trial of Upadacitinib or Abatacept in Rheumatoid Arthritis. N Engl J Med. 2020 Oct 15;383(16):1511-1521. doi: 10.1056/NEJMoa2008250.

DAS28-CRP was a primary endpoint in the 24-week, phase 3 trial comparing the JAK inhibitor, upadacitinib, with abatacept, a T-cell costimulation inhibitor, in a population of patients with RA who exhibited inadequate responses to biologic disease-modifying antirheumatic drugs.

 

 

In the study, investigators prescribed 303 patients upadacitinib, and 309 patients, abatacept. At baseline, the DAS28-CRP was 5.70 in the upadacitinib group vs 5.88 in the abatacept group. There was minus-2.52 average change in DAS28-CRP in the upadacitinib group vs minus-2.00 in the abatacept group. 

 

 

DAS28-ESR vs DAS28-CRP

 

Researchers are currently focused on identifying the differences between DAS28-ESR and DAS28-CRP scores.

“Despite the routine use of disease activity scores in guiding treatment, existing guidelines do not specify how cutoffs for high disease activity differ between DAS28-ESR and DAS28-CRP,” the authors said in their ACR Open Rheumatology study. 

 

Thus, stakeholders, such as individual providers, health systems, and payers, often use these values synonymously when determining the need for therapeutic regimens.

Based on receiver operator characteristic curve and Youden index analysis, in this study of 171 patients, the threshold for high disease activity was a DAS28-CRP >4.1, which corresponds to DAS28-ESR >5.1. Furthermore, DAS28-ESR post-treatment scores were significantly higher compared with those of DAS28-CRP. Finally, patients in the remission group had higher DAS28-ESR scores than DAS28-CRP scores. 

“DAS28-ESR and DAS28-CRP cutoffs for high disease activity, [low-disease activity], and remission are not the same,” the authors concluded. “DAS28-CRP is significantly lower than DAS28-ESR. At the high end of disease activity, DAS28-CRP may underestimate disease activity. At the low end of disease activity, DAS28-CRP may overestimate the number of patients in LDA or remission.”