Two new studies add to a growing body of evidence suggesting that the disease activity score-28 (DAS28), a tool often used to determine the intensity of antirheumatic therapy, is not an appropriate gauge of remission in rheumatoid arthritis (RA).

One study, published online October 15 in the Annals of Rheumatic Diseases,¹ suggests that the original DAS, with its more expansive inclusion criteria, may be more appropriate than the condensed version. The original, more comprehensive DAS includes a 44 swollen joint count; the Ritchie articular index (RAI), which includes 53 joints in 26 units that are graded for tenderness; the erythrocyte sedimentation rate (ESR); and a measure for global health. A cutoff level of 1.6 was proposed to distinguish RA patients in remission from those who are not. 

By contrast, the DAS28 does not include joint tenderness as assessed by RAI. Moreover, the 28-joint counts differ from the original DAS in that they omit feet and ankle joints. While controversial, the cutoff for DAS28 is reported to be 2.6.

DAS28 has high false-positive rate for remissions

"We found so many patients in remission—if remission was based on DAS28—[but] further exploration [revealed] that a proportion of those patients actually were not in remission because they had arthritis in joints not captured by the DAS28," explains lead study author Robert Landewé, MD, a rheumatologist at University Hospital Maastricht in Maastricht, the Netherlands.

"The original DAS definitely does a better job than the DAS28 [in] regard to detecting remission," Dr. Landewé tells CIAOMed. "So, if remission is at stake, and the choice is between DAS and DAS28, I would choose DAS."

To reach their conclusions, the researchers analyzed 620 previously measured paired observations of DAS and DAS28 in 155 RA patients drawn from the COBRA (combinatietherapie Bij Rheumatoide Artritis) study. In separate analyses of discordant and concordant observations, they found that 93/620 (15%) paired DAS observations were discordant. There were 89 (in 54 patients) comprised observations in which the DAS28 remission criterion, but not the DAS remission criterion, was met. (The reverse was found in only four observations and omitted.)

With the original DAS as a standard, DAS28 sensitivity was 95% and specificity was 83%. Probability plots showed that a swollen joint count >0 was found in 75% of discordant pairs compared with 48% of concordant pairs. The same was found for tender joint count (TJC >0 in 90% vs 40%; median TJC: 0 vs 6) and patient global, but not for ESR, the study showed. Individual joint analysis showed that 51% of the discordant observations versus 18% of the concordant observations had involvement of lower extremity joints that are not included in the DAS28 assessment protocol.

Tenderness and swelling in joints not included in the reduced joint count (ie, joints in the ankles and feet), but not differences in ESR, account largely for the discrepancy found between DAS remission and DAS28 remission, the researchers conclude. "Therefore, DAS28 remission at a cutoff level of 2.6 has insufficient construct validity and should not be used in clinical practice and clinical trials," they report.

Separate set of remission criteria are needed

Dr. Landewé concedes that DAS is not perfect, that the assessment takes more time because it is more comprehensive, and includes the almost forgotten RAI. "Since DAS remission is also not real remission in every patient, it is my personal feeling that we need better remission definitions," he tells CIAOMed. "In my view, DAS or DAS28 have a role in monitoring disease activity, but we should have a separate set of remission criteria designed for the individual patient." DAS remission and DAS28 remission is the product of best cutoff, which is not always good for individual patients, he explains.

"My ideal remission set would be a modern modification of the old Pinals criteria," Dr. Landewé says. "First of all, it should include time (remission at three separate occasions within 6 to 8 weeks) since ‘occasional remission' probably is meaningless," he asserts, noting that it should also include "absence of swelling [allowing for example, one swollen joint at one or two occasions], normal acute phase reaction, and absence of pain due to arthritis."

DAS28 not optimal tool for remission in RA

In a related study,² Finnish researchers also report on the limitations of DAS28 as a tool to assess remission in RA, demonstrating that a substantial number of patients below the DAS28 cutoff point for remission continue to have tender and/or swollen joints.

Lead researcher Heidi Mäkinen, MD, a rheumatologist at the Jyväskylä Central Hospital in Jyväskylä, Finland, studied 161 patients with a mean age of 57 years. Over 60% tested positive for rheumatoid factor, and 51 (32%) had erosions. At five years, 19 (12%) patients met the American Rheumatism Association (ARA) remission criteria (also known as the Pinals criteria) and 55 (34%) met the clinical remission criteria. The cutoff value of DAS28 was 2.32 for the ARA remission criteria, and 2.68 for the clinical remission criteria.

In patients with DAS28 <2.32, however, 19% had tender joints, 11% had swollen joints, and 7% had both tender and swollen joints, the study found. "A substantial proportion of patients below the DAS28 cutoff point for remission have tender or swollen joints or both; [thus] DAS28 may not be an appropriate tool for assessment of remission in RA," Dr. Mäkinen and colleagues report.

"The DAS 28 reflects disease activity, but it may not be an optimal tool for the assessment of remission in RA," the Finnish investigators write. "All remission criteria so far have included the domain of signs and symptoms of inflammation, whereas the other two major domains of RA—physical function and structural joint damage—have received less attention.

"We still lack a good definition of remission for daily clinical needs as well as for investigational purposes," the researchers emphasize.

In a previous interview with CIAOMed, Dr. Mäkinen noted that "the ideal criteria to define remission in RA should include disease activity, patient's function, and tissue damage caused by RA; and European League Against Rheumatism (EULAR) and the ACR should develop and agree upon the idea."

References

1. Landewé R, van der Heijde DMFM, van der Linden S, Boers M. 28-joint counts invalidate the DAS28-remission definition due to the omission of the lower extremity joints: a comparison with the original DAS remission.  Ann Rheum Dis [serial online]. October 11, 2005.

2. Mäkinen H, Kautiainen H, Hannonen P, Sokka T. Is DAS28 an appropriate tool to assess remission in rheumatoid arthritis? Ann Rheum Dis. 2005;64:1410-1413.