Background/Purpose: The biological variability in MBDA scores over a 24-hour period and day-to-day in patients with rheumatoid arthritis (RA) has not been well characterized. These data were obtained to determine a minimally important difference (MID) and establish a cut point for a meaningful change in MBDA scores over time.

Methods: 28 adults with clinically stable seropositive RA on stable medication (>8 weeks without changes), were recruited to a single US rheumatology research center. Serum samples were obtained 6 times over the first 24-hour period (8 AM, 12 PM, 4 PM, 8 PM, 12 AM and 8 AM) then at 12 PM in the next 24-hour period and at 8 AM the next two consecutive days, for a total of 9 time points. Diurnal variation was calculated using 6 time-points over the first 24 hours.  Daily variation was determined using 4 time points taken at 8 AM on successive days.  Combined diurnal and daily variation was calculated by using 9 time points over the four days. For each patient (n=28), changes in MBDA scores were calculated for all possible pairs of time points for: (a) Diurnal variation (15 possible pairs/patient, 420 total pairs), (b) Daily variation (6 possible pairs/patient, 168 total pairs) and (c) Diurnal and Daily variation (36 possible pairs/patient, 1008 total pairs).  The mean change in MBDA score was determined for all pairs in each of the 3 analyses. The MID was calculated as twice the standard deviation (SD) using all available data.

Results: 28 patients were recruited for the following MBDA disease activity categories: 6 in low, 13 in moderate and 9 in high.  Patient baseline characteristics were 64.3% women, mean age 61.9 years, mean MBDA score 39.3, and mean CDAI 19.9.  With 96.4% patients on DMARDs, 8 patients were receiving biologics (1 rituximab; 7 anti-TNF, 6 in combination with MTX). No patients were on glucocorticoids. During the first day, the greatest and lowest mean MBDA scores were observed at 12 AM (midnight) and 12 PM (noon), respectively (Figure). The mean absolute change (SD) of MBDA score for diurnal variation was 4.3 (4.2). The largest variability in MBDA scores was observed for patients in the low MBDA category. The mean absolute change was 4.3 (4.4) for daily variation and 4.5 (4.5) in the combined daily and diurnal variation analysis. The MID was calculated as 9. Approximately 91% of the absolute changes determined for all pairs of MBDA score were ≤9. 

Conclusion: Based upon short-term variability in the MBDA score among stable RA patients tested serially over time, the minimally important difference in the MBDA score was 9 units. Changes exceeding this threshold are unlikely to be due to diurnal and daily biological variation alone.