We have undertaken a comprehensive assessment of SLEDAI-2000 index with regards to definition of active disease, minimal clinically meaningful change in score and sensitivity to change of the index. These have involved large sample sizes in routine practice and the analyses were performed from both the cross-sectional and longitudinal perspectives.
This is the first study to assess the sensitivity to change of SLEDAI-2000, since it was revised from the SLEDAI index. Using the robust external responsiveness method, the results confirmed that SLEDAI-2000 index was sensitive to change as the changes in the score correlated well with the corresponding change in therapy. This result is consistent with previous studies on sensitivity to change of SLEDAI [7–11
Our analysis demonstrated that the most appropriate SLEDAI-2000 cut-off score for definition of active disease linked to the need to increase therapy was 3 or 4. This was consistent with the results from our reliability study [15
] and another study by Gladman et al
]. However, this is different from the cut-off score of 6 suggested by Abrahamowicz et al
]. This is most likely due to the difference in the study design. Our study was prospective and derived from a large number of patients within clinical practice, whereas the Abrahamowicz study was based on hypothetical situations derived from 30 abstracted case histories. As such, the result of our study is more applicable to clinical practice.
The longitudinal analysis to determine the minimal clinically meaningful changes in SLEDAI-2000 score (based on the need for treatment) showed that, in general, the performance of cut-points at individual level was not attractive. Although a minimal clinically meaningful increase in score of 1 or 2 provided the best results for sensitivity and specificity, a higher threshold for increase in score of 3 or 4 was more appropriate (and recommended) for prediction of increase in therapy (due to its superior PPV), but with a resultant decrease in the sensitivity. This is similar to the results of two previous studies with SLEDAI index [14
]. However, Liang et al
] suggested a higher cut-off (increase in score of ≥8 for flare and decrease in score of ≥6 for improvement). This discrepancy could be due to the fact that Liang et al
. involved lupus experts reviewing abstracted case histories, whereas this study is based on clinical practice.
Our data suggest a minimal clinically meaningful decrease in score of 1 or 2, which is much smaller in magnitude than that used in the SLE Responder Index (SRI) (decrease in score of ≥4) [28
]. Although SRI uses Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI [29
] instead of SLEDAI-2000, both the indices are almost identical and would be expected to have similar performance. The SELENA-SLEDAI cut-off point for the SRI was based on previous work by Gladman et al
] using the original SLEDAI, not through the analysis of the belimumab trial data. In the analysis of the belimumab trial data, there were significantly more patients with improvement in score of 1 or 2 in the belimumab group than in the placebo group, but there was no significant difference between the groups when the improvement in score of ≥4 was used. This is consistent with our findings and suggests that a lower threshold for improvement in SELENA-SLEDAI score might be considered for the SRI. However, it is acceptable to select a higher threshold that would require the drug to have bigger treatment effect as compared with placebo. For a higher threshold to be used, it would be desirable to have a higher SELENA-SLEDAI score of >4 (instead of ≥4) at study entry to allow the drug to achieve the required treatment effect (decrease in score of ≥4).
More importantly, our results indicate that the use of a single cut-off for change in SLEDAI-2000 score will sacrifice information and performance. In addition, change in SLEDAI-2000 score on its own is inadequate in explaining change in therapy. The score from which it has changed from is equally important. This is not surprising as the score from the previous assessment puts the change in score into context; for example, a change from a score of 18 to 15 may not constitute significant change as the patient continues to have very active disease, whereas a change of similar magnitude from 6 to 3 would indicate improvement in disease activity.
We did assess several alternative models of change in score in the analysis (data not shown), but, nevertheless, the best model to explain change in therapy is with the score of the previous visit and the change in score (as a continuous variable) included. Although the minimal clinically meaningful change at individual level is desirable for definition of response in clinical studies, our analysis highlights the drawback of using such cut-off points with change in score. Therefore, it has to be emphasized that SLEDAI-2000 score is designed as a continuous variable and performs best as such. The use of cut-off points will lead to loss of information and compromise its performance.
Further analysis revealed that the estimated population average difference in change in SLEDAI-2000 score between patients requiring an increase in therapy and those without treatment increase is ~2.6, after adjustment for prior SLEDAI-2000 score. This difference could be recommended as a basis for defining minimal clinically important treatment effects for clinical studies.
We have not performed specific analysis with regards to the effect of differential system involvement on the cut-off values. This is because SLEDAI-2000 index was designed and intended to be used as a global score index. Furthermore, it is not uncommon for SLE disease activity to affect a few systems concomitantly (such as pleurisy with rash and arthritis). It is less common for disease activity to affect only one single system and the numbers would be too small to make meaningful interpretation. We would not recommend using global score index (such as SLEDAI-2000) as the primary outcome end-point for clinical trials assessing the differential effects of therapy on different systems: a system-based index would be more appropriate.