Characteristics & Disease Course of Patients with SLE

The demographics and disease features of the cSLE patients are summarized in . Data from a total of 623 visits (or 526 between-visit intervals) of 98 children were available for analysis. There were 39 patients with biopsy-proven lupus nephritis. As per the managing pediatric rheumatology professionals, the courses of cSLE between consecutive study visits were: 89 episodes of clinically relevant worsening (12 major worsening, 77 minor worsening); 348 episodes of stable disease between visits, and 89 episodes of improvement (14 major improvements, 75 minor improvements).

| **Table 1**Demographics & SLE Features at Baseline |

From the families’ perspective, there were 59 episodes of worsening of well-being (9 major worsening, 50 minor worsening), 253 episodes of stable well-being, and 202 episodes of improved well-being (108 minor improvements, 94 major improvements). For 12 between-visit intervals no family ratings were available.

MCID – Mean Changes in the Scores of Activity Measures with Improvement or Worsening

Between-visit changes of the VAS_{MD} and the scores of the disease indices are summarized in . Despite statistical significance, but irrespective of the index, mean change scores were all small and close to the smallest possible difference in score, which is ‘1’ for each of these tools. Thus increases of the ECLAM scores as small as ‘1’ appeared to be clinically relevant, while for the BILAG_{Liang} increases of ‘3’ could be considered as clinically important. With clinically relevant improvement of cSLE, decreases in the scores of the disease activity indices were somewhat larger.

| **Table 2**Change in Disease Activity Scores with Physician-rated and Parent-rated cSLE Course ^{†} |

MCID - SEM with Stable Disease Course & Chance-Corrected Agreement

Disease measures remained most often unchanged with disease courses rated as *’no change in disease’* by the managing pediatric rheumatology professional (). Chance-corrected agreement of change score of activity index with stable disease course was ‘excellent’ for the MD_{VAS} (ICC= 0.76) and ‘good’ for all other disease indices (all ICC≥ 0.47) ().

| **Table 3**MCID based on the One SEM Criterion Using Physician-rated Change in cSLE as External Standard ^{†}. |

Alternatively, as is shown in , the MCID can be based on the *1-SEM-Criterion*, assuming that important improvement or worsening has occurred if the change score of exceeds −1 SEM or + 1 SEM, respectively. We also tested a more stringent MCID definition, i.e. the 90% CI around the mean change score or ± 1.645 SEM (). As is reflected by the respective detection rates, the tighter the CI limit was set, the more accurately patients with stable disease course could be discriminated from those who experienced clinically relevant change (), but this occurred at the expense of decreased rates of correctly identified patients with clinically relevant change in disease ().

For example, when setting the MCID value of the SLEDAI to the one SEM (63% CI) boundary, only 56% of the patients with stable disease course would be correctly classified, while at the 90% CI mark, 77% of the patients with ‘*no change in disease*’ would be correctly identified as having a stable disease course. However, the 90% CI mark for defining the MCID would have greatly underestimated the frequency of patients in whom change truly had occurred.

Of note, detection rates using the 63% CI thresholds (1-SEM-Criterion) were again small and quite similar to those using the mean change scores as are presented in .

MCID Defined by Optimal Cut-offs as per Discrimination & Classification Analysis

Discrimination and classification analysis provides cut-off values of disease change scores that best discriminate the three groups of patients (worsening, no change, improvement). Such cut-off values could be considered as alternative MCID thresholds. For physician-rated worsening and improvement, respectively, these MCID cut-off values [detection rates are presented in brackets] were for the VAS_{MD} at +0.6 [65%] and −0.5 [71%], the ECLAM at +0.6 [64%] and minus;0.5 [49%], the SLEDAI at +1.2 [48%] and minus;0.9 [58%], the SLAM at +0.9 [57%] and minus;0.9 [57%], the BILAG_{Liang} at +2.6 [55%] and minus;1.3 [61%], the BILAG_{Gladman} at +0.7 [56%] and minus;0.6 [60%], and the BILAG_{Stoll} at +1.6 [60%] and minus;0.8 [52%]. Irrespective of the measure of disease activity considered, none of the MCID cut-offs determined by this statistical approach correctly classified > 64% of all episodes of the three disease courses. , upper panels depicts representative results of these analyses for the VAS_{MD} and the SLEDAI.

Of note, MCID thresholds defined by discrimination and classification analysis were somewhat smaller but again similar to those defined by the *1-SEM-Criterion* and comparable to those using the mean change scores for defining the MCID.

MCID at the 70% Predicted Probability of Worsening or Improvement

It has been suggested (

27), that clinically relevant change in disease activity indices may be defined based on a certain desired probability to correctly detect patients with change of disease. The results of such analyses for predicted probabilities of 70% to 90% for improvement and worsening of cSLE, as would be predicted by discrimination analysis and the physician-rated change in cSLE as an external standard, are summarized in (also ).

| **Table 4**Minimal Clinically Important Differences Considering Certain Predicted Probabilities for Worsening or Improvement^{†} |

Clinically-relevant changes in disease indices defined by such high predicted probabilities were much larger than MCID defined by any of the other approaches to estimating the MCID.

MCID of Disease Activity Scores - Family's Perspective

When considering the ratings of the families (external standard: parent rating of change of patient well-being), the mean change scores of the disease measures were often even smaller than when physician ratings of change in cSLE were used as external standard.

MCID defined the *1-SEM-Criterion* were for the 63% CI as follows: VAS_{MD} at ±0.7, ECLAM at ±0.9, SLEDAI at ±1.9, SLAM at ±3.8, BILAG_{Liang} at ±4.2, BILAG_{Gladman} at ±1.4, and BILAG_{Stoll} at ±3.3, respectively.

Using discrimination and classification analysis, the MCID cut-offs that discriminated best between groups of patients with different disease courses were as follows for worsening and improvement [detection rates are presented in brackets], respectively: for the VAS_{MD} at +0.2 [42%] and minus;0.1 [37%], for the ECLAM at +0.1 [55%] and minus;0.2 [44%], for the SLEDAI at +0.4 [40%] and minus;0.2 [42%], for the SLAM at +0.2 [16%] and minus;0.9 [63%], for the BILAG_{Liang} at +1.1 [53%] and minus;0.6 [44%], for the BILAG_{Gladman} at +0.2 [58%] and minus;0.4 [44%], and for the BILAG_{Stoll} at +0.6 [55%] and minus;0.3 [45%]. This is illustrated the VAS_{MD} and SLEDAI in , lower panels. Families often rated the patients’ well-being as unchanged even when large changes in the VAS_{MD} and the SLEDAI had occurred.

Regardless of the activity measure considered, none of the MCID cut-offs using this statistical approach were able to correctly classify > 47% of all episodes of the three disease courses.

For reaching a 70% predicted probability of clinically important worsening of well- being to have occurred, the VAS_{MD} had to have increased by 5.2, the ECLAM by 6, the SLEDAI by 13, the SLAM by 4, the BILAG_{Liang} by 20, the BILAG_{Gladman} by 6_{,} and the BILAG_{Stoll} by 12, respectively.

Similarly, for achieving 70% predicted probabilities of patients whose well-being importantly improved, the respective MCID thresholds were for the VAS_{MD} at − 8.2, the ECLAM at minus;9, the SLEDAI at minus;18, the SLAM at minus;5, the BILAG_{Liang} at minus;32, the BILAG_{Gladman} at minus;10, and the BILAG_{Stoll} at minus;21, respectively.

Accuracy of the RIFLE for Classifying Disease Courses

The RIFLE correctly identified 26% and 8% of the episodes of disease worsening and disease improvement, respectively. The kappa coefficient ± standard error of the RIFLE was only 0.06 ± 0.02. Alternative criteria for defining improvement or worsening (instead of clinically relevant worsening: ‘*worsening*’ of at least three RIFLE items; clinically important improvement: ‘*partial response*’ and/or ‘*resolution*’ occurs in four or more RIFLE items) did not improve the accuracy of the RIFLE for capturing cSLE disease courses (data not shown).