Global versus organ-specific outcome measures in systemic lupus erythematosus: Comment on the articles by Furie et al, Nikpour et al, Wallace et al, Burgos et al, and Ramos-Casals et al
Article first published online: 30 MAR 2010
Copyright © 2010 by the American College of Rheumatology
Arthritis Care & Research
Volume 62, Issue 4, pages 580–581, April 2010
How to Cite
Monach, P. A. (2010), Global versus organ-specific outcome measures in systemic lupus erythematosus: Comment on the articles by Furie et al, Nikpour et al, Wallace et al, Burgos et al, and Ramos-Casals et al. Arthritis Care Res, 62: 580–581. doi: 10.1002/acr.20053
- Issue published online: 30 MAR 2010
- Article first published online: 30 MAR 2010
To the Editors:
A recent issue of Arthritis Care & Research featured a series of valuable articles that all confronted, from different perspectives, the problem of measuring disease activity in systemic lupus erythematosus (SLE) (1–5). Despite very different messages otherwise, the authors of all of these papers either assume or argue that composite global indices of disease activity comprise a plausible goal and should serve as the primary, or only, outcome analyzed and reported in trials. The purpose of this letter is to question whether that approach is appropriate for all circumstances.
Admittedly, if recent trials of biologic agents in SLE had been spectacularly successful, or if there were no disconnect between physicians' observational experience and trial results (5, 6), then there would be little cause to question the value of composite measures. However, even if new drugs were reducing Safety of Estrogens in Lupus Erythematosus: National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index (SELENA–SLEDAI) or British Isles Lupus Assessment Group (BILAG) scores, or reducing prednisone doses to zero in a substantial fraction of patients, the practicing rheumatologist might still want to know the full list of manifestations that were seen, and which improved and which did not. The analysis of large numbers of subgroups, particularly small subgroups, is widely viewed with distaste because it can be a hallmark of a desperate search for statistically significant findings. But if subgroup analyses are prespecified for sound reasons and are accompanied by the proper caveats, presentation of such data as efficacy outcomes would be more valuable than burying them among the adverse events in a manner that is difficult to interpret (3).
In their article, Furie et al are, of course, correct to note, “In other diseases where manifestations are heterogeneous, combined responder instruments have been used to assess disease activity (1).” However, the American College of Rheumatology 20% (ACR20) improvement criteria in rheumatoid arthritis (RA) is a particularly inappropriate example and could be used to support the opposite position (7). The ACR 20/50/70 and Disease Activity Score criteria essentially summarize multiple, imperfect ways of assessing the same condition: how inflamed are this patient's joints? If clinical trials in RA had focused on patients with extraarticular manifestations and had used an index that included nodules, interstitial lung disease, inflammatory eye disease, cardiovascular events, fatigue, and rheumatoid factor titers alongside arthritis, then we might still be in search of an accepted disease-modifying antirheumatic drug. Similarly, the Crohn's Disease Activity Index is weighted toward measures of bowel disease and constitutional symptoms using multiple assessments.
The Birmingham Vasculitis Activity Score (BVAS) is a better example of a composite measure that has been used successfully in clinical trials (in Wegener's granulomatosis [WG] and microscopic polyangiitis [MPA]), but the differences between these diseases and SLE are relevant to determining the value of a composite global activity score. The majority of patients with WG or MPA achieve complete remission, and the BVAS has found its greatest utility in trials simply as a dichotomous outcome of zero (remission) versus greater than zero (active). Although the severity of disease either before treatment or at a subsequent flare can be estimated by the BVAS score, in practice investigators are quite cautious about using the index in this way and instead consult the particular manifestations to evaluate and report severity of flare.
It is also sobering to acknowledge that the reason the BVAS has been useful in tracking remission and subsequent flare in vasculitis is that the drugs tested in WG and MPA have, fortuitously, been effective in treating virtually all of their manifestations: granulomatous, vasculitic, and musculoskeletal. This has clearly not been the case in recent trials in SLE, which should perhaps not be surprising considering the greater diversity of autoimmune and inflammatory mechanisms likely operating in SLE compared with WG, as well as the greater prevalence of persistently active disease (2), the higher rate of flare (3), and the common clinical impression that many aspects of SLE fluctuate in severity independent of treatment.
Therefore, regardless of the refinements to the use of global summary measures that continue to be made by leaders in SLE research (1), I am concerned that a global disease activity index in SLE requires a degree of abstraction that will inevitably give the clinician inadequate information regarding a drug's effectiveness. Enumeration and analysis of individual manifestations brings 1) a risk of type I errors due to multiple comparisons, 2) a risk of type II errors due to small sample sizes, and 3) is messy to present (8); but since, respectively, 1) findings need to be confirmed in multiple studies anyway, 2) new and expensive treatments should only find widespread use if they are highly effective, and 3) SLE is a messy disease to evaluate and treat due to its diversity, I genuinely hope to see massive tabulations of data on particular manifestations in future reports of clinical trials.
- 1Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum 2009; 61: 1143–51., , , , , , et al.
- 2Frequency and determinants of flare and persistently active disease in systemic lupus erythematosus. Arthritis Rheum 2009; 61: 1152–8., , , .
- 3A phase II, randomized, double-blind, placebo-controlled, dose-ranging study of belimumab in patients with active systemic lupus erythematosus. Arthritis Rheum 2009; 61: 1168–78., , , , , , et al.
- 4Disease activity and damage are not associated with increased levels of fatigue in systemic lupus erythematosus patients from a multiethnic cohort: LXVII. Arthritis Rheum 2009; 61: 1179–86., , , , , .
- 5Rituximab and lupus: good in real life, bad in controlled trials. Comment on the article by Lu et al [letter]. Arthritis Rheum 2009; 61: 1281–2., , .
- 6Rituximab in systemic lupus erythematosus: a systematic review of off-label use in 188 cases. Lupus 2009; 18: 767–76., , , .
- 7American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 727–35., , , , , , et al.
- 8The impact of flare on disease costs of patients with systemic lupus erythematosus. Arthritis Rheum 2009; 61: 1159–67., , , , .
Paul A. Monach MD, PhD*, * Boston University School of Medicine, Boston, MA.