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To the Editors:

We thank Drs. Marks and Tullus for their interest in our work. As we pointed out in our original articles, we did not attempt to create specific combinations of variables for the various types of organ involvement in juvenile SLE. Rather, we attempted to make the core set robust enough to cover all disease phenotypes, focusing on the central features of the physician's subjective estimation of the level of disease activity, global disease activity scoring, parent's global assessment of the patient's overall well-being, and the health-related quality of life; only a specific domain devoted to the assessment of renal disease was included, owing to the major importance of the involvement of this organ in SLE. The variables selected to assess the renal domain during the first consensus conference were 24-hour proteinuria and serum creatinine level (1). In the validation phase, 24-hour proteinuria revealed fair responsiveness to clinical change, whereas serum creatinine proved poorly responsive. For this reason, only 24-hour proteinuria was retained in the final core set. We are of course aware that serum creatinine values need to be related to the body size in children and young adolescents. In responsiveness analyses, we decided to keep absolute values for simplicity. We do not believe the results would have changed using values adjusted for body size because the variation in creatinine level between baseline and the 6-month visit was assessed in each single patient. We agree that in a future core set of response measures devoted specifically to lupus nephritis, more accurate markers of renal function should be used to estimate the GFR.

We understand the concerns of Drs. Marks and Tullus regarding 24-hour urine specimen collection, which, as they pointed out, may be technically difficult to obtain in younger children. The choice of 24-hour proteinuria was made by the attendees of the first consensus conference because they felt it was the most feasible way to assess proteinuria across the numerous centers located throughout the world that participated in the prospective data collection. The feasibility of this procedure was confirmed by the very high percentage of patients who had the 24-hour urine specimen collected at baseline and at 6 months (81% and 74%, respectively). As a result of our analyses, 24-hour proteinuria was incorporated in the core set as a “suggested” variable for the assessment of the renal domain. This means that the measurement of proteinuria is necessary to assess the therapeutic response through the core set, but does not imply that 24-hour data collection is the mandatory method to make the assessment. Investigators are free to use any other tests, including those proposed by Drs. Marks and Tullus (i.e., early morning [spot] urine albumin:creatinine ratio or protein:creatinine ratio), which they deem appropriate for the purposes of their trial.

We agree with Drs. Marks and Tullus that proteinuria may be an inaccurate indicator of renal disease activity in SLE because it may reflect damage, and that some medications may affect proteinuria and render it a less reliable disease marker. We recommended in our first article “because proteinuria may reflect renal damage in the absence of renal activity, a careful assessment of activity parameters of juvenile SLE nephritis should be done to confirm that the patient has active renal disease. Furthermore, the fact that some drugs, such as angiotensin-converting enzyme inhibitors, may lead to a reduction in proteinuria should be taken into account” (2).

Drs. Marks and Tullus suggest that consideration be given to additional parameters of kidney function, such as serum albumin levels, blood pressure, and GFR. We agree that these measures are all important to assess the outcome of renal disease in a clinical trial. However, their inclusion would have been beyond the purposes of our study, which was intended to create a minimal core set of central disease domains that all researchers should report in order to compare their studies with others in the literature. These variables should certainly be taken into account in any effort aimed specifically at devising a set of outcome criteria for lupus nephritis clinical trials (3). Recently, the Renal Disease Subcommittee of the ACR Ad Hoc Committee on SLE Response Criteria recommended a minimum of 4 endpoints for assessment of clinical response in lupus nephritis clinical trials: a measure of renal function, the urinary protein level, abnormalities of urinary sediment, and the frequency and severity of adverse events (4).

With the support of the ACR, we are currently analyzing in detail the statistical properties of a number of renal function parameters (serum creatinine level, 24-hour proteinuria, urine creatinine, urinalysis, creatinine clearance, and blood pressure), which were collected in the validation phase of our study, with the purpose of devising a core set of response variables to be used specifically in juvenile SLE nephritis clinical trials.

  • 1
    Ruperto N, Ravelli A, Murray KJ, Lovell DJ, Andersson-Gare B, Feldman BM, et al. Preliminary core sets of measures for disease activity and damage assessment in juvenile systemic lupus erythematosus and juvenile dermatomyositis. Rheumatology (Oxford) 2003; 42: 14529.
  • 2
    Ruperto N, Ravelli A, Cuttica R, Espada G, Ozen S, Porras O, et al, the Pediatric Rheumatology International Trials Organization (PRINTO), and the Pediatric Rheumatology Collaborative Study Group (PRCSG). The Pediatric Rheumatology International Trials Organization criteria for the evaluation of response to therapy in juvenile systemic lupus erythematosus: prospective validation of the disease activity core set. Arthritis Rheum 2005; 52: 285464.
  • 3
    Boumpas DT, Balow JE. Outcome criteria for lupus nephritis trials: a critical overview [review]. Lupus 1998; 7: 6229.
  • 4
    Renal Disease Subcommittee of the American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Response Criteria. The American College of Rheumatology response criteria for proliferative and membranous renal disease in systemic lupus erythematosus clinical trials. Arthritis Rheum 2006; 54: 42132.

Nicolino Ruperto MD, MPH*, Angelo Ravelli MD*, Alberto Martini MD†, * IRCCS G. Gaslini, Pediatria II, Reumatologia and PRINTO Genoa, Italy, † IRCCS G. Gaslini, Pediatria II, Reumatologia and Università degli Studi Genoa, Italy.