Predictors and outcomes of scleroderma renal crisis: data from the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial.

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Systemic sclerosis (SSc) presents one of the greatest therapeutic challenges in rheumatology. There is limited understanding of its pathogenesis and prognosis; unfortunately, clinicians remain ignorant regarding how best to treat its manifestations. It is difficult to identify those patients who are most likely to benefit from aggressive, potentially toxic therapies, none of which has conclusively been demonstrated to be beneficial in randomized, controlled trials (RCTs). In a quandary about when to treat, given the uncertain benefit– risk profile of currently available therapies, clinicians must still attempt to identify patients with responsive disease. In an article published elsewhere in this issue of Arthritis & Rheumatism, DeMarco and colleagues summarize information from an important active RCT in patients with recent-onset diffuse SSc, comparing lowdose and high-dose D-penicillamine (D-Pen) therapy (1). Although it was considered a “failed” trial, its data offer important information regarding an outcome feared by all who hope to treat these patients: scleroderma renal crisis. Although limited, this RCT methodology represents the best we have been able to accomplish at this time. Furthermore, the data from this protocol population are remarkably consistent with those from previously published longitudinal observational studies in patients with recent-onset diffuse disease (2–5). This RCT failed to document efficacy of an accepted therapy, yet few, if any, previous RCTs in SSc have included such a large number of patients. The authors should be congratulated for once again “mining” data from this “failed” trial to deduce pragmatic lessons about SSc (6–9). Although the results reported by DeMarco et al were not the primary outcome measures, the information is nonetheless derived from a prospectively defined cohort of patients, indicating that scleroderma renal crisis occurred in 18 (13%) of 134 patients with diffuse disease between 6 and 13.2 months (mean 11.0 months) after enrollment in the RCT, an estimated 1.7 1.1 years after diagnosis (1). More importantly, 9 patients (50%) with renal crisis died during the relatively brief followup period of 4.0 1.1 years, within 0.9 1.1 years after the onset of symptoms consistent with renal crisis. This is an important point to emphasize in view of the high regard for angiotensin-converting enzyme (ACE) inhibitor therapy (3). The number of patients who developed scleroderma renal crisis or died is consistent with the numbers in previously published observational studies (2–5,10– 13). The current report identifies clinical outcomes and predictors of scleroderma renal crisis that differ from those from the Lund cohort recently reported by Geirsson et al (11). The study population in the D-Pen trial was slightly larger than the Lund cohort, patients were in a much earlier stage of the disease process (mean duration 0.8 years, versus 4.8 years in the Lund cohort), mean followup was 4 years compared with 7.7 years (range 0.3–12.8 years), and the D-Pen trial specifically recruited patients with diffuse disease. Of the 30 patients in the Lund cohort who died, only 1 death was attributable to renal crisis, suggesting a different mortality pattern in SSc patients who survive after the first few years following diagnosis. Geirsson et al concluded that within the Swedish cohort, organ dysfunction was predominant in the first 5 years of disease, after which organ system function remained stable. Nonetheless, certain predictors of poor outcome are evident in both populations. These predictors include older age, diffuse disease (specified in this RCT population), skin scores 20, and evidence of cardiac involvement, by either chest radiography or electrocardiography. Other differences between the 2 populations are striking, supporting the hypothesis that a different patient population survives 12–24 months after diagnosis of SSc, as characterized by the Lund series. Vibeke Strand, MD, Stanford University, Palo Alto, California. Address correspondence and reprint requests to Vibeke Strand, MD, 306 Ramona Road, Portola Valley, CA 94028. E-mail: vstrand@aol.com. Submitted for publication June 14, 2002; accepted in revised form July 15, 2002.