The Treatment of Lupus Nephritis: Revisiting Galen

The therapeutic approach to the patient with lupus nephritis is controversial. The medical literature contains a surfeit of expert opinion and scant scientific evidence. Many opinions about the treatment of lupus nephritis are based on faith rather than valid observation. When faith rather than evidence is used to support clinical decisions, the treatment chosen becomes, like religion, a matter of personal preference. Despite continuing improvement in outcomes, renal failure and death remain common among patients with lupus nephritis (1). The literature is burdened with clinical anecdotes and suboptimally designed clinical studies. Few controlled clinical trials have been reported, and meta-analyses are plagued by a lack of uniformity in the samples and outcome measures of existing studies. In this issue, Illei and colleagues (2) report a clinical trial comparing parenteral methylprednisolone, parenteral cyclophosphamide, and a combination of these two treatments, all in addition to low-dose oral prednisone. Their study raised hope that a more definitive answer to ideal therapy is on the horizon. Unfortunately, it too has important limitations. Those who study lupus nephritis disagree on the optimal approach to therapy. Although it may have serious adverse effects, including gonadal toxicity, therapy with cytotoxic agents plus high-dose prednisone has become the standard of care for patients with lupus nephritis, most of whom are young. Two meta-analyses support this approach (3, 4). Of the currently available immunosuppressive agents, cyclophosphamide appears to have an advantage in terms of early therapeutic response. The dramatically improved long-term outcome observed in patients whose disease entered early remission has led to use of this cytotoxic agent as induction therapy (5). Cyclophosphamide was developed for oral use, but disagreement exists about the preferred route of administration. While this argument may superficially appear pedantic, daily oral therapy is thought to produce superior results compared with intermittent intravenous treatment in Wegener granulomatosis (6). Unfortunately, no data are available to suggest which mode of administration is preferable in lupus nephritis. Galen is purported to have said, All who drink of this remedy recover in a short time except those whom it does not help, who all die. Therefore it is obvious that it fails only in incurable cases (7). His words apply to cyclophosphamide and lupus nephritis. The outcome of therapy in an individual patient, irrespective of the route of administration, ranges from apparent complete remission of disease to stable or progressive chronic renal morbidity to death from renal and systemic disease. Renal biopsy evidence of severe glomerular inflammation (categorized as World Health Organization [WHO] class IVdiffuse proliferative glomerulonephritis) and biopsy evidence of extensive renal scarring, indicating chronicity in patients with a more protracted course, are associated with a poorer prognosis. Histologic changes on renal biopsy that demonstrate the severity of glomerular inflammation may indicate the degree of risk for poor outcomes but do not predict with any certainty the ultimate response to therapy. It thus becomes critical to examine clinical risk factors that may be associated with response to therapy. In most studies, ethnicity is associated with therapeutic response; white persons are more likely than black persons to attain remission. Renal function at diagnosis of lupus nephritis, generally measured by the serum creatinine concentration, is also an important predictor of outcome (5, 8). The patients in the original cohort in Illei and colleagues' study had an average serum creatinine concentration of 99 mol/L (1.13 mg/dL) (8), and the literature suggests that such patients would have a relatively benign course (5). In addition, 20% of the 82 patients entered into the study were classified as having renal biopsy changes, not of WHO class IV but rather the less severe WHO class III (focal segmental glomerulonephritis, currently defined as inflammatory changes affecting some segments of <50% of glomeruli). The results must be interpreted in the context of data showing that the presence of a normal serum creatinine concentration and less glomerular inflammation at the time of entry are associated with a positive response to therapy and likelihood of complete remission (5, 9). Furthermore, clinical remission has been defined as a return to normal urine protein excretion and attainment and maintenance of a normal serum creatinine concentration (5). Illei and colleagues' somewhat arbitrary definition of renal response involves disappearance of microscopic hematuria and a decrease in proteinuria to less than 1 g/d (2), criteria that are far less rigorous than those that others have used to define clinical remission of lupus nephritis. In fact, the initial report of this study stated that erythrocyturia disappeared in both non-responders to therapy and those who achieved remission (8). Hence, attainment of renal response would actually be based on a decrease in, but not disappearance of, proteinuria (8). In this context, long-term outcomes show that intermittent parenteral methylprednisolone plus relatively low-dose oral prednisone is not adequate to attain the clinical response that would be expected in the study patients. This conclusion may not be surprising given the established position of high-dose prednisone therapy in these patients. Of note, long-term analysis of patient survival revealed that the cyclophosphamide group did not differ significantly from the cyclophosphamide plus methylprednisolone group in risk for death or end-stage renal disease (2). Furthermore, the groups did not differ in the likelihood of doubling of the serum creatinine concentration, a variable that approximates halving of the glomerular filtration rate. In post hoc analysis of a composite end point that the authors called treatment failure, which combined several aspects of treatment response, patients receiving combination therapy appeared to have better response than those receiving cyclophosphamide alone (2). Post hoc analyses may indicate trends that can be applied to the design of future studies, but they should not be considered conclusive. The study data do not clearly support the authors' implication that therapy with cyclophosphamide plus methylprednisolone may provide additional advantage over treatment with cyclophosphamide alone. Physicians should be cautious in adopting this protocol as standard treatment in patients with lupus nephritis. A further consideration is whether use of parenteral cytotoxic therapy offers any advantage. Although such treatment is commonly used, data from meta-analyses and comparison with results of trials of oral cyclophosphamide have not confirmed the belief that parenteral administration should be preferred in patients with lupus nephritis (5, 9). Although some believe that intravenous cyclophosphamide therapy is the standard of care in severe lupus nephritis, few data support this point of view (1, 4, 10). The tendency to recommend parenteral cyclophosphamide may in part reflect the mystique associated with a more invasive intervention. The recommended protocol for parenteral administration of cyclophosphamide includes extensive intravenous hydration, large doses of antiemetics, and use of intravenous cyclophosphamide metabolite (acrolein)-neutralizing mesna and parenteral dexamethasone in a day hospital setting (8). This regimen is certainly more dramatic to both patient and staff than oral ingestion of a few pills every morning in combination with a moderate increase in daily water intake. Variation from this extensive protocol usually produces severe, acute nausea and vomiting and hemorrhagic cystitis. In addition, as noted in the original report of this regimen (8), more than 50% of patients who received intravenous cyclophosphamide with or without methylprednisolone reported amenorrhea and 10% developed cervical dysplasia. Although Illei and colleagues (2) claim that combination therapy produced no additional toxicity, three patients taking intravenous methylprednisolone in the original study developed acute bronchial spasm and an unreported number of patients developed laryngeal edema. Strong evidence from carefully designed clinical trials in lupus nephritis is not currently available. The clinician must therefore weigh the existing evidence, consider its limitations, and make a therapeutic decision guided by his or her own faith in a therapy and the patient's preference. New therapeutic strategies must be tested according to the established principles of clinical trial methods, which have thus far rarely been applied to the study of lupus nephritis treatment. These principles include a generalizable study sample, a sample large enough to assure adequate study power, and predefined end points. Unfortunately, Illei and colleagues' study does not meet these standards. In 1939, William B. Castle, one of the finest clinical scientists to represent Harvard Medical School, remarked, No matter how important are new discoveries and methods, they cannot be considered to have reached fulfillment until generally applied to the sick (11). A great deal of effort has been expended on the development of information about all aspects of systemic lupus erythematosus in mice. We must now turn our attention to man.