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Immunosuppressive Treatment for Lupus in the Next Decade

• By Dimitrios T. Boumpas, MD; George Bertsias, MD

Immunosuppressive Therapy in Lupus

Today most experts agree that the treatment of severe lupus involves a period of intensive immunosuppressive therapy aimed at halting immunological injury (induction therapy), followed by a period of less aggressive maintenance therapy to maintain the response. The latter period is essential to prevent flares and organ damage accrual. Although this strategy seems logical, it has not been formally tested against a “wait and treat the flare” approach.

Studies dating back to as far as the 1960s clearly demonstrated that high-dose glucocorticoids were not effective in halting end-stage renal disease (ESRD) in proliferative lupus nephritis (LN), with most patients requiring hemodialysis after five to 10 years. This observation, coupled with an increased awareness of steroid toxicity, provided the impetus in subsequent years to explore alternative immunosuppressive agents with an emphasis on AZA and CY. In these trials, most of the data originated from two centers in the United States: Mayo Clinic and the National Institutes of Health (NIH).

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Azathioprine

Early studies by Hahn et al failed to demonstrate a significant effect of AZA on severe disease when added to glucocorticoids in early treatment.1 Subsequent studies by the NIH group showed only a trend to superiority of AZA with prednisone over prednisone alone; the studies, however, may have lacked power to detect a smaller treatment effect.2 Nevertheless, these results have led to considerable decrease in the usage of AZA for LN with the exception of some pediatric centers in Canada.

More recently, new studies have given us the opportunity to take another look into the effectiveness of AZA in the context of new therapeutic protocols and a modern standard of care. In a recent head-to-head comparison of AZA with intravenous CY (IV-CY), AZA showed comparable efficacy after a mean follow-up of at least five years.3 The use of intravenous methylprednisolone (IV-MP) pulses at the beginning of treatment for all patients in this study may have improved the performance of AZA. Strong, albeit circumstantial, evidence supports the use of one to three IV-MP pulses especially in patients with moderate or severe nephritis; in addition to expediting remission, IV-MP pulses may allow for the use of lower doses of glucocorticoids during the induction phase. Not surprisingly, patients in the AZA group experienced more flares and progression of scarring in repeat renal biopsies.3,4 Of note, the study involved only European, low-to-moderate–risk patients (see Figure 2 for definitions) treated in a context of the European healthcare system.

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