Combined Immunosuppressive Treatment Safe, More Effective for Treating Lupus Nephritis, Study Finds

Adding an oral immunosuppressive agent and hydroxychloroquine to routine intravenous cyclophosphamide significantly increases response rates among patients with lupus nephritis without increasing the rate of severe adverse events, a randomized study found.

The study, “Combined immunosuppressive treatment (CIST) in lupus nephritis: a multicenter, randomized controlled study,” was published in Clinical Rheumatology.

Lupus nephritis occurs when there is inflammation in the kidneys as a result of systemic lupus erythematosus. It is usually treated with immunosuppressive therapies, which can decrease immune activity.

The standard strategy for treatment is either cyclophosphamide or mycophenolate mofetil. However, only a small portion of patients — up to 1 in 4 — experience complete resolution of inflammation after receiving these treatments.

Researchers in this study examined whether combining cyclophosphamide with an oral immunosuppressant — such as mycophenolate mofetil, azathioprine, or leflunomide — would be safe and effective for treating lupus nephritis.

The study enrolled adults with lupus nephritis from 17 rheumatology or nephrology centers in China. They were randomly assigned cyclophosphamide (77 patients) or the combination (87 patients), given over a 24-week period.

The combination group was also given hydroxychloroquine, an anti-malarial therapy commonly used for lupus treatment, and both groups also received glucocorticoids, steroid hormones that can also help regulate the immune system.

Patients were analyzed for markers of kidney function, including the amount of protein in their urine and serum albumin levels. They were deemed to have a complete response if their levels were near normal or a partial response if they experienced a 50% decrease in urine protein, had serum albumin of at least 30 g/L, and stable kidney function. If neither response was reached, the treatment was deemed a failure.

Overall, 87.2% of patients receiving the combination achieved a response, compared with 68.8% of those receiving cyclophosphamide alone. Complete responses were also higher with the combination — 39.5% versus 20.8% — showing that the combination treatment was more effective than cyclophosphamide treatment alone.

Interestingly, leflunomide was the oral immunosuppressant associated with the best response rates, with 89.8% of patients responding to treatment, and 43.9% achieving a complete response.

After the 24-week trial, researchers followed 96 of the 128 patients who responded to the initial induction treatment. After a median follow-up of 13.5 months, fewer patients receiving the combination experienced a renal flare — worsening of kidney symptoms — than those on cyclophosphamide — 5.1% versus 10.8% — but the results did not reach statistical significance.

Adverse reactions were also assessed, and no significant differences were found between the two groups.

“Patients under combined treatment did not experience more adverse events. Moreover, the incidence of severe adverse events leading to death, hospitalization, or withdrawal from the study did not differ between the two arms,” the researchers wrote.

They also note that the compounds used for combination therapy in this trial are traditional immunosuppressive agents, not biological treatments that can be more costly.

“Combined immunosuppressive treatment is a safe regime and superior to routine [cyclophosphamide] only therapy in inducing remission in patients with LN [lupus nephritis],” the investigators concluded.