A comparison study of the serious infection burden among patients with lupus found no major differences in patients treated with three separate immunosuppressive drug regimens.
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Given that serious infections are among the leading causes of hospitalizations and death in patients with systemic lupus erythematosus (SLE), researchers investigated whether the incident rates differed in patients who recently began drug therapy with mycophenolate mofetil (MMF), azathioprine (AZA) or cyclophosphamide (CYC). Results were published recently in the February issue of Arthritis & Rheumatology.1
“These medications are all used to treat a number of manifestations of lupus, most commonly lupus nephritis,” lead author Candace Feldman, MD, MPH, assistant professor of medicine, Harvard Medical School in Boston, and associate physician at Brigham and Women’s Hospital, Division of Rheumatology, Immunology and Allergy, tells The Rheumatologist.
The three drugs are often interchangeable in the treatment of SLE. Mofetil and AZA frequently are prescribed for maintenance of remission among patients who have lupus nephritis; while for induction of remission, studies have shown minimal differences between use of MMF and CYC, she says.
In this longitudinal cohort study, researchers examined records from 2000 to 2010 of more than 100,000 patients with SLE from the Medicaid database to further analyze outcomes of those who had started one of the three treatments. They aimed to address a lack of head-to-head studies of comparative infection rates associated with these commonly prescribed immunosuppressive medications.
The authors note these data are needed to help inform treatment choices for patients.
“In this population of Medicaid beneficiaries, we found a very high burden of serious infections, which we’ve also shown in prior studies,” Dr. Feldman says. “A number of studies have shown that this population is particularly vulnerable and has an increased risk of comorbidities and poor outcomes.”
The large national study covered results up to 12 months and was designed to compare one drug with another to determine whether there were differences of serious infections between the two. One cohort of patients compared MMF with AZA and the other compared MMF with CYC.
“The reason we did these in two separate groups instead of one group comparing all three is because it tends to be a sicker group of patients with more active lupus who you would be thinking about the interchangeable use of mycophenolate mofetil and cyclophosphamide and a less sick group that you would be thinking about for mycophenolate mofetil vs. azathioprine,” Dr. Feldman says. Thus, the team conducted two separate analyses.
All those included in the cohorts were SLE patients who were new to initiating immunosuppressive therapy with one of the three drugs included in the study. The population involved patients who had been hospitalized with serious infection.
Previous controlled trials and academic studies have described increased rates of infections related to immunosuppressive drugs. But those studies were limited by such factors as small sample size, disease severity exclusions and short follow-up periods, the article authors note.
Further, most clinical trials are powered to determine differences in efficacy and not on adverse events, such as serious infection, Dr. Feldman says. Therefore, there may be an insufficient number of people in a clinical trial to detect clinically meaningful difference in infections.
Looking for Meaningful Difference
“A high percentage of lupus patients in this population had serious infections, which allowed us to look for what we thought would be meaningful differences in serious infections,” Dr. Feldman says.
Greater than 90% of the serious infections reviewed in the study were bacterial, which reflects findings from previous studies, notes Dr. Feldman. The remainder were viral or fungal, with the smallest percentage being mycobacterial.
The research team set out to choose a population with a similar chance of having received one drug or the other and a goal to learn whether there was a difference in serious infection between the two compared drugs. To extract a fair comparison, the study used matched cohorts who were most likely to have interchangeably received one or the other drug examined in the analysis, Dr. Feldman explains.
“In our analysis, we did propensity score matching, meaning we included only people whom we felt had a similar chance of receiving one or the other drug,” Dr. Feldman says.
Using 1:1 propensity score matching, researchers narrowed the number of patients for the first cohort to two groups of 1,350 each who were new to using either MMF or AZA. Likewise, the second cohort had score matching groups of 674 patients new to either MMF or CYC. Estimated propensity scores were based on sociodemographic, comorbidity and medication use information.
The study estimated incidence rates of serious infections up to six and 12 months after a patient began using the drug. Cox regression was used to estimate hazard ratios (HRs) of first infection and death, with 95% confidence intervals (95% CIs).
“We really did not find significant differences in serious infection risks,” defined as serious infection that results in hospitalization, Dr. Feldman says.
Results indicated that after six months, the incidence rate per 100 person-years for first serious hospitalized infection was 14.6 and 15.2 in patients treated with MMF and AZA, respectively (HR of MMF vs. AZA 0.99 [95% CI 0.74–1.32]). Similarly, a comparison of first serious infection between MMF and CYC revealed the incidence rate per 100 person-years was 24.1 and 24.6, respectively (HR 0.95 [95% CI 0.69–1.32]). Researchers also found that there were no differences in death rates among the three regimens.
Although “no differences were observed in our analyses between the specific immunosuppressive drug comparisons, the high burden of serious infections among SLE patients receiving these medications overall is important to consider,” the article states.
The lack of differences among the drugs studied with regard to serious infections could be useful from a clinical standpoint to assist physicians when treating lupus….Choosing one of these drugs over the other is not going to increase the patient’s risk of serious infection.
The lack of differences among the drugs studied with regard to serious infections could be useful from a clinical standpoint to assist physicians when treating lupus, Dr. Feldman says.
Rheumatologists often have a patient with a number of recurring infections. “It will be your time to choose their next drug,” Dr. Feldman explains. “You [should ask yourself, ‘Which] of the drugs I would potentially prescribe [has] the lowest risk of serious infection associated with it?’”
One thing this study reveals is that choosing one of these drugs over the other is not going to increase the patient’s risk of serious infection, Dr. Feldman says.
“[Patients] are going to have an increased risk just by virtue of being put on either immunosuppressive drug, but one drug does not appear to have a stronger association with serious infections than the other,” she says.
More Research Required
Dr. Feldman says there is room for further studies to investigate whether there is any difference in risk of infection after longer-term use of the medications included in the analysis.
Catherine Kolonko is a medical writer based in Oregon.
- Feldman CH, Marty FM, Winkelmayer WC, et al. Comparative rates of serious infections among patients with systemic lupus erythematosus receiving immunosuppressive medications. Arthritis Rheumatol. 2017 Feb;69(2):387–397.