iomis/shutterstock.com
SAN FRANCISCO—Rheumatologists have to look no further than the American College of Rheumatology guidelines to know that the options for patients with lupus nephritis are sometimes not very appealing.
The first-line choices are either mycophenolate mofetil (MMF) plus glucocorticoids or cyclophosphamide (CYC), also with glucocorticoids—and all of their attendant side effects. The problem: evidence, said Joan Merrill, MD, chair of the Clinical Pharmacology Research Program at the Oklahoma Medical Research Foundation. Her work focuses on lupus and she was one of the contributors to the guidelines. The work was presented to attendees of the 2015 ACR/ARHP Annual Meeting.
“Our task was to make recommendations based on the best evidence,” Dr. Merrill said. “And the problem here is that we don’t have sufficient evidence yet to do what our technology has now made possible, which is to approach this disease in a much more rational way.”
The limited recommendations have left clinicians foraging for guidance—tidbits and nuances that can be gleaned from the literature to help them find something that works, especially for their harder-to-treat patients.
Dr. Merrill
Dr. Merrill drew a comparison between lupus nephritis treatment and mixed martial arts (MMA), disclosing that she is the mother of an MMA fighter.
“In MMA, you are going into the octagon to fight some of the most lethal fighters in the world, and you cannot be a one-trick pony—you’ve got to know how to box, you’ve got to know how to kickbox, and you’ve got to know how to roll around on the ground and strangle people,” she said. “And I think that’s a very good analogy for what we’re facing, because lupus nephritis is a formidable opponent.”
MMF vs. CYC
There have been only three rigorous induction trials directly comparing MMF with CYC—and only one of them, a 140-patient trial in 2005, found that MMF was superior.1 Another study, an international trial involving 370 patients, discouragingly found that the six-month response rates for both drugs were not much higher than 50%.2
“This means that we have a slightly under 50% chance of progressing to significant kidney damage,” Dr. Merrill pointed out.
She also noted that the trial in which MMF was found to be superior to CYC had a much higher percentage of African-American subjects, who have been found in other studies to do worse on cyclophosphamide.
But beyond this starting point, other treatment options and strategies are emerging in the literature, if only in morsels, Dr. Merrill suggested.
Tacrolimus
A randomized study in 2014 out of Hong Kong, involving 150 patients, found that tacrolimus and MMF were essentially equivalent as induction therapy in lupus nephritis. Patients were Class III through V.3 This might offer some guidance in the absence of other options, Dr. Merrill said. There were more flares with tacrolimus in the maintenance period, but the difference was not found to be significant.
“We have some evidence growing now that this might be a viable alternative choice,” she said, “particularly when you think about a patient who’s maybe [in] their second or third flare of nephritis.”
Another induction trial out of Asia, a multi-center, open-label study of 360 patients published in 2015, found that a higher percentage of patients (45.9%) on a combination of tacrolimus and MMF reached complete remission than those on cyclophosphamide (25.6%). Dr. Merrill described it as “one of the most exciting papers published for nephritis in the last year and a half.”4
Dr. Merrill asked the audience how many used the two drugs together in difficult cases, and some hands went up.
“It’s starting to happen,” she said. “With or without an evidence base, we’ve gone ahead and become mixed martial artists because our patients aren’t doing so well.”
Antibodies & Protein as Predictors
A recent study found that the odds ratio of treatment failure during induction was 12.7 if patients were positive for anti-dsDNA antibodies at the start of the induction period, and 8.3 for the maintenance period. There were also heightened risks of treatment failure—2.9 OR and 3.5 OR for induction and maintenance, respectively—if the antibody levels weren’t reduced within eight weeks.5
Reducing proteinuria by at least 50% was also associated with better long-term outcomes.6
“Back in the old days when I trained in rheumatology, we were all following the protein, and I don’t think that’s changed,” Dr. Merrill said.
Genetics
Intriguing findings have also emerged in pharmacogenetics recently, she said.
One study found that 44% of those with a GSTA1*A CT heterozygous mutation had a higher non-remission rate (44%) than those without the mutation (20%). The mutation correlated with less active metabolite cyclophosphamide in these patients, suggesting a possible therapeutic remedy.7
“This may be something we can fix by dosing,” Dr. Merrill said.
In another study, patients with a certain variant of the CYP3A5 gene had higher levels of tacrolimus in their blood than other patients, exposing them to greater risk of toxicity and renal dysfunction.8 This could offer another opportunity to solve a problem with a dose adjustment, Dr. Merrill said.
Looking at the full picture of a patient—background drugs, clinical presentation, ethnicity, genetic makeup—offers the nimble clinician a chance to try to optimize treatment, she said.
“I don’t think anybody here,” she said, “really wants to be using cyclophosphamide or endless steroids in our patients too far out into the future.”
Thomas R. Collins is a medical writer based in Florida.
References
- Ginzler EM, Dooley MA, Aranow C, et al. Mycophenolate mofetil or intravenous cyclophosphamide for lupus nephritis. N Engl J Med. 2005 Nov 24;353(21):2219–2228.
- Appel GB, Conteras G, Dooley MA, et al. Mycophenolate mofetil versus cyclophosphamide for induction treatment of lupus nephritis. J Am Soc Nephrol. 2009 May;20(5):1103–1112.
- Mok CC, Ying KY, Yim CW, et al. Tacrolimus versus mycophenolate mofetil for induction therapy of lupus nephritis: A randomised controlled trial and long-term follow-up. Ann Rheum Dis. 2014 Dec 30. [Epub ahead of print]
- Liu Z, Zhang H, Liu Z, et al. Multitarget therapy for induction treatment of lupus nephritis: A randomized trial. Ann Intern Med. 2015 Jan 6;162(1):18–26.
- Dall’Era M, Levesque V, Solomons N, et al. Identification of clinical and serological factors during induction treatment of lupus nephritis that are associated with renal outcome. Lupus Sci Med. 2015 May 20;2(1):e000089. eCollection 2015.
- Korbet SM, Lewis EJ, Collaborative Study Group. Severe lupus nephritis: The predictive value of a ≥ 50% reduction in proteinuria at 6 months. Nephrol Dial Transplant. 2013 Sep;28(9):2313–2318.
- Wang NH, Zhu XY, Zhu Y. The GSTA1 polymorphism and cyclophosphamide therapy outcomes in lupus nephritis patients. Clin Immunol. 2015 Oct;160(2):342–348.
- Niioka T, Komatsuda A, Kato S, et al. Effects of CYP3A5 polymorphism and the tacrolimus 12 h concentration on tacrolimus-induced acute renal dysfunction in patients with lupus nephritis. Xenobiotica. 2015 Dec;45(12):1147–1153.
