BOSTON—For patients with lupus nephritis, multi-targeted therapies combining drugs similar to what oncologists do now to treat cancer is the future of treatment for this complication of lupus, according to Michelle Petri, MD, MPH, professor of medicine, director, Lupus Center, Johns Hopkins University School of Medicine, Baltimore, who emphasized the need for aggressive therapy to achieve a goal of complete response and remission.
Adding rituximab to the mix may permit reducing and avoiding altogether the use of long-term steroids if an international, multicenter trial just underway can demonstrate the efficacy and safety of a rituximab regimen sans steroids for lupus nephritis, according to Liz Lightstone, MD, professor of renal medicine, Imperial Lupus Centre, Imperial College London, Hammersmith Hospital, London, U.K.
These were among the issues discussed in a session titled, Forefronts in Lupus Nephritis, at the ACR/ARHP Annual Meeting in Boston in November 2014, in which Drs. Petri and Lightstone focused on the future of combination therapies that can both effectively treat lupus nephritis, as well as reduce side effects and improve quality of life in these patients.
Multi-Targeted Treatment Approach
For Dr. Petri, treatment of lupus nephritis requires an aggressive approach that includes a variety of treatments targeted at multiple issues. For acute treatment, she described a combination of multi-targeted therapies that she uses, including ACE/ARB to control blood pressure, protect renal function and, perhaps, reduce fibrosis; hydroxychloroquine, which when used with mycophenolate mofetil (MMF) improves complete renal response rates; and vitamin D, which shows a modest benefit on disease activity and urine protein/creatinine levels. Achieving a 25-hydroxy level of 40 or above significantly helps reduce protein/creatinine levels.
For pregnant women, she emphasized the need for continual treatment of lupus nephritis because data show that renal activity can worsen during and after pregnancy and recommended azathioprine and cyclosporine or tacrolimus, but never MMF.
She also emphasized limiting exposure to steroids, saying that she typically doesn’t give high doses of prednisone to patients with mild Class III or IV disease nor any prednisone to some patients with Class II disease. Although guidelines recommend prednisone in all patients with Class IV disease, she highlighted that data also show that prednisone increases the risk of cardiovascular events, and therefore, she emphasized that a high dose is not needed in all patients. She also suggested that oral steroids may not be necessary at all in patients with mild nephritis.
For maintenance therapy, she uses MMF on the basis of results of the ALMS maintenance trial that showed the superiority of MMF over azathioprine.1 She offered a number of hints for administering the drug so that patients can better tolerate it (see Table 1).
| Table 1: Hints for Using MMF as Maintenance Therapy for Lupus Nephritis |
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| Begin at an effective dose of 1,000 mg twice daily for one month. If the urine protein is not improving after one month, she ups the dose to 1,500 mg twice a day. |
| Split dose to take half in the morning and half at night. Because patients often forget their evening dose, she recommends they use their smartphone or some other technique to remind them. |
| Recognize the different dosing requirements based on ethnicity. Caucasians and Asians usually require 2,000 mg per day and African Americans often require 3,000 mg per day. |
| Get trough levels for monitoring whether patients are medication adherent. |
When using MMF, however, she cautioned that talking to the patients about potential adverse effects is needed, including that it interferes with the efficacy of oral contraceptives and causes major fetal malformations.
For the future, she thinks that combination therapy will soon include addition of a biologic or calcineurin inhibitor (CNI) to mycophenolate.
Throw in Rituximab & Throw Out Steroids
Adding the biologic rituximab to combination therapy was the focus of Dr. Lightstone’s talk, in which she described a protocol called Rituxilup used at the Imperial College London Lupus Center that includes rituximab and eliminates oral steroids as part of the treatment regimen to treat lupus nephritis (see Table 2). The protocol has been used since January 2006 in all patients with new and relapsing lupus nephritis who are not already on steroids and do not have rapidly progressive glomerulonephritis (RPGN) or cerebral lupus.
| Table 2: Imperial College London Lupus Center Rituxilup Protocol: First-Line Treatment of Lupus Nephritis |
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| Methylprednisolone (MP) (500 mg IV) + Rituximab (1 g) on Day 1 and Day 15 |
| MMF (initial dose of 500 mg twice daily) and titrate to trough levels 1.4–2.4 mg/L |
| No oral steroids used |
Of key importance in the protocol is reducing or eliminating the use of steroids to treat lupus nephritis. She cited data showing that lower doses of steroids confer similar outcomes and fewer side effects to those found with higher doses to treat lupus nephritis, as well as the most recent data showing a higher remission rate with no long-term adverse events with lower doses.2-4
These data, along with clinical experience in transplantation showing reduced rejection rates and fewer adverse events with lower doses of steroids, as well as data from uncontrolled studies showing the efficacy of rituximab in numerous case studies and registry reports, became the rationale for the protocol, she said.
Published outcomes of this protocol at 1 year show that patients do very well on the protocol.5 At a median follow-up of 37.6 months, 86% of 50 patients treated by the protocol achieved CR or PR. Of these patients, only two received oral steroids for longer than two weeks, and oral steroids were safely avoided in the effective treatment of patients with International Society of Nephrology/Renal Pathology Society (ISN/RPS) Class III, IV and V lupus nephritis.
Outcomes at five years, not yet published, also showed a high proportion of patients achieving CR, according to Dr. Lightstone, with most patients able to remain steroid free over the long term.
| Table 3: Key Findings of Rituxilup Regimen to Treat Lupus Nephritis |
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| Regimen leads to remission, preservation of renal function and minimal oral steroid use in a significant proportion of patients. |
| Relapses occurred only in patients with class IV or V disease, with most patients responding to retreatment without the use of oral steroids. |
| Disease flares were common, but did not predict poor outcomes. |
| Base creatinine >120 umol/L or failure to achieve PR at six months predicted poor outcomes. |
| It is expected that minimal use of oral steroids in most patients will benefit patients in the long term in terms of cardiovascular risk and reduced side effects. |
Table 3 (above) summarizes the key findings to date of the safety and efficacy of the Rituxilup regimen in the treatment of lupus nephritis.
Based on these good results, Dr. Lightstone and her colleagues are initiating an investigator-led open-label, multicenter, international, randomized controlled trial evaluating the noninferiority of the Rituxilup regimen (MP + MMF + rituximab) to the combination regimen (MP + MMF + steroids) in inducing renal remission in patients with lupus nephritis.
Mary Beth Nierengarten is a freelance medical journalist based in St. Paul, Minn.
Second Chance
If you missed this session, Forefronts in Lupus Nephritis, it’s not too late. Catch it on SessionSelect: http://acr.peachnewmedia.com/store/provider/provider09.php.
References
- Dooley MA, Jayne D, Ginzler EM, et al. Mycophenolate versus azathioprine as maintenance therapy for lupus nephritis. N Engl J Med. 2011;365(20):1886–1895.
- Fischer-Betz R, Chehab G, Sander O, et al. Renal outcome in patients with lupus nephritis using a steroid-free regimen of monthly intravenous cyclophosphamide: A prospective observational study. J Rheumatol. 2012;39(11):2111–2117.
- Zeher M, Doria A, Lan J, et al. Efficacy and safety of enteric-coated mycophenolate sodium in combination with two glucocorticoid regimens for the treatment of active lupus nephritis. Lupus. 2011;20(14):1484–1493.
- Ruiz-Irastorza G, Danza A, Perales I, et al. Prednisone in lupus nephritis: How much is enough? Autoimmunity Reviews. 2014;13:206–214.
- Condon MB, Ashby D, Pepper RJ, et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013;72:1280–1286.