Blog from the Guest Lecture Series at East Carolina University – Brody School of Medicine

Lecturer: Gerald Appel, MD
Blogger: Tejas Desai, MD

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Lupus Nephritis: Current Understanding and Future Directions

Prognostic Indicators
Prognostic indicators of lupus nephritis are divided into histologic and clinical features. Dr. Appel emphasized 2 key epidemiologic features: black race and socioeconomic factors. At Columbia, 170 patients with WHO III or IV who were impoverished at a greater risk of renal failure — about 3 times the risk. Moreover, African-Americans have a higher risk than Caucasians. Socioeconomic factors are important all over the world — for example, impoverished patients in China are at greater risk for renal failure than less impoverished patients.

Contresas’ study in Kidney International showed higher blood pressure, higher serum creatinine, and faster doubling of serum creatinine in African-Americans irrespective of poverty level.

All large RCT’s must ensure that there is a similar background of patients in each arm. In addition, international studies from Italy and Asia are not applicable to the US population of lupus nephritis patients.

Treatment of Diffuse Proliferative Lupus Nephritis (WHO Class IV)
In the simplest sense, biopsies with edema and cell proliferation are treatable, whereas those with fibrosis and sclerosis are untreatable. The histopathologic finding that is the best prognostic indicator is interstitial fibrosis.

Older NIH studies (2001) randomized a small number of patients (n = about 20 per arm) to either IV cyclophosphamide, methylprednisolone, or both for diffuse proliferative LN. The combination therapy had the lowest rate of doubling creatinine or development of ESRD. The toxicity was significant and since this trial, all studies have tried to match efficacy with the least amount of toxicity.

Euro-Lupus data shows a different way of giving cyclophosphamide (different than the NIH regimen). 90 lupus nephritis patients with WHO III or IV (without crescents) were given high-dose IV cytoxan (0.5-1.0 gram per meter squared every month) versus low-dose IV cytoxan (500 mg every 2 weeks x 6 doses, then switched to azathioprine) for 4 years. All received ACE-i or ARB’s concomitantly. Both groups showed the same probability of remission and free of renal failure. Change in creatinine and proteinuria were identical in both groups. Probability of renal flares were identical, but complications were better with the low-dose group. Dr. Appel mentioned that the Euro-Lupus data looked at Caucasians primarily (76 of 90 patients) — this makes the applicability of this data somewhat difficult in US patients. Nevertheless, over time, more and more nephrologists are using the low-dose regimen in patients without significant histologic activity (e.g., crescents). In a secondary analysis of 10-year follow-up, the probability of being free of renal disease is the same in both groups, as was the creatinine and 24-hour proteinuria. Over 10 years, the high-dose group received 9.5 grams of IV cyclophosphamide in total, versus 5.5 grams in the low-dose group.

42 patients with diffuse proliferative LN in Hong Kong were randomized to either mycophenolate for 6 months (induction) then a lower maintenance dose for another 6 months (with steroids) versus oral cyclophosphamide maintenance. Dr. Appel emphasized that there is no data showing better efficacy of IV cyclophosphamide than oral cyclophosphamide. Complete and partial remissions were the same, and all deaths were in the cyclophosphamide group. The major limitations were that the population was Asian and the follow-up was short. In a 4.5 year follow-up of 62 patients, infections and amenorrhea were less in mycophenolate, efficacy was the same, and mortality was in the cyclophosphamide group only.

In Contresas et al, 6 months of IV cyclophosphamide was given as induction therapy prior to randomization into 1 of 3 maintenance groups: continued cyclophosphamide, azathioprine, or mycophenolate. About 20 patients in each maintenance arm; 46% were African-American, 40% Hispanic. Patient survival with cyclophosphamide was worse than either azathioprine or mycophenolate. Death and chronic renal failure was worse in cyclophosphamide. Both mycophenolate and azathioprine were the same in all the clinical end points. 32% of patient suffered from amenorrhea in the cyclophosphamide group versus 6-7% in the azathioprine or mycophenolate group.

IV cytoxan (0.5-1.0 gram per meter squared monthly) versus mycophenolate as induction in African-American and Hispanic patients. A 6-month analysis (and again a 3-year analysis) showed 22% complete remission in the mycophenolate versus 4% in the cyclophosphamide group. Partial remissions were not significant but favored mycophenolate. Creatinine decreases greater, as does proteinuria in the mycophenolate group. Limitation of this study is that the entry creatinine, on average, was only 1.2 mg/dl — these were not patients with aggressive lupus nephritis. In addition, if the patients were failing, one could cross-over to the other group (not exactly intention-to-treat).

The ALMS trial looked at 370 patients globally. All had non-aggressive lupus nephritis — 6 months of cyclophosphamide versus mycophenolate for induction. The primary end point was analyzed at 6 months and patients who responded were then re-randomized to either long-term azathioprine or long-term mycophenolate (maintenance phase). In the induction phase, there was no difference in all renal and non-renal end points. In a secondary analysis, 29 patients that had a low GFR (18 in mycophenolate with 24 cc/min vs. 11 in cyclophosphamide with 21 cc/min) had no statistical differences but a favorable trend toward mycophenolate. Most of these patients did poorly overall — ALMS cannot be applied to aggressive lupus nephritis (e.g., crescenteric LN).

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Membranous Lupus Nephritis (WHO Class V)
Up to 20% of biopsies are membranous LN but there are very limited data on treatment.

A study from the NIH of membranous LN patients were randomized to cyclosporine (n = 12), cytoxan (n = 15), or prednisone (n = 15). Probability of remission was better with cyclosporine and cytoxan than prednisone. But the cytoxan arm had lower relapse than the cyclosporine arm. Most nephrologists interpret this study in the following way: use cyclosporine to treat membranous lupus nephritis and change to cytoxan in the 50% of patients who received cyclosporine but relapsed.

Mycophenolate has not been looked at extensively in membranous LN. In a small meta-analysis of all the membranous LN patients in both the ALMS trial and Ginzler et al (n = 84), 66% of the patients had complete or partial remissions at the end of 6 months.

The key point in membranous LN is that most patients will not progress to ESRD quickly — it is a slow disease. Thus, one must use immunosuppressive therapies carefully in this group of LN patients.

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ALMS Maintenance Study (yet unpublished)
Patients who responded to induction (either with cyclophosphamide or mycophenolate) were then re-randomized to receive either mycophenolate or azathioprine maintenance therapy for 3 year follow-up (n = 220 patients). Mycophenolate was better than azathioprine in every primary and secondary outcome. Only one death in total — an auto accident in the azathioprine group. Dr. Appel recommends continuing azathioprine maintenance in patients already receiving the drug and are clinically stable. If patients are not stable, one should consider converting to mycophenolate based on this data.

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New Therapies for Lupus Nephritis
LUNAR is the first double-blind randomized control trial looking at rituximab (an anti-CD 19/20 antibody). All 144 patients had proliferative lupus nephritis (WHO Class III or IV) and received both steroids and mycophenolate for 1 year (both meds were tapered gradually). One group also receives 6 doses of rituximab; the other group simply receives placebo. 54% of the placebo group did not have a response; 43% in the rituximab group (not statistically better). One criticism of this data is that all patients initially received the same dose of steroids and mycophenolate; prior trials have shown this regimen to be effective (see ALMS above). As a result, there was little room for additional improvement in the rituximab group. Dr. Appel’s interpretation of the data is that if one uses a full dose of steroids and mycophenolate for induction therapy, it is unlikely that rituximab will add any additional benefit. If, however, the patient cannot tolerate the full dose of induction therapy, rituximab may help. He believes there is role for rituximab, especially for patients who cannot tolerate full induction therapy.

Mycophenolate + low dose tacrolimus + steroids versus cytoxan + steroids: the former group had a greater rate of remission and slower progression to ESRD. Dr. Appel feels the future will be multi-targeted therapy (the use of multiple agents at lower doses).

Dr. Appel discussed a number of monoclonal antibodies that are in early trials but with mixed results. For the sake of brevity, these antibodies will not be mentioned in this blog.

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