Lupus Nephritis in 2017: An Update

In light of recent progress in the genomics of complex traits, where do we stand with glomerular disease?

Renal involvement is clinically apparent in approximately 50% of systemic lupus erythematosis (SLE) patients and a frequent cause of significant morbidity and mortality (1). On renal biopsy, virtually all lupus patients have some findings indicative of kidney pathology. The clinical presentation of lupus nephritis is highly varied, ranging from asymptomatic hematuria and/or proteinuria to the full nephrotic syndrome or even rapidly progressive glomerulonephritis. In the kidney, the cornerstone mechanism of damage is the formation and deposition of immune complexes (including DNA nucleosome complexes and anti-DNA antibodies), which may occur by nonspecific trapping of circulating immune complexes, in situ formation, or interaction with negatively charged components of the glomerular capillary wall. In general, immune deposits in the mesangium and subendothelial location incite an active inflammatory response, whereas those in a subepithelial location do not as they are separated from the circulation by the glomerular basement membrane. Immune complex formation is followed by the binding and activation of complement and ensuing inflammatory cascades. However, a variety of other mechanisms may be at play, including activation of the coagulation system causing a thrombotic microangiopathy, podocytopathies associated with heavy proteinuria but no active inflammatory lesions, and interstitial or vascular renal disease.

The role of renal biopsy and clinical pathologic correlations

In lupus nephritis, the kidney biopsy provides diagnostic and prognostic information and can serve as a guide to therapy. Current classification describes six classes of pathology (Table 1).

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Multiple studies have shown the prognostic value of this classification. In general, classes I and II have a mild presentation and benign clinical course. Treatment is targeted at blood control with antiproteinuric agents and angiotensin-converting enzyme-I (ACE-I) or angiotensin receptor blockers (ARBs). Classes III and IV are associated with active urinary sediment, substantial proteinuria, and progressive renal damage and thus, deserve vigorous therapy. Class V, membranous lupus nephropathy, is associated with heavy proteinuria (often the nephrotic syndrome) and requires special therapeutic considerations. Patients with class VI, sclerosing lesions, do not respond to immunosuppressive therapy and should be prepared for dialysis and/or transplantation.

Treatment of classes III and IV is divided into two phases: induction and maintenance

Early National Institutes of Health (NIH)-sponsored trials showed that intravenous steroids and six monthly intravenous high doses of cyclophosphamide (0.5 to 1.0 g/m2) followed by quarterly maintenance doses resulted in more clinical remissions than treatment with either steroid or cyclophosphamide alone (2). With concerns about cyclophosphamide toxicity, including infection, infertility, and malignancy development, the Eurolupus Group studied 90 proliferative lupus nephritis patients randomized to receive either a low-dose cyclophosphamide regimen (six pulses of 500-mg doses every 2 weeks) or a high-dose regimen (six monthly pulses) similar to the NIH regimen. Both groups were then maintained on azathioprine, 2 mg/kg per day. At short- and long-term follow-up, there was no significant difference in efficacy or adverse effects. However, the number of patients with severe infection was twice as high in the high-dose cyclophosphamide group, providing support for the low-dose treatment course (3). This new regimen has been validated in other populations, including African Americans, and is now considered one of two standard induction therapies for lupus nephritis.

The alternative standard induction regimen uses mycophenolate mofetil. The Aspreva Lupus Management Study (ALMS) (4), a multicenter, multicultural trial of 370 patients with class III, IV, or V lupus nephritis, randomized induction to either mycophenolate mofetil or six monthly intravenous cyclophosphamide pulses. Both arms initially received high-dose corticosteroids, which were tapered. The trial showed similar efficacy and toxicity with both regimens in a broad range of racial and geographic groups.

Thus, the recommendations by most nephrology and rheumatology organizations are to use either cyclophosphamide or mycophenolate combined with corticosteroids as induction treatment for severe active lupus nephritis. Individual preference, compliance, tolerability, and specific clinical scenarios all influence selection. However, if patients fail therapy with one agent, they are most often switched to rescue with the second therapeutic regimen.

Maintenance therapy of proliferative lupus nephritis

After remission through induction has been achieved, a number of studies have defined optimal maintenance treatment. An early trial randomized 59 patients with class III or IV lupus nephritis postinduction with 6 months of monthly pulse cyclophosphamide to receive either quarterly intravenous cyclophosphamide pulses (0.5 to 1.0 g/m2) or daily oral azathioprine or mycophenolate (5). At follow-up, the study showed that maintenance with either mycophenolate or azathioprine was more efficacious and significantly safer than continuing long-term therapy with intravenous cyclophosphamide. A study by the Euro Lupus group that randomized patients to azathioprine or mycophenolate after induction showed no significant difference in the very good outcome seen in the largely Caucasian European population studied (6). More recently, 227 patients from the ALMS who had a good clinical response to either cyclophosphamide or mycophenolate induction were rerandomized to receive either mycophenolate (1 g twice a day) or azathioprine (2 mg/kg per day) double blind for another 3 years. At follow-up, mycophenolate was superior to azathioprine in maintaining renal response and preventing relapse (7). This was true in different geographic areas, among different racial groups, and regardless of which induction regimen was used.

At present, both mycophenolate and azathioprine seem effective agents for maintenance therapy. Mycophenolate may have advantages in non-Caucasian populations. Azathioprine should be used in women contemplating pregnancy. Cost may be a factor for some patients, and mycophenolate is generally more expensive. Mycophenolate can be used with allopurinol or febuxostat for patients with gout, whereas azathioprine should not be used with xanthine oxidase inhibitors.

Rituximab is a chimeric mAb directed against CD20, an antigen expressed on the surfaces of mature and immature B cells. The Lupus Nephritis Assessment with Rituximab Study investigated the addition of rituximab (1000 mg on days 1, 15, 168, and 182) versus placebo in 144 patients with class III/IV disease on full induction with steroids and mycophenolate. At 52 weeks, the rituximab arm did not result in a statistically significant clinical improvement in complete/partial renal response (8). Thus, at this time, rituximab is not considered a first-line induction agent for lupus nephritis. However, some observational studies suggest efficacy in patients who have failed induction therapy with other agents. A systematic analysis of 26 reports encompassing about 300 lupus nephritis patients refractory to standard therapy treated with rituximab showed the achievement of complete or partial response in greater than 50% (9). Moreover, the ongoing Rituximab and Mycophenolate without Oral Steroids in Lupus Nephritis (RITUXILUP) Trial is a phase 3 randomized multicenter United Kingdom study that tests rituximab as a potential steroid-sparing drug in treating proliferative disease (NCT 01773616).

Treatment of class V—membranous lupus nephropathy

For class V lupus, membranous nephritis, use of immunosuppressant agents is controversial. However, most nephrologists would treat when the proteinuria exceeds 3 g/d, despite the use of ACE-I/ARB agents. In the ALMS, 60 of 370 patients had class V lupus nephritis. At 24 weeks, there was no difference in study end points between treatment with mycophenolate and monthly intravenous cyclophosphamide. Thus, mycophenolate and prednisone seem to be a good first-line agent for treatment. Other choices include cyclophosphamide (intravenous/PO) or a calcineurin inhibitor along with corticosteroids.

A small NIH trial randomized 42 patients with class V lupus nephritis to receive alternate-day prednisone, prednisone plus intravenous cyclophosphamide every other month, or prednisone and daily cyclosporin for a 1-year period. The study concluded that the cyclophosphamide and cyclosporin arms were more than twice as likely to experience a remission of proteinuria than the prednisone arm. Relapses occurred significantly more often after cyclosporin than after cyclophosphamide (10). However, because most cyclosporin patients later respond to cyclophophosphamide, many feel that calcineurin inhibitors are reasonable treatment agents for class V patients. A combined study of patients from two randomized, controlled trials of almost 500 patients included 84 with class V lupus nephritis treated with cyclophosphamide or mycophenolate. Both groups had equal efficacy and side effect profiles (11). Thus, for class V patients with heavy proteinuria, calcineurin inhibitors, cyclophosphamide, and mycophenolate are all reasonable therapies. Indeed, there is uncontrolled evidence that rituximab also is effective in this population. A prospective observational study of 50 patients (44% of whom had pure class V lupus nephritis) (12) using the RITUXILUP Trial regimen (intravenous rituximab, intravenous methylprednisolone, and mycophenolate) attained complete and partial remissions in 52% and 34% of patients, respectively, after 1 year.

Future Therapies

Future treatments of lupus nephritis rest on a better understanding of the immune pathogenesis of the disease. Key players include T and B cells, plasma cells, the costimulatory factors that nurture these cells, and the cytokines that upregulate the inflammatory cascade. Trials of some available agents are ongoing. Rituximab with mycophenolate is being studied as a steroid-sparing regimen in the RITUXILUP Trial as mentioned above. There is interest in multitargeted therapy for severe lupus nephritis, because a positive randomized multicenter Chinese study looked at induction therapy with monthly intravenous cyclophosphamide versus treatment with mycophenolate and tacrolimus, with both groups receiving corticosteroids. Results revealed significantly more complete and partial remission in the mycophenolate/tacrolimus arm (13).

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Anifrolumab, a mAb against the IFN-α receptor I, blocks the effects of IFN-α, a major regulatory cytokine in approximately 50% of SLE patients (14, 15). In a randomized, controlled study of over 300 patients, anifrolumab provided added efficacy in induction when added to mycophenolate and corticosteroids (16). Belimumab, a humanized anti-BLyS mAb, is being evaluated for active lupus nephritis as an add-on drug (versus placebo) to standard of care induction therapy (NCT 01639339). Another trial, the CALIBRATE Study, will test cyclophosphamide, rituximab, and oral prednisone followed by belimumab (NCT 02260934). Obinutuzumab, a humanized anti-CD20 mAb, causes more complete peripheral and lymphoid tissue B cell depletion than rituximab (17). A phase 2 study is currently underway for patients with active lupus nephritis (NCT 02550652). Voclosporin, a novel calcineurin inhibitor with enhanced stability and activity relative to cyclosporin, is currently being studied as add-on therapy as well (NCT02141672). Finally, ACTHAR gel is being studied in both proliferative and membranous lupus.

This is an exciting time for those treating patients with lupus nephritis. We already have good therapies for induction and maintenance that have been studied in large controlled, randomized trials. It is clear that treatments will evolve further as we learn more about the complex immunologic pathways involved in the disease. The quest for more effective and safer therapeutic options for lupus nephritis is paramount.

December 2017 (Vol. 9, Number 12)

References

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