Immunosuppressive treatment for people with proliferative lupus nephritis

What is the issue?

In lupus, the body’s immune system for fighting infection attacks different parts of the body, including the kidneys. About half of all people with lupus have kidney problems. An estimated one in every 10 people who have lupus kidney disease (lupus nephritis) can develop kidney failure. The goal of treatment is to protect kidney function and avoid side-effects.

While the life expectancy of patients who have lupus has dramatically improved, available treatments can cause serious side effects such as hair loss, serious infection, and infertility. It is important to know about which treatments help to treat lupus while causing the fewest side-effects.

What did we do?

We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 and we combined all studies testing treatments aimed to control the body’s immune system for lupus nephritis.

What did we find?

In this review update, 74 studies involving 5175 patients with lupus nephritis could be studied. Treatments included intravenous (given through a vein) cyclophosphamide, oral (tablets by mouth) mycophenolate mofetil (MMF), azathioprine, and tacrolimus (used alone or together with MMF). We also found studies of treatments called “biologic” therapies, that have been designed to change very specific parts of the body’s immune system that cause it to attack itself. We looked particularly at key outcomes such as whether treatment prevented patients from needing dialysis and controlled the lupus damage to the kidney tissue (called remission). We also looked at serious side-effects including death, infection, infertility, and hair loss.

After combining the available studies, compared with cyclophosphamide, MMF may be better at getting the lupus damage to the kidneys under control. However, the range where the actual effect may suggest that MMF may make little or no difference to disease remission compared to treatment with cyclophosphamide. MMF treatment given with tacrolimus may lead to more disease remission. MMF may result in less hair loss and worse diarrhoea, but we were not certain whether MMF reduces infertility or other serious side effects. MMF was better than azathioprine for preventing kidney disease in the longer term. None of the studies told us whether treatment had any effect on death or need for dialysis, and there was very low certainty of evidence for the use of biologics in patients with lupus nephritis.

Conclusions

Patients with lupus nephritis may have similar or slightly better outcomes when treated with MMF or MMF with tacrolimus compared to those patients who receive intravenous cyclophosphamide. We are still not certain which is the best treatment for lupus nephritis to protect against needing dialysis in the longer term.

Authors' conclusions: 

In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.

Read the full abstract...
Background: 

Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end-stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012.

Objectives: 

Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy-proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens?

Search strategy: 

We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.

Selection criteria: 

Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive treatment for biopsy-proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included.

Data collection and analysis: 

Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE.

Main results: 

In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age.

Induction therapy

Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference.

Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD.

MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence.

Maintenance therapy

Nine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates.

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