Systemic lupus erythematosus: lupus nephritis

Abstract

Introduction

Systemic lupus erythematosus (SLE) occurs predominantly in young women, but also in children. The prevalence of SLE varies worldwide, ranging from about 1 in 3500 women (regardless of race) in the UK, to 1 in 1000 women in China, to 1 in 250 African-American women in the US.

Methods and outcomes

We conducted a systematic overview, aiming to answer the following clinical questions: What are the effects of immunosuppressants in people with proliferative lupus nephritis? What are the effects of different immunosuppressants compared with each other in people with proliferative lupus nephritis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to April 2014 (BMJ Clinical Evidence overviews are updated periodically; please check our website for the most up-to-date version of this overview).

Results

At this update, searching of electronic databases retrieved 448 studies. After deduplication and removal of conference abstracts, 120 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 53 studies and the further review of 67 full publications. Of the 67 full articles evaluated, four systematic reviews and one RCT were added at this update. We performed a GRADE evaluation for 13 PICO combinations.

Conclusions

In this systematic overview, we categorised the efficacy for 10 interventions based on the effectiveness and safety of immunosuppressants plus corticosteroids compared with corticosteroids alone, and immunosuppressants plus corticosteroids compared with each other in people with proliferative lupus nephritis (WHO grades III–V).

Key Points

Systemic lupus erythematosus (SLE) is a chronic, multi-system, inflammatory connective tissue disorder of unknown cause that can involve joints, kidneys, serous surfaces, skin, and vessel walls. It occurs predominantly in young women, but also in children. The course of SLE is highly variable, involving non-organ-threatening symptoms (such as arthritis, arthralgia, and rashes), organ-threatening symptoms (such as lupus nephritis), and neuropsychiatric disorders (such as seizures and cognitive dysfunction).

The prevalence of SLE varies worldwide, ranging from about 1 in 3500 women (regardless of race) in the UK, to 1 in 1000 women in China, to 1 in 250 African-American women in the US.

Immunosuppressants are used as an adjunct to corticosteroid therapy for the management of proliferative lupus nephritis, so we don't know how immunosuppressants alone compare with corticosteroids alone in these patients.

We searched for studies that compared cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, or abatacept with corticosteroid, or with each other. Regarding the effects of different immunosuppressants compared with each other, we have only reported comparisons where we found evidence.

In studies that compared immunosuppressants administered with corticosteroids with corticosteroids alone in people with proliferative nephritis, combining azathioprine with a corticosteroid seems to be more effective at reducing all-cause mortality than corticosteroid alone.

Combining cyclophosphamide with corticosteroid does not appear to reduce all-cause mortality or improve most renal outcomes compared with corticosteroid alone, but it may reduce the rate of lupus nephritis relapse at 48 months compared with corticosteroid alone; although, evidence is limited by small study size.

In studies that compared immunosuppressants administered in combination with a corticosteroid with other immunosuppressants plus corticosteroids in people with proliferative nephritis:

• Mycophenolate mofetil seemed to be as effective as cyclophosphamide and as effective as tacrolimus at reducing mortality and improving renal outcomes.

• Cyclophosphamide appeared to be as effective as tacrolimus at reducing mortality.

• Tacrolimus appeared to be as effective as azathioprine at preserving renal function and preventing relapse. We don't know how they compare in terms of mortality.

• Cyclophosphamide may be less effective than azathioprine at reducing mortality at 10 years, but evidence is weak. Cyclophosphamide may be more effective than azathioprine at preventing renal disease relapse.

Mycophenolate appears to be associated with less ovarian failure, leukopenia, infection, and alopecia than cyclophosphamide.

Cyclophosphamide plus corticosteroid may increase the risk of ovarian failure when compared with corticosteroid alone, or irregular menstruation or amenorrhoea when compared with tacrolimus plus corticosteroid.

Cases of pure red cell aplasia have been reported worldwide in association with mycophenolate mofetil.

We found no studies that assessed the effectiveness of abatacept for proliferative lupus nephritis.

Clinical context

General background

Lupus nephritis occurs in around a third of patients with systemic lupus erythematosus (SLE) and is more common in men with SLE than women. The risk of end-stage renal disease (ESRD) is higher in non-white people, especially in those of black ethnicity, in those over the age of 30 years, and if hypertension is present. Immuosuppressants are used with corticosteroids to improve renal outcomes in patients with proliferative nephritis, but even with treatment, up to 25% of patients progress to develop renal insufficiency and ESRD. The use of immunosuppressants can be limited by bone marrow toxicity, the risk of gonadal failure, and infections.

Focus of the review

Evidence that mycophenolate can substitute for cyclophosphamide in the management of proliferative lupus nephritis has resulted in further investigation of the potential benefits, as well as risks. Other immunosuppressants have also been evaluated to show their equivalence/superiority to standard immunosuppressive treatments. For this overview, we have focused on for studies that compared cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, or abatacept with corticosteroid, or with each other. Other treatments are available, including rituximab, but these were outside of our scope for this focused overview.

Comments on evidence

Several high-quality RCTs have been undertaken to investigate the benefits and risks of single immunosuppressants as adjuncts to corticosteroid therapy in people with proliferative nephritis. The use of immunosuppressants can be limited by bone marrow toxicity, the risk of gonadal failure, and infections.

Search and appraisal summary

The update literature search for this overview was carried out from the date of the last search, December 2007, to April 2014. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the overview, please see the Methods section. At this update, searching of electronic databases retrieved 448 studies. After deduplication and removal of conference abstracts, 120 records were screened for inclusion in the overview. Appraisal of titles and abstracts led to the exclusion of 53 studies and the further review of 67 full publications. Of the 67 full articles evaluated, four systematic reviews and one RCT were added at this update.

About this condition

Definition

Systemic lupus erythematosus (SLE) is a chronic, multisystem, inflammatory connective tissue disorder of unknown cause that can involve joints, kidneys, serous surfaces, and vessel walls. It occurs predominantly in young women, but also in children. The course of SLE is highly variable, and may be characterised by exacerbations. Diagnosis The American College of Rheumatology (ACR) has developed classification criteria for SLE. For a diagnosis to be made, four of the following 11 criteria must be met: malar rash; discoid rash; photosensitivity; oral ulcers; arthritis; serositis; renal disorder; neuropsychiatric disorder; haematological disorder; immunological disorder; and antinuclear antibody.[1] Lupus glomerulonephritis (lupus nephritis) is the diagnosis applied to people with renal inflammation occurring in the context of SLE.[2] It occurs in 39% of people.[3] The World Health Organisation (WHO) graded the disease in 1982, based on histological features, as follows: grade I = normal kidney or minor abnormalities; grade II = mesangial proliferation; grade III = focal proliferative glomerulonephritis; grade IV = diffuse proliferative glomerulonephritis; grade V = membranous disease; and grade VI = sclerosing glomerulonephritis.[4] This overview covers treatments of WHO grades III to V. Even though grade V is not proliferative nephritis, we have included it because grade V may complicate grade III or IV. Where reported, we have added the number of people included in any data analysis who had grade V disease alone. In all cases, this was a small percentage of the population studied.

Incidence/ Prevalence

The prevalence of SLE worldwide varies greatly. From population-based epidemiological studies, it has been estimated that 1 in 3500 women (independent of race) in the UK, 1 in 250 African-American women in the US, 1 in 1000 Chinese women, and 1 in 4200 white women in New Zealand may have SLE.[5] [6] [7] [8] Although the prevalence of SLE is higher in black people than in white people in the US and UK, the prevalence of lupus is low in most African countries.[9]

Aetiology/ Risk factors

Although the exact cause of SLE remains unclear, genetic, environmental, and hormonal influences are all thought to play a role.[10] [11]

Prognosis

The manifestations of SLE that determine survival include lupus nephritis, cardiovascular complications, and neuropsychiatric involvement. In cohort studies performed since 1980, survival at 5 years has exceeded 90%, a higher survival rate than in studies performed earlier than 1980.[12] One multi-centre study performed in Europe found a survival probability of 92% at 10 years after diagnosis.[13] A lower survival probability was detected in those people who presented at the beginning of the study with nephropathy (88% in people with nephropathy v 94% in people without nephropathy; P = 0.045). When the causes of death during the initial 5 years of follow-up (1990–1995) were compared with those during the ensuing 5 years (1995–2000), active SLE and infections (29% each) seemed to be the most common causes during the initial 5 years, although thromboses (26%) became the most common cause of death during the last 5 years.[13] Race is an independent predictor of mortality; black people in the US have a worse prognosis than white people, as do Asian people in the UK compared with white people in the UK.

Aims of intervention

To prevent progression of proliferative lupus nephritis, with minimal adverse effects of treatment.

Outcomes

Mortality; renal disease (including serum creatinine as a measure of renal function; end stage renal disease; complete or partial response/remission; relapse); adverse effects.

Methods

Search strategy BMJ Clinical Evidence search and appraisal April 2014. Databases used to identify studies for this systematic overview include: Medline 1966 to April 2014, Embase 1980 to April 2014, The Cochrane Database of Systematic Reviews 2014, issue 3 (1966 to date of issue), the Database of Abstracts of Reviews of Effects (DARE), and the Health Technology Assessment (HTA) database. Inclusion criteria Study design criteria for inclusion in this review were systematic reviews and RCTs published in English, at least single-blinded, and containing 20 or more individuals (10 in each arm), of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. BMJ Clinical Evidence does not necessarily report every study found (e.g., every systematic review). Rather, we report the most recent, relevant, and comprehensive studies identified through an agreed process involving our evidence team, editorial team, and expert contributors. For this review, we searched for studies that compared cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, or abatacept with corticosteroid, or with each other. We have only reported the effects of different immunosuppressants compared with each other where we found evidence. Evidence evaluation A systematic literature search was conducted by our evidence team, who then assessed titles and abstracts, and finally selected articles for full text appraisal against inclusion and exclusion criteria agreed a priori with our expert contributors. In consultation with the expert contributors, studies were selected for inclusion and all data relevant to this overview extracted into the benefits and harms section of the review. In addition, information that did not meet our pre-defined criteria for inclusion in the benefits and harms section may have been reported in the 'Further information on studies' or 'Comment' section. Adverse effects All serious adverse effects, or those adverse effects reported as statistically significant, were included in the harms section of the overview. Pre-specified adverse effects identified as being clinically important were also reported, even if the results were not statistically significant. Although BMJ Clinical Evidence presents data on selected adverse effects reported in included studies, it is not meant to be, and cannot be, a comprehensive list of all adverse effects, contraindications, or interactions of included drugs or interventions. A reliable national or local drug database must be consulted for this information. Comment and Clinical guide sections In the Comment section of each intervention, our expert contributors may have provided additional comment and analysis of the evidence, which may include additional studies (over and above those identified via our systematic search) by way of background data or supporting information. As BMJ Clinical Evidence does not systematically search for studies reported in the Comment section, we cannot guarantee the completeness of the studies listed there or the robustness of methods. Our expert contributors add clinical context and interpretation to the Clinical guide sections where appropriate. Structural changes this update At this update, we have removed the following previously reported questions: What are the effects of treatments on joint symptoms (arthralgia/arthritis) and other non-organ-threatening symptoms (such as serositis and fatigue) in people with systemic lupus erythematosus? What are the effects of interventions for cutaneous involvement in people with systemic lupus erythematosus? What are the effects of treatments in people with proliferative lupus nephritis (WHO grades 3–5)? What are the effects of treatments for neuropsychiatric involvement in people with systemic lupus nephritis? We have added the following questions: What are the effects of immunosuppressants in people with proliferative lupus nephritis (WHO grades III–V)? What are the effects of different immunosuppressants compared with each other in people with proliferative lupus nephritis (WHO grades III–V)? Data and quality To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). BMJ Clinical Evidence does not report all methodological details of included studies. Rather, it reports by exception any methodological issue or more general issue that may affect the weight a reader may put on an individual study, or the generalisability of the result. These issues may be reflected in the overall GRADE analysis. We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Systemic lupus erythematosus: lupus nephritis.

Important outcomes	Mortality, Renal disease
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of immunosuppressants in people with proliferative lupus nephritis?
5 (226)	Mortality	Cyclophosphamide plus corticosteroid compared with corticosteroid alone	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
at least 5 (at least 278)	Renal disease	Cyclophosphamide plus corticosteroid compared with corticosteroid alone	4	–1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
3 (78)	Mortality	Azathioprine plus corticosteroid compared with corticosteroid alone	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
at least 1 (at least 54)	Renal disease	Azathioprine plus corticosteroid compared with corticosteroid alone	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
What are the effects of different immunosuppressants compared with each other in people with proliferative lupus nephritis?
at least 7 (at least 710)	Mortality	Mycophenolate mofetil plus corticosteroid compared with cyclophosphamide plus corticosteroid	4	0	–1	0	0	Moderate	Consistency point deducted for different direction of effect from different meta-analyses
at least 6 (at least 686)	Renal disease	Mycophenolate mofetil plus corticosteroid compared with cyclophosphamide plus corticosteroid	4	–1	–1	0	0	Low	Quality point deducted for incomplete reporting of results in 1 review; consistency point deducted for conflicting results for different outcomes
2 (130)	Mortality	Mycophenolate mofetil plus corticosteroid compared with tacrolimus plus corticosteroid	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
at least 2 (at least 130)	Renal disease	Mycophenolate mofetil plus corticosteroid compared with tacrolimus plus corticosteroid	4	–2	0	0	0	Low	Quality point deducted for sparse data and for heterogeneity in 1 meta-analysis
at least 2 (at least 146)	Mortality	Cyclophosphamide plus corticosteroid compared with azathioprine plus corticosteroid	4	–2	–1	0	0	Very low	Quality points deducted for sparse data and presence of heterogeneity in meta-analysis; consistency point deducted for variation in formulations of cyclophosphamide
at least 2 (at least 144)	Renal disease	Cyclophosphamide plus corticosteroid compared with azathioprine plus corticosteroid	4	–1	–1	0	0	Low	Quality point deducted for sparse data; consistency point deducted for variation in formulations of cyclophosphamide
2 (113)	Mortality	Cyclophosphamide plus corticosteroid compared with tacrolimus plus corticosteroid	4	–1	0	0	0	Moderate	Quality point deducted for sparse data
at least 5 (at least 223)	Renal disease	Cyclophosphamide plus corticosteroid compared with tacrolimus plus corticosteroid	4	0	–1	0	0	Moderate	Consistency point deducted for conflicting results for different outcomes
1 (70)	Renal disease	Tacrolimus plus corticosteroid compared with azathioprine plus corticosteroid	4	–1	0	0	0	Moderate	Quality point deducted for sparse data

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

Very low-quality evidence

Any estimate of effect is very uncertain.

Disclaimer

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