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BMJ Clin Evid. 2015; 2015: 1123.
Published online 2015 December 18.
PMCID: PMC4684150

Systemic lupus erythematosus: lupus nephritis

Rajan Madhok, Consultant Physician and Rheumatologist

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.

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.

Notes

Disclaimer

The information contained in this publication is intended for medical professionals. Categories presented in Clinical Evidence indicate a judgement about the strength of the evidence available to our contributors prior to publication and the relevant importance of benefit and harms. We rely on our contributors to confirm the accuracy of the information presented and to adhere to describe accepted practices. Readers should be aware that professionals in the field may have different opinions. Because of this and regular advances in medical research we strongly recommend that readers' independently verify specified treatments and drugs including manufacturers' guidance. Also, the categories do not indicate whether a particular treatment is generally appropriate or whether it is suitable for a particular individual. Ultimately it is the readers' responsibility to make their own professional judgements, so to appropriately advise and treat their patients. To the fullest extent permitted by law, BMJ Publishing Group Limited and its editors are not responsible for any losses, injury or damage caused to any person or property (including under contract, by negligence, products liability or otherwise) whether they be direct or indirect, special, incidental or consequential, resulting from the application of the information in this publication.

References

1. American College of Rheumatology Ad Hoc Committee on Systemic Lupus Erythematosus Guidelines. Guidelines for referral and management of systemic lupus erythematosus in adults. Arthritis Rheum 1999;42:1785–1796. [PubMed]
2. Flanc RS, Roberts MA, Strippoli GF, et al. Treatment for lupus nephritis. In: The Cochrane Library, Issue 3, 2014. Chichester, UK: John Wiley & Sons, Ltd. Search date 2003.
3. Jiménez S, Cervera R, Font J, et al. The epidemiology of systemic lupus erythematosus. Clin Rev Allergy Immunol 2003;25:3–12. [PubMed]
4. Churg J, Sobin LH. Renal disease: classification and atlas of glomerular diseases. Tokyo; New York: Igaku-Shoin, 1982;127–131.
5. Johnson AE, Gordon C, Palmer RG, et al. The prevalence and incidence of systemic lupus erythematosus in Birmingham, England. Relationship to ethnicity and country of birth. Arthritis Rheum 1995;38:551–558. [PubMed]
6. Hart HH, Grigor RR, Caughey DE. Ethnic difference in the prevalence of systemic lupus erythematosus. Ann Rheum Dis 1983;42:529–532. [PMC free article] [PubMed]
7. McCarty DJ, Manzi S, Medsger TA Jr, et al. Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum 1995;38:1260–1270. [PubMed]
8. Mok CC, Lau CS. Lupus in Hong Kong Chinese. Lupus 2003;12:717–722. [PubMed]
9. Nived O, Sturfelt G. Does the Black population in Africa get SLE? If not, why not? London, UK: Martin Dunitz Ltd, 1997.
10. Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol 2003;56:481–490. [PMC free article] [PubMed]
11. Pisetsky DS. Systemic lupus erythematosus: epidemiology, pathology, and pathogenesis. In: Klippel JH, ed. Primer on the rheumatic diseases. 11th ed. Georgia, USA: Arthritis Foundation, 1997:246–251.
12. Trager J, Ward MM. Mortality and causes of death in systemic lupus erythematosus. Curr Opin Rheumatol 2001;13:345–351. [PubMed]
13. Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore) 2003;82:299–308. [PubMed]
14. Henderson L, Masson P, Craig JC, et al. Treatment for lupus nephritis. In: The Cochrane Library, Issue 3, 2014. Chichester, UK: John Wiley & Sons, Ltd. Search date 2012.
15. Moore RA, Derry S. Systematic review and meta-analysis of randomised trials and cohort studies of mycophenolate mofetil in lupus nephritis. Arthritis Res Ther 2006;8:R182. [PMC free article] [PubMed]
16. Ou S-T, Zhong L-C, Du X, et al. Mycophenolate mofetil for proliferative lupus nephritis: A systematic review. Chin J Evid Med 2006;6:712–720.
17. Medicines and Healthcare products Regulatory Agency. Drug safety update: Mycophenolate mofetil: pure red cell aplasia. 2009. Available at https://www.gov.uk/drug-safety-update/mycophenolate-mofetil-pure-red-cell-aplasia (last accessed 29 September 2015).
18. Deng J, Huo D, Wu Q, et al. A meta-analysis of randomized controlled trials comparing tacrolimus with intravenous cyclophosphamide in the induction treatment for lupus nephritis. Tohoku J Exp Med 2012;227:281–288. [PubMed]
19. Chen W, Liu Q, Chen W, et al. Outcomes of maintenance therapy with tacrolimus versus azathioprine for active lupus nephritis: a multicenter randomized clinical trial. Lupus 2012;21(9):944–952. [PubMed]
2015; 2015: 1123.
Published online 2015 December 18.

Cyclophosphamide plus corticosteroid compared with corticosteroid alone

Summary

In people with proliferative lupus nephritis, treatment with cyclophosphamide plus corticosteroid does not appear to reduce all-cause mortality compared with corticosteroid alone, nor does the combination improve most renal outcomes.

Cyclophosphamide plus corticosteroid may reduce the rate of lupus nephritis relapse at 48 months compared with corticosteroid alone, but the evidence is limited by small study size.

The addition of cyclophosphamide to corticosteroid may increase the risk of ovarian failure compared with corticosteroid alone.

Benefits and harms

Cyclophosphamide plus corticosteroid compared with corticosteroid alone:

We found one systematic review (search date 2012).[14]

Mortality

Cyclophosphamide plus corticosteroid compared with corticosteroid alone Cyclophosphamide plus corticosteroid seems to be no more effective than corticosteroid alone at reducing mortality in people with proliferative lupus nephritis (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
5 RCTs in this analysis
All-cause mortality 15–60 months
29/138 (21%) with cyclophosphamide plus corticosteroid
15/88 (17%) with corticosteroid alone

RR 0.98
95% CI 0.53 to 1.82
Not significant

Renal disease

Cyclophosphamide plus corticosteroid compared with corticosteroid alone Cyclophosphamide plus corticosteroid seems to be no more effective than corticosteroid alone at preserving renal function or reducing the incidence of end-stage renal disease in people with proliferative lupus nephritis. Cyclophosphamide plus corticosteroid may reduce the rate of lupus nephritis relapse at 48 months compared with corticosteroid alone, but the evidence is limited by small study size (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Renal function
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
5 RCTs in this analysis
Maintenance of stable renal function (<20% worsening of serum creatinine) 15–60 months
127/171 (74%) with cyclophosphamide plus corticosteroid
63/107 (59%) with corticosteroid alone

RR 1.20
95% CI 1.00 to 1.45
Result is of borderline significance
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
4 RCTs in this analysis
Doubling of serum creatinine 15–60 months
35/147 (24%) with cyclophosphamide plus corticosteroid
32/81 (40%) with corticosteroid alone

RR 0.59
95% CI 0.40 to 0.88
Small effect sizecyclophosphamide plus corticosteroid
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV) Deterioration of kidney function (>20% worsening of serum creatinine)
32/105 (30%) with cyclophosphamide plus corticosteroid
29/74 (39%) with corticosteroid alone

RR 0.78
95% CI 0.52 to 1.18
P = 0.24
Not significant
[14]
Systematic review
29 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Serum creatinine
269 micromol/L with cyclophosphamide plus corticosteroid
321 micromol/L with corticosteroid alone

Mean difference –52.00
95% CI –111.39 to +7.39
P value not reported
Not significant
End stage renal disease
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
5 RCTs in this analysis
End stage renal disease
27/171 (16%) with cyclophosphamide plus corticosteroid
26/107 (24%) with corticosteroid alone

RR 0.63
95% CI 0.39 to 1.03
P = 0.066
Not significant
Relapse
[14]
Systematic review
42 people with diffuse proliferative lupus nephritis on biopsy
Data from 1 RCT
Relapse of lupus nephritis (relapse not further defined) 48 months
3/21 (14%) with cyclophosphamide plus corticosteroids
10/21 (48%) with corticosteroids alone

RR 0.30
95% CI 0.10 to 0.94
Moderate effect sizecyclophosphamide plus corticosteroid

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
6 RCTs in this analysis
Major infection (excluding herpes zoster)
27/178 (15%) with cyclophosphamide plus corticosteroid
17/113 (15%) with corticosteroid alone

RR 0.87
95% CI 0.50 to 1.51
P = 0.61
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
3 RCTs in this analysis
Herpes zoster infection
30/133 (23%) with cyclophosphamide plus corticosteroid
7/66 (11%) with corticosteroid alone

RR 1.77
95% CI 0.63 to 4.99
P = 0.28
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
3 RCTs in this analysis
Bone toxicity (avascular necrosis or fracture)
15/119 (13%) with cyclophosphamide plus corticosteroid
10/78 (13%) with corticosteroid alone

RR 0.84
95% CI 0.40 to 1.75
P = 0.63
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Malignancy
3/78 (4%) with cyclophosphamide plus corticosteroid
1/39 (3%) with corticosteroid alone

RR 0.82
95% CI 0.07 to 9.90
P = 0.87
Not significant
[14]
Systematic review
147 people
3 RCTs in this analysis
Ovarian failure (sustained amenorrhoea)
47/99 (47%) with cyclophosphamide plus corticosteroid
9/48 (19%) with corticosteroid alone

RR 2.18
95% CI 1.10 to 4.34
Moderate effect sizecorticosteroid alone
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Bladder toxicity (haemorrhagic cystitis)
4/45 (9%) with cyclophosphamide plus corticosteroid
0/20 (0%) with corticosteroid alone

RR 2.66
95% CI 0.33 to 21.68
P = 0.36
Not significant

Further information on studies

The systematic review considered prednisolone, methylprednisolone, azathioprine, cyclophosphamide, mycophenolate mofetil, and tacrolimus for either induction or maintenance therapy for proliferative lupus nephritis.

Comment

Clinical guide

Cyclophosphamide was previously the only recommended immunosuppressant with corticosteroids to induce remission in patients with lupus nephritis. Mycophenolate shows equivalent efficacy to cyclophosphamide as an adjunct to corticosteroids in inducing remission. Cyclophosphamide may be more effective in white people, whereas mycophenolate may be more effective in non-white people, especially in black people. Lower doses are recommended in patients of east Asian origin. Guidelines, expert opinion, and patient preference suggest that mycophenolate may be the preferred agent in inducing remission.

Cyclophosphamide has a higher incidence of gonadal failure compared with mycophenolate. In those treated with cyclophosphamide, concominant use of mesna is recommended to reduce the risk of haemorrhagic cystitis.

Substantive changes

Cyclophosphamide plus corticosteroid compared with corticosteroid alone New option. One systematic review added.[14] Categorised as 'trade-off between benefits and harms'.

2015; 2015: 1123.
Published online 2015 December 18.

Azathioprine plus corticosteroid compared with corticosteroid alone

Summary

Azathioprine plus corticosteroid seems to reduce all-cause mortality compared with corticosteroid alone in people with proliferative lupus nephritis. However, azathioprine plus corticosteroid did not improve renal outcomes compared with corticosteroid alone.

Azathioprine plus corticosteroid did not appear to increase the burden of adverse effects (major infections, herpes zoster, bone marrow toxicity, malignancy, or ovarian failure) compared with corticosteroid alone. The analyses may, however, have been underpowered.

Benefits and harms

Azathioprine plus corticosteroid compared with corticosteroid alone:

We found one systematic review (search date 2012).[14]

Mortality

Azathioprine plus corticosteroid compared with corticosteroid alone Azathioprine plus corticosteroid seems to be more effective than corticosteroid alone at reducing all-cause mortality in people with proliferative lupus nephritis (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
3 RCTs in this analysis
All-cause mortality 2–7 years
15/43 (35%) with azathioprine plus corticosteroid
20/35 (57%) with corticosteroid alone

RR 0.60
95% CI 0.36 to 0.99
P = 0.048
Small effect sizeazathioprine plus corticosteroid

Renal disease

Azathioprine plus corticosteroid compared with corticosteroid alone Azathioprine plus corticosteroid seems to be no more effective than corticosteroid alone at preserving renal function or reducing the incidence of end stage renal disease in people with proliferative lupus nephritis (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Renal function
[14]
Systematic review
26 people with biopsy-proven proliferative lupus nephritis
Data from 1 RCT
Doubling of serum creatinine median follow-up 7 years
8/19 (42%) with azathioprine plus corticosteroid
3/7 (41%) with corticosteroid alone

RR 0.98
95% CI 0.36 to 2.68
P = 0.97
Not significant
[14]
Systematic review
26 people with biopsy-proven proliferative lupus nephritis
Data from 1 RCT
Stable renal function median follow-up 7 years
11/19 (58%) with azathioprine plus corticosteroid
4/7 (57%) with corticosteroid alone)

RR 1.01
95% CI 0.48 to 2.14
P = 0.97
Not significant
End stage renal disease
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
End stage renal disease 36–84 months
9/32 (28%) with azathioprine plus corticosteroid
9/22 (41%) with corticosteroid alone

RR 0.66
95% CI 0.17 to 2.55
P = 0.55
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
4 RCTs in this analysis
Major infection
11/50 (22%) with azathioprine plus corticosteroid
10/44 (23%) with corticosteroid alone

RR 1.06
95% CI 0.56 to 2.01
P = 0.85
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Herpes zoster infection
4/26 (15%) with azathioprine plus corticosteroid
0/16 (0%) with corticosteroid alone

RR 3.56
95% CI 0.46 to 27.79
P = 0.23
Not significant
[14]
Systematic review
24 people
Data from 1 RCT
Bone marrow toxicity
3/11 (27%) with azathioprine plus corticosteroid
1/13 (8%) with corticosteroid alone

RR 3.55
95% CI 0.43 to 29.42
P = 0.24
The analyses may have been underpowered to detect a clinically important difference between groups
Not significant
[14]
Systematic review
26 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Malignancy
2/19 (11%) with azathioprine plus corticosteroid
0/7 (0%) with corticosteroid alone

RR 2.00
95% CI 0.11 to 37.22
P = 0.64
Not significant
[14]
Systematic review
24 people
Data from 1 RCT
Ovarian failure
3/18 (17%) with azathioprine plus corticosteroid
0/6 (0%) with corticosteroid alone

RR 2.58
95% CI 0.15 to 43.86
P = 0.51
The analysis may have been underpowered to detect a clinically important difference between groups
Not significant

Further information on studies

The systematic review considered prednisolone, methylprednisolone, azathioprine, cyclophosphamide, mycophenolate mofetil, and tacrolimus for either induction or maintenance therapy for proliferative lupus nephritis.

Comment

Clinical guide

Azathioprine (prior to the availability of mycophenolate) was the preferred immunosuppressant to maintain and preserve renal function in lupus nephritis after initial treatment with cyclophosphamide.

Although the burden of serious infections and bone marrow toxicity may not differ between azathioprine and corticosteroid compared with corticosteroid alone, high-dose corticosteroid is associated with the familiar features of iatrogenic Cushing's syndrome.

Substantive changes

Azathioprine plus corticosteroid compared with corticosteroid alone New option. One systematic review added.[14] Categorised as 'trade-off between benefits and harms'.

2015; 2015: 1123.
Published online 2015 December 18.

Mycophenolate mofetil plus corticosteroid compared with corticosteroid alone

Summary

We found no systematic review or RCTs comparing the effects of mycophenolate mofetil plus corticosteroid with corticosteroid alone for proliferative lupus nephritis.

Benefits and harms

Mycophenolate mofetil plus corticosteroid compared with corticosteroid alone:

We found no systematic review or RCTs.

Comment

Clinical guide

Mycophenolate plus corticosteroid has been shown to be as effective as cyclophosphamide and corticosteroid in the intial treatment of lupus nephritis. Guidelines, expert opinion, and patient preference favour the use of mycophenolate as the initial immunosuppressant with corticosteroids for managing lupus nephritis. Mycophenolate may be more effective in non-white people, especially black people. Lower doses may be required in those of east Asian ethnicity.

Substantive changes

Mycophenolate mofetil plus corticosteroid compared with corticosteroid alone New option. We found no systematic reviews or RCTs. Categorised as 'unknown effectiveness'.

2015; 2015: 1123.
Published online 2015 December 18.

Tacrolimus plus corticosteroid compared with corticosteroid alone

Summary

We found no systematic review or RCTs comparing the effects of tacrolimus plus corticosteroid with corticosteroid alone for proliferative lupus nephritis.

Benefits and harms

Tacrolimus plus corticosteroid compared with corticosteroid alone:

We found no systematic review or RCTs.

Comment

Clinical guide

Currently, there is no available evidence to advocate the routine use of tacrolimus with corticosteroids as the initial treatment of proliferative lupus nephritis.

Substantive changes

Tacrolimus plus corticosteroid compared with corticosteroid alone New option. We found no systematic reviews or RCTs. Categorised as 'unknown effectiveness'.

2015; 2015: 1123.
Published online 2015 December 18.

Abatacept plus corticosteroid compared with corticosteroid alone

Summary

We found no systematic review or RCTs comparing the effects of abatacept plus corticosteroid with corticosteroid alone for proliferative lupus nephritis.

Benefits and harms

Abatacept plus corticosteroid compared with corticosteroid alone:

We found no systematic review or RCTs.

Comment

Clinical guide

Currently, there is no available evidence to advocate the routine use of abatacept with corticosteroids as the initial treatment of proliferative lupus nephritis.

Substantive changes

Abatacept plus corticosteroid compared with corticosteroid alone New option. We found no systematic reviews or RCTs. Categorised as 'unknown effectiveness'.

2015; 2015: 1123.
Published online 2015 December 18.

Mycophenolate mofetil plus corticosteroid compared with cyclophosphamide plus corticosteroid

Summary

Mycophenolate mofetil plus corticosteroid and cyclophosphamide plus corticosteroid reduced mortality to a similar extent in people with proliferative lupus nephritis.

Renal disease outcomes did not differ discernibly between mycophenolate mofetil plus corticosteroid and cyclophosphamide plus corticosteroid.

Ovarian failure, low white cell count, infection, and hair loss occurred less often with mycophenolate mofetil plus corticosteroid than with cyclophosphamide plus corticosteroid. Pure red cell aplasia may occur with mycophenolate.

Benefits and harms

Mycophenolate mofetil plus corticosteroid compared with cyclophosphamide plus corticosteroid:

We found three systematic reviews (search dates 2006,[15] 2006,[16] and 2012[14]).

Mortality

Mycophenolate mofetil plus corticosteroid compared with cyclophosphamide plus corticosteroid Mycophenolate mofetil plus corticosteroid seems to be as effective as cyclophosphamide plus corticosteroid at reducing mortality in people with proliferative lupus nephritis (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality
[16]
Systematic review
People with proliferative lupus nephritis (WHO grades III–V)
4 RCTs in this analysis
Survival rate
133/135 (99%) with mycophenolate mofetil plus corticosteroid
125/135 (93%) with cyclophosphamide plus corticosteroid

OR 3.90
95% CI 1.07 to 14.27
P = 0.04
Moderate effect sizemycophenolate mofetil plus corticosteroid
[14]
Systematic review
62 people with class IV lupus nephritis
Data from 1 RCT
Mortality median follow-up 63 months
0/32 (0%) with mycophenolate mofetil plus corticosteroid
2/30 (7%) with cyclophosphamide plus corticosteroid

RR 0.19
95% CI 0.01 to 3.76
P = 0.27
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
7 RCTs in this analysis
Mortality (time of outcome not stated)
17/349 (5%) with mycophenolate mofetil plus corticosteroid
17/361 (5%) with cyclophosphamide plus corticosteroid

RR 1.02
95% CI 0.52 to 1.98
P = 0.96
Not significant

No data from the following reference on this outcome.[15]

Renal disease

Mycophenolate mofetil plus corticosteroid compared with cyclophosphamide plus corticosteroid Mycophenolate mofetil plus corticosteroid may be more effective than cyclophosphamide plus corticosteroid at improving renal response in people with proliferative lupus nephritis. We don't know how effective mycophenolate mofetil plus corticosteroid and cyclophosphamide plus corticosteroid are, compared with each other, at preserving renal function, reducing the incidence of end stage renal disease, inducing remission, or preventing relapse (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Renal function
[14]
Systematic review
62 people with class IV lupus nephritis
Data from 1 RCT
Doubling of serum creatinine median follow-up 63 months
2/32 (6%) with mycophenolate mofetil plus corticosteroid
3/30 (10%) with cyclophosphamide plus corticosteroid

RR 0.63
95% CI 0.11 to 3.48
P = 0.59
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
5 RCTs in this analysis
Stable kidney function (not further defined)
178/254 (70%) with mycophenolate mofetil plus corticosteroid
177/269 (66%) with cyclophosphamide plus corticosteroid

RR 1.05
95% CI 0.94 to 1.18
P = 0.39
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
4 RCTs in this analysis
Serum creatinine
with mycophenolate mofetil plus corticosteroid
with cyclophosphamide plus corticosteroid
Absolute results not reported

Mean difference +0.06
95% CI –0.02 to +0.14
P = 0.16
Not significant
End stage renal disease
[14]
Systematic review
62 people with class IV lupus nephritis
Data from 1 RCT
End stage renal disease median follow-up 63 months
0/32 (0%) with mycophenolate mofetil plus corticosteroid
2/30 (7%) with oral cyclophosphamide plus corticosteroid

RR 0.19
95% CI 0.01 to 3.76
P = 0.27
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
3 RCTs in this analysis
End stage renal disease (time of outcome not stated)
7/114 (6%) with mycophenolate mofetil plus corticosteroid
10/117 (9%) with cyclophosphamide plus corticosteroid

RR 0.71
95% CI 0.27 to 1.84
P = 0.48
Not significant
Response
[15]
Systematic review
People with systemic lupus and lupus nephritis (WHO grades III–V)
4 RCTs in this analysis
Complete response
36% with mycophenolate mofetil plus corticosteroid
23% with cyclophosphamide plus corticosteroid
Absolute numbers not reported

RR 1.5
95% CI 1.1 to 2.1
NNT 7.6
95% CI 4.2 to 43
Small effect sizemycophenolate mofetil plus corticosteroid
[15]
Systematic review
People with systemic lupus and lupus nephritis (WHO grades III–V)
5 RCTs in this analysis
Complete or partial response
66% with mycophenolate mofetil plus corticosteroid
54% with cyclophosphamide plus corticosteroid
Absolute numbers not reported

RR 1.2
95% CI 1.03 to 1.4
NNT 8
95% CI 4.3 to 60
Small effect sizemycophenolate mofetil plus corticosteroid
Remission
[16]
Systematic review
People with proliferative lupus nephritis (grades III–V)
4 RCTs in this analysis
Complete remission
58/135 (43%) with mycophenolate mofetil plus corticosteroid
47/135 (35%) with cyclophosphamide plus corticosteroid

OR 1.47
95% CI 0.62 to 2.65
P = 0.20
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
6 RCTs in this analysis
Complete remission
66/339 (19%) with mycophenolate mofetil plus corticosteroid
48/347 (14%) with cyclophosphamide plus corticosteroid

RR 1.39
95% CI 0.99 to 1.95
P = 0.059
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
6 RCTs in this analysis
Partial remission
134/339 (40%) with mycophenolate mofetil plus corticosteroid
133/347 (38%) with cyclophosphamide plus corticosteroid

RR 1.04
95% CI 0.86 to 1.25
P = 0.71
Not significant
Relapse
[16]
Systematic review
People with proliferative lupus nephritis (WHO grades III–V)
2 RCTs in this analysis
Relapse (not further defined)
6/45 (13%) with mycophenolate mofetil plus corticosteroid
10/41 (24%) with cyclophosphamide with corticosteroid

OR 0.49
95% CI 0.16 to 1.51
P = 0.21
Not significant
[14]
Systematic review
62 people with class IV lupus nephritis
Data from 1 RCT
Relapse median follow-up 63 months
11/32 (34%) with mycophenolate mofetil plus corticosteroid
9/30 (30%) with cyclophosphamide plus corticosteroid

RR 1.15
95% CI 0.55 to 2.37
P = 0.71
Not significant
[14]
Systematic review
140 people with biopsy-proven lupus nephritis class III, IV, V
Data from 1 RCT
Relapse (not further defined)
8/71 (11%) with mycophenolate mofetil plus corticosteroid
8/69 (12%) with cyclophosphamide plus corticosteroid

RR 0.97
95% CI 0.39 to 2.44
P = 0.06
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[14]
Systematic review
62 people with class IV lupus nephritis
Data from 1 RCT
Major infection except herpes zoster median follow-up 63 months
2/32 (6%) with mycophenolate mofetil plus corticosteroid
9/30 (30%) with cyclophosphamide plus corticosteroid

RR 0.21
95% CI 0.05 to 0.89
P = 0.034
Moderate effect sizemycophenolate mofetil plus corticosteroid
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
6 RCTs in this analysis
Major infection except herpes zoster
39/341 (11%) with mycophenolate mofetil plus corticosteroid
39/342 (11%) with cyclophosphamide plus corticosteroid

RR 1.11
95% CI 0.74 to 1.68
P = 0.60
Not significant
[14]
Systematic review
62 people with class IV lupus nephritis
Data from 1 RCT
Herpes zoster infection median follow-up 63 months
2/32 (6%) with mycophenolate mofetil plus corticosteroid
5/30 (17%) with oral cyclophosphamide plus corticosteroid

RR 0.38
95% CI 0.08 to 1.79
P value not reported
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
4 RCTs in this analysis
Herpes zoster infection
22/310 (7%) with mycophenolate mofetil plus corticosteroid
16/303 (5%) with cyclophosphamide plus corticosteroid

RR 1.35
95% CI 0.71 to 2.58
P = 0.36
Not significant
[16]
Systematic review
People with proliferative lupus nephritis (WHO grades III–V)
6 RCTs in this analysis
Infection
21/169 (12%) with mycophenolate mofetil plus corticosteroid
40/169 (24%) with cyclophosphamide plus corticosteroid

OR 0.42
95% CI 0.23 to 0.77
P = 0.005
Moderate effect sizemycophenolate mofetil plus corticosteroid
[14]
Systematic review
62 people with class IV lupus nephritis
Data from 1 RCT
Leukopenia median follow-up 63 months
0/32 (0%) with mycophenolate mofetil plus corticosteroid
8/30 (27%) with cyclophosphamide plus corticosteroid

RR 0.06
95% CI 0.00 to 0.92
P = 0.043
Large effect sizemycophenolate mofetil plus corticosteroid
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
5 RCTs in this analysis
Leukopenia
28/330 (8%) with mycophenolate mofetil plus corticosteorid
69/323 (21%) with cyclophosphamide plus corticosteroid

RR 0.49
95% CI 0.28 to 0.88
P = 0.016
Moderate effect sizemycophenolate mofetil plus corticosteroid
[16]
Systematic review
People with proliferative lupus nephritis (WHO grades III–V)
7 RCTs in this analysis
Leukopenia
18/205 (9%) with mycophenolate mofetil plus corticosteroid
39/201 (19%) with cyclophosphamide plus corticosteroid

OR 0.42
95% CI 0.23 to 0.77
P = 0.005
Moderate effect sizemycophenolate mofetil plus corticosteroid
[15]
Systematic review
People with proliferative lupus nephritis (WHO grades III–V)
2 RCTs in this analysis
Hospital admission
2% with mycophenolate mofetil plus corticosteroid
15% with cyclophosphamide plus corticosteroid
Absolute numbers not reported

RR 0.1
95% CI 0.04 to 0.5
NNT 7.4
95% CI 4.8 to 16
Large effect sizemycophenolate mofetil plus corticosteroid
[14]
Systematic review
364 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Malignancy median follow-up 24 weeks
2/184 (1%) with mycophenolate mofetil plus corticosteroid
3/180 (2%) with cyclophosphamide plus corticosteroid

RR 0.65
95% CI 0.11 to 3.86
P value not reported
Not significant
[14]
Systematic review
53 people with class IV lupus nephritis
Data from 1 RCT
Ovarian failure median follow-up 63 months
1/28 (4%) with mycophenolate mofetil plus corticosteroid
9/25 (36%) with cyclophosphamide plus corticosteroid

RR 0.10
95% CI 0.01 to 0.73
P value not reported
Large effect sizemycophenolate mofetil plus corticosteroid
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Ovarian failure
1/249 (0%) with mycophenolate mofetil plus corticosteroid
10/249 (4%) with intravenous cyclophosphamide plus corticosteroid

RR 0.15
95% CI 0.03 to 0.80
P = 0.027
Large effect sizemycophenolate mofetil plus corticosteroid
[15]
Systematic review
People with proliferative lupus nephritis (WHO grades III–V)
5 RCTs in this analysis
Amenorrhoea
2% with mycophenolate mofetil plus corticosteroid
12% with cyclophosphamide plus corticosteroid
Absolute numbers not reported

RR 0.2
95% CI 0.08 to 0.6
NNT 9.5
95% CI 6.2 to 20
Moderate effect sizemycophenolate mofetil plus corticosteroid
[16]
Systematic review
People with proliferative lupus nephritis (WHO grades III–V)
4 RCTs in this analysis
Amenorrhoea
1/122 (1%) with mycophenolate mofetil plus corticosteroid
13/121 (11%) with cyclophosphamide plus corticosteroid

OR 0.14
95% CI 0.03 to 0.54
P = 0.05
Large effect sizemycophenolate mofetil plus corticosteroid
[14]
Systematic review
364 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Bladder toxicity median follow-up 24 weeks
0/184 (0%) with mycophenolate mofetil plus corticosteroid
1/180 (1%) with cyclophosphamide plus corticosteroid

RR 0.33
95% CI 0.01 to 7.95
P value not reported
Not significant
[14]
Systematic review
62 people with class IV lupus nephritis
Data from 1 RCT
Alopecia median follow-up 63 months
0/32 (0%) with mycophenolate mofetil plus corticosteroid
9/30 (30%) with cyclophosphamide plus corticosteroid

RR 0.05
95% CI 0.00 to 0.81
P = 0.035
Large effect sizemycophenolate mofetil plus corticosteroid
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Alopecia
20/267 (7%) with mycophenolate mofetil plus corticosteroid
72/255 (28%) with cyclophosphamide plus corticosteroid

RR 0.22
95% CI 0.06 to 0.86
P = 0.030
Large effect sizemycophenolate mofetil plus corticosteroid
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
3 RCTs in this analysis
Diarrhoea
72/291 (25%) with mycophenolate mofetil plus corticosteroid
27/278 (10%) with cyclophosphamide plus corticosteroid

RR 2.53
95% CI 1.54 to 4.16
P = 0.00026
Moderate effect sizecyclophosphamide plus corticosteroid
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Vomiting
48/267 (18%) with mycophenolate mofetil plus corticosteroid
93/255 (36%) with cyclophosphamide plus corticosteroid

RR 0.54
95% CI 0.24 to 1.24
P = 0.15
Heterogeneity; I2 = 86%
Heterogeneity not discussed
Not significant
[14]
Systematic review
158 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III and V + IV)
Data from 1 RCT
Nausea
23/83 (28%) with mycophenolate mofetil plus corticosteroid
25/75 (33%) with cyclophosphamide plus corticosteroid

RR 0.83
95% CI 0.52 to 1.33
P = 0.44
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
5 RCTs in this analysis
Gastrointestinal upset
129/343 (38%) with mycophenolate mofetil plus corticosteroid
143/328 (44%) with cyclophosphamide plus corticosteroid

RR 0.87
95% CI 0.66 to 1.13
P = 0.29
Not significant

Further information on studies

The systematic review considered prednisolone, methylprednisolone, azathioprine, cyclophosphamide, mycophenolate mofetil, and tacrolimus for either induction or maintenance therapy for proliferative lupus nephritis.

This systematic review included 38 people with WHO grade III disease, 241 with grade IV, 27 with grade V, and 15 with mixed membranoproliferative disease.

Comment

Clinical guide

Mycophenolate and cyclophosphamide are considered equivalent in the initial treatment of lupus nephritis. Mycophenolate, because of its ease of administration and lower risk of toxicity compared with cyclophosphamide, may be the preferred drug for the intial treatment of lupus nephritis.

Drug safety alert

Mycophenolate mofetil (July, 2009)

Healthcare professionals should consider a dose reduction or discontinuation of mycophenolate mofetil if patients develop pure red cell aplasia.[17]

Substantive changes

Mycophenolate mofetil plus corticosteroid compared with cyclophosphamide plus corticosteroid New option. Three systematic reviews added.[14] [15] [16] Categorised as 'trade-off between benefits and harms'.

2015; 2015: 1123.
Published online 2015 December 18.

Mycophenolate mofetil plus corticosteroid compared with tacrolimus plus corticosteroid

Summary

Mycophenolate mofetil plus corticosteroid and tacrolimus plus corticosteroid reduced mortality to a similar extent in people with proliferative lupus nephritis.

Renal disease outcomes did not differ between mycophenolate mofetil plus corticosteroid and tacrolimus plus corticosteroid.

Benefits and harms

Mycophenolate mofetil plus corticosteroid compared with tacrolimus plus corticosteroid:

We found one systematic review (search date 2012).[14]

Mortality

Mycophenolate mofetil plus corticosteroid versus tacrolimus plus corticosteroid Mycophenolate mofetil plus corticosteroid seems to be as effective as tacrolimus plus corticosteroid at reducing mortality in people with proliferative lupus nephritis (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Mortality
4/66 (6%) with mycophenolate mofetil plus corticosteroid
2/64 (3%) with tacrolimus plus corticosteroid

RR 1.87
95% CI 0.34 to 10.44
P = 0.47
Not significant

Renal disease

Mycophenolate mofetil plus corticosteroid versus tacrolimus plus corticosteroid We don't know how effective mycophenolate mofetil plus corticosteroid and tacrolimus plus corticosteroid are, compared with each other, at preserving renal function, reducing the incidence of end stage renal disease, inducing remission, or preventing relapse, in people with proliferative lupus nephritis (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Renal function
[14]
Systematic review
90 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Deterioration in kidney function (not further defined)
5/46 (11%) with mycophenolate mofetil plus corticosteroid
12/44 (27%) with tacrolimus plus corticosteroid

RR 0.40
95% CI 0.15 to 1.04
P value not reported
Not significant
[14]
Systematic review
40 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Stable kidney function (not further defined)
14/20 (70%) with mycophenolate mofetil plus corticosteroid
15/20 (75%) with tacrolimus plus corticosteroid

RR 0.93
95% CI 0.64 to 1.37
P value not reported
Not significant
End stage renal disease
[14]
Systematic review
90 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
End stage renal disease
2/46 (4%) with mycophenolate mofetil plus corticosteroid
2/44 (5%) with tacrolimus plus corticosteroid

RR 0.96
95% CI 0.14 to 6.50
P value not reported
Not significant
Remission
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Complete remission
24/56 (43%) with mycophenolate mofetil plus corticosteroid
14/53 (26%) with tacrolimus plus corticosteroid

RR 1.59
95% CI 0.58 to 4.41
P = 0.37
Heterogeneity; I2 = 70%
Potential source of heterogeneity is unclear
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Complete or partial remission
53/66 (80%) with mycophenolate mofetil plus corticosteroid
53/64 (83%) with tacrolimus plus corticosteroid

RR 0.96
95% CI 0.82 to 1.13
P = 0.66
Not significant
Relapse
[14]
Systematic review
90 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Relapse (not further defined)
10/46 (22%) with mycophenolate mofetil plus corticosteroid
14/44 (32%) with tacrolimus plus corticosteroid

RR 0.68
95% CI 0.34 to 1.37
P value not reported
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Major infection
15/66 (23%) with mycophenolate mofetil plus corticosteroid
7/64 (11%) with tacrolimus plus corticosteroid

RR 2.11
95% CI 0.92 to 4.80
P = 0.076
Not significant
[14]
Systematic review
40 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Leukopenia
1/20 (5%) with mycophenolate mofetil plus corticosteroid
1/20 (5%) with tacrolimus plus corticosteroid

RR 1.00
95% CI 0.07 to 14.90
P value not reported
Not significant

Further information on studies

The systematic review considered prednisolone, methylprednisolone, azathioprine, cyclophosphamide, mycophenolate mofetil, and tacrolimus for either induction or maintenance therapy for proliferative lupus nephritis.

Comment

Clinical guide

Tacrolimus is currently not recommended for the intial treatment of lupus nephritis. It may be considered in patients who cannot tolerate mycophenolate or cyclophosphamide.

Drug safety alert

Mycophenolate mofetil (July, 2009)

Healthcare professionals should consider a dose reduction or discontinuation of mycophenolate mofetil if patients develop pure red cell aplasia.[17]

Substantive changes

Mycophenolate mofetil plus corticosteroid compared with tacrolimus plus corticosteroid New option. One systematic review added.[14] Categorised as 'trade-off between benefits and harms'.

2015; 2015: 1123.
Published online 2015 December 18.

Cyclophosphamide plus corticosteroid compared with azathioprine plus corticosteroid

Summary

Cyclophosphamide plus corticosteroid may be less effective than azathioprine plus corticosteroid at reducing mortality at 10 years in people with proliferative lupus nephritis.

Cyclophosphamide plus corticosteroid may be more effective than azathioprine plus corticosteroid at preventing renal disease relapse.

Benefits and harms

Cyclophosphamide plus corticosteroid compared with azathioprine plus corticosteroid:

We found one systematic review (search date 2012).[14]

Mortality

Cyclophosphamide plus corticosteroid compared with azathioprine plus corticosteroid Cyclophosphamide plus corticosteroid may be less effective than azathioprine plus corticosteroid at reducing mortality at 10 years in people with proliferative lupus nephritis. We don't know how effective cyclophosphamide plus corticosteroid and azathioprine plus corticosteroid are, compared with each other, at reducing mortality at 5 years (very low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality
[14]
Systematic review
59 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Mortality 10 years
16/21 (76%) with cyclophosphamide plus corticosteroid
15/38 (39%) with azathioprine plus corticosteroid

RR 1.93
95% CI 1.22 to 3.06
P = 0.0051
Small effect sizeazathioprine
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Mortality 5 years
10/71 (14%) with cyclophosphamide plus corticosteroid
8/75 (11%) with azathioprine plus corticosteroid

RR 1.39
95% CI 0.25 to 7.77
P = 0.71
Heterogeneity; I2 = 67%
Heterogeneity may be explained by outcome reporting bias
Not significant

Renal disease

Cyclophosphamide plus corticosteroid compared with azathioprine plus corticosteroid Cyclophosphamide plus corticosteroid may be more effective than azathioprine plus corticosteroid at preserving renal function and preventing relapse in people with proliferative lupus nephritis. We don’t know how effective cyclophosphamide plus corticosteroid and azathioprine plus corticosteroid are, compared with each other, at reducing the incidence of end stage renal disease (low-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Renal function
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Doubling of serum creatinine
11/88 (13%) with intravenous cyclophosphamide plus corticosteroid
14/56 (25%) with azathioprine plus corticosteroid

RR 0.48
95% CI 0.24 to 0.95
P = 0.036
Moderate effect sizecyclophosphamide
[14]
Systematic review
30 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Deterioration of kidney function (not further defined)
4/20 (20%) with oral cyclophosphamide plus corticosteroid
3/10 (30%) with azathioprine plus corticosteroid

RR 0.67
95% CI 0.18 to 2.42
P = 0.54
Not significant
[14]
Systematic review
57 people with biopsy-proven lupus nephritis class III, IV, V, or combination
Data from 1 RCT
Stable kidney function (not further defined)
29/38 (76%) with cyclophosphamide plus corticosteroid
11/19 (58%) with azathioprine plus corticosteroid

RR 1.32
95% CI 0.86 to 2.01
P value not reported
Not significant
End stage renal disease
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
End stage renal disease
5/88 (6%) with intravenous cyclophosphamide plus corticosteroid
7/56 (13%) with azathioprine plus corticosteroid

RR 0.40
95% CI 0.15 to 1.07
P = 0.069
Not significant
Relapse
[14]
Systematic review
87 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Relapse (not further defined)
2/50 (4%) with intravenous cyclophosphamide plus corticosteroid
10/37 (27%) with azathioprine plus corticosteroid

RR 0.15
95% CI 0.03 to 0.64
P = 0.01
Large effect sizecyclophosphamide

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[14]
Systematic review
57 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Major infection excluding herpes zoster
5/38 (13%) with cyclophosphamide plus corticosteroid
2/19 (11%) with azathioprine plus corticosteroid

RR 1.25
95% CI 0.27 to 5.86
P value not reported
Not significant
[14]
Systematic review
57 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Herpes zoster infection
11/38 (29%) with cyclophosphamide plus corticosteroid
2/19 (11%) with azathioprine plus corticosteroid

RR 2.75
95% CI 0.68 to 11.18
P value not reported
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Malignancy
3/88 (3%) with cyclophosphamide plus corticosteroid
3/56 (5%) with azathioprine plus corticosteroid

RR 0.59
95% CI 0.13 to 2.63
P = 0.48
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Ovarian failure
17/71 (24%) with cyclophosphamide plus corticosteroid
5/55 (9%) with azathioprine plus corticosteroid

RR 2.11
95% CI 0.59 to 7.53
P = 0.25
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Bladder toxicity
3/88 (3%) with cyclophosphamide plus corticosteroid
0/56 (0%) with azathioprine plus corticosteroid

RR 3.59
95% CI 0.19 to 66.14
P = 0.39
Not significant

Further information on studies

The systematic review considered prednisolone, methylprednisolone, azathioprine, cyclophosphamide, mycophenolate mofetil, and tacrolimus for either induction or maintenance therapy for proliferative lupus nephritis.

Comment

Cyclophosphamide is preferred over azathioprine as the immunosuppressant for the initial treatment of lupus nephritis.

Substantive changes

Cyclophosphamide plus corticosteroid compared with azathioprine plus corticosteroid New option. One systematic review added.[14] Categorised as 'trade-off between benefits and harms'.

2015; 2015: 1123.
Published online 2015 December 18.

Cyclophosphamide plus corticosteroid compared with tacrolimus plus corticosteroid

Summary

Cyclophosphamide plus corticosteroid seems to be as effective as tacrolimus plus corticosteroid at reducing mortality in people with proliferative lupus nephritis.

Both agents seem to be equally effective at improving renal remission and preserving renal function, but cyclophosphamide plus corticosteroid seems to be less effective than tacrolimus plus corticosteroid at improving renal response.

Cyclophosphamide plus corticosteroid may increase the risk of irregular menstruation or amenorrhoea compared with tacrolimus plus corticosteroid.

Benefits and harms

Cyclophosphamide plus corticosteroid compared with tacrolimus plus corticosteroid:

We found two systematic reviews (search dates 2012[14] and 2011[18]).

Mortality

Cyclophosphamide plus corticosteroid compared with tacrolimus plus corticosteroid Cyclophosphamide plus corticosteroid seems to be as effective as tacrolimus plus corticosteroid at reducing mortality in people with proliferative lupus nephritis (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Mortality
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Mortality
8/54 (15%) with cyclophosphamide plus corticosteroid
2/59 (3%) with tacrolimus plus corticosteroid

RR 3.49
95% CI 0.94 to 12.98
P = 0.062
Not significant

No data from the following reference on this outcome.[18]

Renal disease

Cyclophosphamide plus corticosteroid compared with tacrolimus plus corticosteroid Cyclophosphamide plus corticosteroid seems to be less effective than tacrolimus plus corticosteroid at improving renal response in people with proliferative lupus nephritis. Cyclophosphamide plus corticosteroid and tacrolimus plus corticosteroid seem to be equally effective at preserving renal function and inducing renal remission (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Renal function
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Stable kidney function
15/32 (47%) with cyclophosphamide plus corticosteroid
21/33 (64%) with tacrolimus plus corticosteroid

RR 0.76
95% CI 0.51 to 1.15
P = 0.19
Not significant
[18]
Systematic review
People with biopsy-proven lupus nephritis class III, IV, V, V + III, or V + IV
5 RCTs in this analysis
Serum creatinine elevated
8/114 (7%) with tacrolimus plus corticosteroid
5/109 (5%) with cyclophosphamide plus corticosteroid

RR 1.49
95% CI 0.52 to 4.26
P = 0.46
Not significant
Response
[18]
Systematic review
People with biopsy-proven lupus nephritis class III, IV, V, V + III, or V + IV
5 RCTs in this analysis
Response (not further defined)
98/111 (88%) with tacrolimus plus corticosteroid
76/108 (70%) with cyclophosphamide plus corticosteroid

RR 1.25
95% CI 1.09 to 1.44
P = 0.001
Small effect sizetacrolimus plus corticosteroid
Remission
[18]
Systematic review
People with biopsy-proven lupus nephritis class III, IV, V, V + III, or V + IV
5 RCTs in this analysis
Complete remission
57/111 (51%) with tacrolimus plus corticosteroid
34/108 (31%) with cyclophosphamide plus corticosteroid

RR 1.61
95% CI 1.17 to 2.23
P = 0.004
Small effect sizetacrolimus plus corticosteroid
[18]
Systematic review
People with biopsy-proven lupus nephritis class III, IV, V, V + III, or V + IV
5 RCTs in this analysis
Partial remission
41/111 (37%) with tacrolimus plus corticosteroid
42/108 (39%) with cyclophosphamide plus corticosteroid

RR 0.95
95% CI 0.68 to 1.33
P = 0.78
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
3 RCTs in this analysis
Complete remission
24/66 (36%) with cyclophosphamide plus corticosteroid
37/72 (51%) with tacrolimus plus corticosteroid

RR 0.72
95% CI 0.49 to 1.06
P = 0.10
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
3 RCTs in this analysis
Partial remission
25/66 (38%) with cyclophosphamide plus corticosteroid
26/72 (36%) with tacrolimus plus corticosteroid

RR 1.10
95% CI 0.72 to 1.68
P = 0.67
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Major infection
9/32 (28%) with cyclophosphamide plus corticosteroid
4/33 (12%) with tacrolimus plus corticosteroid

RR 2.30
95% CI 0.79 to 6.74
P = 0.13
Not significant
[18]
Systematic review
People with biopsy-proven lupus nephritis class III, IV, V, V + III, or V + IV
5 RCTs in this analysis
Infection
18/114 (16%) with tacrolimus plus corticosteroid
26/109 (24%) with cyclophosphamide plus corticosteroid

RR 0.67
95% CI 0.39 to 1.16
P = 0.15
Not significant
[14]
Systematic review
People with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
2 RCTs in this analysis
Leukopenia
6/54 (11%) with cyclophosphamide plus corticosteroid
1/59 (2%) with tacrolimus plus corticosteroid

RR 3.40
95% CI 0.26 to 44.54
P = 0.35
Not significant
[14]
Systematic review
73 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Ovarian failure
2/34 (6%) with cyclophosphamide plus corticosteroid
0/39 (0%) with tacrolimus plus corticosteroid

RR 5.71
95% CI 0.28 to 115.04
P value not reported
Not significant
[18]
Systematic review
People with biopsy-proven lupus nephritis class III, IV, V, V + III, or V + IV
4 RCTs in this analysis
Irregular menstruation or amenorrhoea
1/94 (1%) with tacrolimus plus corticosteroid
16/89 (18%) with cyclophosphamide plus corticosteroid

RR 0.14
95% CI 0.04 to 0.50
P = 0.003
Large effect sizetacrolimus plus corticosteroid
[18]
Systematic review
People with biopsy-proven lupus nephritis class III, IV, V, V + III, or V + IV
5 RCTs in this analysis
Abnormal liver function
9/114 (8%) with tacrolimus plus corticosteroid
17/109 (16%) with cyclophosphamide plus corticosteroid

RR 0.51
95% CI 0.24 to 1.09
P = 0.08
Not significant
[18]
Systematic review
People with biopsy-proven lupus nephritis class III, IV, V, V + III, or V + IV
3 RCTs in this analysis
Hypertension
7/55 (13%) with tacrolimus plus corticosteroid
2/55 (4%) with cyclophosphamide plus corticosteroid

RR 3.00
95% CI 0.75 to 12.04
P = 0.12
Not significant
[18]
Systematic review
People with biopsy-proven lupus nephritis class III, IV, V, V + III, or V + IV
5 RCTs in this analysis
Hyperglycaemia
18/114 (16%) with tacrolimus plus corticosteroid
9/109 (8%) with cyclophosphamide plus corticosteroid

RR 1.74
95% CI 0.87 to 3.48
P = 0.11
Not significant
[18]
Systematic review
People with biopsy-proven lupus nephritis class III, IV, V, V + III, or V + IV
3 RCTs in this analysis
Alopecia
5/74 (7%) with tacrolimus plus corticosteroid
8/69 (12%) with cyclophosphamide plus corticosteroid

RR 0.63
95% CI 0.23 to 1.71
P = 0.36
Not significant
[14]
Systematic review
73 people with biopsy-proven proliferative lupus nephritis (WHO class III, IV, V + III, and V + IV)
Data from 1 RCT
Gastrointestinal symptoms
10/34 (29%) with cyclophosphamide plus corticosteroid
4/39 (10%) with tacrolimus plus corticosteroid

RR 2.87
95% CI 0.99 to 8.31
P value not reported
Not significant

Further information on studies

The systematic review considered prednisolone, methylprednisolone, azathioprine, cyclophosphamide, mycophenolate mofetil, and tacrolimus for either induction or maintenance therapy for proliferative lupus nephritis.

Only a small proportion of patients included in this systematic review had grade V lupus nephritis alone, with over 90% with grade III, IV, or grade V combined with grades III or IV.

Comment

Clinical guide

Tacrolimus is a potential alternative to cyclophosphamide and mycophenolate in the intial treatment of lupus nephritis. It is not yet recommended for routine use in clinical guidelines.

Substantive changes

Cyclophosphamide plus corticosteroid compared with tacrolimus plus corticosteroid New option. Two systematic reviews added.[14] [18] Categorised as 'trade-off between benefits and harms'.

2015; 2015: 1123.
Published online 2015 December 18.

Tacrolimus plus corticosteroid compared with azathioprine plus corticosteroid

Summary

Tacrolimus plus corticosteroid seems to be as effective as azathioprine plus corticosteroid at preserving renal function and preventing relapse in people with proliferative lupus nephritis.

Benefits and harms

Tacrolimus plus corticosteroid compared with azathioprine plus corticosteroid:

We found one RCT.[19]

Mortality

No data from the following reference on this outcome.[19]

Renal disease

Tacrolimus plus corticosteroid compared with azathioprine plus corticosteroid Tacrolimus plus corticosteroid seems to be as effective as azathioprine plus corticosteroid at preserving renal function and preventing relapse in people with proliferative lupus nephritis (moderate-quality evidence).

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Renal function
[19]
RCT
70 patients with biopsy-proven lupus nephritis who achieved remission Serum creatinine 6 months
0.75 with tacrolimus plus corticosteroid
0.70 with azathioprine plus corticosteroid

P = 0.67
Not significant
Relapse
[19]
RCT
70 patients with biopsy-proven lupus nephritis who achieved remission Relapse 6 months
0/34 (0%) with tacrolimus plus corticosteroid
2/36 (6%) with azathioprine plus corticosteroid

OR 1.06
95% CI 0.98 to 1.15
Not significant

Adverse effects

Ref (type)PopulationOutcome, InterventionsResults and statistical analysisEffect sizeFavours
Adverse effects
[19]
RCT
70 patients with biopsy-proven lupus nephritis who achieved remission Infection, (URTI, UTI, skin) 6 months
3/34 (9%) with tacrolimus plus corticosteroid
3/36 (8%) with azathioprine plus corticosteroid

P >0.99
Not significant
[19]
RCT
70 patients with biopsy-proven lupus nephritis who achieved remission Leukopenia 6 months
3/34 (9%) with tacrolimus plus corticosteroid
17/36 (47%) with azathioprine plus corticosteroid

P <0.001
Effect size not calculatedtacrolimus plus corticosteroid
[19]
RCT
70 patients with biopsy-proven lupus nephritis who achieved remission Liver function disorder 6 months
3/34 (9%) with tacrolimus plus corticosteroid
6/36 (17%) with azathioprine plus corticosteroid

P = 0.53
Not significant
[19]
RCT
70 patients with biopsy-proven lupus nephritis who achieved remission Hyperglycaemia 6 months
1/34 (3%) with tacrolimus plus corticosteroid
1/36 (3%) with azathioprine plus corticosteroid

P >0.99
Not significant
[19]
RCT
70 patients with biopsy-proven lupus nephritis who achieved remission Gastrointestinal complaints 6 months
1/34 (3%) with tacrolimus plus corticosteroid
2/36 (6%) with azathioprine plus corticosteroid

P >0.99
Not significant

Further information on studies

Tacrolimus was titrated to achieve a trough blood concentration of 4–6 nanograms/mL; azathioprine was administered at a dose of 2 mg/kg/day. Prednisolone was administered at a dose of 10 mg/day to both groups. Less than 20% of the population included in the RCT had grade V lupus nephritis alone.

Comment

Clinical guide

Tacrolimus may be a potential alternative immunosuppressant to azathioprine for maintaining improvement in patients who respond to induction therapy. Tacrolimus is not recommended in guidelines and is not frequently used in lupus nephritis.

Substantive changes

Tacrolimus plus corticosteroid compared with azathioprine plus corticosteroid New option. One RCT added.[19] Categorised as 'trade-off between benefits and harms'.


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