Interventions for cutaneous disease in systemic lupus erythematosus

Abstract

Background: Lupus erythematosus is an autoimmune disease with significant morbidity and mortality. Cutaneous disease in systemic lupus erythematosus (SLE) is common. Many interventions are used to treat SLE with varying efficacy, risks, and benefits.

Objectives: To assess the effects of interventions for cutaneous disease in SLE.

Search methods: We searched the following databases up to June 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, Wiley Interscience Online Library, and Biblioteca Virtual em Saude (Virtual Health Library). We updated our search in September 2020, but these results have not yet been fully incorporated.

Selection criteria: We included randomised controlled trials (RCTs) of interventions for cutaneous disease in SLE compared with placebo, another intervention, no treatment, or different doses of the same intervention. We did not evaluate trials of cutaneous lupus in people without a diagnosis of SLE.

Data collection and analysis: We used standard methodological procedures expected by Cochrane. Primary outcomes were complete and partial clinical response. Secondary outcomes included reduction (or change) in number of clinical flares; and severe and minor adverse events. We used GRADE to assess the quality of evidence.

Main results: Sixty-one RCTs, involving 11,232 participants, reported 43 different interventions. Trials predominantly included women from outpatient clinics; the mean age range of participants was 20 to 40 years. Twenty-five studies reported baseline severity, and 22 studies included participants with moderate to severe cutaneous lupus erythematosus (CLE); duration of CLE was not well reported. Studies were conducted mainly in multi-centre settings. Most often treatment duration was 12 months. Risk of bias was highest for the domain of reporting bias, followed by performance/detection bias. We identified too few studies for meta-analysis for most comparisons. We limited this abstract to main comparisons (all administered orally) and outcomes. We did not identify clinical trials of other commonly used treatments, such as topical corticosteroids, that reported complete or partial clinical response or numbers of clinical flares. Complete clinical response Studies comparing oral hydroxychloroquine against placebo did not report complete clinical response. Chloroquine may increase complete clinical response at 12 months' follow-up compared with placebo (absence of skin lesions) (risk ratio (RR) 1.57, 95% confidence interval (CI) 0.95 to 2.61; 1 study, 24 participants; low-quality evidence). There may be little to no difference between methotrexate and chloroquine in complete clinical response (skin rash resolution) at 6 months' follow-up (RR 1.13, 95% CI 0.84 to 1.50; 1 study, 25 participants; low-quality evidence). Methotrexate may be superior to placebo with regard to complete clinical response (absence of malar/discoid rash) at 6 months' follow-up (RR 3.57, 95% CI 1.63 to 7.84; 1 study, 41 participants; low-quality evidence). At 12 months' follow-up, there may be little to no difference between azathioprine and ciclosporin in complete clinical response (malar rash resolution) (RR 0.83, 95% CI 0.46 to 1.52; 1 study, 89 participants; low-quality evidence). Partial clinical response Partial clinical response was reported for only one key comparison: hydroxychloroquine may increase partial clinical response at 12 months compared to placebo, but the 95% CI indicates that hydroxychloroquine may make no difference or may decrease response (RR 7.00, 95% CI 0.41 to 120.16; 20 pregnant participants, 1 trial; low-quality evidence). Clinical flares Clinical flares were reported for only two key comparisons: hydroxychloroquine is probably superior to placebo at 6 months' follow-up for reducing clinical flares (RR 0.49, 95% CI 0.28 to 0.89; 1 study, 47 participants; moderate-quality evidence). At 12 months' follow-up, there may be no difference between methotrexate and placebo, but the 95% CI indicates there may be more or fewer flares with methotrexate (RR 0.77, 95% CI 0.32 to 1.83; 1 study, 86 participants; moderate-quality evidence). Adverse events Data for adverse events were limited and were inconsistently reported, but hydroxychloroquine, chloroquine, and methotrexate have well-documented adverse effects including gastrointestinal symptoms, liver problems, and retinopathy for hydroxychloroquine and chloroquine and teratogenicity during pregnancy for methotrexate.

Authors' conclusions: Evidence supports the commonly-used treatment hydroxychloroquine, and there is also evidence supporting chloroquine and methotrexate for treating cutaneous disease in SLE. Evidence is limited due to the small number of studies reporting key outcomes. Evidence for most key outcomes was low or moderate quality, meaning findings should be interpreted with caution. Head-to-head intervention trials designed to detect differences in efficacy between treatments for specific CLE subtypes are needed. Thirteen further trials are awaiting classification and have not yet been incorporated in this review; they may alter the review conclusions.

Trial registration: ClinicalTrials.gov NCT01597050 NCT02953821 NCT01162681 NCT01438489 NCT01753401 NCT01283139 NCT00299819 NCT01205438 NCT02265744 NCT01112215 NCT01484496 NCT01802740 NCT02349061 NCT00071487 NCT00111306 NCT00383214 NCT00624351 NCT00660881 NCT02708095 NCT02185040 NCT01551069 NCT00775476 NCT02074020 NCT02514967 NCT02711813 NCT02975336 NCT01449071 NCT01649765 NCT02465580 NCT02932137 NCT02665364 NCT02437890 NCT02446899 NCT02446912 NCT02554019 NCT02847598 NCT03958955 NCT01345253 NCT01781611 NCT02270957 NCT02660944 NCT02822989 NCT03161483 NCT03252587 NCT03451422 NCT03517722 NCT03616912 NCT03616964 NCT03845517 NCT03978520 NCT04058028 NCT04060888 NCT03312907.

Conflict of interest statement

Cora W Hannon: has declared that they have no conflict of interest. Collette McCourt: reports consultancy fees from Janssen Pharmaceuticals (paid as a panel member to consult on a medical education steering committee (no relation to SLE/cutaneous lupus or medication); Janssen manufacture STELARA, which is in phase 3 trials for SLE); personal payment. CM reports personal payment to prepare and deliver a lecture on biologic drugs in psoriasis from Janssen Pharmaceuticals. CM reports personal payment from AbbVie (virtual meeting sponsorship for American Academy of Dermatology (AAD) 2020, and meeting travel, accommodation, and attendance for AAD Florida 2017); Janssen Pharmaceuticals (meeting travel, accommodation, and attendance for European Academy of Dermatology and Venereology (EADV) Madrid 2019, AAD Washington 2019, and AAD San Diego 2018); and Celgene (meeting travel, accommodation, and attendance for EADV Paris 2018). CM is currently a co‐author of the British Association of Dermatologists Guideline Group for Cutaneous Lupus Erythematosus (from 2016 to present). This is not financially reimbursed. CM has received financial support for travel, accommodation, and conference attendance by Almirall and UCB; she has received consultancy and guest speaker honorarium from AbbVie and Janssen Pharmaceuticals. She reports that none of these are directly relevant to her role as co‐author of this Cochrane Review. Hermenio C Lima: reports consultancy fees from AbbVie (Abbott), Amgen, AstraZeneca, Bristol‐Myers Squibb, Celgene, Dermira, Eli Lilly, Janssen, La Roche‐Posay, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, and Sanofi; personal payment. HL reports grants/grants pending for clinical trials from AbbVie (Abbott), Amgen, AstraZeneca, Bristol‐Myers Squibb, Celgene, Dermira, Eli Lilly, Janssen, La Roche‐Posay, Merck Sharp & Dohme, Novartis, Pfizer, Regeneron, and Sanofi; personal payment. HL reports payment for lectures from AbbVie, Novartis, Sanofi, and Bausch Health; personal payment. HL reports payment for development of educational presentations from AbbVie (Abbott), Celgene, Janssen, Leo Pharmaceutics, Novartis, Sanofi, and Pediapharma. “I, Hermenio Lima, have received grants, speaker honorarium, consulting fees, and/or advisory boards from the companies listed above. None of these were related to this review or its subject.” Suephy Chen: has declared that they have no conflict of interest. Cathy Bennett: reports consultancy fees paid to her own company, Systematic Research Ltd. "I am the proprietor of Systematic Research Ltd. My company received a consultancy fee to enable me to work as a co‐author of this review. This included drafting text, extracting data, screening searches, co‐ordinating work and producing reports and summaries. Since I am the sole employee of Systematic Research Ltd, the consultancy fees from this and other work are paid to me in the form of a salary and company dividends. I have business relationships with other clients who may provide consultancy fees for evidence‐based medicine reviews, projects, and reports."

Copyright © 2021 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

Figures

1

Study flow diagram: PRISMA diagram showing the screening process.

2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

1.1. Analysis

Comparison 1: Oral methotrexate versus placebo, Outcome 1: Primary outcome (lupus‐specific): absence of malar or discoid rash

1.2. Analysis

Comparison 1: Oral methotrexate versus placebo, Outcome 2: Secondary outcome (lupus‐specific): severe clinical flare (requiring discontinuation of study)

1.3. Analysis

Comparison 1: Oral methotrexate versus placebo, Outcome 3: Adverse events

2.1. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 1: Primary outcome (lupus‐specific): partial improvement in skin lesions during pregnancy

2.2. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 2: Secondary outcome (lupus‐specific): clinical flare in skin disease

2.3. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 3: Secondary outcome (lupus‐non‐specific): vasculitis

2.4. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 4: Secondary outcome (lupus‐non‐specific): major flare in lupus (vasculitis, skin or other system)

2.5. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 5: Secondary outcome (lupus‐specific): systemic lupus flare during pregnancy study

2.6. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 6: Adverse events: severe ‐ toxaemia during pregnancy study

2.7. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 7: Adverse events: severe ‐ adverse event related to medication

2.8. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 8: Adverse events: severe ‐ any severe event

2.9. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 9: Adverse events: severe ‐ rash

2.10. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 10: Adverse events: severe ‐ worsening symptoms leading to study withdrawal (lack of treatment efficacy)

2.11. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 11: Adverse events: severe ‐ sudden death ‐ not thought to be related to medication

2.12. Analysis

Comparison 2: Oral hydroxychloroquine versus placebo, Outcome 12: Adverse events: minor

3.1. Analysis

Comparison 3: Oral dehydroepiandrosterone versus placebo, Outcome 1: Primary outcome (lupus‐specific): absence of oral stomatitis

3.2. Analysis

Comparison 3: Oral dehydroepiandrosterone versus placebo, Outcome 2: Primary outcome (lupus‐specific): absence of cutaneous rash

3.3. Analysis

Comparison 3: Oral dehydroepiandrosterone versus placebo, Outcome 3: Primary outcome (lupus‐non‐specific): absence of alopecia

3.4. Analysis

Comparison 3: Oral dehydroepiandrosterone versus placebo, Outcome 4: Adverse events: severe ‐ any

3.5. Analysis

Comparison 3: Oral dehydroepiandrosterone versus placebo, Outcome 5: Adverse events: severe ‐ death

3.6. Analysis

Comparison 3: Oral dehydroepiandrosterone versus placebo, Outcome 6: Adverse events: severe ‐ cancer diagnosis

3.7. Analysis

Comparison 3: Oral dehydroepiandrosterone versus placebo, Outcome 7: Adverse events: minor ‐ presence of acne

3.8. Analysis

Comparison 3: Oral dehydroepiandrosterone versus placebo, Outcome 8: Adverse events: minor ‐ presence of hirsutism

3.9. Analysis

Comparison 3: Oral dehydroepiandrosterone versus placebo, Outcome 9: Adverse events: minor ‐ presence of rash

4.1. Analysis

Comparison 4: Intravenous belimumab (1.0, 4.0, 10.0 mg/kg) versus placebo, Outcome 1: Adverse events: severe at belimumab 1 mg/kg dose

4.2. Analysis

Comparison 4: Intravenous belimumab (1.0, 4.0, 10.0 mg/kg) versus placebo, Outcome 2: Adverse events: severe, at belimumab 10 mg/kg dose

4.3. Analysis

Comparison 4: Intravenous belimumab (1.0, 4.0, 10.0 mg/kg) versus placebo, Outcome 3: Adverse events: minor ‐ skin and subcutaneous skin combined data for doses of 1.0 mg/kg, 4 mg/kg, and 10 mg/kg

5.1. Analysis

Comparison 5: Oral prednisone versus placebo, Outcome 1: Secondary outcome (lupus‐specific): flare in skin disease

5.2. Analysis

Comparison 5: Oral prednisone versus placebo, Outcome 2: Adverse events: minor

5.3. Analysis

Comparison 5: Oral prednisone versus placebo, Outcome 3: Adverse events: severe

6.1. Analysis

Comparison 6: Oral chloroquine versus placebo, Outcome 1: Primary outcome (lupus‐specific): absence of skin lesions

6.2. Analysis

Comparison 6: Oral chloroquine versus placebo, Outcome 2: Primary outcome (lupus‐non‐specific): absence of alopecia

6.3. Analysis

Comparison 6: Oral chloroquine versus placebo, Outcome 3: Adverse events: severe

7.1. Analysis

Comparison 7: Oral fish oil versus placebo, Outcome 1: Adverse event (severe) requiring withdrawal from study ‐ GI side effect

8.1. Analysis

Comparison 8: Oral nicardipine versus placebo, Outcome 1: Secondary outcome (lupus‐non‐specific): severity of Raynaud's attacks ‐ 150 mm visual analogue scale

8.2. Analysis

Comparison 8: Oral nicardipine versus placebo, Outcome 2: Secondary outcome (lupus‐non‐specific): number of Raynaud's attacks per day

8.3. Analysis

Comparison 8: Oral nicardipine versus placebo, Outcome 3: Adverse events: severe

8.4. Analysis

Comparison 8: Oral nicardipine versus placebo, Outcome 4: Adverse events: minor ‐ cardiovascular or GI side effect

9.1. Analysis

Comparison 9: Oral ginsenosides versus placebo, Outcome 1: Primary outcome (lupus‐specific): complete clearance of facial erythema

9.2. Analysis

Comparison 9: Oral ginsenosides versus placebo, Outcome 2: Primary outcome (lupus‐specific): complete clearance of aphthae

9.3. Analysis

Comparison 9: Oral ginsenosides versus placebo, Outcome 3: Primary outcome (lupus‐specific): complete clearance of erythema of hands

9.4. Analysis

Comparison 9: Oral ginsenosides versus placebo, Outcome 4: Primary outcome (lupus‐non‐specific): complete clearance of alopecia

9.5. Analysis

Comparison 9: Oral ginsenosides versus placebo, Outcome 5: Primary outcome (lupus‐non‐specific): complete clearance of oedema

9.6. Analysis

Comparison 9: Oral ginsenosides versus placebo, Outcome 6: Adverse events: minor ‐ side effect from medication

10.1. Analysis

Comparison 10: Intravenous rituximab versus placebo, Outcome 1: Adverse events: severe ‐ severe event not including death

10.2. Analysis

Comparison 10: Intravenous rituximab versus placebo, Outcome 2: Adverse events: severe ‐ death

11.1. Analysis

Comparison 11: Intravenous abatacept versus placebo, Outcome 1: Secondary outcome (lupus‐specific): BILAG A or B flare in discoid lesions

11.2. Analysis

Comparison 11: Intravenous abatacept versus placebo, Outcome 2: Secondary outcome (lupus‐specific): new BILAG A score for discoid lesions

11.3. Analysis

Comparison 11: Intravenous abatacept versus placebo, Outcome 3: Secondary outcome (lupus‐specific): new flare in discoid lesions (based on physician‐based assessment)

11.4. Analysis

Comparison 11: Intravenous abatacept versus placebo, Outcome 4: Adverse events: severe

12.1. Analysis

Comparison 12: Oral zileuton versus placebo, Outcome 1: Lupus‐non‐specific secondary outcome: SLAM score integument domain (mean change from baseline)

12.2. Analysis

Comparison 12: Oral zileuton versus placebo, Outcome 2: Adverse events: severe

13.1. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 1: Secondary outcome (lupus‐specific): proportion with "SLE flare" for combined doses vs placebo

13.2. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 2: Secondary outcome: proportion with improvement in "CLASI" at 200 mg dose

13.3. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 3: Secondary outcome: proportion with improvement in "CLASI" at 600 mg dose

13.4. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 4: Secondary outcome: proportion with improvement in "CLASI" at 1200 mg dose

13.5. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 5: Secondary outcome: proportion with improvement in "CLASI" at combined doses

13.6. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 6: Adverse events: severe (death)

13.7. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 7: Adverse events: all severe adverse events including death

13.8. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 8: Adverse events: all severe adverse events

13.9. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 9: Adverse events: minor ‐ pruritus, papular rash, or pruritic rash for combined doses

13.10. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 10: Adverse events: minor ‐ viral infection rash such as herpes zoster or herpes simplex for combined doses

13.11. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 11: Adverse events: minor for all doses combined

13.12. Analysis

Comparison 13: Intravenous sifalimumab versus placebo, Outcome 12: Adverse events: minor

14.1. Analysis

Comparison 14: Intravenous sirukumab versus placebo, Outcome 1: Adverse events: severe for combined doses vs placebo

14.2. Analysis

Comparison 14: Intravenous sirukumab versus placebo, Outcome 2: Adverse event: minor for combined doses vs placebo

15.1. Analysis

Comparison 15: Intravenous blisibimod versus placebo, Outcome 1: Adverse events: severe ‐ all severe events including death

16.1. Analysis

Comparison 16: intravenous epratuzumab versus placebo, Outcome 1: Adverse events

17.1. Analysis

Comparison 17: Intravenous atacicept versus placebo, Outcome 1: Adverse events: minor ‐ eczema, atacicept 3 mg/kg

17.2. Analysis

Comparison 17: Intravenous atacicept versus placebo, Outcome 2: Adverse events: minor ‐ local site reaction (redness, bruising, tenderness) for all doses combined

17.3. Analysis

Comparison 17: Intravenous atacicept versus placebo, Outcome 3: Adverse events: minor ‐ other minor reaction (not eczema or local site reaction)

18.1. Analysis

Comparison 18: Subcutaneous tabalumab versus placebo, Outcome 1: Adverse events

19.1. Analysis

Comparison 19: Oral baricitinib versus placebo, Outcome 1: Adverse events

20.1. Analysis

Comparison 20: Intravenous and subcutaneous ustekinumab versus placebo, Outcome 1: Secondary outcome: CLASI activity score: greater than 50% improvement from baseline

20.2. Analysis

Comparison 20: Intravenous and subcutaneous ustekinumab versus placebo, Outcome 2: Adverse events

21.1. Analysis

Comparison 21: Topical R932333 versus placebo vehicle, Outcome 1: Adverse events

22.1. Analysis

Comparison 22: Subcutaneous lulizumab versus placebo, Outcome 1: Adverse events

23.1. Analysis

Comparison 23: Intravenous belimumab versus intravenous belimumab dose comparison, Outcome 1: Adverse events: severe, 1 mg/kg vs 10 mg/kg

23.2. Analysis

Comparison 23: Intravenous belimumab versus intravenous belimumab dose comparison, Outcome 2: Adverse events: skin and subcutaneous tissue, 1 mg/kg vs 4 mg/kg

23.3. Analysis

Comparison 23: Intravenous belimumab versus intravenous belimumab dose comparison, Outcome 3: Adverse events: skin and subcutaneous tissue, 1 mg/kg vs 10 mg/kg

23.4. Analysis

Comparison 23: Intravenous belimumab versus intravenous belimumab dose comparison, Outcome 4: Adverse events: skin and subcutaneous tissue, 4 mg/kg vs 10 mg/kg

24.1. Analysis

Comparison 24: Intravenous atacicept versus intravenous atacicept dose comparison, Outcome 1: Adverse events: minor ‐ eczema

24.2. Analysis

Comparison 24: Intravenous atacicept versus intravenous atacicept dose comparison, Outcome 2: Adverse events: other minor adverse event (not eczema or local site reaction)

25.1. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 1: Secondary outcome: proportion with improvement in "CLASI" at 200 mg dose vs 600 mg dose

25.2. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 2: Secondary outcome: proportion with improvement in "CLASI" at 600 mg dose vs 1200 mg dose

25.3. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 3: Secondary outcome: proportion with improvement in "CLASI" at 200 mg dose vs 1200 mg dose

25.4. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 4: Adverse events: severe ‐ all, including death at 200 mg dose vs 600 mg dose

25.5. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 5: Adverse events: severe ‐ all, including death at 600 mg dose vs 1200 mg dose

25.6. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 6: Adverse events: severe ‐ all, including death at 200 mg dose vs 1200 mg dose

25.7. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 7: Adverse events: severe ‐ all, including death at 0.3 mg/kg dose vs 1 mg/kg dose

25.8. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 8: Adverse events: severe ‐ all, including death at 0.3 mg/kg dose vs 3 mg/kg dose

25.9. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 9: Adverse events: severe ‐ all, including death at 0.3 mg/kg dose vs 10 mg/kg dose

25.10. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 10: Adverse events: severe ‐ all, including death at 1 mg/kg dose vs 3 mg/kg dose

25.11. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 11: Adverse events: severe ‐ all, including death at 1 mg/kg dose vs 10 mg/kg dose

25.12. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 12: Adverse events: severe ‐ all, including death at 3 mg/kg dose vs 10 mg/kg dose

25.13. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 13: Adverse events: severe ‐ death at 0.3 mg/kg dose vs 1 mg/kg dose

25.14. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 14: Adverse events: severe ‐ death at 0.3 mg/kg dose vs 10 mg/kg dose

25.15. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 15: Adverse events: severe ‐ death at 1 mg/kg dose vs 3 mg/kg dose

25.16. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 16: Adverse events: severe ‐ death at 1 mg/kg dose vs 10 mg/kg dose

25.17. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 17: Adverse events: severe ‐ death at 3 mg/kg dose vs 10 mg/kg dose

25.18. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 18: Adverse events: minor ‐ zoster at 0.3 mg/kg dose vs 3 mg/kg dose

25.19. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 19: Adverse events: minor ‐ zoster at 0.3 mg/kg dose vs 10 mg/kg dose

25.20. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 20: Adverse events: minor ‐ zoster at 1 mg/kg dose vs 3 mg/kg dose

25.21. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 21: Adverse events: minor ‐ zoster at 1 mg/kg dose vs 10 mg/kg dose

25.22. Analysis

Comparison 25: Intravenous sifalimumab versus intravenous sifalimumab dose comparison, Outcome 22: Adverse events: minor ‐ zoster at 3 mg/kg dose vs 10 mg/kg dose

26.1. Analysis

Comparison 26: Oral clofazimine versus oral chloroquine, Outcome 1: Primary outcome (lupus‐specific): complete clearance of malar, SCLE, or discoid rash

26.2. Analysis

Comparison 26: Oral clofazimine versus oral chloroquine, Outcome 2: Primary outcome (lupus‐specific): partial clearance of malar, SCLE, or discoid rash

26.3. Analysis

Comparison 26: Oral clofazimine versus oral chloroquine, Outcome 3: Adverse events: severe ‐ severe flare in lupus requiring withdrawal from study

26.4. Analysis

Comparison 26: Oral clofazimine versus oral chloroquine, Outcome 4: Adverse events: minor

27.1. Analysis

Comparison 27: Oral ciclosporin versus oral azathioprine, Outcome 1: Primary outcome (lupus‐specific): complete clearance of malar rash (intent‐to‐treat analysis)

27.2. Analysis

Comparison 27: Oral ciclosporin versus oral azathioprine, Outcome 2: Primary outcome (lupus‐specific): complete clearance of oral ulcers (intent‐to‐treat analysis)

27.3. Analysis

Comparison 27: Oral ciclosporin versus oral azathioprine, Outcome 3: Adverse events: all severe events combined

27.4. Analysis

Comparison 27: Oral ciclosporin versus oral azathioprine, Outcome 4: Adverse events: subset of severe adverse events due to lack of effect of medication only

27.5. Analysis

Comparison 27: Oral ciclosporin versus oral azathioprine, Outcome 5: Adverse events: minor

28.1. Analysis

Comparison 28: Oral methotrexate versus oral chloroquine, Outcome 1: Primary outcome (lupus‐specific): complete clearance of skin rash (ITT analysis)

28.2. Analysis

Comparison 28: Oral methotrexate versus oral chloroquine, Outcome 2: Primary outcome (lupus‐specific): complete clearance of skin rash (authors' per‐protocol analysis)

28.3. Analysis

Comparison 28: Oral methotrexate versus oral chloroquine, Outcome 3: Primary outcome (lupus‐specific): complete clearance of skin rash during 6 month study (subset of patients with skin findings at baseline)

28.4. Analysis

Comparison 28: Oral methotrexate versus oral chloroquine, Outcome 4: Adverse events

29.1. Analysis

Comparison 29: Oral mycophenolate versus azathioprine or dapsone, Outcome 1: Primary outcome (lupus‐specific): partial improvement

29.2. Analysis

Comparison 29: Oral mycophenolate versus azathioprine or dapsone, Outcome 2: Adverse events

30.1. Analysis

Comparison 30: Oral Zi Shen Qing (Chinese herbal medicine) versus hydroxychloroquine, Outcome 1: Adverse events: severe

30.2. Analysis

Comparison 30: Oral Zi Shen Qing (Chinese herbal medicine) versus hydroxychloroquine, Outcome 2: Adverse events: minor

31.1. Analysis

Comparison 31: Intravenous ciclosporin A plus steroids versus intravenous steroids alone, Outcome 1: Primary outcome (lupus‐specific): complete resolution of erythematous manifestations

31.2. Analysis

Comparison 31: Intravenous ciclosporin A plus steroids versus intravenous steroids alone, Outcome 2: Adverse events

32.1. Analysis

Comparison 32: Intravenous rituximab versus intravenous cyclophosphamide, Outcome 1: Adverse events: minor ‐ cutaneous rash, itching

33.1. Analysis

Comparison 33: "Early treatment" (serology) with prednisone and/or cytotoxic agents versus "later treatment" (clinical flare), Outcome 1: Adverse events: minor

33.2. Analysis

Comparison 33: "Early treatment" (serology) with prednisone and/or cytotoxic agents versus "later treatment" (clinical flare), Outcome 2: Adverse events: severe

34.1. Analysis

Comparison 34: Intravenous pulse high‐dose cyclophosphamide versus intravenous monthly lower‐dose cyclophosphamide, Outcome 1: Adverse events: severe ‐ death

34.2. Analysis

Comparison 34: Intravenous pulse high‐dose cyclophosphamide versus intravenous monthly lower‐dose cyclophosphamide, Outcome 2: Adverse events: severe ‐ infection, cardiac arrest (not including death)

35.1. Analysis

Comparison 35: Topical tacrolimus versus topical clobetasol, Outcome 1: Primary outcome (lupus‐specific): erythema

35.2. Analysis

Comparison 35: Topical tacrolimus versus topical clobetasol, Outcome 2: Primary outcome (lupus‐specific): desquamation

35.3. Analysis

Comparison 35: Topical tacrolimus versus topical clobetasol, Outcome 3: Primary outcome (lupus‐specific): skin induration