What are the benefits and risks of different treatments for skin disease in people with systemic lupus erythematosus (an autoimmune disease that affects the whole body)

Why is this question important?

Systemic lupus erythematosus (SLE; also known as ‘lupus’) is a disease in which the body's immune (defence) system mistakenly attacks healthy tissue in many parts of the body. It affects 7.5 million people worldwide. Around 70% of affected people develop skin problems such as rash on the nose or cheeks. Often, SLE also causes pain in joints and muscles and extreme tiredness. Symptoms can improve temporarily, or they can worsen suddenly (flares). In severe cases, SLE can cause life-threatening damage to the heart, lungs, brain, or kidneys.

There is no cure for SLE. However, there are treatments designed to improve symptoms. In particular, there are a range of options for treating skin problems.

• Medicines that can be taken by mouth (orally), applied as creams, or given as injections.

• Therapies to help people cope with their skin problems, such as talking therapies.

• Other approaches, including herbal medicine, light therapy, or make-up.

To find out which treatments work best for people with SLE, and to compare adverse (unwanted) effects, we reviewed the evidence from research studies.

How did we identify and evaluate the evidence?

We searched the medical literature for studies that compared any treatment for skin disease in SLE against:

• a placebo (dummy) treatment;

• no treatment;

• another treatment; or

• a different dose of the same treatment.

We compared the results and summarised the evidence from all the studies. Finally, we rated our confidence in the evidence based on factors such as study methods and sizes and the consistency of findings across studies.

What did we find?

We found 61 studies that included 11,232 people (mostly women) and investigated 43 different treatments. Most treatments lasted one year, and people were followed for up to 48 months.

Here we report the main findings of our review on the effects of five different oral medicines: hydroxychloroquine, chloroquine, methotrexate, ciclosporin, and azathioprine.

Disappearance of skin problems

We do not know if hydroxychloroquine is better or worse than placebo at making skin problems disappear because no studies reported information about this.

The evidence suggests that:

• chloroquine may be better at making skin problems disappear after 12 months than placebo (1 study, 24 people);

• when we compare methotrexate and choloroquine, there may be little to no difference in how often they make skin rashes disappear after six months (1 study, 25 people);

• methotrexate may be better for making skin rashes disappear after six months than placebo (1 study, 41 people); and

• there may be little to no difference in how often skin problems disappear after 12 months between ciclosporin and aziathropine (1 study, 25 people).

Partial disappearance of skin problems (at least 50% improvement in the skin condition)

It is unclear if hydroxycholoroquine is better or worse than placebo at making skin problems disappear at least partially after 12 months. This is because the evidence is too imprecise (1 study, 20 pregnant women).

No other studies have examined how treatments affect the partial disappearance of skin problems.

Flares

The evidence suggests that after six months, fewer flares probably occur with hydroxychloroquine than with placebo (1 study, 47 people).

It is unclear if flares are more, or less, likely to occur after 12 months with methotrexate compared to placebo (1 study, 86 people).

No other studies have reported information on how treatments affect flares.

Adverse events

Evidence is often imprecise, and whether treatments lead to more or fewer adverse events than placebo or other treatments is not clear.

We found limited data for adverse events, and reports were discrepant, but hydroxychloroquine, chloroquine, and methotrexate have well-known adverse effects including stomach and liver problems. Hydroxychloroquine and chloroquine can cause eye problems, and methotrexate can cause serious harm to a developing baby if taken during pregnancy.

Other outcomes

We do not know how treatments affect other aspects of disease severity or quality of life. This is because studies did not report information on this.

What does this mean?

When compared against a placebo, studies in people with SLE show that:

• fewer flares probably occur with hydroxychloroquine; and

• methotrexate and chloroquine may be better at making skin problems disappear.

Information about adverse effects is limited.

How up-to-date is this review?

The evidence in this Cochrane Review is current to June 2019.

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.

Read the full 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 strategy: 

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.

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