What are the benefits and risks of belimumab for treating systemic lupus erythematosus (an autoimmune disease that affects the whole body)?


Why is this question important?

Systemic lupus erythematosus (SLE; or ‘lupus’) is a disease in which the body's immune (defense) system mistakenly attacks healthy tissue in many parts of the body. It is a long-term disease (one that lasts longer than six weeks and is usually life-long). Often, SLE causes pain in joints and muscles, and extreme tiredness. Symptoms can improve temporarily, or worsen suddenly (flares).

There is no cure for SLE. However, treatments can improve symptoms. Inflammation caused by lupus can affect the joints, skin, kidneys, blood cells, brain, heart, and lungs. Most people are treated with glucocorticoids (anti-inflammation medicines; also called "steroids/prednisone/medrol/solumedrol") at some point in their disease course. These medicines reduce the swelling and pain associated with inflammation, but they can have serious adverse (unwanted) effects, such as kidney damage. This is why it is important to study other treatment options, such as belimumab.

Belimumab is a human protein (antibody) that is given as an injection to decrease inflammation. In people with SLE, belimumab prevents the development and survival of the cells that attack the body’s healthy tissues (B cells). The aim of belimumab is to reduce the number of B cells, so that people’s symptoms improve.

To find out about the benefits and risks of belimumab, we reviewed the evidence from research studies. In particular, we wanted to know how belimumab affects:

- disease intensity;

- health-related quality of life;

- use of glucocorticoids; and

- adverse effects, including: serious effects (for example, diseases that affect kidneys or the nervous system), serious infections (since anti-inflammation medicines reduce the body’s ability to fight infections), adverse effects that led people to withdraw from studies, and death.


How did we identify and evaluate the evidence?

First, we searched the medical literature for studies that compared belimumab against a placebo (dummy) treatment or another SLE treatment. We then compared the results and summarized 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 six studies that involved a total of 2917 people (mostly women) aged between 22 and 80 years. People were followed for a minimum of 84 days and a maximum of 76 weeks. All studies compared belimumab against placebo.

Intensity of disease

Belimumab is better than placebo at reducing SLE intensity (4 studies, 2666 people). SLE became less intense in 52% of people treated with belimumab, compared to 39% of people treated with placebo.

Health-related quality of life

The evidence suggests that there is probably little to no difference between belimumab and placebo for changes in health-related quality of life (2 studies, 801 people). The quality of life scores reported by people treated with belimumab were only 1.6 points higher on average than those of people treated with placebo (scale: 0 to 100, higher scores = better quality of life).

Need for glucocorticoids (anti-inflammation medicines)

Belimumab is more likely than placebo to reduce the amount of glucocorticoids required. Glucocorticoid doses were lowered by at least 50% in 30% of people treated with belimumab, compared to 19% of people treated with placebo (2 studies, 537 people).

Serious adverse events

The evidence suggests that there may be little to no difference in the numbers of serious adverse events attributable to belimumab or placebo (5 studies, 2890 people). We have little confidence in this finding, because it is based on relatively small numbers of adverse events and studies reported conflicting findings.

Serious infection

The evidence suggests that there is probably little to no difference in the numbers of serious infections attributable to belimumab or placebo (4 studies, 2185 people). We are only moderately confident about this finding, because it is based on small numbers of infections.

Adverse events causing people to withdraw from studies

The evidence suggests that there is probably little to no difference between belimumab and placebo in the numbers of adverse events that caused people to withdraw from studies (5 studies, 2890 people). We are only moderately confident about this finding, because it is based on relatively small numbers of adverse events.

Death

Few deaths (less than 1%) were reported in association with either belimumab or placebo. This suggests that there may be little to no difference in numbers of deaths between the two treatments, though, because death occurs rarely, it is difficult to be confident about this finding.


What does this mean?

When compared against placebo:

- belimumab is more likely to reduce SLE disease activity, and to reduce the amount of glucocorticoids needed;

- belimumab probably makes little to no difference to: health-related quality of life improvement; numbers of serious adverse events; and deaths; and

- belimumab may make little to no difference to numbers of serious infections, and numbers of adverse events that cause people to withdraw from studies.


How-up-to date is this review?

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

Authors' conclusions: 

The six studies that provided evidence for benefits and harms of belimumab were well-designed, high-quality RCTs. At the FDA-approved dose of 10 mg/kg, based on moderate to high-certainty data, belimumab was probably associated with a clinically meaningful efficacy benefit compared to placebo in participants with SLE at 52 weeks. Evidence related to harms is inconclusive and mostly of moderate to low-certainty evidence. More data are needed for the longer-term efficacy of belimumab.

Read the full abstract...
Background: 

Belimumab, the first biologic approved for the treatment of systemic lupus erythematosus (SLE), has been shown to reduce autoantibody levels in people with SLE and help control disease activity.

Objectives: 

To assess the benefits and harms of belimumab (alone or in combination) in systematic lupus erythematosus.

Search strategy: 

An Information Specialist carried out the searches of CENTRAL, MEDLINE, Embase, CINAHL, Web of Science, the World Health Organization (WHO) International Clinical Trials Registry Platform, and clinicaltrials.gov from inception to 25 September 2019. There were no language or date restrictions.

Selection criteria: 

We included randomized controlled trials (RCTs) or controlled clinical trials (CCTs) of belimumab (alone or in combination) compared to placebo/control treatment (immunosuppressive drugs, such as azathioprine, cyclosporine, mycophenolate mofetil or another biologic), in adults with SLE.

Data collection and analysis: 

We used standard methodologic procedures expected by Cochrane.

Main results: 

Six RCTs (2917 participants) qualified for quantitative analyses. All included studies were multicenter, international or US-based. The age range of the included participants was 22 to 80 years; most were women; and study duration ranged from 84 days to 76 weeks. The risk of bias was generally low except for attrition bias, which was high in 67% of studies.

Compared to placebo, more participants on belimumab 10 mg/kg (Food and Drug Administration (FDA)-approved dose) showed at least a 4-point improvement (reduction) in Safety of Estrogen in Lupus National Assessment (SELENA) - Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, a validated SLE disease activity index: (risk ratio (RR) 1.33, 95% confidence interval (CI) 1.22 to 1.45; 829/1589 in belimumab group and 424/1077 in placebo; I2= 0%; 4 RCTs; high-certainty evidence).

Change in health-related quality of life (HRQOL), assessed by Short Form-36 Physical Component Summary score improvement (range 0 to 100), showed there was probably little or no difference between groups (mean difference 1.6 points, 95% CI 0.30 to 2.90; 401 in belimumab group and 400 in placebo; I2= 0%; 2 RCTs; moderate-certainty evidence). The belimumab 10 mg/kg group showed greater improvement in glucocorticoid dose, with a higher proportion of participants reducing their dose by at least 50% compared to placebo (RR 1.59, 95% CI 1.17 to 2.15; 81/269 in belimumab group and 52/268 in placebo; I2= 0%; 2 RCTs; high-certainty evidence).

The proportion of participants experiencing harm may not differ meaningfully between the belimumab 10 mg/kg and placebo groups: one or more serious adverse event (RR 0.87, 95% CI: 0.68 to 1.11; 238/1700 in belimumab group and 199/1190 in placebo; I2= 48%; 5 RCTs; low-certainty evidence; ); one or more serious infection (RR 1.01, 95% CI: 0.66 to 1.54; 44/1230 in belimumab group and 40/955 in placebo; I2= 0%; 4 RCTs; moderate-certainty evidence); and withdrawals due to adverse events (RR 0.82, 95% CI: 0.63 to 1.07; 113/1700 in belimumab group and 94/1190 in placebo; I2= 0%; 5 RCTs; moderate-certainty evidence). Mortality was rare, and may not differ between belimumab 10 mg/kg and placebo (Peto odds ratio 1.15, 95% CI 0.41 to 3.25; 9/1714 in belimumab group and 6/1203 in placebo; I2= 4%; 6 RCTs; low-certainty evidence).

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