What are the benefits and risks of anti-cytokine medicines for ANCA-associated vasculitis?

Why this question is important

The body’s defence (immune) system fights injury or infection by sending white blood cells to surround and protect the affected area. This causes redness and swelling, called inflammation.

Vasculitis is an inflammation of the blood vessels. In vasculitis, instead of reacting to harm, the immune system attacks healthy blood vessels. The reason for this reaction is often unknown.

One rare type of vasculitis is antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). AAV covers three different conditions that are grouped together because they all affect small blood vessels:

- MPA: microscopic polyangiitis;

- GPA: granulomatosis with polyangiitis; and

- EPGA: eosinophilic granulomatosis with polyangiitis.

The areas of the body most commonly affected are kidneys, lungs, joints, ears, nose and nerves. It is important to treat AAV early, to prevent serious damage to these organs.

Currently, the recommended treatment for AAV is to use medicines that control the immune system and medicines against inflammation (steroids). However, this treatment causes serious unwanted effects. Medicines that target cytokines (small molecules that influence the immune system’s reactions) are an alternative option. To evaluate the benefits and risks of anti-cytokine medicines, we reviewed the evidence from research studies.

How we identified and assessed the evidence

First, we searched for all relevant studies in the medical literature. We then compared the results, and summarised the evidence from all the studies. Finally, we assessed how certain the evidence was. We considered factors such as the way studies were conducted, study sizes, and consistency of findings across studies. Based on our assessments, we categorized the evidence as being of very low, low, moderate or high certainty.

What we found

We found four studies on a total of 440 adults from the USA and Europe. The average age of people ranged between 48 and 56 years. They received treatment for between 2 and 25 months, and were then followed for between 8 weeks and four years. Three studies compared anti-cytokine medicines (mepolizumab, belimumab and etanercept) to a placebo (fake medicine) and one study compared two different anti-cytokine medicines (rituximab versus infliximab). Three studies received at least partial funding from pharmaceutical companies.

Mepolizumab versus placebo in people with EGPA that returned after, or did not respond to, initial treatment

Moderate-certainty evidence indicates that mepolizumab probably reduces the likelihood of the disease returning within a year of treatment.

Low-certainty evidence suggests that mepolizumab:

- may make little or no difference to mortality;

- may increase the likelihood of the disease partially or fully disappearing for at least 24 weeks, and may increase the chances of this disappearance lasting for another six months at least;

- may make little or no difference to unwanted events, serious unwanted events or withdrawal from studies due to unwanted events.

The impact of mepolizumab on disease flare (worsening) is unknown, as this was not measured.

Etanercept or belimumab versus placebo in GPA and MPA

Moderate-certainty evidence indicates that etanercept probably makes little or no difference to disease flare.

Low-certainty evidence suggests that etanercept or belimumab may make little or no difference to:

- mortality;

- the disease fully disappearing for at least 24 weeks, or disappearance lasting at least another six months after that;

- the disease returning strongly;

- unwanted events or severe/serious unwanted events

Evidence of low certainty suggests that etanercept or belimumab may slightly increase chances of people withdrawing from studies due to unwanted events.

Infliximab versus rituximab, plus steroids and cytotoxic agents (substances that kill cells), in people with GPA that did not respond to other treatments

The one study we found was too small to assess the differences between treatments (very low-certainty evidence).

What this means

Mepolizumab probably reduces the likelihood of the disease returning within a year of treatment, and etanercept probably makes little or no difference to disease flare. We are less certain of the other potential benefits or risks of anti-cytokine medicines because the evidence is of low or very low certainty. Further research is likely to change the findings of this review.

How-up-to date is this review?

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

Authors' conclusions: 

We found four studies but concerns about risk of bias and small sample sizes preclude firm conclusions.

We found moderate-certainty evidence that in patients with relapsing or refractory EGPA, mepolizumab compared to placebo probably decreases disease relapse and low-certainty evidence that mepolizumab may increase the probability of accruing at least 24 weeks of disease remission. There were similar frequencies of total and serious AEs in both groups, but the study was too small to reliably assess these outcomes. Mepolizumab may result in little to no difference in mortality. However, there were very few events.

In participants with GPA (and a small subgroup of participants with MPA), etanercept or belimumab may increase the probability of withdrawal due to AEs and may have little to no impact on serious AEs. Etanercept may have little or no impact on durable remission and probably does not reduce disease flare.

Read the full abstract...
Background: 

Anti-neutrophilic cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) are a group of rare auto-inflammatory diseases that affects mainly small vessels. AAV includes: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). Anti-cytokine targeted therapy uses biological agents capable of specifically targeting and neutralising cytokine mediators of the inflammatory response.

Objectives: 

To assess the benefits and harms of anti-cytokine targeted therapy for adults with AAV.

Search strategy: 

We searched the Cochrane Central Register of Controlled Trials (2019, Issue 7), MEDLINE and Embase up to 16 August 2019. We also examined reference lists of articles, clinical trial registries, websites of regulatory agencies and contacted manufacturers.

Selection criteria: 

Randomised controlled trials (RCTs) or controlled clinical trials of targeted anti-cytokine therapy in adults (18 years or older) with AAV compared with placebo, standard therapy or another modality and anti-cytokine therapy of different type or dose.

Data collection and analysis: 

We used standard methodological procedures expected by Cochrane.

Main results: 

We included four RCTs with a total of 440 participants (mean age 48 to 56 years). We analysed the studies in three groups: 1) mepolizumab (300 mg; three separate injections every four weeks for 52 weeks) versus placebo in participants with relapsing or refractory EGPA; 2) belimumab (10 mg/kg on days 0, 14, 28 and every 28 days thereafter until 12 months after the last participant was randomised) or etanercept (25 mg twice a week) with standard therapy (median 25 months) versus placebo with standard therapy (median 19 months) in participants with GPA/MPA; and 3) infliximab (3 mg/kg on days 1 and 14, before the response assessment on day 42) versus rituximab (0.375g/m2 on days 1, 8, 15 and 22) in participants with refractory GPA for up to 12 months. None of the studies were assessed as low risk of bias in all domains: one study did not report randomisation or blinding methods clearly. Three studies were at high risk and one study was at unclear risk of bias for selective outcome reporting.

One trial with 136 participants with relapsing or refractory EGPA compared mepolizumab with placebo during 52 weeks of follow-up and observed one death in the mepolizumab group (1/68, 1.5%) and none in the placebo group (0/68, 0%) (Peto odds ratio (OR) 7.39, 95% confidence interval (CI) 0.15 to 372.38; low-certainty evidence). Low-certainty evidence suggests that more participants in the mepolizumab group had ≥ 24 weeks of accrued remission over 52 weeks compared to placebo (27.9% versus 2.9%; risk ratio (RR) 9.5, 95% CI 2.30 to 39.21), and durable remission within the first 24 weeks sustained until week 52 (19.1% mepolizumab versus 1.5% placebo; RR 13.0, 95% CI 1.75 to 96.63; number needed to treat for an additional beneficial outcome (NNTB) 6, 95% Cl 4 to 13). Mepolizumab probably decreases risk of relapse (55.8% versus 82.4%; RR 0.68, 95% CI 0.53 to 0.86; NNTB 4, 95% CI 3 to 9; moderate-certainty evidence). There was low-certainty evidence regarding similar frequency of adverse events (AEs): total AEs (96.9% versus 94.1%; RR 1.03, 95% CI 0.96 to 1.11), serious AEs (17.7% versus 26.5%; RR 0.67, 95% CI 0.35 to 1.28) and withdrawals due to AEs (2.9% versus 1.5%; RR 2.00, 95% CI 0.19 to 21.54). Disease flares were not measured.

Based on two trials with different follow-up periods (mean of 27 months for etanercept study; up to four years for belimumab study) including people with GPA (n = 263) and a small group of participants with MPA (n = 22) analysed together, we found low-certainty evidence suggesting that adding an active drug (etanercept or belimumab) to standard therapy does not increase or reduce mortality (3.4% versus 1.4%; Peto OR 2.45, 95% CI 0.55 to 10.97). Etanercept may have little or no effect on remission (92.3% versus 89.5%; RR 0.97, 95% CI 0.89 to 1.07), durable remission (70% versus 75.3%; RR 0.93, 95% CI 0.77 to 1.11; low-certainty evidence) and disease flares (56% versus 57.1%; RR 0.98, 95% CI 0.76 to 1.27; moderate-certainty evidence). Low-certainty evidence suggests that belimumab does not increase or reduce major relapse (1.9% versus 0%; RR 2.94, 95% CI 0.12 to 70.67) or any AE (92.5% versus 82.7%; RR 1.12, 95% CI 0.97 to 1.29). Low-certainty evidence suggests a similar frequency of serious or severe AEs (47.6% versus 47.6%; RR 1.00, 95% CI 0.80 to 1.27), but more frequent withdrawals due to AEs in the active drug group (11.2%) compared to the placebo group (4.2%), RR 2.66, 95% CI 1.07 to 6.59).

One trial involving 17 participants with refractory GPA compared infliximab versus rituximab added to steroids and cytotoxic agents for 12 months. One participant died in each group (Peto OR 0.88, 95% CI, 0.05 to 15.51; 11% versus 12.5%). We have very low-certainty evidence for remission (22% versus 50%, RR 0.44, 95% Cl 0.11 to 1.81) and durable remission (11% versus 50%, RR 0.22, 95% CI 0.03 to 1.60), any severe AE (22.3% versus 12.5%; RR 1.78, 95% CI 0.2 to 16.1) and withdrawals due to AEs (0% versus 0%; RR 2.70, 95% CI 0.13 to 58.24). Disease flare/relapse and the frequency of any AE were not reported.

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