Systemic treatments for eczema: a network meta‐analysis
Eczema is a common and chronic, relapsing, inflammatory skin disorder. It seriously impacts quality of life and economic outcomes, especially for those with moderate to severe eczema. Various treatments allow sustained control of the disease; however, their relative benefit remains unclear due to the limited number of trials directly comparing treatments.
To assess the comparative efficacy and safety of different types of systemic immunosuppressive treatments for moderate to severe eczema using NMA and to generate rankings of available systemic immunosuppressive treatments for eczema according to their efficacy and safety.
We searched the following databases up to August 2019: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase.
All randomised controlled trials (RCTs) of systemic immunosuppressive agents for moderate to severe atopic eczema when compared against placebo or any other eligible eczema treatment.
Data collection and analysis
We synthesised data using pair‐wise analysis and NMA to compare treatments and rank them according to their effectiveness.
Effectiveness was assessed primarily by determining the proportion of participants who achieved at least 75% improvement in the Eczema Area and Severity Index (EASI75) and improvement in the Patient‐Oriented Eczema Measure (POEM). Safety was evaluated primarily by considering the proportion of participants with serious adverse events (SAEs) and infection.
We deemed short‐term follow‐up as ≤ 16 weeks and long‐term follow‐up as > 16 weeks.
We assessed the certainty of the body of evidence from the NMA for these primary outcomes using six domains of CiNEMA grading.
We included a total of 74 studies, with 8177 randomised participants. Approximately 55% of participants were male, with average age of 32 years (range 2 to 84 years), although age and gender were unreported for 419 and 902 participants, respectively. Most of the included trials were placebo controlled (65%), 34% were head‐to‐head studies (15% assessed the effects of different doses of the same drug), and 1% were multi‐armed studies with both an active comparator and a placebo.
All trials included participants with moderate to severe eczema, but 62% of studies did not separate data by severity; 38% of studies assessed only severe eczema. The total duration of included trials ranged from 2 weeks to 60 months, whereas treatment duration varied from a single dose (CIM331, KPL‐716) to 60 months (methotrexate (MTX)).
Seventy studies were available for quantitative synthesis; this review assessed 29 immunosuppressive agents from three classes of interventions. These included (1) conventional treatments, with ciclosporin assessed most commonly; (2) small molecule treatments, including phosphodiesterase (PDE)‐4 inhibitors, tyrosine kinase inhibitors, and Janus kinase (JAK) inhibitors; and (3) biological treatments, including anti‐CD31 receptors, anti‐interleukin (IL)‐22, anti‐IL‐31, anti‐IL‐13, anti‐IL‐12/23p40, anti‐OX40, anti‐TSLP, anti‐CRTH2, and anti‐immunoglobulin E (IgE) monoclonal antibodies, but most commonly dupilumab.
Most trials (73) assessed outcomes at a short‐term duration ranging from 2 to 16 weeks, whereas 33 trials assessed long‐term outcomes, with duration ranging from 5 to 60 months. All participants were from a hospital setting. Fifty‐two studies declared a source of funding, and of these, pharmaceutical companies funded 88%. We rated 37 studies as high risk; 21, unclear risk, and 16, low risk of bias, with studies most commonly at high risk of attrition bias.
Network meta‐analysis suggests that dupilumab ranks first for effectiveness when compared with other biological treatments. Dupilumab is more effective than placebo in achieving EASI75 (risk ratio (RR) 3.04, 95% confidence interval (CI) 2.51 to 3.69) and improvement in POEM score (mean difference 7.30, 95% CI 6.61 to 8.00) at short‐term follow‐up (high‐certainty evidence).
Very low‐certainty evidence means we are uncertain of the effects of dupilumab when compared with placebo, in terms of the proportion of participants who achieve EASI75 (RR 2.59, 95% CI 1.87 to 3.60) at longer‐term follow‐up.
Low‐certainty evidence indicates that tralokinumab may be more effective than placebo in achieving short‐term EASI75 (RR 2.54, 95% CI 1.21 to 5.34), but there was no evidence for tralokinumab to allow us to assess short‐term follow‐up of POEM or long‐term follow‐up of EASI75.
We are uncertain of the effect of ustekinumab compared with placebo in achieving EASI75 (long‐term follow‐up: RR 1.17, 95% CI 0.40 to 3.45; short‐term follow‐up: RR 0.91, 95% CI 0.28 to 2.97; both very low certainty). We found no evidence on ustekinumab for the POEM outcome.
We are uncertain whether other immunosuppressive agents that targeted our key outcomes influence the achievement of short‐term EASI75 compared with placebo due to low‐ or very low‐certainty evidence.
Dupilumab and ustekinumab were the only immunosuppressive agents evaluated for longer‐term EASI75. Dupilumab was the only agent evaluated for improvement in POEM during short‐term follow‐up.
Low‐ to moderate‐certainty evidence indicates a lower proportion of participants with SAEs after treatment with QAW039 and dupilumab compared to placebo during short‐term follow‐up, but low‐ to very low‐certainty evidence suggests no difference in SAEs during short‐term follow‐up of other immunosuppressive agents compared to placebo.
Evidence for effects of immunosuppressive agents on risk of any infection during short‐term follow‐up and SAEs during long‐term follow‐up compared with placebo was of low or very low certainty but did not indicate a difference.
We did not identify differences in other adverse events (AEs), but dupilumab is associated with specific AEs, including eye inflammation and eosinophilia.
Our findings indicate that dupilumab is the most effective biological treatment for eczema. Compared to placebo, dupilumab reduces eczema signs and symptoms in the short term for people with moderate to severe atopic eczema. Short‐term safety outcomes from clinical trials did not reveal new safety concerns with dupilumab. Overall, evidence for the efficacy of most other immunosuppressive treatments for moderate to severe atopic eczema is of low or very low certainty.
Given the lack of data comparing conventional with newer biological treatments for the primary outcomes, there remains high uncertainty for ranking the efficacy and safety of conventional treatments such as ciclosporin and biological treatments such as dupilumab.
Most studies were placebo‐controlled and assessed only short‐term efficacy of immunosuppressive agents. Further adequately powered head‐to‐head RCTs should evaluate comparative long‐term efficacy and safety of available treatments for moderate to severe eczema.
Ratree Sawangjit, Piyameth Dilokthornsakul, Antonia Lloyd-Lavery, Nai Ming Lai, Robert Dellavalle, Nathorn Chaiyakunapruk
Plain language summary
Which oral or injected medicines work best to treat moderate to severe eczema?
Why this question is important
Eczema is a persistent condition that causes dry, cracked, and itchy skin. People with mild eczema have small patches of dry skin, and people with moderate eczema have larger, redder, or swollen areas of skin. People with severe eczema have red crusts and broken skin (which may ooze fluid) that develop all over the body.
Although there is currently no cure for eczema, treatments that aim to relieve symptoms are available. Usually, the first treatment option is to apply creams, ointments, or liquids to the affected skin. If this does not work, it is possible to take oral or injected (systemic) medicines that work throughout the body.
Many systemic medicines are available for eczema. To help people decide which one is most appropriate for managing their symptoms, we reviewed the evidence on benefits and risks of different systemic medicines for people with moderate or severe eczema. We particularly wanted to find out:
• whether some medicines were more likely than others to have an important positive effect on symptoms (defined as either at least a 75% improvement on the Eczema Area and Severity Index (EASI), or improvement on the Patient‐Oriented Eczema Measure (POEM)—two scales that are used by clinicians to evaluate changes in eczema symptoms); and
• whether some medicines are associated with more serious unwanted events, including infection, than others.
How we identified and assessed the evidence
First, we searched the medical literature for randomised controlled studies (studies where people are randomly divided into different treatment groups) because these studies provide the most robust evidence about the effects of a treatment. We then compared study results and summarised the evidence from all studies. Finally, we assessed how certain the evidence was. To do this, we considered factors such as the way studies were conducted, the size of studies, and the consistency of findings across studies. Based on our assessments, we categorised the evidence as being of very low, low, moderate, or high certainty.
What we found
We found 74 studies that involved a total of 8177 people with moderate to severe eczema. Studies lasted between 2 weeks and 60 months. Treatments received varied from a single, one‐off dose to weekly doses for 60 months. These studies evaluated 29 different medicines by comparing them to a placebo (fake treatment) or to another medicine, or by comparing different doses of the same medicine. The medicine that was studied most frequently was dupilumab (12 studies), a laboratory‐made version of a protein, which blocks parts of the immune system involved in causing eczema.
Dupilumab versus placebo
High‐certainty evidence shows that, compared to a placebo or other laboratory‐made proteins, dupilumab improves the symptoms of people with moderate to severe eczema in the short term (within 16 weeks of treatment). It is unclear whether this improvement is sustained after 16 weeks because no studies have looked at changes in POEM scores beyond that time, and because the evidence from studies that measured EASI scores was of very low certainty. Dupilumab may be associated with fewer serious unwanted events than placebo (low‐certainty evidence).
Other systemic medicines versus placebo
Evidence on the benefits and risks of other systemic medicines compared to placebo is limited because no studies have measured their effects on symptom improvement or serious unwanted effects, or because the certainty of the evidence is low or very low.
Comparing different systemic medicines with one another
Reviewers found too few studies that compared different systemic medicines against one another to determine which worked best for people with moderate to severe eczema.
What this means
Evidence shows that, compared to placebo, dupilumab improves the symptoms of people with moderate to severe eczema within 16 weeks of treatment and may be associated with fewer serious unwanted events.
Reviewers found too few robust studies to conclude whether dupilumab improves symptoms beyond 16 weeks, or whether this medicine works better than older systemic medicines. Future studies need to compare different systemic treatments beyond 16 weeks in people with moderate to severe eczema.
How up‐to‐date is this review?
The evidence in this Cochrane Review is current to August 2019.
Ratree Sawangjit, Piyameth Dilokthornsakul, Antonia Lloyd-Lavery, Nai Ming Lai, Robert Dellavalle, Nathorn Chaiyakunapruk
Implications for practice
With high certainty of available evidence, we conclude that dupilumab is the most effective of the biological treatments used to treat people with moderate to severe eczema, based on short‐term NMA of EASI75 and POEM. Dupilumab is safer than other agents based on short‐term safety data (≤ 16 weeks).
It is not currently possible to confidently rank the efficacy and safety of conventional immunosuppressive treatments for moderate to severe eczema compared with newer treatments such as biological agents for our primary efficacy and safety outcomes due to limited data.
Based on NMA, when compared to placebo, dupilumab increases the proportion of participants who achieve EASI75 and improves POEM score in the short term (high‐certainty evidence). We are uncertain of the effect of dupilumab on EASI75 in the long term due to very low‐certainty evidence. In addition, lack of long‐term outcome data after cessation of immunosuppressive treatment renders difficulty in drawing conclusion on the long‐term efficacy of any systemic treatment.
Based on NMA, when compared to placebo, tralokinumab may increase the proportion of patients who achieve EASI75 in the short term. Studies evaluating tralokinumab did not assess this outcome in the long term (low‐certainty evidence).
Due to very low‐certainty evidence, we are not certain of the effect of ustekinumab on the proportion of participants achieving EASI75 in the short or long term. This is based on NMA and comparison of ustekinumab to placebo.
Due to low‐ or very low‐certainty evidence, we cannot be sure how other immunosuppressive agents for which our key outcomes were assessed affect the proportion of patients achieving short‐term EASI75. These agents were compared against placebo.
The only immunosuppressive agent used to assess improvement in POEM score in the short term was dupilumab. Dupilumab and ustekinumab were the only immunosuppressive agents for which EASI75 was evaluated in the long term.
Based on low‐ to moderate‐certainty evidence, QAW039 and dupilumab show a lower proportion of participants with SAEs assessed in the short term when compared with placebo. However, no difference is seen in the proportion of participants with SAEs assessed in the short term when other immunosuppressive agents are compared to placebo (low‐ to very low‐certainty evidence).
Based on low‐ or very low‐certainty evidence, we found no evidence of a difference in risk of any infection (measured in the short or long term) or in the proportion of participants with SAEs assessed in the long term when immunosuppressive agents were compared with placebo.
We did not identify differences in other AEs, but dupilumab is associated with specific AEs, including eye inflammation and eosinophilia.
Implications for research
Despite high certainty of evidence for the efficacy of dupilumab in treating atopic eczema, little is known about its comparative efficacy and safety relative to other biological therapies or conventional systemic immunosuppressive treatments. More primary studies of dupilumab reporting head‐to‐head comparisons with other systemic immunosuppressive treatments are required to evaluate comparative safety and efficacy. In addition, most of the trials included in our network meta‐analysis were placebo controlled, which limited our ability to accurately estimate all of the effect sizes, especially those without direct comparison.
More primary studies with head‐to‐head comparisons are required to evaluate the comparative efficacy and safety of these treatments. More important, comparative studies are needed that investigate long‐term safety and longer‐term efficacy after systemic immunosuppressive treatment has ceased. Studies in children, for whom the burden of eczema is high, are also needed to evaluate safety and efficacy in this patient group.
These should ideally be adequately powered, randomised controlled trials that report on recommended core outcome domains to facilitate treatment comparisons, following the global Harmonizing Outcome Measures for Eczema (HOME) initiative to improve the evidence base.