Anti‐TNF agents for paediatric psoriasis Edited (no change to conclusions)
Psoriasis is a chronic skin disease that may develop at any age. Estimates for the United States and Europe suggest that psoriasis accounts for 4% of skin diseases in children. In most cases, the condition is mild and can be treated with creams. However, a small percentage of children have moderate to severe disease that requires drugs, such as ciclosporin or methotrexate, and some will require injections with newer biological agents, such as anti‐TNF (tumour necrosis factor) drugs. Anti‐TNF drugs (among them etanercept, infliximab, and adalimumab) are designed to reduce inflammation in the body caused by tumour necrosis factor. Evidence for the safety and efficacy of these biological agents in paediatric psoriasis is lacking.Objectives
To assess the efficacy and safety of anti‐TNF agents for the treatment of paediatric psoriasis.Search methods
We searched the following databases up to July 2015: the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL; 2015, Issue 6), MEDLINE (from 1946), Embase (from 1974), and LILACS (from 1982). We also searched 13 trials registers and checked the reference lists of included studies and key review articles for further references to relevant randomised controlled trials (RCTs). We handsearched conference proceedings and attempted to contact trial authors and relevant pharmaceutical manufacturers. We searched the US Food and Drug Administration's and European Medicines Agency's adverse effects databases.Selection criteria
All relevant RCTs that evaluated the efficacy and safety of anti‐TNF agents for the treatment of chronic plaque psoriasis in individuals less than 18 years of age.Data collection and analysis
Two review authors independently checked titles and abstracts and performed data extraction and 'Risk of bias' assessment of the included studies. One review author entered data into Review Manager (RevMan), and a second review author checked the data. We also attempted to obtain unclear data from the trial authors where possible.
Our primary outcomes were investigator‐assessed number of participants achieving a 75% improvement in Psoriasis Area and Severity Index‐75 (PASI 75) compared to baseline, improvement in quality of life using an instrument such as Children's Dermatology Life Quality Index (CDLQI), and adverse effects. Our secondary outcomes included the proportion of participants achieving PASI 50 and the Physician's Global Assessment (PGA).Main results
We included one study with 211 participants (median age 13 years), in which etanercept (dosage ranged from 0.8 to 50 mg per kilogram of body weight) was compared to placebo. Follow‐up was over a 48‐week period.
At week 12, 57% versus 11% who received etanercept or placebo, respectively, achieved the PASI 75 (risk ratio 4.95, 95% confidence interval (CI) 2.83 to 8.65; high‐quality evidence). Absolute risk reduction and the number needed to treat to obtain a benefit with etanercept was 45% (95% CI 33.95 to 56.40) and 2 (95% CI 1.77 to 2.95), respectively.
The percentage improvement from baseline of the CDLQI scores at week 12 was better in the etanercept group than the placebo group (52.3% versus 17.5%, respectively (P = 0.0001)). Analysis between the groups showed an effect size that was clinically important (mean difference 2.30, 95% CI 0.85 to 3.75; high‐quality evidence). However, means, medians, and minimal important difference results and results of the Pediatric Quality of Life Inventory, Stein Impact on Family Scale, and Harter Self‐Perception Profile for Children scores must be interpreted with caution, as they were not prespecified outcomes.
Three serious adverse events were reported, but they were resolved without sequelae. Deaths or other events such as malignant tumours, opportunistic infections, tuberculosis, or demyelination were not reported in the included study.
Also, 13% of participants in the placebo group and 53% in the etanercept group had a PGA of clear or almost clear (risk ratio 3.96, 95% CI 2.36 to 6.66; high‐quality evidence) at week 12.Authors' conclusions
This review found only one RCT evaluating the use of this type of biological therapy. Although the risk of publication bias was high, as we included only one industry‐sponsored RCT, the risk of allocation, selection, performance, attrition, and selective reporting biases for all outcomes (except for CDLQI) was low, and no short‐term serious adverse events were found.
We can conclude, based on this single included study, that etanercept seems to be efficacious and safe (at least in the short term) for the treatment of paediatric psoriasis. However, as the GRADE approach refers not to individual studies but to a body of evidence, we shall wait for the results of the ongoing studies in a future update of this review. In addition, future studies should evaluate quality‐of‐life endpoints established a priori and standardise primary outcome measures such as PASI 75, and should include the PGA as a secondary endpoint. Also, collating and reporting adverse events uniformly is required to better evaluate safety.
Gloria Sanclemente, Ruth Murphy, Javier Contreras, Hermenegildo García, Xavier Bonfill Cosp
Plain language summary
Anti‐TNF agents for paediatric psoriasis
Psoriasis is a long‐term skin disease that may develop at any age. Estimates for the United States and Europe suggest that psoriasis accounts for 4% of skin diseases in children. In most cases, the condition is mild and can be treated with creams. However, a small percentage of children have moderate to severe disease that requires drugs, such as ciclosporin or methotrexate, and some will require injections with newer biological agents, such as anti‐TNF (tumour necrosis factor) drugs. Anti‐TNF drugs (among them etanercept, infliximab, and adalimumab) are designed to reduce inflammation in the body caused by tumour necrosis factor.
Are anti‐TNF drugs such as etanercept, infliximab, and adalimumab safe and effective for treating moderate to severe psoriasis in children under 18 years of age?
We searched for all randomised controlled trials (RCTs) that assessed the efficacy and safety of anti‐TNF agents for the treatment of long‐term plaque psoriasis in individuals younger than 18 years of age. We searched databases up to July 2015. Only one study (with three phases: a 12‐week randomised, double‐blind, placebo‐controlled phase; a 24‐week open‐label phase, and a 12‐week phase of a randomised, double‐blind, withdrawal–retreatment design) investigating one anti‐TNF agent (etanercept) in 211 participants met the inclusion criteria.
Evidence from this single included study suggests that by week 12 etanercept reduced the extent of the psoriasis in children when compared with placebo. Although a few adverse events were reported, they were resolved without subsequent problems. We did not find any evidence on long‐term side effects of this drug from this included study.
Quality of the evidence
Although this one RCT provided high‐quality evidence for the Physician's Global Assessment and all Psoriasis Area and Severity Index scores (75, 90, and 50) and moderate‐quality evidence for quality‐of‐life outcomes, we found no further randomised studies either evaluating etanercept or comparing other anti‐TNF agents, highlighting the need for further well‐designed randomised studies involving the use of biological therapies in children and young people with psoriasis. Several studies are ongoing that have not yet been completed or published. We plan to include the results of these in future updates of this review.
Gloria Sanclemente, Ruth Murphy, Javier Contreras, Hermenegildo García, Xavier Bonfill Cosp
Implications for practice
Except for the quality‐of‐life outcomes, the quality of evidence of the sole RCT that evaluated the use of this kind of biological therapy was high. This review has concluded that the anti‐TNF agent etanercept is effective in improving psoriasis in a paediatric population as assessed by PASI 75, 50, and 90 and PGA. During the open‐label treatment, three serious adverse events were observed, but all these adverse events were resolved without sequelae or death. Although no serious adverse events were reported in the other phases of the study, mid‐ and long‐term safety were not evaluated.
The GRADE approach refers not to individual studies but to a body of evidence. As this review assessed the quality of evidence of just one individual trial, so far we cannot make a full recommendation for the use of anti‐TNF agents in paediatric psoriasis. We shall therefore wait for the results of the ongoing studies, as the conclusions of this review may be altered once they are available for inclusion in a future update.
Implications for research
A significant aspect of drug trials is to assess safety alongside efficacy. Well‐designed RCTs assessing the safety (both short and long term) of biological therapies in paediatric psoriasis as one of the main objectives are therefore needed in order to provide high‐quality evidence to ease clinical decision‐making. Furthermore, efficacy and safety trials with a sufficient number of younger participants (less than 11 years old) are also required, as current evidence applies mostly to older children.
Although other RCTs are ongoing, a lack of standardisation of outcomes and time‐frames between studies will impact any meta‐analyses of future evidence in this field. It is therefore necessary to take these factors into account when designing trials in this population in the future. Future studies should preferably consider the following.
- PASI 75 and PGA as main outcomes (unless a better and validated measurement tool arises), as well as quality of life and short‐ and long‐term adverse effects.
- Given the high cost of these therapies, it would be useful to collect information on cost of treatment.
- Standardised outcome measures among RCTs would make studies easier to compare.
- More advanced statistical methods should be investigated to report adverse events, and such results need to be presented in a format that is readily understood by clinicians.
- We believe that head‐to‐head RCTs evaluating the effectiveness of biologics and classical systemic treatments in paediatric psoriasis would be worthwhile.
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