More Data Needed on Using Biologics in Children, Review Says

A recent review explored the evidence of monoclonal antibodies (mAb) and fusion proteins (FP) to examine their safety and efficacy in the most common chronic inflammatory diseases in children—bronchial asthma, psoriasis, juvenile idiopathic arthritis (JIA), and chronic inflammatory bowel diseases (IBD).

These drugs are increasingly being used in children and adolescents, although not as first-line treatments, yet there is a lack of data on the pharmacology of mAbs and FPs in children. For instance, a dosage is given in “weight bands” and there is a lack of clarity about the extent to which data on adult dosages can be extrapolated to children, and about dosage increases during disease exacerbations.

Bronchial asthma (prevalence about 4%), psoriasis (about 0.7%), IBD (0.1%), and JIA (about 0.1%) are immune-mediated diseases involving interleukin (IL)-1; IL-6 is involved in JIA with systemic onset; and tumor necrosis factor-alpha (TNF) is involved some forms of JIA, psoriasis, and chronic IBD.

These cytokines can be selectively blocked by mAbs and FPs, more so than with conventional, nonspecific immunomodulatory drugs. However, they also carry the risk of adverse events (AEs) because the target antigens play an important part in the physiological immune response; while rare, these AEs may sometimes be severe, and can include infection, immune dysregulation, or tumors.

Researchers searched PubMed and other databases for randomized controlled trials with clinical primary end points and guidelines published up to December 10, 2018 that discussed mAbs and FPs approved for pediatric use.

Out of 620 mentions, 25 were high-quality trials, with 20 of them manufacturer-sponsored. Nine dealt with mAbs and FPs (omalizumab, adalimumab, etanercept, ustekinumab, infliximab, golimumab, anakinra, canakinumab, tocilizumab, and abatacept). In addition, there were 6 guidelines regarding the treatment of bronchial asthma, psoriasis, JIA, and chronic IBD.

The researchers said that, despite their finding that the studies suffer from qualitative weaknesses that make it difficult to assess the efficacy and safety, these drugs do represent a therapeutic option for children and adolescents in whom conventional immunomodulatory treatment is ineffective.

By disease, the researchers found the following:

Bronchial asthma

The indication for using omalizumab, which targets immunoglobulin E (IgE), is based on high-quality studies and is given only as a last step. The criteria are IgE-mediated asthma, positive skin test and in-vitro activity against a perennial airborne allergen, serum IgE concentration within the treatable range, and the elimination of avoidable allergen exposure.

In 4 studies (2 of them independent), preseason administration of omalizumab was effective in terms of reducing the number of exacerbations during the fall and spring.

In terms of safety, the authors could not speak specifically to children, but said in general, the most frequent AEs are headache and injection-site reactions. However, anaphylactic reactions can occur hours or days after the injection, even when the antibody has been tolerated for a year or more.

Psoriasis

In cases of moderate or severe psoriasis, systemic methotrexate or anti-TNFs such as adalimumab are indicated.

If there is insufficient response, ustekinumab (which targets IL-12 and IL-23) or etanercept is recommended. “The stated indication for adalimumab, etanercept, and ustekinumab is based partly on distorted data from high-quality studies,” the researchers said.

Regarding the use of other biologics as a last resort, data from high-quality studies are lacking for use in pediatrics. In adults, the following have proved effective: infliximab, certolizumab pegol, guselkumab (targeting IL-12, IL-23), ixekizumab, secukinumab (targeting IL-17A), and brodalumab (targeting IL-17 receptor A).

In studies of severe, refractory, chronic plaque psoriasis, the researchers said of a manufacturer-sponsored head-to-head study of adalimumab versus methotrexate, “the results are distorted by a too-low initial dose of methotrexate in the control group.”

Etanercept and ustekinumab were more effective than placebo, but there is little data on the safety of ustekinumab in pediatrics, the authors noted.

JIA and associated uveitis

No high-quality studies are available for the most common form of JIA, persistent oligoarticular JIA. For the polyarticular form, in 1 independent and 1 company-sponsored study of anti-TNF agents, the primary clinical endpoints were not reached.

In 1 independent study, adalimumab plus methotrexate was more effective in terms of an intraocular inflammation score than was methotrexate alone; etanercept was shown to be ineffective in a very small study.

Etanercept, adalimumab, infliximab, golimumab are usually well tolerated. The role played by biologics in tumor development is the subject of debate, because JIA is itself associated with an increased risk of cancer.

IL-1 and IL-6 blockers are less frequently used than TNF blockers, and the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) blockade even less often.

Severe infections and immune dysregulation have been reported, including 6 fatalities in a tocilizumab study and 4 in a canakinumab study in patients with systemic JIA; however, it is unclear whether there was a direct link to the study drugs.

Chronic IBD

The researchers said that, despite a lack of high-quality studies, anti-TNF agents (adalimumab, infliximab) are recommended for treatment and maintenance of remission if conventional immunomodulators fail for IBD.

For both Crohn disease and ulcerative colitis, infliximab and adalimumab can be used when other treatments have failed.

The use of mAbs and FPs can be justified after a calculation of the risks and benefits, the authors concluded.

The authors stressed the need for high-quality, independent trials initiated by researchers, along with long-term evaluations of AEs, such as tumors.

Reference

Niehues T, Özgür TT. The efficacy and evidence-based use of biologics in children and adolescents: Using monoclonal antibodies and fusion proteins as treatments.

Dtsch Arztebl Int. 2019;116:703-10. doi: 10.3238/arztebl.2019.0703.