The RCTs of biologic therapies in children with JIA have for the most part not raised any significant safety concerns [
32‐
46]. However, limitations of RCTs in the assessment of drug safety include the relatively low number of subjects enrolled and short trial duration, which limit the ability of these studies to detect rare events and long term side effects [
77]. Since TNFi are the oldest class of engineered biologics and the most widely used [
6], existing registries can provide ample real-world assessments of their safety, and these registries have indeed confirmed the safety of TNF inhibition in both the short and long terms [
32‐
42,
78‐
81]. For example, Giannini and colleagues followed 397 subjects over a three-year period who received etanercept either with or without MTX, reporting rates of SAEs that were similar to those seen in children taking MTX as mono-therapy [
81].
Whether TNFi are associated with an increased risk of malignancy in children is unclear. A recent study showed that children treated with etanercept had a higher incidence of Hodgkin’s lymphoma compared to the general population, as indicated by the Surveillance Epidemiology and End Results database [
82]. However, the interpretation of this finding is clouded by the increased baseline incidence of malignancy among children with JIA [
83,
84]. Furthermore, a study of children with Medicaid insurance evaluated from years 2000 – 2005 showed no malignancies among 1,484 patients treated with TNFi, over nearly 3,000 person-years of therapy [
83].
With respect to IL-1 inhibition, abatacept, tocilizumab, and rituximab, there is much less safety data, necessitating that the safety of these medicines either in other populations (e.g. adults with rheumatoid arthritis) or, in the case of rituximab, for other indications (e.g. children with idiopathic thrombocytopenic purpura), must be considered. None of the RCTs involving anakinra, canakinumab, and abatacept showed significant safety signals; likewise, the overall experience in adults with rheumatoid arthritis has shown anakinra and abatacept to be safe, with perhaps a decreased risk of serious adverse events compared even to TNFi [
85]. One study addressed findings of pulmonary complications of interstitial lung disease and pulmonary hypertension in patients with sJIA, concluding that this was likely associated with underlying disease characteristics rather than its treatment in most cases [
86]. Similarly, the limited experience in children with JIA has shown rituximab to be well-tolerated in this population, just as it was in a larger cohort of children with idiopathic thrombocytopenic purpura [
87]. In contrast, pediatric studies involving tocilizumab have revealed several safety concerns, including elevated liver function tests, lymphopenia, neutropenia, gastrointestinal hemorrhage, and possibly an increased risk of serious infections [
37,
43,
88]. Specifically, Yokota et al. (2008) reported “striking” elevations of liver function tests (alanine aminotransferase [ALT] of 676) in a child with Ebstein-Barr Virus infection along with a case of gastrointestinal hemorrhage in the double-blind phase, along with grade 2 elevations of ALT in 12/50 subjects during the 48-week open label extension phase [
37]. Likewise, de Benedetti et al. (2012) reported ALT elevations above 2.5 times the upper limit of normal in 21 out of 112 tocilizumab-treated patients, along with neutrophil counts of less than 1 x 10
9 / liter in 17 patients and less than 0.5 x 10
9 in two patients. They also reported two serious infections among 75 tocilizumab-treated compared to none of 37 placebo-treated patients in the 12-week double blind phase [
43]. Some of these findings have also been seen in adult studies [
89]. Moreover, all of the biologics have been linked in case reports to rare but serious infections, including in the case of rituximab rare reports of progressive multifocal leukoencephalopathy [
90,
91]. Additionally, etanercept and chimeric antibodies administered intravenously, namely infliximab and rituximab, have been associated with anaphylactic reactions [
34,
92,
93]. Finally, TNFi have been linked with additional rare AEs, including induction of autoimmune diseases such as lupus [
94], psoriasis, cutaneous vasculitis, and multiple sclerosis [
95] and rare infections such as tuberculosis and histoplasmosis [
96]. Nevertheless, the overall benefit to side effect ratio of biologic agents used to treat JIA appears to be remarkably high.