Information on use of biologics to treat juvenile idiopathic arthritis (JIA) and other pediatric rheumatic diseases continues to increase due to new therapeutic agents, expanded Food and Drug Administration (FDA) approval and a better understanding of safety concerns.
Biologics are used more frequently and earlier in the disease course as research shows early aggressive treatment and “treat-to-target” strategies can lead to decreased disease burden and a significant number of children achieving clinically inactive disease (Giancane G, Ruperto N. Curr Opin Rheumatol. 2019;31:428-435).
The tumor necrosis factor inhibitors (TNF-I) etanercept, adalimumab and infliximab along with tocilizumab (IL-6 inhibitor), canakinumab (IL-1 inhibitor) and abatacept (T cell activation inhibitor) have been used successfully to treat arthritis in children. Over the past few years, several other agents have become available.
Previously approved biologics
Among biologics, the TNF-I drugs available for JIA include three with published results (etanercept, adalimumab, infliximab). Infliximab is used in children with JIA but does not have an FDA indication. Both adalimumab and infliximab can be used to treat JIA-associated and idiopathic uveitis.
Though TNF-Is carry an FDA black box warning for increased risk of malignancy, no conclusive findings in pediatric populations have been determined from clinical trials or large-scale observational studies. A large retrospective study of patients with JIA, inflammatory bowel disease and psoriasis showed no significant difference in the incidence of malignancy in those with or without TNF-I exposure (Beukelman T, et al. Ann Rheum Dis. 2018;77:1012-1016).
Though used in psoriasis and psoriatic arthritis, TNF-Is paradoxically may induce or worsen psoriasis in patients with autoimmune arthritis (Li S, et al. J Psoriasis Psoriatic Arthritis. 2019;4:70-80).
The IL-6 inhibitor tocilizumab and IL-1 inhibitors anakinra and canakinumab are the most commonly prescribed biologic agents in systemic JIA (sJIA). Tocilizumab also is approved for polyarticular JIA. Anakinra is associated with hepatoxicity, but the injury is self-limited and abates within weeks of discontinuing the medication.
The FDA recently approved a new TNF-I (golimumab) to treat JIA. In addition, research has led to the approval of new therapies that target IL-17, IL-12/23 and janus kinases (JAKs). These interleukins are cytokines that mediate inflammation. JAKs transduce cytokine-mediated signals and function as catalysts in inflammation. These medications are widely used in adults and can be effective treatments for JIA resistant to standard therapies.
A phase 3 trial (JUNIPERA study) of secukinumab (IL-17 inhibitor) demonstrated significantly longer time to flare vs. placebo in patients with two subtypes of JIA — juvenile psoriatic arthritis and enthesitis-related arthritis (Ruperto N, et al. Abstract LB0004 presented at the European Alliance of Associations for Rheumatology 2021 Virtual Congress).
Another clinical trial is studying the use of ixekizumab (also targets IL-17) in these same two subtypes. Ustekinumab (targeting IL 12/23) is approved for the treatment of pediatric psoriasis and is being used off-label for juvenile psoriatic arthritis (Kellen R, et al. Pediatric Health Med Ther. 2016;7:109-120).
In September 2020, the FDA approved the JAK inhibitor (JAKi) tofacitinib for the treatment of JIA based on a phase 3 efficacy and safety study demonstrating a statistically significant lower occurrence of disease flare compared to placebo.
Infection risk and follow-up
Patients receiving biologic and JAKi therapy are at increased risk for infection, and precautions similar to those for immunocompromised children must be taken to reduce risk of infection.
Prior to starting these therapies, children should be evaluated for certain infections including tuberculosis. If a child develops a fever or infectious symptoms, biologic therapy should be held until the acute illness has subsided. Biologics and JAKi may be put on hold for children undergoing surgical procedures to decrease infection risk.
Children on biologic or JAKi therapy should receive age-appropriate vaccinations, but live vaccinations need to be given at least four weeks before starting biologics and avoided while children are taking biologics. Children with JIA should receive COVID-19 vaccine, if eligible, and follow recommendations from the Centers for Disease Control and Prevention and American College of Rheumatology related to boosters.
If patients are taking methotrexate and have well-controlled JIA, methotrexate may be held for one week after each dose of vaccine (or two weeks after a single-dose vaccine) to enable a more robust response (Curtis JR, et al. Arthritis & Rheumatology. 2021;73:e30-e45).
Pediatricians, rheumatologists, ophthalmologists and other providers must work together to coordinate care and manage the long-term risks of these medications.
Dr. Bembry is a fellowship trainee on the AAP Section on Rheumatology Executive Committee. Dr. Syverson is a member of the section’s executive committee.