What you need to know about biologic use in patients with JIA
MarlaGuzman, M.D., FAAP, TimothyHahn, M.D., FAAP and Kristen N.Hayward, M.D., FAAP
Treatment of juvenile idiopathic arthritis (JIA) with biologic agents has become routine
over the past two decades. In addition to tumor necrosis factor inhibitors (TNFi),
newer agents such as tocilizumab, canakinumab and abatacept have gained Food and Drug
Administration (FDA) approval for pediatric use. Multiple biologics also are used
for off-label indications in pediatric rheumatology.
Pediatricians caring for patients receiving these novel medications should be aware
of potential complications and implications for general health care maintenance.
Why start a biologic?
The focus of JIA treatment has shifted toward tight disease control and early complete
remission. The first step toward remission is to achieve a state of clinically inactive
disease (CID) where there are no objective findings of active systemic or joint inflammation.
In modern JIA cohorts, CID is achieved for more than 95% of children (Guzman J, et
al. Ann Rheum Dis. 2015;74:1854-1860). However, up to 40%-50% require a biologic to attain CID (Beukelman
T, et al. Pediatr Rheumatol Online J. 2017;15:30).
Prior to routine use of biologics, a significant number of children with JIA had active
disease years after onset, often associated with radiographic joint damage and functional
limitations. With the addition of biologics to routine care, long-term radiographic
joint damage occurs in as few as 5% of patients, and more than 90% have normal or
only mildly restricted functional ability (Nalbanti P, et al. Rheumatol Int.2018;38:1241-1250).
Historically, patients did not start a biologic until they had failed conventional
disease modifying anti-rheumatic drugs. While these medications continue to play an
important role in treatment, certain patients are likely to benefit from early introduction
of biologic medications.
For those with systemic JIA, early introduction of IL-1 inhibitors (anakinra or canakinumab)
or the IL-6 inhibitor (tocilizumab) have drastically improved outcomes, may halt the
development of chronic arthritis and can reduce complications related to chronic steroid
In other JIA subtypes, age younger than 6 years, more severe disease at onset, presence
of uveitis and symmetric polyarthritis all predict severe disease and the eventual
need for biologics. When these features are present, clinicians may choose to initiate
a biologic as part of first-line therapy.
Risk of malignancy
TNFi carry an FDA black box warning describing a potential association with malignancy.
However, the validity of this association has been controversial.
A large retrospective study of patients with JIA, inflammatory bowel disease and psoriasis
showed no significant difference in the standardized incidence ratio for incident
malignancy in those with or without TNFi exposure (Beukelman T, et al. Ann Rheum Dis. 2018;77:1012-1016). The data suggest that risk for malignancy may be associated
with an underlying auto-immune condition rather than secondary to TNFi treatment.
Though difficult to draw firm conclusions from cohort data, the malignancy association
with TNFi therapy also may be confounded by auto-immune disease severity (i.e., patients
requiring TNFi may have more severe underlying disease). Nevertheless, patients receiving
TNFi therapy undergo routine malignancy surveillance.
Infection risk and health care maintenance
Patients receiving biologics are at increased risk for common and certain opportunistic
infections. They also have unique considerations surrounding immunization schedules
and other aspects of routine pediatric care.
Overall, the odds of a serious infection resulting in hospitalization, intravenous
antibiotics use or death are increased by 37% with biologics use. Fortunately, the
most common infections reported in patients receiving TNFi involve relatively common
upper and lower respiratory tract, viral gastrointestinal and skin infections (Davies
H and the AAP Committee on Infectious Diseases. Pediatrics. 2016;138:e20161209).
The most common opportunistic infection associated with TNFi use is varicella reactivation,
although the absolute risk for opportunistic infections is very low in children (Mehta
J, et al. J Pediatr. 2017;189:31-39). Less common infections reported in children on TNFi include mycobacteria,
histoplasmosis, hepatitis B, Epstein-Barr virus and herpes simplex virus.
Patients on biologics should follow the same precautions as other immunocompromised
children, including adherence to the recommended vaccination schedule (including annual
influenza vaccine), but live vaccinations should not be administered during treatment.
When possible, live vaccinations should be administered at least four weeks before
starting treatment. Prior to initiating treatment, patients should be screened for
latent tuberculosis and hepatitis B immunity to determine the need for re-vaccination.
Consultation with an infectious disease specialist may be necessary.
Febrile or significant infections should prompt a temporary discontinuation of biologics
while evaluation and treatment are pursued. Biologics also may be held temporarily
around invasive surgeries to allow adequate wound healing and to prevent secondary
infection. An individualized approach is required to weigh the risks of underlying
disease flare with the risk of potential infectious complications.
Given the increasing use of biologics, a partnership between general pediatricians
and pediatric rheumatologists is required. General pediatricians are a vital link
between the child’s primary care needs and his/her autoimmune disease, particularly
in relation to infections and long-term risks related to therapy.
Drs. Guzman and Hahn are fellowship trainee members of the AAP Section on Rheumatology
Executive Committee. Dr. Hayward also is an executive committee member.