Update in Biologic Medications for Pediatric Rheumatic Disease

At the 2014 AAP National Conference & Exhibition in San Diego, CA, Carol A. Wallace, MD, reviewed the current state of biologics for treating pediatric rheumatic diseases, focusing mainly on juvenile idiopathic arthritis (JIA) with respect to pathophysiology, clinical outcomes, and recombinant protein technologies used in the development of biologic agents.

Wallace, a professor of Pediatrics at the University of Washington, Seattle Children’s Hospital, specializes in pediatric rheumatology. Her review of changes in practice included understanding the impact that biologic therapies have on children with rheumatic diseases, knowing the commonly used biologics used in pediatric rheumatic diseases, and partnering with pediatric rheumatologists to administer, monitor, and identify possible side effects of biologic medications.

She reviewed the pathogenesis of inflammatory arthritis with respect to histology, immunopathology (activated macrophages and T-cells), and inflammatory mediators, both pro-inflammatory and anti-inflammatory cytokines.

Currently, the majority of children with JIA continue to have active disease into childhood. Joint damage frequently occurs and is greatest in the first two years of the disease process. Although some 44% of patients achieve remission, most experience flares after two years off medication. Less than 10% are successfully off medications for more than 5 years.

Early therapy for inflammatory arthritis is critical for halting progression of structural damage to the tissues. The most effective treatments are the biologics, which also tend to have superior side-effect profiles compared to conventional drugs (gold, corticosteroids, NSAIDs, and antimetabolites like methotrexate) since biologics are more narrowly targeted.

Biologics are recombinant proteins that either mimic naturally occurring molecules (soluble molecules or receptors) or are antibodies to naturally occurring soluble molecules or receptors. Wallace reviewed clinical studies in JIA for etanercept (Enbrel), the first cytokine-specific anti-inflammatory biologic to be approved (a receptor-Fc fusion protein targeting TNF-α); the chimeric anti-TNF-α antibody infliximab (Remicade) and adalimumab (Humira). These agents require intravenous administration.

Wallace also drew attention to the fact that Enbrel was the first drug to be reviewed and approved under the FDA’s Pediatric Rule, promulgated in 1998. The importance of study design is demonstrated by the infliximab study in JIA. Not only were there unexpectedly large placebo responses but also the dosage for the age group was not optimized prior to study initiation. It was realized subsequently that the pediatric dose should have been double the recommended adult RA dose (3 mg/kg) since children metabolized and excreted the drug faster. As a result, the FDA reviewers were not able to approve Remicade for the pediatric indication.

Anti-TNF agents are powerful and effective therapies for JIA, showing marked improvement in signs and symptoms, marked decrease in disability, significant numbers of patients in remission, and normalization of inflammatory markers. They may also halt progression of signs of joint damage. However, since they are such powerful drugs, there are significant side effects such as injection/infusion reactions, infections and immunogenicity. There were fears that anti-TNF therapies might induce malignancies but most studies have not shown an increased risk.

There needs to be long-term monitoring of these drugs in JIA. However, there are multiple registries in the US, mainly specific to individual products and administered by the respective manufacturers. A single consolidated registry of all children is an urgent priority. The Childhood Arthritis and Rheumatology Research Alliance (CARRA) is promoting this initiative.

Wallace discussed some of the newer molecules that have been developed, some of which are quite complex molecules with other targets such as interleukin 1 (IL-1) or its receptor; canakinumab (Ilaris), rilonacept (Arcalyst), and anakinra (Kinaret), respectively. She also mentioned the humanized anti-IL-6 receptor binding antibody, tocilizumab (Actemra). Clinical trial data is emerging for biosimilars for etanercept and infliximab. Wallace listed a number of other agents under development with various biological targets.

Wallace ended with an appeal on behalf of pediatric rheumatologists to community pediatricians for partnerships to provide high-quality, coordinated patient care. This would involve help with orders for infusions at local facilities, the sharing of monitoring laboratories, and feedback from the pediatricians alerting the pediatric rheumatologists as to possible side effects and informing them of significant illnesses and/or hospitalizations.