Carefully monitor patients on biologic response modifiers

H. Dele Davies, MD, MS, MHCM, FAAP,

Fatma Dedeoglu, MD

Biologic response modifiers (BRMs) are a growing part of the armamentarium for rheumatologists and subspecialists who treat immune-mediated diseases. The increased use of these agents extends into the pediatric population where they are most commonly used for the management of inflammatory bowel disease and juvenile idiopathic arthritis.

Although it is unlikely that pediatricians will be prescribing a BRM, it is important for them to understand the complications associated with BRM therapy because as frontline providers, pediatricians have an important role in helping to manage risk, said H. Dele Davies, MD, MS, MHCM, FAAP, at the American Academy of Pediatrics (AAP) 2018 National Conference and Exhibition, Orlando Florida.

A discussion of infectious complications associated with BRMs was a focus of his session titled “Biologic response modifiers: What they are and why you should know.” The session took place on Monday, November 5.

“Children who will be started on a BRM need to be carefully evaluated prior to initiation using a thorough history and appropriate screening tests to determine their level of risk and to guide decisions about ongoing follow-up and care,” says Davies, professor of Pediatric Infectious Diseases and Public Health, College of Medicine, University of Nebraska Medical Center, Omaha, Nebraska.

Davies says there is an increased risk for any type of infection in children on a BRM and that the risk for different types of infections varies across the different classes of BRMs. Most importantly, there is an increased risk for the development or reactivation of serious infections caused by Mycobacterium spp., certain viruses, and fungi. Mycobacterial infections can be caused by both M tuberculosis and nontuberculous strains. The most common viral infections that occur in children on BRMs include herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, and hepatitis B.

Importance of vaccination

Immunizations are an important component of the strategy to prevent infectious complications in children on a BRM. It is recommended that children continue to receive all inactivated and subunit vaccines per the routine immunization schedule. If the child has not yet started a BRM, Davies says, “It is important to be aware that live vaccines should be given at least 4 weeks before starting on a BRM and never to a child who is on a BRM without first consulting with an infectious diseases specialist.”

Also, before starting on a BRM, all children should be screened for tuberculosis (TB) and other opportunistic infections when appropriate. Depending on the child’s age, the screening for TB should be done using either the tuberculin skin test or with the interferon-gamma release assay. In addition, the possibility of endemic fungal infections (ie, Coccidioides, Histoplasma, and Cryptococcus) should be considered based on geographic region or residence or a travel history.

In maintaining vigilance for infections in patients on BRMs, pediatricians need to recognize that atypical presentations are more likely in immunosuppressed individuals. For example, the risk of extrapulmonary tuberculosis is increased in immunosuppressed patients compared with nonimmunosuppressed hosts.

“Be aware of this difference when you are doing your evaluation and workup in a child on a BRM. For example, TB in this population is more likely to be extrapulmonary,” Davies says.

Davies also points out that children being treated with a BRM are often receiving concomitant therapy with another immunosuppressive agent, such as a corticosteroid or methotrexate.

“The recommendations for evaluation, immunization, and management for these children are no different than for patients on a BRM alone other than the need to have an even higher level of alertness to infectious complications because of their elevated risk,” Davies says.

Commentary

Indications for biologic response modifiers (BRMs) continue to expand, and these agents are being used to treat immune-mediated diseases in an increasing number of children. The BRMs have been an exponential advance in the management of diseases that have historically been a cause of significant morbidity and even mortality. With any treatment, however, benefit is accompanied by potential risk, and BRMs are no exception to this rule.

Treatment with BRMs in pediatric patients is managed by various subspecialists, including allergists, dermatologists, gastroenterologists, neuroimmunologists, and rheumatologists. As primary care providers, however, pediatricians should know the unwanted consequences associated with these agents so that they can best manage risk and enable children to safely remain on what represents highly effective therapy. In his session “Biologic response modifiers: What they are and why you should know” at the AAP’s 2018 National Conference, Dr. H. Dele Davies discussed the important topic of BRM-related risk and provided specific guidelines for patient care.

Biologic response modifiers manipulate the immune response in specific ways, which vary depending on the agent used, and these effects have implications for susceptibility to infection as well as host response to infection and vaccines. As reviewed by Dr. Davies, it is important for pediatricians to have a lower threshold to evaluate symptomatic patients for infectious causes and be aware that atypical presentations are more likely in immunocompromised hosts.

Dr. Davies also discussed the need to screen patients for tuberculosis and for opportunistic fungal infections when appropriate based on geographic area of residence. He gave important recommendations for vaccinations, including timing of administration relative to BRM initiation; immunization with vaccines that are not part of a routine protocol (eg, the 23-valent pneumococcal vaccine); and avoidance of live vaccines for patients on BRMs.

Dr. Davies made the critical point that the immune status of children who are on a BRM may be even further compromised secondary to concomitant treatment with another immunosuppressive medication. Adding to his caution, it should be emphasized that children with an autoimmune condition should be considered immunocompromised even in the absence of their receiving immunosuppressive therapy.

Fatma Dedeoglu, MD, is director, Autoinflammatory Clinic, Rheumatology Program/Division of Immunology, Department of Medicine, Boston Children’s Hospital, and assistant professor of Pediatrics, Harvard Medical School, Boston, Massachusetts.