The Great Pediatric Debate 2024: Cessation or Continuation of Biologics in sJIA Lung Disease?

Dr. Randy Q. Cron

Dr. Cron emphasized the risk factors that researchers have uncovered for sJIA-related lung disease, urging some type of lung screening for these high-risk patients. These factors include severe sJIA presentation, young age of onset, trisomy 21 and certain allelic variants of the HLA-DRB1 gene.^2-4

One theory is that sJIA-related lung disease may represent a kind of delayed hypersensitivity response to IL-1 or IL-6 blockers, a “drug reaction with eosinophilia and systemic symptoms” (DRESS) which can cause hematologic manifestations, rash and the involvement of various internal organs. The theory is that IL-1 and IL-6 antagonists might impact antigen presentation to CD4⁺ T cells in a manner that is influenced by inherited HLA variations, ultimately leading to a DRESS-type response.^4,5

Cessation of IL-1/IL-6 in sJIA-Related Lung Disease

“If these [IL-1 and IL-6] drugs are causing this, we probably shouldn’t be continuing them [in sJIA patients with signs of lung disease],” contended Dr. Cron.

However, countervailing pathophysiological theories, such as the cytokine plasticity hypothesis, have also been proposed.⁵

Dr. Onel also pointed out that although many patients with sJIA-related lung disease have had exposure to IL-1 or IL-6 biologics, that is not the case for all. She also emphasized the fact that not everyone with such lung disease possesses the implicated alleles, and conversely, patients can have the allele and sJIA but never present with lung symptoms. Dr. Onel cited studies from parts of the world where biologics are less readily available, showing that some children with sJIA not on these drugs do develop lung disease.

Dr. Onel also explored sJIA complicated by MAS, a form of secondary hemophagocytic lymphohistiocytosis  (HLH) which can cause cytokine storm and sometimes organ failure. Lung involvement is common in patients with HLH, whether from an autoimmune disease like sJIA or another indication like cancer or infection, and lung involvement is more common in patients with sJIA who have MAS than in those who do not.⁶

With respect to the underlying physiology of lung disease in sJIA, Dr. Onel countered, “Is it DRESS? Is it immune plasticity? I would argue that we really have no idea. We have to think about the clinical decisions that we make and decide whether they’re based on a kind of gestalt or whether they’re based on fact.”

Dr. Onel also emphasized the deficiencies of other treatment options, should physicians opt to remove IL-1 or IL-6 blockers in their patients who develop lung involvement. For example, she noted that although some clinicians might move to JAK inhibitors in such a setting, she has reservations related to the lack of studies in this application, and she has concerns about potential side effects documented in adults, such as cardiovascular events and cancer. “What are the alternatives?” she asked. “Do we really want to go back to the old days? I would say that there’s no turning back.”