Pediatric rheumatologists take center stage in battling acute inflammatory syndrome
The emergence of a multisystem inflammatory syndrome in children with COVID-19 has forced pediatric rheumatologists to elevate the understanding of inflammatory events in their patients, according to a presenter at the 2020 Congress of Clinical Rheumatology-East.
“There is no way to cover all of what is new in pediatric rheumatology,” Randy Q. Cron, MD, PhD, of the Children’s Hospital of Alabama and the University of Alabama at Birmingham, said in his presentation. He added that a critical complicating factor in this broad topic is that “coronavirus brought us an inflammatory syndrome.”
That syndrome, currently called multisystem inflammatory syndrome in children (MIS-C) resembles macrophage activation syndrome (MAS), secondary hemophagocytic lymphohistiocytosis (HLH) or cytokine storm syndrome that can occur in children with rheumatic diseases such as systemic juvenile idiopathic arthritis (SJIA). Cron focused the latter section of his presentation on this broad umbrella of inflammatory events, but not before covering juvenile idiopathic arthritis (JIA), SJIA, novel biomarkers and emerging therapeutic options for pediatric rheumatic diseases.
“I focused a lot of this talk on JIA, as it is our most chronic disease in pediatric rheumatology,” Cron said.
Ongoing classification of JIA
Despite the prevalence of this condition, Cron noted that JIA has gone through “various nomenclatures and classifications” in recent years. Currently, clinicians divide the condition into seven subtypes, six of which are defined by criteria and one of which meets no criteria.
The oligoarticular subtype is comprised largely of young girls of Scandinavian descent, according to Cron. These patients are antinuclear antibody (ANA) positive and at increased risk of developing silent uveitis.
The next subtype includes patients who are rheumatoid factor (RF) negative with polyarticular disease. “These are young kids who behave like those in the oligoarticular subtype,” Cron said. “But there are also older kids with small joint involvement.”
The RF-positive, polyarticular subtype is similar to RF-positive adult RA, according to Cron. “They tend to be girls, almost always teenagers,” he said, and described this as a “horrifically destructive arthritis.”
The systemic subtype is the equivalent of adult onset Still’s disease and comprises about 10% of the JIA patient population, according to Cron. “They can present young or at any age,” he said.
The next subtype is enthesitis-related arthritis, which Cron suggested is akin to ankylosing spondylitis. “These patients can have axial involvement,” he said. “They tend to be teenagers.”
The final defined subtype is the psoriatic category, which has two peak population groups. One is young children who present similarly to the oligoarthritis subtype, and one involves slightly older children who can have enthesitis.
Despite these seemingly clearly defined groups, Cron stressed that overlap in phenotype and presentation is common. “There is talk of lumping the various categories together,” he said. “Maybe they are not all that different. Maybe we should not be calling them with different names.”
Linking biomarkers to therapy
Turning to biomarkers in pediatric rheumatology, Cron highlighted serum ferritin, interleukin (IL)-18 and chemokine ligand 2 (CXCL2) as factors commonly seen in patients with elevated inflammation, including MAS and cytokine storm syndrome.
Perhaps the newest biomarker that has gained attention in the MAS space is adenosine deaminase 2 (ADA2). “This is a protein released by macrophages,” Cron said. While it has been implicated in the acute inflammatory syndromes, he noted that the function is “unknown at this time.”
Cron then offered some clinical advice for utilizing biomarkers, suggesting that a “reductionist approach” of dividing serum ferritin by erythrocyte sedimentation rate (ESR) may be useful in distinguishing SJIA without MAS from SJIA with MAS. For clinicians looking for an even more reductive approach, simply looking at serum ferritin levels was 89% sensitive and 95% specific in distinguishing all-cause MAS in pediatric populations. Regardless of the method used, Cron urged clinicians toward one overarching goal. “Hopefully, we can recognize and treat these patients early,” he said.
Fortunately, the range of treatment options is growing. Clinicians have used IL-1 blockade with canakinumab (Ilaris, Novartis) and IL-6 blockade with tocilizumab (Actemra, Genentech) with some efficacy in patients experiencing MAS in SJIA. Data are emerging for interferon blockade using emapalumab (Gamifant, Sobi). “This is another tool in our armamentarium to treat cytokine storm, MAS or secondary HLH,” Cron said.
Finishing with MIS-C, Cron said some patients will meet criteria for Kawasaki disease, although others may not. With that in mind, IV immunoglobulin (IVIG) may have utility.
Other features that may be present in the MIS-C population include prolonged fever and a “shock-like state,” along with elevations in C-reactive protein (CRP), lactate dehydrogenase (LDH), troponins and liver enzymes. Nausea or vomiting may occur, along with rash and conjunctivitis. Children may be swab-positive for SARS-CoV-2 or may have antibodies to COVID-19.
As data emerge, the picture alternately grows clearer and more complex. In short, clinicians are far from certain about any of these factors and what they mean. “We are trying to piece together this MIS-C,” Cron said.
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Cron RQ. MIS-C and What’s New in Pediatric Rheumatology? Presented at: Congress of Clinical Rheumatology-East annual symposium; September 10-13, 2020 (virtual meeting).