Newly described lung disorder strikes children with systemic juvenile idiopathic arthritis


An uncommon but potentially deadly inflammatory lung disease is emerging among children with systemic juvenile idiopathic arthritis, and its history appears to coincide with the rise of powerful biologics as first-line therapy for children with the disease.

Dr. Elizabeth Mellins (right) and Dr. Vivian Saper (left) analyzed 61 cases of the newly described lung disease in children with systemic juvenile idiopathic arthritis Courtesy Dr. Elizabeth Mellins

Dr. Vivian Saper (left) and Dr. Elizabeth Mellins

Most confirmed cases of systemic juvenile idiopathic arthritis with lung disease (sJIA-LD) are in the United States. But it’s popping up in other places that have adopted early biologic treatment for sJIA – including Canada, South America, Europe, and the Middle East.

The respiratory symptoms are relatively subtle, so by the time of lung disease detection, the amount of affected lung can be extensive, said Elizabeth Mellins, MD, a Stanford (Calif.) University researcher who, along with first author Vivian Saper, MD, recently published the largest case series comprising reports from 37 institutions (Ann Rheum Dis. 2019 Sep 27. doi: 10.1136/annrheumdis-2019-216040). By the end of follow-up, 22 of the 61 children in her cohort had died, including all 12 patients who demonstrated excessively high neutrophil levels in bronchoalveolar lavage samples.

Another recent report, authored by Grant Schulert, MD, PhD, and colleagues of the Cincinnati Children’s Hospital Medical Center, described 18 patients, 9 of whom were also included in the Stanford cohort (Arthritis Rheumatol. 2019 Aug 5. doi: 10.1002/art.41073).

Both investigators have now identified new patients.

“We are aware of 60 additional cases beyond what were included in our series,” Dr. Mellins said in an interview, bringing her entire cohort to 121. Dr. Schulert also continues to expand his group, detailing nine new cases at a recent private meeting.

“We are up to 27 now,” he said. “The features of these new patients are all very similar: The children are very young, all have had macrophage activation syndrome in the past and very-difficult-to-control JIA. Reactions to tocilizumab [Actemra] were also not uncommon in this group.”

Dr. Mellins also saw this association with allergic-type tocilizumab reactions, severe delayed hypersensitivity reactions to anakinra (Kineret) or canakinumab (Ilaris). Although serious lung disease in sJIA patients is not unheard of, this phenotype was virtually unknown until about a decade ago. Both investigators said that it’s been rising steadily since 2010 – just about the time that powerful cytokine-inhibiting biologics were changing these patients’ world for the better. After decades of relying almost solely on steroids and methotrexate, with rather poor results and significant long-term side effects, children were not only improving, but thriving. Gone was the life-changing glucocorticoid-related growth inhibition. Biologics could halt fevers, rash, and joint destruction in their tracks.

“For the first time in history, these kids could look forward to a more or less normal life,” Dr. Schulert said.

But the emergence of this particular type of lung disease could throw a pall over that success story, he said. If sJIA-LD is temporally associated with increasing reliance on long-term interleukin-1/IL-6 inhibition in children with early-onset disease, could these drugs actually be the causative agent? The picture remains unclear.

Some of the 18 in his initial series have improved, while 36% of those in the Stanford series died. Most who do recover stay on their IL-1 or IL-6 blocking therapy with good disease control without further lung problems. Both investigators found compelling genetic hints, but nothing conclusive. Children with trisomy 21 appear especially vulnerable. Most patients are very young – around 2 years old – but others are school aged. Some had a history of macrophage activation syndrome. Some had hard-to-control disease and some were clinically well controlled when the lung disease presented.

There are simply no answers yet.

With so many potential links, all unproven, clinicians may question the wisdom of embarking on long-term biologic therapy for their children with sJIA. Peter Nigrovic, MD, of Boston Children’s Hospital, addressed this in an accompanying editorial (Arthritis Rheumatol. 2019 Aug 7. doi: 10.1002/art.41071).

“My take on this is that it’s a very worrisome trend,” he said in an interview. “We’ve been going full bore toward early biologic therapy in sJIA and at the same time we are seeing more of this lung disease. Is it guilt by association? Or is there something more? The challenge for us is not to jump too soon to that conclusion.”

Although the association is there, he said, association does not equal causation. And there’s no doubt that biologics have vastly improved the lives of sJIA patients. “The drugs might be causal, and I worry about that and think we need to study it. But we absolutely need stronger evidence before we change practice.”

“This is a new manifestation of the disease, and it’s coming at the same time we are changing the treatment paradigm,” Dr. Nigrovic continued. “It could be because of interleukin-1 or interleukin-6 blockade. There is biological plausibility for such a link. It could also be related to the fact that we are using less steroids and methotrexate, which might have been preventing this. The appearance of sJIA lung disease could also be that a distinct secular trend unrelated to treatment, just as we saw amyloid come and go in this population in Europe. These other therapies were actually preventing this. We just don’t know.”


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