Searching for the Cause of Lung Disease in Systemic Juvenile Idiopathic Arthritis


According to a recent article in MedPage Today’s 2019 year-end review, the number of life-threatening lung diseases in systemic juvenile idiopathic arthritis (sJIA) patients has been increasing.

sJIA is characterized by high fever, inflammation around an organ’s protective tissues (serositis) and rash. Although it is a rare disease, sJIA is responsible for about seventy-five percent of arthritis deaths among children.

Biologic Drugs: An Impressive Beginning

Approximately fifteen years ago physicians began treating sJIA patients with biologic drugs that were produced from living organisms. Improvements were seen in seventy-five percent of patients.

The impressive biologic drugs included the IL-6 inhibitor tocilizumab and the interleukin IL-1 inhibitors anakinra and canakinumab.

About the Cytokine Network

Dr. Elizabeth Mellins of Stanford University co-authored a paper on tocilizumab and canakinumab for the New England Journal of Medicine in 2012. Dr. Mellins stated that these drugs represented a whole new era for treating sJIA.

However, she cautioned that uncommon complications may arise in the cytokine network where an imbalance may occur due to cytokine blockades.

Cytokines are signaling molecules that regulate inflammation, immunity, and other cellular processes that form the cytokine network.

A paper published in 2013 gave weight to Dr. Mellin’s theory. Twenty-five patients with varying symptoms of lung disease were studied. Since then, other studies have shown the serious impact of the IL-1 blockade.

Pulmonary arterial hypertension and lung damage from interstitial lung diseases were included in the studies. Much of the damage from interstitial lung disease is irreversible and increases over time.

The mortality rate reached about seventy-percent as it neared the ten-month mark after patients were diagnosed with pulmonary disease. Once such a high mortality rate became evident, Dr. Mellins set out to report these findings to others in the medical profession.

Biologics became suspect because of the timing of its usage and the simultaneous discovery of high mortality rates. Yet these factors could be entirely unrelated and may very well be coincidental.

About Macrophage Activation Syndrome (MAS)

MAS is a sometimes fatal complication that affects about ten to fifteen percent of lung disease patients. MAS can result in cytokine storms and severe inflammation. The biologic drug tocilizumab appears to lower the number of occurrences of MAS.

Cytokine storms are exaggerated immune responses caused by the rapid growth of natural killer cells or T-cells that are activated by infected macrophages. Cytokine storms, unless treated immediately, can be fatal.

A Possible Connection to the Death of Five Patients

Tocilizumab is now being investigated due to the death of five patients that occurred during the TENDER clinical trial.

Dr. Michael Ombrello of the National Institute of Arthritis noted that sJIA had been identified over 120 years ago. Therefore he wondered why these complications were only recognized during the last decade.

Dr. Peter Nigrovic of Boston emphasized the urgency and challenge of transforming tocilizumab into a safe biologic treatment for sJIA.

Biologics Are Being Tested From Every Angle

Dr. Mellins and associates have since published a study involving sixty-one patients. Forty-six of these patients exhibited very unusual symptoms.

This group had been exposed to IL-1 and IL-6 inhibitors. Among these children, the five-year survival rate was just forty-two percent.

The children’s data was compared against data of 471 sJIA patients from the CARRA registry. Compared to patients in the CARRA registry, lung cancer patients had a significantly lower survival rate with 159 fatalities over a six-year period. Many of these children had a trisomy 21 chromosome that may cause adverse reactions to drugs.

Lung Disease: Possible Explanations

Several hypotheses were presented as an explanation to this intriguing but lethal problem which Dr. Mellins describes as the connection between IL-1 and IL-6 inhibition and lung disease.

  • Study of sJIA children who developed type I interferon reaction in connection with anakinra
  • A study suggesting anakinra patients had a response to Type I and II interferons
  • Mouse models show that upregulation of interferon may cause a pattern similar to lung inflammation
  • Cytokine inhibitors may influence the cytokine network. Thus the child may be responsive to other cytokines

Dr. Mellins explained that there are many ways that inhibitors could increase vulnerability to lung disease. She currently is of the opinion that many factors may be involved and should be studied.

Dr. Mellins and associates have recently seen over fifty new cases of sJIA patients who have developed lung disease. She has also seen FDA reports of unusual adult lung disorders when rheumatoid arthritis patients were treated with IL-1 and IL-6 inhibitors.

Yet Dr. Mellins underscores the usefulness of these drugs for children who have been affected by lung manifestations.

Dr. Ombrello agreed and added that so far studies have not shown evidence of a connection between lung disease in sJIA and anti-cytokine therapies. He said that until that occurs the sJIA therapeutic approach must not be changed.

Rose Duesterwald

Rose Duesterwald

Rose became acquainted with Patient Worthy after her husband was diagnosed with Acute Myeloid Leukemia (AML) six years ago. During this period of partial remission, Rose researched investigational drugs to be prepared in the event of a relapse. Her husband died February 12, 2021 with a rare and unexplained occurrence of liver cancer possibly unrelated to AML.

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