Head-to-toe rashes, inexplicably swollen limbs, recurrent fevers of 103 to 105 degrees. These were some of the perplexing symptoms that first worried Kathe Barchus of Omaha, Nebraska, when her then-infant son Isaac became seriously ill several weeks after he was born in 2005. Through visits to the NIH Clinical Center, Isaac became one of the first people diagnosed with a rare immunological condition now known as CANDLE/PRAAS syndrome, and in 2011, he was the first patient enrolled in a compassionate use program at the NIH of an experimental therapy to address his symptoms. Now 14, Isaac enjoys playing with dogs and watching sports with his friends.
Like most other participants in this compassionate use program for children and young adults with CANDLE and several similar conditions, Isaac experienced a marked improvement in his symptoms after the administration of a drug that is approved in Europe to treat rheumatoid arthritis in adults. According to NIAID researchers, the successful trial represents a milestone in the care for previously untreatable autoinflammatory diseases. The findings were reported today in the Journal of Clinical Investigation.
Over the past decade, researchers led by Raphaela Goldbach-Mansky, M.D., M.H.S., in NIAID’s Translational Autoinflammatory Disease Studies Section have investigated cases like Isaac’s, in which one or more genetic mutations lead to a surge in levels of an immune messenger molecule called interferon. While interferon helps healthy immune systems fight viruses, the abnormal excess seen in Dr. Goldbach-Mansky’s patients causes chronic, pervasive inflammation that can lead to life-threatening organ damage and other painful and disfiguring complications.
In CANDLE syndrome (which stands for “Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperatures” and is a proteasome associated autoinflammatory syndrome, or PRAAS), children experience recurrent fevers, rashes and joint pain. They also have trouble growing and tend to lose fat tissue in their faces and upper bodies. Several years later, Dr. Goldbach-Mansky’s group identified another syndrome of excess interferon they called SAVI syndrome (short for “Stimulator of IFN genes (STING)-Associated Vasculopathy with onset in Infancy”) which leads to vasculitis that results in the loss of fingers and toes, and serious complications in the lungs. Her group continues to see other patients with similar interferon-based illnesses that stem from different genetic mutations. Each disorder is rare—the team estimates that there may be as few as 100-200 people living with CANDLE or SAVI around the world—but in all cases, patients have severe symptoms that mostly begin in early childhood and severely impact their quality of life.
Because the mutations behind CANDLE and SAVI lead to excess interferon release by many cells, Dr. Goldbach-Mansky and her colleagues, including lead study author Gina A. Montealegre Sanchez, M.D., M.S., wondered if medications intended to thwart haywire interferon production may help. One such medication, baricitinib, blocks the activity of a protein important in the signaling of interferon and was recently approved to treat inflammation in adults with moderately to severely active rheumatoid arthritis in over 40 countries, including European countries, Japan and the United States. The only problem: Most of the team’s patients are children, and before the program started baricitinib had never been used in this young population.
In October 2011, NIH obtained baricitinib through a compassionate use program, which allowed researchers to test the drug for this off-label use given that CANDLE, SAVI and other interferonopathies are life-threatening diseases with no approved treatment. The team launched the Compassionate Use Treatment Protocol I4V-MC-JAGA, sponsored by Eli Lilly, and enrolled 18 participants—10 with CANDLE, four with SAVI and four with similar, presumed interferon-related diseases. Researchers offered baricitinib tablets to each participant in escalating doses until they found safe and tolerable regimens that produced results.
Before enrollment, all volunteers were hospitalized regularly with symptoms poorly controlled by other anti-inflammatory drug regimens. Predictably, some children receiving baricitinib did experience an increase in some viral infections, but the overall clinical response was overwhelmingly positive. Of the 18 enrolled, 15 participants reported marked improvement in their symptoms in quality-of-life surveys after receiving their optimal dose of baricitinib.
Researchers also found that participants’ biomarkers indicating high interferon levels dropped during the study, and improvements in height growth and bone mineral density surpassed expectations while on baricitinib therapy. Among the 14 participants who took the anti-inflammatory corticosteroid prednisone at enrollment, patients were on average able to decrease their daily doses from 0.44 mg/kg to 0.11 mg/kg. Remarkably, half of the 10 participants who enrolled with a CANDLE diagnosis were able to stop corticosteroids and went into prolonged clinical remission defined by an absence of fever, rashes and pain in the muscles and joints.
While Isaac’s symptoms have not disappeared, he has experienced meaningful improvement since beginning treatment seven years ago. Hear more from Isaac and the NIH researchers who treat him:
G Montealegre Sanchez et al. JAK 1/2 Inhibition with Baricitinib in the Treatment of Autoinflammatory Interferonopathies. Journal of Clinical Investigation DOI: 10.1172/JCI98814 (2108)