NIH investigators have talked with Dr. Peter Merkel, principal investigator and director of the Vasculitis Clinical Research Consortium, about conducting collaborative studies to look for variants of ADA2 in others who have nonfamilial PAN and did not have early-onset disease. "Even if they don’t [have variants in ADA2], it may still be the case that the pathway is somehow important and studies of biopsies from those patients would in some way allow us to connect that pathway to their disease. But that’s unknown," Dr. Kastner said.
When Dr. Kastner and his associates were looking for the mutations in other genetics databases, they found that whole-exome sequencing of 47 pairs of siblings with late-onset ischemic stroke in the Siblings With Ischemic Stroke Study had detected two brothers who each were heterozygous carriers of one of the mutations discovered in the study. Their ischemic strokes were similar in distribution to those seen in children with two mutations. "So it’s at least possible, although at this point it’s not formally proven, [that] that perhaps carrying one copy of this mutation, as opposed to having two as these kids have, could put you at some risk for having stroke later on in life. And it may be that, similarly, having one copy of a variant in this gene would predispose to other forms of vasculitis as well."
In three of the patients in the NIH study, treatment with low doses of fresh frozen plasma as a replacement therapy for ADA2 deficiency has appeared to be safe, but getting enough of it into patients and knowing whether it will last long enough are questions that the investigators are currently trying to answer, Dr. Kastner said. Initially, Dr. Kastner said his group was hesitant to use anti–tumor necrosis factor-alpha agents to treat patients because of the known, but small risk of demyelination with their use, which would not have been appropriate to try in patients who already had neurologic problems, because it would be very hard to tell if further lesions would be caused by underlying disease or the drug. However, when the Israeli group reported success with anti-TNF-alpha agents in their patients (and ultimately reported that 10 patients had a clinically significant therapeutic response), the NIH investigators decided to try them. Treatment with etanercept in five patients has reduced the occurrence of fevers in all and improved urticarial papules and plaques observed in three patients.
Pediatric rheumatologists who have patients with vasculitis or are suspected of having vasculitis should keep CECR1 mutations in mind now that the cause and some of the natural history and possible treatments for early-onset disease are known. Rheumatologists seeing adult patients with PAN could consider these mutations as a possible cause and at least note that some of these pathways may be important in their patients even if they don’t have mutations in CECR1, advised Dr. Kastner. He had no financial conflicts to disclose.