The path that led this year’s presenter of the Rheumatology Research Foundation Paul Klemperer, MD, Memorial Lecture: Old Dog, New Tricks: Autoinflammatory Disease to the lectern stretches back three decades to when, as a new rheumatology fellow at the National Institutes of Health, he encountered a patient in his early 20s with an unknown condition causing episodes of recurrent fever and arthritis.
The patient had familial Mediterranean fever (FMF), which the medical community knew little about at the time, said Klemperer honoree Dan Kastner, MD, PhD, Scientific Director of the Division of Intramural Research of the National Human Genome Research Institute (NHGRI).
“The rheumatic inflammatory nature of his disease got me interested in that element and the fact that it was known at that time to be a genetic disease,” he said. “But the gene wasn’t known, and the protein that was mutated wasn’t known, and even the chromosomal location of the gene wasn’t known — not much was known.”
Kastner’s interest was piqued just around the time Human Genome Project was getting underway. So when he decided to probe the genetic basis of FMF, he only had the inspiration of the successful use of positional cloning, an arduous process, in finding the gene that causes cystic fibrosis to lead the way.
A summer spent drawing blood in Israel from families with FMF paved the way for a breakthrough that mapped the FMF gene to chromosome 16p. Five years later, Dr. Kastner’s research group discovered the FMF gene and the protein that it encodes, which the group named pyrin, because of the pyrexia associated with the disease.
Animal model studies carried out in the laboratory demonstrated that the pyrin protein regulates inflammation through IL-1, which has advanced new therapies targeting IL-1 in FMF patients who are unresponsive to, or intolerant of, colchicine, the previously established treatment for this illness.
The groundbreaking work with FMF illustrates a hallmark of Dr. Kastner’s career: A dedication to clinical practice where medical mysteries help his group make research advances. He made the very conscious decision to continue seeing patients right after the discovery of pyrin.
That decision, he said, has “over the course of the last almost 20 years been the source of a lot of very, very interesting clinical cases that have led to new discoveries with regard to genes that cause diseases.”
For instance, in following an Irish patient with prolonged febrile episodes similar to FMF, Dr. Kastner’s group discovered that mutations in the 55 kDa receptor for TNF define a dominantly-inherited syndrome that the group named TNF receptor-associated periodic syndrome, or TRAPS. Drawing upon functional immunologic studies of TRAPS patients, the group pioneered the use of etanercept, a recombinant TNF receptor fusion protein, for the treatment of TRAPS.
Dr. Kastner also noted a case from a few years ago involving a 6-year-old girl from Texas who had suffered six strokes over the course of her life and recurrent fevers. The symptoms were similar to that of a 2-year-old girl the group had seen several years earlier and had continued to follow over the years with little hope of discovering what she had.
So, in a process that he said highlighted the quantum leaps made in genomic testing during his career, Dr. Kastner’s group did whole exome sequencing on the two girls and their parents. They found that the CECR1 gene was responsible for the disease and that gene encodes a protein called ADA 2, leading the group to name the new disease Deficiency of ADA2 (DADA2).
And in a fortuitous observation with colleagues in Israel, the group found that these patients respond well to TNF inhibitors.