For three generations, a Belgian family has been plagued by a mysterious inflammatory condition that causes their skin to break out in lesions. These episodes, starting in childhood, last a few weeks to months at a time and are accompanied by fever, pain, and fatigue. The condition’s cause has eluded researchers for decades. A new study, however, gives hope for treatment with a drug that is already available in some nations.
The disease is known as pyrin-associated autoinflammation with neutrophilic dermatosis, or PAAND. A team lead by Adrian Liston at the University of Leuven analysed the genomes of 20 of the family’s members, 12 of whom were affected by the condition. They discovered a mutation in the gene that codes for pyrin, a protein involved in the body’s inflammatory response. When the body is exposed to bacterial toxins, it responds by producing the immature form of a protein known as interleukin-1. Pyrin is required to make the immature form of IL-1 mature. It starts a cascade of cell signals that lead to fever and inflammation, signs that the body is fighting off an infection.
In a healthy individual, pyrin would only be activated if the body were in danger. In an individual with PAAND, however, pyrin is overactive, causing the body’s immune response to go haywire. An individual with PAAND will appear to be fighting off a life-threatening bacterial infection even where no infection is present.
PAAND is not relegated to a single Belgian family. By searching in a genetic database, Liston’s group identified a family in England and individuals in France and Lebanon that carry the mutation. The condition is autosomal dominant, meaning that only one copy of the gene needs to be passed down for the disease to be present. A child has about a 50% chance of inheriting it from a parent.
After getting to the root cause, Liston’s group had some preliminary success treating a single patient from the English family with anakinra—known commercially as Kineret—an antiarthritis drug that targets interleukin-1. The patient improved rapidly in the first week; after a few weeks, all the symptoms had disappeared. Liston’s group will soon begin clinical trials to confirm these results on a larger scale.
This study was the first to recognise PAAND. It is currently impossible to estimate how many people are affected by the disease worldwide, though it is likely very rare. It has similarities with another inflammatory condition, known as Familial Mediterranean Fever (FMF), which affects a few hundred thousand patients. FMF is caused by a different mutation in the same gene and is typically autosomal recessive.
If these conditions are so rare, one might ask, why invest money in studying them? In addition to potentially bringing relief to the patients and reducing their burden on the health care system, studying these rare genetic diseases can teach researchers a lot about common, complex conditions. For example, with inflammatory bowel disease, many processes go slightly wrong to produce the disease state. With PAAND, one process goes very wrong, making it easier for scientists to study the underlying biology.
Further studies conducted with more patients will be necessary to confirm these clinical results and to help the treatment effort gain momentum. “It’s not like you can declare a new disease in a paper and suddenly it becomes a recognised disease around the world,” says Liston. Of the 17 patients found to carry the genetic mutation, 15 exhibited symptoms. To confirm that PAAND is a distinct condition, rather than a variation of an existing disease, the researchers will need to confirm that the disease is consistent across different families, and that the mutation Liston’s group discovered appears consistently in each case.
Liston sees this case as a strong argument for personalised medicine. “The standard clinical approach didn’t work for these patients,” he says. “It took us looking at their immune systems and sequencing their genomes to work out exactly what was going on.” Genome sequencing is not currently covered by health care systems, making it unsustainable for clinical research in the long term. If this were to change, patients suffering from severe diseases with a suspected genetic component could benefit greatly.
Clinical trials for the treatment are set to begin in Belgium in a few weeks. The preliminary trial took place in England, where anakinra is available to physicians. But this is not the case in Belgium, where the majority of the patients are located. It has taken longer to get approval for the trial as a result. Still, Liston hopes to have results by the end of this year.
Photo: www.publicdomainpictures.net/Junior Libby