Dr. Rosé said that he uses "a lot of oral prednisone" to combat uveitis in his Blau patients, and recommends that all Blau patients undergo a slit-lamp examination every 3 months. Although oral steroids are "not a solution," he said, "sometimes they are the only thing you can offer."
Dr. Martin has been studying an unusual family of uveitis patients and looking for clues to solve some of the many genetic mysteries Blau presents.
Asked to consult on a family with severe bilateral uveitis with onset in early adulthood instead of childhood and no arthritis or other symptoms of Blau, Dr. Martin subsequently found that the family has an NOD2 mutation that is slightly different from the mutation seen in most Blau cases.
Another family in the registry has incomplete penetrance; the father of an affected and mutation-positive child carried the same NOD2 mutation but never developed the disease (Arthritis Rheum. 2009:60:1804-6). "There’s some genetic or environmental modifier that’s quenching that NOD2 mutation," she said.
Finding it will entail deeper investigations into the NOD2 mutations, and other mutations that may produce Blau-like pathology. The 100-plus patients in the international registry who have Blau-like symptoms but lack NOD2 mutations may in fact have other, yet-undescribed syndromes that further genetic work may reveal.
"We’re finding so many new mutations," Dr. Martin said, as well as new sorts of disease within the registry. One small group in the registry presented atypical for Blau and had infantile panniculitis, along with fever, uveitis, and systemic granulomatous inflammation (J. Pediatr. 2007;151:707-9).
The finding suggests, Dr. Martin said, that the registry contains unknown diseases that are not truly Blau syndrome but that may be identified through genotyping, which "is starting to get cheap enough that we can do it for a reasonable amount of money."
The genetics, Dr. Martin said, are "helping us find that Blau," – whatever it is, and however it is ultimately defined – "may not be as rare as we thought."
At the same conference, Kevin Foley, Ph.D., a researcher at GlaxoSmithKline, presented new data on Blau biomarkers (Pediatric Rheumatology 2011, 9 [suppl. 1]:O25), which may prove helpful in developing agents targeting the NOD2 signaling pathway.
GlaxoSmithKline is investigating a medication – currently in preclinical testing – that inhibits RIP-2, one of the proteins involved in NOD2 signaling. The company is also funding a prospective cohort study, led by Dr. Rosé, that aims to describe the natural history of Blau from infancy and to isolate additional biomarkers of inflammation driven by hyperactive RIP-2.
John Bertin, Ph.D., head of GlaxoSmithKline’s pattern recognition receptor discovery unit, said in an interview that he hopes the Blau cohort "will provide information that will enable us to determine the feasibility of performing a clinical study in this patient population."
And because hyperactive RIP-2 signaling drives proinflammatory cytokine production in Crohn’s and ulcerative colitis, Dr. Bertin said, a RIP-2 inhibitor could offer promise treating those diseases as well.
Dr. Martin reported having no relevant financial disclosures. Dr. Rosé has an unrestricted grant to study Blau syndrome funded by GlaxoSmithKline and administered by the University of Leuven. Dr. Bertin and Dr. Foley are employees of GlaxoSmithKline.