Rheumatology News - November 2011 - (Page 3)
N O V E M B E R 2 0 1 1 • W W W. R H E U M AT O L O G Y N E W S . C O M
Registry Data Refine Blau Diagnostic Criteria
BY JENNIE SMITH
he 82 reported cases of Blau syndrome in a 6-year-old international registry are likely far from the entire catalog of affected children. To be included in the registry, cases must have a suspicious phenotype and evidence of granuloma in tissue, according to Dr. Carlos Rosé, who maintains the registry along with his colleagues Tammy Martin, Ph.D., of the Casey Eye Institute at Oregon Health and Science University, Portland, and Dr. Carine Wouters of the Catholic University of Leuven (Belgium). An additional 100-plus patients have symptoms related to those seen in Blau patients, but do not have the nucleotide oligomerization domain 2 (NOD2) gene mutation. Most clinicians “have never seen a case of Blau syndrome, or think they haven’t,” said immunologist Dr. Martin, who with Dr. Rosé documented that Blau syndrome could occur sporadically through a germline mutation ( J. Rheumatol. 2005;32:373-5). Blau – whether familial or sporadic – is by all measures rare. Dr. Martin said that she has introduced Blau families to one another, helping them share information, because “chances are that wherever they live, no one in their local community has Blau.” But new information on Blau is emerging rapidly, thanks in large part to the international registry. At the 18th European Pediatric Rheumatology Congress this fall in Bruges, Belgium, Dr. Rosé of the Alfred I. duPont Hospital for Children in Wilmington, Del., updated physicians on the newly expanded phenotype for Blau, which he published, along with Dr. Martin and Dr. Wouters (Curr. Opin. Rheumatol. 2011;23:411-8). The international registry, established in 2005, has revealed that a up to onethird of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involve-
ment; and severe hypertension. Clinical presentations in the registry vary broadly, from a girl in India with cardiomyopathy and aortoarteritis to a boy in Argentina with severe renal involvement. Fever is also now seen as a characteristic of Blau flare-ups. Little of this was known 6 years ago, Dr. Rosé said. But registry findings suggest that the triad of skin, joint, and eye involvement that was first described by pediatric nephrologist Edward Blau is still considered valid, although “it is a triad over time,” which makes it less diagnostically helpful, Dr. Rosé said. For example, an ichthyosis-like rash in infancy may be a consistent feature of Blau, but it is also transient, and without a biopsy it will resemble common childhood rashes. Rather, “bogginess of joints, familial history of the same phenotype, eye disease, and negative antinuclear antibodies [ANA] are the four bullets that should raise suspicion,” Dr. Rosé said, noting that eye disease in juvenile idiopathic arthritis ( JIA) is usually accompanied by positive ANA. An unexplained fever – one that is “not periodic or hectic, [like those] you see in the autoinflammatory diseases” – should also be considered in the context of possible Blau, according to Dr. Rosé. Dr. Rosé, who currently treats children in two unrelated families with Blau, has found that the inflammatory symptoms can be managed with infliximab, which is a TNF (tumor necrosis factor) inhibitor, and that other symptoms such as hypertension can generally be controlled with appropriate drugs. Infliximab is the most commonly used medication worldwide for Blau, he said. Thalidomide was used by a Japanese team to treat Blau successfully (Arthritis Rheum. 2010;62:250-7). Dr. Rosé said he would be hesitant to try it, however, and didn’t know of clinicians outside Japan who had. Of all the Blau symptoms, uveitis is “by far the most problematic” to man-
age, said Dr. Rosé, who estimates that tous inflammation ( J. Pediatr. 2007;151: 60% of Blau patients develop eye disease. 707-9). Dr. Martin explained that the uveitis At the same conference, Kevin Foley, that occurs in Blau (compared with some Ph.D., a researcher at GlaxoSmithKline, other rheumatic disorders) is typically presented new data on Blau biomarkers “more severe, bilateral, and generally it (Pediatric Rheumatology 2011, 9 [suppl. involves the posterior segment of the 1]:O25), which may prove helpful in deeye,” in addition to the front. The uveitis veloping agents targeting the NOD2 sigin Blau will not resolve spontaneously, naling pathway. which is why frequent monitoring is esGlaxoSmithKline is investigating an sential. And because it involves a differ- agent that inhibits RIP-2, one of the proent part of the teins involved in eye, it may not NOD2 signaling. The inflammatory symptoms of be treated with The company is Blau can be managed with steroid drops also funding a easily. prospective cohort infliximab. A lot of oral Dr. Rosé said study, led by Dr. prednisone may be needed that he uses “a Rosé, that aims to lot of oral describe the naturin children with prednisone” to al history of Blau Blau-associated uveitis. combat uveitis from infancy and in his Blau pato isolate additiontients, and recommends that all Blau pa- al biomarkers of inflammation driven by tients undergo a slit-lamp examination hyperactive RIP-2. In order to be in the coevery 3 months. hort, they need to have mutation in the Dr. Martin has been studying an un- NOD2 gene. usual family of uveitis patients and lookJohn Bertin, Ph.D., head of Glaxoing for clues to solve some of the many SmithKline’s pattern recognition receptor genetic mysteries Blau presents. discovery unit, said in an interview that One family in the registry has incom- he hopes the Blau cohort “will provide inplete penetrance; the father of an affect- formation that will enable us to detered and mutation-positive child carried mine the feasibility of performing a clinthe same NOD2 mutation but never de- ical study in this patient population.” veloped the disease (Arthritis Rheum. And because hyperactive RIP-2 signal2009:60:1804-6). “There’s some genetic or ing drives proinflammatory cytokine environmental modifier that’s quenching production in Crohn’s and ulcerative cothat NOD2 mutation,” she said. litis, Dr. Bertin said, a RIP-2 inhibitor Finding it will require deeper investi- could offer promise treating those disgations into NOD2 and other mutations eases as well. Physicians who have a case that may produce Blau-like pathology. they think may be Blau are welcome to The 100-plus patients in the internation- contact either Dr. Wouters at al registry who have Blau-like symptoms firstname.lastname@example.org or Dr. but lack NOD2 mutations may in fact Rosé at email@example.com. have yet-undescribed syndromes. “We’re Dr. Martin reported having no relevant finding so many new mutations,” as well financial disclosures. Dr. Rosé has an as new sorts of disease within the reg- unrestricted grant to study Blau synistry, Dr. Martin said. One small group in drome funded by GlaxoSmithKline and the registry presented atypical for Blau administered by the University of Leuand had infantile panniculitis, along with ven. Dr. Bertin and Dr. Foley are emfever, uveitis, and systemic granuloma- ployees of GlaxoSmithKline. ■
Homebound RA Patients Are Sicker, With More Disability
BY DENISE NAPOLI
FROM ARTHRITIS CARE & RESEARCH
heumatologists visiting patients who were homebound because of the severity of their rheumatoid arthritis found a high level of disease severity and disability. The finding “underscores the presence of a hidden population with unmet needs,” Dr. Ruchi Jain and her colleagues wrote (Arthritis Care Res. 2011;63: 1482-5 ). As part of a pilot program, physicians from the Mount Sinai Visiting Doctors program sent consult requests to rheumatology fellows there.
“Rheumatology fellows, accompanied by either internal medicine residents or medical students, saw 6 patients per month on average in their homes,” with 2 or 3 patients seen in half a day, twice a month, wrote Dr. Jain, of the Montefiore Medical Center, in the Bronx, New York, and her coauthors. Each visit lasted roughly 25 minutes, she added. Disease activity was assessed according to the Routine Assessment of Patient Index Data 3 (RAPID3) score, which quickly measures physical function, pain, and global assessment
“across different rheumatologic diseases,” they said. A score greater than 13 repThe number of homebound RA patient is expected to increase by 50% to 2 million over the next 20 years.
resents high disease severity. Over 12 months, the rheumatologists participating in the program made a total of 57 visits to 31 patients in the New York City area, including 31 first-time visits and 26 follow-up
appointments. Overall, 94% of patients were women, and 45% were Hispanic; 80% were between 60 years and 101 years old. Twenty-six lived alone or with a home health aide, while the remaining five patients lived with family members. Rheumatoid arthritis was the established diagnosis in 12 (39%) of the patients; 9 (30%) had osteoarthritis, 6 (19%) had crystalline arthropathies, and 1 patient each had psoriatic arthritis, progressive systemic sclerosis, and polymyositis; the last patient was unaccounted for. Most visits fit under the category of medical management of known arthritis/connective tis-
sue disease. Rarely, visits involved procedures, particularly intra-articular injections, arthrocentesis, and bursa drainage. At the initial evaluation, the mean RAPID3 score was 22.4 for patients with RA and 19.3 for patients with crystalline arthropathy, which reflects high severity of disease. According to the investigators, the number of permanently homebound patients with rheumatologic or other conditions is bound to increase by 50% to 2 million in the next 20 years. The investigators made no relevant disclosures of financial conflicts of interest related to this study. ■
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