The Challenge of Blau Syndrome

TY - JOUR

T1 - The Challenge of Blau Syndrome

AU - Holland, Gary N.

AU - Rosenbaum, James T.

N1 - Funding Information: Gary N. Holland a ∗ uveitis@jsei.ucla.edu James T. Rosenbaum b a Ocular Inflammatory Disease Center, UCLA Stein Eye Institute and the Department of Ophthalmology, David Geffen School of Medicine at UCLA, Los Angeles, California Ocular Inflammatory Disease Center UCLA Stein Eye Institute and the Department of Ophthalmology David Geffen School of Medicine at UCLA Los Angeles California b Casey Eye Institute and Department of Ophthalmology, Oregon Health and Science University, and the Legacy Devers Eye Institute, Portland, Oregon Casey Eye Institute and Department of Ophthalmology Oregon Health and Science University, and the Legacy Devers Eye Institute Portland Oregon ∗ Inquiries to Gary N. Holland, UCLA Stein Eye Institute, 100 Stein Plaza, Los Angeles, CA 90095-7000 UCLA Stein Eye Institute 100 Stein Plaza Los Angeles CA 90095-7000 In this issue of the Journal , Sarens and associates describe the preliminary results of a prospective study of patients with familial juvenile systemic granulomatosis, also known as Blau syndrome. 1 The report follows a publication describing the systemic manifestations of the same cohort, drawn from the Pediatric Granulomatous Arthritis International Registry. 2 Many, if not most, ophthalmologists are unfamiliar with this rare but important multisystem disease, which is characterized by dermatitis, arthritis, and severe panuveitis. In our experience, children with Blau syndrome are often misdiagnosed as having juvenile idiopathic arthritis (JIA), despite the fact that the inflammation of JIA-associated uveitis is restricted to the anterior segment, whereas Blau syndrome can result in prominent inflammatory lesions of the fundus. Among those who do, in fact, have experience with the disease, its management is particularly challenging. Outcomes are often poor. In addition, because Blau syndrome is an autosomal dominant disease, each offspring of an affected individual has a 50% chance of developing the same disease. A correct diagnosis therefore has important implications not only for those with Blau syndrome, but for their families as well. Despite the importance of Blau syndrome, study of its ophthalmic features has been hampered by the fact that most reports in the ophthalmic literature have been either isolated case reports or small case series that include fewer than 10 patients. In contrast, the current series includes 50 patients with Blau syndrome. The gene responsible for Blau syndrome, NOD2 , was implicated in disease pathogenesis by Miceli-Richard and associates in 2001. 3 Their discovery came 16 years after Edward Blau, in one publication, 4 and Jabs and associates, in another, 5 described the triad of uveitis, arthritis, and dermatitis that characterizes the disease. NOD2 turned out to be a vital receptor for the innate immune system. The receptor recognizes a portion of bacterial cell wall when a bacterium enters an immune system cell, such as a macrophage. Readers will recall that the immune system includes both adaptive and innate response mechanisms. The portion of the immune system that includes T and B lymphocytes is adaptive, because the cells undergo gene rearrangements (ie, they adapt) to make a highly targeted immune response. Based largely on animal studies, in which uveitis can be transferred by T lymphocytes, the adaptive immune system is widely considered to be responsible for most forms of noninfectious uveitis. In contrast to adaptive immunity, no gene rearrangement is required for innate immunity, because its cells, including neutrophils and macrophages, rely on receptors that recognize broad classes of danger signals, such as bacterial cell wall or viral DNA. Compared to the adaptive immune system, the innate immune system responds more rapidly, but less specifically. The fact that Blau syndrome is autosomal dominant means that changing a single nucleotide, among the 3.1 billion nucleotides that make up the human genome, will induce the disease, offering a tantalizing clue to unraveling the mystery of uveitis. Yet 16 additional years have passed since Miceli-Richard and associates' discovery, and the precise mechanism to account for the NOD2 effect remains speculative. The ongoing study by Sarens and associates and establishment of the Pediatric Granulomatous Arthritis International Registry may help both clinicians and researchers address the challenges associated with Blau syndrome. The current article does, however, suffer from substantial limitations. Results are preliminary. We are disappointed in the imprecision with which data were collected and reported; for example, study terms, such as “mild,” “moderate,” and “severe,” in reference to uveitis, were apparently not defined prospectively. Many descriptions are superficial. The distinction between peripapillary nodules and chorioretinal lesions is not explained. The authors provide no information about the nature of chorioretinal lesions beyond that contained in a 2002 report by Latkany and associates (also a multicenter study), despite the fact that the current series contains 3 times as many patients. 6 There is no information about the nature of retinal detachments. Were they exudative or rhegmatogenous? Both mechanisms could occur in a patient with severe panuveitis, and distinction between the two is critical for management. Likewise, the nature of “retinal vasculitis” (occlusive vs nonocclusive) and its clinical manifestations are not elucidated. Investigators collected data on intraocular pressure (IOP) and use of glaucoma medications, but the severity of elevated IOP is not provided, nor were its risk factors or outcomes explored. Many of these deficiencies are attributable to the fact that data were collected from 25 international sites, but even large multicenter studies can be conducted in a rigorous manner. The authors have made only limited comparisons that relate ophthalmic findings to host and other disease-related factors. Nevertheless, the Journal felt that, even with its deficiencies, the article provides important information for readers. Because of the larger cohort size, authors are better able to assign prevalence to various disease features and complications than previous reports, and they are able to provide some information about disease progression. Importantly, the authors were unable to identify even a single patient for whom uveitis was the sole manifestation of Blau syndrome. Although the study provides no insight into best treatments for the disease, the fact that panuveitis is still active at 3 years in many patients, despite treatment by experienced experts in the field, emphasizes the difficulty with which it is managed. The diversity of treatments reported for this cohort suggests that current therapies often supply only partial benefit. The study also provides further confirmation of the substantial risk of vision loss from the disease, as suggested by previous case reports and small series. Particularly intriguing is the suggestion that some genetic variants are related to worse visual outcomes, although this conclusion will require additional validation. Moreover, the Journal felt that it was important simply to raise awareness at this time about Blau syndrome among members of the ophthalmology community. Can a rare disease like Blau syndrome elucidate more common causes of uveitis? The NOD2 gene dangles alluringly before researchers who study Blau syndrome, but it has consistently evaded their grasp. Although we know the function of the protein for which NOD2 codes, and we know exact mutations that cause Blau syndrome, we still do not know how mutations change the function of NOD2 within the uvea. We do not know how often NOD2 is activated within the uvea of a healthy eye. We do not know the environmental factors (if any) or the interactions among genes that result in the spectrum of disease manifestations that characterize Blau syndrome. The collaboration represented by the Pediatric Granulomatous Arthritis International Registry may be an excellent resource for scientists seeking clues to these conundrums. We do congratulate Dr Sarens and her colleagues for tackling the difficult job of studying the ophthalmic manifestations of Blau syndrome, and we look forward to their 5-year results. In the remaining years of their prospective study, we encourage them to record their data with greater precision, and ultimately to analyze their results in greater detail. We also hope that their study will be a catalyst for continued investigations to address the clinical and research challenges associated with this rare, but important, disease. Funding/Support: Supported by the Skirball Foundation, New York, New York (G.N.H.) and Research to Prevent Blindness, Inc., New York, New York (G.N.H., J.T.R.). J.T.R. also received support from the William and Mary Bauman Foundation (Wilsonville, Oregon) and the Stan and Madelle Rosenfeld Family Trust (Portland, Oregon). Funding entities had no role in the preparation of this Editorial. Financial Disclosures: James T. Rosenbaum has received financial support for research and consultation activities from AbbVie, Inc (North Chicago, Illinois); Gilead Sciences, Inc (Foster City, California); Regeneron Pharmaceuticals, Inc (Tarrytown, New York); UCB Biosciences, Inc (Raleigh, North Carolina); Eyevensys (Paris, France); TopiVert Pharma Limited (London, UK); and Cavtherx, Inc (San Francisco, California); has received royalties from UpToDate, Inc (Waltham, Massachusetts); and is on the Speakers Bureau for Mallincrokdt Pharmaceuticals (St. Louis, Missouri).The following author has no financial disclosures: Gary N. Holland. The authors attest that they meet the current ICMJE criteria for authorship.

PY - 2018/3

Y1 - 2018/3

UR - http://www.scopus.com/inward/record.url?scp=85040440560&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040440560&partnerID=8YFLogxK

U2 - 10.1016/j.ajo.2017.12.006

DO - 10.1016/j.ajo.2017.12.006

M3 - Editorial

C2 - 29338849

AN - SCOPUS:85040440560

VL - 187

SP - xviii-xix

JO - American Journal of Ophthalmology

JF - American Journal of Ophthalmology

SN - 0002-9394

ER -