Registry Updates Blau Diagnostic Criteria

The 82 reported cases of Blau syndrome in the 6-year-old international registry are likely far from the entire catalog of affected children.

To be included in the registry, cases must involve the mutations in the nucleotide oligomerization domain 2 (NOD2) gene, a gene that is also involved in Crohn’s disease, 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 NOD2 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).

Long believed to be strictly familial, Blau syndrome has been found to emerge sporadically from de novo mutations as well; such cases have sometimes been classified as early-onset sarcoidosis.

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." Even Wikipedia’s Blau syndrome entry is classified as a "stub" awaiting further elaboration. Epidemiologic data on Blau are scarce, and are limited mostly to Denmark, although the disease occurs all around the world.

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 in September (Curr. Opin. Rheumatol. 2011;23:411-8).

The international registry, established in 2005, has revealed that a substantial minority – up to one-third – of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involvement; 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, according to Dr. Rosé.

But the registry also points to some consistencies, which should be heartening to pediatric rheumatologists who are presented with a possible Blau case. 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, which targets a different signaling pathway than does a TNF inhibitor, was recently used by a Japanese team to treat Blau patients 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. "We’re a little nervous using thalidomide in children," he said.

Of all the Blau symptoms, uveitis is "by far the most problematic" to manage, said Dr. Rosé, who estimates that 60% of Blau patients will end up with eye disease.

Dr. Martin explained that the uveitis that occurs in Blau (compared with that in JIA and other rheumatic disorders) is typically "more severe, bilateral, and generally it involves the back of the eye," in addition to the front. Unlike JIA, the uveitis in Blau will not resolve spontaneously, which is why frequent monitoring is essential. And because it involves a different part of the eye, it cannot easily be treated with steroid drops.

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.

The 82 reported cases of Blau syndrome in the 6-year-old international registry are likely far from the entire catalog of affected children.

To be included in the registry, cases must involve the mutations in the nucleotide oligomerization domain 2 (NOD2) gene, a gene that is also involved in Crohn’s disease, 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 NOD2 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).

Long believed to be strictly familial, Blau syndrome has been found to emerge sporadically from de novo mutations as well; such cases have sometimes been classified as early-onset sarcoidosis.

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." Even Wikipedia’s Blau syndrome entry is classified as a "stub" awaiting further elaboration. Epidemiologic data on Blau are scarce, and are limited mostly to Denmark, although the disease occurs all around the world.

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 in September (Curr. Opin. Rheumatol. 2011;23:411-8).

The international registry, established in 2005, has revealed that a substantial minority – up to one-third – of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involvement; 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, according to Dr. Rosé.

But the registry also points to some consistencies, which should be heartening to pediatric rheumatologists who are presented with a possible Blau case. 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, which targets a different signaling pathway than does a TNF inhibitor, was recently used by a Japanese team to treat Blau patients 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. "We’re a little nervous using thalidomide in children," he said.

Of all the Blau symptoms, uveitis is "by far the most problematic" to manage, said Dr. Rosé, who estimates that 60% of Blau patients will end up with eye disease.

Dr. Martin explained that the uveitis that occurs in Blau (compared with that in JIA and other rheumatic disorders) is typically "more severe, bilateral, and generally it involves the back of the eye," in addition to the front. Unlike JIA, the uveitis in Blau will not resolve spontaneously, which is why frequent monitoring is essential. And because it involves a different part of the eye, it cannot easily be treated with steroid drops.

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.

The 82 reported cases of Blau syndrome in the 6-year-old international registry are likely far from the entire catalog of affected children.

To be included in the registry, cases must involve the mutations in the nucleotide oligomerization domain 2 (NOD2) gene, a gene that is also involved in Crohn’s disease, 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 NOD2 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).

Long believed to be strictly familial, Blau syndrome has been found to emerge sporadically from de novo mutations as well; such cases have sometimes been classified as early-onset sarcoidosis.

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." Even Wikipedia’s Blau syndrome entry is classified as a "stub" awaiting further elaboration. Epidemiologic data on Blau are scarce, and are limited mostly to Denmark, although the disease occurs all around the world.

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 in September (Curr. Opin. Rheumatol. 2011;23:411-8).

The international registry, established in 2005, has revealed that a substantial minority – up to one-third – of pediatric Blau patients also have systemic disease, which can include vasculitis; renal, hepatic, or lung involvement; 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, according to Dr. Rosé.

But the registry also points to some consistencies, which should be heartening to pediatric rheumatologists who are presented with a possible Blau case. 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, which targets a different signaling pathway than does a TNF inhibitor, was recently used by a Japanese team to treat Blau patients 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. "We’re a little nervous using thalidomide in children," he said.

Of all the Blau symptoms, uveitis is "by far the most problematic" to manage, said Dr. Rosé, who estimates that 60% of Blau patients will end up with eye disease.

Dr. Martin explained that the uveitis that occurs in Blau (compared with that in JIA and other rheumatic disorders) is typically "more severe, bilateral, and generally it involves the back of the eye," in addition to the front. Unlike JIA, the uveitis in Blau will not resolve spontaneously, which is why frequent monitoring is essential. And because it involves a different part of the eye, it cannot easily be treated with steroid drops.

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.