Blau Syndrome Research Articles

Insights into the molecular basis of the NOD2 signalling pathway.

The cytosolic pattern recognition receptor NOD2 is activated by the peptidoglycan fragment muramyl dipeptide to generate a proinflammatory immune response. Downstream effects include the secretion of cytokines such as interleukin 8, the upregulation of pro-interleukin 1β, the induction of autophagy, the production of antimicrobial peptides and defensins, and contributions to the maintenance of the composition of the intestinal microbiota. Polymorphisms in NOD2 are the cause of the inflammatory disorder Blau syndrome and act as susceptibility factors for the inflammatory bowel condition Crohn's disease. The complexity of NOD2 signalling is highlighted by the observation that over 30 cellular proteins interact with NOD2 directly and influence or regulate its functional activity. Previously, the majority of reviews on NOD2 function have focused upon the role of NOD2 in inflammatory disease or in its interaction with and response to microbes. However, the functionality of NOD2 is underpinned by its biochemical interactions. Consequently, in this review, we have taken the opportunity to address the more ‘basic’ elements of NOD2 signalling. In particular, we have focused upon the core interactions of NOD2 with protein factors that influence and modulate the signal transduction pathways involved in NOD2 signalling. Further, where information exists, such as in relation to the role of RIP2, we have drawn comparison with the closely related, but functionally discrete, pattern recognition receptor NOD1. Overall, we provide a comprehensive resource targeted at understanding the complexities of NOD2 signalling.

Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes.

To report baseline articular, functional and ocular findings of the first international prospective cohort study of Blau syndrome (BS). Three-year, multicentre, observational study on articular, functional (HAQ, Childhood HAQ and VAS global and pain), ophthalmological, therapeutic and radiological data in BS patients. Baseline data on the first 31 recruited patients (12 females and 19 males) from 18 centres in 11 countries are presented. Of the 31 patients, 11 carried the p.R334W NOD2 mutation, 9 the p.R334Q and 11 various other NOD2 missense mutations; 20 patients were sporadic and 11 from five BS pedigrees. Median disease duration was 12.8 years (1.1-57). Arthritis, documented in all but one patient, was oligoarticular in 7, polyarticular in 23. The median active joint count was 21. Functional capacity was normal in 41%, mildly impaired in 31% and moderate-severe in 28% of patients. The most frequently involved joints at presentation were wrists, ankles, knees and PIPs. On radiographs, a symmetrical non-erosive arthropathy was shown. Previously unknown dysplastic bony changes were found in two-thirds of patients. Ocular disease was documented in 25 of 31 patients, with vitreous inflammation in 64% and moderate-severe visual loss in 33%. Expanded manifestations (visceral, vascular) beyond the classic clinical triad were seen in 52%. BS is associated with severe ocular and articular morbidity. Visceral involvement is common and may be life-threatening. Bone dysplastic changes may show diagnostic value and suggest a previously unknown role of NOD2 in bone morphogenesis. BS is resistant to current drugs, suggesting the need for novel targeted therapies.

Aberrant interleukin-1 signalling does not increase susceptibility of mice to NOD2-dependent uveitis.

NOD2 is the genetic cause of Blau syndrome, an autoinflammatory disease that manifests as coincident uveitis and arthritis. Since dysregulation of IL-1 signalling is considered a pathogenic mechanism in a number of related autoinflammatory conditions, we examined the extent to which unimpeded interleukin (IL)-1 signalling influences NOD2-dependent inflammation of the eye versus the joint. Mice deficient for IL-1R antagonist (IL-1Ra) were administered the NOD2 agonist muramyl dipeptide (MDP) by systemic (intraperitoneal) or local (intraocular and/or intra-articular) injections. NOD2-deficient mice received an intraocular injection of recombinant IL-1β. Uveitis was evaluated by intravital videomicroscopy and histopathology, and arthritis was assessed by near-infrared imaging and histopathology. Ocular levels of IL-1α, IL-1β and IL-1Ra were quantified by enzyme-linked immunosorbent assay. IL-1Ra deficiency did not render mice more responsive to systemic exposure of MDP. Despite the increased production of IL-1R agonists IL-1α and IL-1β in response to intraocular injection of MDP, deficiency in IL-1Ra did not predispose mice to MDP-triggered uveitis, albeit intravascular cell rolling and adherence were exacerbated. NOD2 expression was dispensable for the potential of IL-1 to elicit uveitis. However, we find that IL-1Ra does play an important protective role in arthritis induced locally by MDP injection in the joint. Our findings highlight the complexity of NOD2 activation and IL-1 signalling effects that can be compounded by local environmental factors of the target organ. These observations may impact how we understand the molecular mechanisms by which NOD2 influences inflammation of the eye versus joint, and consequently, treatment options for uveitis versus arthritis.

M. paratuberculosis and Parkinson’s disease – Is this a trigger

Genetic linkage studies and genome wide analysis have provided insights into complex medical diseases. Mycobacterium avium ss. paratuberculosis (MAP) causes Johne’s disease, an important enteric inflammatory disease mostly studied in ruminant animals. MAP is also the putative cause of Crohn’s disease. Moreover, MAP has been linked to other inflammatory diseases: sarcoidosis, Blau syndrome, autoimmune diabetes, autoimmune thyroiditis and multiple sclerosis. Genetic studies reveal an association between Parkinson’s disease (PD), leprosy and Crohn’s disease and since discovered, these findings have been considered “surprising”. Autophagy and ubiquitin–proteosome systems are cellular systems that both fight intracellular pathogens (xenophagy) and maintain cellular protein quality control. PD is a common neurodegenerative disease that manifests clinically as a profound movement disorder. The recognized genetic defects of PD create disruption of cellular homeostasis that result in protein folding abnormalities of PD called Lewy bodies. Those same genetic defects are associated with susceptibility to intracellular pathogens, including mycobacteria. It is now understood that PD Lewy body pathology starts in the enteric nervous system and “spreads” to the brain in a retrograde fashion via the vagus nerve. This is the same process by which prions affect the brain. Lewy body pathology of the enteric nervous system predates the Lewy body pathology of the central nervous system (CNS) by years or even decades. This article proposes that genetic defects associated with PD also result in a permissive environment for MAP infection – ineffective xenophagy. It postulates that beginning as an enteric infection, MAP – via the vagus nerve – initiates a pathologic process that results in a targeted neuroinvasion of the CNS. The article proposes that MAP infection and resultant PD pathology are due, in the genetically at-risk and age dependant, to the consumptive exhaustion of the protein quality control systems.

Optic nerve and retinal features in uveitis associated with juvenile systemic granulomatous disease (Blau syndrome).

To determine whether patients with juvenile systemic granulomatous disease (JSGD) (Blau syndrome) and uveitis have a characteristic ocular phenotype. Clinical and imaging data were collected retrospectively from patients attending the Regional Combined Paediatric Rheumatology and Ocular Inflammatory Service, Bristol Eye Hospital. General demographic information, laterality of the uveitis, age at onset, anatomical classification and course of the uveitis, clinical phenotype and specific NOD2 mutation were recorded for each patient. Seventeen eyes from nine patients (five males; four females) were included in the study. Mean age at the disease onset was 15 months, range 1-84 months. Eight patients had bilateral uveitis. Anterior uveitis was present in five eyes, intermediate uveitis in two eyes, and there were 10 eyes with panuveitis, manifesting as multifocal choroiditis. Appearance of optic disc included indistinct disc margins in six eyes, optic nerve head pallor in six eyes, optic disc vessel sheathing in four eyes, and there was peripapillary hypo/hyperpigmentation in 13 eyes accompanied with characteristic peripapillary nodular excrescences. Among NOD2 mutations, the p.R334W was the most commonly detected (n: four cases), and three patients carried novel variants, the p.E338D and p.D390V variants in one patient, and the p.H520Y and p.Q809K variants in two different patients. Chronic bilateral panuveitis and a nodular peripapillary appearance in childhood onset uveitis are characteristic features of JSGD, which support the need for an appropriate genetic NOD2 analysis.

A new mutation in blau syndrome: case report

Blau syndrome is a rare autoinflamattory granulomatous disease and inherited as autosomal dominant.The classical triad of Blau syndrome is granulomatous dermatitis, symmetric arthritis and recurrent uveitis. However, all of these findings may not be together in the patients. In the majority of patients, the disease is characterized by early onset that usually before 3-4 years of age. The ocular findings of Blau syndrome ocur usuaaly after the articular and skin findings.

Diagnostics challenges and therapeutic response in Blau syndrome – case report

Blau’s syndrome is an autosomal-dominant, autoinflammatory disease characterized by a non caseous granulomatous inflammation,presenting with arthritis, dermatitis and uveitis, caused by mutations of the CARD15/NOD2. Patients are treated with high doses of oral corticosteroids,and if the therapeutic response is unsatisfactory,additional treatment with immunosuppressive agents is the best choice,such as: Methotrexate,Cyclosporine,Anti-TNF and Canakinumab (Anti-IL1).

Eurofever-lesons from last year

Autoinflammatory diseases are rare disorders secondary to mutation of genes involved in the regulation of innate immunity. The main limitation to a better knowledge of Autoinflammatory diseases is related to the extreme fragmentation of the diagnosed cases that are spread over different centers and countries. The general aim of the Eurofever Project was to build an international registry on Autoinflammatory diseases. A web-based registry collecting baseline and cross-sectional clinical information on Autoinflammatory diseases is available in the member area of the PRINTO web-site (http://www.printo.it). The registry is open to all pediatric and adult Centers with a specific interest in Autoinflammatory diseases. The following monogenic autoinflammatory diseases were considered: Familial Mediterranean Fever (FMF), Cryopyrin-associated periodic syndromes (CAPS), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), Blau syndrome, pyogenic arthritis, pioderma and acne (PAPA) syndrome, deficiency of IL-1 receptor antagonist (DIRA), NLRP12-mediated periodic fever. Information on CRMO, Behcet’s disease, PFAPA and undefined periodic fevers were also collected. 2916 patients, from 95 centers in 53 countries, have been enrolled in the registry during the first 36 months. Baseline demographic data (country of residence, disease onset, disease duration, mutations, family history ect) from all patients are now available. In 2275 (81%) complete information on clinical manifestations and responses to treatments is also available. The disease distribution of enrolled patients is: FMF 787 (621 with complete clinical data); TRAPS 237 (211 with complete clinical data); CAPS 207 (186 with complete clinical data); MKD 153 (133 with complete clinical data); Blau syndrome 62 (21 with complete clinical data); PAPA 19 (18 with complete clinical data); NLRP-12 mediated periodic fever 8 (6 with complete clinical data); DIRA and Majeed 3 and 2 patients, respectively (all with complete clinical data). Among multifactorial autoinflammatory diseases: PFAPA 564 (402 with complete clinical data); CRMO 392 (370 with complete clinical data); pediatric Behcet disease 84 (68 with complete clinical data) and 205 patients with undefined periodic fever (174 with complete clinical data). So far 8 papers involving 56 different authors and 32 centers have been published in high-rank international journals and other papers are in preparation. A large registry of patients with Autoinflammatory diseases is available and, despite the expiring of the initial grant, the enrolment is still ongoing with an increasing number of centers involved. Eurofever represents a good example of how a disease-oriented registry can provide relevant scientific answers to many unknown clinical aspects of ultra-rare diseases. This aspects was the main reason of the relevant success of the enrolment we have observed.

Diagnosis of early-onset sarcoidosis with non–classical symptoms

Results A 15-month-old male patient was referred to pediatric rheumatology for evaluation of non-pruritic skin eruption most prominent on arm and leg, fever and lymphadenopathy. These symptoms began when the patient was four months old. Several antibiotics therapies had been examined. The maximal convelescence period was a month. There were no consanguinity and family history. Physical examination showed generalized, maculopapulary eruption especially on arm and leg, lymph node on left cervical and axillary region, and persistant fever. In laboratory examinations, acute phase reactans were found to be high. The serology of EBV, CMV, toxoplasma, brucella, tularemia, bartonella henselae, and Quantiferron test results were negative. Immunologic evaluations contained hemogram, blood smear, immunoglobulins, fagotest, and CD panel were normal. Urine calcium/creatinin ratio, serum ACE levels were normal. A skin biopsy taken from a papule showed subepidermal nonlangerhas histiocytes and a non-caseating granuloma. A lymph node biopsy showed granulomatous inflammation. Mediastinal lymph node was absent on thorax CT evaluation. His ophtalmological examination was normal. The granulomatous autoinflammatory disease was diagnosed. Prednisolone 2 mg/kg was administered which reduced symptoms and patient’s complaints. Then, the steroid dose was dropped. The fever and rash were absent, but the acute phase reactans were still high. His blood samples were referred for genetic testing NOD2 mutations. Methotrexate was added to the treatment, but the flair was occured two mounths later. NOD2 mutations was detected to be P268S heterozigot and V955I heterozigot. Since the patient’s response to anakinra was poor, TNF bloker was later added to the treatment. Conclusion Granulomatous autoinflammatory diseases include Blau syndrome and early-onset sarcoidosis, both are caused by mutations in the NOD2/CARD15 gene, inherited autosomal dominant and sporodic form of disease, respectively. Clinical triads are uveitis, arthritis and granulomatous dermatitis whereas the symptops we observed were fever, granulomatous dermatitis, and lymphadenopathy.

Blau syndrome, the prototypic auto-inflammatory granulomatous disease.

Blau syndrome is a monogenic disease resulting from mutations in the pattern recognition receptor NOD2, and is phenotypically characterized by the triad of granulomatous polyarthritis, dermatitis and uveitis. This paper reviews briefly the classical clinical features of the disease, as well as more recently described extra-triad symptoms. From an ongoing prospective multicenter study, we provide new data on the natural history of Blau syndrome, focusing on functional status and visual outcome. We also present an update of the range of different NOD2 mutations found in Blau syndrome as well as recent data on morphologic and immunohistochemical characteristics of the Blau granuloma. Finally, emerging insights into pathogenic mechanisms including activation of NOD2 signal transduction, and potential biomarkers of disease activity are discussed.

Blau syndrome polymorphisms in NOD2 identify nucleotide hydrolysis and helical domain 1 as signalling regulators

Understanding how single nucleotide polymorphisms (SNPs) lead to disease at a molecular level provides a starting point for improved therapeutic intervention. SNPs in the innate immune receptor nucleotide oligomerisation domain 2 (NOD2) can cause the inflammatory disorders Blau Syndrome (BS) and early onset sarcoidosis (EOS) through receptor hyperactivation. Here, we show that these polymorphisms cluster into two primary locations: the ATP/Mg2+-binding site and helical domain 1. Polymorphisms in these two locations may consequently dysregulate ATP hydrolysis and NOD2 autoinhibition, respectively. Complementary mutations in NOD1 did not mirror the NOD2 phenotype, which indicates that NOD1 and NOD2 are activated and regulated by distinct methods.

SP0072 Lessons Learned from the Eurofever Project

Autoinflammatory diseases are rare disorders secondary to mutation of genes involved in the regulation of innate immunity. The main limitation to a better knowledge of Autoinflammatory diseases is related to...

AB0012 Functional Characterization of P.E383k Blau Syndrome-Related Mutation

BackgroundThe Blau syndrome (BS) is a rare autosomal dominant autoinflammatory disease clinically characterized by symmetrical arthritis, granulomatous dermatitis and recurrent uveitis. The disease is caused by single mutations in CARD15/NOD2,...

Granulomatous inflammation: The overlap of immune deficiency and inflammation.

Pediatric granulomatous diseases constitute a heterogenous group of conditions in terms of clinical phenotypes, pathogenic mechanisms, and outcomes. The common link is the presence of multinucleated giant cells in the inflammatory infiltrate. The clinical scenario in which a tissue biopsy shows granulomatous inflammation is not an uncommon one for practicing adult and pediatric rheumatologists. Our role as rheumatologists is to develop a diagnostic plan based on a rational differential diagnostic exercise tailored to the individual patient and based mainly on a detailed clinical assessment. This chapter presents a comprehensive differential diagnosis associated with a classification developed by the authors. We describe with some detail extrapulmonary sarcoidosis, Blau syndrome, and immunodeficiency associated granulomatous inflammation, which in our view are the paradigmatic primary forms of granulomatous diseases in childhood. The other entities are presented only as differential diagnoses listing their most relevant clinical features. This chapter shows that almost all granulomatous diseases seen in adults can be found in children and that there are some entities that are essentially pediatric at onset, namely Blau syndrome and most forms of immunodeficiency associated granulomatous diseases.

Blau syndrome and latent tubercular infection: an unresolved partnership

Blau syndrome and latent tubercular infection: an unresolved partnership

A60: Optic Nerve and Retinal Features in Uveitis Associated With Juvenile Systemic Granulomatous Disease (Blau Syndrome)

Background/Purpose:Juvenile systemic granulomatous disease (JSGD), also known as Blau syndrome, is a dominantly‐inherited autoinflammatory disorder associated with gain‐of‐function mutations in the NOD2 gene. The aim of this study was to determine whether patients with JSGD and uveitis have a specific ocular phenotype.Methods:Clinical and imaging data were collected retrospectively from patients attending the Regional Combined Paediatric Rheumatology and Ocular Inflammatory Service, Bristol Eye Hospital. General demographic information, laterality of the uveitis, age at onset, anatomical classification and course of the uveitis, clinical phenotype, and specific NOD2 mutation were recorded for each patient. All data were recorded in a database designed in Microsoft® Access®. Statistical analysis was performed using SPSS 20.0 (Cary, NC).Results:Seventeen eyes from 9 patients (5 males; 4 females) were included in the study. Mean age at the disease onset was 15 months; range 1–84 months. Eight patients had bilateral uveitis. Anterior uveitis was present in five eyes, intermediate uveitis in 2 eyes and there were 10 eyes with panuveitis, manifesting as multifocal choroiditis. Appearance of optic disc included indistinct disc margins in 6 eyes, optic nerve head palor in 6 eyes and optic disc vessels sheathing in 4 eyes. Fundal appearance included peripapillary hypo/hyperpigmention in 13 eyes accompanied with characteristic peripapillary nodular excrescences. Among NOD2 mutations, the p.R334W was the most commonly detected (n: 4 cases) and three patients carried novel variants, the p.E338D and p.D390V variants in one patient, and the p.H520Y and p.Q809K variants in two different patients.Conclusion:Chronic bilateral panuveitis and a nodular peripapillary appearance in childhood onset uveitis are characteristic features of JSGD, which support the need for an appropriate genetic NOD2 analysis.

Early-onset sarcoidosis caused by a rare CARD15/NOD2 de novo mutation and responsive to infliximab: a case report with long-term follow-up and review of the literature

Granulomatous autoinflammatory diseases are monogenic syndromes caused by mutations in the region encoding for the nucleotide-binding domain region of the NOD2/CARD15 gene with subsequent dysregulation of the inflammatory response and formation of noncaseous granulomas. They include Blau syndrome (BS) and early-onset sarcoidosis (EOS); both are clinically and genetically indistinguishable between them and they are the familial (autosomal dominantly inherited) and sporadic forms of the same disease, respectively. We describe a case of EOS, misdiagnosed for 30 years such as "juvenile rheumatoid arthritis" before and "classic sarcoidosis" later. In our patient, we found a new de novo mutation (E383G) in NOD2 that has been reported only in a family of Japanese patients with BS. After long-term follow-up (42 months), infliximab maintained good efficacy and safety without any sign of disease relapse and side effects.

The Misdiagnosis of the Doppelganger Diseases Understanding Similarities in Disease and Treatment by Infliximab

Author(s): Gemellos, John | Abstract: Due to their frequent misidentification for other ailments, a lay audience is likely to be unfamiliar with Early-Onset Sarcoidosis (EOS) and Blau Syndrome (BS), their presentation, their nuances, or developments in their treatments. EOS and BS are two genetic disorders that have often gone misdiagnosed for other conditions such as Juvenile Arthritis or Sarcoidosis due to their similar presentations of granulomas and inflammation. While these two particular disorders confer the same symptoms as their counterparts, the causes for their mutations are subtly defined. It's only been in recent years that the true culprit causing these disorders has been found and addressed. Recent strides in medicine have been taken to properly identify these disorders from their imposters and treat their underlying causes. An antibody known as Infliximab has shown untapped potential in the treatment for EOS and BS. It was only until recently that doctors and researchers questioned Infliximab's ability to treat EOS and BS, as this antibody is well known for treating other inflammatory conditions such as Crohn’s Disease. Multiple case studies have shown promising efficacy when treating EOS and BS with Infliximab, often resulting in total reduction of symptoms when using Infliximab alone. Other case studies involving Sarcoidosis and Infliximab have produced little to no progress, further establishing the distinct differences between EOS and BS from their doppelgangers.

Ultrasonographic assessment reveals detailed distribution of synovial inflammation in Blau syndrome

IntroductionArthritis is the most frequent manifestation of Blau syndrome, an autoinflammatory disorder caused by the genetic mutation of NOD2. However, detailed information on arthritis in Blau syndrome on which the therapeutic strategy should be based on is lacking. This multi-center study aimed to accurately characterize the articular manifestation of Blau syndrome and also to demonstrate the utility of musculoskeletal ultrasound in Blau syndrome.MethodsPatients who had been diagnosed with Blau syndrome by genetic analysis of NOD2 were recruited. A total of 102 synovial sites in 40 joints were assessed semiquantitatively by ultrasound for gray-scale synovitis and synovial power Doppler (PD) signal.ResultsIn total, 10 patients whose age ranged from 10 months to 37 years enrolled in this study. Although only 4 joints (0.8%) were tender on physical examination, 81 joints (16.9%) were clinically swollen. Moreover, 240 (50.0%), and 124 (25.8%) joints showed gray-scale (GS) synovitis and synovial PD signal on ultrasound, respectively. Importantly, GS synovitis was present in 168 out of 399 non-swollen joints, in which 61 also exhibited synovial PD signal. Among 40 joint regions, the ankle, the wrist, and the proximal interphalangeal joints were the most frequently and severely affected joints. Comparisons between different synovial tissues demonstrated a significantly higher proportion of the joints with tenosynovitis as compared with that with intra-articular synovitis (41.5% versus 27.9%, P < 0.0001). In respect of age and treatment, synovial PD signals were minimal in the youngest patient and in the oldest two patients, and were relatively mild in patients receiving treatment with methotrexate plus TNF antagonists. In two patients who underwent the second ultrasound examination, total PD scores markedly decreased after initiating the treatment with a tumor necrosis factor (TNF) antagonist.ConclusionsThe detailed information on synovial inflammation obtained by ultrasound confirms the dissociation between pain and inflammation and the frequently involved joint regions and synovial tissue in the arthritis of Blau syndrome. Our data also demonstrate that ultrasonography can be a potent tool in monitoring the activity of synovial inflammation and in investigating the pathophysiology of arthritis in this rare but archetypical autoinflammatory condition.

A Case of Blau Syndrome

We present a case of systemic granulomatous disorder/Blau syndrome. A patient was seen at our clinic with a diagnosis of Juvenile Idiopathic Arthritis (JIA). He was diagnosed with polyarticular JIA when he was two years old, at that time primary manifestations included inflammation of the hand and wrist joints bilaterally, later he developed ocular symptoms, which were attributed to JIA. He had liver, skin, pulmonary manifestations, and diagnostic workup including biopsy revealed granulomatous inflammation of these sites. During the diagnostic workup, he had worsening of ocular complaints, retinal exam showed panuveitis with multifocal choroiditis. These ocular findings are not seen in JIA, this, along with his other systemic manifestations, led us to revisit the diagnosis. Laboratory testing for genetic mutation for Blau syndrome was done and came back positive. Now all of his systemic findings were placed under one umbrella of systemic granulomatous syndrome/Blau syndrome. Due to worsening of ocular manifestations, he was started on Adalimumab with marked improvement of ocular and systemic manifestations and is followed by team that consists of Rheumatologist, Ophthalmologist, and Gastroenterologist.