Diagnosis and Treatment of Blau Syndrome/Early-onset Sarcoidosis, an Autoinflammatory Granulomatous Disease, in an Infant

Arvesen, Kristian Bakke; Herlin, Troels; Larsen, Dorthe A; Koppelhus, Uffe; Ramsing, Mette; Skytte, Anne‐Bine; Sommerlund, Mette

doi:10.2340/00015555-2485

Cited by 13 publications

(5 citation statements)

References 11 publications

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“…24 The patients treated with biological therapy after 2000 have been summarized in Table 3. [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41] Although our patients with predominantly articular symptoms responded to methotrexate and TNF inhibitor therapies, we could not achieve remission with TNF, interleukin (IL)-6, or IL-1 inhibitor therapies in patient 4. In addition, remission was achieved with a low dose steroid and canakinumab treatment for patient 1 without articular symptoms.…”

Section: Discussionmentioning

confidence: 77%

Blau Syndrome and Early-Onset Sarcoidosis: A Six Case Series and Review of the Literature

et al. 2020

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Objectives: This study aims to discuss the clinical, laboratory and genetic findings, and treatment options for six patients who were diagnosed with Blau syndrome (BS)/early-onset sarcoidosis (EOS). Patients and methods: The study included four patients (2 males,2 females; mean age 7 years; range 4 to 10 years) with EOS and two siblings (1 male, 1 female; mean age 10 years; range, 9 to 11 years) with BS. Age, age of initial symptoms, age of diagnosis; articular involvement, presence of uveitis, dermatitis, or fever, other organ involvement, laboratory findings, results of metabolic tests for mucopolysaccharidosis and mucolipidosis, results of genetic, pathologic, and immunologic tests, radiologic findings to evaluate skeletal dysplasia, and treatment options were collected. Results: The median age at diagnosis of all patients was 6 years (range, 1 to 10 years). Five patients had camptodactyly and bilateral boggy synovitis in the wrists and ankles, one had granulomatous inflammatory changes in the liver and kidney biopsy, and one had attacks of fever and granulomatous dermatitis. None had uveitis. The detected mutations in nucleotide-binding oligomerization domain containing 2 (NOD2) were P268S (rs2066842), M513T (rs104895473), R702W (rs2066844), V955I (rs5743291), H343Y (rs199858111), and M491L (16:50745293). The treatments of patients included corticosteroids, non-steroid anti-inflammatory drugs, methotrexate, infliximab, adalimumab, anakinra, and canacinumab. Conclusion: Camptodactyly and boggy synovitis are important signs of BS/EOS. Methotrexate and tumor necrosis factor blockers are more effective in patients with predominantly articular symptoms. In patients 5 and 6 and their mother, we determined a novel M491L mutation in the NOD2 gene. Currently, this work is in progress towards identifying the pathogenesis and treatment options for this disease.

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Section: Discussionmentioning

confidence: 77%

Blau Syndrome and Early-Onset Sarcoidosis: A Six Case Series and Review of the Literature

et al. 2020

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“…These observations are usually atypical in JIA [16] and might be more compatible with those observed in EOS(SBS) [17]. Although joint destruction and deformity can develop in later phases of the disease [4, 18, 19], the clinical findings observed in this case might be the characteristic features of joint lesions in early stage EOS(SBS) [12, 19]. We should have been more attentive to the manifestations of her joint lesion and suspicious of whether they fit with the clinical picture of JIA.…”

Section: Discussionmentioning

confidence: 95%

“…Methotrexate has been reported to be an effective therapy to prevent the onset of uveitis in JIA [20, 21]. Methotrexate is also used to treat EOS(SBS)/Blau syndrome and has corticosteroid-sparing effects in some EOS(SBS)/Blau syndrome patients [17, 19, 22, 23]. However, no evidence exists showing an inhibitory effect of methotrexate on uveitis onset in EOS(SBS)/Blau syndrome.…”

Section: Discussionmentioning

confidence: 99%

A Case of Sporadic Blau Syndrome with an Uncommon Clinical Course

Imayoshi

Ogata

Yamamoto

2018

Case Reports in Rheumatology

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Background Sporadic Blau syndrome (SBS), a rare systemic inflammatory disease in children, is associated with NOD2 gene mutations. SBS is often misdiagnosed as juvenile idiopathic arthritis (JIA) because of their similar clinical manifestations. Herein, we present a case of SBS with an uncommon clinical course. Case Presentation An 11-year-old girl with recurrent right ankle swelling for 4 years was referred to our hospital. One month before admission, she developed an intermittent high fever. She was diagnosed with systemic-onset JIA on the basis of physical and blood examination results. She was treated with ibuprofen, prednisolone, and methotrexate for 5 years. During this period, her joint lesion showed neither bone destruction nor joint space narrowing on radiography, which are characteristics of JIA. Twelve months after the termination of methotrexate treatment, she presented with bilateral panuveitis. A missense mutation, p.(R587C), was detected in her NOD2 gene, and she was diagnosed with SBS. Then, infliximab treatment was started, and her visual acuity recovered. Conclusion SBS may sometimes be misdiagnosed as JIA. A joint lesion without bone destruction might be a key feature to distinguish SBS from JIA. Analysis of the NOD2 gene is recommended in such cases.

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“…High doses of steroids can improve clinical manifestations when there is a rapid worsening of joint or ocular symptoms ( 43 , 65 ); however, prolonged treatment, especially in children, is difficult due to the side effects, including hypertension, growth retardation ( 48 ), iatrogenic Cushing syndrome, and elevated intraocular pressure ( 51 ). The most common initial diagnosis in our study ( 12 ) was JIA with 16 patients.…”

Section: Treatmentmentioning

confidence: 99%

“…Methotrexate (MTX) is effective for joint symptoms ( 33 ), and useful for steroid sparing ( 39 ), although it often needs to be combined with other treatments ( 12 , 43 , 65 ). In our study ( 12 ), excluding the seven patients with no treatment information, out of 43 patients, 25 patients were treated with MTX (seven were in combination with biologics, seven in combination with prednisolone [PSL] and biologics, five in combination with PSL, four with MTX alone, and two in combination with PSL, tacrolimus, and biologics).…”

Section: Treatmentmentioning

confidence: 99%

Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis

et al. 2022

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Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory cytokines. Clinical manifestations of Blau syndrome appear in patients before the age of four. Skin manifestations resolve spontaneously in some cases; however, joint and eye manifestations are progressive, and lead to serious complications, such as joint contracture and blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new therapies have been reported, including JAK inhibitors, anti-IL-6 and anti-IL-1 therapies, anti-TNF therapy plays a central role in the treatment of Blau syndrome. We recently performed an ex vivo study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in NOD2 lead to granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of Blau syndrome.

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Diagnosis and Treatment of Blau Syndrome/Early-onset Sarcoidosis, an Autoinflammatory Granulomatous Disease, in an Infant

Cited by 13 publications

References 11 publications

Blau Syndrome and Early-Onset Sarcoidosis: A Six Case Series and Review of the Literature

Blau Syndrome and Early-Onset Sarcoidosis: A Six Case Series and Review of the Literature

A Case of Sporadic Blau Syndrome with an Uncommon Clinical Course

Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis

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