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P. acnes detected by PAB antibody within the sarcoid granulomas of biopsied skin lesion. Hematoxylin and eosin stain and IHC with PAB antibody and LAM antibody as control are shown pairwise. a Noncaseating epithelioid cell granulomas in the dermis. b Higher magnification of the granuloma indicated by an arrow in (a). c No positive signal detected by LAM antibody in the identical granuloma. d Many round bodies detected by PAB antibody in the granuloma (arrows). Scale bar; 50 µm. IHC, immunohistochemistry; PAB, Propionibacterium acnes-specific monoclonal; LAM, mycobacteria-specific monoclonal
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Background
Early-onset sarcoidosis (EOS) and Blau syndrome (BS) are systemic inflammatory granulomatous diseases without visible pulmonary involvement, and are distinguishable from their sporadic and familial forms. The diseases are characterized by a triad of skin rashes, symmetrical polyarthritis, and recurrent uveitis. The most common morbidity...
Similar publications
Purpose: The study aimed to report a rare case of a patient with Alport syndrome, which was manifested as unilateral non-infectious uveitis after bilateral cataract surgery.
Methods: A case report.
Results: A 2-year-old boy was diagnosed with unilateral panuveitis based on the clinical and multimodal imaging findings. Intraocular fluid samples for...
Citations
... Sarcoidosis is associated with a high incidence of serious infections. In a large populationbased study that compared 8,737 individuals with sarcoidosis and 86,376 matched control subjects from the general population, patients with sarcoidosis [either untreated or treated with immunosuppressant medication] endure higher risk for severe infections compared to control subjects, suggesting that patients with sarcoidosis may feature an underlying immune deficit [197,[200][201][202]. ...
In humans, insulin resistance is a physiological response to infections developed to supply sufficient energy to the activated immune system. This metabolic adaptation facilitates the immune response but usually persists after the recovery period of the infection and predisposes the hosts to type 2 diabetes and vascular injury. In patients with diabetes, superimposed insulin resistance worsens metabolic control and promotes diabetic ketoacidosis. Pathogenic mechanisms underlying insulin resistance during microbial invasions remain to be fully defined. However, interferons cause insulin resistance in healthy subjects and other population groups, and their production is increased during infections, suggesting that this group of molecules may contribute to reduced insulin sensitivity. In agreement with this notion, gene expression profiles [transcriptomes] from patients with insulin resistance show a robust overexpression of interferon-stimulated genes [interferon signature]. In addition, serum levels of interferon and surrogates for interferon activity are elevated in patients with insulin resistance. Circulating levels of interferon-γ-inducible protein-10, neopterin, and apolipoprotein L1 correlate with insulin resistance manifestations, such as hypertriglyceridemia, reduced HDL-c, visceral fat, and homeostasis model assessment-insulin resistance. Furthermore, interferon downregulation improves insulin resistance. Antimalarials such as hydroxychloroquine reduce interferon production and improve insulin resistance, reducing the risk for type 2 diabetes and cardiovascular disease. In addition, diverse clinical conditions that feature interferon upregulation are associated with insulin resistance, suggesting that interferon may be a common factor promoting this adaptive response. Among these conditions are systemic lupus erythematosus, sarcoidosis, and infections with severe acute respiratory syndrome-coronavirus-2, human immunodeficiency virus, hepatitis C virus, and Mycobacterium tuberculosis.
... Nevertheless, in cases where their effectiveness is limited, alternative medications should be considered [6]. These medications include IL-1 and IL-1β inhibitors such as canakinumab [9], IL-6 inhibitors such as tocilizumab [6], intravenous human immunoglobulin (0.4 g/kg/ month) [10]. ...
... There have also been some novel treatments, including antibiotics (minocycline, doxycycline, and clarithromycin) [10] and thalidomide (less than 25 mg daily) [8]. However, these agents have been examined in case reports, and further, robust studies are required to substantiate these treatments. ...
Introduction
Blau syndrome is a progressive disease with an unknown etiology and pathogenesis. It can cause severe damage, especially in the eye with severe involvement.
Case Presentation
A six-year-old female was referred to us complaining about blurry vision and floaters in both eyes for 1 year. She had been diagnosed with Blau syndrome and Blau syndrome-associated anterior uveitis. Her best-corrected visual acuity in the right and left eyes was 20/70 and 20/80, respectively. Slit-lamp exam revealed faint bilateral band keratopathy along with 1+ anterior chamber cells and posterior synechia 360° in both eyes. During dilated fundoscopy, 2+ haze in the media was observed, along with swollen and hyperemic disc OU. Based on changes in optical coherence tomography, fluorescein angiography, and indocyanine green angiography, she was diagnosed with panuveitis and retinal vasculitis. Given her complicated history, we decided to proceed with an intravitreal fluocinolone acetonide 0.19 mg implant implantation in both eyes. During the 1-month follow-up visit, vitreous haze, retinal vasculitis, and active choroiditis were resolved. At 6-month follow-up visit, no changes were observed compared to the 1-month follow-up visit.
Conclusion
In cases of Blau syndrome that display resistance to systemic immunomodulatory therapies, the inclusion of local treatments, such as the intravitreal fluocinolone acetonide 0.19 mg implant, should be considered as an adjunctive therapeutic option.
... Unlike sporadic early-onset and adult sarcoidosis, BS is a hereditary autosomal dominant disease [4]. This disease is caused by mutations in the nucleotidebinding oligomerization domain containing 2 (NOD2), also called the caspase recruitment domain-containing protein 15 (CARD15) gene, located in chromosome 16, following bacterial interactions [5,6] or after vaccination [7], and leading to NF-κB (nuclear factor-kappa B) activation [7]. The most frequent mutations are p.R334W and p.R334Q [4,8]. ...
... In acute uveitis, high doses of CS, are mandatory and may be administrated orally (1-1.5 mg/kg/day), or pulsed intravenously. Low CS doses may be sufficient in the quiescent stage [4,6,21]. Ocular CS drops seem to be insufficient to control uveitis. ...
Blau syndrome is a rare genetic granulomatosis affecting children. It could be responsible for vision-threatening complications and articular deformation. Due to the rarity of this disease, there are no standardized guidelines for its management. This work aimed to provide an updated overview of the different therapeutic options for Blau syndrome. We conducted research in the PubMed database for the different treatments used in Blau syndrome patients, and we proposed a therapeutic algorithm for disease management. High doses of corticosteroids are considered as a bridging therapy in Blau syndrome. Methotrexate should be initiated if the patient has articular or ocular involvement. An anti-tumor necrosis factor α should be added for patients with uveitis or residual arthritis. If the patient remains symptomatic, a switch to another anti-tumor necrosis factor α is the best option. In non-responders to the first- and second-line biotherapies, a switch to an anti-interleukin 1, an anti-interleukin 6, or tofacitinib is necessary.
Conclusion: This article suggested an algorithm for the treatment of Blau syndrome. Other studies are necessary to confirm the efficacy of these treatments.
What is Known:
• Blau syndrome is a rare but severe granulomatosis that could be responsible for vision-threatening complications and articular deformation.
• Blau syndrome seems to be refractory to treatments.
What is New:
• High doses of corticosteroids are usually insufficient and should be considered only as a bridging therapy.
• Blau syndrome could be considered as a poor factor for uveitis, thus, an anti-tumor necrosis factor α should be initiated for patients with uveitis or with residual arthritis.
... However, the absent or subtle raise of acute phase reactants, lack of joint pain and joint destruction, and relatively well preserved range of motion in the large joints are more commonly observed in patients with BS/EOS and our proband [15]. Non-caseating granulomas in the synovial specimen are also in favor of BS/EOS [17,20]. ...
... Uveitis has been reported to affect up to 75% of the patients suffering BS/EOS and is predominately bilateral. Compared to the uveitis of JIA which is almost always anterior, panuveitis with typical multifocal choroidal scars is the most observed feature in BS/EOS uveitis [20,21]. Optic disc abnormalities, band keratopathy, cataract, glaucoma, retinal vasculitis, and macular edema are ocular complications which have also been reported [20,21]. ...
... Compared to the uveitis of JIA which is almost always anterior, panuveitis with typical multifocal choroidal scars is the most observed feature in BS/EOS uveitis [20,21]. Optic disc abnormalities, band keratopathy, cataract, glaucoma, retinal vasculitis, and macular edema are ocular complications which have also been reported [20,21]. Fortunately, the use of biologics, particularly TNF-α targeting monoclonal antibodies, have been shown to mitigate ocular inflammation and prevent blindness to a certain degree [8,21]. ...
Background
Blau syndrome (BS) is a rare autoinflammatory disorder with NOD2 gain-of-function mutation and characterized by autoactivation of the NFκB pathway. Classically considered a disease of high penetrance, reports on NOD2 mutations underlining BS with incomplete penetrance is limited.
Case presentation
The proband is a 9-year-old girl presented with brownish annular infiltrative plaques and symmetric boggy polyarthritis over bilateral wrists and ankles. Her skin biopsy revealed noncaseating granulomas inflammation with multinucleated giant cells. A novel C483W NOD2 mutation was identify in the proband and her asymptomatic father. Functional examinations including autoactivation of the NFκB pathway demonstrated by in vitro HEK293T NOD2 overexpression test as well as intracellular staining of phosphorylated-NFκB in patient’s CD11b⁺ cells were consistent with BS.
Conclusions
We reported a novel C483W NOD2 mutation underlining BS with incomplete penetrance. Moreover, a phosphorylated-NFκB intracellular staining assay of CD11b⁺ was proposed to assist functional evaluation of NFκB autoactivation in patient with BS.
... Other reports suggest that thalidomide may be effective in the treatment of Blau syndrome (36,48), but the number of cases is limited, and further studies are needed to evaluate the long-term efficacy and side effects. (40,43,44) • Local injection is effective for ocular symptoms (45) • Eye drops is effective for uveitis (43) • Local therapy is effective for uveitis (46) • Effective for skin lesions, joint symptoms, and uveitis (40) • No effect on uveitis (47) • Uveitis cannot be controlled with steroids alone and requires immunosuppressive agents and biologics (48)(49)(50) • Recurrence of ocular symptoms due to steroid reduction (46,51) • Growth retardation (48) • Hypertension (39,48) • Cataract (39) • Diabetes (39) • Avascular necrosis of hip (39) • Iatrogenic Cushing syndrome (51) • Elevated intraocular pressure (51) • Macular edema (52) • Retinal detachment (52) MTX ...
... Other reports suggest that thalidomide may be effective in the treatment of Blau syndrome (36,48), but the number of cases is limited, and further studies are needed to evaluate the long-term efficacy and side effects. (40,43,44) • Local injection is effective for ocular symptoms (45) • Eye drops is effective for uveitis (43) • Local therapy is effective for uveitis (46) • Effective for skin lesions, joint symptoms, and uveitis (40) • No effect on uveitis (47) • Uveitis cannot be controlled with steroids alone and requires immunosuppressive agents and biologics (48)(49)(50) • Recurrence of ocular symptoms due to steroid reduction (46,51) • Growth retardation (48) • Hypertension (39,48) • Cataract (39) • Diabetes (39) • Avascular necrosis of hip (39) • Iatrogenic Cushing syndrome (51) • Elevated intraocular pressure (51) • Macular edema (52) • Retinal detachment (52) MTX ...
... • Used with steroids to help reduce steroid use (39,41,53) • Effective for skin lesions (43) • Effective for joint symptoms (33) • Effective for mild joint symptoms (42) • Steroid combinations are effective for joint symptoms (47) • Relieves skin and joint symptoms (48) • Effective for uveitis (46) • Good visual prognosis with steroid combinations (54) • Often needs to be combined with other treatments (51) • Steroid combinations are not effective for joint symptoms (49,55) • NSAIDs combination is not effective for joint symptoms (55) • No effect on uveitis (47,50) • Steroid combinations are not effective for uveitis (47,48,50,51) • Steroid combinations are not effective for skin lesions, joint symptoms, and uveitis (48) Thalidomide ...
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.
... Table 1 summarizes the onset of symptoms, age at diagnosis, genetic variants, and management in other reported cases of Blau syndrome in Asia. [1][2][3][4][5][6][7][8][9][10] The 50 genetically proven cases in Japan, which are reviewed in a study by Matsuda et al., 11) are not included in the table because detailed information on each patient was not available. In most cases of their report, dermatitis appeared as the first manifestation, followed by arthritis and ocular involvement. ...
Sarcoidosis-associated uveitis, is the predominant ocular sarcoidosis presentation, which affects both adults and children. For adults, international ocular sarcoidosis criteria (IWOS) and sarcoidosis-associated uveitis criteria (SUN) are defined. However, for children they are not yet established internationally. Due to the specificity of pediatric manifestations of sarcoidosis, this task is even more challenging. In children, sarcoidosis is subdivided into Blau syndrome and early-onset sarcoidosis (BS/EOS) affecting younger children (< 5 years) and the one affecting older children with clinical presentation resembling adults. Differential diagnosis, clinical work-up as well as diagnostic criteria should be adapted to each age group. In this article, we review the clinical manifestation of sarcoidosis-associated uveitis in adults and children and the sensitivity and specificity of various ocular sarcoidosis diagnostic modalities, including chest X-ray and CT, FDG PET-CT, gallium-67 scintigraphy, bronchoalveolar lavage fluid, genetic testing for NOD2 mutations and serum biomarkers, such as ACE, lysozyme and IL2R.
Purpose of review:
The main purpose of this review is to present newly reported cutaneous manifestations of systemic vasculitis, updates in investigations to verify systemic involvement in cases with cutaneous vasculitis and new therapeutic guidelines. The spectrum of COVID-19-related vasculitis is also covered.
Recent findings:
Only a few reports highlighted new cutaneous presentations or associations with some systemic vasculitic entities. For example, the association of inflammatory disorders with Takayasu arteritis, the importance of considering Kawasaki disease in febrile children with erythema nodosum, the development of necrotic ulcers on fingers and toes in Behçet's disease and the possible presence of polyarteritis nodosa-like pathological features in vulvar ulcers of Behçet's disease. New attempts to classify cutaneous manifestations of giant cell arteritis (GCA) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and the diagnostic investigations for cutaneous vasculitis cases to verify systemic involvement are discussed. Treatment of systemic vasculitis with cutaneous vasculitis should be tailored according to disease status. A plethora of reports in the past 2 years focused on the broad spectrum of COVID-19 vasculitic manifestations.
Summary:
Although newly reported cutaneous manifestations of systemic vasculitis are relatively uncommon, the plethora of reports in the past 2 years on COVID-19 vasculitis necessitates the expansion of the classification of vasculitis associated with probable cause to include severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) vasculitis.
