Thrombotic Microangiopathy Associated with Macrophage Activation Syndrome: A Multinational Study of 23 Patients.

OBJECTIVE: To describe the clinical characteristics, treatment, and outcomes of a multinational cohort of patients with macrophage activation syndrome (MAS) and thrombotic microangiopathy (TMA). STUDY DESIGN: International pediatric rheumatologists were asked to collect retrospectively the data of patients with the co-occurrence of MAS and TMA. Clinical and laboratory features of patients with systemic juvenile idiopathic arthritis (sJIA)-associated MAS and TMA were compared with those of an historical cohort of patients with sJIA and MAS. RESULTS: Twenty-three patients with MAS and TMA were enrolled: 17 had sJIA, 2 systemic lupus erythematosus, 1 juvenile dermatomyositis, 1 mixed connective tissue disease, and 2 undifferentiated connective tissue disease. Compared with the historical cohort of MAS, patients with sJIA with coexistent MAS and TMA had higher frequencies of renal failure and neurologic involvement, hemorrhage, jaundice, and respiratory symptoms, as well as more severe anemia and thrombocytopenia, higher levels of alanine aminotransferase, lactate dehydrogenase, bilirubin and D-dimer, and lower levels of albumin and fibrinogen. They also required admission to the intensive care unit more frequently. Among patients tested, complement abnormalities and reduced ADAMTS13 activity were observed in 64.3% and 44.4% of cases, respectively. All patients received glucocorticoids. Treatment for TMA included plasma-exchange, eculizumab, and rituximab. CONCLUSIONS: The possible coexistence of MAS and TMA in rheumatic diseases may be underrecognized. This association should be considered in patients with MAS who develop disproportionate anemia, thrombocytopenia, and lactate dehydrogenase increase, or have multiorgan failure.

SEROLOGICAL SCREENING FOR CELIAC DISEASE IN CHILDREN WITH COLCHICINE-RESISTANT FAMILIAL MEDITERRANEAN FEVER.

BACKGROUND: Familial Mediterranean fever and celiac disease share some common clinical features such as abdominal pain, diarrhea, arthralgia and arthritis. Also, both of the diseases are associated with many inflammatory and autoimmune diseases. Previous studies have shown the association between familial Mediterranean fever (FMF) and different clinical conditions. OBJECTIVE: We aimed to investigate the relationship between celiac disease and colchicine-resistant familial Mediterranean fever (crFMF) disease. METHODS: This prospective study was conducted at the Department of Pediatric Gastroenterology and Pediatric Rheumatology from October 2015 to August 2016. A total of 24 patients with crFMF were included in the study. We used 60 sex- and age-matched healthy subjects as a control group. Levels of total IgA and tissue transglutaminase (tTG) IgA antibody were measured in both groups. Those with increased level of tTG IgA were tested for anti-endomysium IgA antibodies (EMA). Gastroduodenoscopy and intestinal biopsy were planned for a definite diagnosis of celiac disease in patients with positive EMA. RESULTS: Of the 24 patients in this study, 18 (75.0%) were female. Only 4 (16.6%) of 24 patients were positive for tTG IgA. Patients with positive tTG IgA were then tested for EMA IgA antibodies and none of them had a positive result. Only one (1.6%) subject from the control group was positive for tTG IgA but EMA positivity was not detected. CONCLUSION: We did not found celiac disease in 24 children with crFMF. Since crFMF disease is rarely seen in general population, further studies with more patients are needed to provide more precise interpretation.

Triagem sorológica para doença celíaca em crianças com febre familiar do mediterrâneo colchicina-resistente / Serological screening for celiac disease in children with colchicine-resistant familial mediterranean fever

ABSTRACT BACKGROUND: Familial Mediterranean fever and celiac disease share some common clinical features such as abdominal pain, diarrhea, arthralgia and arthritis. Also, both of the diseases are associated with many inflammatory and autoimmune diseases. Previous studies have shown the association between familial Mediterranean fever (FMF) and different clinical conditions. OBJECTIVE: We aimed to investigate the relationship between celiac disease and colchicine-resistant familial Mediterranean fever (crFMF) disease. METHODS: This prospective study was conducted at the Department of Pediatric Gastroenterology and Pediatric Rheumatology from October 2015 to August 2016. A total of 24 patients with crFMF were included in the study. We used 60 sex- and age-matched healthy subjects as a control group. Levels of total IgA and tissue transglutaminase (tTG) IgA antibody were measured in both groups. Those with increased level of tTG IgA were tested for anti-endomysium IgA antibodies (EMA). Gastroduodenoscopy and intestinal biopsy were planned for a definite diagnosis of celiac disease in patients with positive EMA. RESULTS: Of the 24 patients in this study, 18 (75.0%) were female. Only 4 (16.6%) of 24 patients were positive for tTG IgA. Patients with positive tTG IgA were then tested for EMA IgA antibodies and none of them had a positive result. Only one (1.6%) subject from the control group was positive for tTG IgA but EMA positivity was not detected. CONCLUSION: We did not found celiac disease in 24 children with crFMF. Since crFMF disease is rarely seen in general population, further studies with more patients are needed to provide more precise interpretation.

RESUMO CONTEXTO: A febre familiar do Mediterrâneo e a doença celíaca compartilham algumas características clínicas comuns, tais como dor abdominal, diarreia, artralgia e artrite. Além disso, ambas as doenças são associadas a muitas doenças auto-imunes e inflamatórias. Estudos anteriores mostraram associação entre febre familiar do Mediterrâneo e diferentes condições clínicas. OBJETIVO: Investigar a relação entre doença celíaca e doença de febre familiar do Mediterrâneo colchicina-resistente (FMFcr). MÉTODOS: Foi realizado um estudo prospectivo no departamento de Gastroenterologia pediátrica e Reumatologia pediátrica de outubro de 2015 até agosto de 2016. Um total de 24 pacientes com FMFcr foram incluídos. Sessenta indivíduos saudáveis combinados por sexo e idade foram utilizados como um grupo de controle. Os níveis de IgA total e transglutaminase tissular (tTG) anticorpo IgA foram medidos em ambos os grupos. Aqueles com maior nível de tTG IgA foram testados para anticorpos de IgA antiendomísio (EMA). Gastroduodenoscopia e biópsia intestinal foram planejadas para um diagnóstico definitivo da doença celíaca em pacientes com EMA positivo. RESULTADOS: Dos 24 pacientes neste estudo, 18 (75,0%) eram do sexo feminino. Somente 4 (16,6%) de 24 pacientes foram positivos para tTG IgA. Pacientes com tTG IgA positivo então foram testados para anticorpos IgA de EMA, e nenhum deles teve um resultado positivo. Somente um (1,6%) indivíduo do grupo controle foi positivo para tTG IgA, mas a positividade EMA não foi detectada. CONCLUSÃO: Não encontramos a doença celíaca em 24 crianças com FMFcr. Desde que a doença FMFcr é raramente vista na população em geral, estudos com mais pacientes são necessários para fornecer interpretação mais precisa.

PFAPA Syndrome in a Population with Endemic Familial Mediterranean Fever.

We reviewed the medical records of patients with periodic fever, aphthosis, pharyngitis, and adenitis (PFAPA) to investigate the clinical course, treatment response, and association with MEFV gene mutation. Familial Mediterranean fever should be considered in patients with PFAPA who do not respond to adenotonsillectomy.

Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome.

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

An unusual case of childhood sarcoidosis: an unusual clinical case.

Sarcoidosis is a systemic granulomatous disease of unknown etiology that may affect many systems, mainly lungs. Most of the patients present at stages I and II lung involvement. Pulmonary infltrates without hilar lymphadenopathy (state III) rarely occurs. Extrapulmonary organ involvement is common in pediatric sarcoidosis. The aim of this report is to present an unusual case of childhood sarcoidosis with stage III lung involvement without any extrapulmonary organ involvement. A 7-year-old girl presented with the complaints of malaise, fatigue, weight loss and dyspnea. There was patchy, bilateral ground glass view at high resolution computer tomography. Video assisted thoracoscopic lung biopsy was performed and histopathological examination showed nonnecrotising epitheloid-cell granulomas with giant cells. She did not have any hilar or extrapulmonary organ involvement and pulmonary sarcoidosis at stage III was diagnosed. Sarcoidosis should be considered in the differential diagnosis of children with interstitial lung disease.

An unusual case of childhood sarcoidosis: Un caso clínico infrecuente / Sarcoidosis infantil

Sarcoidosis is a systemic granulomatous disease of unknown etiology that may affect many systems, mainly lungs. Most of the patients present at stages I and II lung involvement. Pulmonary infltrates without hilar lymphadenopathy (state III) rarely occurs. Extrapulmonary organ involvement is common in pediatric sarcoidosis. The aim of this report is to present an unusual case of childhood sarcoidosis with stage III lung involvement without any extrapulmonary organ involvement. A 7-year-old girl presented with the complaints of malaise, fatigue, weight loss and dyspnea. There was patchy, bilateral ground glass view at high resolution computer tomography. Video assisted thoracoscopic lung biopsy was performed and histopathological examination showed nonnecrotising epitheloid-cell granulomas with giant cells. She did not have any hilar or extrapulmonary organ involvement and pulmonary sarcoidosis at stage III was diagnosed. Sarcoidosis should be considered in the differential diagnosis of children with interstitial lung disease.

La sarcoidosis es una enfermedad granulomatosa sistémica de etiología desconocida que puede afectar varios órganos, principalmente el pulmón. La mayoría de los pacientes presentan estadios I y II de compromiso pulmonar. Los infltrados pulmonares, sin linfadenopatías hiliares (estadio III), son infrecuentes. El compromiso de órganos extrapulmonares es común en la sarcoidosis infantil. El objetivo es presentar un caso infrecuente de sarcoidosis infantil con compromiso pulmonar en estadio III sin afectación de los órganos extrapulmonares. Una niña de 7 años consultó por malestar general, fatiga, pérdida de peso y disnea. En la tomografía computarizada de alta resolución se observó un infltrado bilateral de tipo esmerilado. Se realizó una biopsia pulmonar por videotoracoscopia. La histopatología mostró granulomas no necrosantes de células epitelioides con células gigantes. No había compromiso hiliar ni de otros órganos, por lo que el diagnóstico fue de sarcoidosis en estadio III. La sarcoidosis debe considerarse en el diagnóstico diferencial de los niños con enfermedad intersticial pulmonar.

An unusual case of childhood sarcoidosis: Un caso clínico infrecuente / Sarcoidosis infantil

Sarcoidosis is a systemic granulomatous disease of unknown etiology that may affect many systems, mainly lungs. Most of the patients present at stages I and II lung involvement. Pulmonary infltrates without hilar lymphadenopathy (state III) rarely occurs. Extrapulmonary organ involvement is common in pediatric sarcoidosis. The aim of this report is to present an unusual case of childhood sarcoidosis with stage III lung involvement without any extrapulmonary organ involvement. A 7-year-old girl presented with the complaints of malaise, fatigue, weight loss and dyspnea. There was patchy, bilateral ground glass view at high resolution computer tomography. Video assisted thoracoscopic lung biopsy was performed and histopathological examination showed nonnecrotising epitheloid-cell granulomas with giant cells. She did not have any hilar or extrapulmonary organ involvement and pulmonary sarcoidosis at stage III was diagnosed. Sarcoidosis should be considered in the differential diagnosis of children with interstitial lung disease.(AU)

La sarcoidosis es una enfermedad granulomatosa sistémica de etiología desconocida que puede afectar varios órganos, principalmente el pulmón. La mayoría de los pacientes presentan estadios I y II de compromiso pulmonar. Los infltrados pulmonares, sin linfadenopatías hiliares (estadio III), son infrecuentes. El compromiso de órganos extrapulmonares es común en la sarcoidosis infantil. El objetivo es presentar un caso infrecuente de sarcoidosis infantil con compromiso pulmonar en estadio III sin afectación de los órganos extrapulmonares. Una niña de 7 años consultó por malestar general, fatiga, pérdida de peso y disnea. En la tomografía computarizada de alta resolución se observó un infltrado bilateral de tipo esmerilado. Se realizó una biopsia pulmonar por videotoracoscopia. La histopatología mostró granulomas no necrosantes de células epitelioides con células gigantes. No había compromiso hiliar ni de otros órganos, por lo que el diagnóstico fue de sarcoidosis en estadio III. La sarcoidosis debe considerarse en el diagnóstico diferencial de los niños con enfermedad intersticial pulmonar.(AU)

An unusual case of childhood sarcoidosis: an unusual clinical case / An unusual case of childhood sarcoidosis: an unusual clinical case.

Sarcoidosis is a systemic granulomatous disease of unknown etiology that may affect many systems, mainly lungs. Most of the patients present at stages I and II lung involvement. Pulmonary infltrates without hilar lymphadenopathy (state III) rarely occurs. Extrapulmonary organ involvement is common in pediatric sarcoidosis. The aim of this report is to present an unusual case of childhood sarcoidosis with stage III lung involvement without any extrapulmonary organ involvement. A 7-year-old girl presented with the complaints of malaise, fatigue, weight loss and dyspnea. There was patchy, bilateral ground glass view at high resolution computer tomography. Video assisted thoracoscopic lung biopsy was performed and histopathological examination showed nonnecrotising epitheloid-cell granulomas with giant cells. She did not have any hilar or extrapulmonary organ involvement and pulmonary sarcoidosis at stage III was diagnosed. Sarcoidosis should be considered in the differential diagnosis of children with interstitial lung disease.

An unusual case of childhood sarcoidosis: an unusual clinical case. / An unusual case of childhood sarcoidosis: an unusual clinical case.

Sarcoidosis is a systemic granulomatous disease of unknown etiology that may affect many systems, mainly lungs. Most of the patients present at stages I and II lung involvement. Pulmonary infltrates without hilar lymphadenopathy (state III) rarely occurs. Extrapulmonary organ involvement is common in pediatric sarcoidosis. The aim of this report is to present an unusual case of childhood sarcoidosis with stage III lung involvement without any extrapulmonary organ involvement. A 7-year-old girl presented with the complaints of malaise, fatigue, weight loss and dyspnea. There was patchy, bilateral ground glass view at high resolution computer tomography. Video assisted thoracoscopic lung biopsy was performed and histopathological examination showed nonnecrotising epitheloid-cell granulomas with giant cells. She did not have any hilar or extrapulmonary organ involvement and pulmonary sarcoidosis at stage III was diagnosed. Sarcoidosis should be considered in the differential diagnosis of children with interstitial lung disease.

Prevalence of the MEFV gene mutations in childhood polyarteritis nodosa.

OBJECTIVES: To test the hypothesis that alterations in the Mediterranean fever (MEFV) gene are a susceptibility factor for the development of polyarteritis nodosa (PAN) we investigated the prevalence of MEFV mutations in patients with PAN without any symptoms of familial Mediterranean fever (FMF). STUDY DESIGN: Pediatric patients with PAN (n = 29) were enrolled in this study. Six predominant mutations (p.M694V, p.M680I, p.M694I, p.V726A, p.K695R, p.E148Q) in the MEFV gene were studied. RESULTS: Fifteen MEFV mutations were identified in 58 chromosomes. Eleven of the 29 patients (38%) were found to carry MEFV mutations. Three (10.3%) of them had homozygous p.M694V mutation, and one of the patients (3.4%) had compound heterozygous mutation (p.V726A/p.E148Q). CONCLUSIONS: Our study confirms that alterations in the MEFV gene are important susceptibility factors for the development of PAN. We believe that mutations in MEFV gene provide a basis for the development of PAN both by forming a proinflammatory state and by possibly giving exaggerated response to streptococcal infections.

Juvenile polyarteritis: results of a multicenter survey of 110 children.

OBJECTIVE: To characterize pediatric patients who had been diagnosed with polyarteritis nodosa (PAN) through necrotizing vasculitis of the small and mid-size arteries or those with characteristic findings on angiograms data were collected. STUDY DESIGN: Pediatricians were asked to classify their patients into one of the four suggested groups for juvenile PAN. Twenty-one pediatric centers worldwide participated with 110 patients. RESULTS: The girl:boy ratio was 56:54, with a mean age of 9.05 +/- 3.57 years. The cases were classified as: 33 (30%) cutaneous PAN; 5 (4.6%) classic PAN associated with hepatitis B surface antigen (HBs Ag); 9 (8.1%) microscopic polyarteritis of adults associated with antineutrophil cytoplasmic antibodies (ANCA); and 63 (57.2%) systemic PAN. Cutaneous PAN was disease confined to the skin and musculoskeletal system. All patients with HBs Ag-associated classic PAN were diagnosed with renal angiograms. Antiviral treatment was administered in most cases. Microscopic PAN patients had pulmonary-renal disease, in combination or separately. ANCA was present in 87%, and 2 patients progressed to end-stage renal failure. Patients classified with systemic PAN had multiple system involvement, almost all had constitutional symptoms, and all had elevated acute phase reactants. Corticosteroids and cyclophosphamide were the first choices of immunosuppressive treatment. The overall mortality was 1.1%. CONCLUSIONS: There were remarkable differences among pediatric patients with PAN, with different clinical manifestations and overall better survival and lower relapse rates when compared with adults.