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1.
Pediatr Rheumatol Online J ; 18(1): 17, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066461

RESUMO

BACKGROUND: Rare autoinflammatory diseases (AIDs) including Cryopyrin-Associated Periodic Syndrome (CAPS), Tumor Necrosis Receptor-Associated Periodic Syndrome (TRAPS) and Mevalonate Kinase Deficiency Syndrome (MKD)/ Hyper-IgD Syndrome (HIDS) are genetically defined and characterized by recurrent fever episodes and inflammatory organ manifestations. Early diagnosis and early start of effective therapies control the inflammation and prevent organ damage. The PRO-KIND initiative of the German Society of Pediatric Rheumatology (GKJR) aims to harmonize the diagnosis and management of children with rheumatic diseases nationally. The task of the PRO-KIND CAPS/TRAPS/MKD/HIDS working group was to develop evidence-based, consensus diagnosis and management protocols including the first AID treat-to-target strategies. METHODS: The national CAPS/TRAPS/MKD/HIDS expert working group was established, defined its aims and conducted a comprehensive literature review synthesising the recent (2013 to 2018) published evidence including all available recommendations for diagnosis and management. General and disease-specific statements were anchored in the 2015 SHARE recommendations. An iterative expert review process discussed, adapted and refined these statements. Ultimately the GKJR membership vetted the proposed consensus statements, agreement of 80% was mandatory for inclusion. The approved statements were integrated into three disease specific consensus treatment plans (CTPs). These were developed to enable the implementation of evidence-based, standardized care into clinical practice. RESULTS: The CAPS/TRAPS/MKD/HIDS expert working group of 12 German and Austrian paediatric rheumatologists completed the evidence synthesis and modified a total of 38 statements based on the SHARE recommendation framework. In iterative reviews 36 reached the mandatory agreement threshold of 80% in the final GKJR member survey. These included 9 overarching principles and 27 disease-specific statements (7 for CAPS, 11 TRAPS, 9 MKD/HIDS). A diagnostic algorithm was established based on the synthesized evidence. Statements were integrated into diagnosis- and disease activity specific treat-to-target CTPs for CAPS, TRAPS and MKD/HIDS. CONCLUSIONS: The PRO-KIND CAPS/TRAPS/MKD/HIDS working group established the first evidence-based, actionable treat-to-target consensus treatment plans for three rare hereditary autoinflammatory diseases. These provide a path to a rapid evaluation, effective control of disease activity and tailored adjustment of therapies. Their implementation will decrease variation in care and optimize health outcomes for children with AID.

2.
Vaccine ; 38(7): 1810-1817, 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-31879123

RESUMO

BACKGROUND AND AIMS: Immunosuppressed patients are at risk of severe infections with vaccination preventable diseases. We evaluated vaccination rate and immunity of children and adolescents with inflammatory bowel disease (IBD) and autoimmune hepatitis (AIH). METHODS: Immunization rate of 329 children with IBD (n = 300) and AIH (n = 29) was assessed in seven German centres using vaccination certificates, history of chicken pox and by determining anti-varicella zoster virus (VZV) and anti-measles IgG antibodies. RESULTS: Of the total cohort 86% received long-term immunosuppression. Four doses of a hexavalent vaccine were documented in 89%, at least one dose of measles, mumps, and rubella (MMR) vaccination was documented in 325 (99%), with 300 (92%) receiving two doses. Anti-measles IgG concentrations were insufficient in 11% of the immunized patients. VZV vaccination was officially recommended in Germany since 2004, and implemented in 88% born from 2005 onwards. In patients born earlier VZV catch up vaccination only reached 25% (n = 67). Of 118 patients with documented VZV vaccination 25 (21%) did not display sufficient anti-VZV IgG. Of 198 patients with a history of chicken pox, six had undetectable anti-VZV IgG. Of 29 patients having neither had chicken pox nor VZV vaccination, 20 were found to have sufficient anti-VZV IgG. CONCLUSIONS: In our cohort vaccination coverage for hexavalent and MMR vaccinations was good, but insufficient for VZV vaccination in patients born before 2005. Neither the vaccination certificate nor the history of chicken pox is reliable to predict VZV immunity indicating a need for serologic investigations and if needed vaccination before initiating immunosuppressive therapy.

3.
Genet Med ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31761904

RESUMO

PURPOSE: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. METHODS: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. RESULTS: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the ß-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). CONCLUSION: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

4.
Arthritis Rheumatol ; 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31599092

RESUMO

OBJECTIVE: To analyze the reported association of IL1RN polymorphisms with response to interleukin-1 (IL-1) blockade in a German cohort of patients with systemic juvenile idiopathic arthritis (JIA), and to assess the impact of other factors on treatment response. METHODS: Sixty-one patients with systemic JIA who had received IL-1 blockade were identified within the German Autoinflammatory Disease registry DNA biobank. Response to IL-1 blockade was assessed according to 1) the clinical response (initially at least a transient response or good response compared to a poor response), 2) switch (or no switch) to anti-IL-6 receptor therapy following IL-1 blockade, 3) achievement of clinically inactive disease within 6 months of IL-1 blockade, 4) improvement in disease activity measured using the modified Juvenile Arthritis Disease Activity Score, and 5) achievement of a glucocorticoid-free state. In addition, basic demographic data, key features of the disease course, laboratory data, and IL1RN single-nucleotide polymorphisms (SNPs) were assessed. RESULTS: Six of 7 IL1RN SNPs reported to be associated with response to anakinra therapy were analyzed. These 6 IL1RN SNPs were inherited as haplotypes. An association of IL1RN haplotypes and SNPs with response to IL-1 blockade could not be confirmed in this cohort of patients with systemic JIA. Patients who received tocilizumab following IL-1 blockade had a longer duration from disease onset to diagnosis than those who did not receive tocilizumab (median 0.27 years versus 0.08 years). CONCLUSION: The results of this study could not confirm an impact of IL1RN SNPs on response to IL-1 blockade therapy with either anakinra or canakinumab in a cohort of patients with systemic JIA. However, a longer time frame from disease onset to diagnosis was associated with poorer long-term treatment response, thereby supporting the "window of opportunity" hypothesis that suggests improved long-term treatment response with shorter time from disease onset to diagnosis (and treatment).

5.
Ann Rheum Dis ; 78(8): 1107-1113, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31005900

RESUMO

OBJECTIVES: The International League of Associations for Rheumatology classification criteria define systemic juvenile idiopathic arthritis (SJIA) by the presence of fever, rash and chronic arthritis. Recent initiatives to revise current criteria recognise that a lack of arthritis complicates making the diagnosis early, while later a subgroup of patients develops aggressive joint disease. The proposed biphasic model of SJIA also implies a 'window of opportunity' to abrogate the development of chronic arthritis. We aimed to identify novel SJIA biomarkers during different disease phases. METHODS: Children with active SJIA were subgrouped clinically as systemic autoinflammatory disease with fever (SJIA syst ) or polyarticular disease (SJIA poly ). A discovery cohort of n=10 patients per SJIA group, plus n=10 with infection, was subjected to unbiased label-free liquid chromatography mass spectrometry (LC-MS/MS) and immunoassay screens. In a separate verification cohort (SJIA syst , n=45; SJIA poly , n=29; infection, n=32), candidate biomarkers were measured by multiple reaction monitoring MS (MRM-MS) and targeted immunoassays. RESULTS: Signatures differentiating the two phenotypes of SJIA could be identified. LC-MS/MS in the discovery cohort differentiated SJIA syst from SJIA poly well, but less effectively from infection. Targeted MRM verified the discovery data and, combined with targeted immunoassays, correctly identified 91% (SJIA syst vs SJIA poly ) and 77% (SJIA syst vs infection) of all cases. CONCLUSIONS: Molecular signatures differentiating two phenotypes of SJIA were identified suggesting shifts in underlying immunological processes in this biphasic disease. Biomarker signatures separating SJIA in its initial autoinflammatory phase from the main differential diagnosis (ie, infection) could aid early-stage diagnostic decisions, while markers of a phenotype switch could inform treat-to-target strategies.

6.
Pediatrics ; 143(2)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30705142

RESUMO

Pediatric intractable autoimmune hepatitis is rare and may be responsible for acute liver failure. Mutations in the itchy E3 ubiquitin protein ligase (ITCH) gene (located on chromosome 20q11.22) can lead to a deficiency of the encoded protein, resulting in increased T-cell activity with lack of immune tolerance and manifestation of a complex systemic autoimmune disease. A 1-year-old girl of consanguineous parents received a liver transplant (LT) because of acute liver failure attributed to a drug-induced hypereosinophilic syndrome with positive liver-kidney-mikrosome-2 antibodies. Notable findings were syndromic features, dystrophy, short stature, psychomotor retardation, and muscular hypotonia. Later, we saw corticosteroid-sensitive rejections as well as a systemic autoimmune disease with detection of specific antibodies (de novo autoimmune hepatitis, thyroiditis with exophthalmos, diabetes mellitus type 1, and immune neutropenia). Histologically, liver cirrhosis with lobular inflammatory infiltrates, giant-cell hepatitis, and ductopenia was verified in chronic cholestasis. Shortly after a second LT, a comparable liver histology could be detected, and viral, bacterial, and mycotic infections deteriorated the general health condition. Because of refractory pancytopenia related to portal hypertension and hypersplenism, a posttransplant lymphoproliferative disorder was excluded. One year after the second LT, epidural and subdural bleeding occurred. Three months afterward, the girl died of sepsis. Postmortem, whole-exome sequencing revealed a homozygous mutation in the ITCH gene. A biallelic mutation in ITCH can cause a severe syndromic multisystem autoimmune disease with the above phenotypic characteristics and acute liver failure because of autoimmune hepatitis. This case reveals the importance of ubiquitin pathways for regulation of the immune system.


Assuntos
Hepatite Autoimune/genética , Falência Hepática Aguda/genética , Transplante de Fígado/tendências , Mutação/genética , Proteínas Repressoras/genética , Ubiquitina-Proteína Ligases/genética , Sequência de Bases , Pré-Escolar , Evolução Fatal , Feminino , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/cirurgia , Humanos , Lactente , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/cirurgia
7.
J Pediatr Surg ; 54(8): 1686-1690, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30497819

RESUMO

PURPOSE: Extrahepatic portal vein thrombosis (EPVT) is one major cause of portal hypertension in children. Surgical reinstallation of portal venous flow can be achieved in patients with patent intrahepatic portal venous system/Rex recess. Our study aimed to compare the ability of magnetic resonance imaging (MRI) and retrograde portography (RP) to assess patency of the intrahepatic portal venous system in children with EPVT. METHODS: All pediatric patients with EPVT who were examined with contrast enhanced MRI (1.5 T) and invasive RP between 2013 and 2017 were included in this retrospective study. Medical records were reviewed for demographic, biochemical and clinical data. Patency of the Rex recess as detected by MRI and RP was retrospectively reviewed. RESULTS: Sixteen children (7.6 ±â€¯5.0 years) with EPVT were included. Sensitivity, specificity, positive and negative predictive value for the detection of patent Rex recess by MRI compared to RP were 55%, 57%, 63% and 50%. Diagnostic accuracy was 56%. Diagnostic failure of MRI compared to RP was explained by the following: I. Problems differentiating collaterals from portal venous vessels II. Incapability showing dynamic blood flow in compromised portal venous flow III. Poor spatial resolution, especially in small children. CONCLUSION: RP is a reliable method for the visualization of the Rex recess and the intrahepatic portal venous system in children with EPVT, whereas MRI has shown to be unsuitable for the assessment of the intrahepatic portal vein in these patients. In the preoperative setup, we recommend both procedures, RP and MRI for the visualization of the intrahepatic portal venous system, and the extrahepatic vessels, respectively. LEVEL OF EVIDENCE: Level III.


Assuntos
Imagem por Ressonância Magnética , Veia Porta/diagnóstico por imagem , Portografia , Trombose Venosa/diagnóstico por imagem , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Veia Porta/cirurgia , Valor Preditivo dos Testes , Estudos Retrospectivos , Trombose Venosa/cirurgia
8.
Pediatr Rheumatol Online J ; 16(1): 40, 2018 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-29940960

RESUMO

BACKGROUND: Juvenile dermatomyositis (JDM) is the most common inflammatory myopathy in childhood and a major cause of morbidity among children with pediatric rheumatic diseases. The management of JDM is very heterogeneous. The JDM working group of the Society for Pediatric Rheumatology (GKJR) aims to define consensus- and practice-based strategies in order to harmonize diagnosis, treatment and monitoring of JDM. METHODS: The JDM working group was established in 2015 consisting of 23 pediatric rheumatologists, pediatric neurologists and dermatologists with expertise in the management of JDM. Current practice patterns of management in JDM had previously been identified via an online survey among pediatric rheumatologists and neurologists. Using a consensus process consisting of online surveys and a face-to-face consensus conference statements were defined regarding the diagnosis, treatment and monitoring of JDM. During the conference consensus was achieved via nominal group technique. Voting took place using an electronic audience response system, and at least 80% consensus was required for individual statements. RESULTS: Overall 10 individual statements were developed, finally reaching a consensus of 92 to 100% regarding (1) establishing a diagnosis, (2) case definitions for the application of the strategies (moderate and severe JDM), (3) initial diagnostic testing, (4) monitoring and documentation, (5) treatment targets within the context of a treat-to-target strategy, (6) supportive therapies, (7) explicit definition of a treat-to-target strategy, (8) various glucocorticoid regimens, including intermittent intravenous methylprednisolone pulse and high-dose oral glucocorticoid therapies with tapering, (9) initial glucocorticoid-sparing therapy and (10) management of refractory disease. CONCLUSION: Using a consensus process among JDM experts, statements regarding the management of JDM were defined. These statements and the strategies aid in the management of patients with moderate and severe JDM.


Assuntos
Dermatomiosite/tratamento farmacológico , Antirreumáticos/uso terapêutico , Áustria , Criança , Consenso , Dermatomiosite/diagnóstico , Gerenciamento Clínico , Alemanha , Glucocorticoides/uso terapêutico , Humanos , Inquéritos e Questionários
9.
Pediatr Rheumatol Online J ; 16(1): 7, 2018 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-29357887

RESUMO

BACKGROUND: Systemic juvenile idiopathic arthritis (SJIA) is an autoinflammatory disease associated with chronic arthritis. Early diagnosis and effective therapy of SJIA is desirable, so that complications are avoided. The PRO-KIND initiative of the German Society for Pediatric Rheumatology (GKJR) aims to define consensus-based strategies to harmonize diagnostic and therapeutic approaches in Germany. METHODS: We analyzed data on patients diagnosed with SJIA from 3 national registries in Germany. Subsequently, via online surveys and teleconferences among pediatric rheumatologists with a special expertise in the treatment of SJIA, we identified current diagnostic and treatment approaches in Germany. Those were harmonized via the formulation of statements and, supported by findings from a literature search. Finally, an in-person consensus conference using nominal group technique was held to further modify and consent the statements. RESULTS: Up to 50% of patients diagnosed with SJIA in Germany do not fulfill the International League of Associations for Rheumatology (ILAR) classification criteria, mostly due to the absence of chronic arthritis. Our findings suggest that chronic arthritis is not obligatory for the diagnosis and treatment of SJIA, allowing a diagnosis of probable SJIA. Malignant, infectious and hereditary autoinflammatory diseases should be considered before rendering a diagnosis of probable SJIA. There is substantial variability in the initial treatment of SJIA. Based on registry data, most patients initially receive systemic glucocorticoids, however, increasingly substituted or accompanied by biological agents, i.e. interleukin (IL)-1 and IL-6 blockade (up to 27.2% of patients). We identified preferred initial therapies for probable and definitive SJIA, including step-up patterns and treatment targets for the short-term (resolution of fever, decrease in C-reactive protein by 50% within 7 days), the mid-term (improvement in physician global and active joint count by at least 50% or a JADAS-10 score of maximally 5.4 within 4 weeks) and the long-term (glucocorticoid-free clinically inactive disease within 6 to 12 months), and an explicit treat-to-target strategy. CONCLUSIONS: We developed consensus-based strategies regarding the diagnosis and treatment of probable or definitive SJIA in Germany.


Assuntos
Artrite Juvenil/diagnóstico , Padrões de Prática Médica/estatística & dados numéricos , Antirreumáticos/uso terapêutico , Artrite Juvenil/tratamento farmacológico , Fatores Biológicos/uso terapêutico , Criança , Pré-Escolar , Consenso , Bases de Dados Factuais , Alemanha , Glucocorticoides/uso terapêutico , Humanos , Sistema de Registros
10.
Rheumatology (Oxford) ; 56(9): 1597-1606, 2017 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-28859329

RESUMO

Objectives: The aim was to analyse factors influencing the individual colchicine dose in children with FMF, to evaluate the impact of dose adjustment on the clinical course and inflammation and to identify clinical parameters and biomarkers that predict dose increase in the near future. Methods: Data from 409 paediatric FMF patients (4566 visits) derived from the national auto-inflammatory diseases registry were analysed. Serum concentrations of S100 molecules were determined by ELISA. Results: The age-dependent colchicine dose is influenced by the present genotype. The body surface area is the anthropometric parameter that correlates best with the applied dosages. Colchicine introduction and dose increase lead to significant reduction of clinical symptoms and inflammation. During established colchicine therapy, an increase of one single biomarker increases the likelihood of a dose increment in the next 12 months with a factor of 1.62-1.94. A combination of biomarkers including S100 molecules increases this odds ratio up to 4.66 when analysing all patients and up to 7.27 when analysing patients with a high risk of severe disease. Conclusion: Colchicine therapy is currently guided mainly by the occurrence of clinical symptoms and serological inflammation. Other factors, such as the genotype, the body surface area and biomarkers, will help to manage colchicine therapy in a more individualized fashion. The additional analysis of S100 molecules as sensitive biomarkers will help to identify patients at risk for dose increases in the near future.


Assuntos
Colchicina/administração & dosagem , Febre Familiar do Mediterrâneo/tratamento farmacológico , Adolescente , Fatores Etários , Antropometria/métodos , Biomarcadores/sangue , Superfície Corporal , Criança , Pré-Escolar , Colchicina/efeitos adversos , Colchicina/uso terapêutico , Relação Dose-Resposta a Droga , Esquema de Medicação , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/genética , Feminino , Genótipo , Humanos , Masculino , Prognóstico , Sistema de Registros , Proteínas S100/sangue , Índice de Gravidade de Doença
11.
J Hepatol ; 67(6): 1253-1264, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28733223

RESUMO

BACKGROUND & AIMS: The bile salt export pump (BSEP, ABCB11), multidrug resistance protein 3 (MDR3, ABCB4) and the ATPase familial intrahepatic cholestasis 1 (FIC1, ATP8B1) mediate bile formation. This study aimed to determine the contribution of mutations and common variants in the FIC1, BSEP and MDR3 genes to cholestatic disorders of differing disease onset and severity. METHODS: Coding exons with flanking intron regions of ATP8B1, ABCB11, and ABCB4 were sequenced in cholestatic patients with assumed genetic cause. The effects of new variants were evaluated by bioinformatic tools and 3D protein modeling. RESULTS: In 427 patients with suspected inherited cholestasis, 149 patients carried at least one disease-causing mutation in FIC1, BSEP or MDR3, respectively. Overall, 154 different mutations were identified, of which 25 were novel. All 13 novel missense mutations were disease-causing according to bioinformatics analyses and homology modeling. Eighty-two percent of patients with at least one disease-causing mutation in either of the three genes were children. One or more common polymorphism(s) were found in FIC1 in 35.3%, BSEP in 64.3% and MDR3 in 72.6% of patients without disease-causing mutations in the respective gene. Minor allele frequencies of common polymorphisms in BSEP and MDR3 varied in our cohort compared to the general population, as described by gnomAD. However, differences in ethnic background may contribute to this effect. CONCLUSIONS: In a large cohort of patients, 154 different variants were detected in FIC1, BSEP, and MDR3, 25 of which were novel. In our cohort, frequencies for risk alleles of BSEP (p.V444A) and MDR3 (p.I237I) polymorphisms were significantly overrepresented in patients without disease-causing mutation in the respective gene, indicating that these common variants can contribute to a cholestatic phenotype. LAY SUMMARY: FIC1, BSEP, and MDR3 represent hepatobiliary transport proteins essential for bile formation. Genetic variants in these transporters underlie a broad spectrum of cholestatic liver diseases. To confirm a genetic contribution to the patients' phenotypes, gene sequencing of these three major cholestasis-related genes was performed in 427 patients and revealed 154 different variants of which 25 have not been previously reported in a database. In patients without a disease-causing mutation, common genetic variants were detected in a high number of cases, indicating that these common variants may contribute to cholestasis development.


Assuntos
Membro 11 da Subfamília B de Transportadores de Cassetes de Ligação de ATP/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Adenosina Trifosfatases/genética , Colestase/genética , Mutação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Variação Genética , Humanos , Lactente , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Adulto Jovem
12.
Int J Rheum Dis ; 20(12): 2093-2100, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24467729

RESUMO

AIM: To determine the prevalence of anxiety and depression among patients with familial Mediterranean fever (FMF) living in Germany or Turkey a prospective study was conducted. METHODS: Forty FMF patients living in Turkey (T), 40 FMF patients living in Germany (G) and 40 healthy controls living in Germany (C) were included. Patients and controls were of Turkish ancestry. G were compared to T and C. The Hospital Anxiety and Depression Scale (HADS) was used with a cut-off of ≥ 8 for each subdomain score (HADS-A, HADS-D). RESULTS: Baseline characteristics of G were comparable to T and C except for age (T: 30.5 years, G: 35.2 years, C: 34.6 years; T vs. G P = 0.045), duration of disease (T: 14.4 years, G: 24; P < 0.001), C-reactive protein (T: 0.78 mg/dL, G: 0.78 mg/dL, C: 0.35 mg/dL; G vs. C P = 0.03). Prevalence of anxiety was higher in G compared to C (T: 65%, G: 52.5%, C: 22.5%: G vs. C P < 0.05). No difference was found for the prevalence of depression (T: 30%, G: 35%, C: 20%). The association between FMF and anxiety in subjects living in Germany persisted after adjusting for age and gender in a regression analysis and was robust to an adjustment for coexisting depression. Anxiety and depression did not correlate with FMF disease severity assessed with the Pras score. CONCLUSION: Anxiety, but not depression is more common among FMF patients living in Germany compared to healthy controls. No significant difference could be found between FMF patients living in Germany or Turkey concerning the prevalence of anxiety or depression.


Assuntos
Ansiedade/epidemiologia , Depressão/epidemiologia , Febre Familiar do Mediterrâneo/epidemiologia , Adulto , Ansiedade/diagnóstico , Ansiedade/psicologia , Estudos de Casos e Controles , Depressão/diagnóstico , Depressão/psicologia , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/psicologia , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Fatores de Risco , Índice de Gravidade de Doença , Turquia/epidemiologia , Adulto Jovem
13.
Arthritis Rheumatol ; 68(12): 3010-3022, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27333294

RESUMO

OBJECTIVE: Familial Mediterranean fever (FMF) is an autoinflammatory disorder caused by pyrin-encoding MEFV mutations. Patients present with recurrent but self-limiting episodes of acute inflammation and often have persistent subclinical inflammation. The pathophysiology is only partially understood, but neutrophil overactivation is a hallmark of the disease. S100A12 is a neutrophil-derived proinflammatory danger signal that is strongly elevated in active FMF. This study was undertaken to characterize the secretory activity of neutrophils in vitro and investigate the association of S100A12 with disease activity and genotype in patients with FMF. METHODS: Neutrophils from FMF patients carrying the p.M694V mutation (1 compound heterozygous and 5 homozygous) and neutrophils from 4 healthy control subjects were purified and stimulated in vitro. Neutrophil secretion of S100A12, interleukin-18 (IL-18), IL-1ß, and caspase 1 was determined. Based on these in vitro analyses, serum concentrations of S100A12, IL-18, and IL-1ß were also analyzed in 128 clinically and genetically characterized patients with FMF. RESULTS: In vitro, unstimulated neutrophils from p.M694V-positive patients spontaneously secreted more S100A12, IL-18, and caspase 1 compared to neutrophils from healthy controls. Serum concentrations of S100A12 correlated with disease activity and genotype, with the levels being highest in homozygous patients and with compound heterozygotes displaying higher levels than heterozygotes. Compared to individuals negative for the p.M694V mutation, heterozygous, compound heterozygous, or homozygous p.M694V-positive patients had higher serum levels of S100A12 and IL-18 during inactive and subclinical disease. CONCLUSION: The FMF phenotype is known to be more severe in patients carrying the p.M694V mutation. This report describes 2 molecules secreted by unconventional secretory pathways, S100A12 and IL-18, whose concentrations correlated with clinical disease activity and genotype in patients with FMF. In this clinically and genetically heterogeneous disease, management of these surrogate markers might help to improve patient care and outcomes.


Assuntos
Caspase 1/metabolismo , Febre Familiar do Mediterrâneo/genética , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Neutrófilos/metabolismo , Pirina/genética , Proteína S100A12/metabolismo , Adolescente , Adulto , Estudos de Casos e Controles , Caspase 1/sangue , Criança , Pré-Escolar , Febre Familiar do Mediterrâneo/sangue , Febre Familiar do Mediterrâneo/imunologia , Feminino , Genótipo , Heterozigoto , Homozigoto , Humanos , Técnicas In Vitro , Interleucina-18/sangue , Interleucina-1beta/sangue , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Proteína S100A12/sangue , Adulto Jovem
14.
J Allergy Clin Immunol ; 138(4): 1161-1169.e6, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27040374

RESUMO

BACKGROUND: TH17 cells have so far been considered to be crucial mediators of autoimmune inflammation. Two distinct types of TH17 cells have been described recently, which differed in their polarization requirement for IL-1ß and in their cytokine repertoire. Whether these distinct TH17 phenotypes translate into distinct TH17 cell functions with implications for human health or disease has not been addressed yet. OBJECTIVE: We hypothesized the existence of proinflammatory and anti-inflammatory human TH17 cell functions based on the differential expression of IL-10, which is regulated by IL-1ß. Considering the crucial role of IL-1ß in the pathogenesis of autoinflammatory syndromes, we hypothesized that IL-1ß mediates the loss of anti-inflammatory TH17 cell functionalities in patients with Schnitzler syndrome, an autoinflammatory disease. METHODS: To assess proinflammatory versus anti-inflammatory TH17 cell functions, we performed suppression assays and tested the effects of IL-1ß dependent and independent TH17 subsets on modulating proinflammatory cytokine secretion by monocytes. Patients with Schnitzler syndrome were analyzed for changes in TH17 cell functions before and during therapy with IL-1ß-blocking drugs. RESULTS: Both TH17 cell subsets differ in their ability to suppress T-cell proliferation and their ability to modulate proinflammatory cytokine production by antigen-presenting cells because of their differential IL-10 expression properties. In patients with Schnitzler syndrome, systemic overproduction of IL-1ß translates into a profound loss of anti-inflammatory TH17 cell functionalities, which can be reversed by anti-IL-1ß treatment. CONCLUSION: IL-1ß signaling determines the differential expression pattern of IL-10, which is necessary and sufficient to induce proinflammatory versus anti-inflammatory TH17 cell functions. Our data introduce TH17 cell subsets as novel players in autoinflammation and thus novel therapeutic targets in autoinflammatory syndromes including other IL-1ß mediated diseases. This demonstrates for the first time alterations in the adaptive immune system in patients with autoinflammatory syndromes.


Assuntos
Síndrome de Schnitzler/fisiopatologia , Células Th17/imunologia , Células Cultivadas , Citocinas/metabolismo , Sistemas de Liberação de Medicamentos , Humanos , Inflamação/fisiopatologia , Interleucina-1beta/imunologia , Síndrome de Schnitzler/imunologia
15.
Ann Hepatol ; 14(5): 722-8, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26256901

RESUMO

Pediatric acute liver failure (PALF) is a progressive, potentially fatal clinical syndrome occurring in previously healthy children. Our study aimed to determine the current leading causes of PALF in a single center in Germany, identifying possible prognostic markers. Thirty-seven pediatric patients with PALF were included. Medical records were reviewed for demographic, laboratory and clinical data. Laboratory results on admission and at peak value, PELD and MELD score on admission, and intensive care support were assessed. Fifteen patients recovered spontaneously, 14 died without transplantation, and 8 received a liver transplant. Patients who survived were significantly older than patients who died. Specific causes of PALF could be identified as infectious diseases (16%), metabolic diseases (14%), toxic liver injury (11%), immunologic diseases (8%), or vascular diseases (8%). Causes of PALF remained indeterminate in 43%. High ammonia, low albumin, and low ALT levels on admission were associated with worse outcome. Absence of need of ventilation, hemodialysis, and circulatory support predicted spontaneous recovery. In conclusion, infections are the most common known cause of PALF. However, in a large proportion of patients the cause for PALF remains cryptic. Ammonia and albumin levels may be of prognostic value to predict outcomes.


Assuntos
Falência Hepática Aguda/etiologia , Adolescente , Fatores Etários , Amônia/sangue , Aspartato Aminotransferases/sangue , Biomarcadores/sangue , Criança , Pré-Escolar , Creatinina/sangue , Cuidados Críticos , Feminino , Alemanha , Humanos , Lactente , Recém-Nascido , Falência Hepática Aguda/sangue , Falência Hepática Aguda/diagnóstico , Falência Hepática Aguda/mortalidade , Falência Hepática Aguda/terapia , Transplante de Fígado , Masculino , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica/metabolismo , Albumina Sérica Humana , Análise de Sobrevida , Resultado do Tratamento
16.
Dig Endosc ; 27(4): 505-11, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25545826

RESUMO

BACKGROUND AND AIM: Biliary complications (BC) after liver transplantation (LT) are associated with significant morbidity and mortality. Incidence of BC after pediatric LT is more than 10%. In adults, treatment by endoscopic retrograde cholangiopancreaticography (ERCP) is successful. As data in pediatric patients are limited, endoscopic treatment of BC in a pediatric cohort in a German transplant center was analyzed. METHODS: LT recipients <18 years of age who were endoscopically treated for BC at University Hospital Essen were retrospectively analyzed. Characteristics of LT, endoscopic treatment measures, clinical and endoscopic presentation of BC, and outcomes after endoscopic treatment were evaluated. RESULTS: Seventeen patients (median age 12 years) with clinical signs of BC were treated endoscopically using ERCP. Eleven patients had received a full-size liver, and six a left-sided living-donor transplant graft. In 12 patients, the bile ducts were accessible via Vater's papilla and five patients had a bilioenteric anastomosis. Biliary sphincterotomy was done in 13 patients. Eleven patients presented with stricture of the biliary anastomosis (AST), either isolated (nine) or in combination with biliary cast syndrome (BCS) or biliary leakage (one patient each). Ischemia-type biliary lesions (ITBL) were found in two patients. Five patients suffered from BCS, either as isolated pathology (two) or in combination with AST, bile leak or ITBL. In one patient, biliary access via the major papilla was not obtainable. CONCLUSIONS: BC in pediatric LT were treated safely and successfully in pediatric patients when the biliary tract was accessible. The most common complications were AST, BCS and ITBL.


Assuntos
Doenças Biliares/etiologia , Doenças Biliares/cirurgia , Colangiopancreatografia Retrógrada Endoscópica , Doença Hepática Terminal/cirurgia , Transplante de Fígado/efeitos adversos , Esfinterotomia Endoscópica , Adolescente , Fatores Etários , Doenças Biliares/diagnóstico , Criança , Pré-Escolar , Doença Hepática Terminal/etiologia , Doença Hepática Terminal/patologia , Estudos de Viabilidade , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento
17.
Artigo em Inglês | MEDLINE | ID: mdl-25114627

RESUMO

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is commonly considered an autoinflammatory disease. However, sJIA patients may develop aggressive arthritis without systemic inflammation later in the disease, resembling an autoimmune phenotype similar to other subtypes of JIA. The objective of this study was to determine whether antinuclear antibodies (ANA) and rheumatoid factor (RF) will develop in patients with sJIA over the course of the disease. FINDINGS: A single center sample of sJIA patients with follow-up of more than one year was obtained. A retrospective chart survey was used to extract demographic and clinical data as well as presence and titers of ANA and RF at diagnosis and during follow-up. 32 patients were included in the study, with a median age of 4.2 years and median follow-up of 6.0 years. 8/32 patients had ANA titers ≥ 1:80 at diagnosis, with 22/32 patients showing rising ANA titers with titers ≥ 1:80 at last follow-up (p =0.001). 10/32 patients had a positive RF at least once during follow-up, compared to 0/32 at diagnosis (p = 0.001). In 5/10 patients, positive RF was documented at least twice, more than twelve weeks apart. Patients treated with TNF antagonists were not significantly more likely to develop positive ANA titers (p = 0.425) or positive RF (p = 0.703). CONCLUSIONS: Patients with sJIA developed increased ANA titers and positive RF over the course of the disease, independent of treatment with TNF antagonists. This might point towards an autoimmune, rather than an autoinflammatory phenotype later in the course of sJIA.


Assuntos
Anticorpos Antinucleares/sangue , Artrite Juvenil/diagnóstico , Doenças Autoimunes/diagnóstico , Progressão da Doença , Fenótipo , Fator Reumatoide/sangue , Antirreumáticos/uso terapêutico , Artrite Juvenil/sangue , Artrite Juvenil/tratamento farmacológico , Doenças Autoimunes/sangue , Biomarcadores/sangue , Criança , Pré-Escolar , Feminino , Seguimentos , Inquéritos Epidemiológicos , Humanos , Lactente , Masculino , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Fatores de Tempo , Fator de Necrose Tumoral alfa/antagonistas & inibidores
18.
J Pediatr ; 164(3): 546-52.e1-2, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24321540

RESUMO

OBJECTIVE: To prospectively investigate the prevalence of hepatopulmonary syndrome (HPS), the importance of pulse oximetry in diagnosing HPS, and the longitudinal course after liver transplantation in children with cirrhosis referred for liver transplantation. STUDY DESIGN: Fifty-six patients aged 1-17 years (mean age, 4.6 ± 5.0 years) with liver cirrhosis were screened for HPS by hyperemic capillary blood gas (CBG) analysis and contrast-enhanced transthoracic echocardiography. Eleven patients were excluded owing to conditions that can produce cardiopulmonary dysfunction, including 5 with cystic fibrosis, 1 with pulmonary arterial hypertension, and 5 with an intracardial shunt. HPS was classified in accordance with the European Respiratory Society Task Force criteria on pulmonary-hepatic disorders. Patient groups were compared for biochemical and clinical characteristics. RESULTS: Eighteen children (40%) with cirrhosis were intrapulmonary vasodilatation (IPVD)-positive and had a pulse oximetry oxygen saturation level >98%. Two of these patients (11%) exhibited moderate HPS with an elevated alveolar arterial oxygen gradient >15 mm Hg and PaO2 <70 mm Hg; they died before undergoing liver transplantation. The sensitivity and specificity of CBG analysis for detecting elevated alveolar arterial oxygen gradient in children with IPVD was 94% and 53%, respectively. HPS was associated with late hepatoportoenterostomy (P < .04). Liver transplantation led to resolution of HPS in all patients. CONCLUSION: IPVD is frequent in children with liver cirrhosis (40%). Pulse oximetry is insufficient for timely HPS diagnosis. Pathological CBG analysis data indicate IPVD in the majority of cases, but are imprecise in children aged <2 years. Contrast-enhanced transthoracic echocardiography and CBG analysis are recommended for evaluation of HPS in children with cirrhosis, regardless of liver synthesis capacity and clinical chemistry data.


Assuntos
Diagnóstico Precoce , Síndrome Hepatopulmonar/diagnóstico , Cirrose Hepática/complicações , Oximetria , Adolescente , Gasometria , Capilares/química , Criança , Pré-Escolar , Meios de Contraste , Ecocardiografia , Feminino , Humanos , Lactente , Circulação Hepática , Cirrose Hepática/cirurgia , Transplante de Fígado , Masculino , Oxigênio/sangue , Portoenterostomia Hepática/estatística & dados numéricos , Estudos Prospectivos , Alvéolos Pulmonares/metabolismo , Sensibilidade e Especificidade , Índice de Gravidade de Doença
19.
J Clin Rheumatol ; 19(5): 246-51, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23872541

RESUMO

BACKGROUND: The environment may affect the course of familial Mediterranean fever (FMF). OBJECTIVE: The objective of this study was to compare disease severity between adult FMF patients in Turkey (TR) and Germany (G). METHODS: Adult FMF patients of Turkish ancestry on colchicine living in Turkey (n = 40) or G (n = 35) were compared. Disease severity, C-reactive protein (CRP), and erythrocyte sedimentation rate were assessed. RESULTS: Groups differed significantly in the following aspects: age at onset of disease (TR: 15.6, G: 10.8 years; P = 0.02), delay between onset and initiation of colchicine treatment (TR: 6.8 years, G: 14.9 years; P < 0.001), female gender (TR: 80%, G: 57.1%; P = 0.04), and duration of disease (TR: 14.4 years, G: 23.4 years; P < 0.001). There was no significant difference in colchicine treatment concerning average dosing and duration of therapy. No significant difference could be found between the 2 groups in CRP and disease severity as assessed by the score of Pras et al. (Am J Med Genet. 1998;75:216-219) even after adjusting for potential confounding variables. Mean erythrocyte sedimentation rate was significantly higher among patients living in G (TR: 13.2 mm/first hour, G: 26.3 mm/first hour; P < 0.001). Among patients living in Germany, there was a significant difference in age at FMF onset depending on their country of birth (born in TR: 14.9 years, born in G: 6.9 years; P = 0.0001). CONCLUSIONS: In adult FMF patients living in Turkey or Germany, no difference in disease activity or CRP could be found. German patients were younger at onset of disease and had a longer delay between onset and initiation of colchicine treatment.


Assuntos
Febre Familiar do Mediterrâneo/etnologia , Adolescente , Adulto , Idade de Início , Sedimentação Sanguínea , Proteína C-Reativa/metabolismo , Criança , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/epidemiologia , Feminino , Alemanha/etnologia , Supressores da Gota/uso terapêutico , Humanos , Modelos Lineares , Masculino , Índice de Gravidade de Doença , Fatores Sexuais , Fatores de Tempo , Turquia/epidemiologia , Turquia/etnologia
20.
Rheumatol Int ; 33(7): 1713-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23274441

RESUMO

We assessed quality of life (QOL) and disease activity in patients with Familial Mediterranean fever (FMF) of Turkish ancestry living in Germany or Turkey and conducted a correlation with FMF disease activity. 40 FMF patients in Turkey (TR), 40 FMF patients in Germany (G) and 40 healthy controls in Germany (C) were included. QOL was evaluated with the short form of the World Health Organisation Quality of Life scale (WHOQOL-BREF). FMF disease activity was examined with the Pras score. Mean age was TR 30.5 ± 10.6, G 35.2 ± 10.2, C 34.6 ± 10.7. Of the 120 participants, 77 were female. FMF patients in TR and G had a significantly decreased QOL physical health domain compared to controls (TR 59.7 ± 18.8, G 60.4 ± 19.4, C 76.5 ± 14.6). Turkish FMF patients had a lower QOL environment domain compared to controls (TR 62.3 ± 17.5, G 69.7 ± 16.5, C 72.3 ± 13.5). In the other QOL domains, no significant differences were found. The differences in QOL were robust to a regression analysis. No significant correlation between QOL and FMF disease activity was found. German FMF patients had longer duration of disease, younger age at onset and longer delay from disease onset to colchicine treatment. A total of 5 of 40 German FMF patients were not taking colchicine (TR:0). Erythrocyte sedimentation rate was lowest in TR with significant difference between TR and G as well as G and C (TR 13.2 ± 10.3, G 27.8 ± 19.4, C 16.3 ± 12.8 mm/h). C-reactive protein did not differ between TR and G. FMF has an important impact on QOL physical health domain. No correlation between FMF disease activity and the WHOQOL-BREF could be found.


Assuntos
Febre Familiar do Mediterrâneo/epidemiologia , Febre Familiar do Mediterrâneo/psicologia , Qualidade de Vida , Características de Residência , Adolescente , Adulto , Idade de Início , Anti-Inflamatórios/uso terapêutico , Estudos de Casos e Controles , Criança , Pré-Escolar , Colchicina/uso terapêutico , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Feminino , Alemanha/epidemiologia , Nível de Saúde , Humanos , Modelos Lineares , Masculino , Análise Multivariada , Estudos Prospectivos , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Tempo para o Tratamento , Turquia/epidemiologia , Adulto Jovem
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