[Evidence-based treatment recommendations for familial Mediterranean fever : A joint statement by the Society for Pediatric and Adolescent Rheumatology and the German Society for Rheumatology]. / Evidenzbasierte Therapieempfehlungen für das familiäre Mittelmeerfieber : Eine gemeinsame Stellungnahme der Gesellschaft für Kinder- und Jugendrheumatologie und der Deutschen Gesellschaft für Rheumatologie.

BACKGROUND: Familial Mediterranean fever (FMF) in Germany is a rare, genetically linked disease of childhood and adolescence, which is characterized by recurrent febrile episodes and clinical signs of peritonitis, pleuritis and arthritis. Treatment with colchicine is effective and well-tolerated in the majority of patients; however, some patients do not sufficiently respond to this treatment or are intolerant to colchicine. For these patients first-line treatment with biologics which block interleukin-1 can be used. OBJECTIVE: The aim was to formulate evidence-based treatment recommendations for patients with an insufficient response and intolerance to colchicine treatment. METHODS: Based on a literature search and the European League Against Rheumatism (EULAR) recommendations on FMF from 2016 the appointed members of the Society for Pediatric and Adolescent Rheumatology (GKJR) and the German Society for Rheumatology (DGRh) convened to work out and form a consensus in a joint statement on evidence-based treatment recommendations on FMF. RESULTS: After intensive discussions all decisions were in concordance. A total of 5 superordinate principles and 10 recommendations were agreed upon. DISCUSSION: The joint activities of the GKJR and the DGRh were successfully concluded in a timely manner. The recommendations form a good basis for optimal treatment of all age groups of patients with FMF.

Update of the evidence based, interdisciplinary guideline for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

BACKGROUND: Uveitis in juvenile idiopathic arthritis (JIAU) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first line therapy, and disease modifying anti-rheumatic drugs (DMARDs) are commonly used. However, treatment has not been standardized. METHODS: Interdisciplinary guideline were developed with representatives from the German Ophthalmological Society, Society for Paediatric Rheumatology, Professional Association of Ophthalmologists, German Society for Rheumatology, parents' group, moderated by the Association of the Scientific Medical Societies in Germany. A systematic literature analysis in MEDLINE was performed, evidence and recommendations were graded, an algorithm for anti-inflammatory treatment and final statements were discussed in a consensus meeting (Nominal Group Technique), a preliminary draft was fine-tuned and discussed thereafter by all participants (Delphi procedure). RESULTS: Consensus was reached on recommendations, including a standardized treatment strategy according to uveitis severity in the individual patient. Thus, methotrexate shall be introduced for uveitis not responding to low-dose (≤ 2 applications/day) topical corticosteroids, and a TNFalpha antibody (preferably adalimumab) used, if uveitis inactivity is not achieved. In very severe active uveitis with uveitis-related deterioration of vision, systemic corticosteroids should be considered for bridging until DMARDs take effect. If TNFalpha antibodies fail to take effect or lose effect, another biological should be selected (tocilizumab, abatacept or rituximab). De-escalation of DMARDs should be preceded by a period of  ≥ 2 years of uveitis inactivity. CONCLUSIONS: An interdisciplinary, evidence-based treatment guideline for JIAU is presented.

IL-6 blockade in systemic juvenile idiopathic arthritis - achievement of inactive disease and remission (data from the German AID-registry).

BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting. METHODS: In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) ( https://aid-register.de ). Data for this retrospective TCZ study were documented by 13 centers. RESULTS: From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1-18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%. CONCLUSION: Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%. TRIAL REGISTRATION: The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D).

Genotype-phenotype and genotype-origin correlations in children with mediterranean fever in Germany - an AID-net study.

Familial Mediterranean fever (FMF) is the most inherited common autoinflammatory disease (AID) with mutations in the MEFV (MEditerraneanFeVer) gene.The Mor- and Pras-Score modified for children and C-reactive protein (CRP) were used to assess FMF disease severity in Germany. We evaluate the applicability of the 2 severity scores and the correlations between ethnic origin, phenotype, and genotype.Among 242 children (median 5 age at diagnosis), we detected 431 pyrin mutations and 22 different sequence variants, including one new mutation (p.Gly488Asp). The 5 most -frequent alterations were p.Met694Val (55.2%), p.Met680lle (11.8%), p.Val726Ala (10%), p.Glu148Gln (7.9%) and p.Met694IIe (2.3%). The prevailing ancestries of 223 cases were Turkish (82.5%) and Lebanese (8.1%). Homozygous p.Met694Val substitution (30.2%) was associated with a more severe disease activity by Mor-Score, as well as with a higher mean CRP (74 mg/l) compared to patients with other mutations. Indeed, Mor- and Pras-Score were inconsistent with each other. A typical distribution of mutations in different ethnic populations was obvious, but not statistically verifiable due to the low number of cases.The homozygous p.Met694Val substitution was associated with a more severe disease activity in our German cohort. The common severity scores were inconsistent in -children.

[Genetic fever syndromes. Hereditary recurrent (periodic) fever syndromes]. / Genetische Fiebersyndrome. Hereditäre rekurrierende (periodische) Fiebersyndrome.

Genetic fever syndromes or hereditary recurrent fever syndromes (HRF) are considered to be part of the autoinflammatory diseases (AID) which result from errors in the innate immune system. Patients typically have self-limiting episodes of fever and high levels of inflammation markers. The mode of inheritance is autosomal recessive or autosomal dominant. The diseases of the HRF include familial Mediterranean fever, tumor necrosis factor receptor 1-associated periodic syndrome, hyper-IgD syndrome and cryopyrin-associated periodic fever syndromes. The disease known as deficiency of interleukin 1 (IL1) receptor antagonist does not fully belong to this group because fever is not a typical symptom. The therapy depends on the type and severity of the disease. Effective prophylaxis is possible for FMF. Biologicals, especially IL1 blocking agents are highly effective in very severe fever syndromes. In order to collect more information on AID, to establish a biobank and coordinate research in this field the AID-Net project was founded. Currently 606 patients with AID are registered of whom 381 have HRF.

Familial Mediterranean fever in Germany: epidemiological, clinical, and genetic characteristics of a pediatric population.

UNLABELLED: Familial Mediterranean fever (FMF) is an autoinflammatory disease and belongs to the heterogeneous group of hereditary recurrent fever syndromes (HRFs). AIMS: The aims of the study were to determine the incidence of FMF in Germany and to describe the spectrum of pyrin mutations and the clinical characteristics in children. A prospective surveillance of children with HRF including FMF was conducted in Germany during a time period of 3 years by the German paediatric surveillance unit for rare paediatric diseases (ESPED). Monthly inquiries were sent to 370 children's hospitals (Clinic-ESPED, n1) and to 23 laboratories (Laboratory-ESPED, n2). Inclusion criteria were children ≤ 16 years of age, disease-associated pyrin mutations, and more than three self-limiting episodes of fever >38.5 °C with increased inflammation markers. In n1, 122 patients with FMF and 225 pyrin mutations were identified. Ninety-two of 122 (75 %) children were of Turkish origin. The minimum incidence of FMF was estimated to be 3 (95 % CI: 2.48-3.54) per 10(6) person-years in the whole children population and 55 (95 % CI: 46-66) per 10(6) person-years in Turkish children living in Germany. N1 U n2 amounted to 593 asymptomatic and symptomatic carriers of 895 mutations (overlap of 73 cases with 134 mutations). p.Met694Val (45 %), p.Met680Ile (14 %), p.Val726Ala (12 %), and p.Glu148Gln (11.5 %) were the most common pyrin mutations. CONCLUSIONS: Despite FMF being the most frequent of the HRFs, its incidence in Germany is low. Twenty-five to 50 FMF patients ≤ 16 years are newly diagnosed per year. The disease is most commonly observed in individuals of Turkish ancestry.

Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

Uveitis in juvenile idiopathic arthritis (JIA) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first-choice therapy, and immunosuppression is commonly used. However, treatment has not been standardized. Representatives from the German Ophthalmological Society, Society for Childhood and Adolescent Rheumatology, and the German Society for Rheumatology reached consensus on a standardized treatment strategy according to disease severity in the individual patient. The recommendations were based on a systematic literature analysis in MEDLINE and consensus expert meetings. Evidence and recommendations were graded, and an algorithm for anti-inflammatory treatment and final statements confirmed in a Delphi method. An interdisciplinary, evidence-based treatment guideline for JIA uveitis is presented.

Incidence and clinical features of hyperimmunoglobulinemia D and periodic fever syndrome (HIDS) and spectrum of mevalonate kinase (MVK) mutations in German children.

Autoinflammatory diseases (AIDs) are characterized by recurrent, self-limiting systemic inflammation. Disorders include hereditary recurrent fever (HRF) syndromes such as hyperimmunoglobulinemia D and periodic fever syndrome (HIDS). To determine the incidence of HIDS and report clinical and genetic characteristics together with the underlying MVK genotypes in German children, a prospective active surveillance was conducted in Germany during a period of 3 years. Monthly inquiries were sent to 370 children's hospitals by the German Paediatric Surveillance Unit (Clinic-ESPED, n1) and to two laboratories (Laboratory-ESPED, n2) performing genetic analyses. Inclusion criteria were a MVK mutation-positive patient ≤16 years of age with more than three self-limiting episodes of fever >38.5°C associated with increased inflammation markers. Clinical, epidemiological, and genetic data were assessed via questionnaires. Eight out of 16 patients were identified in Clinic-ESPED (n1) and 15 of 16 in Laboratory-ESPED (n2). Clinical and laboratory surveys overlapped in 7 of 16 cases. Incidence of HIDS was estimated to be 0.39 (95% CI: 0.22, 0.64) per 10(6) person-years. HIDS symptoms generally started in infancy with recurrent fever episodes lasting 3-12 (median, 4.5) days and recurring every 1-12 weeks. Fever was accompanied by abdominal pain, vomiting, diarrhea, cervical lymphadenopathy, and sometimes by headache, skin and joint symptoms. The patients carried 11 different MVK mutations mostly in compound heterozygosity (75%, 12 out of 16). The most frequent mutation was p.Val377Ile (81%, 13 out of 16). In Germany, the incidence of HIDS is very low with 0.39 per 10(6) person-years.

[Kawasaki disease in children and adolescents]. / Kawasaki-Erkrankung bei Kindern und Jugendlichen.

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. The diagnostic criteria are fulfilled with fever of unknown origin and 4 of the following 5 criteria: bilateral conjunctival injection, cervical lymphadenopathy, polymorphous rash, oral mucous membrane changes (injected lips, strawberry tongue) and peripheral extremity changes (erythema, edema, desquamation). If less than 4 criteria are found incomplete KD can be diagnosed. The therapy is 2 g/kg body weight single dose intravenous immunoglobulin and acetylsalicylic acid (ASS). In the long-term follow-up the main focus is on the coronary arteries because coronary changes play a key role in the intensity of long-term management. There is some evidence that KD is a risk factor for cardiovascular diseases in adults.

Analysis of cryopyrin-associated periodic syndromes (CAPS) in German children: epidemiological, clinical and genetic characteristics.

BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) are rare disorders belonging to the group of hereditary periodic fever (HPF)syndromes. These auto-inflammatory diseases(AID) are characterized by recurrent episodes of inflammation with attacks of fever variably associated with serosal, synovial and / or cutaneous inflammation, usually in a self-limiting manner, and with a mostly monogenic origin. The aims were to determine the incidence of CAPS and the spectrum of mutations in the NLRP3 (formerly= CIAS1) gene and to describe the clinical manifestations. PATIENTS AND METHODS: A prospective surveillance of children with CAPS was conducted in Germany during a time period of 3 years(2003-2006). Monthly inquiries were sent to 370 children's hospitals by the German Paediatric Surveillance Unit (Clinic-ESPED, n1) and to 2 laboratories (Laboratory-ESPED, n2). Inclusion criteria were children ≤ 16 years of age, disease-associated NLRP3 mutation, more than 3 self-limiting episodes of fever > 38.5 ° C, and increased inflammation markers. Clinical, epidemiological and genetic data were evaluated via questionnaires. FINDINGS: 6 out of 14 patients were identified in Clinic-ESPED (n1) and 13 / 14 in Laboratory-ESPED(n2). Clinical and laboratory surveys overlapped in 5 of 14 cases. The incidence of CAPS in German children was estimated to be 3.43 per 107 person-years. The patients carried 11 different NLRP3 mutations and were classified as MWS(n = 6), CINCA (n = 4), FCAS (n = 1) and undefined CAPS (n = 3). INTERPRETATION: The incidence of CAPS in Germany is very low and corresponds to 2-7 newly diagnosed patients ≤ 16 years per year.

[Infectious uveitis in infancy: borreliosis, tuberculosis, lues]. / Infektiöse Uveitis im Kindesalter: Borreliose, Tuberkulose, Lues.

Infectious uveitis caused by Borrelia, tuberculosis or syphilis is a rare condition, even in childhood. Because these diseases can be treated successfully, knowledge of their diagnosis and therapy is highly important. The clinical aspects vary from simple conjunctivitis to endophthalmitis or neuro-ophthalmological diseases. The diagnosis of and therapy for borreliosis depend on the stage of the disease. The involvement of different organ systems or positive indirect tests (tuberculin skin test, interferon gamma assays) are important factors in the diagnosis of tuberculosis as the cause of a uveitis. Serology is essential for the diagnosis and monitoring of syphilis.

[Diagnostics in childhood uveitis: what tests for which uveitis?]. / Diagnostik bei Uveitis im Kindesalter: Welche Tests bei welcher Uveitis?

BACKGROUND: Intraocular inflammation in children differs considerably from that found in adults. Therefore the diagnostic work-up has to be adapted to the age and specific diseases. MATERIALS AND METHODS: The published literature was reviewed for results of clinical trials and consensus meetings. In addition, the authors have incorporated their own experience. RESULTS: Recommendations for a systematic and complete diagnostic work-up are given using tables where possible. CONCLUSIONS: A close cooperation between ophthalmologists and paediatricians is very important.

A newborn with severe liver failure, cardiomyopathy and transaldolase deficiency.

This paper describes the second patient found to be affected with a deficiency of transaldolase (TALDO1; EC 2.2.1.2). Clinically, this patient presented in the neonatal period with several signs of severe liver failure: severe coagulopathy, low serum protein, elevated blood ammonia, and hypoglycaemia. She had generalized oedema, moderate muscular hypotonia, and dysmorphic signs. Liver size was decreased, and the spleen was moderately enlarged. There was severe cardiomegaly. The clinical course was characterized by intractable liver failure and progressive myocardial hypertrophy. The child died at the age of 18 days from respiratory failure. In urine, elevations of erythritol, arabitol and ribitol were found, suggesting a deficiency of transaldolase. Enzyme studies in cultured fibroblasts showed undetectable transaldolase activity. DNA sequence analysis of the TALDO1 gene showed a homozygous missense mutation (575G>A), resulting in an amino acid alteration at position 192 (arginine to histidine, R192H). This amino acid is part of the catalytic site of the transaldolase protein. Discovery of this second patient affected with transaldolase deficiency and liver failure suggests that this disorder has a heterogeneous clinical presentation with highly variable severity.

Enzyme replacement therapy in classical infantile pompe disease: results of a ten-month follow-up study.

Infantile Pompe disease (IPD) is a fatal, autosomal recessive muscle-wasting disorder. Due to a deficiency of the lysosomal enzyme acid alpha-glucosidase patients develop a generalized myopathy, diaphragmatic weakness, and cardiomyopathy leading to death usually within the first year of life. So far there is no therapy available. We report on the safety and efficacy of transgenically derived recombinant human precursor acid alpha-glucosidase (rhGAA) in a 10-month follow-up study in two children with IPD who previously completed a 48-week course of enzyme replacement therapy (ERT) with the same medication at the same dose in a phase II clinical trial. Under this therapy cardiac status and muscle strength had improved, leading to survival beyond the age of one year. These results, together with data from two other phase II clinical trials encouraged further evaluation of the long-term safety and efficacy of enzyme replacement therapy in patients with infantile-onset Pompe disease. During the 10-month follow-up period, ERT was well-tolerated and neither patient experienced a single infusion-associated reaction. The initial improvements in cardiac size and function, as measured by left ventricular mass index and the fractional shortening, were maintained in both patients, and a continued improvement of motor function, as measured by the Alberta infant motor scale, was observed.

Safety and efficacy of recombinant acid alpha-glucosidase (rhGAA) in patients with classical infantile Pompe disease: results of a phase II clinical trial.

Pompe disease is an autosomal recessive muscle-wasting disorder caused by the deficiency of the lysosomal enzyme acid alpha-glucosidase. Due to virtual absence of acid alpha-glucosidase, patients with classical infantile Pompe disease develop progressive cardiomyopathy, skeletal muscle weakness and respiratory insufficiency leading to death in early infancy. We report on the results of a phase II clinical trial including two patients with classical infantile Pompe disease receiving enzyme replacement therapy over a period of 48 weeks by weekly infusions. Recombinant acid alpha-glucosidase was derived from the milk of transgenic rabbits. Safety was evaluated by recording adverse events while clinical efficacy was evaluated by ventilator-free survival, left ventricular mass index, motor development as well as histologic and biochemical analysis of muscle biopsies. This therapy was in general well-tolerated. There was an overall improvement in left ventricular mass, cardiac function, skeletal muscle function and histological appearance of skeletal muscle.

[Ventricular septal defect and aortic regurgitation-pathophysiological aspects and therapeutic consequences]. / Ventrikelseptumdefekt und Aorteninsuffizienz. Pathophysiologische Aspekte und therapeutische Konsequenzen.

The development of aortic regurgitation (AI) is a rare but serious complication of subaortic ventricular septal defects (VSD). Over a period of 5 years we observed VSD-related AI in 24 patients, a frequency of 4.5% of all isolated VSD's encountered during that time frame. The location of the defects was in the infundibular septum in 59%, it was perimembranous in 25% and in the trabecular septum in 16%. Hemodynamically the defects were small except for 2 where the Q(p)/Q(s) ratio was > 2. Of the 24 pts, 16 had surgical closure of their VSD accompanied in 9 by aortic valvuloplasty. AI was caused by elongation or defect of the right coronary leaflet in 42%, of the noncoronary leaflet in 25% and a combination of both, in 8%. In 6 pts with infundibular VSD absence of part of the aortic valve ring above the defect was the underlying mechanism for AI. Postoperatively AI was improved to moderate in one pt and to none to trivial in 15. LV end-diastolic diameter decreased significantly in all pts operated. Pathogenetic mechanisms for the development of AI are a deficiency in the aorto-infundibular junction with prolaps of the right-or non-coronary leaflet, deficiency of the valve supporting structures including the valve ring as well as suction of the already elongated leaflet into the VSD with further damage to the antiregurgitant mechanism of the semilunar valve at risk. In perimembranous VSD's, late AI is probably related to turbulent flow through the adjacent LVOT. Surgical closure of isolated VSD's with a location immediately beneath the aortic valve is indicated regardless of their size to prevent the development of AI. If AI has occurred, VSD closure including aortic valvuloplasty improves the amount of regurgitation and normalizes LV enddiastolic dimension.

Clinical features of isolated noncompaction of the myocardium in children.

Isolated noncompaction of the myocardium, also known as "spongy myocardium", is a rare disease in children and adults. It is suggested that, during early development of the heart, the primary spongy structure persists due to an arrest of compaction. No other cardiac malformations are found, but there are familial occurences, relations to genetic disorders or syndromes such as Melnick-needles-syndrome or Xq28-linked cardiomyopathy, and reports of conduction disorders. We have now diagnosed isolated noncompaction in seven children aged between five weeks and 5.5 years. Three are doing well with anticongestive therapy, while transplantation of the heart was performed in one. Three of the children have died, but in only one case due to cardiac failure. Our experience emphasises the need rapidly to establish the diagnosis, to search for associated extracardiac abnormalities, and to consider transplantation at an early stage.