[Updated statement by the German Society for Pediatric and Adolescent Rheumatology (GKJR) on the FDA's report regarding malignancies in anti-TNF-treated patients from Aug. 4, 2009]. / Aktualisierte Stellungnahme der GKJR zur Meldung der FDA über Fälle von Malignomen bei Anti-TNF-behandelten Patienten vom 04.08.2009.

TNF inhibitors and other biologicals have greatly expanded the therapeutic options for juvenile idiopathic arthritis (JIA). While the efficacy of etanercept and adalimumab has been proven in randomized controlled clinical trials, their long-term safety remains the subject of ongoing investigations. Reports of leukaemia and tumours in children and adolescents treated with etanercept, infliximab and adalimumab have raised questions about an increased risk for malignancies, with lymphoma accounting for the largest group at 50% of all 48 malignancies reported by the FDA.Consequently, TNF inhibitors should be indicated under careful consideration of individual risk factors, such as increased family occurrence of malignancies, or pre-treatment with carcinogenic substances such as cyclophosphamide. This is particularly true for non-approved substances, and non-approved indications, and for combination therapy of TNF inhibitors with immunosuppressive drugs. On the other hand, however, treatment should not be stopped or started in any patient in whom treatment is necessary due to the current knowledge. Adequate patient information, surveillance and documentation of treatment in the registry of the GKJR is strongly recommended.

Exercise-induced hyperthermia in childhood: a case report and pilot study.

UNLABELLED: Hyperthermia is characterized by an increase of body core temperature due to exogenous heat exposure and/or endogenous heat production. Contrary to fever the hypothalamic-controlled temperature set point remains unchanged. AIM: To demonstrate that exercise-induced hyperthermia is a common phenomenon in childhood. CASE: We describe a 5-year-old boy, who attended our outpatient clinic with a 6-month observation period of exercise-induced hyperthermia with rectal temperatures up to 39.0 degrees C. Characteristically temperature dropped to normal values after cessation of exercise. METHOD: In eight children aged 5-8, tympanic and rectal temperatures were measured before and after exercise. RESULTS: The rectal temperature increases frequently after exercise (p < 0.001), whereas tympanic temperature did not (p = 0.2). CONCLUSION: Benign hyperthermia should be considered in children with increased body temperature of unknown sources. The site of temperature measurement might be critical in the identification of this condition.

Successful infliximab treatment of posterior scleritis in a 13-year-old child refractory to other immunosuppressive therapy.

BACKGROUND: Posterior scleritis is a potentially blinding inflammatory disorder rarely seen in children. Standard care consists of systemic administration of steroids and immunosuppressants such as methotrexate or ciclosporin A. We describe the case of a young girl suffering from therapy refractory posterior scleritis successfully treated with the tumor necrosis factor (TNF) inhibitor infliximab. METHODS: This study was an interventional case report. The medical chart of a 13-year-old child treated with infliximab (5 mg/kg, 10 applications at a 4-8 week interval) was reviewed for changes of visual acuity, fundoscopy, optic choherence tomography, ultrasound imaging, and adverse events. RESULTS: Infliximab therapy (5 mg/kg, 10 applications at a 4-8 week interval) led to a long-term remission of posterior scleritis after unsuccessful therapy with high dose prednisolone, methotrexate, and ciclosporin A. To date no side effects have been reported. CONCLUSIONS: Administration of infliximab may be considered under appropriate circumstances to treat children with posterior scleritis.

"Periodic fever" without fever: two cases of non-febrile TRAPS with mutations in the TNFRSF1A gene presenting with episodes of inflammation or monosymptomatic amyloidosis.

BACKGROUND: Tumour necrosis factor (TNF) receptor associated periodic syndrome (TRAPS) is caused by dominant mutations in the TNFRSF1A gene. In typical cases TRAPS begins early in childhood and is characterised by high and remittent fever over a period of 1-4 weeks or longer, accompanied by systemic and local inflammation. CASE REPORTS: Patient 1 presented with recurrent episodes of weakness, migrating myalgias, arthralgias, exanthema, and chest pain lasting for 1-4 weeks, but without any fever over an initial period of 4 years at least. Diagnosis of TRAPS was confirmed by the heterozygous mutation Y20H in TNFRSF1A. Patient 2, a 23 year old woman never had any symptoms indicative of TRAPS. Genetic evaluation of all members of her family with a TRAPS index patient disclosed the T50M mutation in TNFRSF1A. A medical check up showed proteinuria, and renal biopsy disclosed AA amyloidosis. CONCLUSIONS: TRAPS associated mutations can induce considerable inflammation that is not necessarily accompanied by fever. Even monosymptomatic severe amyloidosis can occur in these patients. Genetic counselling and appropriate management to prevent or mitigate amyloidosis may be necessary.

[The Vogt-Koyanagi-Harada syndrome: a rare differential diagnosis of uveitis in childhood. A case report taking into account the revised diagnostic criteria]. / Das Vogt-Koyanagi-Harada-Syndrom: Seltene Differenzialdiagnose der Uveitis im Kindesalter--Eine Kasuistik unter Berücksichtigung der revidierten Diagnosekriterien.

BACKGROUND: The diagnosis of the multisystemic Vogt-Koyanagi-Harada (VKH) syndrome including ocular, neurological and dermatological manifestations is difficult due to the absence of diagnostic serological parameters and the variable onset of clinical signs and symptoms in the course of the disease. PATIENT: A 12 year old female patient was admitted to our clinic , presenting with bilateral choroiditis, vitiligo and episodes of headache. After having ruled out an underlying rheumatological or infectious disease, a VKH syndrome was suspected and effectively treated with systemic steroids. The initial diagnosis of VKH syndrome would not have been possible, if the existing diagnostic criteria had been applied. DISCUSSION: As can be seen in the case of our patient, the existing diagnostic criteria of VKH syndrome may prove to be inadequate in diagnosing VKH syndrome, particularly at the onset of the disease. Considering, that early diagnosis and treatment is crucial in improving the outcome of the disease, current diagnostic criteria have been revised. Recent retrospective data suggest a higher sensitivity for the revised diagnostic criteria.

The clinical course of a child with CINCA/NOMID syndrome improved during and after treatment with thalidomide.

Chronic, infantile, neurological, cutaneous, and articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a rare autosomal dominant inherited disease. It is characterized by a persistent rash with onset during the neonatal period, neurological and ocular manifestations, and articular involvement with abnormal ossification. Mutations within the CIAS1 gene are found in up to 60% of CINCA cases, but the exact underlying pathogenetic mechanisms causing this disorder are still unclear. Although the interleukin-1 (IL-1) receptor antagonist anakinra (rHuIL-1Ra) has recently been reported to be effective, no formal recommended treatment protocols exist thus far. Herein, we describe a 17-year-old girl with CINCA for whom numerous medication trials had been unsuccessful. After the introduction of thalidomide, the symptoms of arthropathy improved dramatically even months after the medication was discontinued by the patient. We propose that thalidomide can be beneficial in select patients with CINCA syndrome.

[Acute rheumatic fever (ARF) and poststreptococcal reactive arthritis (PSRA)--an update]. / Akutes rheumatisches Fieber (ARF) und Poststreptokokken reaktive Arthritis (PSRA). Ein Update.

Betahemolytic strains of streptococcus A are able to induce a spectrum of immunologically induced diseases, depending on the immunogenic M structure of the bacteria as well as on the genetic determined reaction of the host. In acute rheumatic fever (ARF) the Jones criteria, revised and modified several times and updated in 1992, remain the diagnostic standard. Echocardiography, still not included in the Jones criteria, has become a very important diagnostic tool, especially as half of the ARF induced carditis cases are clinically inapparent. Diagnosis may be very difficult if arthritis is the only major sign, especially if not occurring in the typical migrating pattern, a fact frequently reported from countries with a high risk of ARF. Poststreptococcal reactive arthritis (PSRA) has been described as a different entity as well as a part of rheumatic fever. There is a lack of validated diagnostic criteria to establish a reliable diagnosis. There are no accepted recommendations for antibiotic prophylaxis in PSRA.

[Uveitis in conjunction with rheumatological diseases in childhood]. / Uveitis bei rheumatologischen Erkrankungen im Kindesalter.

Children with juvenile chronic arthritis are at risk to develop intraocular inflammation depending on the type of arthritis. The pathogenic mechanisms are unclear; however, an association with antinuclear antibodies is well known. In particular young girls with oligoarticular onset of arthritis are affected most often. Regular ophthalmologic examinations should allow early diagnosis and effective therapy. Complications such as synechiae, cataract, or macula edema are seen especially in uveitis patients with late diagnosis and insufficient anti-inflammatory therapy. Better therapeutic regimens have led to a better overall prognosis of intraocular inflammation in recent years.

Association study of polymorphisms within interleukin-18 in juvenile idiopathic arthritis and bronchial asthma.

BACKGROUND: Interleukin-18 (IL-18) plays an important role in the regulation of TH1 as well as TH2 immunologic responses and thus in the development of chronic inflammatory diseases. Positive association studies of polymorphisms in IL-18 with different diseases have underlined the involvement of IL-18 in the pathogenetics processes. Our interest was to test polymorphisms of IL-18 for association with a typical TH1-mediated disease--juvenile idiopathic arthritis--and the TH2-mediated disease bronchial asthma in Caucasian children. METHODS: We genotyped five polymorphisms that were in association with chronic inflammatory diseases (-607C, -137C, 113G, 127T, and -133G). This was performed by restriction fragment length polymorphism in populations of asthmatic children, control individuals, and children with antinuclear antibodies (ANA)-positive juvenile idiopathic arthritis. Statistical analysis was performed by the Armitage trend test; haplotypes were calculated by the Arlequine program. RESULTS: No significant association was found between any single nucleotide polymorphism or any haplotype and bronchial asthma or ANA-positive juvenile idiopathic arthritis. CONCLUSION: We conclude that the effect of IL-18 in the immunologic context of diseases like bronchial asthma or juvenile arthritis might be too complex to be reflected in a simple one-way association study. Furthermore, the polymorphisms under investigation might be nonfunctional.

The German etanercept registry for treatment of juvenile idiopathic arthritis.

OBJECTIVE: To describe a registry set up to monitor children treated with etanercept in Germany and Austria. METHODS: Giannini's criteria, duration of morning stiffness, number of swollen, tender and contracted joints, adverse events, and reasons for discontinuation were assessed. RESULTS: 322 patients with juvenile idiopathic arthritis (JIA) and 12 additional patients with non-JIA rheumatic diagnoses were included. Therapeutic efficacy was observed from one month after treatment was started. The number of patients with significant improvement and the degree of improvement increased during the first year. The mean (SD) number of tender and swollen joints decreased from 9 (9) and 8.4 (9) to 3.0 (6.5) and 4.5 (7) after one month, and to 2.2 (5.5) and 3.3 (5.5) after three months; morning stiffness decreased from 45 (65) minutes to 12 (30) and 7 (19) after one and three months (p<0.001 for all). Using Gianinni's criteria of 30%, 50%, and 70% improvement, a therapeutic response in JIA patients was achieved in, respectively, 66%, 54%, and 30% after one month, 78%, 61%, and 38% after three months, and 83%, 72%, and 52% after six months. Therapeutic efficacy was lower in patients with systemic onset arthritis. Overall tolerability was good: in 592 patient treatment-years there were 69 reports of adverse events in 56 patients, including one CNS demyelination. There were no opportunistic infections or lupus-like reactions. Treatment was discontinued in 53 JIA patients, in 25 because of lack of efficacy. CONCLUSION: Etanercept treatment was safe and led to a significant improvement in most JIA patients resistant to conventional treatment.

Perturbations of peripheral B lymphocyte homoeostasis in children with systemic lupus erythematosus.

OBJECTIVE: To investigate the distribution of peripheral B cell subpopulations of children with active and inactive systemic lupus erythematosus (SLE) compared with healthy controls. METHODS: Peripheral B cell subpopulations of 11 children with SLE (6 with active and 5 with inactive disease) and 14 age matched normal healthy children were analysed. Active disease was diagnosed in children with a flare of SLE, who received treatment by i.v. cyclophosphamide or i.v. methylprednisolone pulse to control the disease. Additionally, the peripheral B cells of the children with SLE were compared with those of 13 consecutive patients with adult onset SLE. RESULTS: No major difference was found in the frequency and total number of CD27(-)/CD19(+) naïve B cells and CD27(+)/CD19(+) memory B cells between patients with active and inactive lupus and healthy controls, but there was a significant increase in CD27(high) expressing plasma blasts in patients with active SLE. These cells coexpress CD38(+), HLA-DR(dim), surface Ig(low) and lack the expression of CD20 but are clearly positive for intracellular Ig, indicative of early plasma cells. Most CD138(+) cells coexpress CD27(high)/CD19(+). The enhanced frequency of peripheral plasma blasts in children with active SLE is consistent with previous findings in adult patients with SLE, whereas a relative predominance of CD27(+) memory B cells was only identified in the adult patients. CONCLUSIONS: Profound abnormalities in the distribution of B cell compartments are more pronounced in older patients with SLE, but an enhanced frequency and cell number of peripheral plasma blasts is characteristic of both diseases during active stages. Thus detection of CD27(high) plasma blasts significantly correlates with active lupus in both children and adults.

[Infections with group A ß-hemolytic streptococci and poststreptococcal sequelae]. / Infektionen mit ß-hämolysierenden Streptokokken der Gruppe A (GABS) und Streptokokkenfolgeerkrankungen.

Group A ß-hemolytic streptococci (GABS) are among the most frequent causes of bacterial infections during childhood. In addition to well-known local infections, scarlet fever, and sepsis, streptococcal toxic shock syndrome (STSS) and necrotizing fasciitis (NF) have been noted with increasing frequency.NF can also be induced in children by superinfected varicella, which is associated with a higher mortality rate.Triggering factors include pathogen-specific capsular proteins, virulent factors, and toxins as superantigens. Immunological quick tests display high reliability, and PCR enables analyses of types and toxins.Furthermore, type-specific streptococcal sequelae can be caused by group C streptococci.Rheumatic fever is rather rare in industrialized nations, but cardiac involvement accurs more frequent than previously assumed.Chorea apparently correlates with neuronal antibodies, as do pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS),and a series of cases of acute disseminated encephalomyelitis (ADEM) associated with streptococci have also been reported. No resistance to penicillin exists, but pathogenic persistence remains a problem.A 26-M valent vaccine is in clinical trials, but is still subject to controversy.

Effect of glucocorticoid therapy on glucocorticoid receptors in children with autoimmune diseases.

Low-dose glucocorticoids (GC) achieve their action completely by classical genomic effects, mediated by the glucocorticoid receptor (GCR). In high doses of GC, nongenomic effects have also been found, but it is still unclear to what extent they contribute to a beneficial outcome. In this study, we present a determination of the number of lymphocyte GCR sites and the binding affinity in healthy children and children with autoimmune diseases. We further assess the effect of GC administration, especially of high-dose pulse therapy on the number of binding sites. The number of GCR sites per cell was analyzed with [(3)H]-dexamethasone radioligand binding assay and binding affinity (Kd given in nM) in peripheral blood mononuclear cells isolated from 48 healthy children and 35 patients. The patients were divided into three groups based on GC treatment: 0 mg/kg (group 1), 0.01-0.3 mg/kg orally (group 2), and 10-15 mg/kg i.v. pulse therapy (group 3) of prednisolone equivalent per day. Gender- and age-independent normal values of 4338 +/- 1687 sites/lymphocytes and Kd 6.7 +/- 2.2 nM were found. At 3463 +/- 1574, the number of receptor sites in patients without GC (group 1) was significantly lower than that of healthy volunteers (p < 0.05). In patients receiving GC treatment, this value was reduced to 2952 +/- 512 (group 2). Significant down-regulation to a minimum of 479 +/- 168 (group 3) was found after pulse therapy compared with untreated patients (p < 0.01). In pulse therapy, GC lead to a fast and dramatic receptor down-regulation. We suppose that the increase in therapeutic success of pulse-therapy may partly be mediated through additional nongenomic effects.