Anakinra: a safe and effective first-line treatment in systemic onset juvenile idiopathic arthritis (SoJIA).

Systemic onset juvenile idiopathic arthritis (SoJIA) is a rare inflammatory disorder. It can result in disease and treatment-related disability. SoJIA is characterized by remitting fevers, evanescent rash, generalized lymphadenopathy, hepatomegaly/splenomegaly, and/or serositis. Non-responsiveness to standard therapy with corticosteroids and disease modifying antirheumatic drugs is not uncommon. IL-1ß has been shown to be a main contributor to the pathogenesis of SoJIA. Anakinra, a recombinant IL-1ß receptor antagonist, was shown to be effective in small cohorts of therapy-resistant adult and pediatric Still's patients. In order to assess the efficacy and safety of first-line anakinra treatment in SoJIA, we reviewed the charts of all SoJIA patients in our institution from 2005 to 2010, searching for first-line anakinra-treated patients. We report the clinical and laboratory course of four SoJIA patients. The mean follow-up was 13.5 (range: 2-50) months. Anakinra was started at doses from 1.5 to 4 mg/kg for a median duration of 3 (range: 3-18) months. Two patients responded to anakinra mono-therapy; two cases required corticosteroids. Normalized body temperatures and the absence of evanescent rashes were achieved after a median of 4 (range: 2-10) days. We did not see treatment-related adverse reactions other than local injection site inflammation. This is the first single-center series, reporting anakinra as first-line treatment in SoJIA. We show rapid efficacy of anakinra in early SoJIA with reduced treatment-related side effects. A subset of patients remains corticosteroid dependent. Further studies are warranted to follow larger cohorts and to assess long-term safety.

Functional analysis of splice site mutations in the human hairless (HR) gene using a minigene assay.

BACKGROUND: Congenital atrichia is a rare autosomal recessive form of isolated alopecia which is caused by mutations in the human hairless (HR) gene. Patients are born with normal hair that is shed almost completely and irreversibly during the first weeks of life. OBJECTIVES: To investigate the molecular genetic basis of congenital atrichia in two patients, and to analyse the functional consequences of one newly identified and all seven previously identified HR splice site mutations using a minigene assay. METHODS: Molecular analysis of the HR gene was performed by direct DNA sequencing. To analyse the functional consequences of the splice site mutations, the respective sequences were cloned into a vector which allows directed splicing. After transfection of COS7 cells, isolation of RNA and cDNA synthesis, sequencing was performed to analyse the products. RESULTS: Two novel mutations were identified: an insertion in exon 2 (c.485insT; p.C162LfsX17), and a splice site mutation (c.2847-1G>A). In vitro analysis revealed aberrant splicing for all eight of the investigated HR splice site mutations. Comparison with the results of two biocomputational programs (neural network splice server and CRYP-SKIP) and calculation of consensus values revealed that the predictions of these two programs were consistent in only five and two of the eight mutations, respectively. CONCLUSIONS: This is the first report to analyse the consequences of HR splice site mutations using a cell-based in vitro assay. The results highlight the importance of performing splicing experiments to clarify the consequences of putative splice site mutations.

[Evidence-based diagnostic approach to inherited retinal dystrophies 2009]. / Evidenzbasierte Diagnostik hereditärer Netzhautdystrophien 2009.

BACKGROUND: Hereditary retinal dystrophies comprise a heterogeneous group of inherited retinal disorders with variable clinical presentation and multiple associated genes. Clinical diagnosis and differential diagnosis are difficult. The purpose of the current paper is to provide guidelines for an effective diagnostic approach. METHODS: A literature search was carried out and our own data on clinical (n = 3200) and molecular genetic (n = 4050) diagnosis of patients with retinal dystrophies were evaluated. RESULTS: For an early diagnosis it is of importance to include inherited retinal dystrophies in the differential diagnosis of unexplained visual disturbances. The most important clinical test is the full-field electroretinogram (ERG), which allows detection or exclusion of generalised retinal dystrophies. If the full-field ERG is normal, a multifocal ERG will distinguish macular dystrophies. Fundus autofluorescence, near-infrared autofluorescence and high resolution optical coherence tomography improve the early diagnosis because morphological alterations can be detected prior to their ophthalmoscopic visibility. In addition, these non-invasive imaging techniques reveal new phenomena which are important for the differential diagnosis and follow-up of retinal dystrophies as well as for an improved understanding of their pathogenesis. Routine molecular genetic diagnosis is available for an increasing number of retinal dystrophies. A succinct clinical diagnosis is a prerequisite to allow selection of the gene(s) to be analysed. If genetic testing is indicated, a human geneticist should be involved for counselling of the patient and possibly further family members and initiation of the necessary steps for DNA testing. CONCLUSION: The combination of electrophysiological testing, retinal imaging and molecular genetic analysis allows a differentiated diagnosis of inherited retinal dystrophies and an individual counselling of patients. If inherited retinal dystrophies are suspected, a detailed examination in a retinal centre specialised on inherited retinal dystrophies is recommended.

Lipofuscin- and melanin-related fundus autofluorescence visualize different retinal pigment epithelial alterations in patients with retinitis pigmentosa.

AIMS: To compare melanin-related near-infrared fundus autofluorescence (FAF; NIA, excitation 787 nm, emission >800 nm) with lipofuscin-related FAF (excitation 488 nm, emission >500 nm) in retinitis pigmentosa (RP). METHODS: Thirty-three consecutive RP patients with different modes of inheritance were diagnosed clinically, with full-field ERG, and if possible with molecular genetic methods. FAF and NIA imaging were performed with a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2). RESULTS: Rings of increased FAF were present within an area of preserved retinal pigment epithelium (RPE) at the posterior pole (31/33). Rings of increased NIA were located in the same region as rings of increased FAF. In contrast to FAF, NIA showed a precipitous decline of NIA peripheral to the ring. In larger areas of preserved NIA (11/31), pericentral and foveal NIA were of similar intensity with an area of lower NIA in between. In smaller areas of preserved NIA (20/31), NIA was homogeneous from the perifovea to the fovea. In one patient without a ring of increased FAF, NIA distribution was normal. In the remaining patient with severely advanced RP, no residual RPE as well as no FAF and NIA were detectable. CONCLUSION: Characteristic features for FAF and NIA alterations in a heterogeneous group of RP patients indicate a common pathway of RPE degeneration. Patterns of NIA and FAF indicate different pathophysiologic processes involving melanin and lipofuscin. Combined NIA and FAF imaging will provide further insight into the pathogenesis of RP and non-invasive monitoring of future therapeutic interventions.

Good response to IL-1beta blockade by anakinra in a 23-year-old CINCA/NOMID patient without mutations in the CIAS1 gene. Cytokine profiles and functional studies.

Chronic infantile neurological cutaneous and articular (CINCA) syndrome is an autoinflammatory disease, defined by the triad of urticarial rash, neurological manifestations, and arthropathy, accompanied by recurrent fevers and systemic inflammation. Increasing neurological deficits result from aseptic meningitis. Sensorineural hearing loss and progressive loss of vision caused by keratoconjunctivitis or papilloedema may emerge. An autosomal-dominant inheritance is suspected although sporadic cases are reported frequently. Sixty per cent of CINCA patients carry mutations in the cold-induced autoinflammatory syndrome (CIAS1) gene. We report the favourable response of a 23-year-old CINCA patient without CIAS1 mutations to treatment with the recombinant interleukin-1 (IL-1) receptor antagonist anakinra.

Chilblain lupus erythematosus--a review of literature.

Chilblain lupus erythematosus (CHLE) is a rare, chronic form of cutaneous lupus erythematosus. Sporadic cases and two families with autosomal dominant-inherited CHLE have been reported. In familial CHLE, two missense mutations in TREX1 encoding the 3'-5' repair exonuclease 1 were described in affected individuals. The pathogenesis of sporadic CHLE remains unknown. Up to 20% of patients develop systemic lupus erythematosus (SLE). An association with anorexia is discussed. In many cases, there is good response to symptomatic therapy. SLE therapeutics have good effects on SLE-typical symptoms but not on chilblains themselves. This article reviews the clinical presentation, pathogenesis, diagnosis and treatment of CHLE. As an index patient with unique features, we report a 13-year-old boy developing CHLE after anorexia nervosa. Sequencing of TREX1 was normal. With psychotherapeutic support for anorexia and after antibiotic therapy, topical steroids, physical warming and calcium channel blockers, the patient experienced significant relief. Improvement of phalangeal perfusion was demonstrated by angio-MRI.

[Osteoid osteomas of the fingers: an atypical localization? Two case reports and a review of the literature]. / Osteoidosteome der Finger: eine atypische Lokalisation? Fallberichte von zwei Patienten und Literaturübersicht.

Osteoid osteomas are painful bone tumors that usually occur in childhood or adolescence. Despite the small size of the bony lesions osteoid osteomas can cause persistent pain. Pathogenesis has not been completely understood. Remission usually occurs within several months to years. Therefore surgical therapy is not indicated in all cases. Nevertheless, as a result of reduced quality of life due to pain, sufficient analgesic/antiinflammatory therapy needs to be provided. We report on two male patients, aged 10 and 14 years, who presented with arthritis of the finger joints. As a result of both patients' histories, and following radiographic imaging and magnetic resonance imaging, a diagnosis of osteoid osteoma was made. Remission could be achieved in both patients following treatment with nonsteroidal antiinflammatory drugs (NSAIDs).In addition to the typical sites at the long bones of the lower extremity, osteoid osteomas can also localize to other sites such as fingers. In the case of definitive diagnosis and under close follow-up, medical treatment with NSAIDs is an alternative to surgical strategies. The operative risk should be weighed against the risk of long-term treatment with NSAIDs.

[Wegener's granulomatosis in pediatric patients]. / Wegener-Granulomatose bei pädiatrischen Patienten.

Wegener's Granulomatosis (WG) is a disease occurring rarely in childhood and adolescence. Together with the Churg-Strauss-Syndrome and the microscopic Polyangiitis it belongs to the vasculitis syndromes associated with ANCA. WG mostly affects the upper and lower respiratory tract and kidneys. It is characterized by a chronic development and high tendency to relapse. In cases of persistent disturbances of the respiratory system which do not have infectious or allergic geneses differential diagnosis should also consider WG. Although clinical course and prognosis have improved since the introduction of immunosuppressive therapy, WG, leading to renal failure in about one third of all cases, remains a disease which has to be taken seriously. Early treatment has been proven to improve prognosis. Due to the necessity of longterm treatment less toxic immunosuppressive therapy should be applied (e.g. Methotrexate).

[Systemic lupus erythematosus in children and adolescents]. / Systemischer Lupus erythematodes im Kindes- und Jugendalter.

Children and adolescents represent 15-20% of all systemic lupus erythematosus (SLE) patients. Although the clinical presentation and immunological findings are similar to those of adult SLE, children usually have a more severe disease at onset with higher rates of organ involvement. Rapid diagnosis and subsequent therapy are necessary to prevent major organ damage. The survival of children with SLE has improved dramatically over the past decades due to the introduction of steroids and immunosuppressive drugs. New strategies to improve the long-term course of the disease and to reduce potential drug toxicities are necessary. A common concept does not exist. There are some promising new drugs. This review article summarizes the epidemiology, pathogenesis, clinical manifestations and therapy of childhood and adolescent-onset SLE.