[Evidence of treatment of chronic inflammation in childhood and adolescence with biologics]. / Evidenz der Therapie chronisch-entzündlicher Erkrankungen in Kindheit und Adoleszenz mit Biologika.

BACKGROUND: Biologics, usually monoclonal antibodies or fusion proteins, are thought to specifically interfere with immunopathogenesis of chronic inflammatory diseases. In order to test these substances also in children and adolescents, financial incentives for manufacturers were created and classification of chronic inflammatory diseases and definition of disease activity, improvement, relapse and remission were established and large international research cooperation projects were founded. METHODS: A selective literature search was carried out for treatment of chronic inflammatory diseases in children and adolescents with biologics including current guidelines. RESULTS: Only 7 out of 18 prescribed biologics have been approved for children and mostly within narrow limits. The evidence for efficacy is based on four randomized double blind placebo-controlled studies, seven withdrawal studies and seven observational studies. In spite of the limited evidence in comparison to their use in adult patients these substances are broadly used worldwide and have enlarged and substantially improved the therapeutic choices in children when conventional treatment failed or proved to be toxic. Severe adverse events including infections occasionally occur (0.01-0.03 events per patient year) but the rate of malignancies is not obviously increased; however, only two thirds of patients respond to treatment. Improvement is often incomplete, some patients deteriorate and definite termination of drug treatment is possible in only a few patients. CONCLUSION: As the prescription of biologics has become an important issue of treatment but is based on insufficient evidence data, further studies are necessary in children and adolescents with diseases, such as juvenile idiopathic arthritis, Crohn's disease, ulcerative colitis and inherited fever syndromes. As many drugs are available these studies can be conducted against verum.

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.

[Acanthamoeba meningoencephalitis: a case in an adolescent female patient with systemic lupus erythematosus]. / Acanthamöben-Meningoenzephalitis : Ein Fall bei einer jugendlichen Patientin mit systemischem Lupus erythematodes.

Meningoencephalitis caused by Acanthamoeba spp . is a rare opportunistic infection, difficult to diagnose and difficult to treat, which causes death in almost all cases. We report the neuropathologic findings of a 16-year-old girl with systemic lupus erythematosus (SLE) treated with immunosuppression who died of fulminant Acanthamoeba meningoencephalitis. Neuropathologic examination revealed multiple supratentorial and infratentorial hemorrhagic necrotizing lesions with encephalitis and vasculitis with mixed inflammatory infiltrates, fibrinoid necrosis of vessel walls, and local leptomeningitis. Acanthamoeba in the lesions may be misinterpreted as macrophages. Taking them into differential diagnostic consideration, cytological differences should be detected, and relevant additional stains for reliable differentiation of these cells can be performed. To our knowledge, this is the first published case of Acanthamoeba meningoencephalitis in a patient with SLE in Germany.

Composition and posttranslational modification of individual collagen chains from osteosarcomas and osteofibrous dysplasias.

The composition of collagen was analyzed and the degree of lysyl hydroxylation of individual collagen chains was determined in four osteosarcomas and two osteofibrous dysplasias. In addition, the tumor proliferation (number of mitoses, proliferating-nuclear-antigen-positive cells, MIB) as well as the response to chemotherapy (morphological regression grade) were checked. All tumors contained a high proportion of collagen III and, in all but one osteosarcoma, pepsin-extracted collagens I and III were overmodified. Furthermore, the proportion of diglycosides in collagen I was about four times higher than in controls. The collagen composition and modification resembled those of bones at early stages of human development. One osteosarcoma and both osteofibrous dysplasias were in the normal range of lysyl hydroxylation. There was no correlation between the collagen properties and the histopathological marker of tumor proliferation.

Ehlers-Danlos syndrome type VII: phenotype and genotype.

A patient suffering from a severe form of Ehlers-Danlos syndrome is presented (EDS type VII). The presence of bilateral congenital hip dislocation, generalized joint hypermobility and a soft hyperelastic skin with abnormal scarring suggested a specific collagen type I defect. SDS-PAGE analysis of collagens secreted into the medium of fibroblast cultures showed a retarded migration of more than half of the alpha 2(I) chains. CNBr peptide mapping of the HPLC-purified altered chain localized the mutant locus to the N-terminal region of the protein. cDNA analysis of the corresponding gene COL1A2 revealed, in addition to the expected collagen sequence, a transcript missing the entire exon 6. This exon encodes a major crosslinking site within collagen fibres as well as the N-propeptidase cleavage site. The skipping of exon 6 is caused by a splice site mutation substituting an A for a G at the first nucleotide of intron 6.

Hyperplastic callus formation in osteogenesis imperfecta.

Osteogenesis imperfecta, an inherited disorder of connective tissues, affects roughly (OI) 4000 people in Germany (11). The main clinical symptoms are fragile bones, progressing skeletal deformities, generalized osteoporosis and short stature. Incidentally, the clinical manifestations can range from perinatal lethal forms to phenotypical normal adults. In many instances the underlying causes of the disease are mutations in gene coding for collagen I, the predominant protein in most connective tissues. Fracture healing is usually not impaired, although in a unique group of OI-patients, a tumor-like hyperplastic callus occurs with excessive deposition of extracellular matrix constituents. Biochemical analysis of the callus is reminiscent of bone from early stages of human development and normal fracture healing (e.g. collagen type composition, degree of posttranslational modification). This underlines that, besides collagen mutations, the regulation of collagen synthesis and their posttranslational processing might be disturbed in patients with hyperplastic callus formation.

Optimizing deposition parameters of electron beam evaporated TiO(2) films.

A study of the major deposition parameters including source material, oxygen partial pressure, substrate temperature, and deposition rate affecting the optical quality of electron beam evaporated TiO(2) films is presented. After careful optimization of these parameters it is possible to reproducibly deposit TiO(2) films from TiO(2) source material mixed with 5% CeO(2) at an oxygen partial pressure of 5 x 10(-5) Torr, a substrate temperature of 320 degrees C, and a deposition rate of 2 A/s.

Identification of a new heterozygous point mutation in the COL1A2 gene leading to skipping of exon 9 in a patient with joint laxity, hyperextensibility of skin and blue sclerae. Mutations in brief no. 166. Online.

A heterozygous deletion of exon 9 in the COL1A2-mRNA of a patient with symptoms of both the Ehlers-Danlos-Syndrome and the Osteogensis Imperfecta is described. In the genomic DNA of the patient, exon 9 is homozygously present. We identified a novel heterozygous point mutation in the splice donor site of intron 9, leading to a G-->A substitution in position +5. This mutation leads to heterozygous skipping of exon 9 in the COL1A2-mRNA of this patient. The deletion results in a shortened (by 18 amino acids) but in frame 12(1) chain, which probably leads to the formation of abberantly processed triple helices.

Lysyl hydroxylation in collagens from hyperplastic callus and embryonic bones.

Tissue from two patients with osteogenesis imperfecta suffering from a hyperplastic callus was studied. Although collagen type I from the compact bone and the skin and fibroblast cultures of these patients showed normal lysyl hydroxylation, collagen types I, II, III and V from the callus tissue were markedly overhydroxylated. Furthermore, the overhydroxylation of lysine residues covered almost equally the entire alpha 1 (I) collagen chain, as demonstrated by the analysis of individual CNBr-derived peptides. In addition, collagen type I was isolated from femoral compact bone of 33 individuals who died between the 16th week of gestational age and 22 years. Lysyl hydroxylation rapidly decreased in both collagen alpha 1 (I) and alpha 2 (I) chains during fetal development, and only little in the postnatal period. The transient increase in lysyl hydroxylation and the involvement of various collagen types in callus tissue argue for a regulatory mechanism that may operate in bone repair and during fetal development.

Hydroxylation of collagen type I: evidence that both lysyl and prolyl residues are overhydroxylated in osteogenesis imperfecta.

The composition of the collagens secreted into the media of fibroblast cultures of 39 patients with osteogenesis imperfecta (OI) was the same in controls and OI cultures. An abnormal migration pattern of collagens upon SDS-PAGE was evident in one third of the cultures investigated. Lysyl and prolyl hydroxylation of HPLC-purified alpha 1(I) chains was elevated in about 60% of cultures. The degree of hydroxylation was highest in the lethal forms. The extent of lysyl and prolyl hydroxylation showed a strong correlation (r = 0.74, P < 0.001). While high levels of hydroxylation are frequently observed in OI patients, a direct correlation between lysyl or prolyl hydroxylation and fracture rate or growth retardation could not be established.