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      CLARITY – ChiLdhood Arthritis Risk factor Identification sTudY

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          Abstract

          Background

          The aetiology of juvenile idiopathic arthritis (JIA) is largely unknown. We have established a JIA biobank in Melbourne, Australia called CLARITY – Chi Ldhood Arthritis Risk factor Identification s Tud Y, with the broad aim of identifying genomic and environmental disease risk factors. We present here study protocols, and a comparison of socio-demographic, pregnancy, birth and early life characteristics of cases and controls collected over the first 3 years of the study.

          Methods

          Cases are children aged ≤18 years with a diagnosis of JIA by 16 years. Controls are healthy children aged ≤18 years, born in the state of Victoria, undergoing a minor elective surgical procedure. Participant families provide clinical, epidemiological and environmental data via questionnaire, and a blood sample is collected.

          Results

          Clinical characteristics of cases (n = 262) are similar to those previously reported. Demographically, cases were from families of higher socio-economic status. After taking this into account, the residual pregnancy and perinatal profiles of cases were similar to control children. No case-control differences in breastfeeding commencement or duration were detected, nor was there evidence of increased case exposure to tobacco smoke in utero. At interview, cases were less likely to be exposed to active parental smoking, but disease-related changes to parent behaviour may partly underlie this.

          Conclusions

          We show that, after taking into account socio-economic status, CLARITY cases and controls are well matched on basic epidemiological characteristics. CLARITY represents a new study platform with which to generate new knowledge as to the environmental and biological risk factors for JIA.

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          Most cited references22

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          Juvenile idiopathic arthritis.

          Juvenile idiopathic arthritis is a broad term that describes a clinically heterogeneous group of arthritides of unknown cause, which begin before 16 years of age. This term encompasses several disease categories, each of which has distinct methods of presentation, clinical signs, and symptoms, and, in some cases, genetic background. The cause of disease is still poorly understood but seems to be related to both genetic and environmental factors, which result in the heterogeneity of the illness. Although none of the available drugs has a curative potential, prognosis has greatly improved as a result of substantial progresses in disease management. The most important new development has been the introduction of drugs such as anticytokine agents, which constitute a valuable treatment option for patients who are resistant to conventional antirheumatic agents. Further insights into the disease pathogenesis and treatment will be provided by the continuous advances in understanding of the mechanisms connected to the immune response and inflammatory process, and by the development of new drugs that are able to inhibit selectively single molecules or pathways.
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            Infections and autoimmune diseases.

            The high percentage of disease-discordant pairs of monozygotic twins demonstrates the central role of environmental factors in the etiology of autoimmune diseases. Efforts were first focussed on the search for triggering factors. The study of animal models has clearly shown that infections may trigger autoimmune diseases, as in the case of Coxsackie B4 virus in type I diabetes and the encephalomyocarditis virus in autoimmune myositis, two models in which viruses are thought to act by increasing immunogenicity of autoantigens secondary to local inflammation. The induction of a Guillain-Barré syndrome in rabbits after immunization with a peptide derived from Campylobacter jejuni is explained by mimicry between C. jejuni antigens and peripheral nerve axonal antigens. Other models involve chemical modification of autoantigens, as in the case of iodine-induced autoimmune thyroiditis. These mechanisms have so far only limited clinical counterparts (rheumatic fever, Guillain-Barré syndrome and drug-induced lupus or myasthenia gravis) but one may assume that unknown viruses may be at the origin of a number of chronic autoimmune diseases, such as type I diabetes and multiple sclerosis) as illustrated by the convergent data incriminating IFN-alpha in the pathophysiology of type I diabetes and systemic lupus erythematosus. Perhaps the difficulties met in identifying the etiologic viruses are due to the long lag time between the initial causal infection and onset of clinical disease. More surprisingly, infections may also protect from autoimmune diseases. Western countries are being confronted with a disturbing increase in the incidence of most immune disorders, including autoimmune and allergic diseases, inflammatory bowel diseases, and some lymphocyte malignancies. Converging epidemiological evidence indicates that this increase is linked to improvement of the socio-economic level of these countries, posing the question of the causal relationship and more precisely the nature of the link. Epidemiological and clinical data support the hygiene hypothesis according to which the decrease of infections observed over the last three decades is the main cause of the incessant increase in immune disorders. The hypothesis does not exclude an etiological role for specific pathogens in a given immune disorder as might notably be the case in inflammatory bowel diseases. Even in this setting, infections could still have a non-specific protective role. Independently of the need for confirmation by epidemiological prospective studies, the hygiene hypothesis still poses numerous questions concerning the nature of protective infectious agents, the timing of their involvement with regard to the natural history of immune diseases and, most importantly, the mechanisms of protection. Four orders of mechanisms are being explored. Antigenic competition is the first hypothesis (immune responses against pathogens compete with autoimmune and allergic responses). This is probably an important mechanism but its modalities are still elusive in spite of considerable experimental data. Its discussion in the context of homeostatic regulation of lymphocyte pools has shed new light on this hypothesis with possible competition for self MHC peptide recognition and interleukin-7. Another hypothesis deals with immunoregulation. Infectious agents stimulate a large variety of regulatory cells (Th2, CD25+, Tr1, NKT, ...) whose effects extend to other specificities than those which triggered their differentiation (bystander suppression). Infectious agents may also intervene through components which are not recognized as antigens but bind to specific receptors on cells of the immune system. Major attention has recently been drawn to Toll receptors (expressed on macrophages and possibly on regulatory T cells) and TIM proteins present on Th cells, which may express the function of the virus receptor (as in the case of the Hepatitis A virus and Tim-1). Experimental data will be presented to support each of these hypotheses. In any event, the final proof of principle will be derived from therapeutic trials where the immune disorders in question will be prevented or better cured by products derived from protective infectious agents. Numerous experimental data are already available in several models. Preliminary results have also been reported in atopic dermatitis using bacterial extracts and probiotics.
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              Dietary intervention in infancy and later signs of beta-cell autoimmunity.

              Early exposure to complex dietary proteins may increase the risk of beta-cell autoimmunity and type 1 diabetes in children with genetic susceptibility. We tested the hypothesis that supplementing breast milk with highly hydrolyzed milk formula would decrease the cumulative incidence of diabetes-associated autoantibodies in such children. In this double-blind, randomized trial, we assigned 230 infants with HLA-conferred susceptibility to type 1 diabetes and at least one family member with type 1 diabetes to receive either a casein hydrolysate formula or a conventional, cow's-milk-based formula (control) whenever breast milk was not available during the first 6 to 8 months of life. Autoantibodies to insulin, glutamic acid decarboxylase (GAD), the insulinoma-associated 2 molecule (IA-2), and zinc transporter 8 were analyzed with the use of radiobinding assays, and islet-cell antibodies were analyzed with the use of immunofluorescence, during a median observation period of 10 years (mean, 7.5). The children were monitored for incident type 1 diabetes until they were 10 years of age. The unadjusted hazard ratio for positivity for one or more autoantibodies in the casein hydrolysate group, as compared with the control group, was 0.54 (95% confidence interval [CI], 0.29 to 0.95), and the hazard ratio adjusted for an observed difference in the duration of exposure to the study formula was 0.51 (95% CI, 0.28 to 0.91). The unadjusted hazard ratio for positivity for two or more autoantibodies was 0.52 (95% CI, 0.21 to 1.17), and the adjusted hazard ratio was 0.47 (95% CI, 0.19 to 1.07). The rate of reported adverse events was similar in the two groups. Dietary intervention during infancy appears to have a long-lasting effect on markers of beta-cell autoimmunity--markers that may reflect an autoimmune process leading to type 1 diabetes. (ClinicalTrials.gov number, NCT00570102.).
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                Author and article information

                Journal
                Pediatr Rheumatol Online J
                Pediatr Rheumatol Online J
                Pediatric Rheumatology Online Journal
                BioMed Central
                1546-0096
                2012
                15 November 2012
                : 10
                : 37
                Affiliations
                [1 ]Genes, Environment and Complex Disease, Murdoch Childrens Research Institute, Parkville, VIC, Australia
                [2 ]Environmental and Genetic Epidemiology Research, Murdoch Childrens Research Institute, Parkville, VIC, Australia
                [3 ]Arthritis & Rheumatology, Murdoch Childrens Research Institute, Parkville, VIC, Australia
                [4 ]Paediatric Rheumatology Unit, Department of General Medicine, The Royal Children’s Hospital, Parkville, VIC, Australia
                [5 ]Department of Physiology, The University of Melbourne, Parkville, VIC, Australia
                Article
                1546-0096-10-37
                10.1186/1546-0096-10-37
                3551677
                23153063
                edda40a1-6c5f-4851-ad13-a2573aeb3f63
                Copyright ©2012 Ellis et al.; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 August 2012
                : 8 November 2012
                Categories
                Research

                Pediatrics
                early life,demographics,epidemiology,risk factors,juvenile idiopathic arthritis
                Pediatrics
                early life, demographics, epidemiology, risk factors, juvenile idiopathic arthritis

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