NEIHS Study

Table of Contents

Pathogenic Studies in Families with Twins or Siblings Discordant for Systemic Rheumatic Disorders Study Design

Most autoimmune diseases are thought to develop as a result of chronic immune activation and dysregulation after selected environmental exposures in genetically susceptible individuals. Current evidence suggests that the adult and juvenile forms of systemic rheumatic disorders -- defined here as Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE), Systemic Sclerosis (SSc), and Idiopathic Inflammatory Myopathies (IIM) -- share many common clinical manifestations, immune responses, genetic, hormonal and environmental risk factors, and possible pathogeneses. Conversely, other studies imply that each rheumatic disease, as currently defined, may be composed of more homogeneous subgroups, known as elemental disorders, with different pathogeneses. This protocol will explore pathogenic mechanisms for systemic rheumatic disorders and possible elemental disorders through the evaluation of families with monozygotic or dizygotic twins or other siblings discordant for systemic rheumatic disorders (twin-sib pairs). Parents, normal volunteers and offspring of microchimeric female twin-sibs will also be evaluated as needed for the experimental designs of each portion of the protocol. A clinical evaluation, using standardized physician and patient clinical and environmental exposure questionnaires, and specimen collections from 400 twin-sib pairs discordant for systemic rheumatic disorders will be performed to confirm diagnoses, document medical histories and assess possible risk factors implicated in the development of autoimmunity. This study will evaluate children, who will make up 25-50% of the twin-sib pairs, and adults in similar ways to attempt to understand possible similarities and differences in pathogeneses of systemic rheumatic disorders based upon age of onset. Hypothesis-testing studies will assess differences in peripheral blood cell gene activation/suppression, levels and types of microchimerism between affected and unaffected individuals, selected genetic risk factors for these disorders and occupational and hormonal exposures hypothesized to be potential risk factors for these diseases. Exploratory studies will be conducted to begin to assess other environmental risk factors for systemic rheumatic disorders and to better understand associations among phenotypes and genotypes. Biologic specimens -- including blood, urine, and other clinical specimens or biopsies no longer necessary for clinical care -- will be collected for directed biomarker assays and the development of repositories for future research. Yearly follow-up of all twin-sib pairs for five years will be performed to assess clinical changes and a final comprehensive assessment will repeat the initial studies at five years after enrollment. more information...