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

Physicians' Information

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.

Subjects
Subjects with systemic rheumatic diseases (RA/Polyarticular JRA, Lupus, Scleroderma, or Myositis) and unaffected twins and other siblings, their parents, selected offspring and other normal volunteers

Number of Subjects
400 probands with systemic rheumatic disorders, 400-500 twin-sibs of the probands, 400-600 parents, 100 normal volunteers and 100-150 offspring of microchimeric female twin-sibs

Study Plan
Adults or children are eligible to participate if they have been diagnosed with a systemic rheumatic disease (RA/Polyarticular JRA, Lupus, Scleroderma, or Myositis) within 47 months and they have a twin or same sex sibling who is well and within 47 months of age. Parents and matched-normal volunteers will also be asked to participate. This is a blood, urine and data collection study and subjects may be enrolled at the NIH in their local health care provider's office.

Study Duration
An initial evaluation and annual follow-up for 5 years with re-evaluations if new autoimmune disease develops.

Study Evaluations
Evaluations include history and physical examinations and CBC, differential, platelets, PT/PTT, chemistry panel, urinalysis, hepatitis B surface antigen, hepatitis C antibody, RPR, ELISA and Western blot for HIV, ANA/anti-dsDNA, RF, quantitative IgG, HLA testing, and research studies evaluating microchimerism. Blood and urine will also be collected for storage.

Sponsoring Institute
National Institute of Environmental Health Sciences (NIEHS)

Recruitment Detail
Type: Active Accrual Of New Subjects
Gender: Male & Female
Ages: Children and adults

Referral Letter Required: Yes

Population Exclusion(s): None

Eligibility Criteria

• Inclusion Criteria
  • Adults or children are eligible to participate if they have been diagnosed with a systemic rheumatic disease (RA/Polyarticular JRA, Lupus, Scleroderma, or Myositis - see Appendix 1) within 47 months and they have a twin or same sex sibling who is well and within 47 months of age.
  • Willing to participate for the planned duration of the study (5 years).
  • Able and willing to give informed consent.
  • Agree to have blood stored for future studies.
• Exclusion Criteria
  • Exclusion criteria for probands
    • Active infections requiring therapy or alteration in daily occupation or antibiotics, severe trauma or vaccinations within 8 weeks of enrollment
    • Still's disease/systemic-onset or pauciarticular JRA
    • Medical illness that in the judgment of the investigators does not allow safe blood draws or other clinical evaluations needed for study participation
    • Cognitive impairment
    • Inability to give informed assent or consent
  • Exclusion criteria for twin-sibs
    • Not sharing the same biological parents (being half-brothers or half-sisters)
    • Known criteria for systemic rheumatic disease or autoimmune disease (for example: RA/Polyarticular JRA, SLE/JSLE, SSc/JSSc, IIM/JIIM, Type 1 Diabetes, Psoriasis, Still's Disease/Systemic-Onset or Pauciarticular JRA, Celiac Sprue, Autoimmune Thyroid Disease, Idiopathic Thrombocytopenia Purpura, Multiple Sclerosis, Myasthenia Gravis, Systemic Vasculitis or Vitiligo).
  • Exclusion criteria for normal volunteers
    • Recognized systemic rheumatic disorder or other autoimmune disease
    • History of cancer or taking anti-inflammatory medicines, including nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids
    • Severe trauma
    • Vaccinations within 8 weeks
    • HIV+

Special Instructions: Currently Not Provided

Recruitment Keywords: None

Investigational Drug(s): None

Investigational Device(s): None

Study Contacts

Citations: None

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