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.
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
- Principal Investigator
Frederick W. Miller, M.D.,
Ph.D.
Chief, Environmental Autoimmunity Group
Office of Clinical
Research
National Institute of Environmental Health Sciences
National Institutes of Health
9 Memorial Drive, NIH Building
9, Room 1W107, MSC 0958
Bethesda, MD 20892-0958
Phone: (301)
451-6273
FAX: (301) 451-5585
Email:
TwinSibsStudy@mail.nih.gov
- Referral
Patient Recruitment
Warren Grant Magnuson
Clinical Center
National Institutes of Health
Bethesda, Maryland
20892-2655
Phone: 1-800-411-1222 (For TTY: 1-866-411-1010)
Fax: 301-480-9793
E-mail:
prpl@mail.cc.nih.gov
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