Study of Families With Twins or Siblings Discordant for Rheumatic Disorders

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.

- INCLUSION CRITERIA:

The minimum inclusion criteria needed for enrollment are a twin pair or sibling pair, as
defined by an eligible proband and his/her eligible twin or sibling, willing and able to
give informed consent, to enroll in the study, to complete the questionnaires and to donate
blood and urine samples (in case of children, parent/legal guardian must also be willing
and able to provide informed consent).

Proband inclusion criteria:

- Children (< 18 years of age) or adults (18 or more years of age) require a diagnosis of a
systemic rheumatic disorder (by American College of Rheumatology (ACR) or other criteria
for the adult or juvenile forms of RA, SLE, SSc, or IIM (per (92;93)). Regarding the
childhood-onset diseases: JRA will be defined by age of onset <17 years of age; for other
diseases age of onset will be < 18 years. Probands will be diagnosed within 5 years of
enrollment in the study, with at least one twin or other sibling of the same gender within
5 years of age and without a recognized systemic rheumatic disorder or other autoimmune
disease available for study.

Twin-sibling inclusion criteria:

-Children or adults who are twins or other siblings of a proband sharing the same
biological parents, but without a recognized systemic rheumatic or autoimmune disorder, of
the same gender and within 5 years of age of the proband. If monozygotic twins are enrolled
from a family, another unaffected non-twin sibling sharing the same biological parents will
be enrolled for each proband if available to allow for log-linear genetic analyses. All
probands and unaffected siblings need to be at least one year of age at the time of
autoimmune disease diagnosis. In the case of triplets or greater multiples, all such
siblings are eligible for enrollment.

Parent inclusion criteria:

-Individuals who are the genetic father and mother of the proband and twin-sib. Both
parents will be enrolled whenever possible.

Normal volunteer inclusion

-criteria: Healthy controls, recruited in part via the NIH Normal Volunteers program, and
age- (within 5 years), gender- and race-matched (when feasible) to a subset of probands as
controls needed for specific studies. Normal volunteers should be in good health, without a
recognized systemic rheumatic disorder or other autoimmune disease, and should not be
taking anti-inflammatory medicines, including nonsteroidal anti-inflammatory drugs (NSAIDs)
or corticosteroids.

Offspring of microchimeric women criteria: Biological offspring of women who are probands
and are found to be microchimeric. These offspring will be enrolled as normal volunteers in
an attempt to confirm the source of their mothers microchimerism.

For all subjects: ability of the subject or parents/legal guardians to provide informed
consent to all aspects of the study after full protocol information is provided.

Should a participant enroll at a time when his/her twin/sibling is willing and able to give
informed consent, but his/her twin/sibling never enrolls (eg. Due to no longer being
willing or able to give informed consent), the enrolled participant will remain in the
study and his/her data will be used in the analyses not pertinent to his/her twin/sibling.
Data analysis will also occur in this manner should the enrolled participant s sibling
enroll, but never send in blood samples and/or questionnaires.

EXCLUSION CRITERIA:

Exclusion criteria for all protocol subjects:

1. severe trauma or vaccinations within 8 weeks of enrollment;

2. Still s disease/systemic-onset or pauciarticular JRA;

3. medical illness that in the judgment of the investigators does not allow safe blood
draws or other clinical evaluations needed for study participation;

4. cognitive impairment;

5. 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/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 or vaccinations within 8 weeks.