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Study of Families With Twins or Siblings Discordant for Rheumatic Disorders

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT00055055
Recruitment Status : Recruiting
First Posted : February 17, 2003
Last Update Posted : May 15, 2020
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) )

Brief Summary:

This study will examine families in which one sibling of a sibling pair, or twin pair, has developed a systemic rheumatic disease and one has not, to see if and how the two differ in the following:

  • Blood cell metabolism;
  • Types of cells in the blood;
  • Environmental exposures or genetic factors that might explain why one developed disease and the other did not.

Families in which one sibling has developed a systemic rheumatic disease, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, dermatomyositis, or myositis, and the other has not, are eligible for this study. The siblings may or may not be twins, but must be of the same gender and be within a 5-year age difference. Biological parents, or, in some cases, children, will also be included in the study. Normal, healthy volunteers will serve as control subjects.

Participants will undergo some or all of the following tests and procedures:

  • Medical history and physical examination. Participants will also be asked permission to obtain medical records for review.
  • Questionnaires about environmental exposures at work, at home, and elsewhere. Probands (participants with rheumatic disease) and their healthy siblings will also answer questions about infections, vaccinations, medications or dietary supplements, sun exposure, and stressful events during the year before disease diagnosis in the affected sibling.
  • Blood and urine collection for the following tests:
  • Routine blood chemistries and other studies to rule out certain diseases or medical problems;
  • Evidence of past toxic exposures and certain infections;
  • Presence of cells from the mother in the child s blood and vice versa. (Recent studies suggest that during pregnancy or delivery, cells from the mother and baby may be exchanged and circulate in the body for many years, possibly causing problems);
  • In twin or sibling pairs, presence of certain genes that may be more common in patients with systematic rheumatic diseases as compared with their unaffected siblings and normal volunteers;
  • In identical twins, comparison of their blood cell metabolism to see if and how the metabolism differs in people with rheumatic disease.

Participants may be asked for permission to have some of their blood and urine samples stored and to obtain previously collected blood or tissue biopsy specimens that are no longer needed for clinical care, for research purposes. They may also be asked to give additional blood or urine samples.

Participants will be followed every year for 5 years (either in person or by questionnaire) to evaluate any changes in their condition. The final 5-year evaluation will repeat some of the questionnaires and procedures described above.

Condition or disease
Rheumatic Diseases Rheumatoid Arthritis Systemic Lupus Erythematosus Scleroderma Dermatomyositis Myositis Inclusion Body Myositis Juvenile Dermatomyositis Juvenile Polymyositis Juvenile Idiopathic Arthritis

Detailed Description:
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.

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Study Type : Observational
Estimated Enrollment : 1550 participants
Observational Model: Case-Control
Time Perspective: Prospective
Official Title: Pathogenic Studies In Families With Twins Or Siblings Discordant For Systemic Rheumatic Disorders
Actual Study Start Date : April 21, 2003

Primary Outcome Measures :
  1. Physician Global Assesment Questionnaire [ Time Frame: Time of enrollment ]

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes

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.

Healthy volunteer inclusion criteria:

Healthy controls, recruited in part via the NIH Healthy Volunteers program, and as reasonably as possible, matched to a subset of probands based on age (within 5 years), gender, and race (when feasible). Healthy volunteers should be in good health, without

a recognized systemic rheumatic disorder or other autoimmune disease, and should not be taking antiinflammatory medicines, including nonsteroidal anti-inflammatory drugs (NSAIDs) or corticosteroids.

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 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 healthy 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00055055

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Contact: Frederick W Miller, M.D. (984) 287-3593

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United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)    800-411-1222 ext TTY8664111010   
United States, North Carolina
NIEHS Clinical Research Unit (CRU) Recruiting
Research Triangle Park, North Carolina, United States
Contact: Frederick Miller, M.D.    301-451-6273   
United States, Wisconsin
University of Wisconsin Recruiting
Madison, Wisconsin, United States, 53792
Sponsors and Collaborators
National Institute of Environmental Health Sciences (NIEHS)
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Principal Investigator: Frederick W Miller, M.D. National Institute of Environmental Health Sciences (NIEHS)
Additional Information:
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Responsible Party: National Institute of Environmental Health Sciences (NIEHS) Identifier: NCT00055055    
Other Study ID Numbers: 030099
First Posted: February 17, 2003    Key Record Dates
Last Update Posted: May 15, 2020
Last Verified: January 2, 2020
Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Environmental Health Sciences (NIEHS) ):
Genetic and Environmental Risk Factors
Adult and Pediatric Disease
Systemic Lupus Erythematosus
Autoimmunity Pathogenesis
Microarray Analyses
Rheumatoid Arthritis
Systemic Sclerosis
Idiopathic Inflammatory Myopathies
Juvenile Polymyositis
Juvenile Idiopathic Arthritis
Inflammatory Myopathies
Rheumatic Disease
Healthy Volunteer
Additional relevant MeSH terms:
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Lupus Erythematosus, Systemic
Arthritis, Rheumatoid
Rheumatic Diseases
Arthritis, Juvenile
Myositis, Inclusion Body
Scleroderma, Systemic
Scleroderma, Diffuse
Collagen Diseases
Joint Diseases
Musculoskeletal Diseases
Connective Tissue Diseases
Autoimmune Diseases
Immune System Diseases
Skin Diseases
Muscular Diseases
Neuromuscular Diseases
Nervous System Diseases