Natural History, Pathogenesis, and Outcome of Autoinflammatory Diseases (NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still'S-like Diseases, and Other Undifferentiated Autoinflammatory Diseases)

January 12, 2024 updated by: National Institute of Allergy and Infectious Diseases (NIAID)

Studies of the Natural History, Pathogenesis, and Outcome of Autoinflammatory Diseases (NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still'S-like Diseases, and Other Undifferentiated Autoinflammatory Diseases)

Background:

Some diseases cause chronic inflammation with intermittent flares in the body. These are called autoinflammatory diseases. They can cause fevers, rashes, ulcers, and other problems. Researchers want to learn more about the causes and effects of these diseases. They hope this will improve how the disease is managed in the future.

Objectives:

To understand the underlying immune dysregulation

To identify the genetic cause

To translate our findings into novel treatments that improve patients disease outcomes

Eligibility:

Patients with known NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still's Disease, and with other yet undifferentiated autoinflammatory diseases.

Unaffected relatives of participants with a known or undifferentiated autoinflammatory disease

Healthy adult volunteers at least 18 years of age

Design:

Participants will be screened with blood sample and medical history. They may provide copies of their medical records.

Enrolled participants will be evaluated at the NIH for 2-5 days. All participants will have a detailed medical history, physical exam, blood tests, and other evaluations depending on the extent of their autoinflammatory disease.

Participants may also expect the following assessments:

  1. Clinical tests that help assess organ damage and function such as hearing, vision, memory, and learning tests.
  2. Imaging studies to characterize organ involvement of the inflammatory disease including: X-rays, CT scans, special MRIs, and bone scans.
  3. Laboratory evaluations including clinical markers of disease activity, research samples for genetic studies, blood samples for cytokine/biomarker assessment, and gene expression profiling.
  4. Questionnaires to assess disease activity and quality of life.
  5. If indicated, other procedures may be administered that include: a lumbar puncture if CNS inflammation is suspected, a skin biopsy if skin inflammation is present, and/or gastrointestinal and pulmonary procedures if they are clinically indicated.

Participants may return for a single follow-up visit or for long-term follow-up visits depending on their disease and willingness to return. Long-term follow-up may occur for up to 15 years on this protocol.

Study Overview

Status

Recruiting

Conditions

Detailed Description

Autoinflammatory diseases are a group of immune dysregulatory diseases that are characterized by recurrent episodes of systemic as well as organ-specific inflammation that can involve the skin, eyes, joints, bones, muscles, lungs, serosal surfaces, inner ear, brain, and other organs. The prominent role of IL-1 in the pathogenesis of these disorders first became evident through the discovery of mutations in the gene NLRP3 and IL1RN. Since then, we have identified additional mutations that cause autoinflammatory diseases, including mutations in proteasome components and STING1 that suggest a role of increased type I IFN signaling as a contributor to the disease pathogenesis of autoinflammatory diseases and in NLRC4 and CDC42 that suggest a role of IL-18 in some autoinflammatory diseases. In this natural history study, we seek to comprehensively evaluate people with autoinflammatory diseases that include clinical, genetic, immunologic, andendocrinologic characterizations. Other rare diseases not mediated by IL-1, IL-18 or type I IFN and presumed to be autoinflammatory diseases with unknown genetic causes may also be eligible under this protocol. In addition, we intend to evaluate long-term outcomes and biomarkers over time in selected diseases. We plan to follow most participants for the duration of this study (15 years). Relatives who do not have autoinflammatory diseases as well as healthy volunteers will also be recruited to serve as controls for biomarker, genetic, and other molecular analyses.

Study Type

Observational

Enrollment (Estimated)

3200

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • Maryland
      • Bethesda, Maryland, United States, 20892
        • Recruiting
        • National Institutes of Health Clinical Center
        • Contact:
          • For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)
          • Phone Number: TTY8664111010 800-411-1222
          • Email: prpl@cc.nih.gov

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

No older than 99 years (Child, Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Sampling Method

Non-Probability Sample

Study Population

Study population is quite diverse as affected participants are from all over the world, different age ranges, and all race/ethnic groups.

Description

  • INCLUSION CRITERIA - AFFECTED PARTICIPANTS:

    1. Be 2 to 99 years old for participants who will be seen at the NIH CC; be 0 (newborn) to 99 years old for participants who participate remotely via a virtual protocol visit and will submit mail-in samples. Participants younger than 3 years will be seen in the outpatient clinic at the NIH CC if approved by the Pediatric

      Consult Service as per NIH CC policy and guidelines.

    2. Is willing to allow storage of biological specimens for future use in medical research.
    3. Is willing to allow genetic testing on collected biological samples.
    4. Has a primary care or other physician who will manage all health conditions related or unrelated to the study objectives.

    5. Fulfills one of the following criteria:

      • Has a known disease-causing genetic mutation associated with NOMID/CAPS, DIRA, CANDLE, SAVI, or NLRC4-MAS.

      • Has clinical signs or symptoms not explained by any other disorder (eg, infections, malignancies) and are consistent with a possible IL-1 mediated autoinflammatory disease. Participants must meet both of the following criteria:

        • Clinical characteristics strongly consistent with an IL-1 mediated autoinflammatory disease per the following criteria and at the discretion of the principal investigator (PI). Individuals must have a past or present history of one of the following to be considered for study enrollment:

          • Recurrent fever that has gone undiagnosed after reasonable attempts, and that is consistent with the conditions under study in this protocol
          • Neutrophilic urticaria, pustular dermatitis, erysipelas-like erythema, or urticarial rash
          • Epiphyseal and/or patella enlargement, periostitis, myalgias, arthralgias, arthritis, or recurrent multifocal aseptic osteomyelitis
          • Sensorineural hearing loss
          • Chronic aseptic meningitis or CNS vasculitis
          • Conjunctivitis, episcleritis, uveitis, papilledema, pleuritis, pericarditis, aseptic peritonitis, early onset enterocolitis, hepatosplenomegaly, or lymphadenopathies
        • Laboratory characteristics strongly consistent with an IL-1mediated autoinflammatory disease per the following criteria. Individuals must havepast or present history of evidence of systemic inflammation (eg, elevation of C-reactive protein [CRP] and/or erythrocyte sedimentation rate [ESR], anemia, thrombocytosis).

      • Has clinical signs or symptoms not explained by any other disorder (eg, infections, malignancies) and are consistent with a possible IFN-mediated, autoinflammatory disease.1,36 Participants must meet both of the following criteria:

        • Clinical characteristics strongly consistent with an IFN-mediated autoinflammatory disease per the following criteria and at the discretion of the PI. Individuals must have a past or present history of one of the following to be considered for study enrollment:

          • Recurrent fevers that has gone undiagnosed after reasonable attempts, and that is consistent with the conditions under study in this protocol
          • Panniculitis, ischemic ulcerative skin lesions, chilblain lesions, or livedo reticularis
          • Lipodystrophy
          • Myositis, arthralgias, arthritis, or joint contractures
          • Basal ganglia calcifications or white matter CNS disease
          • Interstitial lung disease, lung fibrosis, or pulmonary hypertension
          • Conjunctivitis, episcleritis, cortical blindness, glaucoma, papilledema, or hepatosplenomegaly
          • Laboratory characteristics strongly consistent with an IFN-mediated autoinflammatory disease per the following criteria. Individuals must have past or present history one or more of the following to be considered for study enrollment:
          • Evidence of systemic inflammation (eg, ESR or CRP)
          • Cytopenias (eg. leukopenia, anemia, or thrombocytopenia)
          • Dyslipidemia or insulin resistance
          • Abnormal liver function test, creatinine kinase (CK), or LDH

      • Has clinical signs or symptoms consistent with an undifferentiated autoinflammatory disease (including but not limited to dysregulation in other proinflammatory cytokines such as IL-17, TNF, IL-18, and others). Participants must meet one of the following criteria:

        • Clinical characteristics strongly consistent with an undifferentiated autoinflammatory disease. Individuals must have a past or present history of one of the clinical and one of the laboratory characteristics mentioned above to be considered for study enrollment.
        • Individuals with defined organ inflammation associated with past or current evidence of systemic inflammation.
    6. Alternatively to #5, had been enrolled in the past as an affected participant on NIAMS study 03-AR-0173 and or had samples collected on 03-AR-0173.

INCLUSION CRITERIA - UNAFFECTED RELATIVES OF AFFECTED PARTICIPANTS:

  1. Be 2 to 99 years old for participants who will be seen at the NIH CC; be 0 (newborn) to 99 years old for participants who participate remotely via a virtual protocol visit and will submit mail-in samples. Participants younger than 3 years will be seen in the outpatient clinic at the NIH CC if approved by the Pediatric Consult Service as per NIH CC policy and guidelines.)
  2. Be related by blood to an affected participant.
  3. Is willing to allow storage of biological samples for future use in medical research.
  4. Is willing to allow genetic testing on collected biological samples.
  5. Does not fulfill any of inclusion criterion #5 for affected participants.
  6. Is able to provide informed consent.

INCLUSION CRITERIA - HEALTHY VOLUNTEERS:

  1. Be at least 18 years old.
  2. Not be related to an affected participant.
  3. s willing to allow storage of biological samples for future use in medical research.
  4. Is willing to allow genetic testing on collected biological samples.
  5. Does not fulfill any of inclusion criterion #5 for affected participants.
  6. Is able to provide informed consent.

PARTICIPANT EXCLUSION CRITERIA:

  1. Presence of conditions that, in the judgment of the investigator, may put the participant at undue risk or make them unsuitable for participation in the study.
  2. Oncological evaluation suggestive of lymphoma, leukemia or multiple myeloma, except for participants with a known primary diagnosis of an autoinflammatory disease who subsequently developed a malignancy. These patients will not be excluded from the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

Cohorts and Interventions

Group / Cohort
Affected Participants
Individuals with undifferentiated autoinflammatory diseases or genetically defined conditions, such as NOMID/CAPS, DIRA, CANDLE, SAVI, and NLRC4 MAS.
Healthy Volunteer
Volunteers without known autoinflammatory disease who consent to providing blood specimen for genetic testing.
Unaffected Relatives
Blood relatives of the affected patients without known autoinflammatory disease who consent to providing specimen for genetic testing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
To study the pathogenesis of patients affected with auto-inflammatory diseases, including their clinical, immunological, genetic and metabolic/endocrinological characteristics.
Time Frame: 1-2 years, 3-5 years, 10 years
To study the pathogenesis of patients affected with autoinflammatory diseases, including their clinical, immunological, genetic and metabolic/endocrinological characteristics.
1-2 years, 3-5 years, 10 years

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Longitudinal fluctuations in clinical and biomarker characteristics of autoinflammatory diseases
Time Frame: 1-2 years, 3-5 years, 10 years
To evaluate clinical characteristics/disease manifestations and blood, body fluids, and tissue biomarkers during disease flares and quiescence.
1-2 years, 3-5 years, 10 years
Long term Organ specific outcome (clinical and biomarker evidence of both inflammation and damage accrual)
Time Frame: 1-2 years, 3-5 years, 10 years
To collect long-term clinical and laboratory outcome parameters of the multiorgan inflammatory involvement and/or organ damage in patients with genetically defined or undifferentiated autoinflammatory (immune-dysregulatory) diseases.
1-2 years, 3-5 years, 10 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

  • Principal Investigator: Raphaela T Goldbach-Mansky, M.D., National Institute of Allergy and Infectious Diseases (NIAID)

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

December 9, 2016

Primary Completion (Estimated)

August 31, 2031

Study Completion (Estimated)

September 30, 2032

Study Registration Dates

First Submitted

November 23, 2016

First Submitted That Met QC Criteria

November 23, 2016

First Posted (Estimated)

November 28, 2016

Study Record Updates

Last Update Posted (Estimated)

January 15, 2024

Last Update Submitted That Met QC Criteria

January 12, 2024

Last Verified

January 11, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 170016
  • 17-I-0016

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

.As outlined in our approved GDS Plan (dated 09/27/2019): Whole exome and whole genome sequencing data

IPD Sharing Time Frame

As outlined in our approved GDS Plan (dated 09/27/2019) and protocol: Following genetic testing, the data will be shared in a controlled-access public database for other investigators to benefit from it (eg, dbGaP, the Database of Genotypes and Phenotypes).

IPD Sharing Access Criteria

Other NIH and non-NIH investigators may use these data/specimens for research purposes. @@@IRB review and approval will be obtained for all research involving identifiable data/specimen, including any coded and linked samples or data that can be linked back to the respective subjects.@@@@@@We will share human data generated in this study for future research through:@@@Our NIH-funded and approved public repository for genetic and RNA sequence data: De-identified data will be shared per our approved Genetic Data Sharing Plan. @@@BTRIS (Biomedical Translational Research Information System) sharing activities in the NIH Clinical Center (CC): includes Identifiable data generated in CC. @@@Appropriate individual regulatory approvals will govern sharing of data/specimens with outside collaborators.@@@Data will be shared with medical professionals involved in clinical care of each patient to assist with medical care of the patient. @@@Publication and/or public presentations. @@@

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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