<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT02974595</url>
  </required_header>
  <id_info>
    <org_study_id>170016</org_study_id>
    <secondary_id>17-I-0016</secondary_id>
    <nct_id>NCT02974595</nct_id>
  </id_info>
  <brief_title>Natural History, Pathogenesis, and Outcome of Autoinflammatory Diseases (NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still'S-like Diseases, and Other Undifferentiated Autoinflammatory Diseases)</brief_title>
  <official_title>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)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      Some diseases cause chronic inflammation with intermittent flares in the body. These are&#xD;
      called autoinflammatory diseases. They can cause fevers, rashes, ulcers, and other problems.&#xD;
      Researchers want to learn more about the causes and effects of these diseases. They hope this&#xD;
      will improve how the disease is managed in the future.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      To understand the underlying immune dysregulation&#xD;
&#xD;
      To identify the genetic cause&#xD;
&#xD;
      To translate our findings into novel treatments that improve patients disease outcomes&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      Patients with known NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still's Disease, and with&#xD;
      other yet undifferentiated autoinflammatory diseases.&#xD;
&#xD;
      Unaffected relatives of participants with a known or undifferentiated autoinflammatory&#xD;
      disease&#xD;
&#xD;
      Healthy adult volunteers at least 18 years of age&#xD;
&#xD;
      Design:&#xD;
&#xD;
      Participants will be screened with blood sample and medical history. They may provide copies&#xD;
      of their medical records.&#xD;
&#xD;
      Enrolled participants will be evaluated at the NIH for 2-5 days. All participants will have a&#xD;
      detailed medical history, physical exam, blood tests, and other evaluations depending on the&#xD;
      extent of their autoinflammatory disease.&#xD;
&#xD;
      Participants may also expect the following assessments:&#xD;
&#xD;
        1. Clinical tests that help assess organ damage and function such as hearing, vision,&#xD;
           memory, and learning tests.&#xD;
&#xD;
        2. Imaging studies to characterize organ involvement of the inflammatory disease including:&#xD;
           X-rays, CT scans, special MRIs, and bone scans.&#xD;
&#xD;
        3. Laboratory evaluations including clinical markers of disease activity, research samples&#xD;
           for genetic studies, blood samples for cytokine/biomarker assessment, and gene&#xD;
           expression profiling.&#xD;
&#xD;
        4. Questionnaires to assess disease activity and quality of life.&#xD;
&#xD;
        5. If indicated, other procedures may be administered that include: a lumbar puncture if&#xD;
           CNS inflammation is suspected, a skin biopsy if skin inflammation is present, and/or&#xD;
           gastrointestinal and pulmonary procedures if they are clinically indicated.&#xD;
&#xD;
      Participants may return for a single follow-up visit or for long-term follow-up visits&#xD;
      depending on their disease and willingness to return. Long-term follow-up may occur for up to&#xD;
      15 years on this protocol.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Autoinflammatory diseases are a group of immune dysregulatory diseases that are characterized&#xD;
      by recurrent episodes of systemic as well as organ-specific inflammation that can involve the&#xD;
      skin, eyes, joints, bones, muscles, lungs, serosal surfaces, inner ear, brain, and other&#xD;
      organs. The prominent role of IL-1 in the pathogenesis of these disorders first became&#xD;
      evident through the discovery of mutations in the gene NLRP3 and IL1RN. Since then, we have&#xD;
      identified additional mutations that cause autoinflammatory diseases, including mutations in&#xD;
      proteasome components and STING1 that suggest a role of increased type I IFN signaling as a&#xD;
      contributor to the disease pathogenesis of autoinflammatory diseases and in NLRC4 and CDC42&#xD;
      that suggest a role of IL-18 in some autoinflammatory diseases. In this natural history&#xD;
      study, we seek to comprehensively evaluate people with autoinflammatory diseases that include&#xD;
      clinical, genetic, immunologic, andendocrinologic characterizations. Other rare diseases not&#xD;
      mediated by IL-1, IL-18 or type I IFN and presumed to be autoinflammatory diseases with&#xD;
      unknown genetic causes may also be eligible under this protocol. In addition, we intend to&#xD;
      evaluate long-term outcomes and biomarkers over time in selected diseases. We plan to follow&#xD;
      most participants for the duration of this study (15 years). Relatives who do not have&#xD;
      autoinflammatory diseases as well as healthy volunteers will also be recruited to serve as&#xD;
      controls for biomarker, genetic, and other molecular analyses.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 9, 2016</start_date>
  <completion_date type="Anticipated">September 30, 2032</completion_date>
  <primary_completion_date type="Anticipated">August 31, 2031</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>To study the pathogenesis of patients affected with auto-inflammatory diseases, including their clinical, immunological, genetic and metabolic/endocrinological characteristics.</measure>
    <time_frame>1-2 years, 3-5 years, 10 years</time_frame>
    <description>To study the pathogenesis of patients affected with autoinflammatory diseases, including their clinical, immunological, genetic and metabolic/endocrinological characteristics.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Longitudinal fluctuations in clinical and biomarker characteristics of autoinflammatory diseases</measure>
    <time_frame>1-2 years, 3-5 years, 10 years</time_frame>
    <description>To evaluate clinical characteristics/disease manifestations and blood, body fluids, and tissue biomarkers during disease flares and quiescence.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Long term Organ specific outcome (clinical and biomarker evidence of both inflammation and damage accrual)</measure>
    <time_frame>1-2 years, 3-5 years, 10 years</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_groups>3</number_of_groups>
  <enrollment type="Anticipated">3200</enrollment>
  <condition>NOMID</condition>
  <condition>DIRA</condition>
  <condition>NLRC4-MAS</condition>
  <condition>SAVI</condition>
  <condition>CANDLE</condition>
  <arm_group>
    <arm_group_label>Affected Participants</arm_group_label>
    <description>Individuals with undifferentiated autoinflammatory diseases or genetically defined conditions, such as NOMID/CAPS, DIRA, CANDLE, SAVI, and NLRC4 MAS.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Healthy Volunteer</arm_group_label>
    <description>Volunteers without known autoinflammatory disease who consent to providing blood specimen for genetic testing.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Unaffected Relatives</arm_group_label>
    <description>Blood relatives of the affected patients without known autoinflammatory disease who consent to providing specimen for genetic testing.</description>
  </arm_group>
  <eligibility>
    <study_pop>
      <textblock>
        Study population is quite diverse as affected participants are from all over the world,&#xD;
        different age ranges, and all race/ethnic groups.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA - AFFECTED PARTICIPANTS:&#xD;
&#xD;
               1. Be 2 to 99 years old for participants who will be seen at the NIH CC; be 0&#xD;
                  (newborn) to 99 years old for participants who participate remotely via a virtual&#xD;
                  protocol visit and will submit mail-in samples. Participants younger than 3 years&#xD;
                  will be seen in the outpatient clinic at the NIH CC if approved by the Pediatric&#xD;
&#xD;
                  Consult Service as per NIH CC policy and guidelines.&#xD;
&#xD;
               2. Is willing to allow storage of biological specimens for future use in medical&#xD;
                  research.&#xD;
&#xD;
               3. Is willing to allow genetic testing on collected biological samples.&#xD;
&#xD;
               4. Has a primary care or other physician who will manage all health conditions&#xD;
                  related or unrelated to the study objectives.&#xD;
&#xD;
               5. Fulfills one of the following criteria:&#xD;
&#xD;
                    -  Has a known disease-causing genetic mutation associated with NOMID/CAPS,&#xD;
                       DIRA, CANDLE, SAVI, or NLRC4-MAS.&#xD;
&#xD;
                    -  Has clinical signs or symptoms not explained by any other disorder (eg,&#xD;
                       infections, malignancies) and are consistent with a possible IL-1 mediated&#xD;
                       autoinflammatory disease. Participants must meet both of the following&#xD;
                       criteria:&#xD;
&#xD;
                         -  Clinical characteristics strongly consistent with an IL-1 mediated&#xD;
                            autoinflammatory disease per the following criteria and at the&#xD;
                            discretion of the principal investigator (PI). Individuals must have a&#xD;
                            past or present history of one of the following to be considered for&#xD;
                            study enrollment:&#xD;
&#xD;
                              -  Recurrent fever that has gone undiagnosed after reasonable&#xD;
                                 attempts, and that is consistent with the conditions under study&#xD;
                                 in this protocol&#xD;
&#xD;
                              -  Neutrophilic urticaria, pustular dermatitis, erysipelas-like&#xD;
                                 erythema, or urticarial rash&#xD;
&#xD;
                              -  Epiphyseal and/or patella enlargement, periostitis, myalgias,&#xD;
                                 arthralgias, arthritis, or recurrent multifocal aseptic&#xD;
                                 osteomyelitis&#xD;
&#xD;
                              -  Sensorineural hearing loss&#xD;
&#xD;
                              -  Chronic aseptic meningitis or CNS vasculitis&#xD;
&#xD;
                              -  Conjunctivitis, episcleritis, uveitis, papilledema, pleuritis,&#xD;
                                 pericarditis, aseptic peritonitis, early onset enterocolitis,&#xD;
                                 hepatosplenomegaly, or lymphadenopathies&#xD;
&#xD;
                         -  Laboratory characteristics strongly consistent with an IL-1mediated&#xD;
                            autoinflammatory disease per the following criteria. Individuals must&#xD;
                            havepast or present history of evidence of systemic inflammation (eg,&#xD;
                            elevation of C-reactive protein [CRP] and/or erythrocyte sedimentation&#xD;
                            rate [ESR], anemia, thrombocytosis).&#xD;
&#xD;
                    -  Has clinical signs or symptoms not explained by any other disorder (eg,&#xD;
                       infections, malignancies) and are consistent with a possible IFN-mediated,&#xD;
                       autoinflammatory disease.1,36 Participants must meet both of the following&#xD;
                       criteria:&#xD;
&#xD;
                         -  Clinical characteristics strongly consistent with an IFN-mediated&#xD;
                            autoinflammatory disease per the following criteria and at the&#xD;
                            discretion of the PI. Individuals must have a past or present history&#xD;
                            of one of the following to be considered for study enrollment:&#xD;
&#xD;
                              -  Recurrent fevers that has gone undiagnosed after reasonable&#xD;
                                 attempts, and that is consistent with the conditions under study&#xD;
                                 in this protocol&#xD;
&#xD;
                              -  Panniculitis, ischemic ulcerative skin lesions, chilblain lesions,&#xD;
                                 or livedo reticularis&#xD;
&#xD;
                              -  Lipodystrophy&#xD;
&#xD;
                              -  Myositis, arthralgias, arthritis, or joint contractures&#xD;
&#xD;
                              -  Basal ganglia calcifications or white matter CNS disease&#xD;
&#xD;
                              -  Interstitial lung disease, lung fibrosis, or pulmonary&#xD;
                                 hypertension&#xD;
&#xD;
                              -  Conjunctivitis, episcleritis, cortical blindness, glaucoma,&#xD;
                                 papilledema, or hepatosplenomegaly&#xD;
&#xD;
                              -  Laboratory characteristics strongly consistent with an&#xD;
                                 IFN-mediated autoinflammatory disease per the following criteria.&#xD;
                                 Individuals must have past or present history one or more of the&#xD;
                                 following to be considered for study enrollment:&#xD;
&#xD;
                              -  Evidence of systemic inflammation (eg, ESR or CRP)&#xD;
&#xD;
                              -  Cytopenias (eg. leukopenia, anemia, or thrombocytopenia)&#xD;
&#xD;
                              -  Dyslipidemia or insulin resistance&#xD;
&#xD;
                              -  Abnormal liver function test, creatinine kinase (CK), or LDH&#xD;
&#xD;
                    -  Has clinical signs or symptoms consistent with an undifferentiated&#xD;
                       autoinflammatory disease (including but not limited to dysregulation in&#xD;
                       other proinflammatory cytokines such as IL-17, TNF, IL-18, and others).&#xD;
                       Participants must meet one of the following criteria:&#xD;
&#xD;
                         -  Clinical characteristics strongly consistent with an undifferentiated&#xD;
                            autoinflammatory disease. Individuals must have a past or present&#xD;
                            history of one of the clinical and one of the laboratory&#xD;
                            characteristics mentioned above to be considered for study enrollment.&#xD;
&#xD;
                         -  Individuals with defined organ inflammation associated with past or&#xD;
                            current evidence of systemic inflammation.&#xD;
&#xD;
               6. Alternatively to #5, had been enrolled in the past as an affected participant on&#xD;
                  NIAMS study 03-AR-0173 and or had samples collected on 03-AR-0173.&#xD;
&#xD;
        INCLUSION CRITERIA - UNAFFECTED RELATIVES OF AFFECTED PARTICIPANTS:&#xD;
&#xD;
          1. Be 2 to 99 years old for participants who will be seen at the NIH CC; be 0 (newborn)&#xD;
             to 99 years old for participants who participate remotely via a virtual protocol visit&#xD;
             and will submit mail-in samples. Participants younger than 3 years will be seen in the&#xD;
             outpatient clinic at the NIH CC if approved by the Pediatric Consult Service as per&#xD;
             NIH CC policy and guidelines.)&#xD;
&#xD;
          2. Be related by blood to an affected participant.&#xD;
&#xD;
          3. Is willing to allow storage of biological samples for future use in medical research.&#xD;
&#xD;
          4. Is willing to allow genetic testing on collected biological samples.&#xD;
&#xD;
          5. Does not fulfill any of inclusion criterion #5 for affected participants.&#xD;
&#xD;
          6. Is able to provide informed consent.&#xD;
&#xD;
        INCLUSION CRITERIA - HEALTHY VOLUNTEERS:&#xD;
&#xD;
          1. Be at least 18 years old.&#xD;
&#xD;
          2. Not be related to an affected participant.&#xD;
&#xD;
          3. s willing to allow storage of biological samples for future use in medical research.&#xD;
&#xD;
          4. Is willing to allow genetic testing on collected biological samples.&#xD;
&#xD;
          5. Does not fulfill any of inclusion criterion #5 for affected participants.&#xD;
&#xD;
          6. Is able to provide informed consent.&#xD;
&#xD;
        PARTICIPANT EXCLUSION CRITERIA:&#xD;
&#xD;
          1. Presence of conditions that, in the judgment of the investigator, may put the&#xD;
             participant at undue risk or make them unsuitable for participation in the study.&#xD;
&#xD;
          2. Oncological evaluation suggestive of lymphoma, leukemia or multiple myeloma, except&#xD;
             for participants with a known primary diagnosis of an autoinflammatory disease who&#xD;
             subsequently developed a malignancy. These patients will not be excluded from the&#xD;
             study.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Raphaela T Goldbach-Mansky, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Allergy and Infectious Diseases (NIAID)</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Katsiaryna Uss</last_name>
    <phone>(240) 292-4709</phone>
    <email>kat.uss@nih.gov</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Raphaela T Goldbach-Mansky, M.D.</last_name>
    <phone>(301) 761-7553</phone>
    <email>goldbacr@mail.nih.gov</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>For more information at the NIH Clinical Center contact Office of Patient Recruitment (OPR)</last_name>
      <phone>800-411-1222</phone>
      <phone_ext>TTY8664111010</phone_ext>
      <email>prpl@cc.nih.gov</email>
    </contact>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2017-I-0016.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <reference>
    <citation>Bhuyan F, de Jesus AA, Mitchell J, Leikina E, VanTries R, Herzog R, Onel KB, Oler A, Montealegre Sanchez GA, Johnson KA, Bichell L, Marrero B, De Castro LF, Huang Y, Calvo KR, Collins MT, Ganesan S, Chernomordik LV, Ferguson PJ, Goldbach-Mansky R. Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2 Macrophages and Accelerated Osteoclastogenesis. Arthritis Rheumatol. 2021 Jun;73(6):1021-1032. doi: 10.1002/art.41624. Epub 2021 May 9.</citation>
    <PMID>33314777</PMID>
  </reference>
  <reference>
    <citation>Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak SR, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O'Neil K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, Cole JL, Paul SM, Hawkins PN, Pham TH, Snyder C, Wesley RA, Hoffmann SC, Holland SM, Butman JA, Kastner DL. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006 Aug 10;355(6):581-92. doi: 10.1056/NEJMoa055137.</citation>
    <PMID>16899778</PMID>
  </reference>
  <reference>
    <citation>Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, Kim PW, Sheikh A, Lee CC, Chen Y, Vera A, Zhang X, Goldbach-Mansky R, Zlotogorski A. Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 2012 Mar;64(3):895-907. doi: 10.1002/art.33368.</citation>
    <PMID>21953331</PMID>
  </reference>
  <reference>
    <citation>Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GAM, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CR, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014 Aug 7;371(6):507-518. doi: 10.1056/NEJMoa1312625. Epub 2014 Jul 16.</citation>
    <PMID>25029335</PMID>
  </reference>
  <verification_date>January 12, 2023</verification_date>
  <study_first_submitted>November 23, 2016</study_first_submitted>
  <study_first_submitted_qc>November 23, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 28, 2016</study_first_posted>
  <last_update_submitted>January 14, 2023</last_update_submitted>
  <last_update_submitted_qc>January 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">January 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Study of pathogenesis of patients affected with autoinflammatory diseases</keyword>
  <keyword>This Includes the Clinical, Immunological , Genetic, and Metabolic Characteristi</keyword>
  <keyword>Collection of Clinical and Laboratory Outcome Data</keyword>
  <keyword>Evaluation of Characteristics/Disease Manifestations</keyword>
  <keyword>Natural History</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cryopyrin-Associated Periodic Syndromes</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>.As outlined in our approved GDS Plan (dated 09/27/2019): Whole exome and whole genome sequencing data</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_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_time_frame>
    <ipd_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_access_criteria>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT02974595
org study id: 170016
secondary id: 17-I-0016
nct id: NCT02974595
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
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.
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.
observational model: Cohort
time perspective: Prospective
measure: 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
description: To study the pathogenesis of patients affected with autoinflammatory diseases, including their clinical, immunological, genetic and metabolic/endocrinological characteristics.
measure: Longitudinal fluctuations in clinical and biomarker characteristics of autoinflammatory diseases
time frame: 1-2 years, 3-5 years, 10 years
description: To evaluate clinical characteristics/disease manifestations and blood, body fluids, and tissue biomarkers during disease flares and quiescence.
measure: 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
description: 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.
arm group label: Affected Participants
description: Individuals with undifferentiated autoinflammatory diseases or genetically defined conditions, such as NOMID/CAPS, DIRA, CANDLE, SAVI, and NLRC4 MAS.
arm group label: Healthy Volunteer
description: Volunteers without known autoinflammatory disease who consent to providing blood specimen for genetic testing.
arm group label: Unaffected Relatives
description: Blood relatives of the affected patients without known autoinflammatory disease who consent to providing specimen for genetic testing.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: 99 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Raphaela T Goldbach-Mansky, M.D.
role: Principal Investigator
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
last name: Katsiaryna Uss
phone: (240) 292-4709
email: kat.uss@nih.gov
last name: Raphaela T Goldbach-Mansky, M.D.
phone: (301) 761-7553
email: goldbacr@mail.nih.gov
facility: 
status: Recruiting
contact: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_2017-I-0016.html
description: NIH Clinical Center Detailed Web Page
citation: Bhuyan F, de Jesus AA, Mitchell J, Leikina E, VanTries R, Herzog R, Onel KB, Oler A, Montealegre Sanchez GA, Johnson KA, Bichell L, Marrero B, De Castro LF, Huang Y, Calvo KR, Collins MT, Ganesan S, Chernomordik LV, Ferguson PJ, Goldbach-Mansky R. Novel Majeed Syndrome-Causing LPIN2 Mutations Link Bone Inflammation to Inflammatory M2 Macrophages and Accelerated Osteoclastogenesis. Arthritis Rheumatol. 2021 Jun;73(6):1021-1032. doi: 10.1002/art.41624. Epub 2021 May 9.
PMID: 33314777
citation: Goldbach-Mansky R, Dailey NJ, Canna SW, Gelabert A, Jones J, Rubin BI, Kim HJ, Brewer C, Zalewski C, Wiggs E, Hill S, Turner ML, Karp BI, Aksentijevich I, Pucino F, Penzak SR, Haverkamp MH, Stein L, Adams BS, Moore TL, Fuhlbrigge RC, Shaham B, Jarvis JN, O'Neil K, Vehe RK, Beitz LO, Gardner G, Hannan WP, Warren RW, Horn W, Cole JL, Paul SM, Hawkins PN, Pham TH, Snyder C, Wesley RA, Hoffmann SC, Holland SM, Butman JA, Kastner DL. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006 Aug 10;355(6):581-92. doi: 10.1056/NEJMoa055137.
PMID: 16899778
citation: Liu Y, Ramot Y, Torrelo A, Paller AS, Si N, Babay S, Kim PW, Sheikh A, Lee CC, Chen Y, Vera A, Zhang X, Goldbach-Mansky R, Zlotogorski A. Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum. 2012 Mar;64(3):895-907. doi: 10.1002/art.33368.
PMID: 21953331
citation: Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE, Sanchez GAM, Tenbrock K, Wittkowski H, Jones OY, Kuehn HS, Lee CR, DiMattia MA, Cowen EW, Gonzalez B, Palmer I, DiGiovanna JJ, Biancotto A, Kim H, Tsai WL, Trier AM, Huang Y, Stone DL, Hill S, Kim HJ, St Hilaire C, Gurprasad S, Plass N, Chapelle D, Horkayne-Szakaly I, Foell D, Barysenka A, Candotti F, Holland SM, Hughes JD, Mehmet H, Issekutz AC, Raffeld M, McElwee J, Fontana JR, Minniti CP, Moir S, Kastner DL, Gadina M, Steven AC, Wingfield PT, Brooks SR, Rosenzweig SD, Fleisher TA, Deng Z, Boehm M, Paller AS, Goldbach-Mansky R. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014 Aug 7;371(6):507-518. doi: 10.1056/NEJMoa1312625. Epub 2014 Jul 16.
PMID: 25029335
responsible party type: Sponsor
mesh term: Cryopyrin-Associated Periodic Syndromes
sharing ipd: Yes
ipd description: .As outlined in our approved GDS Plan (dated 09/27/2019): Whole exome and whole genome sequencing data
ipd info type: Study Protocol
ipd 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 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. @@@