natural history, pathogenesis, and outcome of autoinflammatory diseases (nomid/caps, dira, candle, savi, nlrc4-mas, still's-like diseases, and other undifferentiated autoinflammatory diseases)

Conditions: NOMID; DIRA; NLRC4-MAS; SAVI; CANDLE

Summary: 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.

Eligibility criteria:
* 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.

Keywords: study of pathogenesis of patients affected with autoinflammatory diseases this includes the clinical, immunological , genetic, and metabolic characteristi collection of clinical and laboratory outcome data evaluation of characteristics/disease manifestations natural history