Studies of the Natural History, Pathogenesis, and Outcome of Autoinflammatory Diseases Including Juvenile Dermatomyositis

Studies of Natural History, Pathogenesis, and Outcomes in Autoimmune and Inflammatory Diseases Including Juvenile Dermatomyositis

Purpose:

The purpose of this protocol is 1. To comprehensively evaluate patients with autoinflammatory diseases clinically, genetically and immunologically at the autoinflammatory disease clinic at the NIH. 2. To follow patients with autoinflammatory Diseases that are genetically defined including Neonatal-Onset Multisystem Inflammatory Disease (NOMID), the most severe clinical phenotype of Cryopyrin-Associated Periodic Syndromes (CAPS), Deficiency of IL-1 Receptor Antagonist (DIRA), Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated temperatures (CANDLE), and STING-Associated Vasculopathy with onset in Infancy (SAVI), and those with genetically undefined autoinflammatory disorders to determine long-term disease outcomes. 3. To develop biomarkers that help us assess disease activity and response to treatment. 4. To assess the eligibility of affected patients for inclusion in ongoing and planned treatment protocols.

Goal: The goals of our studies are to understand the underlying immune dysregulation, to identify the genetic cause and to translate our findings into novel treatments that improve patients disease outcome.

Eligibility:

• Patients with known NOMID/CAPS, DIRA, CANDLE, SAVI, CRMO, Still's Disease, and with other yet undifferentiated autoinflammatory diseases.
• Healthy adult and pediatric relatives.
• Volunteers

Design:

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 extend of their autoinflammatory disease.

Participants may also expect the following assessments:

1. Clinical test that help assess organ damage and functional impact such as hearing vision, memory and learning tests.
2. Imaging studies to characterize the organ involvement of the inflammatory disease including: X-rays, CT scans, special MRIs, bone scans.
3. Laboratory evaluations including clinical markers of disease activity, research samples for genetic studies, and blood samples for cytokine/biomarker assessment, and gene expression profiling.<TAB>
4. Completion of 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 and a skin biopsy if skin inflammation is present. other gastrointestinal procedures as they are clinically indicated.
6. Patients my have a research skin biopsy taken.

Participants may return for a single follow-up visits or for long term-follow up depending on their disease and willingness to be followed long-term.

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Study Overview

• Status: Recruiting
• Conditions: Autoinflammatory Disease; Juvenile Dermatomyositis

Detailed Description

Autoinflammatory multisystem diseases are a group of diseases that are characterized by recurrent episodes of systemic inflammation as well as organ specific inflammation that can involve the skin, eyes, joints, bones, serosal surfaces, inner ear, and brain. The prominent role of IL-1 in the pathogenesis of these disorders has first become evident through the discovery of mutations in CIAS1 causing the cryopyrin-associated periodic syndromes (CAPS) including the most severe presentation Neonatal Onset Multisystem Inflammatory Disease (NOMID). Over the years we identified additional autoinflammatory diseases including DIRA (Deficiency of IL-1 Receptor Antagonist), a disease that is caused by mutations in IL1RN. Therapy with anakinra, the IL-1 receptor antagonist, can be life-saving. We also study additional rare diseases not IL-1 mediated including CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures) caused by mutations in proteasome components, and recently SAVI (STING associated vasculopathy with onset in infancy) caused by mutations in TMEM173, and juvenile dematomyositis (JDM) which shares some phenotypic features as well as an interferon (IFN) signature with SAVI and CANDLE. Many additional autoinflammatory phenotypes have no genetic causes, including autoinflammatory disorders that are not even clinically defined. Clinical conditions including the spectrum CRMO (Chronic Recurrent Multifocal Osteomyelitis), Still s disease, and Beh(SqrRoot)(Beta)et s disease (BD) with possible involvement of IL-1 dysregulation are also of interest.. In this research protocol we seek to comprehensively evaluate affected patients clinically, genetically, immunologically, and endocrinologically. In addition we intend to evaluate longterm outcomes and biomarkers over the time of observations. Eligibility for ongoing and planned treatment protocols will be determined by screening patients in this protocol. We plan to evaluate patients on a consultative basis for other autoinflammatory diseases for possible enrollment into this study.

• Study Type: Observational
• Enrollment (Estimated): 5000

Contacts and Locations

• Study Contact: Name: Hanna Kim, M.D.; Phone Number: (301) 594-6196; Email: kimh11@mail.nih.gov

Study Locations

• United States
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • Recruiting
      • National Institutes of Health Clinical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients with auto inflammatory diseases

Description

• INCLUSION CRITERIA:
• Patients with CANDLE, SAVI, and JDM who are mutation positive for the disease or fulfill clinical criteria of the disease.
• Patients who fulfill criteria for definite or probable JDM
• Patients with other suspected autoinflammatory diseases

• There is:

  • 2 years old or older
  • Patients or their legal guardians need to be able and willing to give informed consent and a pediatric patient needs to be willing to assent to the protocol whenever possible.

Relatives of patients with autoinflammatory diseases or healthy volunteers may be included for genetic testing. The genetic evaluations will be conducted in collaboration with Dr. Fleisher s laboratory at the Clinical Center laboratory and other groups. See genetics consent form. We may also collect blood for serum and RNA analyses to establish a cohort of healthy controls that is matched in age, gender and ethnicity to the study patients. Skin biopsies for research may be requested from patients, patient relatives and healthy volunteers

EXCLUSION CRITERIA:

• Active malignancy or any medical condition that in the opinion of the investigator would warrant exclusion
• Inability to return for follow up visits
• Pregnancy
• Adults without the capacity to consent

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Patients affected with autoinflammatory diseases; Subjects with known or suspected diagnosis of NOMID / CAPS, DIRA, CANDLE, SAVI, CRMO, Still s disease, Behcet s disease, JDM, and other autoinflammatory diseases.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of disease pathogenesis	Clinical, immunological, genetic and endocrinological characteristics of the disease	each visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To develop long term clinical and laboratory outcome parameters of multiorgan involvement in patients and evaluation of blood, body fluid, and tissue biomarkers during disease flares and quiescence.	Subject is determined to be eligible or not eligible for enrollment onto a treatment or intervention protocol.	each visit

Collaborators and Investigators

• Sponsor: National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• Investigators: Principal Investigator: Hanna Kim, M.D., National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

Publications and helpful links

General Publications

• Rodriguez-Smith J, Lin YC, Tsai WL, Kim H, Montealegre-Sanchez G, Chapelle D, Huang Y, Sibley CH, Gadina M, Wesley R, Bielekova B, Goldbach-Mansky R. Cerebrospinal Fluid Cytokines Correlate With Aseptic Meningitis and Blood-Brain Barrier Function in Neonatal-Onset Multisystem Inflammatory Disease: Central Nervous System Biomarkers in Neonatal-Onset Multisystem Inflammatory Disease Correlate With Central Nervous System Inflammation. Arthritis Rheumatol. 2017 Jun;69(6):1325-1336. doi: 10.1002/art.40055. Epub 2017 May 10.
• Chang Z, Spong CY, Jesus AA, Davis MA, Plass N, Stone DL, Chapelle D, Hoffmann P, Kastner DL, Barron K, Goldbach-Mansky RT, Stratton P. Anakinra use during pregnancy in patients with cryopyrin-associated periodic syndromes (CAPS). Arthritis Rheumatol. 2014 Nov;66(11):3227-32. doi: 10.1002/art.38811.
• 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.
• Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J, van Royen-Kerkhoff A, Laxer R, Tedgard U, Cowen EW, Pham TH, Booty M, Estes JD, Sandler NG, Plass N, Stone DL, Turner ML, Hill S, Butman JA, Schneider R, Babyn P, El-Shanti HI, Pope E, Barron K, Bing X, Laurence A, Lee CC, Chapelle D, Clarke GI, Ohson K, Nicholson M, Gadina M, Yang B, Korman BD, Gregersen PK, van Hagen PM, Hak AE, Huizing M, Rahman P, Douek DC, Remmers EF, Kastner DL, Goldbach-Mansky R. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009 Jun 4;360(23):2426-37. doi: 10.1056/NEJMoa0807865.

Helpful Links

• NIH Clinical Center Detailed Web Page

Study record dates

Study Major Dates

• Study Start (Actual): May 9, 2003

Study Registration Dates

• First Submitted: May 5, 2003
• First Submitted That Met QC Criteria: May 5, 2003
• First Posted (Estimated): May 6, 2003

Study Record Updates

• Last Update Posted (Actual): April 11, 2024
• Last Update Submitted That Met QC Criteria: April 10, 2024
• Last Verified: December 19, 2023

More Information

Terms related to this study

• Keywords: Inflammation; Natural History; Myositis; Immune Dysregulation; JDM; Skin Rash
• Additional Relevant MeSH Terms: Nervous System Diseases; Skin Diseases; Musculoskeletal Diseases; Connective Tissue Diseases; Muscular Diseases; Neuromuscular Diseases; Polymyositis; Myositis; Dermatomyositis
• Other Study ID Numbers: 030173; 03-AR-0173

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No