Anakinra to Treat Patients With Neonatal Onset Multisystem Inflammatory Disease

This study will evaluate the safety and effectiveness of anakinra (Kineret(Registered Trademark)) for treating patients with neonatal onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome. This disease can cause rash, joint deformities, brain inflammation, eye problems, and learning difficulties. Immune suppressing medicines commonly used to treat NOMID do not completely get rid of the disease symptoms and, if used for a long time in high doses, can cause harmful side effects. Anakinra, approved by The Food and Drug Administration for treating rheumatoid arthritis in adults, blocks a substance called IL-1 that may be an important factor in causing the inflammation in NOMID.

Patients 2 years of age and older with NOMID whose disease symptoms appeared by at least 6 months of age may be eligible for this study.

During a 3-week observation before beginning medication, patients will have a physical examination and evaluation of their condition. They will keep a daily diary of symptoms ratings, and will have blood drawn once a week to measure inflammation and monitor disease. At the end of this period, patients will be admitted to the NIH Clinical Center for 5 days to start daily anakinra injections, given under the skin of the thigh, upper arm, or belly. They will also be taught how to self-inject the medication. After 3 months on medication, patients will be randomly assigned to: 1) continue taking anakinra, or 2) receive a placebo injection (an inactive substance identical in appearance to the study drug). Follow-up visits at NIH for 5 days each will be scheduled at 1, 3, and 12 months, plus one visit between months 5 and 7. During this time, patients will undergo the following procedures:

• Magnetic resonance imaging (MRI) scans of the brain and of affected joints. This test uses a magnetic field and radio waves to image the parts of the body under study. Patients who cannot lie still during the brain scan will be sedated. Only patients who do not require sedation will have their joints scanned.
• Lumbar puncture (spinal tap). A local anesthetic is given and a needle is inserted in the space between the bones in the lower back where the cerebrospinal fluid circulates below the spinal cord. A small amount of fluid is collected through the needle for analysis.
• Examinations by specialists, including an ophthalmologist (eye exam); otolaryngologist (ear, nose and throat exam and hearing test); neurologist (evaluate neurological symptoms such as headache, weakness, walking difficulties, blurred vision); dermatologist (skin exam with photography for record of rashes and joint changes); psychologist or psychiatrist (test memory and learning ability); rehabilitation medicine specialist (evaluate ability walk, move, and use the hands); speech therapist (evaluate ability to talk).
• X-rays of joints and bones to look for changes during treatment with anakinra.
• DEXA scan to examine bone density.
• Blood samples to assess overall clinical condition, measure blood levels of anakinra, and - with the patient's agreement - to perform DNA studies to look for gene differences associated with NOMID.
• Skin biopsy (optional) to examine how gene differences in NOMID are related to the rash.
• Quality of life questionnaires and review of symptom ratings diaries.

Between NIH visits, patients will be evaluated by their local doctor once a month for a checkup, blood tests, symptoms review, evaluation of drug side effects, and completion of quality of life questionnaires.

This is a long-term outcome study using the IL-1 receptor antagonist anakinra to treat children and adults with Neonatal Onset Multisystem Inflammatory Disease (NOMID), also known as chronic infantile neurological, cutaneous and arthropathy (CINCA) syndrome. NOMID/CINCA syndrome is a rare genetic systemic auto-inflammatory disease that is characterized by a triad of symptoms, including a persistent urticaria-like skin rash, an arthropathy associated with patellar and epiphyseal osseous overgrowth, and neurological manifestations, including chronic aseptic meningitis, optic disc edema, high frequency hearing loss, and mental retardation. Spontaneous genetic mutations in the NACHT domain of CIAS1, a gene located on chromosome 1 have been recently identified in about half of the patients with NOMID/CINCA syndrome. CIAS1 encodes a protein, cryopyrin that is associated with up-regulation of IL-1 production in vitro, which has formed the rationale to target the IL-1 pathway in children with NOMID. During an up to 3- week enrollment period before initiating therapy, we will collect self/parent reported daily diary data and serological samples on up to 3 occasions one week apart, to determine baseline disease activity. These data may be gathered by collaborating centers. At the end of the observation period, patients will be admitted to the NIH for a standardized clinical evaluation and initiation of treatment with anakinra administered at 1 mg/kg/day by regular daily subcutaneous injections. If patients do not fulfill improvement criteria at 1 month, the dose will be escalated between 0.5 and 1 mg/kg/day increments to obtain inflammatory remission. An initial withdrawal study in a subset of 11 patients was performed. The clinical improvement at 3-4 months and the change in serum amyloid A levels (SAA) (a sensitive inflammatory marker) from before treatment to 3-4 months post treatment, and drug safety are the primary clinical outcomes of this study. To assess long-term safety and efficacy, all patients will be observed during an open ended extension phase of the study. Clinical and laboratory parameters will be used to assess safety and efficacy throughout the trial. All patients will be seen every 6 months and annually (as calculated from initiation of anakinra treatment) to further evaluate safety and long term outcomes. During the open ended extension phase of the study, patients who have residual clinical or laboratory evidence of active inflammation may have their dose increased between 0.5 and 1 mg/kg/day increments to a maximum dose of 10 mg/kg/per day to achieve clinical remission. In addition, since no data on the pharmacokinetics (PK) of anakinra in pediatric patients is available with doses exceeding 2 mg/kg/day, we plan to determine the PK of anakinra with each dose escalation.

• Nervous System Malformations
• Arthropathy, Neurogenic
• Urticaria
• Papilledema

• Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S, Cortis E, Teillac-Hamel D, Fischer A, de Saint Basile G. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet. 2002 Jul;71(1):198-203. Epub 2002 May 24.
• Hashkes PJ, Lovell DJ. Recognition of infantile-onset multisystem inflammatory disease as a unique entity. J Pediatr. 1997 Apr;130(4):513-5. No abstract available.
• Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001 Nov;29(3):301-5.
• Sibley CH, Plass N, Snow J, Wiggs EA, Brewer CC, King KA, Zalewski C, Kim HJ, Bishop R, Hill S, Paul SM, Kicker P, Phillips Z, Dolan JG, Widemann B, Jayaprakash N, Pucino F, Stone DL, Chapelle D, Snyder C, Butman JA, Wesley R, Goldbach-Mansky R. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes. Arthritis Rheum. 2012 Jul;64(7):2375-86. doi: 10.1002/art.34409.
• 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.

-INCLUSION CRITERIA:

1. There is no age limitation.

2. Patients fulfill at least 2 of the following 3 clinical manifestations:

   • Typical NOMID rash
   • CNS involvement (papilledema, CSF pleocytosis, sensorineural hearing loss)
   • Typical arthropathic changes on radiograph (epiphyseal and/or patellar overgrowth.
3. Onset of manifestations of NOMID/CINCA at less than or equal to 6 months of age.
4. Stable dose of steroids, NSAIDs, DMARDs for 4 weeks prior to enrollment visit.
5. Washout period for biologics: 6 half-lives before anakinra administration for all drugs with anti TNF properties. For etanercept (6 half-lives=24 days) this calculates to drug discontinuation 3 days before enrollment into the observation period, for infliximab and adalimumab (6 half-lives=48 days) drug will be discontinued 27 before the observation period, and for thalidomide (6 half-lives=3 days) drug will be discontinued for 3 days prior to anakinra administration.
6. Patient's or legal guardian's ability and willingness to give informed consent.
7. Females of childbearing potential (young women who have had at least one menstrual period regardless of age) must have a negative urine pregnancy test at baseline prior to performance of any radiologic procedure or administration of study medication. Women of childbearing age and men able to father a child, who are sexually active, will be asked to use a form of effective birth control, including abstinence.
8. Negative PPD test using 5 T.U. intradermal testing per CDC guidelines with exception of inclusion criteria #9 below.
9. Patients with latent TB (positive PPD test) must have adequate therapy for TB initiated prior to first dose of study medication as recommended in published guidelines.

EXCLUSION CRITERIA:

1. Having received live virus vaccine during 3 months prior to baseline visit (1st visit to NIH).
2. Patients with active infections or a history of pulmonary TB infection with or without documented adequate therapy, Patients with current active TB, or recent close exposure to an individual with active TB are excluded from the study.
3. Positive testing for HIV, Hepatitis B or C known or documented at screening, enrollment or baseline visit.
4. Have a history of or concomitant diagnosis of congestive heart failure.
5. History of malignancy.
6. Recent use of IL-1 antagonist within the last three months or prior use of anti CD4 antibody.
7. Known hypersensitivity to E. coli derived products or any components of anakinra.
8. Presence of any other rheumatic disease or major chronic infectious/inflammatory/immunologic disease (e.g. inflammatory bowel disease, psoriatic arthritis, spondyloarthropathy, SLE in addition to NOMID/CINCA).
9. Presence of the following at enrollment visit: ALT or AST greater than 2.0 x upper limit of normal (ULN) of the local laboratories values, creatinine greater than 1.5 xULN, WBC less than 3.6x10(9)/l; platelet count less than 150,000 mm(3).
10. Enrollment in any other investigational clinical study or receiving an investigational agent, or has not yet completed at least 4 weeks since ending another investigational device or drug trial.
11. Subjects for whom there is concern about compliance with the protocol procedures by subject and/or parent/s and legally acceptable representative/s.
12. Lactating females or pregnant females.
13. Patients with asthma will only be included after evaluation by a pulmonary and infectious disease consultation.