Anakinra to Treat Patients With Neonatal Onset Multisystem Inflammatory Disease

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.

-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.