Treatment of Macrophage Activation Syndrome (MAS) With Anakinra

Macrophage activation syndrome (MAS) is a disorder whereby the immune system generates very
high levels of substances (cytokines) that promote inflammation to the extent dysfunction
occurs in multiple organ systems which if unchecked, is frequently fatal to the affected
individual. This can occur in the setting of a number of different immune system disorders
including, systemic lupus, systemic-onset juvenile arthritis, and adult-onset Still's
disease. MAS can also occur in response to infection with certain viruses such as
Epstein-Barr virus (EBV) and malignancies involving lymphocytes.

Because of the high fatality of MAS (>50%), a number of different treatments have been tried
to manage this disorder, including use of high-dose steroids, immune suppressants such as
cyclosporine, and cytotoxic chemotherapy treatments (etoposide) with variable success and/or
severe complications of immune suppression (as may occur with etoposide). A number of recent
case reports and case series have reported success using cytokine-blocking therapies such as
anakinra in the treatment of MAS that is associated with systemic-onset juvenile idiopathic
arthritis and adult Still's disease. Anakinra is a bio-engineered form of the naturally
occurring interleukin-1 receptor antagonist (IL-1ra), that blocks the action of
interleukin-1, one of the cytokines that is expressed and present in very high amounts in
patients who have MAS. Anakinra/Il-1ra is an attractive treatment for patients presenting
with clinical features of MAS because it has a relatively short half-life and is easy to
administer by subcutaneous injection. In previous trials of its use in patients with clinical
features of bacterial sepsis (fever, elevated heart rate, low/falling blood pressure) , it
was shown that anakinra does not have a harmful effect but also did not appear to have any
benefit with repect to the defined primary outcome of improved survival. However, a recent
re-analysis of the data accumulated in these same previous sepsis trials (for which the
primary defined outcome was survival) indicates that survival was actually increased in the
subgroup of sepsis patients with features of MAS (ferritin elevations in excess of 2,000
ng/ml, signs of coagulopathy, and liver enzyme elevations) who were randomized to receive
anakinra compared to the subgroup of sepsis patients with features of MAS who were randomized
to receive placebo.

Previous doses of anakinra up to 3500 mg/day over 72 hours that were employed in the trials
of adult patients with sepsis were noted to be well tolerated without increased adverse
outcomes compared to patients randomized to placebo. Recent case reports have shown that
doses up to 100 mg every 6 hours were efficacious and well tolerated in children with
systemic onset juvenile arthritis complicated by refractory macrophage activation syndrome.

This study will be the first controlled study to confirm whether anakinra at dose of 10
mg/kg/day to a maximum of dose of 200 mg/day divided every 12 hours (for children ≤40 kg) or
5 mg/kg/day up to a maximum dose of 400 mg/day divided every 6 hours (children > 40 kg and
adults) does not result in increased mortality or infection complications when administered
in addition to current UAB standard of care treatment (corticosteroids) to children and
adults hospitalized with suspected macrophage activation syndrome.

Inclusion Criteria:1] Previous diagnosis of systemic juvenile idiopathic arthritis (sJIA)
and fulfills the Ravelli criteria (4) for macrophage activation syndrome with either:

two or more Laboratory criteria: 1. Decreased platelet count (≤262 ×10 9/L) 2. Elevated
levels of aspartate aminotransferase (>59 U/L) 3. Decreased white blood cell count (≤4.0 ×
109/L) 4. Hypofibrinogenemia (≤2.5 g/L) or, three or more combined clinical/laboratory
criteria:

1. Decreased platelet count (≤262 × 109/L)

2. Elevated levels of aspartate aminotransferase (>59 U/L)

3. Decreased white blood cell count (≤4.0 × 109/L)

4. Hypofibrinogenemia (≤2.5 g/L)

5. Central nervous system dysfunction (irritability, disorientation, lethargy, seizures,
coma)

6. Hemorrhages (purpura, easy bruising, mucosal bleeding)

7. Hepatomegaly (≥3 cm below the costal margin or confirmed by imaging)

OR

2] No previous diagnosis of sJIA and serum ferritin > 2,000 ng/ml and 3 out of the
following:

1. Bicytopenia with two of the following:

1. Absolute Neutrophil Count < 1,000,

2. Platelets < 100, 000/mm3,

3. Hemoglobin < 9 mg/dl

2. Fasting triglyceride >265 mg/dL

3. Splenomegaly

4. ALT OR AST > 120 IU/L (or > 2x upper limit of normal)

5. Fever with temp ≥ 101° F

6. Fibrinogen < 1.5 g/L (150 mg/dl) or INR > 1.5 or d-dimer > 500 ng/ml

Exclusion Criteria:

1. Evidence of malignancy

2. Culture evidence of systemic bacterial infection at the time of screening

3. Known EBV viremia by PCR at time of screening (positive serologies are not an
exclusion; results of EBV testing will not be necessary for enrollment, but may be
ordered as part of the standard of care assessment to guide future management as
results become available)

4. Previous treatment for the current MAS episode with corticosteroids, anakinra,
tocilizumab, anti-TNF therapy or cyclosporine

5. <1 year of age

6. Family history of familial HLH

7. Evidence of any of the following

1. Creatinine at the time of screening > 2X ULN or > twofold increase from patient's
baseline creatinine within past 3 months (if known)

2. Albumin < 1.5 at the time of screening

3. Mechanical ventilation at the time of screening

4. Hypotension requiring use of pressors at the time of screening