A Phase 2 Study of Anakinra in Inflammatory Pustular Dermatoses: Evaluation of Therapeutic Efficacy and Validation of PathogenicMechanisms
Inflammatory disorders that present with neutrophilic pustular skin lesions, including
generalized pustular psoriasis, are characterized by severe cutaneous manifestations,
generalized inflammation and significant morbidity. Recent studies in patients with
phenotypically similar pustular diseases have identified two monogenic forms of neutrophilic
pustular psoriasis implicating interleukin (IL)-1 in disease pathogenesis. Deficiency of
the IL-1 receptor antagonist (IL1RN, DIRA) is an autosomal recessive condition characterized
by severe generalized pustular eruptions in the neonatal period, osteopenia, lytic bone
lesions, joint pain, respiratory insufficiency, thrombosis, elevated acute phase reactants
and significant mortality. Patients with this condition have responded rapidly to IL-1
receptor antagonist, anakinra. Deficiency of IL-36 receptor antagonist (IL-36RN/IL1F5,
DITRA) is an autosomal recessive condition with episodic widespread pustular skin lesions,
fevers and systemic inflammation defined by marked leukocytosis and elevated creactive
protein. Both IL1RN and IL36RN/IL1F5 are highly expressed in epidermal keratinocytes,
suggesting a role for keratinocytes in initiating innate immunity-mediated inflammatory skin
diseases, and ultimately manifesting in a pustular phenotype. Patients with inflammatory
pustular diseases often respond poorly to conventional treatment with methotrexate,
cyclosporine and anti-TNF agents. Two recent case reports describe patients with pustular
psoriasis unresponsive to TNF inhibition who responded to anti-IL-1 receptor therapy with
anakinra. We hypothesize that monogenic and polygenic inflammatory pustular skin diseases
share common pathogenic mechanisms mediated by IL-1. We propose a phase 2 study that will
utilize a collaborative bench-to-bedside approach, applying targeted anti-IL-1 therapy,
novel imaging modalities, and laboratory techniques including immunohistochemistry, gene
expression and cytokine studies, and in vitro manipulations of skin to dissect and validate
pathways in these complex diseases.
To characterize the clinical efficacy, optimal dosing and safety of anakinra in patients
with pustular dermatoses.
Age >= 18 years.
Active macroscopic noninfectious pustular skin lesions involving >= 5% of the total body
surface area, or palmoplantar involvement.
Histopathologic confirmation of epidermal neutrophilic pustulosis.
Patients must have maintained a stable dose of immunosuppressant therapy, retinoids or
anti-neutrophil therapy for 2 weeks prior to study initiation with resultant stable or
worsening skin disease.
Use of biologic agents requires a washout period of at least 3 half-lives prior to study
Patients must have organ and marrow function as defined below:
leukocytes > 3,000/mcL
absolute neutrophil count > 1,500/mcL
platelets > 100,000/mcL
creatinine within normal institutional limits OR creatinine clearance > 60 mL/min/1.73 m2
for patients with creatinine levels above institutional normal.
A 16-week, open-label phase 2 study. Patients will initially receive treatment with
anakinra 100 mg/day by self-administered subcutaneous injection. Disease response will be
assessed every 4 weeks, and determination of dose escalation will be made based on clinical
assessment. Dose escalation can increase up to 200 mg/day, and for patients > 75 kg up to
300 mg/day at the end of week 8. If a response is achieved with anakinra, other
immunosuppressants administered for the purpose of treatment of pustular skin disease may be
tapered per physician discretion. Clinical assessment, and laboratory and subjective data
will be collected in-person every 4 weeks to determine disease response. Telephone
assessments will be performed weekly. Twenty-five evaluable patients will be enrolled onto
this trial. The accrual ceiling for this study will be set to 30.
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Obtain an estimate of the response rate to treatment
Edward W Cowen, M.D.
National Cancer Institute (NCI)
United States: Federal Government
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