Anakinra for Inflammatory Pustular Skin Diseases
Condition: Sneddon-Wilkinson; Acrodermatitis Continua of Hallopeau; Pustular Psoriasis; Palmoplantar Pustulosis
MeSH terms: Acrodermatitis; Psoriasis
Study type: Interventional
Phase: Phase 2

Summary: 
      Background:

        -  Inflammatory pustular skin diseases are a type of autoinflammatory disease in which the
           immune system attacks the bodys tissues. These diseases cause painful and itchy skin
           rashes, eye and mouth irritation, joint pain and fever. Several drugs for treating these
           diseases suppress the immune system. However, they can cause severe side effects when
           taken over a long period of time.

        -  Interleukin 1 (IL-1) is a small protein that may be important in causing the
           inflammation seen in pustular skin disease. Anakinra is a drug that works by blocking
           IL-1. It has been effective in treating some inflammatory conditions such as rheumatoid
           arthritis. However, anakinra has not been studied for use in patients with pustular skin
           disease. Researchers want to see whether anakinra will be effective in treating pustular
           skin disease.

      Objectives:

      - To see if anakinra can be used to treat inflammatory pustular skin disease.

      Eligibility:

      - Individuals at least 18 years of age who have inflammatory pustular skin disease.

      Design:

        -  Participants will be screened with a physical exam and medical history. Their disease
           will be evaluated with blood tests, urine tests and imaging studies. Skin biopsies may
           also be collected.

        -  Participants will have an initial visit to receive the first dose of anakinra. They will
           be shown how to give themselves daily injections of anakinra.

        -  Participants will take anakinra for up to 12 weeks as long as there are no severe side
           effects. During this time, they will keep a study diary to record the severity of any
           rashes, pustules, itching, fevers, and skin or joint pain. They will bring this diary to
           their study visits.

        -  Participants will have study visits at weeks 4, 8 and 12. Treatment will be monitored at
           these visits with blood tests, urine tests and physical exams. Depending on the effects
           of the treatment, participants may have the dose of anakinra increased or decreased.

        -  Participants will have a final study visit 4 weeks after they stop taking anakinra.
    

Detailed description: 
      Background:

        -  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 Interleukin 1 (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 c-reactive
                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- tumor necrosis factor (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.

      Objectives:

      -To characterize the clinical efficacy, optimal dosing and safety of anakinra in patients
      with pustular dermatoses.

      Eligibility:

        -  Age greater than or equal to 18 years.

        -  Active macroscopic noninfectious pustular skin lesions involving greater than or equal
           to 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
           initiation.

        -  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 m^2 for patients with creatinine levels above institutional normal.

      Design:

        -  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.
    

Intervention name(s): Anakinra
Intervention type(s): Drug
Intervention description(s): An initial dose of anakinra 100 mg/day will be administered daily via self-administered subcutaneous injection. If active disease persists at this dose, anakinra dose may be escalated up to 200 mg/day injected subcutaneously daily at week 4 and 300mg/day at week 8.
Other intervention name(s): Kineret
Intervention MeSH terms: Interleukin 1 Receptor Antagonist Protein
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Anakinra; Pustular Psoriasis; Palmoplantar Pustulosis; DITRA; Subcorneal Pustular Dermatosis