Anakinra for Inflammatory Pustular Skin Diseases

Palmoplantar Pustulosis Clinical Trial

Official title: A Phase 2 Study of Anakinra in Inflammatory Pustular Dermatoses: Evaluation of Therapeutic Efficacy and Validation of Pathogenic Mechanisms

Status Completed

Clinical Trial 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.

Clinical Trial 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. ;

Related Conditions & MeSH terms

• Acrodermatitis Continua of Hallopeau
• Palmoplantar Pustulosis
• Psoriasis
• Pustular Psoriasis
• Sneddon-Wilkinson

• NCT number: NCT01794117
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 2
• Start date: July 22, 2013
• Completion date: October 7, 2019