Background
Acute pericarditis is the cause of 5% of emergency room admissions for chest pain in adult patients in Western countries. The prevalence and incidence of this condition in the paediatric population is unknown. In Western countries, acute pericarditis is predominantly viral; however, in most cases the cause of the disease remains unknown: such cases are labelled as "idiopathic pericarditis." Acute pericarditis can also occur after interventional procedures on the heart . Relapses are the most common and difficult-to-treat complication of acute pericarditis: in fact, it has been estimated that 15-30% of acute pericarditis become recurrent, with patients experiencing one or more recurrences of the disease. When pericarditis has a recurrence of disease after a period of well-being, it is labelled as recurrent pericarditis (PR).
The long-term outcome of this condition is generally good. However, many patients have several recurrences of the disease, requiring prolonged treatment to control the clinical picture; many of them become steroid-dependent with consequent side effects.
In 2015, the European Society of Cardiology published new guidelines for the management of acute and recurrent pericarditis in the adult population; an adaptation to paediatric age was also proposed in the same paper, although data on the efficacy of different treatments are lacking in this population. According to these guidelines, NSAIDs are the first-line treatment for acute pericarditis along with low doses of colchicine. In fact, a study showed that colchicine reduces the risk of hospitalization and disease recurrence, while increases the probability of remission after 7 days, in treated patients. Steroids are not recommended as first-line treatment of pericarditis, increasing the risk of dependence and chronicity; for adult patients the guidelines indicate to use low doses of steroids (less than 0.5 mg/kg/day prednisone or equivalent), along with colchicine, in patients who do not respond to NSAIDs (1). High doses of steroids should be avoided, as they are associated with an increased risk of relapse, hospitalization, and serious side effects. Furthermore, steroid therapy should be gradually tapered as soon as disease control is achieved. There are no specific guidelines regarding steroid dosage in the pediatric patient with recurrent pericarditis. In chronic pathologies of the immuno-rheumatologic field, steroid therapy is generally started at a dosage of 1-2 mg/kg/day of prednisone or equivalent. Various immunosuppressive drugs have been suggested as third-line treatment in patients not responsive to first- and second-line therapy, although there was no clear evidence of their efficacy.
The use of anakinra in the treatment of recurrent pericarditis
The clear efficacy of interleukin-1 (IL-1) inhibition with anakinra (the recombinant IL-1 receptor antagonist) in children with colchicine-resistant and steroid-dependent recurrent pericarditis was first described in 2008. The same results were subsequently observed in different series of paediatric and adult patients. Finally, a randomized placebo-controlled clinical trial demonstrated the efficacy of anakinra in 21 patients (20 adults and 1 child) with recurrent pericarditis with colchicine resistance and steroid dependence (the AIRTRIP study, Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence).
Based on evidence from the AIRTRIP study, the use of anakinra is currently permitted in Italy for patients with recurrent pericarditis (children or adults) only in cases of colchicine-resistance or failure and with evidence of dependence on steroid use, even at low doses.
Objective of the study
The purpose of this study is to demonstrate that anakinra is more effective, than steoirds – in case of relapse of pericarditis, in preventing further flare in paediatric patients (aged eight months to eighteen years) with idiopathic or post-procedural pericarditis, who do not respond to first-line treatment with NSAIDs and colchicine at the appropriate dosage, or in case of colchicine intolerance.
Study design
The study will be an open-label, randomized, controlled, multicentre, prospective superiority study of two different therapeutic strategies. It will last 6 months (24 weeks) for each patient enrolled and the screening evaluations will have a 60-day validity.
After signing informed consent, patients will be randomized into two treatment arms: steroid (Arm 1) or anakinra (Arm 2). Patients with both idiopathic and post-procedural recurrent pericarditis will be included in the study and proportionally randomized into the 2 arms. It is planned to randomize 48 patients.
Patients in Arm 1 will be treated according to conventional therapy (steroid), while patients in Arm 2 will be early treated with anakinra.
The study consists of two parts: in Part 1, patients with recurrence of pericarditis will be treated at full dose to assess whether they achieve a complete response to treatment. Patients who show a complete response to treatment at the end of Part 1 (week 4) will enter Part 2 of the study, while patients who have not achieved a complete response to treatment at the end of Part 1 will terminate the treatment with the experimental drug . In Part 2 of the study, treatment will be progressively reduced until discontinuation. Patients will stop experimental drug administration according to the dosage reported in the protocol, at the time of disease relapse; if relapse does not occur, patients will continue taking the experimental drug, gradually reducing the dosage until week 24, according to what is reported in the protocol.
Once terminated the treatment with the experimental drug, at the end of 24 weeks or sooner in case of relapse or absence of complete response at the end of Part 1, all patients enrolled in the study will be followed according to normal clinical practice; in addition a Follow-up visit at 12 months after the end of study treatment is planned by Protocol to assess disease progression, presence and number of relapses, need for treatment, adverse events, and long-term complications of the disease.
During the 12 months between discontinuation of the study drug and the follow-up visit, both in case of symptoms suggestive of disease relapse and in any other case according to the Investigator’s judgement, optional visits may be performed. The maximum duration of the study for each single patient will be 84 weeks.