This study aims to investigate the pathophysiology of recurrent pericarditis (RP) by testing for neutralizing autoantibodies against interleukin-1 receptor antagonist (IL-1RA) and measuring soluble urokinase plasminogen activator receptor (suPAR) levels. The hypothesis is that these tests will provide insights into both the inflammatory and non-inflammatory phenotypes of RP, shedding light on the underlying mechanisms. The study will assess the correlation between antibody levels, suPAR levels, and markers of cardiac damage and inflammation. Longitudinal testing during acute episodes and intercritical phases is also planned. The results may guide the use of anakinra, an IL-1 receptor antagonist, in specific clinical scenarios and optimize treatment strategies for RP.

Recurrent pericarditis (RP) is a complex challenging condition, which significantly impacts patients' quality of life, both from the physical and emotional point of view, and can lead to dangerous complications such as cardiac tamponade and constrictive pericarditis. Moreover, patients experiencing several recurrences also tend to need substantial healthcare resources without necessarily experiencing clinical improvement. Understanding more into details the pathophysiology underlying RP is certainly of pivotal importance for optimizing workup strategies and treatment protocols. It is now recognized that pericarditis stems from a bidirectional cross-talk between environmental triggers and the innate and adaptive immune systems in a genetically susceptible host, with a central role of the pro-inflammatory agonistic molecule IL-1 (IL-1α and IL-1β) and the so-called inflammasome.

Neutralizing autoantibodies have been identified targeting the endogenous interleukin-1 receptor antagonist (IL-1RA) in conditions characterized by severe systemic inflammation such as myocarditis after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination, Coronavirus Disease (COVID-19) and Multisystem Inflammatory Syndrome (MIS-C). Therefore, it is possible to hypothesize that testing patients with RP for these antibodies might add significant insights into the knowledge of the pathophysiology of this condition. This may help uncover different underlying mechanisms with similar clinical presentations. New mechanisms involving hyperphosphorylation of IL-1RA precede peripheral immune tolerance breakdown, which may also contribute to certain pericarditis phenotypes.

Therefore, it is possible to hypothesize that IL-1RA antibody testing could provide important information to better profile RP patients with an inflammatory phenotype (as indicated by common biochemical markers like CRP) and those with a complicated clinical course. These patients often exhibit marked activation of the IL-1 signaling pathway, and IL-1RA antibody testing may help uncover underlying mechanisms and improve their characterization. Given the negative correlation between neutralizing antibodies against IL-1RA (and low circulating levels of IL-1RA) and markers of cardiac damage and inflammation, testing these antibodies in RP might be of value. High titers of IL-1RA antibodies in RP may indicate uncontrolled activation of the IL-1 pathway, shedding light on why some patients experience recurrences when tapering treatment with the naturally occurring IL-1 receptor antagonist, anakinra. Testing these IL-1RA antibodies in other types of pericarditis could also help explore their correlation with clinical phenotypes, including presentation, clinical course, and response to treatment strategies. Key exclusion criteria include pericarditis secondary to specific etiologies (except post-cardiac injury), history of immunosuppression, and any clinical conditions that may influence the results.

Additionally, suPAR testing can complementarily highlight chronic low-grade inflammation, which may underlie certain pericarditis cases that do not exhibit an overt "inflammatory phenotype" (e.g., normal CRP) but are challenging to manage.

Longitudinal testing of patients during acute episodes and intercritical phases is planned if feasible.

In both IL-1RA antibody and suPAR testing, this study aims to provide more accurate markers compared to commonly used markers for the "inflammatory phenotype" and potentially uncover unknown pathophysiological mechanisms. Currently, there is a lack of literature on this topic.

The results of this study may provide a rationale for the selective use of anakinra in specific clinical scenarios and/or guide the evaluation of its dosing with an individualized approach.

Inclusion Criteria:

• Written informed consent from patients aged ≥ 18 years before any evaluation is performed.
• Written informed consent from parents or legal guardian and assent from minors aged under 18 years before any evaluation is performed.
• Recurrent acute pericarditis during the acute phase of the disease. The diagnosis of pericarditis is based on the presence of at least two of the following criteria: typical pericarditic chest pain (acute and pleuritic, worsened by positional changes or breathing), pericardial friction rub, diffuse ST segment elevation or PR depressions not previously reported, and pericardial effusion.
• Post-cardiac injury pericarditis (e.g., post-cardiac surgery) that is new or worsening. Recurrence is diagnosed based on the same criteria.

In all patients, the previous history of CRP values should be known to distinguish individuals with inflammatory forms (characterized by significantly elevated CRP values in the clinical history) from those with pericarditis and normal or near-normal CRP levels (clinical history of normal or at most less than 2 times the normal value).

The acute phase of the disease is defined as follows: for pericarditis forms with elevated CRP, the presence of a CRP that is at least double the normal value of the test. For forms with normal CRP, it is based on clinical judgment, as there are no other recognized and validated criteria.

Exclusion Criteria:

• Specific etiologies, including tuberculosis, neoplastic or purulent etiologies, post-cardiac injury syndromes, and autoimmune rheumatic diseases.
• Subjects under 18 years of age.
• Pregnant or lactating women.
• History of immunosuppression, including a positive result on HIV screening tests (ELISA and Western blot).
• Positive QuantiFERON test (QFT-Tuberculosis G In-Tube) or positive Purified Protein Derivative (PPD) test after the initial clinical evaluation.
• History of other significant medical conditions that, according to the investigator, could compromise the outcome or interpretation of the results (e.g., systemic diseases that are not directly the cause of pericarditis but may cause a state of chronic inflammation).
• Use of any medication that the investigator believes could alter the result of the tests to be performed (except those used for the treatment of pericarditis).

Throughout the study, patients will continue to receive the most appropriate therapies for their clinical condition, following current guidelines and good clinical practice, without the participation in the study prejudicing or influencing the choice of therapeutic strategies to be employed.

Consecutive patients with different phenotypes of pericarditis