Clinical Phenotypes in Pericarditis: IL-1RA Antibodies and suPAR Levels (PERIPLO)

June 22, 2023 updated by: Maddalena Alessandra Wu, ASST Fatebenefratelli Sacco

Observational Study on Anti-interleukin-1 Receptor Antagonist Antibodies and Soluble Urokinase Plasminogen Activator Receptor (suPAR) in Pericarditis: PERIPLO (PERicarditis: IL-1 RA Antibodies and suPAR Levels Observational) Study

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.

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

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.

Study Type

Observational

Enrollment (Estimated)

146

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Germany
      • Homburg, Germany
        • Saarland University
        • Contact:
          • Lorenz Thurner
        • Principal Investigator:
          • Lorenz Thurner
        • Sub-Investigator:
          • Natalie Fadle
        • Sub-Investigator:
          • Evi Regitz
      • Muenster, Germany
        • University Children's Hospital Muenster
        • Contact:
          • Christoph Kessel
        • Principal Investigator:
          • Christoph Kessel
      • Tübingen, Germany
        • University Hospital Tübingen
        • Contact:
          • Karin Klingel
        • Principal Investigator:
          • Karin Klingel
  • Italy
      • Florence, Italy
        • A.O.U. Careggi
        • Contact:
          • Giacomo Emmi
        • Principal Investigator:
          • Giacomo Emmi
      • Milan, Italy, 20157
        • Luigi Sacco Hospital - ASST Fatebenefratelli Sacco
      • Milan, Italy
        • Fatebenefratelli Hospital - ASST Fatebenefratelli Sacco
        • Contact:
          • Antonio Brucato
        • Principal Investigator:
          • Antonio Brucato
      • Milan, Italy
        • Ospedale Galeazzi Sant'Ambrogio - IRCCS, Poliambulatorio Cardiovascolare Cardiologia Universitaria
        • Contact:
          • Edoardo Conte
        • Principal Investigator:
          • Edoardo Conte
      • Milan, Italy
        • Policlinico di Milano Ospedale Maggiore, Fondazione IRCCS Ca' Granda
        • Contact:
          • Ferruccio Ceriotti
        • Principal Investigator:
          • Ferruccio Ceriotti
        • Sub-Investigator:
          • Matteo Vidali
      • Udine, Italy
        • Ospedale Santa Maria della Misericordia dell'ASU-FC
        • Contact:
          • Massimo Imazio
        • Principal Investigator:
          • Massimo Imazio

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

Consecutive patients with different phenotypes of pericarditis

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Intervention / Treatment
Inflammatory phenotype

Patients with the inflammatory phenotype of recurrent pericarditis exhibit signs indicating the presence of an inflammatory process during a recurrence. These signs may include one or more of the following:

  • Fever
  • Elevated C-reactive protein (CRP)
  • Elevated white blood cell (WBC) count
  • Elevated erythrocyte sedimentation rate (ESR)
  • Pericardial late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR)
  • Pericardial contrast enhancement on computed tomography (CT)
Diagnostic test: IL1RA Antibody Assay
-The measurement of anti-interleukin-1 receptor antagonist (IL1RA) antibodies will be performed using the ELISA (Enzyme-Linked Immunosorbent Assay) method,as previously described [Thurner, L., et al., IL-1RA Antibodies in Myocarditis after SARS-CoV-2 Vaccination. N Engl J Med, 2022. 387(16): p. 1524-1527].
Diagnostic test: suPAR Testing
-The quantitative determination of soluble urokinase plasminogen activator receptor (suPAR) levels in blood will be conducted using the commercially available "CHORUS suPAR Extended" kit (cod. 81414, DIESSE Diagnostica Senese S.p.A., Siena, Italy), based on the principle of the sandwich ELISA method.
Non-inflammatory phenotype

Patients with the non-inflammatory phenotype of recurrent pericarditis do not exhibit any of the signs typically associated with an active inflammatory process during a recurrence. These patients present without:

  • Fever
  • Elevated CRP
  • Elevated WBC count
  • Elevated ESR
  • Pericardial LGE on CMR
  • Pericardial contrast enhancement on CT
Diagnostic test: IL1RA Antibody Assay
-The measurement of anti-interleukin-1 receptor antagonist (IL1RA) antibodies will be performed using the ELISA (Enzyme-Linked Immunosorbent Assay) method,as previously described [Thurner, L., et al., IL-1RA Antibodies in Myocarditis after SARS-CoV-2 Vaccination. N Engl J Med, 2022. 387(16): p. 1524-1527].
Diagnostic test: suPAR Testing
-The quantitative determination of soluble urokinase plasminogen activator receptor (suPAR) levels in blood will be conducted using the commercially available "CHORUS suPAR Extended" kit (cod. 81414, DIESSE Diagnostica Senese S.p.A., Siena, Italy), based on the principle of the sandwich ELISA method.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Assessment of IL-1RA antibodies across pericarditis phenotypes
Time Frame: 24 months
  • Levels of anti-IL-1RA antibodies in different phenotypes of pericarditis.
  • Levels of anti-IL-1RA antibodies during acute episodes and intercritical phases.
24 months
Assessment of suPAR levels across pericarditis phenotypes
Time Frame: 24 months
  • Levels of suPAR in acute and recurrent pericarditis with normal C-reactive protein (CRP).
  • Levels of suPAR during acute episodes and intercritical phases.
24 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Correlation of Time to Recurrence and Disease Activity with Anti-IL-1RA Antibodies in Pericarditis
Time Frame: 24 months
  • Correlate the time to recurrence with the levels of anti-IL-1RA antibodies.
  • Correlate overall disease activity indices with the levels of anti-IL-1RA antibodies.
24 months
Correlation of Time to Recurrence and Disease Activity with suPAR Levels in Pericarditis
Time Frame: 24 months
  • Correlate the time to recurrence with the levels of suPAR.
  • Correlate overall disease activity indices with the levels of suPAR.
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

ASST Fatebenefratelli Sacco

Collaborators

Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
Careggi Hospital
University Hospital Tuebingen
Children's Medical Hospital, University of Muenster, Muenster, Germany
Fatebenefratelli Hospital
University of Homburg
Azienda Ospedaliero Universitaria, Santa Maria della Misericordia di Udine, Italy
Ospedale Galeazzi Sant'Ambrogio - IRCCS

Investigators

  • Principal Investigator: Maddalena A Wu, ASST Fatebenefratelli Sacco
  • Study Director: Antonio L Brucato, Fatebenefratelli Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Estimated)

July 1, 2023

Primary Completion (Estimated)

July 1, 2025

Study Completion (Estimated)

December 20, 2025

Study Registration Dates

First Submitted

May 28, 2023

First Submitted That Met QC Criteria

June 22, 2023

First Posted (Actual)

June 29, 2023

Study Record Updates

Last Update Posted (Actual)

June 29, 2023

Last Update Submitted That Met QC Criteria

June 22, 2023

Last Verified

June 1, 2023

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2023/ST/094

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

UNDECIDED

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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