Cardioimmunology Review
Abstract
In the French Vasculitis Study Group cohort, nearly one in three deaths among patients with eosinophilic granulomatosis with polyangiitis was cardiac. The French national protocol for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, updated in January 2026, requires an electrocardiogram and echocardiography in every patient and advises against screening cardiac MRI. Silent cardiac involvement is frequent and associated with mortality, yet no trial has shown that treating it improves outcomes. Trials have had no cardiac end point; avacopan has lost its European authorization and its pivotal trial has been retracted. A cardioimmunology reading proposes to describe cardiac involvement by lesion activity, as is done for the kidney.
Résumé (français)
Dans la cohorte du Groupe français d’étude des vascularites, près d’un décès sur trois au cours de la granulomatose éosinophilique avec polyangéite est d’origine cardiaque. Le protocole national de diagnostic et de soins des vascularites associées aux anticorps anticytoplasme des polynucléaires neutrophiles (ANCA), actualisé en janvier 2026, prescrit à tous un électrocardiogramme et une échocardiographie, et déconseille l’IRM cardiaque de dépistage. L’atteinte silencieuse est fréquente et associée à la mortalité, mais aucun essai n’a montré que la traiter améliore le pronostic. Les essais n’ont eu aucun critère de jugement cardiaque ; l’avacopan a perdu son autorisation européenne et son essai pivot a été rétracté. Une lecture cardioimmunologique propose de décrire l’atteinte cardiaque selon l’activité de ses lésions, comme pour le rein.
Introduction
In eosinophilic granulomatosis with polyangiitis (EGPA), nearly one death in three is cardiac, although a cardiomyopathy is recognized at diagnosis in only one patient in six.1
In January 2026, the French Vasculitis Study Group (FVSG) published a national diagnostic and care protocol (PNDS) dedicated to antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, under the aegis of the FAI²R rare disease network.2 It covers granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and EGPA, following a method provided by the French National Authority for Health, which did not validate it.2
Cardioimmunology studies the contribution of immune mechanisms to cardiovascular disease.3 Read from this angle, the protocol leaves open a question that the available evidence does not settle: should the heart be sought before it speaks?
The Heart, First Determinant of Prognosis
In GPA, 10-year survival reaches 75%. Infections and severe flares dominate mortality in the first year, cardiovascular complications in the long term.2 In EGPA, 10-year survival is about 85%, and deaths stem above all from cardiac involvement or from treatment complications.2
The FVSG cohort shows its weight. Of 383 patients, 16.4% had a cardiomyopathy at diagnosis, and it remained an independent risk factor for death.1 Of the 45 deaths, 14 were cardiac, 10 of them in ANCA-negative patients. The heart ranked first, far ahead of infections and cancers, with five deaths each.1
The prognostic score gives a particular image of this heart. Its revised 2009 version retains “cardiac symptoms.”4 In the score definitions taken up by the PNDS, specific cardiomyopathy rests on clinical symptoms, without regard to natriuretic peptide or echocardiography.2 The score counts the heart that speaks. The protocol keeps the 1996 version for EGPA; in GPA and MPA, it prefers the distinction between severe and nonsevere disease, with specific cardiomyopathy among the severe manifestations.2
The score counts the heart that speaks.
Screening for Silent Involvement: What the Protocol Retains
The PNDS requires, in every patient, a cardiac examination, an electrocardiogram, transthoracic echocardiography and, when in doubt, coronary assessment.2 In EGPA or when involvement is suspected, it adds troponin, natriuretic peptide and, if needed, cardiac magnetic resonance imaging (MRI).2
It frames MRI precisely. Its value would be mainly prognostic, by comparing lesions before and after induction. Using it to screen for asymptomatic involvement would risk overtreatment, since the adverse effect on survival has been established for clinically overt cardiomyopathy.2
Screening studies require this choice to be discussed. In 32 patients with EGPA in remission and no known cardiac involvement, a systematic workup found involvement in 62%, compared with 3% of matched controls.5 Among patients without symptoms and with a normal electrocardiogram, 38% still had an abnormality on echocardiography or MRI.5
A prospective cohort of 91 patients in remission, 50 with EGPA and 41 with GPA, found electrocardiographic or echocardiographic abnormalities in 62% and 46% of them, respectively, compared with 20% of controls.6 These abnormalities were associated with increased all-cause and cardiovascular mortality, and the authors recommended risk stratification by cardiac imaging in all patients.6 The frequency of cardiac involvement therefore depends on how it is sought (figure 1).
Proportion of patients with cardiac involvement according to the method of detection: clinical cardiomyopathy at diagnosis (EGPA, FVSG cohort, n = 383)1; systematic cardiac workup in remission (EGPA without known involvement, n = 32)5; systematic electrocardiography and echocardiography in remission (n = 91)6. The series differ in population, timing and tests and cannot be compared with one another. EGPA: eosinophilic granulomatosis with polyangiitis; FVSG: French Vasculitis Study Group; GPA: granulomatosis with polyangiitis.
What Imaging Shows and What It Leaves Open
Two findings support the protocol’s restraint. For cardiac involvement in EGPA, late gadolinium enhancement on MRI has a sensitivity of 83% and a specificity of 56%, and the review reporting these figures considers the modality and frequency of screening uncertain.7 The European recommendations observe that the prognosis of cardiac involvement appears better than in the past, which may partly reflect the diagnosis of milder forms by MRI.8
A detected abnormality can therefore signal a risk without indicating a treatment. Between blindness and overtreatment, the protocol has chosen caution, and the current evidence supports it. What remains is to know what the silent abnormality represents: active inflammation, which treatment can extinguish, or a scar, which it will not repair.
Counting the Heart as the Kidney Is Counted
The kidney in vasculitis has what the heart lacks. Its glomerular classification links the immune mechanism to the tissue lesion, and it offers a model of etiological precision for cardiovascular interfaces.3 The protocol itself envisages that positron emission tomography may one day separate, in EGPA, active cardiac lesions from fibrous sequelae.2
The proposal that follows changes the way of counting. It consists of describing cardiac involvement along two axes, lesion activity and sequelae, rather than by the presence of symptoms alone. It calls for a trial in asymptomatic patients, stratified by lesion activity and judged on a cardiac end point.
This proposal has not yet been tested. Such a trial could prove negative; it would then show which lesions warrant no additional treatment, which no one knows today.
One Disease, Two Phenotypes: The Heart of the Antibody-Negative Form
About 30% of patients with EGPA carry ANCA, directed against myeloperoxidase.9 In the French cohort, their presence was associated with more ear, nose and throat involvement, peripheral neuropathy and renal involvement, and with less cardiac involvement.1
The genome-wide association study of EGPA gave this partition a biological basis. It describes two syndromes distinct in their genetics as in their clinical features: an autoimmune disease associated with HLA-DQ in ANCA-positive patients and, in the others, a disease that may arise from mucosal or barrier dysfunction.9 A Mendelian randomization analysis supports a causal role of a primary tendency to eosinophilia.9
The heart of EGPA is above all that of the ANCA-negative form.1 Eosinophilic infiltration of the myocardium can progress through three stages: necrosis, thrombosis, then fibrosis.3 The question of lesion activity finds its cellular basis there.
Treating a Heart That Trials Have Not Measured
For EGPA with a poor prognostic factor, the PNDS recommends glucocorticoids combined with an immunosuppressant, preferably cyclophosphamide, with rituximab as an alternative, particularly in patients with anti-myeloperoxidase ANCA.2 The REOVAS trial compared rituximab with the conventional strategy in 105 patients. Remission at six months was achieved in 63.5% vs 60.4% of patients (relative risk, 1.05; 95% CI, 0.78 to 1.42).10 Rituximab was not superior, and the trial design did not allow conclusions on its equivalence with cyclophosphamide in severe forms.10
This negative result opens a new line of inquiry. The PNDS reports that, in an analysis restricted to patients with anti-myeloperoxidase ANCA, rituximab was associated with better long-term relapse-free survival.2 The signal requires confirmation, since the European recommendations found no difference in response according to ANCA status in two randomized trials.8 The phenotype-based reading suggested by genetics becomes a hypothesis to be tested.
Interleukin-5 blockade leaves the heart in the same shadow. The MIRRA trial of mepolizumab excluded organ- or life-threatening disease in the preceding three months and included no cardiac end point.11 The MANDARA trial established the noninferiority of benralizumab to mepolizumab, with remission in 59% and 56% of patients, respectively, also without a cardiac end point.12
The European recommendations therefore reserve mepolizumab for refractory or relapsing disease without organ- or life-threatening involvement.8 Its use for induction is under study in a French trial.2 In the face of active cardiac involvement in EGPA, induction relies on glucocorticoids combined with cyclophosphamide, with rituximab as an alternative.2
Cardiovascular Risk beyond the Flare
According to the European recommendations, the excess cardiovascular risk of these patients is not explained by traditional risk factors alone and follows the burden of disease activity.8 They call for control of vascular inflammation and screening for risk factors, but consider the evidence insufficient to propose an assessment specific to these vasculitides.8
The PNDS reports that, in population data, systemic glucocorticoid therapy even below 5 mg per day is associated with reduced survival, notably through an excess of cardiovascular events.2 In EGPA, it derives from this the goal of glucocorticoid withdrawal.2 The disease and its treatment thus weigh on the same risk.
When the Evidence Changes after the Protocol
The PNDS devotes a section to avacopan, an oral C5a receptor inhibitor, combined with rituximab or cyclophosphamide to spare glucocorticoids in GPA and MPA.2 On June 29, 2026, the New England Journal of Medicine retracted the ADVOCATE trial at the request of its two academic authors.13 Primary end point assessments in 9 of 331 patients had been readjudicated after database lock and unblinding, without disclosure in the article.13
The Committee for Medicinal Products for Human Use of the European Medicines Agency concluded on June 25, 2026, that the marketing authorization should be revoked, and the European Commission made the revocation binding on August 4.14 Swissmedic considers the benefit-risk balance negative, because of violations of good clinical practice in the ADVOCATE trial and of hepatotoxicity, and is revoking the Swiss authorization as of November 30, 2026.15
Completed before these decisions, the protocol could not take them into account. A protocol is worth what the trials on which it rests are worth on the day it is read.
| Question | What the 2026 PNDS says | What the data show | Cardioimmunology reading |
|---|---|---|---|
| Prognostic weight | Cardiovascular complications, the leading cause of late death in GPA; EGPA deaths due mainly to the heart or to treatment2 | 14 of 45 deaths were cardiac in the FVSG cohort (383 patients)1 | The heart is the leading cause of death, though it accounts for less than half |
| What the score counts | Specific cardiomyopathy defined by clinical symptoms, without natriuretic peptide or echocardiography2,4 | Involvement on screening in 62% of patients with EGPA in remission, vs 3% of controls5 | The score counts the heart that speaks |
| Screening | ECG and echocardiography for all; troponin, natriuretic peptide and, if needed, MRI in EGPA or on suspicion2 | Abnormalities associated with excess mortality6; late enhancement: sensitivity 83%, specificity 56%7 | MRI assesses a risk; it does not yet designate a treatment |
| Activity or sequela | PET may one day separate active lesions from fibrous sequelae in EGPA2 | No interventional data | Proposal: describe involvement by activity and sequela |
| Phenotype | Signal favoring rituximab in patients with anti-MPO, in a restricted analysis2 | Two distinct syndromes by ANCA status9; heart more often involved without ANCA1 | A hypothesis to be tested by phenotype |
| Induction of cardiac forms | In EGPA: glucocorticoids combined preferably with cyclophosphamide, or with rituximab2 | REOVAS: rituximab not superior10; MIRRA and MANDARA without a cardiac end point11,12 | No trial has a cardiac end point |
| Long-term risk | Glucocorticoid withdrawal; control of risk factors2 | Risk linked to disease activity, not to traditional factors alone8 | The disease and its treatment weigh on the same risk |
| Avacopan | Dedicated section, in GPA and MPA2 | Pivotal trial retracted; authorization revoked in the EU and, as of November 30, 2026, in Switzerland13–15 | No longer initiate |
ECG: electrocardiogram; EGPA: eosinophilic granulomatosis with polyangiitis; EU: European Union; FVSG: French Vasculitis Study Group; GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; MPO: myeloperoxidase; MRI: magnetic resonance imaging; PET: positron emission tomography; PNDS: French national diagnostic and care protocol. The last column is the author’s interpretation, not a recommendation.
Conclusion
The 2026 PNDS gives the heart its place in the prognosis of ANCA-associated vasculitis (table 1), and its restraint toward screening by MRI rests on the available evidence. What comes next comes down to two requirements: describing cardiac involvement by the activity of its lesions, and conducting trials that make it their end point.
Practice Points
- Every patient with ANCA-associated vasculitis should undergo, at diagnosis, a cardiac examination, an electrocardiogram and echocardiography.
- In EGPA or when involvement is suspected, troponin, natriuretic peptide and, if needed, cardiac MRI complete the workup; in an asymptomatic patient, MRI is not a screening test.
- Clinical cardiac involvement classifies the disease as severe; in EGPA, it leads to induction with glucocorticoids combined with an immunosuppressant, preferably cyclophosphamide.
- Glucocorticoid withdrawal and control of cardiovascular risk factors are part of long-term treatment.
- Avacopan should no longer be initiated: its authorization has been revoked in the European Union and will be revoked in Switzerland on November 30, 2026.
Multiple-Choice Question
According to the 2026 PNDS, which of these statements is correct?
- A. Cardiac MRI is recommended for screening in every asymptomatic patient
- B. An electrocardiogram and echocardiography are recommended in every patient
- C. Natriuretic peptide is sufficient to score specific cardiomyopathy
- D. The MIRRA trial included life-threatening cardiac disease at the time of enrollment
- E. Avacopan is indicated in EGPA
Show the answer
Answer B. The protocol requires an electrocardiogram and echocardiography in every patient; it advises against screening MRI and excludes natriuretic peptide from the definition of specific cardiomyopathy; avacopan concerns only GPA and MPA. The MIRRA trial excluded organ- or life-threatening disease in the three months before enrollment.
Use of Artificial Intelligence. Generative artificial intelligence tools (Claude, by Anthropic) were used under the author’s control to search and verify sources, draft the text and produce the English translation. The author reviewed and validated the text and is solely responsible for it.
Disclosure of Interests. The author declares no conflict of interest related to this article. Relationships: invitations to meals by GSK, AstraZeneca, Lilly and Menarini, without fees, research funding or other remuneration.
References
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- Guillevin L, Pagnoux C, Seror R, et al. The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Baltimore) 2011;90:19-27. doi:10.1097/MD.0b013e318205a4c6
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- Springer JM, Kalot MA, Husainat NM, et al. Eosinophilic granulomatosis with polyangiitis: a systematic review and meta-analysis of test accuracy and benefits and harms of common treatments. ACR Open Rheumatol 2021;3:101-10. doi:10.1002/acr2.11194
- Hellmich B, Sanchez-Alamo B, Schirmer JH, et al. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis 2024;83:30-47. doi:10.1136/ard-2022-223764
- Lyons PA, Peters JE, Alberici F, et al. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nat Commun 2019;10:5120. doi:10.1038/s41467-019-12515-9
- Terrier B, Pugnet G, de Moreuil C, et al. Rituximab versus conventional therapy for remission induction in eosinophilic granulomatosis with polyangiitis: a randomized controlled trial. Ann Intern Med 2025;178:1249-57. doi:10.7326/ANNALS-24-03947
- Wechsler ME, Akuthota P, Jayne D, et al. Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med 2017;376:1921-32. doi:10.1056/NEJMoa1702079
- Wechsler ME, Nair P, Terrier B, et al. Benralizumab versus mepolizumab for eosinophilic granulomatosis with polyangiitis. N Engl J Med 2024;390:911-21. doi:10.1056/NEJMoa2311155
- Rubin EJ. Retraction: Jayne DRW et al. Avacopan for the treatment of ANCA-associated vasculitis. N Engl J Med 2021;384:599-609. N Engl J Med 2026 (June 29). doi:10.1056/NEJMe2608684
- European Medicines Agency. Tavneos – referral. Amsterdam: EMA; 2026. source
- Vifor Fresenius Medical Care Renal Pharma, Swissmedic. Tavneos (avacopan): rapport bénéfice-risque négatif – révocation de l’autorisation de mise sur le marché [negative benefit-risk balance, revocation of the marketing authorization]. Direct healthcare professional communication. Bern: Swissmedic; September 9, 2026. In French. source
How to cite this article. Abdelouaeb B. The Silent Heart in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis. Cardioimmunology Review 2026;1 (October). English translation of the French original.