# Histological pattern of non-infectious thoracic aortitis impacts mortality

Olivier Espitia, Patrick Bruneval, Eric Liozon, Jacques Pouchot, Hubert de Boysson, Julien Gaudric, Laurent Chiche, Paul Achouh, Jean-Christian Roussel, Sébastien Miranda, et al.

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## ► To cite this version:

Olivier Espitia, Patrick Bruneval, Eric Liozon, Jacques Pouchot, Hubert de Boysson, et al. Histological pattern of non-infectious thoracic aortitis impacts mortality. Journal of Autoimmunity, 2025, 151, pp.103360. 10.1016/j.jaut.2025.103360. hal-05115867

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Histological pattern of non-infectious thoracic aortitis impacts mortality

Olivier Espitia<sup>a, *, ◎</sup>, Patrick Bruneval<sup>b</sup>, Eric Liozon<sup>c</sup>, Jacques Pouchot<sup>d</sup>, Hubert de Boysson<sup>e</sup>, Julien Gaudric<sup>f,g</sup>, Laurent Chiche<sup>f,g</sup>, Paul Achouh<sup>h</sup>, Jean-Christian Roussel<sup>i</sup>, Sébastien Miranda<sup>j</sup>, Tristan Mirault<sup>k</sup>, Alban Redheuil<sup>l,m</sup>, Jean-Michel Serfaty<sup>n</sup>, Antoine Bénichou<sup>a</sup>, Christian Agard<sup>a</sup>, Alexis F. Guédon<sup>a</sup>, Patrice Cacoub<sup>o,p,q</sup>, François Paraf<sup>r</sup>, Pierre-Jean Fouret<sup>l,s</sup>, Claire Toquet<sup>t</sup>, Sylvain Le Jeune<sup>u,v</sup>, Lucie Biard<sup>w,x</sup>, David Saadoun<sup>o,p,q,**</sup>, For the French study group for large vessel vasculitides (GEFA)

ARTICLE INFO

Handling editor: C Selmi

Keywords:

Aortitis

Aortic aneurysm

Aortic dissection giant cell arteritis

Takayasu arteritis

Clinically isolated aortitis

A B S T R A C T

**Background:** Non-infectious aortitis encompasses various histological patterns, but their specific cardiovascular outcomes remain unclear.

**Objective:** To evaluate the mortality associated with non-infectious surgical thoracic aortitis.

**Methods:** This retrospective multicenter study included patients who underwent thoracic aortic surgery and had histological evidence of aortitis. The study analyzed the characteristics of patients with non-infectious aortitis presenting either a granulomatous/giant cell histological pattern or a lymphoplasmacytic pattern. Factors associated with mortality were identified using multivariate analysis.

<footnote><sup>a</sup> Nantes Université, CHU Nantes, Department of Internal and Vascular Medicine, l'institut du Thorax, INSERM UMR1087/CNRS UMR 6291, Team III Vascular & Pulmonary diseases, F-44000, Nantes, France</footnote>

<footnote><sup>b</sup> Department of Cardiology, Hôpital Européen Georges Pompidou, Paris, France</footnote>

<footnote><sup>c</sup> Department of Internal Medicine, CHU Limoges, France</footnote>

<footnote><sup>d</sup> Department of Internal Medicine, Hôpital Européen Georges Pompidou, Paris, France</footnote>

<footnote><sup>e</sup> Department of Internal Medicine CHU Caen, France</footnote>

<footnote><sup>f</sup> Department of Vascular Surgery, F-75005, Paris, France</footnote>

<footnote><sup>g</sup> AP-HP, Groupe Hospitalier Pitié-Salpetrière, France</footnote>

<footnote><sup>h</sup> Department of Cardiothoracic Surgery, Hôpital Européen Georges Pompidou, Paris, France</footnote>

<footnote><sup>i</sup> Department of Cardiothoracic Surgery, Nantes Université, CHU Nantes, Department of Internal and Vascular Medicine, F-44000, Nantes, France</footnote>

<footnote><sup>j</sup> Department of Internal Medicine CHU Rouen, France</footnote>

<footnote><sup>k</sup> Université Paris Cité, Department of Vascular Medicine, Hôpital Européen Georges Pompidou, APHP, INSERM U970 PARCC, Paris, France</footnote>

<footnote><sup>l</sup> Sorbonne Universités, Pitié-Salpetrière University Hospital, Paris, France</footnote>

<footnote><sup>m</sup> Department of Cardiovascular Imaging, Paris, France</footnote>

<footnote><sup>n</sup> Nantes Université, CHU Nantes, Department of Cardiovascular Imaging, F-44000, Nantes, France</footnote>

<footnote><sup>o</sup> Sorbonne Universités, Department of Internal Medicine and Clinical Immunology, Centre de Référence des Maladies Auto-Immunes Systémiques Rares, Centre de Référence des Maladies Auto-Inflammatoires et de l'Amylose Inflammatoire (CEREMAIA), F-75013, Paris, France</footnote>

<footnote><sup>p</sup> INSERM, UMR_S 959, F-75013, Paris, France</footnote>

<footnote><sup>q</sup> DMU 3ID, AP-HP, Groupe Hospitalier Pitié-Salpetrière, France</footnote>

<footnote><sup>r</sup> Department of Pathology, CHU Limoges, France</footnote>

<footnote><sup>s</sup> Service d'anatomopathologie, UPMC-Paris VI, Paris, France</footnote>

<footnote><sup>t</sup> Nantes Université, CHU Nantes, Department of Pathology, F-44000, Nantes, France</footnote>

<footnote><sup>u</sup> Department of Internal Medicine, APHP Avicenne University Hospital, Bobigny, France</footnote>

<footnote><sup>v</sup> Université Paris Cité, INSERM U970 PARCC, Paris, France</footnote>

<footnote><sup>w</sup> APHP Department of Biostatistics and Medical Information, Saint-Louis Hospital, France</footnote>

<footnote><sup>x</sup> ECSTRRA Team, CRESS UMR 1153, INSERM, Paris Cité University, Paris, France</footnote>

<footnote>* Corresponding author. Nantes Université, CHU Nantes, Department of internal and vascular medicine, F-44000, Nantes, France, 1 place Alexis Ricordeau, 44093, Nantes, France.</footnote>

<footnote>** Corresponding author. Department of Internal Medicine and Clinical Immunology, Groupe Hospitalier Pitié-Salpetrière, Assistance Publique-Hôpitaux de Paris (AP-HP), 75013, Paris, France, Immunology-Immunopathology-Immunotherapy (i3) Laboratory, INSERM UMR-S 959, Sorbonne Université, 75005, Paris, France. da vid.saadoun@aphp.fr</footnote>

<footnote>E-mail address: olivier.espitia@chu-nantes.fr (O. Espitia).</footnote>
Granulomatous/giant cell
Lymphoplasmacytic
Mortality

**Results:** Among 5666 patients who underwent thoracic aortic surgery, 197 were found to have non-infectious aortitis with either a granulomatous/giant cell histological pattern (n = 138) or a lymphoplasmacytic pattern (n = 59). The overall standardized mortality rate (SMR) for patients with non-infectious surgical thoracic aortitis was 1.61 (95 % CI: 1.05; 2.39), with 31.5 % of patients dying within 10 years of the initial procedure. After a median follow-up of 3.5 years [IQR: 0.5–6.8] post-surgery, 31 % of deaths were due to aortic dissection or rupture. The 10-year cumulative incidence of death was 40.1 % (95 % CI, 17.7–61.8) for patients with a granulomatous/giant cell pattern and 14.4 % (95 % CI, 2.6–35.6) for those with a lymphoplasmacytic pattern. Granulomatous/giant cell histological pattern (HR 4.71 [vs lymphoplasmacytic pattern]; 95 % CI, 1.37–16.2; p = 0.023) and aortic dissection at diagnosis (HR 6.07 [vs aneurysm]; 95 % CI, 2.89–12.7; p < 0.0001) were independently associated with increased mortality.

**Conclusion:** This multicenter study found that 31.5 % of patients with non-infectious surgical thoracic aortitis are expected to die within 10 years of their initial surgery. The granulomatous/giant cell histological pattern is associated with higher mortality.

# 1. Introduction

Non-infectious aortitis is defined as an inflammatory process affecting one or more layers of the aortic wall. Following thoracic aortic surgery, an aortitis is histologically identified between 2.6 % and 3.8 % of cases [1,2]. In studies primarily focused on the thoracic aorta, non-infectious aortitis has been reported to involve in 2 %–16 % of aortic resections. Aortitis can be caused by several systemic rheumatologic diseases. The most common etiologies are large-vessel vasculitis: giant cell arteritis (GCA), clinically isolated aortitis (CIA) or Takayasu arteritis (TA) [3–5]. Aortitis can be identified either pathologically or radiologically in the absence of clinical evidence of a systemic aortitis.

With the development of newer biologic therapies that target specific inflammatory molecules such as tumor necrosis factor-α, CD20, and interleukin (IL)-6, treatments for aortitis are becoming increasingly tailored to the specific type of aortitis. As a result, accurate subclassification of aortitis has become even more important. It is recommended that the aortitis be primarily subclassified pathologically based on the pattern of the inflammatory infiltrate.

The pathology of aortitis is best classified into four patterns of inflammation: granulomatous/giant cell pattern, lymphoplasmacytic pattern, suppurative pattern, and the mixed inflammatory pattern. The granulomatous/giant cell pattern is characterized by the presence of large epithelioid macrophages with or without giant cells and compact granulomas. The lymphoplasmacytic pattern consists of lymphocytes and plasma cells without a granulomatous/giant cell component. The suppurative pattern and the mixed inflammatory pattern are less common or more likely to be observed in infectious aortitis.

Aortitis is associated with significant cardiovascular morbidity and mortality [6], through the development of aortic aneurysms, aortic dissection [7,8] and thrombotic luminal obstruction. In the context of GCA, aortitis is associated with a worse vascular prognosis, with increased cardiovascular events, more relapses, and reduced survival, due to early or late aortic dissections [9–11].

The specific cardiovascular outcomes of histological patterns in non-infectious aortitis remain largely unknown. The relationship between histological patterns and patient outcomes has not been systematically studied in cases of surgical thoracic aortitis. In this multicenter study, we aimed to evaluate the impact of aortic histopathology on cardiovascular outcomes and mortality in patients with surgical thoracic aortitis.

# 2. Methods

## 2.1. Patients

### 2.1.1. Study population

We conducted a retrospective multicenter study at referral centers affiliated with the French study group for large vessel vasculitides (GEFA). We identified 197 patients with histologically confirmed non-infectious thoracic aortitis who underwent aortic surgery between

January 1997 and February 2022, presenting either a granulomatous/giant cell histological pattern or a lymphoplasmacytic pattern (Fig. 1). The inflammatory patterns in aortitis were defined based on the consensus statement on surgical pathology of the aorta [12] when active inflammatory infiltrates that involve the intima and/or media were demonstrated. The etiological classification of diseases associated with aortitis was as follows: Giant cell arteritis (GCA) fulfilling the 2022 American College of Rheumatology (ACR)/EULAR criteria for GCA [13], Takayasu Arteritis (TA) fulfilling the TA 2022 ACR criteria [14], clinically isolated aortitis (CIA) defined in the absence of an underlying defined inflammatory condition as defined in the revised Chapel Hill vasculitides nomenclature [5]. After reviewing charts, patients were excluded if they had periaortitis, retroperitoneal fibrosis, infectious aortitis, atherosclerosis, inherited vascular diseases and non-inflammatory histology findings.

We reviewed the electronic medical records of all patients, recording the following data for the study: age at diagnosis of aortitis, etiology of aortitis, geographic origin, sex, cardiovascular risk factors, topography of arterial lesion (ascending aorta, arch of aorta, descending aorta, abdominal aorta), C reactive protein (CRP) level at time of surgery, imaging features (computed tomography angiography (CTA), magnetic resonance angiography (MRA), and/or Fluorodeoxyglucose-positron emission tomography-computed tomography (PET/CT)), histological data, treatments (corticosteroids, immunosuppressive treatments, anti-platelet therapy, statins) before and after surgery, vascular complications (dissection or aneurysms), death and vascular revascularization including open or endovascular aortic procedures. Participating sites collected this information from routine patient care records, from the date of the initial surgery up until the last available visit or the most recent data (e.g., imaging summary) as of October 2022.

### 2.1.2. Ethical approval

This study was approved by the local ethics committee (Paris VI Ethics Committee, ethics approval number: 1867484) and was conducted in accordance with the STROBE guidelines.

## 2.2. Definitions of study end points

Overall mortality analyzed, including mortality within the first 30 days after aortic surgery and beyond. The causes of death according to histological types of aortitis was studied. To compare observed mortality with expected mortality a standardized mortality ratio (SMR) was calculated. SMR is the ratio of the observed patient mortality to the mortality rate of the general French population matched for sex and year of birth. Expected mortality rates were obtained from French national Statistical Institute (INSEE, http://www.ined.fr/fr/pop_chiffres/france/mortalite_causes_deces/deces_sexe_age).
## 2.3. Statistical analysis

Continuous variables are reported as median (interquartile range), and categorical variables are reported as count (percentage). Aortitis overall survival was defined as the time from the date of aortitis diagnosis to the date of the death. In the absence of event, observations were considered right-censored at the date of the last available information (e.g. follow-up visit, consultation, hospital discharge, imaging test). Cumulative incidences of death were estimated using standard methods [15,16].

Multiple imputation by chained equations was performed prior to the evaluation of factors associated with the risk of death, using the cumulative hazard approach for missing covariates [17]. In total, 50 imputed datasets were generated by multiple imputation chained equation with 20 iterations [18]. Rubin rules were applied to obtain final estimates and tests, in univariable and multivariable models. Sensitivity analysis on complete cases samples was also performed, with consistent results.

In the two main aortitis histological patterns, factors associated with time to death were evaluated using Cox models, for the estimation of cause-specific hazard ratios (CSHRs) and their 95 % confidence intervals (CIs) to focus on the rate of events over time [19]. The proportional hazards assumption was assessed with examination of Schoenfeld's residuals and Grambsch and Therneau's test. The multivariable model was selected using a majority approach combined with Wald testing (variable selection procedure using Akaike's information criterion performed on each imputed data set, variables being selected on more than 50 % imputed datasets being considered then confirmed for inclusion in the

final model using Wald testing when appropriate [20,21]). All tests were two-sided; P values < 0.05 were considered as indicating significant associations. Analyses were performed using R statistical platform version 4.2.2.

# 3. Results

## 3.1. Characteristics of the study population

The main clinical and demographic characteristics of the 197 patients with granulomatous/giant cell pattern (GP) (n = 138) or lymphoplasmacytic pattern (LP) (n = 59) thoracic aortitis (Fig. 1) are presented in Table 1 and Fig. 2. The median (interquartile range) age at diagnosis was 70 [31–77] years and 83 patients (43 %) were men. Aortitis involved the ascending aorta in 182 (93 %) cases, the aortic arch in 28 (15 %) and the descending thoracic aorta in 22 (12 %).

The aortitis etiologies included clinically isolated aortitis 48 % (n = 94), giant cell arteritis 37 % (n = 73), Takayasu arteritis 8 % (n = 15) and aortitis secondary to systemic autoimmune/inflammatory diseases 8 % (n = 15) [rheumatoid arthritis (n = 3), IgG4 related disease (n = 2), systemic lupus erythematosus (n = 2), spondyloarthropathy (n = 2), relapsing polychondritis (n = 2), ANCA vasculitis (n = 2), Behçet's disease (n = 1), granulomatous hepatitis (n = 1)]. No patient with CIA had aortitis diagnosis prior to aortic surgery. In contrast, all patients with Takayasu arteritis diseases had a definitive diagnosis before undergoing aortic surgery.

No significant difference was observed between the granulomatous/giant cell pattern, and the lymphoplasmacytic pattern groups in terms of

<figure><img src="image_4.png" /><figcaption>**Fig. 1.** Typical histological patterns of aortitis: Granulomatous/giant cell aortitis (A and B): Panel A: Whole thickness section of the aortic wall from the thick fibrous intima (top) to the not thickened adventitia (bottom). Collections of inflammatory cells are prominent in the media (tagged area) and include a giant cell (arrow). Note the marked loss of smooth muscle cell nuclei reflecting a severe damage to the media. Panel B: High magnification of the tagged area: The inflammatory cells include many mononuclear cells and a giant cell (arrow). Lymphoplasmacytic aortitis (C and D): Panel C: Whole thickness section of the aortic wall from the mildly thickened intima (top) to the not thickened adventitia (bottom). Collections of inflammatory cells are prominent in the media (tagged area). Note fibrotic changes in the media. Panel D: High magnification of the tagged area: The inflammatory cells are exclusively made of mononuclear cells including quite numerous plasma cells. No granuloma or giant cells are observed. H&E stain; Panels A and C: Original magnification X5; Panels B and D: Original magnification X20.</figcaption></figure>
<table><caption>**Table 1**
Main characteristics of the 197 patients with non-infectious surgical thoracic aortitis according to aortitis histological pattern.</caption><thead><tr><th></th><th>Aortitis n = 197</th><th>Lymphoplasmacytic aortitis pattern n = 59</th><th>Granulomatous/giant cell aortitis pattern n = 138</th><th>p-value</th></tr></thead><tbody><tr><td>Median follow-up in years (IQR)</td><td>3.5 (0.5:6.8)<br>85 (43 %)</td><td>3.3 (0.5; 7.6)<br>24 (41 %)</td><td>3.6 (0.5:6.7)<br>61 (44 %)</td><td>0.50*<br>0.75</td></tr><tr><td>Male gender n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Median age at pathological diagnosis in years (IQR) [Min; Max]</td><td>70 (61; 77) [20; 87]</td><td>68 (53; 73) [20; 87]</td><td>73 (65; 77) [22; 85]</td><td>0.001</td></tr><tr><td>Median CRP level (mg/l) before aortic surgery (IQR) [Min; Max]</td><td>5 (2; 11) [0; 139]</td><td>9 (3; 28) [0; 139]</td><td>3 (2; 7) [0; 100]</td><td>0.02</td></tr><tr><td>Cardiovascular risk factors n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Hypertension</td><td>133 (68 %)</td><td>40 (68 %)</td><td>93 (68 %)</td><td>1</td></tr><tr><td>Smokers</td><td>53 (28 %)</td><td>13 (22 %)</td><td>40 (30 %)</td><td>0.30</td></tr><tr><td>Dyslipidemia</td><td>50 (26 %)</td><td>17 (29 %)</td><td>33 (24 %)</td><td>0.48</td></tr><tr><td>Diabetes mellitus</td><td>10 (5 %)</td><td>4 (7 %)</td><td>6 (4 %)</td><td>0.49</td></tr><tr><td>Median BMI kg/m² (IQR) [Min; Max]</td><td>24 (22; 28) [0; 46]</td><td>25 (22; 29) [18; 46]</td><td>24 (21; 28) [0; 41]</td><td>0.21</td></tr><tr><td>Indication for aortic surgery n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Asymptomatic aneurysm with a critical size</td><td>137 (70 %)</td><td>41 (69 %)</td><td>96 (70 %)</td><td>1</td></tr><tr><td>Symptomatic aortic aneurysm</td><td>26 (13 %)</td><td>9 (15 %)</td><td>17 (12 %)</td><td>0.65</td></tr><tr><td>Aortic dissection</td><td>26 (13 %)</td><td>5 (8 %)</td><td>21 (15 %)</td><td>0.25</td></tr><tr><td>Topography of thoracic aortic lesions n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Ascending aorta</td><td>182 (93 %)</td><td>51 (88 %)</td><td>131 (96 %)</td><td>0.06</td></tr><tr><td>Aortic arch</td><td>28 (15 %)</td><td>5 (9 %)</td><td>23 (17 %)</td><td>0.18</td></tr><tr><td>Descending aorta</td><td>22 (12 %)</td><td>7 (12 %)</td><td>15 (11 %)</td><td>1</td></tr><tr><td>Etiologies of aortitis n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Clinically isolated aortitis</td><td>94 (48 %)</td><td>23 (39 %)</td><td>71 (51 %)</td><td></td></tr><tr><td>Giant cell arteritis</td><td>73 (37 %)</td><td>19 (32 %)</td><td>54 (39 %)</td><td></td></tr><tr><td>Takayasu arteritis</td><td>15 (8 %)</td><td>8 (14 %)</td><td>7 (5 %)</td><td></td></tr><tr><td>Other systemic autoimmune diseases</td><td>15 (8 %)</td><td>9 (15 %)</td><td>6 (4 %)</td><td></td></tr><tr><td>Treatment after surgery n (%)</td><td></td><td></td><td></td><td></td></tr><tr><td>Change or initiation of corticosteroid or immunosuppressive therapy</td><td>44 (23 %)</td><td>7 (12 %)</td><td>37 (27 %)</td><td>0.02</td></tr><tr><td>Change or initiation of immunosuppressive therapy</td><td>23 (12 %)</td><td>7 (12 %)</td><td>16 (12 %)</td><td>1</td></tr><tr><td>Antiplatelet therapy</td><td>142 (74 %)</td><td>41 (71 %)</td><td>101 (75 %)</td><td>0.77</td></tr><tr><td>Statin</td><td>83 (43 %)</td><td>22 (38 %)</td><td>61 (46 %)</td><td>0.58</td></tr><tr><td>ACE inhibitor</td><td>83 (44 %)</td><td>23 (40 %)</td><td>60 (45 %)</td><td>0.80</td></tr></tbody></table>

(ACE: angiotensin-converting enzyme inhibitor; BMI: body mass index; CRP: C reactive protein; IQR, interquartile range; * LogRank test).

<figure><img src="image_5.png" /><figcaption>**Fig. 2.** Study flow chart. Flow chart of non-infectious surgical thoracic aortitis selection patients.</figcaption></figure>
gender, cardiovascular risk factors, localization of aortitis, indication for surgery, aortitis etiology or treatment (Table 1). The patients of the granulomatous/giant cell group were older at diagnosis while those in the lymphoplasmacytic pattern group had higher CRP level at diagnosis (median [IQR]: 9 [3,28] versus 3 [2,7] mg/L).

Before aortic surgery, 28 % (n = 55) of patients received corticosteroids and 5 % (n = 10) immunosuppressive therapy. Of those, 4 patients were treated with methotrexate, 3 with cyclophosphamide, 3 with azathioprine, 2 with mycophenolate mofetil, 2 with tocilizumab, 1 with tacrolimus and 1 with leflunomide.

## 3.2. Incidence and cause of deaths

The median follow-up was 3.5 years [IQR: 0.5–6.8] from the initial surgery. The five-year cumulative incidence of aortic and vascular complication was 53.8 % (95%CI: 42.3; 64). During follow-up, 7 patients developed aortic dissections (5 granulomatous/giant cell pattern (GP), 2 lymphoplasmacytic pattern (LP)), 45 developed aortic aneurysms (30 GP, 15 LP), 4 developed aortic stenosis (3 GP, 1 LP) and 20 developed peripheral vascular complications (11 GP, 9 LP). Cumulative incidence of death according to histological aortitis patterns is shown in Fig. 3. The 1-, 3-, 5- and 10-year incidence of death was 2.1 %, 2.1 %, 2.1 % and 14.4 %, in the lymphoplasmacytic pattern group, respectively. The 1-, 3-, 5- and 10-year incidence of death was 10.5 %, 12.8 %, 17.5 % and 40.1 %, in the granulomatous/giant cell pattern group, respectively.

Twenty-nine (14.7 %) patients died (Table 2) with 25 patients (18 %) from the granulomatous/giant cell group and 4 patients (6.8 %) from the lymphoplasmacytic pattern group (Table 2). Two-thirds of deaths occurred more than one month after the initial surgery. The main causes of death were aortic dissections/ruptures (n = 9, 31 %), infection (n = 4, 14 %), heart failure (n = 3, 10 %), stroke (n = 1, 3 %) and mesenteric ischemia (n = 1, 3 %) (Table 2).

Overall, the standardized mortality rate (SMR) observed in this population of patients with surgical non-infectious thoracic aortitis was 1.61 (95%CI: 1.05; 2.39). SMR was 1.64 (1.03; 2.51) and 1.44 (0.52; 3.47) in patients with granulomatous/giant cell pattern and with lymphoplasmacytic pattern, respectively.

## 3.3. Factors associated with death

Overall, twenty-nine (14.7 %) of the 197 patients with surgical non-infectious thoracic aortitis patients died during the follow-up period, with a median time of 3.5 years after initial surgery. The 1-, 3-, 5-, 10-

<figure><img src="image_6.png" /><figcaption>**Fig. 3.** Cumulative incidence of death according to aortitis histological patterns. Number of patients (No.) at risk of event over time are reported, accounting for non-informative censoring and competing events.</figcaption></figure>

<table><caption>**Table 2**

Causes of death according to granulomatous/giant cell or lymphoplasmacytic aortitis pattern.</caption><thead><tr><th></th><th>Number of events</th><th>Lymphoplasmacytic aortitis pattern n = 59</th><th>Granulomatous/giant cell aortitis pattern n = 138</th></tr></thead><tbody><tr><td><strong>Death</strong></td><td>29</td><td>4</td><td>25</td></tr><tr><td>• Early event occurring within 30 days of aortic surgery</td><td>7 (24 %)</td><td>0 (0)</td><td>7 (28 %)</td></tr><tr><td>• Event occurring more than 30 days after aortic surgery</td><td>18 (62 %)</td><td>3 (75 %)</td><td>15 (60 %)</td></tr><tr><td>• Unknown</td><td>4 (14 %)</td><td>1 (25 %)</td><td>3 (12 %)</td></tr><tr><td><strong>Cause of death</strong></td><td></td><td></td><td></td></tr><tr><td>• Aortic dissection/rupture</td><td>9 (31 %)</td><td>0 (0)</td><td>9 (36 %)</td></tr><tr><td>• Heart failure</td><td>3 (10 %)</td><td>1 (25 %)</td><td>2 (8 %)</td></tr><tr><td>• Stroke</td><td>1 (3 %)</td><td>0 (0)</td><td>1 (4 %)</td></tr><tr><td>• Mesenteric ischemia</td><td>1 (3 %)</td><td>0 (0)</td><td>1 (4 %)</td></tr><tr><td>• Infection</td><td>4 (14 %)</td><td>2 (50 %)</td><td>2 (8 %)</td></tr><tr><td>• Unknown</td><td>11 (38 %)</td><td>1 (25 %)</td><td>10 (40 %)</td></tr></tbody></table>

year cumulative death rates were 8 % (95 % CI, 4.6–12.8), 9.6 % (95 % CI, 5.7–14.8), 12.9 % (95 % CI, 7.8–19.2), and 31.5 % (95 % CI, 16.5–47.7), respectively (Table 2 and Fig. 3).

In univariable analysis, age (p = 0.01), granulomatous/giant cell pattern (p = 0.04), aortic dissection at diagnosis (p < 0.0001) and absence of antiplatelet therapy after aortitis diagnosis (p = 0.02) were associated with an increased risk of death (Table 3). In multivariable analysis (Fig. 4), granulomatous/giant cell pattern (HR 4.71; 95%CI, 1.37; 16.2 p = 0.023) and aortic dissection at diagnosis (HR6.07; 95%CI, 2.89; 12.7 p < 0.0001) were both associated with a significantly increased risk of death.

# 4. Discussion

This multicenter study of thoracic aorta surgery patients provides important new insights into the relationship between histological pattern of aortitis and cardiovascular outcomes or mortality. The pathology of aortitis is characterized by two main patterns of inflammation: granulomatous/giant cell pattern and lymphoplasmacytic pattern.

The most striking conclusions from this study are: 1) the granulomatous/giant cell pattern increases by 4.7 times the odds of death regardless of underlying etiology of aortitis; and 2) the mortality in granulomatous/giant cell aortitis, is mainly driven by aortic dissection/rupture.

Notably, the etiologies of aortitis were evenly distributed across histological pattern in this study. In large series of histologically proven aortitis [1,2,22], the etiologies of aortitis were similar to those described here: 48 % of CIA, 37 % of GCA and 8 % of TA. Currently, limited data are available on the natural history of histologically proven aortitis. Aortitis etiology (e.g. GCA or CIA) did not appear to influence aortitis mortality in this study.

The nature of aortic cellular infiltration appears to play a critical role in cardiovascular outcome and survival in surgical thoracic aortitis. Consistent with this, aortic dissection accounted for one third of death in the granulomatous/giant cell pattern, while no deaths occurred in lymphoplasmacytic pattern. Macrophage fusion leads to the formation of multinucleated giant cells, a hallmark of granulomatous reactions. Granulomas exhibit a unique architecture, with highly activated macrophages surrounding a nucleus. In granulomatous aortitis, M1-type macrophages contribute lamina elastica rupture. Activated macrophages located at the intima-media junctions produce matrix
<table><caption>**Table 3**
Univariate analysis of factors associated with death.</caption><thead><tr><th></th><th>HR (95% CI)</th><th>P value</th></tr></thead><tbody><tr><td>Male gender</td><td>0.80<br>(0.36-1.79)</td><td>0.59</td></tr><tr><td>Age (HR per 1-year increment)</td><td>1.05<br>(1.01-1.09)</td><td>0.01</td></tr><tr><td><strong>CV risk factors</strong></td><td></td><td></td></tr><tr><td>BMI (HR per 1 kg/m² increment)</td><td>1.00<br>(0.92-1.08)</td><td>0.95</td></tr><tr><td>Hypertension</td><td>2.29<br>(0.86-6.13)</td><td>0.10</td></tr><tr><td>Diabetes mellitus</td><td>0.82<br>(0.11-6.09)</td><td>0.85</td></tr><tr><td>Dyslipidemia</td><td>0.89<br>(0.33-2.40)</td><td>0.82</td></tr><tr><td>Smoker</td><td>1.17<br>(0.40-3.44)</td><td>0.78</td></tr><tr><td>History of CV event</td><td>0.80<br>(0.24-2.70)</td><td>0.72</td></tr><tr><td><strong>Topography of thoracic aortitis</strong></td><td></td><td></td></tr><tr><td>Ascending aorta</td><td>0.93<br>(0.22-3.94)</td><td>0.92</td></tr><tr><td>Aortic arch</td><td>1.33<br>(0.50-3.56)</td><td>0.57</td></tr><tr><td>Descending aorta</td><td>1.49<br>(0.51-4.36)</td><td>0.46</td></tr><tr><td><strong>Etiology of aortitis</strong></td><td></td><td></td></tr><tr><td>Giant cell arteritis</td><td>1</td><td>-</td></tr><tr><td>Takayasu arteritis</td><td>0.38<br>(0.05-3.02)</td><td>0.36</td></tr><tr><td>CIA</td><td>1.42<br>(0.60-3.33)</td><td>0.42</td></tr><tr><td>Secondary to AI/inflammatory disease</td><td>1.24<br>(0.27-5.80)</td><td>0.78</td></tr><tr><td><strong>Histological pattern</strong></td><td></td><td></td></tr><tr><td>Granulomatous/giant cell pattern</td><td>3.66<br>(1.09-12.2)</td><td>0.04</td></tr><tr><td>Lymphoplasmacytic pattern</td><td>1</td><td>-</td></tr><tr><td><strong>Indication for aortic surgery</strong></td><td></td><td></td></tr><tr><td>Aneurysm</td><td>1</td><td>-</td></tr><tr><td>Aortic dissection</td><td>6.25<br>(2.82-13.9)</td><td>&lt;0.0001</td></tr><tr><td>Elevated CRP before surgery (HR per 10 mg/L increment)</td><td>1.03<br>(0.87-1.23)</td><td>0.72</td></tr><tr><td><strong>Treatment after surgery</strong></td><td></td><td></td></tr><tr><td>GC or IS after aortitis diagnosis</td><td>0.48<br>(0.16-1.42)</td><td>0.19</td></tr><tr><td>IS after aortitis diagnosis</td><td>0.55<br>(0.16-1.88)</td><td>0.34</td></tr><tr><td>Antiplatelet therapy after aortitis diagnosis</td><td>0.38<br>(0.17-0.85)</td><td>0.02</td></tr><tr><td>Statin after aortitis diagnosis</td><td>0.53<br>(0.22-1.23)</td><td>0.14</td></tr><tr><td>ACE inhibitor after aortitis diagnosis</td><td>0.74<br>(0.32-1.72)</td><td>0.49</td></tr></tbody></table>

(ACE: angiotensin-converting enzyme inhibitor, AI: autoimmune, BMI: body mass index, CIA: clinically isolated aortitis, CRP: C-reactive protein, CV: cardiovascular, GC: glucocorticosteroids, HR: hazard ratio, IS: immunosuppressive therapy).

metalloproteinases and reactive oxygen species and playing a crucial role in damaging the medial layer [23,24]. The presence of giant cell granulomas could, modify the biomechanical properties of the aortic wall by altering shear stress and reducing wall elasticity It may also reflect an older, more organized inflammatory process, which can independently contribute to parietal fragility, regardless of the underlying disease associated with aortitis. Difference in prognosis based on histological features in large vessel vasculitis had already been reported for permanent vision loss (PVL) during GCA, where the presence and number of giant cells in the temporal arterial wall strongly predicted PVL [25].

Taken together, the presence of granulomas and macrophages

significantly alters the structure of the aortic wall, which may explain the poorer prognosis in comparison to lymphoplasmacytic aortitis, as well as the higher mortality due to aortic dissection.

Factors independently associated with death were granulomatous/giant cell pattern and aortic dissection at diagnosis. This study highlighted that cardiovascular complications accounted for more than 60% of the causes of death. The standardized mortality rate of patients with non-infectious surgical thoracic aortitis was 1.61 times higher compared with age- and sex-matched general population over the same period. Our results are in line with those of Svensson et al. where 10.9% of subsequent aortic replacements occurred after the initial aortic surgery and 30-day mortality rate reached 3.2% [22]. In patients with GCA with large vessel vasculitis, cardiovascular mortality was significantly higher than in age- and sex-matched controls [26].

The therapeutic management and the natural history of patients with histologically-proven aortitis remains to be defined. Treatment encompasses the conventional management of cardiovascular risk factors. Notably, statins have been shown to reduce the risk of vascular complications (HR: 0.47) in post-operative aortic surgery of histologically proven aortitis [2]. Additionally, patients with histologically proven aortitis could benefit from immunosuppressive therapy. Persistent inflammation of the vascular wall has been histologically demonstrated in 50% of second aortic surgeries in patients who initially underwent surgery for aortitis [2]. Identifying active aortitis prior to surgery remains challenging. For instance, in a series of patients who underwent PET scans prior to aortic surgery, 31% of cases with histologically proven aortitis cases showed no aortic abnormalities on PET [27]. This may suggest the presence of persistent asymptomatic inflammation in the vessel wall, undetected by current vascular imaging [28].

The data gathered in our study point to the need of taking into account the histological pattern of aortitis in the management of patients, independently of the underlying etiology.

In this study, the 10-year cumulative incidence of death was 40.1% and 14.4% in patients with granulomatous/giant cell pattern and lymphoplasmacytic pattern, respectively. Patients with granulomatous aortitis had a 4.7 times higher risk of mortality with aortic dissection accounting for 36% of deaths. Taken together, these findings suggest that patients with granulomatous/giant cell aortitis require closer clinical and imaging monitoring. It is crucial to manage cardiovascular risk factors in these patients, although the optimal therapeutic approach has yet to be determined.

## 4.1. Study limitations

Limitations of this study include the retrospective nature of data collection, the relatively small number of patients, heterogeneity in follow-up imaging, and the lack of standardized review. Nevertheless, this study represents one of the largest cohorts of this rare disease; and, for instance, given the sample size and event rate, the magnitude of the estimated mortality hazards ratio between the two pathology groups (HR = 4.71, 95%CI: 1.37; 16.2 in the OS multivariable model) was consistent with a range of 80-90% power for such an effect size using a two-sided Wald test in a Cox regression model. However, patients with granulomatous/giant cell aortitis were significantly more likely to have changes or initiation of corticosteroid or immunosuppressive therapy after surgery compared to those with lymphoplasmacytic pattern. This study was not designed to compare mortality of surgical thoracic aortitis to that of patients undergoing thoracic aortic surgery without aortitis.

## 5. Conclusion

Mortality from non-infectious surgical thoracic aortitis is substantial as evidenced by a standardized mortality rate of 1.61 (95%CI: 1.05; 2.39) and a 10-year death rate of 31.5% following the initial procedure. The granulomatous/giant cell histological pattern of aortitis and aortic dissection at diagnosis increase the odds of death by 4.7 and 6 times,
<figure><img src="image_7.png" /><figcaption>**Fig. 4.** Predictive factors for death in patients with histologically proven thoracic aortitis. Forest plot of multivariable Cox regression models of factors for cause specific hazards of events. Black squares represent cause-specific hazard ratios and horizontal segments their 95 % confidence intervals.</figcaption></figure>

respectively. Prospective studies are essential to further assess the management and natural history of this rare condition.

## CRediT authorship contribution statement

**Olivier Espitia:** Writing – review & editing, Writing – original draft, Validation, Methodology, Formal analysis, Data curation, Conceptualization. **Patrick Bruneval:** Writing – review & editing, Validation, Investigation, Data curation. **Eric Liozon:** Writing – review & editing, Conceptualization. **Jacques Pouchot:** Writing – review & editing, Data curation. **Hubert de Boysson:** Writing – review & editing, Data curation. **Julien Gaudric:** Writing – review & editing, Validation. **Laurent Chiche:** Writing – review & editing, Supervision. **Paul Achouh:** Writing – review & editing. **Jean-Christian Roussel:** Writing – review & editing. **Sébastien Miranda:** Writing – review & editing. **Tristan Mirault:** Writing – review & editing. **Alban Redheuil:** Writing – review & editing, Resources. **Jean-Michel Serfaty:** Writing – review & editing, Visualization. **Antoine Bénichou:** Writing – review & editing, Investigation. **Christian Agard:** Writing – review & editing. **Alexis F. Guédon:** Writing – review & editing. **Patrice Cacoub:** Writing – review & editing, Validation. **François Paraf:** Writing – review & editing. **Pierre-Jean Fouret:** Writing – review & editing. **Claire Toquet:** Writing – review & editing. **Sylvain Le Jeune:** Writing – review & editing. **Lucie Biard:** Writing – review & editing, Writing – original draft, Validation, Methodology, Conceptualization. **David Saadoun:** Writing – review & editing, Writing – original draft, Methodology, Formal analysis, Data curation, Conceptualization.

## Financial disclosure

Authors have nothing to disclose.

## Data availability statement

Data are available on request from the corresponding authors.

## Funding

No funding was received for this study.

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