Persistent Aortic Inflammation in Patients with Giant Cell Arteritis

Abstract

Objectives

To investigate the clinicopathologic features of patients with giant cell arteritis (GCA) who had thoracic aorta aneurysm or dissection surgery.

Methods

Patients who had thoracic aorta surgery between January 1, 2000, and December 31, 2021, at the Mayo Clinic, Rochester, Minnesota, were identified with current procedural terminology (CPT) codes. The identified patients were screened for a prior diagnosis of GCA with diagnostic codes and electronic text search. The available medical records of all the patients of interest were manually reviewed. Thoracic aorta tissues obtained during surgery were re-evaluated in detail by pathologists. The clinicopathologic features of these patients were analyzed. Overall observed survival was compared with lifetable rates from the United States population.

Results

Of the 4621 patients with a CPT code for thoracic aorta surgery, 49 had a previous diagnosis of GCA. Histopathologic evaluation of the aortic tissue revealed active aortitis in most patients with GCA (40/49, 82%) after a median (IQR) of 6.0 (2.6– 10.3) years from GCA diagnosis. All patients were considered in clinical remission at the time of aortic surgery. The overall mortality compared to age and sex-matched general population was significantly increased with a standardized mortality ratio of 1.55 (95% CI, 1.05– 2.19).

Conclusion

Histopathologic evaluation of the thoracic aorta obtained during surgery revealed active aortitis in most patients with GCA despite being considered in clinical remission several years after GCA diagnosis. Chronic, smoldering aortic inflammation likely contributes to the development of aortic aneurysm and dissection in GCA.

1. Introduction

Giant cell arteritis (GCA) is a systemic vasculitis of unknown etiology seen mostly in individuals of Northern European descent over age 50 years [1,2]. In GCA, granulomatous inflammation affects large and medium-sized vessels, and involvement of cranial arteries is typical of this condition [3,4]. In addition to cranial arteries, involvement of the aorta and its main branches is increasingly recognized in recent decades given the use of advanced imaging techniques [5–8]. Patients with GCA are at increased risk of vascular damage leading to vision loss, stroke, and thoracic aortic aneurysm [2,3]. Specifically, aortic aneurysms generally occur at a late stage of the disease when patients are in clinical remission [5,8–10]. The risk of aneurysm formation increases with disease duration, and may be as high as 17-fold greater compared with the general population [5,9,10].

Risk factors for developing aortic aneurysm are incompletely understood, and whether persistent subclinical vascular inflammation contributes to aneurysm formation remains unclear. Clinical features found to be associated with the development of aortic dilatation/aneurysm in GCA include smoking [11,12], hypertension [13,14], and male sex [7,12,13,15].

Radiographic studies have shown that aortic dilatation is preceded by radiologically detectable inflammation, and aortitis on positron emission tomography scan is a risk factor for progressive aortic dilatation [13,16–19]. Furthermore, different types of imaging modalities have shown persistent radiologic abnormalities (i.e., low grade fluorodeoxyglucose [FDG] uptake, wall thickening) in the aorta in treated patients who are in clinical remission [20–23]. However, it is unknown whether these radiologic abnormalities represent vascular remodeling or active inflammation [13,19–23].

Histopathologic inflammation of the arteries tends to persist in some patients with GCA [24–26]. A study in which repeat temporal artery biopsies were performed in treated patients showed that 44% of patients had ongoing vascular inflammation after 12 months from diagnosis [26]. However, a thorough histopathologic evaluation of the aorta has not been performed to date and whether aortic dilatation is reflecting prior damage or ongoing active inflammation is largely unknown [19].

The objective of this study was to investigate whether aortic inflammation persists chronically in patients with GCA and may therefore contribute to progressive aortic dilatation. We describe the clinicopathologic findings of patients with GCA who had thoracic aorta surgery at the Mayo Clinic, Rochester, Minnesota, between January 1, 2000, and December 31, 2021.

2. Patients and Methods

2.1. Identification of study population

In this retrospective study, all patients evaluated at Mayo Clinic, Rochester, Minnesota, between January 1, 2000, and December 31, 2021, with current procedural terminology (CPT) codes (33858–33877) for thoracic aorta surgery were included. All the patients with at least one CPT code of interest were further screened for a prior diagnosis of GCA with International Classification of Diseases (ICD) 9^th and 10^th revisions, clinical modifications codes (446.5 and M31.5/M31.6, respectively) and electronic text search (giant cell arteritis, temporal artery vasculitis, temporal arteritis, GCA, cranial arteritis). All patients with an ICD code and/or text search for GCA were manually reviewed for documentation of the diagnosis of GCA prior to the thoracic aorta surgery. Patients with clinically isolated aortitis with no previous documentation of GCA were excluded. The 1990 American College of Rheumatology (ACR) and 2022 ACR/European Alliance of Associations for Rheumatology (EULAR) classification criteria for GCA were retrospectively applied to all patients included in this study [27,28].

2.2. Data abstraction and definitions

The available medical records of all patients were manually reviewed. Demographics, clinical characteristics, laboratory parameters, and treatment data were retrospectively collected by a physician (MSK). Patients were followed up through December 31, 2022, the last follow-up, or death.

Remission was defined as the absence of active disease based on clinical and laboratory data, according to the treating physician.

According to our institution’s policy, all resected aortic tissues are routinely reviewed by a cardiovascular pathologist for clinical diagnosis and stored in the tissue registry. For this study, all available aortic specimens were re-examined by a cardiovascular pathologist (MCB) with pre-specified, well-defined data collection forms.

2.3. Histopathologic characterization

Aortic patterns were broadly classified in each case as “active” or “healed” aortitis, or as “no evidence of healed or active aortitis.” In the case of the former, inflammatory pattern was classified according to previously defined criteria [29] as granulomatous/giant cell, lymphoplasmacytic, mixed or suppurative. Inflammation in each case was further characterized semi-quantitatively, with grade 1 inflammation defined as inflammation limited to peri-vasa vasorum aortic media or focal medial involvement, grade 2 inflammation as involvement beyond the peri-vasa vasorum or multifocal involvement but less than 50% of the medial thickness, and grade 3 inflammation as diffuse inflammation with involvement of equal or more than 50% of the medial thickness. The present and relative quantities of individual cell types was assessed, including lymphocytes, plasma cells, eosinophils, neutrophils, and giant cells.

Medial changes were characterized according to previously defined guidelines [30]. Mucoid extracellular matrix accumulation (MEMA) was defined as MEMA-intralamellar (MEMA-I) or MEMA-translamellar (MEMA-T), with semiquantitative parameters defined as 0–3 (0=none, 1=up to 2 foci of MEMA, 2=3–5 foci of MEMA in sampled tissue, and 3=>5 foci of MEMA). Laminar medial collapse was assessed on a 0–3 scale as follows: 0=none, 1=<10% of medial wall thickness and <10% longitudinally of sampled media, 2=10–25% of medial wall thickness or 10–50% longitudinally of sampled media, and 3=>25% medial wall thickness or >50% longitudinally of sampled media.

The degree of medial fibrosis and elastic fiber breakdown were characterized independently on a 0–3 scale for none, mild, moderate/multifocal, and severe (respectively). “Swath-like” medial necrosis was defined as linear and continuous smooth muscle cell loss in the middle third of the aortic media, and semiquantitavely 0–3, with 0=none, 1=less than 10% of the aortic media, 2=10–50% of the aortic media, and 3=greater than 50%. Adventitial inflammation was characterized as granulomatous, necrotizing granulomatous, lymphocytic, lymphoplasmacytic or other (if present).

Intimal changes were defined as the presence of atherosclerosis (0–3; 0=none, 1=less than 10% of the sampled intima, 2=10–50% involvement of sampled intima, 3=greater than 50% involvement of sampled intima), as well as intimal fibroplasia (absent, mild, moderate, or severe).

2.4. Immunofluorescence staining

Immunofluorescence staining was performed as previously described [31]. Briefly, the paraffinembedded sections were deparaffinized with xylene, rehydrated, and then steam-heated for 15 minutes. The sections were incubated with 5% serum appropriate to the secondary antibody for 1 hour at room temperature, and then incubated overnight at 4°C with the primary antibodies (CD3: Abcam, ab5690; PU.1, BD, 554268). All staining samples were visualized using the appropriate secondary antibodies (1/300), counterstained with DAPI.

2.5. Bulk RNA-sequencing analysis

Bulk RNA-sequencing analysis was performed as previously described [32]. The raw reads were preprocessed using the nf-core RNA-seq pipeline (v.3.3), aligned to the human reference genome GRCh38. For PCA, the counts were normalized by ‘regularized log’ transformation using DESeq2 (v.1.34.0) [33] followed by removing gender effect using limma (v.3.50.3) [34].

2.6. Statistical analyses

Descriptive statistics were used to summarize the cohort. Fisher’s exact and Kruskal-Wallis tests were used to compare laboratory parameters and clinical symptoms between aortitis groups. Survival rates were estimated using Kaplan-Meier methods. Overall observed survival was compared with lifetable rates from the United States population. The standardized mortality ratio was estimated as the ratio of the observed and expected number of deaths. Statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).

2.7. Patient safety

This study was performed in accordance with the ethical standards of Helsinki Declaration and was approved by the Institutional Review Board of the Mayo Clinic prior to study conduction. All the screened and included subjects gave research authorization.

3. Results

3.1. Study population

A total of 4621 patients with at least one CPT code for thoracic aorta surgery were identified. After a comprehensive screening and manual review based on both ICD codes and electronic text search, 49 patients with a diagnosis of GCA prior to thoracic aorta repair surgery were included. Forty-three (88%) patients had either positive temporal artery biopsy or met the 1990 ACR or 2022 ACR/EULAR classification criteria for GCA. Temporal artery biopsy was performed in 41 patients and biopsy was positive for GCA in 32/41 (78%). Large vessel imaging was positive for vasculitis in 8 patients at GCA diagnosis.

The features of study cohort are shown in Table 1. The mean (SD) age at GCA diagnosis was 68.4 (7.66) years and 32 (65%) were female. Most patients (n= 41) had cranial symptoms, whereas PMR like symptoms were evident in 14/41 (34%) at GCA diagnosis. Constitutional symptoms were reported in majority of the cohort (weight loss, 20/37; night sweats, 16/34; fever, 16/37).

Table 1.

Summary of the study cohort.

	Total (n=49)	Active Aortitis (n=40)	Healed Aortitis (n=5)	No Evidence of Active or Healed Aortitis (n=4)
Age at GCA diagnosis, mean (SD) years	68.4 (7.66)	68.3 (7.52)	64.3 (7.90)	74.0 (7.12)
Age at aortic surgery, mean (SD) years	75.3 (7.25)	75.3 (7.42)	74.9 (7.90)	75.7 (6.42)
Sex, female	32 (65%)	28 (70%)	4 (80%)	0 (0%)
Race, white	48 (98%)	39 (98%) a	5 (100%)	4 (100%)
Smoking, ever	27 (55%)	21 (53%)	3 (60%)	3 (75%)
BMI, kg/m 2 , mean (SD)	26.05 (4.22)	25.84 (3.93)	24.58 (5.80)	29.65 (4.77)
Polymyalgia rheumatica	23 (47%)	20 (50%)	1 (20%)	2 (50%)
Hypertension	43 (88%)	34 (85%)	5 (100%)	4 (100%)
Diabetes mellitus	7 (14%)	6 (15%)	0 (0%)	1 (25%)
Hyperlipidemia	37 (76%)	30 (75%)	4 (80%)	3 (75%)
Length of time between GCA diagnosis and aorta surgery, median (IQR) years	5.6 (2.5–10.4)	6.0 (2.6–10.3)	11.5 (9.5–11.6)	1.9 (0.9– 2.6)
Follow-up duration, median (IQR) years	6.3 (2.8–8.7)	6.4 (3.0–8.6)	8.5 (2.5–11.4)	4.3 (2.6– 8.9)
Positive temporal artery biopsy	32/41 (78%)	27/35 (77%)	4/4 (100%)	1/2 (50%)
Fulfilled 1990 ACR criteria for GCA	39 (80%)b	33 (83%)	3 (60%)	3 (75%)
Fulfilled 2022 ACR/EULAR criteria for GCA	36 (73%)c	31 (78%)	4 (80%)	1 (25%)
Duration of treatment with GCs prior to aortic surgery, median (IQR) years	2.0 (1.0–3.4) (n=45)	2.2 (1.0–3.9) (n=37)	2.5 (1.7–6.3) (n=4)	0.6 (0.4– 1.6) (n=4)
Number of patients on immunosuppressive treatment at aortic surgery	19 (39%)	16 (40%)	1 (20%)	2 (50%)
Prednisone dose at the time of aortic surgery, mean (SD) mg	9.6 (10.64) (n=18)	9.3 (10.87) (n=16)	3.0 (−) (n=1)	20.0 (−) (n=1)
Starting prednisone dose at GCA	54.6	53.8	60.0 (−)	60.0 (16.33)
diagnosis, mean (SD) mg	(10.95) (n=37)	(10.40) (n=32)	(n=1)	(n=4)
Ascending aorta diameter at the time of surgery, mean (SD) cm	5.5 (0.68) (n=46)	5.5 (0.66) (n=40)	6.2 (0.21) (n=2)	5.4 (1.0) (n=4)

^aIn one patient, race was unknown.

^b6/10 patients who did not meet the 1990 ACR Criteria had limited data for at least one of the criteria questions.

^c7/13 patients who did not meet the 2022 ACR/EULAR Criteria had limited data for at least one of the criteria questions.

Abbreviations: ACR, American College of Rheumatology; BMI, body mass index; EULAR, European Alliance of Associations for Rheumatology; GCs, glucocorticoids; GCA, giant cell arteritis; IQR, interquartile range; SD, standard deviation.

3.2. Medical treatment

Forty-seven (96%) patients with GCA were treated with GCs prior to the aortic surgery (in one patient treatment data for GCA was unavailable; one patient was diagnosed with large-vessel GCA one day prior to aortic surgery). The mean (SD) starting dose of prednisone was 54.6 (10.95) mg. The median (IQR) duration of treatment with GCs was 2.0 (1.0– 3.4) years. In addition to GC treatment, 4 patients received methotrexate, 1 was treated with tocilizumab, and 1 was enrolled in the abatacept trial before the aortic surgery[35].

Nineteen (39%) patients were on immunosuppressive treatment at the time of aortic surgery (15 patients were on prednisone monotherapy, 1 patient was on both tocilizumab and prednisone, 2 patients were on both methotrexate and prednisone, and 1 patient was only on methotrexate). Mean (SD) prednisone dose at the time of aortic surgery was 9.6 (10.64) mg.

3.3. Preoperative evaluation

All patients were considered in clinical remission at the time of aortic surgery according to the treating physician.

Inflammatory parameters (median [IQR]) were significantly improved at the time of aortic surgery compared to baseline (at GCA diagnosis): erythrocyte sedimentation rate [ESR]: 10 mm/hour [5.0– 20.0] vs. 91 mm/hour [54.0– 109.5]; c-reactive protein [CRP]: 3.1 mg/l [3.0– 8.0] vs. 76.5 mg/l [28.0– 139.0].

3.4. Surgical intervention

Four (8%) and 6 (12%) patients had acute and chronic aortic dissection, respectively. The remaining patients (n=39, 80%) had surgery for an aortic aneurysm. The majority of the patients (n=47, 96%) had ascending thoracic aorta graft repair surgery, whereas only 2 (4%) had descending thoracic aorta graft repair surgery. The mean (SD) size of the ascending aorta was 5.5 (0.68) cm (among 46 patients; missing in 1 patient, and the other 2 had descending thoracic aorta repair surgery). Concomitant coronary artery bypass graft surgery was performed in 8/49 (16%) patients.

3.5. Histopathologic evaluation

Histopathologic evaluation of the thoracic aorta tissue obtained during surgery revealed active aortitis in most patients (n=40, 82%) after a median (IQR) of 6 (2.6– 10.3) years from GCA diagnosis.

The majority of cases 43/49 (88%) underwent detailed re-evaluation by an expert cardiovascular pathologist (Table 2). The remaining 6 [12%] patients had active aortitis on routine clinical histopathology, but tissue was unavailable for re-review for purposes of this study. The detailed histopathologic re-evaluation of the 43 aortic samples revealed active aortitis in 34 patients (grade 1 aortitis in 17/43 [40%] patients, grade 2 in 12/43 [28%], grade 3 in 5/43 [12%]) (Figure 1A, 1B, 1C, 1D). Healed aortitis was detected in 5/49 (10%) patients (3 in ascending aorta, and 2 in descending aorta) (Figure 1E, 1F) and in 4/49 (8%) patients there was no evidence of active or healed aortitis.

Table 2.

Detailed histopathologic re-evaluation of 43 aorta specimens.

	Active Aortitis (n=34)	Healed Aortitis (n=5)	No Evidence of Active or Healed Aortitis (n=4)
Inflammation Grade
Grade 0	0 (0%)	5 (100%)	4 (100%)
Grade 1	17 (50%)	0 (0%)	0 (0%)
Grade 2	12 (35%)	0 (0%)	0 (0%)
Grade 3	5 (15%)	0 (0%)	0 (0%)
Inflammatory Pattern
Granulomatous	15 (44%)	-	-
Lymphoplasmacytic	12 (35%)	-	-
Mixed*	3 (9%)	-	-
Suppurative	0 (0%)
Other**	4 (12%)	-	-
Inflammation Pattern
Peri-vasa vasorum	26 (76%)	-	-
Non-specific medial inflammation	8 (24%)	-	-
Adventitial Inflammation
Absent	0 (0%)	0 (0%)	3 (75%)
Mild	18 (53%)	3 (60%)	1 (25%)
Moderate	12 (35%)	2 (40%)	0 (0%)
Severe	4 (12%)	0 (0%)	0 (0%)
Type of Adventitial Inflammation
Granulomatous	0 (0%)	0 (0%)	0 (0%)
Necrotizing granulomatous	0 (0%)	0 (0%)	0 (0%)
Lymphocytic	32 (94%)	5 (100%)	1 (100%)
Lymphoplasmacytic	2 (6%)	0 (0%)	0 (0%)
Intimal Inflammation
Absent	29 (85%)	5 (100%)	4 (100%)
Mild	3 (9%)	0 (0%)	0 (0%)
Moderate	2 (6%)	0 (0%)	0 (0%)
Severe	0 (0%)	0 (0%)	0 (0%)

^*Both granulomatous and lymphoplasmacytic inflammation.

^**Three lymphohistiocytic, and 1 predominantly granulomatous, focally suppurative.

Figure 1. Analysis of the aortic tissues.

A: Aortic histopathology showing minimal (grade 1) inflammation of the aortic media (arrows), defined as inflammation limited to the peri-vasa vasorum or aortic media with focal involvement (hematoxylin and eosin; 40x original magnification), B: Minimal (grade 1) inflammation affecting the peri-vasa vasorum (hematoxylin and eosin; 200x original magnification), C: Diffuse (grade 3) aortitis, showing inflammation affecting >50% of the medial thickness (hematoxylin and eosin; 40x original magnification), D: Diffuse (grade 3) inflammation showing both granulomatous and lymphoplasmacytic features (hematoxylin and eosin; 200x original magnification), E: Histopathology of healed aortitis, showing an absence of inflammation within the media (hematoxylin and eosin stain; 40x original magnification), F: Histopathology of healed aortitis with extensive medial remodeling and elastic fiber loss (Verhoeff van Gieson stain; 40x original magnification), G: Representative immunofluorescence image from aortic specimens of patients with aortitis; CD3: T cell marker, PU.1: macrophage marker, scale bars: 50 mm, H: Gene expression levels of T cell markers (CD4, CD8A) and macrophage markers (CD14 and CD68) by bulk RNA-seq analysis of surgically resected ascending aneurysms derived from patients with noninflammatory aortopathy (n = 10) and aortitis (n = 7).

There was no significant difference between 3 groups in terms of duration of treatment with GCs prior to the aortic surgery (p= 0.165). There was no statistically significant difference between those with active aortitis and healed aortitis in terms of duration of time from GCA diagnosis to the aortic surgery (6.0 years vs. 11.5 years, p= 0.08).

There was no significant difference between active aortitis group and rest of the patients in terms of ESR and CRP levels both at GCA diagnosis and at aortic surgery (Table 3).

Table 3.

Laboratory parameters at giant cell arteritis diagnosis and at the time of aortic surgery.

	Total (n=49)	Active Aortitis (n=40)	Healed Aortitis (n=5)	No Evidence of Active or Healed Aortitis (n=4)	P value
At GCA Diagnosis
ESR, mm/hour, median (IQR)	91 (54.0–109.5) (n= 36)	90 (57.0–113.0) (n= 31)	88 (51.0–125.0) (n= 2)	92 (21.0– 98.0) (n=3)	0.755
CRP, mg/liter, median (IQR)	76.5 (28.0–139.0) (n=18)	78.9 (28.0–139.0) (n=15)	33 (−) (n=1)	93.0 (7.0– 179.0) (n=2)	0.795
HGB, g/dL, median (IQR)	12 (11.1–13.0) (n=32)	12 (11.1–13.1) (n=28)	11.3 (10.3–12.3) (n=2)	11.7 (11.2– 12.1) (n=2)	0.762
PLTs, 109 /liter, median (IQR)	382 (279–445) (n=31)	360 (274–415) (n=27)	418.5 (292–545) (n=2)	465 (445– 485) (n=2)	0.316
At Aortic Surgery
ESR, mm/hour, median (IQR)	10 (5.0–20.0) (n= 34)	9.5 (5.0–20.0) (n= 30)	8 (2.0– 14.0) (n=2)	20.5 (19.0– 22.0) (n=2)	0.371
CRP, mg/liter, median (IQR)	3.1 (3.0– 8.0) (n=30)	4.4 (3.0– 9.0) (n=27)	-	3.0 (3.0– 3.0) (n=3)	0.096
HGB, g/dL, median (IQR)	13.5 (12.7–14.1) (n=47)	13.5 (12.7–14.2) (n=39)	13.4 (12.3–14.4) (n=4)	13.0 (12.5– 13.6) (n=4)	0.767
PLTs, 109 /liter, median (IQR)	214 (191–259) (n=47)	224 (199–261) (n=39)	233 (187–256.5) (n=4)	160.5 (131.5– 178.5) (n=4)	0.013

Abbreviations: CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GCA, giant cell arteritis; HGB, hemoglobin; IQR, interquartile range; PLTs, platelets.

In addition, there was no significant difference between active aortitis group and rest of the patients in terms of clinical symptoms at the time of GCA diagnosis (Supplementary Table 1).

The inflammatory pattern of the 34 patients with active aortitis were of mostly granulomatous (15/34, 44%) and lymphoplasmacytic (12/34, 35%) type. Inflammatory pattern of the remaining patients were as follows: 3/34 (9%) mixed (both granulomatous and lymphoplasmacytic), 3/34 (9%) lymphohistiocytic and 1/34 (3%) with predominantly granulomatous with focally suppurative pattern. The predominant immune cell populations were macrophages and T cells (Figure 1G, 1H). Lymphocytes and histiocytes were present in all of the active aortitis tissues, whereas giant cells were present in 22/34 (65%) patients. All 34 patients with active aortitis had adventitial inflammation as well.

The histopathologic examination of all 5 patients with healed aortitis showed adventitial lymphocytic inflammation, whereas only 1 out of 4 patients with no evidence of active or healed aortitis showed adventitial inflammation. Further details regarding the histopathologic analysis are shown in Supplementary Tables 2 and 3.

Of the 4 patients with no evidence of active or healed aortitis, 1 was diagnosed with GCA by temporal artery biopsy while 3 patients had a clinical diagnosis of GCA.

3.6. Survival rates

The survival rate of this cohort at 1, 5, and 10 years was 89.7% (95% CI, 81.6– 98.7%), 67.0% (95% CI, 54.6– 82.3%), 35.3% (95% CI, 22.6– 55.1%), respectively. Thirty-one deaths were observed during follow-up period after the aortic surgery. According to the age and sex matched United Stated total lifetables 20.06 deaths were expected. The overall mortality was significantly increased with a standardized mortality ratio of 1.55 (95% CI, 1.05– 2.19) (Figure 2).

Figure 2. Overall survival of patients with giant cell arteritis and thoracic aorta repair.

Overall survival of patients with giant cell arteritis compared to expected rates from United States total lifetables (observed: solid blue line; expected: dashed red line).

4. Discussion

To our knowledge, this is the largest study to date systematically investigating the clinicopathologic features of patients with GCA who had thoracic aorta surgery over two decades. Histopathologic evaluation of the thoracic aorta obtained during surgery revealed active aortitis in most patients with GCA despite being considered in clinical remission after a median of 6 years from initial diagnosis. The duration of treatment with GCs was similar in those with active and healed aortitis. Patients with GCA who require thoracic aorta repair are at increased mortality compared with the general population.

The study findings underscore the chronicity of GCA and suggest that smoldering aortic inflammation contributes to progressive aortic dilatation in some patients. Radiographic studies have shown that treated patients have radiologic abnormalities suggestive of ongoing aortitis for many months [19–23]. Our results support the hypothesis that persistent radiologic abnormalities seen in patients in clinical remission represent active inflammation [13,19–23]. FDG uptake on positron emission tomography-computed tomography (PET-CT) was previously shown to be correlated with the severity of adventitial inflammation in the histopathologic analysis of the aorta [36]. Furthermore, the histopathologic inflammation could be seen even in the absence of radiographic signs. Even though PET-CT is considered as the most sensitive imaging modality in large vessel vasculitis [19], it is not able to detect up to one third of the cases with active histopathologic inflammation in the aorta [36].

Smaller prior studies have shown persistent subclinical vasculitis on histopathology. In a prospective study, patients diagnosed with GCA with positive temporal artery biopsy were started on treatment and followed for 1 year. At the end of 1 year, a contralateral temporal artery biopsy showed persistent inflammation in 44% of patients while they were in clinical remission and on a median prednisone dose of 5 mg [26].

Homme et al. reviewed 513 patients with ascending aortic surgery identified between 1985 and 1999 [37]. Of those 513 patients, 21 had a previous diagnosis of GCA; and of these 21 patients, 11 (52%) had active giant cell aortitis (6 aortitis, 5 cystic medial degeneration and aortitis) [37]. Evans et al. have shown that histopathologic analysis of the thoracic aorta in 20 patients with GCA who have died or had aortic surgery revealed active aortitis in 10 (50%) patients [38]. A population-based study in Olmsted County has shown active aortitis at autopsy in 5 out of 7 (71%) patients with GCA who had thoracic aorta dissection [39]. A French multicenter study has identified active inflammation in 4 out of 7 (57%) patients who have undergone aortic root replacement surgery and had available histopathologic analysis [16]. Another French study has reported active giant cell aortitis in 5 out of 8 (63%) patients with GCA who had available histopathological examination of the aorta [40]. In the report of Klein et al., 3 out of 34 patients with large vessel GCA died due to aortic rupture, and all 3 (100%) patients had active giant cell aortitis at autopsy [41].

Other investigators have questioned the role of persistent aortic inflammation in the development of aortic aneurysms. In a prospective cohort of patients with biopsy-proven GCA, around one-third developed aortic dilatation/aneurysm over a median of 10.3 years [42]. Interestingly, those who had sustained remission and those who had less number of relapses were more likely to develop aortic dilatation and aneurysm [7,42]. The histopathologic examination of the aorta of 6 patients after a median of 9.2 years from GCA diagnosis revealed scattered inflammatory infiltrates at the media in only 2 patients. The authors concluded that their data does not suggest that persistent and smoldering subclinical inflammatory activity is playing a major role in the aortic aneurysm formation. However, in a recent retrospective study with a larger cohort size patients with more GCA relapses were more likely to develop subsequent aortic complications [43].

The discordance between steroid-responsive clinical symptoms and persistent histopathologic inflammation has been partially explained by the presence of tissue-resident memory T cells [44]. Tissue resident memory T cells play a prominent role in sustaining chronic inflammation by their self-renewal abilities [44]. While these cells are resistant to GCs, targeted therapies, such as Janus kinase inhibitors, might be an effective treatment option [26,44,45].

Two major T cell subsets, Th1 and Th17, were discovered to be playing an important role in the pathogenesis of GCA [46,47]. Both were found to be elevated in the blood and temporal arteries of untreated patients with GCA [46]. While GCs were able to deplete Th17 cells, IFN-γ producing Th1 cells were resistant to GCs [46]. Th1 immunity is suggested to be partly responsible from the chronic, smoldering nature of vascular inflammation. In addition to GCs, targeted therapies against Th1 immunity may be required for controlling the chronic and smoldering nature of this disease [46]. Indeed, the chronic aortic inflammation seen in our study population underscores the GC-refractory nature of the disease. Further research is required for delineating the efficacy of targeted therapies against aortic complications in GCA.

The majority of population-based studies have identified similar mortality ratios between patients with GCA and general population [5,48,49]. However, patients with GCA and aortic aneurysm or dissection were found to be at higher risk of death [5]. In our study, the overall mortality was significantly higher than general population.

The main limitation of this study was its retrospective design and limited availability of data in some patients. Referral bias might have been played a role as our institution is a tertiary medical center. The relapse rate and duration of sustained remission could not have been identified due to limited availability of data.

The results of our study have several important implications for clinicians. Firstly, patients with GCA (including those in clinical remission) require active surveillance to detect aortic aneurysms. Secondly, patients with GCA and persistent aortic inflammation may benefit from novel targeted therapies in addition to GCs [45]. Lastly, patients with GCA are not exempt from the hemodynamic effects that may contribute to progressive aortic dilatation and traditional cardiovascular risk factors should be carefully managed.

5. Conclusions

Histopathologic evaluation of the thoracic aorta obtained during surgery revealed active aortitis in most patients with GCA despite being considered in clinical remission several years after GCA diagnosis. Chronic, smoldering aortic inflammation likely contributes to the development of aortic aneurysm and dissection in GCA. Patients with GCA and thoracic aorta repair have increased mortality rates. Further research is required for delineating the efficacy of targeted therapies against aortic complications in GCA.

Abbreviations

ACR

American college of rheumatology

BMI

body mass index

CPT

current procedural terminology

CRP

reactive protein

DM

diabetes mellitus

ESR

erythrocyte sedimentation rate

EULAR

European alliance of associations for rheumatology

FDG

fluorodeoxyglucose

GCs

glucocorticoids

GCA

giant cell arteritis

HGB

hemoglobin

HTN

hypertension

ICD

international classification of diseases

IQR

interquartile range

PET-CT

positron emission tomography-computed tomography

PLTs

platelets

PMR

polymyalgia rheumatic

SD

standard deviation

Data Availability Statement

Mayo Clinic Institutional Review Board (IRB) policy does not allow full access of patient information to be provided to a third party without prior approval from the IRB committee overseeing this study. However, access to the complete de-identified data can be made available following approval. Requests for study related data can be sent to the corresponding author from researchers involved in rigorous research.