High Risk of Stroke in ANCA-associated Vasculitis

A Population-Based Study

Dennis Tabakovic; Rona Smith; David Jayne; Aladdin J. Mohammad

Rheumatology. 2023;62(8):2806-2812.

Abstract and Introduction

Abstract

Objective: To determine the incidence rate, predictors and outcome of stroke in a population-based cohort of individuals with ANCA-associated vasculitis (AAV).

Methods: The study included 325 patients diagnosed with AAV from 1997 through 2016 in a defined geographic area of Sweden. Patients who suffered a stroke were identified from Riksstroke, a national Swedish stroke register established in 1994, and the Skåne Healthcare Register (SHR), which includes data for all inhabitants of Skåne since 1998. Case record review was carried out to confirm the diagnosis of stroke in AAV patients identified in the SHR. The incidence rate of stroke was calculated per 1000 person-years of follow-up. Using data from the Swedish general population, the standardized incidence ratio (SIR) of stroke was estimated. Cox regression analysis was utilized to investigate survival and predictors of stroke.

Results: Twenty-five subjects (8%) suffered a stroke during 2206 person-years of follow-up. The incidence rate of stroke in AAV was 11.3/1000 person-years (95% CI 6.9, 15.8). Patients with AAV showed an increased risk of stroke compared with the general population [SIR 1.85 (95% CI 1.27, 2.59)], with a greater risk for those <65 years of age [SIR 3.19 (95% CI 1.53, 5.88)]. Higher platelet count at AAV diagnosis was an independent predictor of stroke [hazard ratio 1.14 (95% CI 1.00, 1.29)]. There were no differences in survival or other outcome measures between AAV patients with and without stroke.

Conclusions: The incidence rate of stroke in AAV is higher than in the general population. High platelet count at AAV diagnosis was associated with an increased risk of stroke.

Introduction

ANCA-associated vasculitis (AAV) is an umbrella term for a group of autoimmune diseases characterized by inflammation of the small blood vessels, including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). AAV is characterized by systemic inflammation causing dysfunction of or damage to multiple organs including the kidneys, lungs and upper respiratory tract.

Since the introduction of AAV treatment with cytostatic drugs such as cyclophosphamide combined with high doses of glucocorticosteroids, the prognosis and survival has improved dramatically,^[1] transforming AAV from a disease with 80% mortality in the 12 months following diagnosis to a more stable and manageable condition with a 5 year survival rate of 72%.^[2] However, patients with AAV exhibit a higher rate of comorbidities compared with the general population. This includes a 4-fold rate of venous thromboembolic disease and a 5-fold rate of severe infection and septicaemia,^[3] comorbidities with consequences to the individual and to the economic and societal burden of AAV.^[4]

Research has shown an increased risk of cardiovascular events in individuals with AAV.^[5–7] A population-based study of a cohort of AAV patients in southern Sweden demonstrated an increased rate of ischaemic heart disease compared with the general population as well as a more frequent presence of traditional risk factors for cardiac disease, including hypertension and diabetes.^[3] An increased rate of atherosclerosis in patients with chronic inflammatory disease, including AAV, has also been identified and is a possible risk factor contributing to cardiovascular events in AAV.^[8,9]

While the risk of cardiovascular events in AAV has been well researched, only a few studies have investigated the incidence of stroke in patients with AAV,^{[6,7,10–12]} and results have been inconsistent with respect to stroke risk. In addition, most of the available studies originate from tertiary referral centres and, unlike population-based studies, can be associated with selection and referral bias.

In this population-based study from southern Sweden utilizing a large, validated cohort of patients with ANCA-associated vasculitis, we aimed to determine the incidence rate of stroke in AAV compared with the general population and explore possible predictors and outcomes of stroke in AAV.

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Abstract and Introduction
Methods
Results
Discussion
References
Sidebar

Table 1. Characteristics of AAV patients with and without stroke
Characteristics	All patients (N = 325)	Patients with stroke (n = 25)	Patients without stroke (n = 300)	P-value
Age at AAV diagnosis, years, mean (S.D.)	64.6 (16.3)	67 (12.5)	64 (17)	0.34
Female, n (%)	152 (47)	141 (47)	11 (44)	0.77
GPA, MPA and EGPA diagnosis, n	169, 134, 22	16, 8, 1	153, 126, 21	0.44
PR3-ANCA positive^a, n (%)	158 (52)	11 (48)	147 (52)	0.70
MPO-ANCA positive^b, n (%)	138 (45)	13 (52)	125 (44)	0.45
Organ involvement at AAV diagnosis, n (%)
General	247 (76)	19 (76)	228 (76)	1.00
Cutaneous	28 (9)	2 (8)	26 (9)	0.90
Mucous membranes/eyes	24 (7)	3 (12)	21 (7)	0.35
ENT	149 (46)	14 (56)	135 (45)	0.28
Cardiovascular	15 (5)	0 0	15 (5)	0.61
Abdominal	18 (6)	0 0	15 (6)	0.39
Chest	164 (51)	16 (64)	148 (49)	0.15
Renal	218 (67)	15 (60)	203 (68)	0.43
Nervous system	36 (11)	5 (20)	31 (10)	0.13
Laboratory data at diagnosis
S-creatinine, μmol/l, median (IQR)	134 (74–304)	115 (80–410)	135 (73–293)	0.68
Haemoglobin, g/l, mean (S.D.)	110 (19)	111 (20)	110 (19)	0.76
White blood cell count, × 10⁹, mean (S.D.)	13 (4.9)	15 (4.9)	13 (5)	0.25
Platelet count, × 10⁹/l, mean (S.D.)	372 (145)	419 (182)	367 (141)	0.09
CRP, mg/l, median (IQR)	79 (23–134)	99 (26–36)	77 (22–135)	0.71
ESR, mm/h, mean (S.D.)	64 (33)	61 (42)	64 (33)	0.75
BVAS at diagnosis, mean (S.D.)	15 (6)	16 (7)	15 (6)	0.14
VDI at 12 months, median (IQR)	1 (0–2)	2 (0–3)	1 (0–2)	0.34
ESKD, n (%)	51 (16)	5 (20)	46 (15)	0.53
Deaths, n (%)	143 (44)	13 (52)	130 (43)	0.40

^aResults available for 308 patients.
^bResults available for 309 patients.
AAV: ANCA-associated vasculitis; GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis; EGPA: eosinophil granulomatosis with polyangiitis; PR3: proteinase 3; MPO: myeloperoxidase; SD: standard deviation; ENT: ear-nose-throat; IQR: interquartile range; CRP: c-reactive protein; ESR: erythrocyte sedimentation rate; BVAS: Birmingham Vasculitis Activity Score; VDI: vasculitis damage index; ESKD: end stage kidney disease.

Table 2. Incidence rate of stroke in 325 patients with AAV
Time of follow-up	Events, n	Person-years	Incidence/1000 person-years	95% CI
0–3 months	6	76	78.5	15.7, 141.4
4–6 months	0	72	0	0.0, 0.0
7–12 months	1	144	7.0	0.0, 20.6
2 years	2	259	7.7	0.0, 18.4
3–5 years	6	617	9.7	1.9, 17.5
6–10 years	7	654	10.7	2.8, 18.6
10 years–end of follow-up	3	380	7.9	0.0, 16.8
Entire follow-up	25	2206	11.3	7.6, 16.7

Follow-up: time from diagnosis of AAV to stroke, death or end of study (31 December 2018).

Table 3. Incidence rate of stroke in AAV with respect to age group at diagnosis
Age category (years)	Events, n	Person-years	Incidence/1000 person-years	95% CI
<50	3	572	5.2	0, 11.2
50–59	1	363	2.8	0, 8.2
60–69	8	491	16.3	5.0, 27.6
70–79	7	562	12.5	3.2, 21.7
≥80	6	218	27.6	5.5, 49.6

Table 4. SIR of stroke in AAV
Variables	Observed	Expected	SIR	95% CI
All patients	33	17.86	1.85	1.27, 2.59
Age <65 years	10	3.13	3.19	1.53, 5.88
Age >65 years	23	14.74	1.56	0.99, 2.34
MPO-ANCA positive	15	8.10	1.85	1.04, 3.05
PR3-ANCA positive	17	8.68	1.96	1.14, 3.14
GPA	14	9.92	1.41	0.77, 2.37
MPA	16	7.35	2.18	1.24, 3.54

CI: confidence interval; MPO: myeloperoxidase; PR3: proteinase 3; GPA: granulomatosis with polyangiitis; MPA: microscopic polyangiitis.

Table 5. Cox regression analysis of predictors of stroke in 325 patients with AAV
Potential predictors	Univariate analysis			Multivariate analysis
Potential predictors	HR	95% CI	P-value	HR	95% CI	P-value
Age at AAV diagnosis^a	1.36	1.01, 1.85	0.04	1.30	0.94, 1.80	0.10
ANCA: MPO⁺ (reference PR3⁺)	1.50	0.67, 3.36	0.31	2.26	0.92, 5.56	0.07
Female (reference male)	0.82	0.37, 1.81	0.63	0.62	0.26, 1.51	0.29
Serum creatinine at diagnosis^b	1.14	1.00, 1.29	0.05	–	–	–
Platelet count^c	1.08	0.96, 1.23	0.17	1.14	1.00, 1.29	0.04
BVAS
Quartile 1 (2–10)	1.00
Quartile 2 (11–14)	0.29	0.06, 1.42	0.12	0.30	0.60, 1.31	0.14
Quartile 3 (15–17)	0.72	0.21, 2.49	0.61	0.84	0.23, 3.05	0.79
Quartile 4 (18–32)	1.61	0.62, 4.18	0.32	1.66	0.59, 4.70	0.33

^aAge at diagnosis in 10 year increments.
^bSerum creatinine in 100 μmol/l increments.
^cPlatelet increase increment of 50 × 10⁹/l.
HR: hazard ratio; CI: confidence interval; MPA: microscopic polyangiitis; ANCA: anti-neutrophil cytoplasmic antibodies; MPO: myeloperoxidase; BVAS: Birmingham vasculitis activity score.