Incidence of thromboembolic events in patients with a systemic form of vasculitis and cutaneous vasculitis

Abstract

Objectives: Vasculitis is a rare disease characterized by inflammation and necrosis of blood vessels. Inflammation-induced thrombosis is a hallmark of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), and systemic vasculitis. In this study, we aimed to investigate the frequency of thromboembolic (TE) events in the systemic form of vasculitis and cutaneous vasculitis and to determine the possible risk factors for developing thromboembolic events. Methods: In this single-centre retrospective study, the patients diagnosed with systemic vasculitis and cutaneous leukocytoclastic vasculitis were included. Medical records of the patients that were treated at the Division of Rheumatology, Clinical Immunology, and Allergology University Hospital Centre Osijek in the period of 30 months (from November 2016. to June 2019.) were analysed. Results: Out of a total of 46 patients who were included in the study, 30 were diagnosed with systemic vasculitis, and 16 with cutaneous vasculitis. Statistically significant differences in relation to gender were found between the two groups (systemic vasculitis vs cutaneous vasculitis: the female gender 76.67% vs 43.75%; p=0.026), but there was no difference between the groups in relation to the age of disease onset. Thromboembolic events were found to be more frequent in the systemic form of the disease (p=0.0321). In the systemic vasculitis group, TE events were found in patients who suffered from involvement of multiple organ systems and in younger patients. Conclusion: Our research found that patients with systemic vasculitis, who are younger, with high disease activity, and who suffered from the involvement of multiple organ system, have an increased risk for developing TE events. In those patients, special attention should be paid to searching for additional TE risk factors, such as genetics, for the purpose of preventing unwanted events and applying TE prophylaxis on time.

Keywords: Systemic vasculitis, cutaneous leukocytoclastic vasculitis, thromboembolism

Introduction

Vasculitis is a rare disease characterized by inflammation and necrosis of blood vessels. Inflammation-induced thrombosis is a hallmark of several autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), and systemic vasculitis (2,3). The incidence of thromboembolic (TE) events is an important clinical manifestation of systemic vasculitis. The reason for this incidence is due to the pathomechanism of the disease and it is also related to the pathogenesis of thrombosis (2–6).

Previous research has led to gaining new insights about the prothrombotic effect of systemic inflammation in vasculitis. In the pathophysiology of thrombosis in Behçet’s syndrome (BS), a generalized disorder of CD4+ lymphocytes, monocytes, neutrophils is observed, as well as an increased production of pro-inflammatory cytokines such as interferon gamma (IFN -γ), tumour necrosis factor alpha, TNF -α), interleukin-1 (IL-1), IL-6, IL-8, IL-12 which causes the occurrence of the prothrombotic state (2). The incidence of TE events in vasculitis associated with antineutrophil cytoplasmic autoantibodies (ANCA) and large-vessel vasculitis has been confirmed (1,2). The highest frequency of ANCA-associated vasculitis occurs in eosinophilic granulomatosis with polyangiitis (EGPA) (1, 7, 8). One of the possible reasons is the role of eosinophils in the release of major basic protein as well as eosinophil cationic protein, which inhibit natural anticoagulant activity and activate platelets, leading to increased thrombin generation (1, 2). Endothelial dysfunction is also a characteristic of ANCA-associated vasculitis and is most likely caused by the interaction between neutrophils (activated by TNF -α and ANCA antibodies) and endothelial cells, with consequent massive oxidative stress leading to atherothrombotic complications (1, 2, 8–11).

In large-vessel vasculitis, anti-endothelial cell antibodies play a possible role in endothelial damage (12,13). One of the possible vascular complications is the development of aneurysms as a consequence of inflammatory damage (12, 13). Reshaping of the blood vessel wall begins in the adventitia with an infiltrate consisting mainly of auxiliary lymphocytes (T-helper cells, Th) Th1 /Th17 that activate residual dendritic cells and macrophages, which produce pro-inflammatory cytokines and growth factor that causes intimal hyperplasia (12, 13, 14, 15). The objective of this paper was to compare the incidence of TE events in systemic vasculitis and localized cutaneous vasculitis and to determine the possible risk factors for the development of TE events on a sample of patients in a tertiary care rheumatology centre.

Subjects and methods

In this research, a retrospective, systematic analysis and comparison of two groups of patients diagnosed with systemic vasculitis and cutaneous vasculitis are carried out, in order to determine the incidence of TE events in each group. The inclusion criterion for the study was the diagnosis of primary vasculitis according to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasulitides (16) set by a rheumatologist/immunologist, and the exclusion criterion was the occurrence of another inflammatory rheumatic disease, malignant disease or proven infection at the time of diagnosis. 46 patients with diagnosed systemic vasculitis and cutaneous vasculitis, who were treated at the University Hospital Centre Osijek during a period of 30 months (from November 2016 to June 2019) were included in the study. Retrograde assessment was used to determine disease activity in patients with systemic vasculitis by using medical records according to the Birmingham Vasculitis Activity Score (BVAS). Data from the patient’s medical history and clinical status at the time of diagnosis were analysed in relation to the incidence and type of cutaneous manifestations and manifestations on visible mucous membranes, muscle involvement, symptoms related to the respiratory and cardiovascular systems, neurological symptoms and symptoms of gastrointestinal system involvement, as well as laboratory findings (including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), detection of nitrogen-containing metabolites, etc.) in addition to various imaging methods that were performed depending on the symptoms (e.g. echocardiogram, multislice computed tomography (MSCT) of the thorax and abdomen, positron emission tomography / computed tomography (PET/CT), electromyography, etc.). The data were collected from the available medical documentation of the Division of Rheumatology, Clinical Immunology and Allergology at the University Hospital Centre Osijek (outpatient clinics, day hospitals and inpatient facilities). The research was conducted in accordance with the ethical standards of the institution and with the International Code of Medical Ethics of the World Medical Association (1964 Declaration of Helsinki and its updated versions) (17) with the approval of the institution’s Ethics Committee (approval no. R2-13170/2020).

In terms of statistical methods for testing the difference in distributions for two variables, the Mann-Whitney test was used. Chi-squared test and Fisher’s exact test were used to test the dependence between two categorical variables. The threshold value for the significance of the difference was set at p<0.05.

Results

Out of a total of 46 patients, 30 were diagnosed with systemic vasculitis, and 16 with cutaneous vasculitis. Statistically significant differences in relation to gender were found between the two groups (systemic vasculitis vs cutaneous vasculitis: the female gender 76.67% vs 43.75%; p=0.026), but there was no difference between the groups in relation to the age of disease onset. A total of 5 TE events were recorded, 2 of which were a case of deep vein thrombosis, 1 was a case of arterial thrombosis, 1 was a case of pulmonary embolism and 1 was a case of cerebrovascular insult. TE events occurred more often in patients with systemic vasculitis (16.67% vs 0%; p=0.032). (Table 1). When analysing patients with systemic vasculitis, it became apparent that TE events occurred in those who suffered from the involvement of multiple organ systems (4 vs 3; p=0.0425) and in those patients who were younger (47 vs 65 years of age, p=0.018). No difference was found in relation to BVAS in the two groups of patients (19 vs 12, p=0.169) (Table 2). Distribution of patients by gender, age and occurrence of thromboembolic events (TE) according to the basic diagnosis is presented in Table 3. All patients who experienced a TE event were diagnosed with hereditary thrombophilia, which is defined by the lack of antithrombin, protein C, protein S, and mutation of factor V Leiden and prothrombin variants.

Discussion

In our research, we analysed patients with systemic vasculitis and cutaneous vasculitis. Between the two groups, the incidence of TE events was exclusively characteristic of patients with systemic vasculitis.

According to the data published so far in the literature, when it comes to vasculitis, the incidence of TE events in Behçet’s syndrome is the most frequently researched topic, in addition to the incidence of venous thromboembolism and arterial thrombosis (2, 18–20). According to our results, in accordance with previous knowledge, in one patient, who is also the only one diagnosed with Behçet’s syndrome during that period, a TE event was determined as the outcome of an active disease.

In their retrospective cohort study, Kang et al. studied the incidence of TE events in patients with ANCA-associated vasculitis and demonstrated an increased incidence of TE events in comparison to the reported rates of the general population of UK, especially in the first year of diagnosis, which they associate with disease activity or with treatment (21). In our research, TE events occurred in those patients who suffered from multiple organ systems involvement and in patients who were younger. Similar observations were published by Salmela et al. in their observational study in which they demonstrated increased D-dimer values during active disease in ANCA-associated vasculitis, and in correlation with BVAS, they suggested that activation of coagulation is associated with ANCA-associated vasculitis which involves multiple organ systems (22). A similar study from the Netherlands reported an incidence of venous TE events of 1.8 per 100 person-years, increasing to 6.7 per 100 person-years during active disease, which was characterized by a time interval of two months before and after diagnosis, or relapse in patients with ANCA-associated vasculitis, excluding eosinophilic granulomatosis with polyangiitis (EGPA) (3). The data from that study confirm that active disease is a risk factor for the incidence of TE events (3). According to a study conducted in 2007 by Stassen et al., they found that the risk of developing venous TE events in ANCA-associated vasculitis is increased, especially in active disease, which they associated with endothelial dysfunction and hypercoagulability (5). The results of the 2017 Kronbichler report highlight the role of C-reactive protein, baseline creatinine, cutaneous and gastrointestinal involvement in risk stratification associated with thromboembolic events (23).

In a 2016 meta-analysis, Ungprasert and Koster showed a significantly increased risk of venous TE events in patients suffering from granulomatosis with polyangiitis (GPA), polyarteritis nodosa (PAN) and giant cell arteritis (GCA) (6). They also showed that the frequency of hereditary thrombophilia is not increased in patients with GPA and GCA and that it is not a risk factor in the incidence of TE (6). In our study, genetic diagnosis of hereditary thrombophilia was not performed routinely in all patients, but only in patients with a proven TE event. Given that the results of our research showed an increased TE event in patients with high disease activity, hereditary haemophilia was an additional factor that contributed to the development of thrombosis in patients with a more severe clinical features with involvement of multiple organ systems.

Hereditary thrombophilia is a known factor in the incidence of venous thromboembolism in the general population (24, 25, 26). In their research, Sebastian et al. proved that the prevalence of cardiolipin antibodies as a prothrombin gene mutation (PGM) and methylenetetrahydrofolate reductase mutation (MTHFR) is not higher in patients with GPA in comparison to the general population, and they proved that the increased risk of TE events is not explained by the increased prevalence of anticardiolipin antibodies (aCL), anti-beta-2-glycoproteins or PGM and MTHFR mutations (26). In their paper, Espinosa et al. proved that patients with GCA have a high prevalence of antiphospholipid antibodies (aPL) which is not related to ischemic manifestations and that ischemic manifestations in GCA patients are not related to congenital thrombophilic risk factors (27).

The ageing process in humans is accompanied by changes in the coagulation system and thereby the risk of thrombosis is increased in older people (24). Concentrations of coagulation factors such as factor V, factor VII, factor VII, factor IX and fibrinogen gradually increase with age (24, 28). In our study, thromboembolic events occurred in younger patients, and a possible explanation for this lies in the increased activity of the disease and involvement of multiple organ systems in younger patients in comparison to the older population.

In our study, not a single thromboembolic event was recorded in patients with cutaneous vasculitis. By researching the available literature, no study was found that would compare the incidence of thromboembolic events in patients with cutaneous vasculitis. To our knowledge, we are the first to report an increased risk of thromboembolic events in systemic vasculitides compared to cutaneous vasculitides, so we were unable to compare our results to results from other studies.

The limitation of this research study is the small sample of subjects, considering that it is a study of a disease with a low incidence conducted in one hospital centre. Therefore, it would be preferable to expand it in the future by including more centres in the study. In addition to that, another limitation of this study is that it is a retrospective study. Also, considering that the genetic diagnosis of hereditary thrombophilia was performed only in patients with a proven TE event, so in future trials it would be necessary to determine the frequency of hereditary thrombophilia in all subjects.

Conclusion

Our research shows that younger patients with systemic vasculitis, high disease activity and involvement of multiple organ systems have an increased risk of thromboembolic events. The results of our research may have several clinical implications for the treatment of systemic vasculitis, and the most important objective of this research is to increase awareness of the risks for TE development. In addition to that, the objective is to propagate the performance of additional clinical trials in order to determine the need for the introduction of prophylactic anticoagulant and/or antiplatelet therapy for the prevention of TE event development.

Conflict of interest statement: The authors declare no conflict of interest

REFERENCES / Literatura

17. Cantín M. World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human subjects. Reviewing the Latest Version. International Journal of Medical and Surgical Sciences. 2018;1(4):339–46.

Table 1 Comparison of the main features of interest to a group of patients with systemic vasculitis and cutaneous vaculitis

Tablica 1. Usporedba glavnih obilježja od interesa skupine bolesnika sa sistemskim vaskulitisom i vaskulitisom ograničenim na kožu

P < 0.05

Table 2 Features of patients with Systemic Vasculitis

Tablica 2. Osobitosti bolesnika sa sistemskim vaskulitisom

P < 0.05; BVAS – Birmingham Vasculitis Activity Score

Table 3 Distribution of patients by gender, age and occurrence of thromboembolic events (TE) according to the basic diagnosis

Tablica 3. Raspodjela bolesnika po spolu i dobi i pojavnosti tromboembolijskih događaja (TE) s obzirom na osnovnu dijagnozu

GPA – granulomatosis with polyangiitis / granulomatoza s poliangiitisom; EGPA – eosinophilic granulomatosis with polyangiitis / eozinoflina granulomatoza s poliangiitisom; GCA – giant cell arteritis / gigantoceulularni arteritis; MPA – microscopic polyangiitis / mikroskopski poliangitis