Acute phase reactant proteins in Buerger’s disease: Is it a systemic disease?

Abstract

Aim: The aim of this study was evaluating acute phase reactant (APR) proteins including high sensitivity C-reactive protein (hsCRP), pentraxin 3 (PTX3), fibrinogen, complement C3, hepcidin, and albumin in patients suffering from Buerger’s disease (BD) compared to controls.

Methods: The APRs were evaluated in 92 cases of BD patients and 90 healthy age and sex matched controls of blood from Iran and Turkey. The diagnosis was done according to Shionoya’s criteria. However, patients with age less than 40 were included, instead of those less than 50. The diagnosis was confirmed by angiography or CT angiography. The patients were categorized into active and quiescent phases of the disease according to clinical manifestation. Patients with rest pain, non-healing ulcer, and gangrene were categorized in the active phase of the disease and the patients with unchanged claudication for more than 6 months without trophic lesions or gangrene were categorized in the quiescent phase of the disease.

Results: The serum level of PTX3, hsCRP, fibrinogen, C3, and hepcidin in BD was significantly higher than controls (p < 0.004). Also, albumin in the BD group was significantly lower than controls (p < 0.001). In patients that categorized in the active phase, fibrinogen, C3, and hsCRP were significantly higher and albumin was significantly lower compared to patients in the quiescent phase. No significant difference was found between the level of PTX3 and hepcidin in the patients in active and quiescent phases of the disease.

Conclusion: The pattern of the level of APRs in BD seems more likely systemic inflammatory disorder than atherosclerosis obliterans. More clinical trials for evaluating the efficacy of anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids as a part of management of BD are required. Also, according to low level of albumin in TAO, a protein rich diet might be beneficial for BD patients in the active phase of their disease.

Keywords

Thromboangiitis obliterans Buerger’s disease pentraxin 3 vasculitis C-reactive protein hepcidin fibrinogen albumin complement C3 acute phase reactant proteins peripheral arterial disease

Introduction

Thromboangiitis obliterans or Buerger’s disease (BD) is an episodic, inflammatory, non-atherosclerotic peripheral vascular disease usually seen in young male smokers. Buerger’s disease is more prevalent in the Middle East, the Far East, Southeast Asia, and Eastern Europe.¹ Its etiology has been remained unknown, and it is not known yet whether BD is a systemic vasculitis or localized vasculopathy. Therefore, the management of BD remained challenging.²

Although, infiltration of inflammatory cells in the medium- and small-sized vessels of the BD has been reported, its management is more like arteriosclerosis obliterans rather than vasculitis.³ BD patients are usually referred to vascular surgeons rather than to rheumatologists. Therefore, studies on vascular and endovascular interventions of BD patients outnumber the studies of medical management or use of immunomodulatory agents for BD.⁴

Several studies have suggested that raised erythrocyte sedimentation rate or high CRP rules out BD.⁵ Recently, high CRP has been reported in BD patients with chronic ulcers or gangrene.⁶ However, considering BD a systemic inflammatory vasculitis or a localized vasculopathy has remained challenging.^4,7 Therefore, studying the systemic inflammation in BD patients by measuring the acute phase reactant proteins (APRs) can give a good perspective on the inflammatory nature of BD. The aim of this study was evaluating the APRs as the markers of systemic inflammation in BD patients with different clinical manifestation compared to controls.

Methods

Data on APRs level of 92 cases of BD patients from Iran and Turkey and 90 healthy age- and sex-matched controls from November of 2018 to December 2019, before the COVID pandemic started, were gathered and evaluated.

From APRs, the data for hsCRP, long pentraxin (PTX3), fibrinogen, complement C3, hepcidin, and albumin was available from the patients and controls.

The included patients matched Shionoya’s criteria,⁸ but the upper limit of the age of disease onset for including these patients was reduced from 50 to 40 years. Also, the diagnosis of included patients was confirmed by angiography or CT angiography.

The patients were categorized into active and quiescent phases of the disease according to clinical manifestation. Patients with rest pain, non-healing ulcer, and gangrene were categorized in the active phase of the disease and the patients with unchanged claudication for more than 6 months without trophic lesions or gangrene were categorized in the quiescent phase of the disease.

Also, any evidence of superficial thrombophlebitis at the visit or its history within the past 6 months of the visit was considered as an exclusion criterion of this study. In addition, for better investigation, patients with suspected infections, tumors caused by smoking, or other systemic immune conditions were excluded from the study.

Ethical code for patient from Iran was IR.MUMS.MEDICAL.REC.1399.186 and for the patients from Turkey was ALKU-KAEK 2019.8.2.

Results

The demographic data of the patients are summarized in Table 1.

Table 1.

The demographic data of the BD patients. All of the patients were male and Caucasian.

Variables	Unit	Mean ± SD	Maximum	Minimum
Age	Years	32.3 ± 7	47	29
Daily cigarette smoking	Cigarettes per day	18 ± 13	60	2
Duration of smoking	Years	21 ± 8	37	2
Duration of disease diagnosis	Years	7.7 ± 5.3	16	1

The CRP was positive in 51.4% of the samples of the BD group and in none of the controls. The hsCRP in BD and controls was 7.98 ± 1.26 μg/ml and 2.5 ± 1.02 μg/ml, respectively (normal range: >6.6 µg/ml). The hsCRP was significantly higher in BD patients in comparison to controls (p < 0.001).

The hsCRP in active and quiescent phases of BD was 10 ± 2.1 μg/ml and 4 ± 2.02 µg/ml, respectively. The hsCRP was significantly higher in the active phase of the disease (p = 0.045).

The mean serum level of albumin in BD and controls was 2.12 ± 0.67 g/dl and 3.65 ± 0.54 g/dl, respectively (normal range: 3.5–5.5 g/dl). The serum level of albumin in BD was significantly lower than controls (p < 0.001).

The serum level of albumin in active and quiescent phases of BD was 1.8 ± 0.54 g/mL and 4.4 ± 0.31 g/mL, respectively. Albumin was significantly lower in BD patients in the active phase of the disease (p < 0.001).

The mean serum level of fibrinogen in BD and controls was 6.95 ± 2.8 g/L and 2.62 ± 0.41 g/L, respectively (normal range: 2–4 g/L). The serum level of fibrinogen in BD was significantly higher than controls (p < 0.001).

The serum level of fibrinogen in active and quiescent phases of BD was 7.23 ± 1.7 ng/mL and 3.64 ± 1.52 g/L, respectively. Fibrinogen was significantly higher in the active phase of the disease (p < 0.001).

The mean serum level of PTX3 in BD and controls was 3.23 ± 1.2 ng/mL and 2.05 ± 1.02 ng/mL, respectively. The serum level of PTX3 in BD was significantly higher than controls (p = 0.004).

The serum level of PTX3 in active and quiescent phases of BD was 3.49 ± 0.96 ng/mL and 2.51 ± 1.6 ng/mL, respectively. No significant difference was found in PTX3 of active and quiescent phases of BD (p = 0.25).

The mean serum level of hepcidin in BD and controls was 43.86 ± 24.47 ng/mL and 19.2 ± 7.7 ng/mL, respectively (normal range: >55 ng/mL). The serum level of hepcidin in BD was significantly higher than controls (p < 0.001).

The serum level of hepcidin in active and quiescent phases of BD was 42.6 ± 36.4 ng/mL and 42.48 ± 14.4 ng/mL, respectively. No significant difference was found in hepcidin of active and quiescent phases of BD (p = 0.9).

Notably, no correlation between the level of hepcidin and hemoglobin was found in BD patients (CC: −0.19, p = 0.09) and no significant difference between the level of hepcidin in BD patients with and without anemia was demonstrated (p = 0.85).

The mean serum level of C3 in BD and controls was 189.84 ± 21.1 mg/dl, 97 ± 10.4 mg/dl, respectively (normal range: 90–180 mg/dl). The serum level of C3 in BD was significantly higher than controls (p = 0.019).

The serum level of C3 in active and quiescent phases of BD was 210.66 ± 27.8 mg/dl and 143 ± 18.5 mg/dl, respectively. C3 was significantly higher in BD patients in the active phase of the disease (p = 0.045).

Discussion

Until recently, BD diagnosis was made by ruling out atherosclerosis obliterans (ASO) and other vasculitis.⁹ Though infiltration of inflammatory cells in the walls of small- and medium-sized arteries and veins has been demonstrated in BD, it is still debated if BD is a systemic inflammatory disease.¹⁰ In particular, the vascular lesions in BD are segmental with preserved internal elastic lamina which differentiate it from other types of vasculitis.¹¹ This is probably why management of BD so far has been traditionally carried out as is done for ASO rather than looking at it as a manifestation of vasculitis. The long-term benefit from localized treatment with endovascular procedures, though quite successful in management of ASO, when applied to management of BD is still controversial.⁴

In this study, some common APRs as the markers of systemic inflammation including hsCRP, PTX3, fibrinogen, C3, hepcidin, and albumin were evaluated in reasonable sample size of BD patients from Iran and Turkey. Notably, hsCRP, PTX3, fibrinogen, C3, and hepcidin as positive APRs were significantly higher in BD patients than controls. Also, albumin levels were significantly lower in BD patients than controls. Therefore, based on the results, it can be assumed that there is a systemic inflammatory reaction in BD.¹² Also, hsCRP and fibrinogen were significantly higher, and albumin was significantly lower in the active phase of BD than in the quiescent phase, like other autoimmune or auto-inflammatory diseases.^13,14

The serum level of C3, as the key player component of complement pathways, was also significantly higher in BD patients than controls.¹⁵ The level of C3 is usually reduced in immune complex–mediated vasculitis such as lupus erythematosus.¹⁶ However, high level of C3 has been demonstrated in infection, infection-induced autoinflammatory diseases such as Behcet’s disease, cancers, and peripheral arterial diseases.^17-19 However, in contrast to our BD results, C3 level did not have any association with severity and progression of ASO.²⁰

Notably, albumin has an important role in preventing platelet aggregation with thromboxane synthase inhibition by enhancing the production of prostaglandin D2.²¹ Hence, low albumin along with high level of fibrinogen increases the risk of thrombosis.²² The low socio-economic level of BD patients and consequently poor nutrition may even lead to lower albumin level and a higher chance of thrombus formation.¹

Also, PTX3 as an inflammatory marker which is produced by several cells including endothelial cells, dendritic cells, macrophages, cardiomyocytes, and neutrophils²³ was evaluated in BD patients. Although PTX3 was significantly higher in BD patients than controls, it was not associated with disease activity. The results of PTX3 in BD were like those seen in some autoimmune-induced vasculitis such as Behcet’s disease.²⁴ Also, in contrast to BD, a significant association between the level of PTX3 and severity of ASO has been reported.²⁵

Moreover, the level of hepcidin was significantly higher in BD patients than controls, but like PTX3, it was not associated with disease activity and severity of the disease. As well as, the level of hepcidin was significantly higher in ASO patients than controls.²⁶ Although there is a lack of studies about the association between hepcidin and disease activity in ASO. In vasculitis, the association between the level of hepcidin and anemia has been demonstrated.²⁷ Notably, in this study, no correlation between hepcidin and anemia of BD patients was found.

Conclusion

Based on the results, it could be assumed that systemic inflammation plays an essential role in the pathogenesis of Buerger’s disease and BD is more like a vasculitis such as Behcet’s disease rather than ASO. Therefore, it seems that the treatment and management of BD needs rethinking and a revision. More clinical trials for evaluating the efficacy of anti-inflammatory medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), colchicine, and corticosteroids as a part of management of BD are required. Also, according to low level of albumin in TAO, a protein-rich diet might be beneficial for BD patients in the active phase of their disease.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Oguz Karahan

Bahare Fazeli

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