Dermatologica Sinica

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 37  |  Issue : 2  |  Page : 67--71

The role and relationship of the serum D-dimer level and autologous serum skin test response in chronic spontaneous urticaria


Bok Won Park, Ye Ji Jang, Eun Byul Cho, Eun Joo Park, Kwang Ho Kim, Kwang Joong Kim 
 Department of Dermatology, College of Medicine, Hallym University, Anyang, Korea

Correspondence Address:
Dr. Eun Joo Park
Department of Dermatology, Hallym University Sacred Heart Hospital, 22, Gwanpyeong-ro 170 Beon-gil, Dongan-gu, Anyang, Gyeonggi-do, 431-796
Korea

Abstract

Background: The severity of chronic urticaria (CU) may be associated with the D-dimer level, and CU patients often have other autoimmune disorders. The autologous serum skin test (ASST) is believed to identify autoimmune/autoreactive diseases in CU patients. Aim: This study evaluated whether the levels of D-dimer, total immunoglobulin E (IgE), and autoimmune markers, such as antithyroid peroxidase (TPO) and antithyroglobulin (TG), differ between ASST-positive and ASST-negative patients among CU patients. In addition, the study assessed whether these laboratory findings were related to CU severity. Methods: The study enrolled 54 adults with CU (16 ASST positive, 38 ASST negative). D-dimer, total IgE, autoimmune marker (anti-TPO and anti-TG), and thyroid hormone levels and the urticaria activity score (UAS) were measured. Results: The levels of D-dimer, total IgE, anti-TPO, and anti-TG and the thyroid function test result showed no difference between the ASST-positive and ASST-negative groups. The UAS was higher in the ASST-positive group than in the ASST-negative group, but the ASST-positive group showed a better treatment response. The UAS was higher in patients with an elevated D-dimer level than in those with a normal level. Total IgE was related to the UAS in only the ASST-negative group, and anti-TPO and anti-TG levels were not related to the UAS. Conclusions: There were no associations between the ASST response and the D-dimer level, total IgE level, thyroid function test results, and thyroid autoantibody levels. However, our findings suggest that the ASST response, D-dimer level, and total IgE level are potential predictors of CU severity.



How to cite this article:
Park BW, Jang YJ, Cho EB, Park EJ, Kim KH, Kim KJ. The role and relationship of the serum D-dimer level and autologous serum skin test response in chronic spontaneous urticaria.Dermatol Sin 2019;37:67-71


How to cite this URL:
Park BW, Jang YJ, Cho EB, Park EJ, Kim KH, Kim KJ. The role and relationship of the serum D-dimer level and autologous serum skin test response in chronic spontaneous urticaria. Dermatol Sin [serial online] 2019 [cited 2019 Sep 15 ];37:67-71
Available from: http://www.dermsinica.org/text.asp?2019/37/2/67/258932


Full Text



 Introduction



Chronic idiopathic urticaria is a disease in which wheals occur, recur, and persist for over 6 weeks with or without angioedema.[1] The term “autoimmune urticaria” was proposed after the detection of circulating autoantibodies in 25%–35% of patients with chronic idiopathic urticaria.[2],[3] These autoantibodies are believed to influence the severity and duration of the disease, and clinical symptoms may be more severe in patients with chronic urticaria (CU) who carry autoantibodies than in those without autoantibodies.[4],[5],[6] The autologous serum skin test (ASST) is a simple assessment that can be used to detect these autoantibodies. The test can be easily performed on outpatients, and the results can be quickly interpreted.

It has been reported that the coagulation cascade is activated in the pathomechanism of CU, and many studies have assessed the relationship between plasma markers produced during the activation of the coagulation cascade, such as D-dimer, and the severity of urticaria.[7],[8],[9],[10]

There have been relatively consistent reports on the increased frequency of autoimmune diseases in CU patients,[11],[12] and autoimmune markers, such as antithyroid peroxidase (TPO) and antithyroglobulin (TG) antibodies, are believed to help in the diagnosis of CU.[13] However, little is known about the relationship between the ASST response and autoimmune markers. A previous study reported that there was no association between immunoglobulin E (IgE)–anti-TPO antibodies and the ASST response.[14]

In addition, no prospective study has investigated the correlations of the ASST response with D-dimer and autoimmune markers in CU patients. The present study prospectively investigated whether there were differences in D-dimer, total IgE, thyroid function, and thyroid autoimmune levels between ASST-positive and ASST-negative patients among CU patients. In addition, the study assessed whether correlations were present among the obtained measurements, clinical severity, and treatment response.

 Methods



Study subjects

The present study prospectively enrolled 54 patients who were diagnosed with CU. Patients were diagnosed with CU if they had continuous or recurrent wheals accompanied or not accompanied by angioedema for over 6 weeks. The study only included patients whose condition was not associated with causal factors, such as drugs, food, and infections, or with increased levels of specific IgE. Patients who used immunosuppressants, including corticosteroids, in the last 2 months or used antihistamines in the last 3 days were excluded from the study. All patients underwent the ASST and were divided into a chronic autoimmune urticaria group (ASST-positive group; n = 16) and a chronic idiopathic urticaria group (ASST-negative group; n = 38). Blood sampling was simultaneously performed, and blood test parameters, including the levels of D-dimer, total IgE, and thyroid test factors (e.g., T3, free T4, thyroid-stimulating hormone, anti-TPO, and anti-TG), were measured. All patients had active urticaria at the time of sample collection. Disease severity was measured using the urticaria activity score (UAS) questionnaire.[15] All patients provided informed consent for the study procedures, and the study was approved by the institutional review board (approval number: 2014-I018).

Autologous serum skin test

Over 5 mL of venous blood was collected from each patient, and the blood sample was allowed to clot for 30 min at room temperature. Serum was separated by centrifugation. Two 0.05-mL samples of autologous serum and 0.05 mL of normal saline were prepared and were intradermally injected into the forearm at 5-cm intervals using an insulin syringe. Next, 0.05 mL of histamine (10 μg/mL) was injected at a 5-cm interval as a positive control. The wheal-and-flare response and saline-induced response were assessed. The result was considered positive if the wheal-and-flare response was observed 30 min later and if the wheal-and-flare response was greater than the saline-induced response by 1.5 mm or more.

Urticaria activity score

In all patients, disease activity was determined using the UAS7, which evaluates disease severity over 7 consecutive days. Patients recorded the number of wheals and the severity of pruritus daily throughout the week after the first visit. As each patient could score a maximum of 6 points per day and scores were recorded for 7 days, the total score ranged from 0 to 42 points. The details of the UAS are provided in [Table 1].{Table 1}

Follow-up

The patients were followed up and checked for improvements at 3 and 6 months after the initial examination. The patients were treated by oral antihistamine. Patients who need more excessive pharmacotherapy such as systemic corticosteroid or cyclosporine were excluded from the study. Improvements observed over the 6 months of follow-up were considered to indicate remission or well-controlled CU. Remission was defined as no urticaria symptoms, even in the absence of pharmacotherapy, and well-controlled CU was defined as no urticaria symptoms, such as wheals and itching, while undergoing pharmacotherapy. Patients who did not experience improvements were categorized into a partly controlled group and an uncontrolled group. The partly controlled group included patients who showed symptom improvement after drug administration but intermittently showed symptoms. The uncontrolled group included patients whose symptoms did not improve or worsened after pharmacotherapy.

Statistical analysis

Proportions were compared using the Chi-square test or Fisher's exact test. Means were compared using the independent t-test or Mann–Whitney U-test. Correlations between disease severity and laboratory findings were assessed using the Pearson correlation analysis. All statistical analyses were performed using SPSS, version 12.0 (SPSS Inc., Chicago, IL, USA). P  0.05 was considered statistically significant.

 Results



Patients' demographic characteristics; D-dimer, total IgE, and thyroid autoantibody levels; thyroid function test results; and UAS results, according to the ASST response, are shown in [Table 2]. No significant differences in the D-dimer level, total IgE level, thyroid function test result, and thyroid autoantibody levels were found between the ASST-positive and ASST-negative groups. On the other hand, the mean UAS was significantly higher in the ASST-positive group than in the ASST-negative group.{Table 2}

The CU patients were further categorized into an elevated D-dimer group (D-dimer level >0.5 μg/mL) and a normal D-dimer group (D-dimer level <0.5 μg/mL). The UAS was significantly higher in the elevated D-dimer group than in the normal D-dimer group [Table 3].{Table 3}

Pearson correlation analysis revealed that there were no statistically significant correlations between the UAS and total IgE, T3, free T4, thyroid-stimulating hormone, anti-TPO, and anti-TG levels. However, when analyses were performed after dichotomizing patients according to the ASST response, the total IgE level and UAS showed a significant positive correlation in only the ASST-negative group (r = 0.509, P = 0.031).

Patients in the ASST-positive and ASST-negative groups were checked for improvements in the response to antihistamine treatment during the 6-month follow-up. Improvements were observed in a greater proportion of patients from the ASST-positive group than from the ASST-negative group. Prognosis was better in the ASST-positive group than in the ASST-negative group (odds ratio = 7.6, P = 0.01) [Table 4].{Table 4}

 Discussion



In the present study, although we anticipated a synergistic relationship between the activation of the coagulation cascade and serum autoantibody would exist, no correlation was found between the ASST response and D-dimer level. Two studies compared the coagulation cascade between CU patients and controls and found that the coagulation cascade was more activated in the autologous plasma skin test (ASPT)-positive and ASPT-negative groups than in the control group.[10],[16] One study[10] revealed that coagulation markers such as D-dimer and F1+2 level are slightly more elevated in ASPT-positive patient than ASPT-negative group. The other study[16] revealed that D-dimer level showed no difference between ASPT-positive and ASPT-negative group. Regarding those inconsistent results, the relationship between the presence of autoreactive antibody and the activation of coagulation cascade is controversial. However, the result of our study suggests that the coagulation system may be activated in CU patients, regardless of the disease subset. The D-dimer level may not be associated with the pathogenic mechanism of autologous plasma. Moreover, other wheal-inducing factors may cause a false-positive result in the ASST.[17] Additional research on the correlation between circulating autoantibodies, which may play an important role in the pathomechanism of CU, and the coagulation pathway is necessary.

Studies have consistently reported on the correlation between CU and other autoimmune diseases, particularly autoimmune thyroid disease.[13] However, autoimmune antibodies (e.g., anti-TPO and anti-TG) were not correlated with the ASST response in CU patients in this study. This finding is consistent with the findings in some previous studies.[14],[18] In addition, the disease severity (UAS) was greater in the ASST-positive group than in the ASST-negative group. Although numerous studies have reported a higher incidence and range of wheals and a greater need for medications, such as antihistamines, in ASST-positive patients,[5],[6],[13] some studies have reported no difference in disease severity, disease duration, and quality of life between ASST-positive and ASST-negative patients.[19],[20] Although the association between ASST results and disease severity is unclear, the results of the present study support the notion that ASST results and disease severity are related.

With regard to prognosis, the treatment response was better in the ASST-positive group than in the ASST-negative group. Although there is no consensus regarding the relationship between ASST results and prognosis, it has been reported that ASST-positive patients show a good treatment response to antihistamines and thus have a better prognosis.[21] The relation of serum factors with the disease course is not known. However, in ASST-positive patients, serum factors facilitated the release of histamine and vasodilators, and as histamine plays an important role in the pathogenesis, antihistamine treatment will cause a positive response. On the other hand, in ASST-negative patients, other inflammatory factors and lower levels of histamine are involved in the pathogenesis of CU, and thus, these patients do not respond well to antihistamine treatment. Therefore, although ASST-positive patients may experience more severe symptoms, they respond better to antihistamine treatment. Further research on the severity and long-term prognosis of ASST reactivity and CU is necessary.

Disease severity was significantly higher in the group with elevated D-dimer levels than in the group with normal D-dimer levels. Although it has recently been reported that D-dimer is associated with disease severity,[9] the mechanism responsible for this relationship is unclear. A series of studies by Asero et al.[7],[8],[9],[10] revealed that the relationship between CU and the coagulation cascade is attributed to eosinophil infiltration and hyperexpression of tissue factors by eosinophils in skin lesions of CU patients. Therefore, prothrombin is activated to thrombin by tissue factors in CU patients.[8],[22] Thrombin activates mast cells and increases vascular permeability.[23] During this process, F1+2 is generated, and thrombin converts fibrinogen to fibrin, and fibrin is subsequently degraded by plasmin to produce fibrin degradation products and D-dimer.[24] Therefore, these biomarkers could be used for assessment of the severity of the CU. However, studies are needed to investigate whether this phenomenon is the cause of CU or is merely an amplification system.

The ASST-negative group showed a significant positive correlation between the total IgE level and UAS. Total IgE has been reported to be associated with CU severity,[25] possibly because of its role in mast cell activation and degranulation. In this study, although the total IgE level and disease severity were not associated in CU patients, the total IgE level and UAS were positively correlated in the ASST-negative group. This finding suggests that total IgE plays different roles in the pathogenesis of CU, depending on the presence of circulating autoantibodies. However, the exact mechanism is unknown.

The present study has some limitations. The study had a single-center design and a relatively small sample size. As the laboratory markers were not repeatedly measured, it was difficult to accurately assess changes in serum markers. Furthermore, markers that reflect the coagulation cascade, such as fibrin degradation products and F1+2, were not assessed in this study. Despite these limitations, this study was meaningful in that it prospectively investigated the association of laboratory markers with the ASST response and disease severity instead of using a retrospective approach, which has been commonly adopted in previous studies. Furthermore, this study is significant, as few studies have examined the association between D-dimer and the ASST response, although they have been extensively investigated in relation to the mechanism of CU.

 Conclusions



There were no associations between the ASST response and the D-dimer level, total IgE level, thyroid function test results, and thyroid autoantibody levels. Although ASST-positive patients showed a higher disease severity, they had a better treatment response. In addition, elevated D-dimer levels were associated with a higher disease severity, and the total IgE level and disease severity were positively correlated in ASST-negative patients. Therefore, the ASST response, D-dimer level, and total IgE level may be considered as potential predictors of CU severity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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