|Ahead of print
|Serum indoleamine 2,3-dioxygenase level and diagnostic value in patients with rosacea
Merve Sena Odabasi1, Serkan Yazici2, Guven Ozkaya3, Emel Bulbul Baskan2, Arzu Yilmaztepe Oral4
1 Department of Biochemistry, University of Health Sciences, Sisli Hamidiye Etfal Research and Training Hospital, Istanbul, Turkey
2 Department of Dermatology and Venereology, Faculty of Medicine, Uludağ University, Bursa, Turkey
3 Department of Biostatistic, Faculty of Medicine, Uludağ University, Bursa, Turkey
4 Department of Biochemistry, Faculty of Medicine, Uludağ University, Bursa, Turkey
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|Date of Submission||07-Apr-2022|
|Date of Decision||12-Nov-2022|
|Date of Acceptance||15-Nov-2022|
|Date of Web Publication||01-Feb-2023|
Background: Indoleamine 2,3-dioxygenase (IDO), an enzyme in the first step of tryptophan catabolism, plays a role in the pathogenesis of various malignancies and inflammatory diseases. Although its pathogenesis is unclear, vascular dysregulation and chronic inflammation are the most common culprits for rosacea. Objectives: The aim of this study is to evaluate the relationship between IDO and rosacea and whether there is a correlation with disease severity. Methods: Fifty-two patients with rosacea and 29 healthy volunteers were recruited. The patients were grouped according to severity stage, period, and subtype of the disease. Serum IDO levels were measured with enzyme-linked immunosorbent assay. Results: Serum IDO levels were significantly higher in the patients with rosacea compared to the healthy controls (P < 0.001) and were significantly higher in the patients in remission period and with papulopustular type rosacea compared to the controls (P = 0.002 and P = 0.001, respectively). The serum IDO levels of the female rosacea patients were higher than those of the healthy female controls (P < 0.001). When the diagnostic value of the parameter was investigated, it was observed that the serum IDO level has high sensitivity (83.3%) and specificity (76.1%), with a cutoff value of 47.1 ng/mL for female rosacea patients. Conclusion: IDO was found to increase in rosacea patients. With the high specificity and sensitivity observed, especially in female patients, IDO may be a supporting parameter in the diagnosis of rosacea.
Keywords: Indoleamine 2,3-dioxygenase, inflammatory skin disease, rosacea
|How to cite this URL:|
Odabasi MS, Yazici S, Ozkaya G, Baskan EB, Oral AY. Serum indoleamine 2,3-dioxygenase level and diagnostic value in patients with rosacea. Dermatol Sin [Epub ahead of print] [cited 2023 Mar 23]. Available from: https://www.dermsinica.org/preprintarticle.asp?id=369009
| Introduction|| |
Rosacea is a chronic inflammatory skin disease mainly affecting the face. It is characterized by flushing, facial erythema, inflammatory papules, pustules, and telangiectatic lesions. Other common regions involved are the scalp, neck, and area behind the ear. Rosacea is more frequent in women than in men, and its first signs usually begin with redness in the ages of 20–30. The cutaneous findings of rosacea entirely appear in the ages of 40–50 years. About 0.5%–10% of individuals with light skin and light eye color are affected by rosacea. There are four subtypes of rosacea, the most common types being papulopustular and erythematotelangiectatic rosacea. Although its pathogenesis is not entirely clear, vascular dysregulation and chronic inflammation are the most common culprits for rosacea. Numerous triggering factors such as ultraviolet radiation, high temperature (rarely extreme cold), spicy foods, alcohol, and stress are responsible for the onset and exacerbation of rosacea lesions. Burns and redness attacks are often affected by the patient's mood and psychological stress. Furthermore, various infectious agents (Demodex mites and Helicobacter pylori) have been implicated in the etiology of rosacea. Environmental changes, altered hormone balances, and microbial stimulation via Toll-like receptors (TLRs) and other pattern recognition receptor signals induce effector molecules. Effector molecules, such as cathelicidin, kallikrein, matrix metalloproteinases, reactive oxygen species (ROS), nitric oxide, cytokines, and chemokines, secreted by inflammatory cells change the vascular structure and cause collagen destruction.
Indoleamine 2,3-dioxygenase (IDO, EC.113.11.17) catabolizes tryptophan into kynurenine and other metabolites (quinolinic acid, etc.). It is activated in response to inflammatory stimuli and exerts immunosuppressive effects. Recent studies have shown that IDO expression is associated with infectious diseases, inflammation, fetomaternal tolerance, transplantation, autoimmunity, allergy, and malignancy. Furthermore, dendritic cells, B-lymphocytes, macrophages, fibroblasts, keratinocytes, and epithelial cells express IDO in response to various cytokines such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha. High levels of IDO have been observed in some chronic inflammatory dermatological diseases such as psoriasis and lichen planus., Furthermore, there are reports demonstrating elevated serum IDO levels related to disease severity in some systemic inflammatory conditions., Despite the apparent influence of inflammatory cytokines on IDO expression, how serum IDO levels change in rosacea patients has not been studied. This study was designed to investigate IDO levels in rosacea patients and shed light on its relationship with the subtype and severity of the disease.
| Materials and Methods|| |
This study was carried out between January 10, 2016, and January 10, 2017, among the patients who applied to our University Hospital's Clinics of Dermatology Department. For the study, 52 patients with diagnosed rosacea (36 females, 16 males) and 29 healthy volunteers (21 females, 8 males) were recruited. Volunteers diagnosed with cancer, rheumatological and chronic diseases (such as diabetes and chronic kidney failure), and allergies and those who used analgesic-anti-inflammatory drugs 1 week before the sampling date were excluded from the study. The inclusion criteria for patients were clinical diagnoses of erythematotelangiectatic and papulopustular type rosacea. Ocular and phymatous types were not included in the study. An experienced dermatologist made the diagnosis of rosacea according to the guidelines in “Report of the National Rosacea Society Expert Committee on the Classification and Staging of Rosacea.”
The rosacea patients were grouped according to the disease activation stage, either in remission or exacerbation. Remission has been defined as the lack of cutaneous findings for at least 3 months, and exacerbation has been defined as the development of new lesions and uncontrolled symptoms in the last month. Therefore, the patients were followed by dermatologists for at least 3 months, most of them for 6 months. This study was approved by Uludag University Clinical Research Ethics Committee on 12 July 2016 (2016-13/22). All subjects gave written informed consent regarding participation in the study. The volunteers filled out a questionnaire that questioned the parameters such as spice consumption, sun exposure, and stress which could potentially be associated with rosacea. The Perceived Stress Scale was used to evaluate the stressed personality characteristics of the subjects.
Fasting blood samples were collected from volunteers in tubes and centrifuged at 3000 rpm for 10 min to obtain serum. The serum samples obtained were stored at − 80°C until the analysis. According to the instruction manuals, serum IDO levels were measured by micro-enzyme-linked immunosorbent assay using the Elabscience “Human IDO ELISA” Kit.
Statistical analysis was performed with the statistical package for the social sciences (SPSS v. 23; SPSS Inc., Chicago, IL, USA). Data comparisons between the rosacea and control groups were carried out using Student's t and Mann–Whitney U-tests. Relationships between variables were examined by Pearson correlation and Spearman correlation coefficients. P ≤ 0.05 was considered statistically significant.
| Results|| |
There were 52 volunteers (36 females, 16 males) in the rosacea group and 29 healthy volunteers (21 females, 8 males) in the control group. Twenty-three rosacea patients were classified as erythematotelangiectatic type, and 29 were papulopustular type. The demographic characteristics of the rosacea and control groups are shown in [Table 1].
There was a statistically significant difference between the groups in terms of age (P < 0.001), but no difference was detected in terms of gender (P = 0.760). The groups were assessed according to sun exposure, spice, alcohol and cigarette consumption, and stressful personality. The only remarkable difference between the groups was that the subjects in the rosacea group had higher perceived stress levels (P = 0.006).
Serum IDO levels of all rosacea patients, without any grouping (57.0 ± 18.1 ng/ml), were significantly higher than those of the controls (44.5 ± 10.6 ng/ml) (P < 0.001) [Figure 1].
|Figure 1: *Comparison of serum IDO levels between rosacea and healthy groups (P < 0.001). IDO: Indoleamine 2,3-dioxygenase.|
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Fifty percent (n = 16) of the patients in remission period (n = 32) had an erythematotelangiectatic type, and the other half had papulopustular type rosacea, whereas the patients in the exacerbation group (n = 20) had mainly papulopustular type rosacea (n = 13; 65%). Serum IDO levels in the two rosacea subtypes were not statistically different. On the other hand, the patients with papulopustular type rosacea had statistically higher serum IDO levels than the controls (P = 0.001). Furthermore, serum IDO levels were higher in remission period rosacea patients than in the controls (P = 0.002) [Figure 2].
|Figure 2: Comparison of serum IDO levels (a) in disease subtypes and controls, (b) disease periods and controls. *Significantly different from controls (P = 0.001), **Significantly different from controls (P = 0.002). IDO: Indoleamine 2,3-dioxygenase.|
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When serum IDO levels were analyzed according to gender, although there was no significant difference between male and female rosacea patients, serum IDO levels were lower in the healthy females than in the healthy males (P = 0.019). However, the serum IDO levels of the female rosacea patients (60.0 ± 17.8 ng/mL) (n = 36) were significantly higher than those of the healthy females (n = 21) (41.7 ± 9.0 ng/mL) (P < 0.001) [Figure 3].
|Figure 3: Comparison of serum IDO levels between rosacea patients and control groups according to gender. *Significantly different from healthy females (P = 0.019), **Significantly different from healthy females (P < 0.001). IDO: Indoleamine 2,3-dioxygenase.|
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The serum IDO levels of the female patients in the two subtypes and two periods of rosacea are compared with those of the female controls in [Figure 4]. The serum IDO levels in the erythematotelangiectatic and papulopustular groups were higher than in the controls (P = 0.024 and P < 0.001, respectively). Furthermore, the serum IDO levels of the remission and exacerbation groups were higher than those of the controls (P < 0.001).
|Figure 4: (a) Comparison of serum IDO levels between controls and subtypes of rosacea in female subjects. *Significantly different from control (P = 0.024). **Significantly different from control (P < 0.001). (b) Comparison of serum IDO levels between controls and period of rosacea in female subjects. ***Significantly different from control (P < 0.001). IDO: Indoleamine 2,3-dioxygenase.|
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Receiver operating characteristic (ROC) analysis was performed for serum IDO level to determine its optimal cutoff value and diagnostic validity for rosacea. At a cutoff value of 47.1 ng/ml, a sensitivity and specificity of 78.8% and 60%, respectively, were determined. The diagnostic value of IDO was not significant in males. The sensitivity was 83.3%, and the specificity was 76.1%, with a 47.1 ng/mL cutoff value for females [Figure 5].
|Figure 5: ROC analysis of serum IDO levels in female subjects. ROC: Receiver operating characteristic, IDO: Indoleamine 2,3-dioxygenase.|
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| Discussion|| |
Rosacea is a chronic inflammatory disease triggered by a variety of factors. The present study evaluated whether there was a difference between the groups in triggering factors such as sun exposure, spice, alcohol and cigarette consumption, and stress perception. The only difference between the groups was that the number of the individuals with stressful personalities was higher in the rosacea group (P = 0.006). In a survey of 1066 rosacea patients, it was found that emotional stress was the second most common trigger after sun exposure (81%), with a rate of 79%. In the present study, the Perceived Stress Scale questionnaire was applied to the subjects, and analysis was made according to the data obtained by scoring. In the literature, the effects of rosacea on the patient's quality of life and emotional state have been demonstrated using some questionnaires, such as the Rosacea-Specific Quality of Life questionnaire or the Impact Assessment questionnaire for Rosacea Facial Redness., However, there are limited studies on how emotional state affects rosacea.
This study aimed to determine if any association exists between serum IDO levels and rosacea. Although there are many studies in the literature about the relationship between IDO and inflammatory skin diseases like psoriasis, the relationship between serum IDO levels and rosacea has not been examined before. Some factors involved in psoriasis pathophysiology are epidermal hyperproliferation, T helper cell (Th1)-induced cytokine production and increased angiogenesis. The expression of type I IFNs and IFN-inducible proteins was high in Th1-mediated skin diseases.,, The most potent inducer of IDO is IFN-γ. Psoriatic plaques consist of capillary angiogenesis and infiltration of immune cells. In a previous study, Eminel et al. showed that IDO and kynurenine expression was significantly high in psoriatic plaques. In another study conducted by Kwidzinski et al., it was reported that psoriatic patients had elevated serum IDO activity (tryptophan/kynurenine ratio) and that IDO activity levels negatively correlated with the Psoriatic Area and Severity Index. Similarly, in the current study, serum IDO levels were statistically higher in the rosacea patients than in the controls (P = 0.001). However, there was no statistically significant difference in terms of the status of rosacea in the patients with rosacea.
Atopic dermatitis (AD) is another chronic autoimmune skin disease. In a mouse model AD study conducted by Kim et al., IDO expression was found to be higher in lesions that are coherent with the distribution of IFN-γ-expressing cells compared to healthy ones. Scheler et al. studied IDO expressions in biopsy materials with different inflammatory skin diseases such as chronic discoid lupus erythematosus (n = 9), lichen planus (n = 5), cutaneous herpes simplex infection (n = 5), psoriasis vulgaris (n = 5), AD (n = 6), and all above skin controls (n = 5). In that study, IFN-γ and IDO expressions were significantly higher in disease materials compared to healthy ones, supporting the involvement of type I IFNs in their pathogenesis. In addition, another study showed higher IFN expressions in patients with papulopustular type rosacea compared to controls. In our study, similar to these findings, serum IDO levels were significantly higher (P < 0.001) in the patients with rosacea. Furthermore, the papulopustular rosacea group had elevated serum IDO levels than both controls and rosacea patients in remission. These findings were consistent with the literature reporting the increase in polymorphonuclear leukocyte and cytokine levels in papulopustular rosacea.
There was no significant difference in serum IDO levels of male subjects in contrast to females. The small number of male participants in the study and the high difference between the number of participants in the patient and control groups may have caused this discrepancy. Therefore, the IDO levels of females were evaluated separately in terms of both their diagnostic value and the difference between the groups. Accordingly, the female subjects were further divided according to subtype and rosacea period. The IDO level of the control group was significantly lower than that of both types and both periods in the female subjects. When ROC analysis was performed to find the diagnostic value of IDO in females for rosacea, serum IDO levels had a high sensitivity (83.3%) and specificity (76.1%) to support the diagnosis of rosacea, with a cutoff value of 47.1 ng/mL in females.
The results of the present study suggest that serum IDO levels may support the diagnosis of rosacea, especially in female patients. Studies discussing the possible influence of some treatment strategies in rosacea through inhibition of IDO highlight the significance of this enzyme in rosacea etiopathogenesis.,, However, changes in IDO level in rosacea have not been investigated before. In a case report, acyclovir, an antiviral drug, was found to diminish rosacea symptoms. The researchers thought that acyclovir achieved this effect by inhibiting IDO enzyme and thus decreasing quinolinic acid. Quinolinic acid, a product of IDO enzyme, induces the formation of ROS and promotes lipid peroxidation. Both of them are responsible for rosacea pathogenesis. The researchers considered that decreasing quinolinic acid levels may help prevent rosacea's pathogenesis. In addition, acyclovir may have a potential ability against TLR2 activation and diminish the severity of symptoms. TLRs are recognition receptors that detect environmental factors that trigger rosacea. Their signals induce effector molecules that activate IDO such as ROS, cytokines, and chemokines. It is proposed that the inactivation of TLRs that trigger all these factors involved in the etiopathogenesis of rosacea may improve the prognosis of the disease. Based on this knowledge, the researchers suggested that improvement in acyclovir-treated rosacea patients was due to decreased IDO levels. All these findings support the role of IDO in the etiopathogenesis of rosacea, and the higher serum IDO levels detected in rosacea patients in the present study strengthen this assumption. Further studies on the relation of serum IDO levels with different treatment protocols in rosacea patients would provide valuable contributions to the literature. Future studies better defining the role of IDO in the etiopathogenesis of rosacea would give a chance to IDO inhibitors to provide clinical benefit in therapy.
The small population size of the groups and the dissimilarity of male and female numbers are some of the limitations of this study. With larger groups, patients can also be grouped according to triggering factors, and their relationship with IDO levels can be examined. Evaluation of IDO levels together with agents involved in the pathogenesis of rosacea, such as ROS, NO, and TLR, may shed light on its role in etiopathogenesis. Determining the clinical course of rosacea with studies using IDO inhibitors may also support the role of IDO in the pathogenesis of the disease.
| Conclusions|| |
Clarifying the causes of diseases whose etiopathogenesis is not fully known plays a vital role in the treatment steps. The etiopathogenesis of rosacea has not yet been fully elucidated, and people worldwide still complain of not being able to receive a definite treatment, which profoundly affects their social lives. IDO, associated with many pathways shown so far in the etiopathogenesis of rosacea, was evaluated for the first time in this study. This study was designed to shed light on the need for a laboratory parameter that supports the diagnosis of rosacea and helps determine disease severity. Our results indicate that IDO is a significant marker, especially in female rosacea patients. When considered with other parameters, the diagnostic value of IDO in rosacea and its role in etiopathogenesis can be better evaluated with studies conducted with larger populations.
We thank the laboratory staff for their assistance in sampling and all preanalytical processes.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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Merve Sena Odabasi,
Department of Biochemistry, University of Health Sciences, Sisli Hamidiye Etfal Research and Training Hospital, Istanbul
Source of Support: None, Conflict of Interest: None
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