Egyptian Journal of Dermatology and Venerology

ORIGINAL ARTICLE
Year
: 2020  |  Volume : 40  |  Issue : 1  |  Page : 9--14

Correlation between squamous cell carcinoma antigen 1 and 2 levels and disease severity and clinical type of atopic dermatitis


Mohamed H Khatter1, Fathia M Khattab1, Amal A Zidan2, Mai M Al-Hakim3,  
1 Department of Dermatology, Venerology and Andrology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
3 Dermatology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Correspondence Address:
MD Fathia M Khattab
Assistant Professor of Dermatology, Venereology and Andrology, Faculty of Medicine, Zagazig University, 44511
Egypt

Abstract

Background Serum levels of squamous cell carcinoma antigen (SCCA) 1 and 2 induced by type 2 cytokines such as interleukin 4 and interleukin 13 are increased in patients with atopic dermatitis (AD). Objective This study aimed to assess and correlate the severity and clinical types of AD by serum level of SCC antigen 1 and SCC antigen 2 in AD patients. Patients and methods Twenty-four AD patients (12 adults and 12 children) and 24 healthy controls were included in this study to assess the SCORAD score and to measure SCCA1 and SCCA2. Results There was a statistically significant difference between the children and adult groups in SCCA1 and SCCA2 with higher levels in adults than children maybe due to the long duration of disease, chronicity, and severity of disease and there was a positive correlation between SCCA1 and SCCA2, and severity of disease. Conclusion Serum levels of SCCA1 and SCCA2 correlate with severity of disease and clinical types and provide its role in the pathogenesis of Atopic Dermatitis. Further studies may evaluate the therapeutic effect of their blockage in the improvement of Atopic Dermatitis.



How to cite this article:
Khatter MH, Khattab FM, Zidan AA, Al-Hakim MM. Correlation between squamous cell carcinoma antigen 1 and 2 levels and disease severity and clinical type of atopic dermatitis.Egypt J Dermatol Venerol 2020;40:9-14


How to cite this URL:
Khatter MH, Khattab FM, Zidan AA, Al-Hakim MM. Correlation between squamous cell carcinoma antigen 1 and 2 levels and disease severity and clinical type of atopic dermatitis. Egypt J Dermatol Venerol [serial online] 2020 [cited 2020 May 28 ];40:9-14
Available from: http://www.ejdv.eg.net/text.asp?2020/40/1/9/275187


Full Text



 Introduction



Squamous cell carcinoma antigen (SCCA) is known as a tumor biomarker for various squamous cell tumors. Total SCCA comprises two nearly identical proteins, SCCA1 and SCCA2. Both belong to the ovalbumin-serpin proteinase inhibitor family [1]. Although SCCA1 and SCCA2 are closely homologous at the amino acid level, they are active against different proteases [2].

SCCA1 inhibits parasite-derived cysteine proteases, and staphylococcal cysteine proteases, and cysteine proteases such as papain, cathepsin K, L, and S1. On the other hand, SCCA2 inhibits serine protease such as cathepsin G, human mast cell chymase, and cysteine protease. These findings indicate that SCCA proteins play some roles in the defense mechanisms against extrinsic proteases [3].

Although it is thought that both Th1-type and Th2-type inflammations are involved in the pathogenesis of atopic dermatitis (AD), it is controversial which immune response is more involved in regulating the clinical severity of AD. The SCCA1 and SCCA2 are novel biomarkers of bronchial asthma, downstream of interleukin 4 and interleukin 13 [4].

The SCCA1 content showed a very high correlation with the number of para-keratotic cells in the cornified layer of the skin. It was reported that SCCA2 is also related to barrier dysfunction and early inflammatory response following cutaneous allergen exposure [5]. Besides, severe AD patients have higher serum levels of SCCA proteins [6].

 Aim



Evaluation of the severity and clinical types of AD by estimation of serum level of SCCA1 and SCCA2 in AD patients.

 Patients and methods



Patients

Twenty-four AD patients (12 adults and 12 children) and 24 healthy controls were included in this study, from the outpatient clinics of the Department of Dermatology, Venereology, and Andrology, Zagazig University Hospitals during the period from April 2018 to April 2019.

They were diagnosed with AD by a dermatologist. Diagnosis of AD was made based on the criteria of Hanifin Rajka. The severity of skin eruption was determined as mild, moderate, and severe according to Hanifin criteria.

Written informed consent was obtained from all patients and the study was carried according to the research ethics committee of the Faculty of Medicine, Zagazig University. The study has been carried out according to The Code of Ethics of the World Medical Association (Declaration of Helsinki) for studies involving humans.

AD patients were further grouped as having the erythroderma type, widespread of various types, prurigo type, limb type, or head/face/neck/chest/back type based on individual clinical characteristics [7].

The diagnosis is made based on clinical presentation.

The selected patients were divided into two groups, group I: 24 adults (12 diseased, 12 healthy) and group II: 24 children (diseased, healthy).

Inclusion criteria are all AD patients more than 2 years, age: any age and both sexes.

Exclusion criteria are those with acute febrile illness, immunosuppression, with associated autoimmune disease. Pregnant women or those intending to become pregnant, those with abnormal blood count, abnormal liver and renal function tests, total protein, albumin, and lipid profile.

Methods

The patients were subjected to the following:Completed history taking.Personal history, including name, age, sex, residence, and occupation.The present history of the disease, family history of similar conditions and other diseases and history of previous medications.Complete general examination.Dermatological examination for the baseline characteristics of AD including itchy, red, swollen, and cracked skin.Blood sample.SCCA1 and SCCA2 in serum.

Measurement of serum squamous cell carcinoma antigen 1 and squamous cell carcinoma antigen 2 levels

Serum samples were obtained from 24 adult AD patients and children age-matched and sex-matched healthy and then the samples were immediately stored at 80°C. Serum SCCA1 and SCCA2 levels were measured using a sandwich enzyme-linked immunosorbent assay.

Statistical analysis

Data were collected, tabulated, and analyzed by SPSS 20 (IBM Corp, Armonk, NY, USA), software for Windows. The level of significance was less than 0.05.

 Results



This study included 48 participants. There was no statistically significant difference between children and adult groups in sex and family history. Sociodemographic characteristics of them are listed in [Table 1] SCORAD score is 50.9±23.2 which ranged from 13 to 90 ([Table 2] and [Table 3]). Of the case group, 50.0% had AD of moderate severity and 25.0% had mild and severe AD.{Table 1}{Table 2}{Table 3}

There was a highly statistically significant difference between case and control groups in SCCA1 and SCCA2 with higher levels in patients than control groups ([Figure 1] and [Figure 2]).{Figure 1}{Figure 2}

Regarding the case group, there was a statistically significant difference between the children and adult groups in SCCA1 and SCCA2 with higher levels in adults than children groups. Regarding the control group, SCC1 and SCC2 were higher levels in adults than children groups but this difference was not statistically significant between the children and adult groups.

There was a highly statistically significant difference between patients with a widespread and localized lesion in SCC1 and SCC2 with higher levels in widespread than localized groups ([Table 4]).{Table 4}

There was a statistically significant difference between the patients with different severity in SCC1 and SCC2 with higher levels in patients with severe AD ([Table 5] and [Table 6]). There was positive correlation between SCC1 and SCC2 levels with disease duration ([Figure 3]).{Table 5}{Table 6}{Figure 3}

Regarding both SCC1 and SCC2 levels, there was highly statistically significant positive correlation between SCC1 and SCC2 levels with disease duration and SCORAD score (increased disease duration and SCORAD score are associated with a higher level of SCC1 and SCC2) ([Figure 4]). But regarding age, there was no statistically significant correlation with SCC1 and SCC2 levels. There was no statistically significant correlation between age, SCC1 and SCC2 levels in the control group.{Figure 4}

 Discussion



SCCA1 and SCCA2 members of the ovalbumin-serpin (Nov-serpin)/clade B serpin family were originally discovered as tumor-specific antigens and are used as tumor markers for various kinds of squamous cell carcinomas. Moreover, it has been shown that SCCA1/2 are involved in the pathogenesis of several inflammatory diseases: asthma, psoriasis, and AD. These findings indicate that SCCA proteins play some roles in defense mechanisms against extrinsic proteases [8].

Our study showed that there was a statistically significant difference between the children and adult groups in SCCA1 and SCCA2 with higher levels in adults than children maybe due to the long duration of disease, chronicity, and severity of disease and there was a positive correlation between SCCA1 and SCCA2 and severity of disease.

In our study, there was no statistically significant difference detected between children subgroups of the case and control groups in sex and age. Nagao, et al. [9] performed on children cases only 159 control and 176 AD children, serum level of SCC2 only estimated and correlated to the severity of lesion according to SCORAD score the found no statistically significant difference detected between children subgroups of the case and control groups in sex and age. And also no statistically significant difference detected between adult subgroup of the case and control groups in sex and age.

According to the family history of AD patients, our study showed that 54.2% of patients had a positive family history, but in the control group, no one had a family history of AD and no statistically significant difference between children and adult groups regarding family history, which agrees with the results of Liu et al. [10], who made a cross-sectional study using a questionnaire on 2662 patients with AD which resulted in 43% of AD patients having a positive family history.

In our study, a comparison of the case group and the control group according to the levels of SCCA1 and SCCA2 in the serum, a highly statistically significant difference was observed with increased levels in AD patient children and adult groups. The level of SCCA1 was 2.1±1.03 which ranged from 0.31 to 3.92 and SCCA2 was 2.27±1.8 which ranged from 0.69 to 3.47.

Regarding the comparison between children subgroups in the case group SCC1 1.89±1.1 (0.31–3.92) and SCC2 2.03±0.92 (0.69–3.47) compared with the control children group SCC1 0.36±0.04 (0.29–0.45) and SCC2 0.57±0.04 (0.52–0.66) we found that SCC1 and SCC2 were significantly elevated in AD children than in the control group.

A study of Nagao, et al. [9] found, there was a highly statistically significant difference with increased levels of SCCA2 levels in patients with severe AD which had the same result with our study.

Regarding the comparison between adult subgroups in the case group SCC1 2.4±0.86 (0.81–3.52) and SCC2 2.5±0.74 (0.78–3.39) compared with the control adult group SCC1 0.41±0.17 (0.29–0.97) SCC2 0.6±0.13 (0.51–0.97) we found that SCC1 and SCC2 were significantly elevated in the AD adult group than the control group.

The same result in a study of Ohta et al. [6] which performed on adult patients only they obtained 188 case (116 men and 72 women) 49 control cases and on estimating the serum SCC1 and SCC2 level they found that SCC1 and SCC2 were significantly elevated in AD patients (n=188; 2.9±2.4 ng/ml for SCC1; 3.2±5.6 ng/ml for SCC2) compared with the control group (n=49; 0.8±0.2 ng/ml for SCC1; 0.6 ±2 ng/ml).

In our study regarding the lesion site in the case group, the lesion was localized in 54.2% of the case group and in 45.8% widespread, regarding the lesion types, lichenification was the most common (50.0%) of the case group followed by papules, dryness of skin (20.8%), and cracked skin (16%). There was a statistically significant difference between the patients with different severity in SCCA1 and SCCA2 with higher levels in patients with severe AD.

Regarding the site of the lesion the SCC1 level in localized lesion 1.9±0.8 (0.31–3.90), SCC2 level 2.23±0.8 (0.69–3.24) in widespread lesion SCC1 2.1±1.03 (0.35–3.92). It was shown that there was a highly statistically significant difference between the patients with a widespread and localized lesion in SCC1 and SCC2 with higher levels in widespread than the localized lesion.

The study of Okawa et al. [11] performed on 240 adult patients and 25 healthy control level of SCC1 and SCC2 assessed the site of lesion and was recognized and classified to localized and widespread lesion; the study resulted that on comparison of the case group and control group according to the levels of SCCA1 and SCCA2 in the serum, there was highly statistically significant difference with increased levels in AD patients than controls and widespread groups had high level of SCC1 and SCC2 than the control group which was the same result as our study.

The severity of AD was classified according to the SCORAD score into mild (25%), moderate (50%), and severe (25%). In mild cases, the SCC1 level was 1.19±0.49 (0.72–1.85), in moderate cases the SCC1 level was 2.05±0.6 (0.31–3.53), and in severe cases the SCC1 level was 3.26±0.4 (2.53–3.92) which has shown there was highly statistically significant difference between the patients with different severities in SCC1 with higher levels with severe AD.

The SCC2 level in mild cases was 1.26±0.3 (0.69–1.92), in moderate cases the SCC2 level was 2.38±0.6 (1.53–3.39), and in severe cases the SCC2 level was 3.04±0.4 (2.2–3.47) which has shown that there was highly statistically significant difference between patients with different severities in SCC2 with higher levels with severe AD.The study of Izuhara et al. [12] performed on AD patients, measured the level of SCC2 only in AD and its correlation to clinical types and severity of AD; the severity of lesion was determined as mild, moderate, and severe. The study has shown that there was a highly statistically significant difference between patients with different severities in SCC2 with higher levels with severe AD.

The study of Okawa et al. [11] also assessed the severity of the lesion and determined it as mild, moderate, and severe according to the Japanese guidelines for AD and correlated with the SCC2 level. There was a highly statistically significant difference between the patients with different severities in SCC2 with higher levels with severe AD.

Mitsuishi et al. [13] performed a study on 30 AD patients and 16 healthy volunteers. As reported the expression of SCCA is highly expressed in the AD skin and there was a highly statistically significant difference between patients with different severities in SCCA with higher levels with severe AD.

 Conclusion



Serum levels of SCCA1 and SCCA2 correlate with severity of disease and clinical types and provide its role in the pathogenesis of Atopic Dermatitis. Further studies may evaluate the therapeutic effect of their blockage in the improvement of Atopic Dermatitis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Gatto M, Iaccarino L, Ghirardello A, Bassi N, Pontisso P, Punzi L et al. Serpins, immunity and autoimmunity: old molecules, new functions. Clinic Rev Allergy Immunol 2013; 45:267–280.
2Kanaji S, Tanaka Y, Sakata Y, Takeshita K, Arima K, Ohta S et al. Squamous cell carcinoma antigen 1 is an inhibitor of parasite-derived cysteine proteases. FEBS Lett 2007; 581:4260–4464.
3Sakata Y, Arima K, Takai T, Sakurai W, Masumoto K, Yuyama N et al. The squamous cell carcinoma antigen 2 inhibits the cysteine proteinase activity of a major mite allergen, Der p 1. J Biol Chem 2004; 279:5081–5087.
4Kantyka T, Potenpa J. Human SCCA serpins inhibit staphylococcal cysteine proteases by forming classic ‘Serpin-like’ covalent complexes. Methods Enzymol 2011; 499:331–345.
5Sivaprasad U, Warrier MR, Gibson AM, Chen W, Tabata Y, Bass SA et al. IL-13Ralpha2 has a protective role in a mouse model of cutaneous inflammation. J Immunol 2010; 185:6802–6808.
6Ohta S, Shibata R, Nakao Y, Azuma Y, Taniguchi K, Arima K et al. The usefulness of combined measurements of squamous cell carcinoma antigens 1 and 2 in diagnosing atopic dermatitis. Ann Clin Biochem 2012; 49:277–284
7Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol Suppl (Stockh) 1980; 92:44–47.
8Izuhara K, Ohta S, Kanaji S, Shiraishi H, Arima K. Recent progress in understanding the diversity of the human ov-serpin/clade B serpin family. Cell Mol Life Sci 2008; 65:2541–2543.
9Nagao M, Inagaki S, Kawano T, Azuma Y, Nomura N, Noguchi Y et al. SCCA2 is a reliable biomarker for evaluating pediatric atopic dermatitis. J Allergy Clin Immunol 2018; 141:1934–1936.
10Liu P, Zhao Y, Mu ZL, Lu QJ, Zhang L, Yao X et al. Clinical Features of Adult/ adolescent atopic dermatitis and Chinese criteria for atopic. Derm Chin Med J 2016; 129:757–762.
11Okawa T, Yamaguchi Y, Kou K, Ono J, Azuma Y, Komitsu N et al. Serum levels of squamous cell carcinoma antigens 1 and 2 reflect disease severity and clinical type of atopic dermatitis in adult patients. Allergol Int 2018; 67:124–130.
12Izuhara K, Yamaguchi Y, Ohta S, Nunomura S, Nanri Y, Azuma Y et al. Squamous cell carcinoma antigen 2,an emerging biomarker for skin inflammatory diseases. Int J Mol Sci 2018; 19:1102.
13Mitsuishi K, Nakamura T, Sakata Y, Yuyama N, Arima K, Sugita Y et al. The squamous cell carcinoma antigens as relevant biomarkers of atopic dermatitis. Clin Exp Allergy 2005; 35:1327–1333.