Serum Soluble Intercellular Adhesion Molecule-1 (sICAM-1): A Novel Potential Biomarker in Severe Acne Vulgaris

Abstract

Background:

Acne vulgaris (AV) is a chronic inflammatory disorder. Intercellular adhesion molecule-1 (ICAM-1) is a vital adhesion molecule mediating cellular adhesion during the inflammatory process.

Aims and Objectives:

To evaluate serum soluble intercellular adhesion molecule-1 (sICAM-1) level in AV patients as an attempt to elucidate its role in acne pathogenesis and to relate with studied clinical parameters.

Materials and Methods:

Serum sICAM-1 level was measured using ELISA technique in 60 patients and 60 controls.

Results:

Serum sICAM-1 level was significantly elevated in studied patients than controls (P < 0.001). Additionally, its level increased significantly with increased acne severity (P < 0.001) but not in patients with post acne scars (P > 0.05).

Conclusion:

Serum sICAM-1 could be a marker for acne etiopathogenesis. Furthermore, it might be considered as a predictor for disease severity.

Introduction

Acne vulgaris (AV) is a widespread chronic disorder involving the pilosebaceous units.[1] Its prevalence reaches up to 80% during adolescence.[2] It can manifest as non-inflamed lesions and inflamed lesions or both.[3] Several factors are implicated in AV pathogenesis, but inflammation is considered to be a primary factor. The process underlying the occurrence and continuity of the inflammatory response is not completely understood, but Cutibacterium acnes is a role player in these mechanisms.[4,5] Inflammation precedes hyperkeratinization in early acne lesions.[6]

Intercellular adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein in the immunoglobulin superfamily found at minimal amounts in a large array of cells and increases in response to various inflammation mediators. During inflammation, expressed ICAM-1 on the endothelial cells interacts with counter receptors on the surface of immune cells, enabling their trans-endothelial migration to the inflammatory sites.[7]

High levels of soluble intercellular adhesion molecule-1 (sICAM-1) were detected in different inflammatory and immune-mediated diseases.[8,9,10,11,12,13] In spite of, the persistent inflammatory nature of AV, the role of sICAM-1 in this disease is not investigated. This work aims to assess serum sICAM-1 level in acne patients to elucidate its relationship with this common disease pathogenesis and its severity.

Materials and Methods

Studied groups

There were 120 people in this case–control research; 60 patients suffering from AV in addition to 60 apparently healthy control subjects. The purpose and nature of the study were described to all subjects, and informed consents form were taken from all participant as an agreement to be included in this research study. This study was conducted after local ethics committee approval and in agreement with Helsinki Declaration. Acne patients suffering from thyroid dysfunction, diabetes mellitus, hypertension, polycystic ovaries syndrome, chronic inflammatory or immune-mediated diseases, using treatment for acne 1 month before inclusion in the study, and pregnant or lactating females were all excluded from this work. Acne severity was assessed according to the Global Acne Grading System.[14]

Laboratory investigations

In plain test tubes, each subject's venous blood was collected in 5 ml under perfect aseptic conditions. Following coagulation, samples were centrifuged (at 1500 g for 15 min) and the separated serum was aliquoted and stored at –20°C for later assays of serum sICAM-1 level by using sICAM-1 ELISA Kit for research use (Cat#: E-EL-H2585, Elabscience Biotechnology Inc, USA).

Statistical analytic methods

SPSS version 25.0 was used to analyze the data. The significance of difference between the means of two investigated groups was determined using the Student's “t” test. The Mann–Whitney test (U test) was used to determine the significance of non-parametric variable differences between two groups. The Kruskal–Wallis test was used to determine the significance of differences in non-parametric variables between more than two groups. To investigate the relationship between two qualitative variables, the Chi-square test was performed. The strength of the link between two quantitative variables was determined using correlation analysis. The cutoff value for serum sICAM-1 level in illness prediction was determined using a receiver operating characteristic (ROC) curve. The risk factors for acne and acne scars were predicted using logistic and ordinal regression models. In this investigation, the significant level was set at a P value of 0.05.

Results

Baseline data of the study groups

Studied groups had matched age and sex. Among studied patients, 18 (30%) patients had mild, 26 (43.3%) patients had moderate, and 16 (26.7%) patients had severe acne lesions. Studied acne patients showed significantly higher serum sICAM-1 level compared to controls (P < 0.001; [Table 1]).

Table 1.

Baseline studied parameters in AV patients and control groups

Variable		Control n=60	AV n=60	P
Age (years)	Mean±SD	22±4.4	21.9±4.6	0.903
Sex
Males	n (%)	28 (46.7)	26 (43.3)	0.714
Females	n (%)	32 (53.3)	34 (56.7)
Positive family history	n (%)	18 (30)	36 (60)	0.001
Disease duration (years)	Median (Minimum–maximum)	–	2 (0.2–8)
Course	Stationary	–	34 (56.7%)	–
	Progressive		26 (43.3%)
Grading	Mild	–	18 (30%)	–
	Moderate		26 (43.3%)
	Severe		16 (26.7%)	–
Post acne scars	Present	–	32 (53.3%)
Serum sICAM-1(ng/mL)	Median (Minimum-maximum)	211.75 (118.4–289.1)	379 (263.52345.2)	<0.001

AV=Acne vulgaris

Serum sICAM-1 level showed an excellent Area under the ROC curve (AUC) (AUC = 0.988). At cutoff value of 277.8 ng/mL, sensitivity was 93.3%, specificity was 96.7%, Positive predictive value (PPV) was 96.6%, Negative predictive value (NPV) was 93.5%, and accuracy was 95% when ROC curve was conducted for diagnosis of AV [Figure 1].

Figure 1.

ROC curve of serum sICAM-1level for diagnosis of AV

Serum sICAM-1 level regarding studied clinical parameters

Significantly higher serum sICAM-1 level was detected in patients with severe AV than those with mild and moderate disease (P < 0.001). Otherwise, no significant relation was detected between serum sICAM-1 and other studied variables [Tables 2 and 3].

Table 2.

Relation between serum sICAM-1 level and studied parameters in AV patients group

Variable	ICAM-1 (ng/ml)			P
	n	Mean±SE	Minimum–Maximum
Gender
Male	26	634.6±105.6	263.5–1536.6	0.950
Female	34	838.4±198.0	266.2–2345.2
Family history
Negative	24	581.4±158.6	285.8–2201.1	0.374
Positive	36	862.6±169.8	263.5–2345.2
Course
Stationary	34	611.8±141.5	263.5–2345.2	0.286
Progressive	26	930.9±204.3	266.2–2201.1
Grading
Mild	18	296.5±8.5	263.5–336.6	<0.001
Moderate	26	575.0±105.6	313.7–1536.6
severe	16	1544.9±255.7	655.6–2345.2
Post acne scars
Absent	28	489.0±143.5	266.2–2345.2	0.174
Present	32	978.6±172.9	263.5–2201.1

AV=Acne vulgaris, SE=standard error. Man–Whitney and Kruskal– Wallis tests were used for comparison

Table 3.

Correlations between sICAM-1 level, patients’ age, and disease duration

Variable	ICAM-1
	rs	P
Age	0.040	0.834
Disease duration	0.148	0.434

Rs=Spearman’s correlation coefficient

Prediction of AV susceptibility

Logistic regression analysis was conducted for prediction of AV development. Higher frequency of positive family history and higher serum sICAM-1 level were associated with the increased risk of AV susceptibility in univariable analysis. However, when significant confounders were analyzed jointly in multivariable analysis, only serum sICAM-1 level was suggested to be an independent risk predictor for AV development [Table 4].

Table 4.

Regression analysis for prediction of AV susceptibility

	Univariable			Multivariable
	P	OR	95% CI	P	OR	95% CI
Age	0.931	0.997	0.929–1.070
Sex	0.795	1.088	0.575–2.059
Positive family history	0.020	2.180	1.131–4.202	0.400	4.332	0.143–13.219
ICAM-1	0.014	1.064	1.013–1.118	0.037	1.123	1.185–1.275

AV=Acne vulgaris, OR=odds ratio, CI=confidence interval. Logistic regression test was used

Prediction of AV severity and post acne scars formation

Ordinal regression analysis was conducted for prediction of AV severity. Higher serum sICAM-1 was suggested to be an independent risk predictor for AV severity [Table 5]. But none of the studied factors was associated with post acne scars formation in studied AV patients when logistic regression analysis was conducted [Table 6].

Table 5.

Regression analysis for prediction of AV severity

Variable	P	OR	95% CI
Age	0.756	1.014	0.931–1.104
Sex	0.440	1.375	0.613–3.085
Positive family history	0.429	1.390	0.615–3.141
Progressive course	0.232	1.643	0.728–3.707
Disease duration	0.195	1.171	0.923–1.486
Serum sICAM-1 level	0.001	1.002	1.001–1.004

AV=Acne vulgaris, OR=odds ratio, CI=confidence interval. Ordinal regression test was used

Table 6.

Regression analysis for prediction of post acne scars formation

Variable	P	OR	95% CI
Age	0.580	1.006	0.986	1.026
Sex	0.104	1.925	0.874	4.241
Positive family history	0.765	1.150	0.460	2.876
Progressive course	0.406	1.341	0.671	2.679
Disease duration	0.344	1.076	0.924	1.253
Acne grades	0.436	1.090	0.878	1.353
Serum sICAM-1 level	0.109	1.012	0.995	1.031

OR=odds ratio, CI=confidence interval. Logistic regression test was used

Discussion

Emerging data point that AV is an inflammatory disease, with multiple evidences indicating that the inflammatory response occurs during the entire stages of its development. The immunologic mechanisms beneath the onset and progression of inflammation in acne are not fully delineated.[15] Acne lesions cause a shift in T helper type 1 (Th1) cells, and Th1-positive cells are more common in acne lesions than in normal skin.[16] In terms of host responses to C. acnes in acne pathogenesis, bacteriological factors are more important than host immunological factors against C. acnes produced by peripheral blood mononuclear cells (PBMCs).[17] Th17 cytokines, in addition to Th1 cytokines, play a role in acne development. C. acnes is a strong Th17 and Th1 inducer, and IL-17 is expressed in large numbers in acne lesions. Acne inflammation is mediated by IL-1 and TNF-α.[18] As a result, controlling these cytokines could be a viable approach to treating acne.

Macrophages, CD3(+) cells, and CD4(+) cells are seen, as well as vascular adhesion molecules, E-selectin, and integrin activation. Inflammatory mediators implicated in acne as prospective targets are now part of our updated understanding of acne pathophysiology.[19] Release of ICAM-1 controls cellular adhesion and circulating sICAM-1 level may be related to the variability in cell adhesion molecules expression and cell adhesion, hallmark of inflammation.[20]

Elevated serum level of sICAM-1 reflects different pathologic conditions inflammatory in nature, such as Behcet's disease,[21] systemic lupus erythematosus,[22] rheumatoid arthritis,[23] bullous pemphigoid,[24] chronic urticarial,[25] cutaneous vasculitis,[26] and psoriasis.[27]

In this study, serum sICAM-1 level was significantly higher in AV patients compared with control subjects. Additionally, when ROC curve of serum sICAM-1 level was conducted for diagnosis of AV, at a cutoff value of 277.8 ng/ml, sensitivity was 93.3%, specificity was 96.7%, PPV was 96.6%, NPV was 93.5%, and accuracy was 95%.

Different inflammatory cytokines are significantly increased in acne-involved skin when compared to the normal adjacent skin because of C. acnes colonization and through Toll-like receptors (TLRs) activation.[26,28] Qin et al.[29] provided an evidence on C. acnes contribution to the inflammation process in AV through activating NLRP3 inflammasome in antigen-presenting cells and eventually enhanced IL-1β production. It was found that the release of proinflammatory cytokine IL-1β induces sICAM-1 expression, through the p38 MAPK signalling pathway.[30] Such mechanisms lead to inflammatory response and tissue damage in acne patients and increased severity of acne lesions.

Current findings revealed that serum sICAM-1 level increased significantly with increased disease severity and this could be related to the more prominent proinflammatory response. Also, ordinal regression analysis was conducted for prediction of AV severity. Higher serum sICAM-1 level was suggested to be an independent risk predictor for AV severity. Such finding is in accordance with other previous results reporting that ICAM-1 is constitutively expressed on the surface of endothelial cells and expression level increased as a result of tissue damage, inflammation, cellular stresses, virus infection, and environmental factors.[7,31,32] Therefore, the more severe inflammation is, the higher expression of sICAM-1 will be. Otherwise, no significant associations were found regarding sICAM-1 level according to studied clinical data in the patients' group.

The association between sICAM-1 and fibrosis liability has been investigated in previous studies. High serum sICAM-1 levels had been reported in patients with idiopathic pulmonary fibrosis.[33] Also, it was suggested that endothelial ICAM-1 is implicated in bleomycin-induced lung injury subsequent fibrosis.[34] In addition, ICAM-1 signalling was reported to induce renal fibrosis.[35] However, this study results did not find any relation between this biomarker levels and the liability for acne scars formation, possibly because of the modest sample included in this study and this needs future investigational work up.

The limitations of this study were the fairly small sample included in this work and it might be necessary to conduct future wide-ranging studies. Additionally, enrolled patients were included before or after treatment; therefore, future research measuring sICAM-1 levels prior to and after therapy would be more useful in evaluating the relation between its serum levels variation and therapeutic effectiveness. Finally, this work did not assess sICAM-1-producing cells, and so additional research is needed.

Conclusions

From the results of this work, it was concluded that serum sICAM-1 level was suggested to be an independent predictor of acne susceptibility and severity, but not post acne scars formation. Because acne is a problem in adolescence, the early assessment of this biomarker level may aid in management of this common disorder. A new knowledge of acne pathogenesis could help guide future treatment options.

Compliance with Ethics Guidelines

The study was approved by the Local Ethics Committee on research involving human subjects in the Faculty of Medicine; Benha University in agreement with the Declaration of Helsinki. An informed consent was obtained from each subject prior to participation.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.