A Novel Inflammatory Marker in the Follow-up of Moderate-to-Severe Acne Vulgaris Administered Isotretinoin: Systemic Immune-Inflammation Index (SII).

BACKGROUND: Systemic immune-inflammation index (SII) is calculated by multiplying the neutrophil-lymphocyte ratio (NLR) and the platelet count. In this study, we aimed to investigate the difference of SII and other inflammatory markers in patients with acne vulgaris compared to healthy controls and themselves after Oral isotretinoin (ISO) treatment.
MATERIALS AND METHODS: In this study 190 patients with severe acne vulgaris who received at least 3 months of ISO treatment (0.5-1mg/kg/day) and 66 healthy individuals were evaluated. Hemoglobin, neutrophil, lymphocyte, monocyte, and platelet counts, mean platelet volume (MPV), Plateletcrit (PCT), NLR, platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and SII were analyzed.
RESULTS: Before ISO treatment, patients with moderate-to-severe acne vulgaris had significantly higher neutrophil counts and SII levels than healthy controls (p=0.036, p=0.028; respectively). In the third month of ISO treatment, both neutrophil count and SII level were similar to healthy control (p=0.376, p=0.379; respectively). In the follow-up of patients using ISO, a significant decrease was observed especially in SII levels (p=0.037). Although the lymphocyte count was not significantly different from the control group before treatment, it increased significantly after ISO and was significantly higher than both the control and pretreatment period (p=0.134, P=0.026, p=0.017; respectively). Although NLR was not different from control in the pre- and post-treatment period, the change in neutrophil and lymphocyte counts after treatment caused a statistically significant decrease in NLR (p=0.682, p=0.289, p=0.043; respectively).
CONCLUSIONS: We believe that SII is a more useful parameter as an indicator of the anti-inflammatory effect of isotretinoin.

Introduction

Acne is a multifactorial, chronic inflammatory skin disease involving the pilosebaceous unit.

Therefore, the prediliction zones are primarily the face, chest, back, and shoulders.

It was reported to occur in 85% of people aged 12-24 years [1].

Inflammatory lesions such as comedones, papules, pustules, nodules, and cysts can be seen depending on the clinical severity.

Increased sebum production, hyperkeratinization in the follicular infundibulum, and Propionibacterium acnes play a role in etiopathogenesis [2].

Various topical or oral treatment options that blocked the etiopathogenic processes at different stages are administered based on the severity of lesions.

Isotretinoin (ISO, 13-cis-retinoic acid) is the only systemic agent that is effective in all stages of acne pathogenesis, including inflammation [2].

Although it is commonly used in moderate to severe acne, it is also preferred in patients with resistance to other treatments and aesthetic concerns.

It can be used also in many immune-mediated skin diseases such as rosacea, psoriasis, and lichen planus [3].

Numerous inflammatory parameters associated with complete blood count (CBC) have been identified, such as mean platelet volume (MPV), plateletcrit (PTC), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and red blood cell distribution width (RDW).

However, some inconsistent results have been reported about the relationship between ISO and these inflammatory markers [4,5,6,7].

New parameters with reliable and reproducible results are waiting to be found out.

A new parameter called the systemic immune-inflammation index (SII) (calculated by neutrophil x platelet/lymphocyte) has been suggested to be used as a measure of inflammation, prognosis, and activity in many inflammatory diseases, especially in the field of oncology, since 2014 [8,9].

SII has recently been investigated in dermatology and its relationship with activity has only been reported in psoriasis and Behçet's diseases so far [10,11].

There is no similar study yet in patients with acne vulgaris.

In this study, we aimed to investigate the difference of SII as an inflammatory parameter in patients with moderate and severe acne vulgaris compared to healthy controls and themselves after ISO treatment.

Materials and Methods

All participants were retrospectively enrolled from outpatient clinic applications to the Dermatology and Venereal Diseases Department between January 1 and July 31, 2021.

Adult patients using oral ISO (0.5-1mg/kg/day) due to moderate-severe acne vulgaris and whose laboratory tests were seen immediately before and 3 months after the treatment were included in the study.

Age-and sex-matched healthy control group without any known systemic disease, consisted of individuals diagnosed with non-inflammatory dermatological diseases.

All required data were obtained from the electronic database.

Hemoglobin, neutrophil, lymphocyte, monocyte, and platelet counts, MPV, Plateletcrit (PCT), NLR, PLR, MLR, and SII were analyzed. SII is calculated by multiplying the NLR and the platelet count.

Parameters such as MCV, and platelet count are known to be closely related to hemoglobin levels.

Therefore, individuals with low and high hemoglobin levels (<12.0g/dl in women, <13.5g/dl in men and >17g/dl in both genders) were excluded.

Considering the effects of atherosclerosis and obesity on hemogram parameters, those over 30 years old and obese (Body mass index, BMI≥30kg/m2) were excluded from the study.

Patients who were found to have used any drugs (iron, vitamin supplements, statins, non-steroidal anti-inflammatory drugs, etc.) in the last 3 months were excluded from the study.

Patients with cancer, any infection, hematological disease, heart failure, chronic kidney disease and lung disease were not included.

This single-center retrospective cohort study was approved by the Ethics Committee of the Regional Training and Research Hospital, Erzurum, Turkey (Decision No: 2020/12-134).

As the study was retrospective, the requirement for informed consent was waived, provided the data was anonymized.

This study was conducted per the latest version of the "Helsinki Declaration" and "Guidelines for Good Clinical Practice”.

Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS v22; IBM SPSS, Armonk, NY, USA).

Kolmogorov-Smirnov test was used to determine normality of distribution.

As the data were not normally distributed. Wilcoxon and Mann-Whitney U tests were used for pairwise comparison of dependent and independent samples, respectively.

Pearson’s chi-square test was used for categorical variables.

Two-sided p-values less than 0.05 were considered statistically significant.

Results

A total of 256 participants, 190 with acne vulgaris and 66 healthy individuals, were included in the study.

There were 73.2% and 65.2% women in the patient and control groups, respectively.

The groups were identical in terms of age and gender (p=0.093, p=0.216; respectively).

The BMI of the participants ranged from 17.4 to 29.9, and there was no statistical difference between the patient and control groups (Table 1).

Table 1

Evaluation of the demographic characteristics of the participants

		Healthy control	Acne vulgaris	p-value
		(n=66)	(n=190)
Age (years); mean±SD (range)		22.4±3.6 (18-30)	21.5±3.1 (18-30)	0.093*
Sex	Man	23 (34.8%)	51 (26.8%)	0.216
	Woman	43 (65.2%)	139 (73.2%)
BMI (kg/m2); mean±SD (range)		22.5±2.4 (17.6-28.8)	23.1±2.8 (17.4-29.9)	0.122*
Current smoking		9 (13.8%)	25 (13.3%)	0.911

SD-standard deviation; BMI-body mass index; N/A-not applicable

Data were expressed as mean±SD (min-max) and n (%) in scale and categoric variables; respectively.

Mann-Whitney U (*) and Pearson's chi-square tests were used.

-value

Before ISO treatment, patients with moderate-to-severe acne vulgaris had significantly higher neutrophil counts and SII levels than healthy controls (p=0.036, p=0.028; respectively).

In the third month of ISO treatment, both neutrophil count and SII level were similar to healthy control (p=0.376, p=0.379; respectively).

In the follow-up of patients using ISO, a significant decrease was observed especially in SII levels (p=0.037).

Although the lymphocyte count was not significantly different from the control group before treatment, it increased significantly after ISO and was significantly higher than both the control and pretreatment period (p=0.134, P=0.026, p=0.017; respectively).

Although NLR was not different from control in the pre-and post-treatment period, the change in neutrophil and lymphocyte counts after treatment caused a statistically significant decrease in NLR (p=0.682, p=0.289, p=0.043; respectively).

Monocyte, platelet count and PCT were significantly higher than the control both before and after treatment, and did not show any significant change after ISO treatment (Table 2).

Table 2

Change in blood parameters compared to 0th month in the 3rd month of ISO treatment

Parameters	Independent sample, n=66	Dependent samples, n=190 Isotretinoin treatment		p1-value*	p2-value*	p3-value**
	Healthy control (A)	0th month (B)	3rd month (C)	A vs. B	A vs. C	B vs. C
Hemoglobin (g/dl)	14.4±1.3	14.6±1.4	14.6±1.5	0.446	0.473	0.381
Neutrophil (103/mm3)	4.243±1.690	4.525±1.483	4.386±1.628	0.036	0.376	0.068
Lymphocyte (103/mm3)	2.30±0.60	2.42±0.68	2.52±0.71	0.134	0.026	0.017
Monocytes (103/mm3)	0.54±0.13	0.62±0.21	0.63±0.21	0.005	0.002	0.790
Platelet (103/mm3)	269±61	304±65	308±67	<0.001	<0.001	0.297
PCT (10-2)	27±6	31±6	31±6	<0.001	<0.001	0.311
MPV (fl)	10.3±0.9	10.3±1.0	10.2±1.2	0.797	0.971	0.093
NLR (10-2)	193±79	193±66	183±77	0.682	0.289	0.043
MLR (10-2)	25±7	27±10	26±10	0.296	0.398	0.656
PLR	123±35	133±43	130±42	0.189	0.324	0.214
SII (103/mm3)	522.6±247.7	577.8±224.1	543.1±244.9	0.028	0.379	0.037

PCT: Plateletcrit; MPV: Mean platelet volume; NLR: Neutrophil/lymphocyte ratio; MLR: Monocytes/lymphocyte ratio; PLR: Platelet/lymphocyte ratio; SII: Systemic immune-inflammation index, it is calculated by multiplying the NLR and the platelet count.

Mann-Whitney U* test and Wilcoxon test** were used for independent and dependent group analyzes, respectively. Data are expressed as mean±standard deviation. Significant values were shown in bold.

p1 value for the difference between control (A) and 0th month (B) groups; p2 value for the difference between control (A) and 3rd month (C) groups; p3 value for the difference between 0th month (B) and 3rd month group

-value*

-value*

-value**

0(B)

3(C)

Discussion

All acne lesions, including early stages such as microcomedones or comedones, have inflammation in the background.

Perivascular lymphoid infiltration is predominant in early-stage lesions and polymorphonuclear infiltration in late-stages [12,13].

Besides, it was emphasized that inflammatory markers such as neutrophil count and NLR were higher in moderate-severe acne patients than in healthy controls [14].

Our study revealed that there was a significant increase in monocyte and platelet counts and PCT, as well as confirming the high neutrophil count in patients with acne compared to controls.

Systemic retinoids inhibit follicular hyperkeratosis and sebum production and reduce bacterial colonization of sebaceous follicles.

Norris et al. reported that isotretinoin has a strong anti-inflammatory effect by inhibiting monocyte and neutrophil chemotaxis [13].

In addition, Karadağ et al. [15] reported that TNF-α, IL-4, IL-17, and IFN-γ levels were significantly decreased after isotretinoin in patients with acne vulgaris.

Moreover, it was underlined that TNF-α and IL-4 decreased to a similar level with the control group after isotretinoin, but IL-17 was still higher [15].

In recent years, studies have focused on hemogram parameters such as MPV, NLR, PLR, PCT, and RDW as an indicator of the anti-inflammatory activity of isotretinoin in acne patients.

Significant reduction in such inflammatory markers after systemic isotretinoin treatment has been confirmed in many studies, despite conflicting results [4,5,6,7].

However, since there was no sex-and age-matched healthy controls in any of the studies, the treatment group was not examined in this respect.

We observed a remarkable decrease in neutrophil count and NLR, and a significant increase in lymphocyte count after treatment.

While the SII value was significantly higher in acne patients before isotretinoin than in healthy controls, it decreased to a similar level after treatment.

Therefore, we thought that SII might be more qualified than NLR in the evaluation of the anti-inflammatory effect of isotretinoin.

Besides, SII may also be a parameter that indicates the severity of acne, though there is no evidence yet.

Hu et al. reported the association of high SII value with increased recurrence and poor prognosis in patients with hepatocellular cancer in 2014.

It was stated that SII may be a marker reflecting the inflammatory and immune response status more objectively compared to NLR and PLR [8].

After that, it has been reported as an indicator of prognosis (severe clinical manifestations, low survival, and high recurrence) in myriad malignant and pre-malign diseases such as lung, gastrointestinal tract, esophageal, urinary system, breast, and gynecological cancers and squamous intraepithelial neoplasia [16,17,18,19].

The association of increased SII with clinical severity has been reported in acute coronary syndrome, acute pulmonary embolism, and infective endocarditis, in addition to oncological diseases [20,21,22].

SII has been a new research topic in dermatology, and its relationship with clinical activity has only been reported in two inflammatory skin diseases such as Behçet's disease and psoriasis, so far [10,11].

In the light of these data, we consider that SII can be used successfully as an indicator of inflammation, activity, and prognosis in dermatology.

Although the retrospective design of the study is the most important limitation, it is notable that it was the first study to evaluate SII in patients with acne.

The second limitation is that the relationship between ISO and other inflammation parameters such as CRP, sedimentation, ferritin and d-dimer could not be evaluated.

In conclusion, new simple, cheap, and useful parameters are needed to reflect the balance between the inflammatory status of patients, due to conflicting results in hemogram parameters.

SII value calculated with three parameters including neutrophil, platelet, and lymphocyte counts may be a better indicator of inflammation compared to other hemogram markers.

We believe that SII is a useful parameter as an indicator of the anti-inflammatory effect of isotretinoin.

However, further studies are needed.

Conflict of interests

The authors declare no potential conflicts of interest.