Acne is a worldwide dermatological problem 1,2. It is characterized by multifactorial pathogenic processes of the pilosebaceous unit. Acne was previously considered as an infectious disease. However, newly developing data have clarified it as an inflammatory process with an important interplay between Propionibacterium acnes and innate immunity resulting in developing and propagating abnormal hyperkeratinization and inflammation. Changes in composition of sebum and hypersensitivity to androgens also are responsible for the inflammatory process 3.
Histamine is one of the inflammatory mediators involved in the immune process of inflammatory acne 4,5. It is released locally by mast cells and basophils 4 and, to a lesser extent, by keratinocytes 6. P. acnes change the pH of the microenvironment of the acne follicle, which is an optimal environment for the production of histamine or histamine-like products that may be the cause of itching in some patients with acne 7.
Pelle et al.5 had proved the presence of histamine receptors in sebocytes and demonstrated how an antagonist to these receptors can modulate cellular function by reduction of squalene production. Thus, they suggested that acne therapy targeting H1-receptors may reduce sebum production and, consequently, the resulting inflammation.
Until now, only one study has evaluated the efficacy of antihistamines for treating acne vulgaris patients in the clinical settings. In the present study, we investigate the clinical efficacy and tolerability of using H1-antagonist and isotretinoin for treating different lesions of acne vulgaris.
Patients and methods
This study was conducted on 50 patients of both sexes with different grades of acne vulgaris. It was designed as a systematic randomized controlled study over a period of 16 weeks. Two different examiners were blinded while assessing the patients, both at the beginning of the study and during follow-up. Patients above 16 years of age were randomly selected from the outpatient dermatology clinic, taking into consideration the known contraindications for using isotretinoin in therapy (women of childbearing age were included only if they were using two safe methods of contraception; patients with disorders of lipid metabolism, such as familial hypercholesterolemia, were excluded). They were categorized into two groups: (a) the control group (25 patients), which included patients treated with isotretinoin alone (0.4–0.6 mg/kg/day), and (b) the antihistamine-treated group (25 patients), which included patients treated with a combination of isotretinoin (0.4–0.6 mg/kg/day) and antihistamine levocitrizine hydrochloride (5 mg/day). The patients were not allowed to use any topical or systemic treatment for acne or any other dermatologic disease. Written consent form was taken from every participant before being included in the study in accordance with Helsinky Declaration in 2008.
All patients were assessed at the beginning of treatment, every 4 weeks, and finally at 16 weeks after treatment. At the beginning, personal demographic data and duration of the disease were recorded and digital photograph was taken. Both comedones (open and closed) and other primary lesions (papules, pustules, and nodules) were counted at baseline and during each visit. Acne was graded and scored according to the global acne grading system (GAGS) total score into mild (1–18), moderate (19–30), severe (31–38), and very severe (≥39) 8.
During treatment, the occurrence of acne flare and cutaneous side effects such as xerosis, chelitis, and pruritus were recorded. Finally, at the end of the study (16 weeks), improvement (improved, cured, or worsened) was evaluated by examiners, and patients’ satisfaction and quality of life were documented and graded using the Dermatology Life Quality Index (DLQI) questionnaire into five grades as follows 9.
- VS: no effect at all on patient’s life.
- S: small effect on patient’s life.
- SS: moderate effect on patient’s life.
- NS: very large effect on patient’s life.
- VNS: extremely large effect on patient’s life.
Results were collected, tabulated, and IBM statistical package for the social sciences version 20.0 (SPSS Inc., Illinois, Chicago, USA). The χ2-test was used to study the association between two qualitative variables. Thereafter, t-test was used for comparison between quantitative variables normally distributed. P value less than 0.05 was considered significant.
Studied population and baseline characteristics
This study included 50 acne vulgaris patients. Twenty-five patients (11 male and 14 female) constituted the control group and the other 25 patients (nine male and 16 female) constituted the antihistamine-treated group. Both groups were matched as regards age, sex, BMI, disease duration, and the dose of the prescribed isotretinoin (P>0.05) (Table 1).
Acne lesion count
As regards acne lesions at the beginning of the study, both groups showed different types of acne lesions. The mean comedones’ count was 30.04 and 29.48, whereas the mean count of the other lesions was 23.76 and 23.52 in the control and the antihistamine-treated group, respectively, with no significant difference between the two groups (P>0.05) (Fig. 1a and b).
Global acne grading system
Baseline GAGS of both groups ranged from severe to very severe (Table 2), and the mean GAGS score was 53.08 and 53.36 in the antihistamine-treated and control groups, respectively, with no significant difference between the two groups as regards both GAGS grade and mean score (P>0.05) (Fig. 1d).
Clinical evaluation after 16 weeks
Acne lesion count
Both comedonal lesions and noncomedonal lesions decreased significantly after 16 weeks in both groups (Fig. 2). The mean comedones’ count reduced to 4.32 in the antihistamine-treated group and to 8.2 in the control group (Fig. 1a). Similarly, the mean noncomedonal lesion counts were reduced to 3.44 in the treated group and to 6.6 in the control group (Fig. 1b). Accordingly, comedones were reduced significantly in the antihistamine-treated group compared with the control group (P=0.003), and the same was observed for noncomedonal lesions (P=0.019) (Fig 1a and b). Both groups showed a significant reduction in their total acne lesion count after 16 weeks of treatment; however, this change was more significantly apparent in the antihistamine-treated group compared with the control group (P=0.006) (Fig. 1c).
Global acne grading system
After 16 weeks, GAGS improved significantly in both groups. In the antihistamine-treated group, all patients showed mild GAGS (100%). However, the control group still had moderate, severe, and very severe acne cases (4, 8, and 4%, respectively) (Table 2). Although there was no significant difference between the two groups as regards GAGS grade (Table 2), the mean GAGS scores were significantly lower in antihistamine-treated cases compared with controls (P=0.006) (Fig. 1d).
Acne flare and other side effects
No significant difference was detected between the two groups as regards the occurrence of acne flare and other side effects including xerosis, chelitis, and pruritus either at the beginning or within the course of treatment (P>0.05) (Table 3).
There was a significant difference between the two groups as regards clinical improvement as 72% of antihistamine-treated patients showed complete cure, whereas only 28% of the control group showed similar cure. Moreover, no patient from the antihistamine-treated group showed worsening of their acne, whereas 8% of the control group showed some relative worsening (P=0.005) (Table 3).
Patient satisfaction and quality of life
Patient satisfaction according to the DLQI tended to be better among antihistamine-treated patients compared with controls, as 64% of antihistamine-treated patients were very satisfied, whereas 36, 24, and 8% of controls were satisfied, slightly satisfied, and nonsatisfied, respectively (P=0.07) (Table 4).
Although oral isotretinoin is the most effective treatment for severe acne, the use of isotretinoin has been modified to treat those patients with less severe but scarring acne who are responding unsatisfactorily to conventional therapies 10.
Resistance to isotretinoin therapy has been noted in the clinical settings; some factors may be responsible for this as predicted by Cakir et al.11, such as age of patients, type and number of lesions, heredity, and presence of polycystic ovary disease in women. Moreover, Preneau et al.12 proposed positive factors of response to isotretinoin in female patients. Those factors included absence of smoking and early-onset acne, low glycemic-load diet, low BMI, and absence of lesions on the neck. Hence, researchers are trying to enhance response to isotretinoin either by modulating its regimens or by introducing other drugs in combination.
Isotretinoin is the only drug, currently available, that affects each of the pathogenic factors involved in acne 13,14. However, its use is associated with many side effects, some of which can result in very disastrous consequences. To overcome these concerns, several reports indicate that acne patients have been benefiting from the low dose or intermittent treatment protocols rather than conventional recommended daily dose of 0.5–1.0 mg/kg 10.
Understanding the mechanism of sebum reduction may develop new alternatives to retinoids. Pelle et al.5 examined the possibility of sebum reduction in a sebocyte cell-culture model system using an antihistamine.
In 2006, Yavari 15 hypothesized that antihistamines may be used as an ‘adjuvant’ in the treatment of all kinds of acne. Accordingly, in the present study, we tried to evaluate the efficacy and tolerability of using H1-antagonist, levocetrizine hydrochloride 5 mg daily, as an adjuvant therapy to oral retinoids in treating acne vulgaris in the clinical setting.
Cetirizine and levocetirizine are piperazine derivative antihistamines. Levocetirizine is a newer second-generation antihistamine with greater affinity to H1-receptors and fewer anticholinergic side effects 16. Thus, it has a broad safety profile and is well tolerated 17.
Taking into consideration the general concept of inflammation (redness, hotness, and pain), acne is traditionally classified as noninflammatory (open and closed comedones) and inflammatory (other lesions including papules, pustules, and nodules). With the knowledge advancement, this concept seems to be wrong and therefore acne would be an inflammatory disease even before the onset of their clinical lesions 18.
In the current study, both GAGS score and acne lesion counts decreased significantly after 16 weeks both in the group that used isotretinoin alone and the other group that used combined isotretinoin and H1-antagonist. However, the lesions’ count (comedones, noncomedonal lesions, and total) and the mean GAGS score were significantly lower in the antihistamine-treated group compared with the control group. This is in agreement with the findings of Lee et al.19, who reported a highly statistically significant decrease in acne lesion counts in isotretinoin with additional antihistamine group compared with the isotretinoin only group.
This could be attributed to the fact that the inflammatory process of the acne is mediated by the histamines and leukotrienes. Thus, the use of antihistamine may effectively prevent the development of new lesions and enhance the resolution of old ones. In addition, it has been proved that H1-receptor is present in sebaceous glands, and a H1-receptor antagonist significantly decreases squalene levels 5. As retinoids had been shown to reduce sebum, antihistamine activity in sebocytes might represent an adjunctive or, perhaps, an alternative treatment to retinoid therapy for acne. The combination of a squalene-reducing agent with a retinoid is particularly interesting because, although retinoids reduce sebum in general, they have little effect on squalene 20.
On the basis of our finding and the previous finding of Lee et al.19 that comedones are affected with the use of antihistamine, we present clinical evidence that acne is an inflammatory disease from the start as explained above. However, this result also may be attributed to decreased squalene production by antihistamines that may affect comedone formation. Thus, the pathomechanism of how histamine antagonist can affect comedones particularly is in need for further larger scale in-vivo and in-vitro investigations.
Acne has a large negative impact on patients’ psychosocial health, especially when severe 21. Successful treatment of acne using either topical or systemic therapy reduces both depressive and anxiety symptoms and improves the quality of life 22. As known, isotretinoin has some negative influence on patients’ mood, including depression with suicidal ideation, psychosis, and mania 23,24. Among many studies, some revealed those adverse effects, and, in contrast, some others showed its improving effect on mood 25. Definitely, the remarkable effect of isotretinoin treatment on acne will improve the DLQI irrespective of its mood effect, if occurred. This has been proved by previous studies 26–28. In our study, although isotretinoin significantly improved patients’ DLQI in both groups, the concomitant use of antihistamine showed better DLQI than that using isotretinoin alone. This may be attributed to the significant clinical cure of the antihistamine-treated patients.
The absence of side effects tended to be higher in antihistamine-treated patients than in control patients (eight vs. five patients, respectively); however, no difference has been detected between two groups as regards the occurrence of acne flare or other cutaneous side effects of isotretinoin. This is in contrast to the findings of Lee et al.19, who reported that antihistamines might assist in minimizing the adverse effects of isotretinoin and in preventing the occurrence and severity of acne flares. This controversy may be attributed to the different studied populations, type of the prescribed antihistamine, and follow-up period. In addition, itching in acne patients is multifactorial and there is a debate about its pathomechanisms that certainly differ among patients.
Interestingly, many patients with acne scratch their skin lesions, but acne is not usually considered to be a pruritic skin disease, and scratching per se does not necessarily mean that the patient has pruritus 7. It seems that patients with acne may experience itching because of subclinical dermographism. Those patients reported that their acne lesions produced symptoms of itching, burning, soreness, and/or tenderness. In most of these individuals, itching resolved after antihistaminic therapy 29. However, in other acne patients, itching may be affected by patient’s psychological state. McEvoy et al.30, observed that young patients with acne usually overestimate the severity of this disease and even itching of mild intensity might be perceived as a very bothersome or disturbing symptom. Moreover, pruritus may be a complication of topical or systemic acne therapy or a consequence of the use of different cosmetics for acne. In summary, Reich et al.7, reported that ‘It seems that, in some teenagers, acne itching should be considered an important target for antipruritic therapy. The use of antihistaminic agents has not been sufficiently proved; however, they seem to be of help in selected patients at least, especially those presenting with symptoms of dermographism. Further studies are required to better determine the clinical characteristics of itching in acne patients and to understand the underlying pathogenetic mechanism’.
Acne patients may benefit from the use of H1-antagonists as an adjuvant therapy to systemic isotrertinoin with better efficacy and clinical cure. The occurrence of cutaneous side effects of isotretinoin is not affected by the concomitant use of antihistamines, although the patients experienced better satisfaction. It is also recommended to test (investigate) the use of systemic antihistamines as a single therapeutic agent for acne.
The relatively small sample size limits the power of this study, and hence the results should not be confirmatory. Therefore, these data are in need for further larger scale investigations to be proved.
This manuscript has been read and approved by all authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest work.
Conflicts of interest
There are no conflicts of interest.
1. Harper JC, Thiboutot DM. Pathogenesis of acne: recent research advances. Adv Dermatol 2003; 19:1–10.
2. Webster GF. The pathophysiology of acne. Cutis 2005; 76:4–7.
3. Das S, Reynolds RV. Recent advances in acne pathogenesis: implications for therapy. Am J Clin Dermatol 2014; 15:479–488.
4. Artuc M, Steckelings UM, Grutzkau A, Smorodchenko A, Henz BM. A long-term coculture model for the study of mast cell-keratinocyte interactions. J Invest Dermatol 2002; 119:411–415.
5. Pelle E, McCarthy J, Seltmann H, Huang X, Mammone T, Zouboulis CC, et al. Identification of histamine receptors and reduction of squalene levels by an anthistamine in sebocytes. J Invest Dermatol 2008; 128:1280–1285.
6. Malaviya R, Morrison AR, Pentland AP. Histamine in human epidermal cells is induced by ultraviolet light injury. J Invest Dermatol 1996; 106:785–789.
7. Reich A, Trybucka K, Tracinska A, Samotij D, Jasiuk B, Srama M, et al. Acne itch: do acne patients suffer from itching? Acta Derm Venereol 2008; 88:38–42.
8. Doshi A, Zaheer A, Stiller MJ. A comparison of current acne grading systems and proposal of a novel system. Int J Dermatol 1997; 36:416–418.
9. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI) – A simple practical measure for routine clinical use. Clin Exp Dermatol 1994; 19:210–216.
10. Akman A, Durusoy C, Senturk M, Koc CK, Soyturk D, Alpsoy E. Treatment of acne with intermittent and conventional isotretinoin
: a randomized, controlled multicenter study. Arch Dermatol Res 2007; 299:467–473.
11. Cakir GA, Erdogan FG, Gurler A. Isotretinoin
treatment in nodulocystic acne with and without polycystic ovary syndrome: efficacy and determinants of relapse. Int J Dermatol 2013; 52:371–376.
12. Preneau S, Dessinioti C, Nguyen JM, Katsambas A, Dreno B. Predictive markers of response to isotretinoin
in female acne. Eur J Dermatol 2013; 23:478–486.
13. Melnik BC. FoxO1 – the key for the pathogenesis and therapy of acne? J Dtsch Dermatol Ges 2010; 8:105–114.
14. Lee JW, Yoo KH, Park KY, Han TY, Li K, Seo SJ, et al. Effectiveness of conventional, low-dose and intermittent oral isotretinoin
in the treatment of acne: a randomized, controlled comparative study. Br J Dermatol 2011; 164:1369–1375.
15. Yavari V. Antihistamines
may be used as an ‘adjuvant’ in treatment of all kinds of acne. Med Hypotheses 2006; 66:447–448.
16. Cravo M, Gonçalo M, Figueiredo A. Fixed drug eruption to cetirizine with positive lesional patch tests to the three piperazine derivatives. Int J Dermatol 2007; 46:760–762.
17. Badawi AH, Tefft K, Fraga GR, Liu DY. Cetirizine-induced acute generalized exanthematous pustulosis: a serious reaction to a commonly used drug. Dermatol Online J 2014; 20:22613.
18. Rocha MA, Costa CS, Bagatin E. Acne vulgaris
: an inflammatory disease even before the onset of clinical lesions. Inflamm Allergy Drug Targets 2014; 13:162–167.
19. Lee HE, Chang IK, Lee Y, Kim CD, Seo YJ, Lee JH, et al. Effect of antihistamine as an adjuvant treatment of isotretinoin
in acne: a randomized, controlled comparative study. J Eur Acad Dermatol Venereol 2014; 28:1654–1660.
20. Zouboulis CC, Korge B, Akamatsu H, Xia LQ, Schiller S, Gollnick H, et al. Effects of 13-cis-retinoic acid, and acitretin on the proliferation, lipid synthesis and keratin expression of cultured human sebocytes in vitro. J Invest Dermatol 1991; 96:792–797.
21. Jones-Caballero M, Chren M, Soler B, Pedrosa E, Peñas PF. Quality of life in mild to moderate acne: relationship to clinical severity and factors influencing change with treatment. J Eur Acad Dermatol Venereol 2007; 21:219–226.
22. Kaymak Y, Taner E, Taner Y. Comparison of depression, anxiety and life quality in acne vulgaris
patients who were treated with either isotretinoin
or topical agents. Int J Dermatol 2009; 48:41–46.
23. Byrne A, Costello M, Greene E, Zibin T. Isotretinoin
therapy and depression-evidence for an association. Irish J Psychosom Med 1998; 15:58–60.
24. Cott AD, Wisner KL. Isotretinoin
treatment of a woman with bipolar disorder. J Clin Psychiatry 1999; 60:407–408.
25. Golchai J, Khani SH, Heidarzadeh A, Eshkevari SS, Alizade N, Eftekhari H. Comparison of anxiety and depression in patients with acne vulgaris
and healthy individuals. Indian J Dermatol 2010; 55:352–354.
26. McGrath EJ, Lovell CR, Gillison F, Darvay A, Hickey JR, Skevington SM. A prospective trial of the effects of isotretinoin
on quality of life and depressive symptoms. Br J Dermatol 2010; 163:1323–1329.
27. Dunn LK, O’Neill JL, Feldman SR. Acne in adolescents: quality of life, self-esteem, mood, and psychological disorders. Dermatol Online J 2011; 17:1.
28. Fakour Y, Noormohammadpour P, Ameri H, Ehsani AH, Mokhtari L, Khosrovanmehr N, et al. The effect of isotretinoin
(roaccutane) therapy on depression and quality of life of patients with severe acne. Iran J Psychiatry 2014; 9:237–240.
29. Fisher DA. A syndrome of acne vulgaris
and subclinical demographic urticaria. Cutis 1991; 47:429–432.
30. McEvoy B, Nydegger R, Williams G. Factors related to patient compliance in the treatment of acne vulgaris
. Int J Dermatol 2003; 42:274–280.