Abstract
Introduction
Rosacea is a common chronic inflammatory dermatosis characterized by erythema, telangiectasia, papules, and pustules on the central face. The frequency of contact sensitization complicating rosacea and its therapy is unknown, with only few studies published in the literature. In the present study, we aimed to evaluate contact sensitivity in patients with rosacea.
Methods
A total of 50 rosacea patients and 50 age- and sex-matched healthy controls were enrolled. Both groups were patch tested with the European Baseline Series.
Results
A positive reaction to at least one allergen of the European Baseline Series was observed in 15 (30%) of rosacea patients and 10 (20%) of the healthy controls. Although the rate of positive reaction in the rosacea group was higher than in the controls, no statistically significant difference was documented. In addition, the total number of positive reactions to allergens in the rosacea group was higher than the control group, namely, 26 versus 17.
Conclusion
Contact hypersensitivity may coexist with rosacea. Its identification holds significant clinical relevance, influencing the long-term management and justifying the application of patch testing in rosacea patients.
Keywords: Rosacea, Patch tests, Contact allergy, Contact dermatitis, European Baseline Series
Introduction
Rosacea is a chronic, relapsing, inflammatory skin disorder characterized by the presence of intermittent or persistent erythema, inflammatory papules and pustules, and telangiectasias. It usually affects the central face (cheeks, chin, nose, and central forehead) and less commonly occurs on the neck and chest area [1]. Rosacea prevalence ranges from less than 1% to more than 20% in Europe and North America. Rosacea appears to be more prevalent among middle-aged adults, especially those with lighter skin phototypes [2]. It is more common in females, while the phymatous subtype more commonly affects elderly males [3].
Rosacea is classified into 4 clinical subtypes: erythematotelangiectatic, papulopustular, phymatous, and ocular [4]. The pathogenesis is multifactorial and remains largely unclear [5]. Genetic predisposition; dysregulation of the innate and adaptive immune system, including upregulated cathelicidin and kallikrein; microorganisms, especially Demodex folliculorum and possibly Helicobacter pylori; ultraviolet light radiation; neurogenic dysregulation; and abnormal epidermal barrier function have all been implicated in the development of rosacea [4]. There are well-known trigger factors for rosacea, such as sun exposure, warm and cold weather, hot beverages, spicy food, alcohol, as well as physical and emotional stress [4].
Rosacea patients often exhibit adverse reactions to topical agents, making the selection of the appropriate therapeutic and cosmetic formulations rather challenging. Moisturizers and cosmetics have been reported to play a role by activating peripheral sensory nerve endings [6]. Moreover, sensitive and inflamed skin may be more prone to delayed-type hypersensitivity [7].
The frequency of contact sensitization complicating rosacea and its therapy is unknown, with only a few data available in the literature [8–19]. In the present study, we sought to evaluate the development of contact delayed hypersensitivity among patients with rosacea.
Materials and Methods
A total of 50 adult (aged ≥18 years) patients with rosacea, attending the outpatient clinics of the 2nd Department of Dermatology and Venereology at “Attikon” General University Hospital and of the 1st Department of Dermatology and Venereology at “Andreas Syggros” Hospital, Athens, Greece, have been included in the study. The patients had not been treated for rosacea during the last 6 months. Exclusion criteria were pregnant or nursing females, those under treatment with systemic antihistamines or topical steroids within 1 week of the test or during the test, and those who had used systemic steroids or other immunosuppressive treatment during the last month. Fifty age- and sex-matched healthy volunteers served as controls. All participants were informed about the purpose and the methods of the study and gave their signed consent. The study was approved by the Ethics Committee of both hospitals.
The diagnosis of rosacea was based on the updated diagnostic criteria of the new standard classification of rosacea by the National Rosacea Society Expert Committee [19]. All participants, patients and healthy controls, were tested using the “European Baseline Series” (Chemotechnique Diagnostics, Malmo, Sweden), which contains 30 allergens, using the IQ Chamber test material (Chemotechnique IQ Chamber®; Chemotechnique Diagnostics). The tests were immediately applied on patients’ upper back to prevent evaporation and left under occlusion for 48 h. Patch test reactions were read on days 2, 4, and 7. The reactions were assessed as recommended by the “International Contact Dermatitis Research Group.”
Statistical analysis involved the Pearson χ2 when assessing the sex and the positivity of patch testing. Α t test was used for age. The Stata SE ver. 11.0 software was used for the analyses. A p value <0.05 was accepted as the criterion for statistical significance.
Results
Of the 50 rosacea patients enrolled, 40 (80%) were females. The mean age was 51.2 years (range: 30–78 years). There were 29 (58%) Fitzpatrick skin phototype II patients, 17 (34%) type III, and 4 (8%) type IV. As far as the clinical subtype is concerned, there were 22 (44%) patients with erythematotelangiectatic rosacea, 17 (34%) with papulopustular type, 10 (20%) with phymatous type, and 1 (2%) with granulomatous type. Ocular involvement was observed in 21 patients (42%). In the control group, there were 38 (76%) females, with a mean age of 48.28 years (range: 23–85 years). There was no statistical significance between the two groups as far as sex and age are concerned (p = 0.629 and 0.295, respectively). The epidemiological and clinical characteristics of rosacea patients and controls are summarized in Table 1.
Table 1.
Clinical and epidemiological features of rosacea patients and healthy controls in our study
| Clinical and epidemiological features | Patients, n (%) | Controls, n (%) |
|---|---|---|
| Gender | ||
| Male | 10 (20) | 12 (24) |
| Female | 40 (80) | 38 (76) |
| Age, years | ||
| Mean age | 51.2 | 48.28 |
| Range | 30–78 | 23–85 |
| Fitzpatrick skin type | ||
| I | 0 | 0 |
| II | 29 (58) | 20 (40) |
| III | 17 (34) | 22 (44) |
| IV | 4 (8) | 8 (16) |
| Rosacea subtype | ||
| Erythematotelangiectatic | 22 (44) | Not applicable |
| Papulopustular | 17 (34) | |
| Phymatous | 10 (20) | |
| Ocular | 21 (42) | |
| Granulomatous | 1 (2) | |
A positive reaction to at least 1 allergen in the European Baseline Series was found in 15 (30%) subjects in the patient group and in 10 (20%) subjects in the control group. Although the percentage of individuals with a positive reaction to at least one allergen was higher in the patient group, compared to the control, the difference did not reach a statistical significance (p = 0.248). There were: 9 patients (18%) and 6 controls (12%) with a positive reaction to only 1 allergen; 3 patients (6%) and 3 controls (6%) with a positive reaction to 2 allergens; 3 patients (8%) and no controls with a positive reaction to 3 allergens; and one control with positive reactions to 6 allergens. The distribution of patients according to the number of positive reactions to allergens of the European Baseline Series is depicted in Table 2.
Table 2.
Number of positive reactions to allergens of the European Baseline Series for patients and controls in our study
| No. of positive reactions to allergens | Patients, n (%) | Controls, n (%) |
|---|---|---|
| ≥1 | 15 (30) | 10 (20) |
| 1 | 9 (18) | 6 (12) |
| 2 | 3 (6) | 3 (6) |
| 3 | 3 (6) | 0 |
| 6 | 0 | 1 (2) |
Among patients, positive reaction was most commonly observed for colophonium in 5 (10%) patients, followed by nickel sulfate and Balsam of Peru in 4 (8%), and paraphenylenediamine (PPD) in 3 (6%). Allergens to which positive reactions were observed among patients and controls are listed in Table 3.
Table 3.
Distribution of positive reactions to allergens of the European Baseline Series among rosacea patients and healthy controls in our study
| Allergens of the European Baseline Series | Patients, n (%) | Controls, n (%) |
|---|---|---|
| Colophonium | 5 (10) | 0 |
| Nickel sulfate | 4 (8) | 7 (14) |
| Balsam of Peru | 4 (8) | 2 (4) |
| Paraphenylenediamine (PPD) | 3 (6) | 1 (2) |
| Textile dye Mix | 2 (4) | 0 |
| Fragrance mixture I | 1 (2) | 0 |
| Fragrance mixture II | 1 (2) | 2 (4) |
| Sesquiterpene lactone mix | 1 (2) | 1 (2) |
| Potassium dichromate | 1 (2) | 1 (2) |
| Neomycin sulfate | 1 (2) | 0 |
| Cobalt | 1 (2) | 2 (4) |
| Methylisothiazolinone + methylchloroisothiazolinone | 0 | 1 (2) |
| Methyldibromo glutaronitrile (MDBGN) | 0 | 1 (2) |
Discussion
This prospective study aimed to investigate delayed contact hypersensitivity in patients with rosacea. The current popular theory on the pathogenesis of rosacea is based on the interaction between the neuroimmune system and innate immunity. Until the day of writing, few published studies have evaluated the role of delayed hypersensitivity reactions and T-cell-mediated inflammation in the pathogenesis of rosacea.
Corazza et al. [8] were the first to investigate the incidence of contact dermatitis in 29 rosacea patients. They found a positive reaction to at least 1 allergen in 41% of the patients. Jappe et al. [9] retrospectively analyzed data from 361 patch-tested patients with rosacea. Of them, 138 (38.2%) had shown positive reactions to baseline, cosmetic, and topical medicaments series. Çakmak et al. [10] evaluated contact allergy using the patch test with the European Cosmetic Series in 25 rosacea patients and 20 control subjects and found a positive reaction to at least 1 allergen in 32% of the patients. There was no positive reaction to the cosmetic series in the control group. In a later prospective study, Jappe et al. [11] patch tested 78 patients with rosacea, of whom 49 (62.8%) showed at least one positive reaction. Pónyai et al. [12] found evidence of contact hypersensitivity in 35.4% of 82 rosacea patients. Darlenski et al. [13] tested 28 rosacea patients and 32 controls with the European Baseline Series, and no significant difference was documented in the number of positive reactions between the two groups. However, the total number of positive reactions was three times higher in rosacea patients than in healthy controls. Diczig et al. [14] showed contact hypersensitivity in 37.8% of the 143 rosacea patients. Erdogan et al. [15] found a positive reaction to at least 1 allergen in 32.3% of the rosacea group and 20% of the control subjects. Nickel sensitivity in rosacea was evaluated in a study with 40 rosacea patients and 40 age- and sex-matched volunteers. The positivity rates in the two groups were 52.5% and 22.5%, respectively [16]. In a recent study involving 103 rosacea patients and 104 healthy individuals tested with the European Cosmetic Series, a strikingly high prevalence of contact sensitization to cosmetic allergens among rosacea patients compared to the control group (60.2% vs. 24% positive reaction to at least one allergen, respectively) was observed [17]. In a similar study from China, testing 267 rosacea patients and 100 age- and sex-matched individuals with the European Cosmetic Series, positive reactions were seen in 57.3% of rosacea patients versus 27% of controls [18]. Finally, in the most recent study, a 46.5% rate of positive reactions was noted among 200 rosacea patients, highlighting the high prevalence of allergic contact sensitization in patients with rosacea [19].
All but one (conducted in China) of the aforementioned studies were conducted in European countries, such as Spain, Germany, Austria, Italy, Bulgaria, Turkey, and Hungary. It must be noted that a wide heterogeneity, not only in the characteristics of the rosacea patients but also in the patch test series employed, was evident. Table 4 summarizes the methods and the results of the published experience on contact allergy in rosacea patients. The distribution of allergens to which positive reactions were observed in each study is presented in Table 5. Our comprehensive analysis suggests a potential correlation between rosacea and contact hypersensitivity. While a statistically significant disparity is not always evident, the heightened incidence of positive reactions in patch testing among rosacea patients compared to healthy controls may be pathogenetically relevant. In our study, the rate of contact allergy among rosacea patients stands at 30%, aligning with previous reports in the literature. Building upon earlier research, a positive association between rosacea and contact hypersensitivity may exist.
Table 4.
Previous studies investigating contact delayed hypersensitivity in rosacea patients
| Study | Country | Patch test series | No. of rosacea patients | No. of controls | Percentage of rosacea patients with positive reaction to ≥1 allergen | Percentage of controls with positive reaction to ≥1 allergen |
|---|---|---|---|---|---|---|
| Corazza et al. [8] (1997) | Italy | GIRDA standard series | 29 | _ | 41% | _ |
| Jappe et al. [9] (2005) | Germany, Austria, Switzerland | ICDRG standard series extended by DKG | 361 | _ | 38.2% | _ |
| Cakmak et al. [10] (2007) | Turkey | European Cosmetic Series | 25 | 20 | 32% | 0% |
| Jappe et al. [11] (2008) | Germany | ICDRG standard series extended by DKG | 78 | _ | 62.8% | _ |
| Pónyai et al. [12] (2012) | Hungary | Brial GmbH D-Greven series | 82 | _ | 35.4% | _ |
| Darlenski et al. [13] (2013) | Bulgaria | European Baseline Series | 28 | 32 | Equal | Equal |
| Diczig et al. [14] (2018) | Hungary | Unknown | 143 | _ | 37.8% | _ |
| Erdogan et al. [15] (2018) | Turkey | European Baseline Series | 65 | 60 | 32.3% | 20% |
| Cifci et al. [16] (2019) | Turkey | Nickel units from European Standard Series | 40 | 40 | 52.5% | 22.5% |
| Ozbagcivan et al. [17] (2020) | Turkey | European Cosmetic Series | 103 | 104 | 60.2% | 24% |
| Chen et al. [18] (2021) | China | Skin patch tests with C-1000 cosmetic series (Chemotechnique Diagnostics, Malmo, Sweden | 267 | 100 | 57.3% | 27% |
| Magdaleno-Tapial et al. [19] (2022) | Spain | Standard series of Spanish Contact Dermatitis and Skin Allergy Research Group | 200 | – | 46.5% | – |
Table 5.
Rates (%) of positive reactions to allergens in previously published studies
| Allergen | Corazza et al. [8] (1997) | Jappe et al. [9] (2005) | Jappe et al. [11] (2008) | Pónyai et al. [12] (2012) | Diczig et al. [14] (2018) | Erdogan et al. [15] (2018) | Cifci et al. [16] (2019) | Ozbagcivan et al. [17] (2020) | Chen et al. [18] (2021) | Magdaleno-Tapial et al. [19] (2022) |
|---|---|---|---|---|---|---|---|---|---|---|
| Potassium dichromate | 3.4 | 4.6 | 5.1 | |||||||
| Paraphenylenediamine (PPD) | 3.4 | 3.7 | 3.5 | 1.5 | 5.5 | |||||
| Thiuram mix | ||||||||||
| Neomycin sulfate | 1.3 | |||||||||
| Cobalt | 3.1 | 6.5 | ||||||||
| Caine mix III | ||||||||||
| Nickel | 3.4 | 9.3 | 15.4 | 7.3 | + | 20 | 52.5 | 26 | ||
| 2-Hydroxyethyl methacrylate | ||||||||||
| Colophonium | 3.4 | 2 | ||||||||
| Paraben mix | ||||||||||
| N-isopropyl-N’-phenyl paraphenylenediamine (IPPD) | 3.7 | |||||||||
| Lanolin alcohol | 3.4 | 3.7 | 3.5 | |||||||
| Mercapto mix | ||||||||||
| Epoxy resin | 1.5 | |||||||||
| Peru Balsam | 6.9 | 5.9 | 10.4 | 6.1 | 6.3 | 13.9 | ||||
| Para tertiary butylphenol (PTBP) formaldehyde resin | ||||||||||
| 2-Mercaptobenzothiazole (MBT) | 1.5 | |||||||||
| Formaldehyde | 14.8 | |||||||||
| Fragrance mix I | 10.3 | 8.8 | 5.2 | 4.9 | 1.5 | 21.3 | 1 | |||
| Sesquiterpene lactone | ||||||||||
| Sodium metabisulfate | ||||||||||
| Propolis | 2.8 | 10.7 | ||||||||
| Methylisothiazolinone + methylchloroisothiazolinone | 28.7 | |||||||||
| Budesonide | 1.5 | |||||||||
| Tixocortol | 1.5 | 1 | ||||||||
| Methyldibromo glutaronitrile | ||||||||||
| Fragrance mix II | 3.1 | 5.5 | ||||||||
| Hydroxyisohexyl 3-cyclohexenecarboxaldehyde | 3.8 | 3.1 | ||||||||
| Methylisothiazolinone | 17.2 | 6 | ||||||||
| Benzisothiazolinone | ||||||||||
| Textile dye mix | 4.6 | |||||||||
| Decyl glucoside | ||||||||||
| Thiomersal | 13.7 | 6.9 | 6.8 | 3.5 | ||||||
| Ammoniated Mercury | ||||||||||
| Methyldibromo glutaronitrile (MDBGN) | − | − | − | − | − | − | − | − | − | − |
| Gentamycin | 8.0 | |||||||||
| Framycetin | 5.3 | |||||||||
| Propylene glycol | 4.2 | |||||||||
| Quanterium 15 | 1.5 | |||||||||
| Phenylbutazone | ||||||||||
| Cosmetic series | ||||||||||
| Octyl gallate | 10.7 | |||||||||
| Dodecyl gallate | 8.7 | |||||||||
| Tert-Butylhydroquinone | 7.8 | |||||||||
| Euxyl K 400 | 6.8 | |||||||||
| Cocamidopropyl betaine | 5.8 | |||||||||
| 2,6-Di-tert-butyl-4-cresol | 4.9 | |||||||||
| Wood Tar | 3.5 | |||||||||
| Linalool hydroperoxide | 27.1 | |||||||||
| Limonene hydroperoxides | 16.4 | |||||||||
| Toluenesulfonamide formaldehyde | 2 |
+, positive reaction documented, but rate (%) of positive reactions was not quantified; −, no data available/no positive reaction documented.
The notion that contact allergy could serve as a potential trigger for rosacea has been postulated, suggesting the involvement of the adaptive immune system in this intricate relationship. Although the role of the adaptive immune system is unequivocal in the context of contact dermatitis, its involvement in rosacea pathogenesis remains obscure [20]. Rosacea pathophysiology involves a complex interplay of the innate and adaptive immune systems, vasoregulatory genes, neuroimmune communication, significant vascular and possibly lymphatic vessel alterations, and activation of various resident skin cells [21]. Though limited, extant studies point to the presence of T cells and B cells in the cellular infiltrate associated with rosacea. Specifically, CD4+ T cells are more frequently observed than CD8+ T cells in papulopustular and non-pustular rosacea [22]. A lympho-monocytic infiltrate composed mainly of CD4+ T cells, CD20+ B cells, and histiocytes has been described [23]. In all rosacea subtypes, the T-cell response is characterized by a prevalent Th1/Th17 polarization, as evidenced by substantial upregulation of key cytokines, such as IFN-γ or IL-17, while a notable increase in macrophages and mast cells is consistently observed [24]. Furthermore, a type IV immunologic response, coupled with lymphocyte infiltration around Demodex folliculorum-containing follicles, has been documented in the perivascular region [25]. Increased expression of genes related to both adaptive and innate immune responses has been documented in individuals with erythematotelangiectatic, papulopustular, and phymatous rosacea, suggesting a substantial contribution from the adaptive immune system, albeit with incomplete comprehension [26].
Another possible connection between rosacea and contact dermatitis may be the compromised epidermal barrier function, which may be responsible for symptoms commonly encountered in rosacea, such as itching, burning, and stinging sensation [27]. Inflammation is known to impair the skin barrier function, resulting in increased transepidermal water loss; this may further potentiate the inflammatory process and, consequently, render the skin more susceptible to allergens [28]. The observed high prevalence of contact dermatitis in rosacea patients surpasses that documented in other inflammatory skin conditions, such as psoriasis [28]. This possibly elucidates the etiologico-pathogenic hypothesis, implicating a compromised skin barrier fostering allergic contact dermatitis development in these patients. Moreover, the investigation into papulopustular rosacea by Medgyesi et al. [29] highlights stratum corneum impairment, reduced intracellular lipids, and diminished antimicrobial peptides, paralleling findings in atopic dermatitis. Thus, clinicians should be vigilant regarding contact allergy in cases of rosacea patients reporting sensitivity to cleansers, cosmetics, and topical treatments.
This study is subject to several limitations that warrant cautious interpretation of its findings. First, the sample size employed in this research is relatively small, which may compromise the generalizability of the results to a broader population. Additionally, the omission of cosmetic series and the exclusive reliance on European Standard Series for patch testing introduce a constraint, given that cosmetic-associated allergens seem to prevail in rosacea patients. These limitations underscore the need for future research with larger samples, as well as a comprehensive inclusion of relevant allergen series for a more nuanced understanding of contact allergies in the context of rosacea.
Conclusions
This is the first study evaluating contact hypersensitivity in rosacea patients in Greece, with our findings corroborating previously published data. In our study, an increased frequency of positive reactions to allergens compared to healthy controls was observed, suggesting that delayed contact hypersensitivity may underlie rosacea. This association may be attributed to the activation of the adaptive immune system and concurrent impairment of the epidermal barrier function. The identification of contact hypersensitivity in rosacea patients holds significant clinical relevance, influencing their long-term management and justifying the application of patch tests, particularly for those experiencing exacerbated symptoms with cosmetic products or topical drugs. The exploration of skin allergy proves valuable for secondary prevention through allergen avoidance, extending to primary prevention by advising on fragrance-free, non-sensitizing cosmetic product choices. It is imperative to inform rosacea patients about potential testing before regular product application and recognize that topical drugs may contribute to worsened condition, warranting consideration as potential allergens in diagnostic evaluations. Nevertheless, further research is needed to affirm whether contact dermatitis plays a role in exacerbating rosacea or if rosacea renders the skin more susceptible to contact dermatitis.
Statement of Ethics
The study was conducted according to the principles expressed in the Declaration of Helsinki. This study protocol was reviewed and approved by the Scientific Committee of “Attikon” General University Hospital (approval number: 1647/28-6-16) and of “Andreas Syggros” Hospital (approval number: 2813/14-2-2018). All participants provided a signed informed consent.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors have no funding sources to declare relevant to this work.
Author Contributions
Conceptualization: Alexander Katoulis; methodology and writing – original draft: Antigoni Alevizou; project administration: Alexander Katoulis and Stamatios Gregoriou; validation: Dimitris Rigopoulos; investigation and writing – review and editing: Antigoni Alevizou and Georgia Pappa; data curation: Antonios Tsimpidakis and Georgia Pappa; visualization: Stamatios Gregoriou; and supervision: Alexander Katoulis, Stamatios Gregoriou, and Dimitris Rigopoulos. All authors have read and agreed to the published version of the manuscript.
Funding Statement
The authors have no funding sources to declare relevant to this work.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author, Dr. Georgia Pappa.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author, Dr. Georgia Pappa.