Dermatology: Practical and Conceptual Original Article | Dermatol Pract Concept. 2024;14(1):e2024034 1 Efficacy of Topical Dapsone 5% Gel for the Treatment of Erythematotelangiectatic Rosacea: New Treatment Option With Old Drug Şule Gökşin1, Işıl Göğem İmren2, Nida Kaçar1 1 Pamukkale University Medical Faculty, Dermatology Department, Denizli, Turkey 2 Denizli State Hospital, Dermatology Department, Denizli, Turkey Key words: Dapsone gel, treatment, adverse events, erythematotelangiectatic rosacea. Citation: Gökşin Ş, Göğem İmre I, Kaçar N. Efficacy of Topical Dapsone 5% Gel for the Treatment of Erythematotelangiectatic Rosacea: New Treatment Option With Old Drug. Dermatol Pract Concept. 2024;14(1):e2024034. DOI: https://doi.org/10.5826 /dpc.1401a34 Accepted: July 26, 2023; Published: January 2024 Copyright: ©2024 Gökşin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: Şule Gökşin; Design, Concept, Literature search, Analysis and Interpretation, Writing, Critical Review, Işıl İmren Göğem; Design, Concept, Data Collection and Processing, Literature search, Statistical Analysis, Nida Kaçar; Supervision. Corresponding Author: Şule Gökşin, Çamlaraltı Mahallesi, Doğan Demircioğlu Caddesi, No:71 Aytuğ Apt. Daire:5, PK:20160, Kınıklı – Denizli / TURKEY. Tel. Mobil: +90.532.2520634 Fax: +90.258.2966001. E-mail: sule.goksin@hotmail.com Introduction: Many topical drugs are used in the treatment of erythematotelangiectatic rosacea (ETR). However, dapsone 5% gel has never been used in ETR to date. Objectives: To evaluate the efficacy of dapsone 5% gel as a new treatment option for ETR. Methods: Thirty-five patients with ETR were included in the study. Diagnosis was made with Nation- al Rosacea Society criteria. Dapsone 5% gel was used topically twice a day for 12 weeks. Investigator Global Assessment (IGA) 4-point scale ( 0 → Clean, 1 → mild, 2 → moderate, 3 → severe, 4 → very severe), Visual Analogue Scale (VAS) and Dermatology Life Quality Index (DLQI) were used for eval- uation (at baseline, 2nd, 6th, and 12th weeks). Results: IGA scores among baseline (2 → 62.9%, 3 → 34.3%, 4 → 2.9%) and 2nd (1 → 14.3%, 2 → 77, 1%, 3 → 8.6%), 6th (1 → 45, 7%, 2 → 54.3%) and 12th weeks (1 → 62.9%, 2 → 37.1%) were found to be statistically significant (P < 0.001). Median VAS scores among baseline (median = 7 [5-9]) and 2nd (median=5 [3-8]), 6th (median=5 [3-6]) and 12th weeks (median = 4 [2-6]) were statistically significant (P < 0.001). Median DLQI scores among baseline (median = 8 [6-14]) and 2nd (median = 5 [3-11]), 6th (median = 5 [3-11]) and 12th weeks (median = 4 [2-9]) were statistically significant (p<0.001). Concurrent systemic disease was a risk factor for poor treatment response (P = 0.034). Mild irritation was observed in 3 patients (8.5%) during treatment. Conclusions: Dapsone 5% gel was effective and well tolerated in ETR treatment. ABSTRACT 2 Original Article | Dermatol Pract Concept. 2024;14(1):e2024034 Introduction Rosacea is a chronic, recurrent, inflammatory skin dis- ease localized in the centrofacial region, characterized by transient flushing, persistent erythema, telangiectasia, and papulopustular lesions. Rosacea affects 5–10% of the popu- lation and is usually seen after the third decade of life [1,2]. Rosacea can be classified into four subtypes; erythemato- telangiectatic, papulopustular, phymatous, and ocular rosa- cea [3]. Erythematotelangiectatic Rosacea (ETR) is the most common and has the most prominent vascular component among the other subtypes [4]. An exaggerated innate immune response and neurovas- cular dysregulation are the two main pathophysiological factors in the emergence of ETR [5]. Bacterial proteases, products of Demodex folliculorum and Staphylococcus epidermidis, heat, stress, irritants, ultraviolet B radiation, products of cellular metabolism such as reactive oxygen spe- cies (ROS), other known triggers such as spicy food, stren- uous exercise activate certain specific receptors and channel over the skin. All of these triggers lead to the secretion of proinflammatory cytokines, chemokines, proteases, and pro-angiogenic factors [1,6]. These factors cause inflamma- tion in the dermis, which play a major role in the occurrence of rosacea [6]. Density of inflammation in the dermis varies in rosacea between individuals and over time. In the ETR subtype of rosacea, inflammation is seen in both perivascu- lar and interstitial regions [5]. Cytokines such as vascular endothelial growth factor (VEGF), and proangiogenic fac- tors contribute to angiogenesis by both direct and indirect mechanisms [7]. Many evidences shows that there is an as- sociation between inflammation and angiogenesis [6]. The molecular mechanisms underlying the relationship between chronic inflammation and angiogenesis in rosacea have been clearly demonstrated [6]. Dapsone is an antibiotic which is a member of the sul- fone family [8]. Dapsone has anti-inflammatory activity in addition to its antibiotic activity. Dapsone also blocks an- giogenesis by inhibiting some molecular mechanisms such as VEGF formation [9] In the light of this knowledge, we used topical dapsone to treat ETR by targeting chronic inflammation and angio- genesis. The absence of a study in the literature investigating the effectiveness of topical dapsone on ETR makes our study a first. Objectives In this study, we primarily evaluated the efficacy of dap- sone 5% gel in treatment of ETR and additionally aimed to determine the side effects during treatment in this pa- tient’s group. Methods Study Design and Patient Population This is a single-centre prospective experimental clinical study. A total of 35 patients with ETR who applied to the outpatient clinic between March and November 2022 were enrolled in the study. Diagnosis, Classification, and Staging of the Disease Rosacea diagnosis, classification, and staging was done ac- cording to the criteria of the National Rosacea Society Ex- pert Committee [10]. Inclusion Criteria of the Patients Patients over 16 years old diagnosed with ETR by at least two dermatologists were included in the study. The diagnosis of rosacea was made after comprehensive clinical and der- moscopic evaluation, including histopathologic evaluation when needed. Exclusion Criteria of the Patients The exclusion criteria included pregnancy, lactation, immu- nosuppression, glucose 6 phosphate dehydrogenase enzyme deficiency, anemia, and methemoglobinemia. Ethics Committee Approval and Informed Consent Approval of the Ethics Committee of the Non-Invasive Clin- ical Research was taken for this study (Decision number / year, E-60116787-020-258589 / 2022). Informed consent was taken for all of the patients. This study has been con- ducted in accordance with the principles of the Declaration of Helsinki. Treatment Method Only topical dapsone 5% gel was used in the treatment of ETR without any topical or systemic agent. Dapson 5% Gel Application Dapson 5% gel was applied on the facial lesion (right and left cheeks, forehead, chin and nose) as a thin layer twice a day for 12 weeks by sparing the perioral, periorbital regions. Determination of Clinical Status and Treatment Efficacy Patients underwent 4 visits: a baseline evaluation and visits at weeks 2, 6, and 12. Clinical status of the patients and treatment efficacy were evaluated by Investigator’s Global Assessment (IGA), Visual Analogue Scale (VAS), and and Dermatology Life Quality Index (DLQI) scales. The IGA was a grading method used by the physician to show the severity of skin disease. Zero to 4 point scale Original Article | Dermatol Pract Concept. 2024;14(1):e2024034 3 was used for determining the severity of ETR and clini- cal status for each patient (Grade; 0 → Clean, 1 → mild, 2 → moderate, 3 → severe, 4 → very severe) [11-13]. To assess subjective disease perception, participants were asked to mark on a 10-cm continuous VAS how disturbing their rosacea had been during the past 4 weeks. The place of every mark on VAS was measured to 1 mm and was scored from 0 to 10 (0 = not at all disturbing; 10 = maximally disturbing) [14]. The DLQI is planned to evaluate the health-related qual- ity of life of adult patients complaining of skin disease. The DLQI occurs 10 questions regarding patients’ perception of the effect of skin diseases on different aspects of their health-related quality of life over the last week. Each ques- tion is scored on a four-point Likert scale (Very much = 3, lot = 2, little = 1, not at all = 0, not relevant = 0, question un- answered = 0). The DLQI questionnaire (10 questions, max- imum 30 points) was administered to all patients at baseline and at each visit [15]. Treatment Success Treatment success was accepted as an IGA score of 0 or 1, or a two-point reduction in score. Adverse Events Adverse events were recorded at each visit. Statistical Analysis Analyses were performed with IBM Statistical Package for the Social Sciences (SPSS) for Windows 23.0 (IBM Corp). Continuous variables were stated as median, minimum, maximum, descriptive values, while categorical variables were stated as number and frequency. In addition to qual- itative statistical methods, the Wilcoxon signed-rank test was used to compare the quantitative data. The risk factors affecting the efficacy of therapy were established by using logistic regression analysis. The statistical significance was accepted as P < 0.05. Results Patient Data Analysis The mean age of ERT onset was 34. Female patients were more common (female to male ratio:1.7). All patients had cheek involvement. Almost all patients had a triggering cause. Detailed baseline demographic and clinical character- istics of the patients have been shown in Table 1. Response to Treatment While all patients had an IGA score of 2 or higher at base- line, there was no patient with an IGA score of 3 or 4 at the 12th week of treatment (Table 2). The decrease in IGA score during and at the end of the treatment was statistically significant according to baseline (P < 0.001). Treatment suc- cess rate was 62.9% at the end of treatment. The clinical improvement in ERT with dapsone 5% gel treatment in two different patients has been shown in Figure 1. VAS score started to decrease after the 2nd week of treat- ment and reached lower values at the end of the treatment (Table 3). The decrease in VAS score during and at the end of the treatment was statistically significant according to base- line (P < 0.001). The increase in DLQI after using topical dapsone 5% gel treatment was statistically significant (P < 0.001) (Table 4). Table 1. Baseline demographic and clinical characteristics of the patients. Parameters N (%) or Median (Min-Max) Age 38 (19-62) Gender • Male 13 (37.1) • Female 22 (62.9) Onset age of rosacea 34 (16-57) Disease duration, month 4 (2-10) Rosacea involvement site • Cheek 35 (100) • Forehead 15 (42.9) • Nose 24 (68.6) • Chin 8 (22.9) Smoking • No 24 (68.6) • Yes 11 (31.4) Alcohol • No 19 (54.3) • Yes 16 (45.7) Triggering factorsa 34 (97.1) Skin type • Type I 15 (42.9) • Type II 19 (54.3) • Type III 1 (2.9) Systemic diseaseb 11 (31.4) Additional dermatological disease 19 (54.3) Systemic drug use 9 (25.7) aSunlight exposure, psychological stress, warm environment, hot beverages, spicy food alcohol intake, strenuous exercise, cold weather. bCardiovascular disease, diabetes mellitus, hypertension, lung dis- eases, endocrine and metabolic problems… etc. Hypothyroidism is the most common (11.4%). 4 Original Article | Dermatol Pract Concept. 2024;14(1):e2024034 Conclusions The current study demonstrated that dapsone 5% gel was effective in the treatment of ETR. IGA scores and patient-assessed VAS scores showed a significant improve- ment and good results during and after dapsone 5% gel treatment in patients with ETR. Adverse Events Mild adverse events were observed in 3 patients (totally 8.5%, itching in two, burning in one) during treatment. Risk Factor Analysis The absence of systemic disease increased the success rate of the treatment (P = 0.034) (Table 5). Table 2. Investigators Global Assessment score of erythematotelangiectatic rosacea patients in Baseline and Second, Sixth and Twelfth weeks of treatment. IGA-ETR scale Baseline 2nd week 6th week 12th week Clinical Grade Score N (%) N (%) N (%) N (%) Clean 0 0 (0) 0 (0) 0 (0) 0 (0) Mild 1 0 (0) 5 (14,3) 16 (45,7) 22 (62,9) Moderate 2 22 (62,9) 27 (77,1) 19 (54,3) 13 (37,1) Severe 3 12 (34,3) 3 (8,6) 0 (0) 0 (0) Very Severe 4 1 (2,9) 0 (0) 0 (0) 0 (0) P - <0,001 <0,001 <0,001 ETR = erythematotelangiectatic rosacea; IGA = Investigators Global Assessment. Figure 1. Clinical improvement in erythematotelangiectatic rosacea with Dapsone 5% gel treatment. Clin- ical improvement is seen from grade 3 to 2 in the first patient and from grade 2 to 1 in the second patient. Original Article | Dermatol Pract Concept. 2024;14(1):e2024034 5 Furthermore, burning sensation and erythema were sig- nificantly reduced after dapsone 5% gel treatment even in the second week compared to baseline. Moreover, the side effects of the drug were subtle, like only mild irritation. This result showed that the tolerability of dapsone 5% gel was also very well. Table 3. Visual Analog Scale scores of the patients at Baseline and Second, Sixth and Twelfth weeks of treatment. VAS scores Baseline 2. week 6. week 12. week Median (Min-Max) Median (Min-Max) Median (Min-Max) Median (Min-Max) VAS 7 (5-9) 5 (3-8) 4 (3-6) 4 (2-6) p - <0.001 <0.001 <0.001 VAS-burning sensation 5 (2-9) 3 (1-7) 4 (1-7) 3 (1-6) p - <0.001 <0.001 <0.001 VAS-erythema 6 (4-10) 4 (2-7) 4 (2-6) 3 (2-6) p - <0.001 <0.001 <0.001 VAS-pruritus 2 (1-9) 3 (0-6) 2 (0-5) 2 (0-4) p - 0.232 0.018 0.005 VAS-edema 2 (1-6) 2 (0-6) 2 (0-4) 2 (0-5) p - 0.080 0.005 0.005 VAS = Visual Analog Scale. Table 4. Dermatology Life Quality Index (DLQI) score of the patients at Baseline and Second, Sixth and Twelfth weeks of treatment. Baseline 2. week 6. week 12. week Median (Min-Max) Median (Min-Max) Median (Min-Max) Median (Min-Max) DLQI score 8 (6-14) 5 (3-11) 5 (3-11) 4 (2-9) P - <0.001 0.001 <0.001 DLQI = Dermatology Life Quality Index. Table 5. Risk factors analysis for treatment efficacy. Variables Odds ratio (95% CI) P Age 0.96 (0.90-1.02) 0.153 Gender 0.64 (0.15-2.74) 0.550 Onset age of rosacea 0.96 (0.90-1.02) 0.214 Disease duration 0.81 (0.58-1.12) 0.197 Smoking 0.53 (0.11-2.49) 0.417 Alcohol 0.63 (0.16-2.52) 0.509 Concomitant systemic disease 5.25 (1.13-24.42) 0.034 Additional dermatologic diseases 2.70 (0.64-11.47) 0.178 Skin type 0.49 (0.12-1.98) 0.316 CI = confidence interval. Rosacea treatment starts with avoidance of triggers and use of mild cleansing and moisturizing agents, as well as photoprotection [3]. Topical, oral medications, laser or light- based treatments, and injection therapies are used alone or in combination in the treatment of rosacea [3,16,17]. Met- ronidazole, azelaic acid; sulfacetamide/sülfür, brimonidine, oxymetazoline have been approved by FDA in the treatment of erythema in rosacea [3,18]. Vascular laser and light-based therapies (pulsed dye laser, intense pulsed light, Nd: YAG la- ser) can be used for erythema and telangiectasia as a second step or combined with topical therapy [3,5,18]. Various therapeutic strategies may be needed to achieve a better clinical outcome in patients with rosacea because of an overlapping clinical feature of the subtypes [3]. Phy- sicians should individualize the treatment according to the subtype and severity of the disease, clinical grade of inflam- mation and erythema, presence of telangiectasia, triggering factors, and comorbidities. The efficacy of combined treat- ments in rosacea has been shown to be better than mono- therapy [19-23]. Topical treatments are usually preferred in ETR [3]. Topical treatments were generally used for an aver- age of 12-16 weeks in the studies [3,23,24]. We used topical dapsone 5% gel for 12 weeks. We found that the success rate of treatment was 14.3% at the end of the 2nd week, 45.7% 6 Original Article | Dermatol Pract Concept. 2024;14(1):e2024034 To sum up, using dapsone 5% gel was safe, effective, and well tolerated in the treatment of ETR. We conclude that dapsone 5% gel treatment in ETR can be acceptable. However, we think that further multicentered, randomized, controlled, large-scale studies with longer follow-up period are needed. References 1. Lee HJ, Hong YJ, Kim M. Angiogenesis in Chronic Inflammatory Skin Disorders. Int J Mol Sci. 2021;22(21):12035. DOI: 10.3390 /ijms222112035. PMID: 34769465. PMCID: PMC8584589. 2. Dall’Oglio F, Nasca MR, Micali G. Emerging topical drugs for the treatment of rosacea. Expert Opin Emerg Drugs. 2021;26(1):27- 38. DOI: 10.1080/14728214.2021.1887138. PMID: 33596752. 3. Abokwidir M, Feldman SR. Rosacea Management. Skin Ap- pendage Disord. 2016;2(1-2):26-34. DOI: 10.1159/000446215. PMID: 27843919. PMCID: PMC5096126. 4. 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Furthermore, the expected duration of maintenance treatment still remains unclear. Regardless of topical or systemic treatment, adverse events are inevitable. It has been reported that the rates of adverse events are observed higher in combined treatments than topical treatments alone [17,19,23]. Brimonidine tartrate gel is the first medication approved by the FDA for the topical treatment of persistent facial er- ythema associated with rosacea, and has been using in the first line treatment of ETR for years [5,25]. The rates of ad- verse events have been reported to range from 6 to 14% for various concentrations of brimonidine tartrate [17]. When its use is extended, these rates increase to 11-19% [17]. The most commonly reported side effects are irritation, flushing, worsened erythema, burning sensation, and pruritus [17]. Many case reports of contact dermatitis and rebound ery- thema have been documented with regard to brimonidine use [17,26-28]. Oxymetazoline side effects are reported as dryness (7%), tingling sensation (3%), and papule formation (3%) [23]. Metronidazole is generally well tolerated. Side effects such as burning and stinging, dryness, redness, pruritus, and worsening of erythema were reported to be seen less than 5% of the patients [2]. The common side effects reported during the treat- ment of dapsone 5% gel in acne are dryness, erythema, and burning sensation, along with systemic symptoms such as rhinitis, pharyngitis, upper respiratory tract infection, and headache [24]. In our study, adverse events were mild, transient, and skin-limited, seen with a lower rate. There was no worsening of erythema during treatment and no re- bound erythema was observed after treatment in any of our patients. Dapsone 5% gel has only been used in the papulopus- tular subtype of rosacea to date, and its efficacy has been reported to be as much as metronidazole 0.75% gel [29]. 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