DOI: 10.31662/jmaj.2023-0100
https://www.jmaj.jp/

Original Research Article

Real-world Evidence for the Treatment of Rosacea with Sulfur orMetronidazole Preparation in Japanese Patients
Yoshimasa Nobeyama2), Yoshiko Aihara1), and Akihiko Asahina2)
Abstract:
Introduction: There remains to be lacking real-world evidence for the treatment of rosacea with a topical sulfur preparation (TSP) or topical metronidazole preparation (TMP) among Japanese patients. Therefore, in this study, we examined theeffects of TSP and TMP on rosacea in Japanese patients in real-world clinical settings.
Methods: This retrospective observational analysis reviewed the medical records of 47 Japanese patients who were treatedwith TSP or TMP for more than 8 weeks in our clinic. Disease severity was evaluated using the Investigator Global Assessment (IGA) and the visual analog scale (VAS) for itching, burning sensation, flushing, and hypersensitivity before and 8
weeks after the initiation of the intervention.
Results: In total, 10 erythematotelangiectatic rosacea (ETR) and 12 papulopustular rosacea (PPR) patients treated with
TSP and 12 ETR and 13 PPR patients treated with TMP were analyzed. IGA and VAS scores for itching, burning sensation, flushing, and hypersensitivity were noted to significantly improve in the ETR and PPR patient groups treated with
TSP and both groups treated with TMP, except for the VAS score for itching in the TSP-treated ETR group. No significant
differences were observed in terms of the improvement rates of IGA, VAS scores, or the prevalence of adverse events between the TSP- and TMP-treated groups.
Conclusions: As per our findings, TSP and TMP have similarly favorable effects on both ETR and PPR in Japanese patients in real-world settings.
Key Words:
topical treatment, sulfur, metronidazole, erythematotelangiectatic rosacea, papulopustular rosacea

Introduction

injective agents. Therefore, topical agents are deemed essential
for the treatment of rosacea.
A few studies in Western countries concurrently indicatedthe similar effectiveness of a topical sulfur preparation (TSP)and topical metronidazole preparation (TMP) for rosacea. In
fact, Torok et al. reported a complete, excellent, or good improvement in 51 out of 75 patients treated with 10% sulfacetamide plus 5% sulfur cream and in 43 out of 77 patients treatedwith 0.75% metronidazole cream (5). Moreover, in a study by
Lebwohl et al. wherein 63 patients with rosacea were examined, it was determined that the effects of 10% sulfacetamide
plus 5% sulfur lotion were similar to those of 0.75% metronidazole gel (6). On the other hand, racial differences in the development of rosacea have been suggested in real-world clinicalsettings. Rosacea appears to be less frequent in patients withdarker skin tones (7). Furthermore, the subtype distribution of
rosacea in Japanese individuals significantly differs from thatin Caucasian individuals (8); the former rarely develop the

Rosacea is a common cutaneous disease characterized bychronic inflammation; it mainly affects the cheeks, nose, andforehead (1). The National Rosacea Society (NRS) Expert
Committee in 2002 classified rosacea into the following subtypes: (i) erythematotelangiectatic rosacea (ETR), (ii) papulopustular rosacea (PPR), (iii) phymatous rosacea, and iv) ocularrosacea (2). However, this classification was not adopted by the
global ROSacea COnsensus (ROSCO) panel, a conference organized in 2016 (3). According to this classification, many therapeutic options have been evaluated. Currently, there are anumber of available therapeutic options for rosacea including
oral medicines, injective agents, electromagnetic wave-based
treatments, and topical agents (4). Among them, topical agents
have a number of merits, including a lower risk of systemic adverse events than systemic treatments and lower costs thanelectromagnetic wave-based treatments and treatments with

Ai Dermatology Clinic, Utsunomiya, Japan. 2) Department of Dermatology, The Jikei University School of Medicine, Tokyo, Japan
Corresponding author: Yoshimasa Nobeyama, nobederm@jikei.ac.jp
JMA J. 2023;6(4):448-454
Received: June 24, 2023 / Accepted: July 26, 2023 / Advance Publication: September 20, 2023 / Published: October 16, 2023
Copyright © Japan Medical Association

1)

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JMA Journal: Volume 6, Issue 4

phymatous type of rosacea, in contrast to the latter. In that
context, data on responses to treatments for rosacea are thus
required for each racial population.
In Japan, sulfur and camphor lotionⓇ (60 mg sulfur and 5
mg dl-camphor per 1 mL; TSP) was the only topical agent approved for the treatment of rosacea by the Ministry of Health,Labour and Welfare by April 2022. In May 2022, Rozex GelⓇ
(metronidazole 7.5 mg per 1g; TMP) was approved as a topical agent based on the findings of a randomized, vehicle-controlled, phase 3 study on 130 Japanese patients showing the favorable effects of TMP (Rozex GelⓇ) for rosacea (9). Rosacea
patients with an Investigator Global Assessment (IGA) scoreof ≥3 and an inflammatory lesion count (papules/pustules)of ≥11 and ≤ 40 on the whole face were enrolled in thisphase 3 study; therefore, the conditions of the participatingrosacea patients were restricted.
Dermatologists can now select TSP or TMP as a topicalagent for the treatment of rosacea in Japan. However, there iscurrently very limited real-world evidence for the efficacy andsafety of TSP for both ETR and PPR and TMP for ETR, particularly in Japanese patients. Therefore, in this study, we aim
to obtain real-world evidence for the treatment of rosacea by
TSP and TMP in Japanese patients.

persistent centrofacial erythema associated with periodic intensification by potential triggering factors (3). Other inflammatory facial diseases, such as seborrheic dermatitis, acne vulgaris, malar rash of lupus erythematosus, and contact dermatitis, were excluded.
The clinical subtypes of rosacea were classified according
to the subtype classification of NRS in 2002: (i) ETR was defined as facial lesions presenting with flushing and persistentcentral facial erythema with or without telangiectasia, (ii) PPR
was defined as facial lesions presenting with persistent central
facial erythema with transient central facial papules, pustules,
or both, (iii) phymatous rosacea was defined as facial lesions
presenting with thickening skin and irregular surface nodules,and (iv) ocular rosacea was defined as rosacea-associated ophthalmologic lesions, including blepharoconjunctivitis witheyelid margin inflammation, meibomian gland dysfunction,and corneal complications, such as vascularization, ulceration,
scarring, and perforation (2), (10). However, ocular rosacea was
not examined, as this present study has focused on the topicaltreatments for cutaneous manifestations.
We considered rosacea with one or more papules/pustules
and without phymatous changes to be PPR. Meanwhile, rosacea without both papules/pustules and phymatous changes
was regarded as ETR. These subtypes were identified exclusively by the criteria of NRS (2002) at entry. Therefore, subtypes did not overlap in the patients examined in this study.
We have observed facial lesions macroscopically and dermoscopically on cleaned skin.
Adverse events due to TSP and TMP were defined as any
cutaneous and systemic manifestations which occurred after
the initiation of the topical intervention.

Materials and Methods
Patients
This retrospective observational study was approved by the
Ethics Committee of the Jikei University School of Medicine(approval code: 33-223). Informed consent was obtained in an
opt-out form on the website. In total, 47 Japanese patientswere analyzed after meeting the following criteria (Supplementary Table 1): (i) referral to the Ai Dermatology Clinic between June 2022 and October 2022; (ii) fulfillment of the diagnostic criteria for rosacea as defined in the “Diagnostic criteria” subsection; (iii) receiving the treatment with TSP or TMP
for more than 8 weeks in our clinic; (iv) evaluated with IGA
scores, visual analog scale (VAS) scores for itching, burning
sensation, flushing, and hypersensitivity, and a Demodex mite
examination before and 8 weeks after the initiation of thetreatment intervention; and (v) not receiving systemic treatments within at least 6 weeks immediately before the assessments. Meanwhile, the exclusion criteria are as follows: (i) ongoing pregnancy; (ii) receiving topical or systemic treatment
for any disease at the first visit; and (iii) having systemic diseasepotentially affecting systemic or cutaneous manifestations at
the first visit. Clinical manifestations were evaluated by at least
two Japanese Dermatological Association-certified dermatologists.

Assessment of severity
The IGA score was recorded based on a 5-point scale from 0(clear; no inflammatory lesions and no erythema) to 4 (severe;
many small to large papules and pustules or severe erythema) (11). The effects of the treatment intervention on rosacea
were assessed as follows: the improvement value for VAS
scores was defined as the value of the pre-intervention VAS
score − the post-intervention VAS score; the improvement
rate of IGA scores was defined as a value of (1 − post-intervention IGA score/pre-intervention IGA score) × 100 (%). Patients recorded a VAS score between 0 and 100 with a measure
ranging from 0 to 100 mm. A VAS score of 100 was defined as
the worst condition and that of 0 as no symptoms.
Demodex mite examination
Scales obtained by brushing the affected cutaneous regions
and/or contents obtained by extruding follicular pustules weretreated with potassium hydroxide, and samples were thereafter
examined under a microscope. The result of the examination
was considered to be positive when more than one Demodex
mite was detected.

Diagnostic criteria
Rosacea was diagnosed according to the criteria of the ROSCO panel, namely, facial lesions presenting with more than
one of the following criteria: (i) phymatous changes and (ii)449

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Table 1. Comparison of Patients’ Profiles between TSP and TMP before the Intervention.
Topical treatment
Parameters
Age (years)

TSP

TMP

p-value46.2 ± 21.3

48.1 ± 11.9

0.469

Sex (number of patients)

0.237

Male

3

1

Female19

24Type of rosacea (number of patients)

0.861

ETR

10

12

PPR

12

13

Results of Demodex exam. (number of patients)

0.632

Positive

18

20

Negative

44

Not examined01

IGA score (number of patients)

0.600

2

5

9

3

9

9

4

8

7

VAS score (mean value ± standard deviation)Itch50.2 ± 31.4

37.2 ± 25.7

0.094

Burning sensation

24.5 ± 28.8

29.1 ± 26.2

0.303

Flushing

27.1 ± 27.6

28.1 ± 27.5

0.839

Hypersensitivity

50.4 ± 29.9

54.6 ± 28.9

0.654

3.14 ± 0.77

2.92 ± 0.81

0.353

IGA score (mean value ± standard deviation)

Statistical analysis
Statistical analyses were performed using Statistical Package
for the Social Sciences version 22 software (IBM, Armonk,
NY). Friedman test was conducted to examine quantitative
differences, whereas Pearson’s chi-squared test was used to assess qualitative differences. The p values of <0.05 were considered to be significant.

recorded immediately before the initiation of the intervention(Figure 1a and 2). In ETR patients treated with TMP, IGA
scores and VAS scores for itching, burning sensation, flushing,and hypersensitivity were also noted to be significantly lower
than the baseline scores (Figure 1a and 2).
In PPR patients treated with TSP, IGA scores and VAS
scores for itching, burning sensation, flushing, and hypersensitivity were significantly lower than the baseline scores(Figure 1b and 2). In PPR patients treated with TMP, IGA
scores and VAS scores for itching, burning sensation, flushing,and hypersensitivity were significantly lower than the baseline
scores (Figure 1b and 2).
Among the 22 TSP-treated patients who underwent the
Demodex mite examination, the result was positive in 18 patients (81.2%) (Table 1). Eight weeks after the initiation of theintervention, the positivity rate has significantly decreased to 6
from the initial 18 positive patients (28.6%) (p < 0.001, Pearson’s chi-squared test) (Table 2). On the other hand, amongthe 24 TMP-treated patients who underwent the Demodex
mite examination, the result was positive in 20 patients(83.3%) (Table 1). Eight weeks after the initiation of the intervention, the positivity rate significantly decreased to 8/20 patients (40.0%) (p = 0.003, Pearson’s chi-squared test)

Results
Effects on ETR and PPR in TSP- and TMP-treatedgroupsAmong the 47 patients whose relevant data were mentionedon their medical records, 22 (46.8%), 25 (53.2%), and 0 (0.0%)
patients were diagnosed with ETR, PPR, and phymatous rosacea, respectively, before the initiation of the therapeutic intervention (Supplementary Table 1). In total, 22 patientstreated with TSP, including 10 ETR and 12 PPR patients,
and 25 patients treated with TMP, including 12 ETR and 13
PPR patients, were assessed in this study (Table 1).
In ETR patients treated with TSP, IGA scores and VAS
scores for burning sensation, flushing, and hypersensitivity
were significantly lower than the baseline scores, which were450

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Figure 1. Changes in VAS scores in rosacea patients treated with TSP and TMP
Values examined before and 8 weeks after the initiation of the therapeutic intervention for each patient are plotted. The points
indicating values in each patient are connected by a straight line on the graph. Star marks indicate significant differences. BL,
baseline before the therapeutic intervention. a) Line graph for patients with ETR. b) Line graph for patients with PPR.

Comparison of adverse events between TSP- and
TMP-treated groups
During the 8-week study period, adverse events were reported,that is, contact dermatitis or an unpleasant sensation in 9/22
(40.9%) and 6/25 (24.0%) of TSP- and TMP-treated patients,
respectively (Table 2). No significant difference was noted interms of the prevalence of adverse events including contact
dermatitis and an unpleasant sensation. Among the adverse
events reported, contact dermatitis developed in seven TSPand two TMP-treated patients (31.8% and 8.0%, respectively);
contact dermatitis appeared more frequently in TSP-treatedpatients than TMP-treated patients (p = 0.038, Pearson’s chisquared test). Unpleasant sensation developed in two TSPand four TMP-treated patients (9.1% and 16.0%, respectively)
with no significant difference between them.

(Table 2).
Comparison of patients’ profiles between TSPand TMP-treated groups
Before the initiation of the intervention, the distributions ofage, sex, and rosacea subtypes did not significantly differ between the TSP- and TMP-treated groups (Table 1). Furthermore, IGA scores; VAS scores for itching, burning sensation,
flushing, and hypersensitivity; and positivity rates in the Demodex mite examination were not significantly different.
Based on these results, the TSP- and TMP-treated groups
were considered to be comparable.
Comparison of effects between TSP- and TMPtreated groups
Between the TSP- and TMP-treated groups, the decrease in
the number of patients with a positive result in the Demodex
mite examination did not significantly differ (Table 2). Moreover, no significant differences were observed in terms of the
improvement rate in IGA scores or decreases in VAS scores foritching, burning sensation, flushing, and hypersensitivity(Supplementary Figure 1).

Discussion
In this present study, we aimed to provide real-world evidence
for the treatment of rosacea using TSP and TMP in Japanesepatients. As per our results, TSP and TMP have similarly favorable effects for both ETR and PPR in Japanese patients.
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Figure 2. Changes in IGA scores in rosacea patients treated with TSP and TMP
Mean values with standard deviations for IGA scores recorded before and 8 weeks after the initiation of the therapeutic intervention for each patient are presented as bar graphs. Star marks indicate significant differences. BL, baseline before the therapeuticintervention.

Table 2. Comparison of Outcomes between TSP and TMP.
Topical treatment
Parameters

TSP

TMP

Results of Demodex exam. (number of patients)

p-value
0.212

Positive

6

8

Negative

15

12

Not examined1

5

Absent13

19

Present

96Adverse events (number of patients)

0.215

The basic patient profiles in our study have been noted tobe similar to those in the phase 3 study conducted by Miyachi
et al. that examined a patient group with a mean age of 43.8
years and a sex distribution of 23 male and 107 female patients (9). However, our study has included 14 patients with an
IGA score of 2 before the initiation of the intervention,
whereas Miyachi et al. have excluded these patients. Furthermore, our study included 22 patients with ETR, whereas theabovementioned phase 3 study did not because the latter’s inclusion criterion was ≥11 papules/pustules. We initially suggested that TMP was also effective for ETR in Japanese patients, which was eventually determined to be true as per our
results.
Limited information is available on the effects of TSP on
rosacea, particularly in Japanese patients. Therefore, some dermatologists have avoided using TSP to treat rosacea in Japa452

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nese patients, even though TSP was the only topical agent approved for the treatment of rosacea by the Japanese Ministryof Health, Labour and Welfare until April 2022. However,this present study clearly showed that TSP is significantly effective for ETR as well as PPR in Japanese patients. These results include the effects of the treatment for adverse events toclinical outcomes in real-world settings, although the effect oftreatment for adverse events by itself was not evaluated in thispresent study. These results may be regarded as objective evidence for the favorable effects of TSP on ETR and PPR, thus
encouraging dermatologists to use TSP as well as TMP totreat rosacea in Japanese patients.
This present study failed to demonstrate a significant improvement of itching in the ETR patient group treated with
TSP unlike in the ETR patient group treated with TMP. On
the other hand, this direct comparison showed no significant
differences in terms of the improvement rates of clinical parameters including itching between TSP and TMP. Also, no
significant difference was noted in terms of the prevalence ofadverse events including contact dermatitis and an unpleasantsensation, although contact dermatitis by itself appeared more
frequently in TSP-treated patients than in TMP-treated patients. Based on these findings, similar effectiveness and risks
between TSP and TMP are suggested at least 8 weeks after theintervention. Therefore, the choice of treatment may dependon the preference of each patient; patients may be allowed to
select a topical treatment with different drug formulations
and odors. TSP may be suitable for patients with a preference
for a lotion over a cream and acceptance of its characteristic
odor. Similarly, TMP may be suitable for patients with a preference for a cream over a lotion and those who cannot tolerate
the odor of TSP.
Many trials not only on TSP and TMP but also on theother topical agents for the treatment of rosacea have been
conducted in Western countries (12). Taieb et al. reported that
topical 1% ivermectin cream once a day was more effective
than TMP (0.75%) twice a day (13). The effectiveness of topicalminocycline, azelaic acid, and benzyl benzoate for PPR has also been reported (4), (14), (15). Topical oxymetazoline and brimonidine, adrenergic receptor agonists, were also shown to be effective for facial erythema associated with rosacea (16), (17). However,information on the effects of these agents in Japanese patientswith rosacea remains to be very limited. Thus, the efficacy andsafety of these topical agents for rosacea in Japanese patients
also need to be examined in the near future.
This study has a few limitations that need to be addressed.
First, this present study was conducted without placebo control, although we had no choice in real-world clinical settings.
Second, this present study was a retrospective study. Therefore, bias may have been present in the selection of TSP or
TMP for a rosacea patient by an attending physician. Third,
the number of patients examined in this present study was
small; therefore, more patients should be examined in futurestudies to obtain stronger evidence. Fourth, bias may havebeen present in the assessment of IGA scores because we evaluated the cutaneous manifestations of our patients before and8 weeks after the initiation of the intervention. Fifth, the detailed data on the concomitant medications with TSP or TMP
were not available in this present study. Such data might encourage a greater understanding of the results.
In conclusion, this present study provides real-world evidence for the treatment of rosacea with TSP or TMP in Japanese patients. The results obtained indicate the similarly favorable effects of TSP and TMP for both ETR and PPR in Japanese patients under real-world clinical settings. These present
results will allow Japanese patients with rosacea to have better
topical therapy options.

Article Information
Conflicts of Interest

Yoshimasa Nobeyama is a paid consultant/advisor of Maruho.
Akihiko Asahina is a paid consultant/advisor of Maruho.
Author Contributions

Y. N. designed and analyzed the data and wrote the manuscript.
Y. I. contributed to the concept and helped in the collection of the data.
A. A. is a supervisor and edited the manuscript.
All authors reviewed and approved the final manuscript.
Approval by Institutional Review Board (IRB)

This study protocol was approved by the Ethics Committee of
the Jikei University School of Medicine (approval code:33-223).
Data Availability Statement

All raw data are available in Supplementary Table 1

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Supplement
Supplementary Table 1
Supplementary Figure 1

Comparison of improvements between TSP and TMP
Mean values with standard deviations for improvement
values in VAS scores and improvement rates in IGA scores arepresented as bar graphs. The improvement value of VAS
scores is defined as the value of the pre-intervention VAS score- the post-intervention VAS score. The improvement rate of
IGA scores is defined as a value of (1 − post-intervention IGA
score/pre-intervention IGA score) × 100 (%). Vertical and horizontal axes indicate topical therapeutic options and improvement values/rates, respectively. NS, not significantly different.
JMA Journal is an Open Access journal distributed under the Creative Commons Attribution 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/
licenses/by/4.0/).

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