10.5826/dpc.1204a201
Background: Topical ivermectin is an anti-inflammatory and anti-Demodex drug for papulopustular rosacea. Rosacea is a relapsing disease and the time between recurrences should be considered alongside efficacy
Objectives: The aims of this study were to assess the time of first relapse and relapse rates of Demodex mite infestation and papulopustular rosacea
Methods: We conducted a prospective study of subjects affected by different degrees of papulopustular rosacea. Patients that achieved a complete response after treatment were monitored every 4 weeks and up to 32 additional weeks. For each patient, we evaluated recording the time to first relapse and relapse rate of Demodex mite infestation and rosacea.
Results: The overall success rate on Demodex infestation was 87.5%. only 12.5% relapse. Ivermectin leads to complete response in 70% of patients. Median time to relapse was 140 days, the mean time was 152 days. The global success rate was 54.76%.
Conclusions: Topical ivermectin keeps a remission of Demodex infestation and clinical remission for long time. We proposed a twice-weekly ivermectin maintenance therapy to reduce recurrences.
text/xml
2160-9381
2357
en
Aurora Parodi
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
papulopustular rosacea
Papulopustular rosacea treated with ivermectin 1% cream: remission of the Demodex mite infestation over the time and evaluation of clinical relapses
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2022-10-31
2022-01-31
2022-10-31
2022-12-05
e2022201
Dermatol Pract Concept
Background: Topical ivermectin is an anti-inflammatory and anti-Demodex drug for papulopustular rosacea. Rosacea is a relapsing disease and the time between recurrences should be considered alongside efficacy
Objectives: The aims of this study were to assess the time of first relapse and relapse rates of Demodex mite infestation and papulopustular rosacea
Methods: We conducted a prospective study of subjects affected by different degrees of papulopustular rosacea. Patients that achieved a complete response after treatment were monitored every 4 weeks and up to 32 additional weeks. For each patient, we evaluated recording the time to first relapse and relapse rate of Demodex mite infestation and rosacea.
Results: The overall success rate on Demodex infestation was 87.5%. only 12.5% relapse. Ivermectin leads to complete response in 70% of patients. Median time to relapse was 140 days, the mean time was 152 days. The global success rate was 54.76%.
Conclusions: Topical ivermectin keeps a remission of Demodex infestation and clinical remission for long time. We proposed a twice-weekly ivermectin maintenance therapy to reduce recurrences.
Aurora Parodi
2022/10/31
10.5826/dpc.1204a201
e2022201
Section of Dermatology - Department of Health Sciences, University of Genoa, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy
2160-9381
papulopustular rosacea
en
e2022201
Thibaut de Ménonville S, Rosignoli C, Soares E, et al. Topical treatment of rosacea with ivermectin inhibits gene expression of cathelicidin innate immune mediators, LL-37 and KLK5, in reconstructed and ex vivo skin models. Dermatol Ther (Heidelb). 2017; 7:213–225.
Papulopustular rosacea treated with ivermectin 1% cream: remission of the Demodex mite infestation over the time and evaluation of clinical relapses
https://dpcj.org/index.php/dpc/article/download/2357/1757
    Papulopustular Rosacea Treated With Ivermectin
        1% Cream: Remission of the Demodex
      Mite Infestation Over Time and Evaluation
                 of Clinical Relapses
    Ilaria Trave1, Claudia Micalizzi1, Emanuele Cozzani1, Giulia Gasparini1, Aurora Parodi1


1 Section of Dermatology - Department of Health Sciences, University of Genoa, IRCCS - Ospedale Policlinico San Martino, Genoa, Italy



Key words: ivermectin, rosacea, papulopustular rosacea
Citation: Trave I, Micalizzi C, Cozzani E, Gasparini G, Parodi A. Papulopustular rosacea treated with ivermectin 1% cream: remission
of the Demodex mite infestation over the time and evaluation of clinical relapses. Dermatol Pract Concept. 2022;12(4):e2022201.
DOI: https://doi.org/10.5826/dpc.1204a201
Accepted: March 3, 2022; Published: October 2022
Copyright: ©2022 Trave 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: All authors have contributed significantly to this publication.
Corresponding author: Ilaria Trave, Section of Dermatology - Department of Health Sciences, University of Genoa, IRCCS - Ospedale
Policlinico San Martino, Genoa, Italy. Tell: 0105555750 E-mail: ilaria.trave@gmail.com




  ABSTRACT             Introduction: Topical ivermectin is an anti-inflammatory and anti-Demodex drug for papulopus-
                       tular rosacea. Rosacea is a relapsing disease and the time between recurrences should be considered
                       alongside efficacy.
                       Objectives: The aims of this study were to assess the time of first relapse and relapse rates of Demo-
                       dex mite infestation and papulopustular rosacea.
                       Methods: We conducted a prospective study of subjects affected by different degrees of papulopustu-
                       lar rosacea. Patients that achieved a complete response after treatment were monitored every 4 weeks
                       and up to 32 additional weeks. For each patient, we evaluated recording the time to first relapse and
                       relapse rate of Demodex mite infestation and rosacea.
                       Results: The overall success rate on Demodex infestation was 87.5% only 12.5% relapse. Ivermectin
                       leads to complete response in 70% of patients. Median time to relapse was 140 days, the mean time
                       was 152 days. The global success rate was 54.76%.
                       Conclusions: Topical ivermectin keeps a remission of Demodex infestation and clinical remission for
                       long time. We proposed a twice weekly ivermectin maintenance therapy to reduce recurrences.




Original Article | Dermatol Pract Concept. 2022;12(4):e2022201                                                                          1
Introduction                                                           Subjects that had been treated with topical and systemic
                                                                    therapies during the previous year were not included in the
Rosacea is a chronic, inflammatory skin disease that starts         study. For each patient, disease severity was assessed by In-
between 30-50 years of age with a large prevalence in the           vestigator Global Assessment score (IGA score) [11]. IGA
general population [1]. Papulopustular rosacea (PPR) is             score defines disease severity from 0 to 4: IGA 0 = no in-
characterized by multiple small dome-shaped erythematous            flammatory lesions, no erythema; IGA 1 = very few small
papules and pustules arising on erythema in a centrofacial          papules/pustules, very mild erythema; IGA 2 = few small
distribution [2].                                                   papules/pustules, mild erythema; IGA 3 = several small or
    Topical ivermectin cream 1% (IVM) is a drug charac-             large papules/pustules, moderate erythema; IGA 4 = numer-
terized by both antiparasitic and anti-inflammatory effects         ous small or large papules/pustules, severe erythema [15].
[3-7], which gained the Food and Drug Administration (FDA)             In order to study Demodex mites count, a standardized
approval for the treatment of PPR in December 2014, and by          skin surface biopsy (SSSB) was performed by a trained der-
European Medicines Agency (EMA) in March 2015 [5].                  matologist on the target area [8]. SSSB is a sampling method
    Demodex mites are standing human ectoparasites that             in which 1 cm2 of the superficial layer of the stratum cor-
have a higher concentration in PPR (a mean of 12.8 D/cm2)           neum and its follicular content is recovered for analysis [8].
[8] than other people. Demodicosis in humans is associated          Samples obtained by SSSB were examined with an optical
with the common inflammatory skin condition rosacea but             microscope at × 10 and × 40 magnifications. Samples with
also with pityriasis folliculorum, where it is not accompa-         ≥5 Demodex/cm2 (D/cm2) was considered positive (D+) [8].
nied by inflammation, and with other rarer clinical settings,       Antiparasitic efficacy assessments were time to first relapse
including patients with symptoms of perioral dermatitis             and relapse rate of positive SSSB test.
[9,10] and granulomatous rosacea [11].                                 We defined a successful therapeutic intervention when pa-
    Although is well know the anti-parasitic effect of iver-        tients affected by IGA 1, 2 and 3 rosacea at baseline achieved
mectin, up to now, there are not studies that consider the          IGA= 0 after 16 weeks of therapy. After this treatment pe-
time of relapse and relapse rates of Demodex mite infestation       riod, patients that achieved IGA=0 were followed e­very
in patients affected by rosacea and treated with ivermectin.        4 weeks for up to 32 additional weeks (Weeks 16-48) [3].
    Following the onset of the disease, patients with rosacea          Efficacy assessments were the time to first relapse and
will experience cycles of relapse and remission of symptoms         relapse rate [3]. Time to first relapse was defined as the time
through their lives [3]. There are only very few studies that       relapse between Week 16 (end of treatment) and the first
have analyzed patterns of relapse in moderate-to-severe and         relapse (IGA ≥ 1) during follow up. Relapse rate was defined
mild-to-moderate PPR treated with ivermectin [3,12].                as the percentage of patients who relapsed within the course
                                                                    of the 32 weeks.
Objectives                                                             Descriptive statistical analyses were performed, and data
                                                                    were shown as median (range), mean (SD), or number (per-
The main aim of this study was to assess the time of first          centage). Relapse rates and time to relapse were evaluated
relapse and relapse rates of Demodex mite proliferation after       for patients divided for IGA score and analyzed using the
interruption of ivermectin therapy [13]. The secondary goal         Kaplan-Meier method and log-rank test. Patients who re-
was to study the time to first clinical relapse and relapse rates   lapsed were considered censored in the analysis. For cate-
in patients affected by almost clear, mild and moderate PPR.        gorical variables, data were analyzed using the χ2 test and
                                                                    Fisher exact test.
Methods                                                                The study was approved by the local Ethical Review
                                                                    Board (Comitato Etico Regione Liguria. N. Registro CER
The prospective study was conducted at the Dermatology Cen-         Liguria: 467/2021 – DB id 11726)
tre of Ospedale Policlinico San Martino IRCCS in Genoa (It-
aly) from May 1st, 2020 to May 31st, 2021 on subjects suffering
from papulopustular rosacea. Diagnosis of rosacea was made          Results
by an experienced dermatologist and based on the following
                                                                    We recruited 60 Caucasian patients, including 45 women
National Rosacea Society (NRS) expert panel criteria [1]:
                                                                    (75%) and 15 men (25%) with a mean age of 57 years (SD
1. fixed centrofacial erythema in a characteristic pattern          11.2, range 30-81 years). Demographic and clinical data are
    that may periodically intensify                                 summarized in Table 1. Thirty-one/60 patients (51.67%) had
2. papules and pustules (with or without telangiectasias,           an IGA score 1, 16/60 patients (26.67%) had an IGA score 2
    flushing and ocular manifestations) [14]                        and 13/60 (21.66%) had an IGA score 3.




2                                                                       Original Article | Dermatol Pract Concept. 2022;12(4):e2022201
Demodex Mite Density                                                                                            differences to achieve IGA = 0 among IGA1-2-3 at baseline
Using SSSB, Demodex mites were found (D+) in 20/60                                                              (P = 0.725, P = 0.1552, P = 0.47, respectively).
(33.33%) patients of whom 7 had IGA 1, 7 had IGA 2 and 6
had IGA3. After 16 weeks of therapy, SSSB resulted negative                                                     Relapse Evaluation
(D-) in 16/20 (80%) of whom 5/7 (71.43%) had IGA 1, 6/7                                                         Kaplan-Meier curves show no different median time of first
(85.71%) had IGA2 and 5/6 (83.33%) had IGA3. There are                                                          relapse (IGA ≥ 1) among IGA 1-2-3 (P log rank test = 0.551)
not statistical differences to become D- (P > 0.999, P > 0.999,                                                 (­Figure 1). At week 48, the percentages of patients who expe-
P > 0.999) after 16 weeks of therapy.                                                                           rienced a relapse (IGA ≥ 1) after discontinuation of ivermectin
                                                                                                                treatment (relapse rate) was 45.24%, and in particular, they
Relapse Evaluation and Demodex Mite Infestation                                                                 were 45.83% for IGA1, 45.45% for IGA 2 e 28.57% for IGA
Only 2/16 (12.5%) IGA 2 PPR D- relapsed after 224 days.                                                         3. The global success rate (percentage of patients who reached
The global success rate of Demodex infestation was 87.5%.                                                       0 at the end of treatment and had no relapse in follow up) was
Regarding 4 D+ patients positive after 16 weeks of ther-                                                        54.76% and in particular, they were 54.17% for IGA1, 54.54%
apy, 2/4 achieved D- at Day 150, ¼ at Day 224 while ¼                                                           for IGA 2 and 71.43% for IGA3. Median time to relapse was
remained D+.                                                                                                    140 days (84-224 days), in particular, 154 days (range: 84-224)
                                                                                                                for IGA 1, 196 days (range: 98-224) for IGA 2, 105 days (range:
IGA Score and Effectiveness                                                                                     98-112) for IGA 3. The mean time to relapse was 152.44 ±
Patients that reached IGA=0 after 16 weeks of treatment are                                                     51.47 days, in particular, 154 ± 50.47 days for IGA 1, 168 ±
summarized in Table 1. There are not statistical significative                                                  58.57 days for IGA 2 and 105 days ± 9.90 days for IGA 3.


                                                                  Table 1. Demographic and Clinical Data of Patients Divided by IGA Score.
                                                                                                                IGA 1 (31)       IGA 2 (16)      IGA 3 (13)        Total (60)
 Age, years, mean (SD)                                                                                           58 (10.1)        56 (14,0)       57 (9.5)         57 (11.2)
 Gender
 Female, N (%)                                                                                                  20 (64.52)       13 (81.25)      12 (92.31)         45 (75)
 Male, N (%)                                                                                                    11 (35.48)        3 (18.75)        1 (7.69)         15 (25)
 Patients reaching IGA= 0 at 16 weeks, N (%)                                                                    24 (77.42)       11 (68.75)       7 (53.85)         42 (70)
 Patients positive for Demodex at baseline, N (%)                                                               7 (22.58)         7 (43.75)       6 (46.15)        20 (33.33)
 Patients negative for Demodex at 16 weeks, N (%)                                                               5 (16.13)          6 (37.5)       5 (38.46)        16 (26.67)

IGA= Investigal Global Assessment; SD = standard deviation.
           Percentage of patients remaining without relapse (%)




                                                                                                                                                              IGA 1
                                                                  100
                                                                                                                                                              IGA 2

                                                                                                                                                              IGA 3



                                                                   50




                                                                    0
                                                                        0   14 28 42 56 70 84 98 112 126 140 154 168 182 196 210 224
                                                                                    Time from end of ivermectin treatment (days)

      Figure 1. Time to first relapse of patients in ivermectin 1% cream. Kaplan-Meier plot demonstrates that there are not differences
      among patients treated with ivermectin divided to IGA score (P = 0.551).




Original Article | Dermatol Pract Concept. 2022;12(4):e2022201                                                                                                                  3
Conclusions                                                            versus 85 days) [3]. In addition, relapse rate was lower for pa-
                                                                       tients previously treated with ivermectin 1% compared with
Similarly, to previous study, we found 33% of Demodex pos-             metronidazole 0.75% (62.7% versus 68.4%) [3]. Dall’Oglio
itive samples at baseline [7]. The great anti-parasitic effect         found only 2/20 mild and moderate PPR patients that relapsed
of ivermectin was confirmed by the overall success rate of             [12]. In our study, we found a longer median time of first relapse
Demodex infestation (87.5%). In the literature, there are not          (140 days) with a lower relapse rate (45.24%) than studies in
studies that consider the time of relapse and relapse rates of         the literature. As we have just shown, relapse rates are difficult
Demodex mite infestation in patients affected by rosacea and           to compare between different studies. We suppose that our re-
treated with ivermectin. In our study, we observed a low re-           sults are better than those of Shaub et al because we considered
lapse rate of Demodex mite infestation (12.5%) in PPR show-            mild forms instead of moderate-severe forms of rosacea base-
ing as ivermectin has an excellent antiparasitic effect that last      line [3]. In fact, patients with IGA 3-4 rosacea had higher num-
over time. It acts by blocking ligand-gated chloride channels,         ber of inflammatory lesions than patients with IGA 1-2 rosacea
especially glutamate-gated anion channels in the peripheral            that keep clinical remission for longer days. Moreover, differ-
nervous system of Demodex mites causing their paralysis and            ences among studies could be justified by a different definition
death [16]. The two patients that showed a relapse of Demo-            of relapse; while Shaub et al considered a relapse as IGA ≥ 2 we
dex mite infestation presented an erythemato-telangiectatic            regarded as IGA ≥ 1 PPR [3]. This is because we take on IGA
rosacea (ETR) with few papules (Figure 2). This result is ac-          = 0 as desirable ideal goal of maintenance, crucial for patient’s
cording to the hypothesis that ETR may be associated with              outcome and for an effective improvement of his quality of life.
non-visible Demodex proliferation, possibly corresponding to           However, patients that relapsed in our study showed mainly
a subclinical stage of demodicosis [17-19]. Few papules may            IGA = 1 PPR (22/27) without serious cases after suspension of
be an early sign of relapsed Demodex mite proliferation [20].          therapy. Finally, the difficulties may also be due to the different
    Our study confirms the efficacy of ivermectin 1% cream             follow-up periods. In fact, while we tracked our patients for 32
leading to complete response in 70% of almost clear, mild and          weeks, Shaub et al followed them for 36 weeks and Dall’Oglio]
moderate PPR after 16 weeks of therapy. Regarding relapses             for 12-to-24 weeks after treatment: a longer follow-up periods
in patients with rosacea, a study from 2016 showing that pa-           correspond to higher probability of relapse [3,12].
tients affected by moderate-severe rosacea and treated with iv-             Since our results, ivermectin work with an anti-parasitic ef-
ermectin had median times of first relapse significantly longer        fect in Demodex positive PPRs eliminating mites as cause of
than those treated with metronidazole 0.75% cream (115 days            inflammation and enabling a long remission of PPR with a low




Figure 2. Relapse of erythemato-telangiectatic after 224 days of suspension of therapy.



4                                                                           Original Article | Dermatol Pract Concept. 2022;12(4):e2022201
risk of relapse. In addition, ivermectin acts as anti-inflammatory             Br J Dermatol. 1993;128(6):650-659. DOI: 10.1111/j.1365-
drug inducing a downregulation of the pro-inflammatory genes                   2133.1993.tb00261.x. PMID: 8338749.
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tion of cathelicidin innate immune mediators, LL-3720 21 and                   PMID: 31341946. PMCID: PMC6630018.
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    Our study has different limitations: we did not have patients              G. Clinical and erythema-directed imaging evaluation of
with severe rosacea and we did not evaluated patients with ob-                 papulo-pustular rosacea with topical ivermectin: a 32 weeks
ject instruments like erythema-directed digital photography.                   duration study. J Dermatolog Treat. 2019;30(7):703-707. DOI:
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Original Article | Dermatol Pract Concept. 2022;12(4):e2022201                                                                               5
