Actas Dermo-Sifiliográficas (English Edition) Actas Dermo-Sifiliográficas (English Edition)
Actas Dermosifiliogr 2018;109:91-2 - Vol. 109 Num.1 DOI: 10.1016/j.adengl.2017.07.015
Letter to the Editor
The Possible Combined Action of Different Trigger Agents in Rosacea
Posible acción combinada de los diferentes agentes desencadenantes en la rosácea
G. Ciccarese, , A. Parodi, A. Rebora, F. Drago
DISSAL, Department of Dermatology, IRCCS San Martino IST, Genoa, Italy
Dear Editor,

We read with great interest the paper entitled “Oral ivermectin to treat papulopustular rosacea in a immunocompetent patient.” by Hernández-Martín1 that prompted us to make some observations and to report our experience. The Author described a patient with papulopustular rosacea that has been considered immunocompetent but it was not specified whether laboratory examinations have been performed to investigate the immune status of the patient (as complete blood count, human immunodeficiency virus test). Moreover, the Author stated that the past medical history of the patient included topical immunomodulators, but without defining the specific drug.1 Due to the only partial and/or transient rosacea improvement after several topical and systemic treatments, Hernández-Martín recommended a single 250μg/kg dose of oral ivermectin leading to complete remission of the rosacea lesions.1 However, the Author did not demonstrate by skin scraping or standardized skin surface biopsy neither the presence nor an excessive number of Demodex folliculorum (DF) mites in the pilosebaceous units to justify the oral antiparasitic therapy.2 It is known that patients with papulopustular rosacea may have a higher density of DF mites on their faces than controls. However, in the absence of any qualitative and quantitative information on DF, it could be hypothesized that ivermectin may have operated through immunomodulating mechanism rather than through a true acaricidal action. The immunomodulatory effect of ivermectin has been reported long ago in mice,3 and very recently confirmed by Schaller et al.4 who found, in 20 Caucasian patients with moderate to severe rosacea treated with topical ivermectin for ≥12 weeks, that the gene expression levels LL-37, HBD3 and TNF-α was significantly reduced after and during treatment.

Regrettably, Hernández-Martín1 neglected that also a DF-related bacterium, Bacillus oleronius, may express antigens that stimulates an inflammatory immune response5 and that other different triggers may contribute in the pathogenesis of rosacea, more specifically gastrointestinal disorders like Helicobacter pylori (HP) infection and small intestine bacterial overgrowth (SIBO).6,7 In two previous studies, we reported our experience on 60 rosacea patients that were followed up for 3 years, in which we have investigated the prevalence of three possible trigger agents: DF (through SSSB on rosacea lesions [test was considered positive for density >5 mites/cm2]), HP infections (through urea breath test) and SIBO (through lactulose breath test).8,9 Recently, we completed the study with a 5-year follow up. Shortly after enrolment, DF was the agent most frequently found (75%) followed by SIBO (67%) and HP infection (13%). HP infection prevailed in patients with erythrosis, SIBO in patients with papulo-pustular rosacea whereas DF was not associated with specific rosacea types. DF was found as the only trigger in 16 patients whereas 29 patients were positive for more than one trigger agent (23 patients had DF+SIBO, 4 patients DF+HP and 2 patients DF+HP+SIBO). Patients that proved positive for more than one triggering agent were treated in the following order: DF acaricidal treatment (crotamiton cream once/daily associated with azelaic acid gel once/daily for 3 weeks); antibiotic therapy for SIBO (rifaximin 1200mg/daily for 10 days), antibiotic therapy for HP (rabeprazole 10mg+amoxicillin 1000mg+metronidazole 250mg twice/daily for 2 weeks). The topical therapy for DF was effective in reducing its population and in improving the cutaneous lesions but only 26% of the patients remitted. The 23 patients positive for both DF and SIBO underwent acaricidal treatment but the majority of them (74%) remitted only after rifaximin treatment. Among the 40 exclusively SIBO positive patients treated with rifaximin, 31 remitted, 8 improved and 1 did not. Overall, most of our patients (61%), treated in accordance with the specific causal agent, cleared and had no relapsed in the following 5 years, confirming our previous studies.8,9 In conclusion, we emphasize that the eradication of the underlying trigger agents in rosacea may be crucial in improving the disease and in maintaining the clinical remission over time. However, the search for the presence of SIBO should be done in rosacea patients since its treatment seems to be relevant in improving the disease and maintaining the clinical remission, also when more than one microorganisms are still present.

References
1
Á. Hernández-Martín
Tratamiento con ivermectina oral en un paciente inmunocompetente con rosacea pápulo-pustulosa
Actas Dermosifiliogr, (2017), http://dx.doi.org/10.1016/j.ad.2017.01.011
2
S. Bunyaratavej,C. Rujitharanawong,P. Kasemsarn,W. Boonchai,C. Muanprasert,L. Matthapan
Skin scrapings versus standardized skin surface biopsy to detect Demodex mites in patients with facial erythema of uncertain cause – a comparative study
Indian J Dermatol Venereol Leprol, 82 (2016), pp. 519-522 http://dx.doi.org/10.4103/0378-6323.174423
3
B.R. Blakley,C.G. Rousseaux
Effect of ivermectin on the immune response in mice
Am J Vet Res, 52 (1991), pp. 593-595
4
M. Schaller,L. Gonser,K. Belge,C. Braunsdorf,R. Nordin,A. Scheu
Dual anti-inflammatory and antiparasitic action of topical ivermectin 1% in papulopustular rosacea
J Eur Acad Dermatol Venereol, (2017), http://dx.doi.org/10.1111/jdv.14437
5
N. Lacey,S. Delaney,K. Kavanagh,F.C. Powell
Mite-related bacterial antigens stimulate inflammatory cells in rosacea
Br J Dermatol, 157 (2007), pp. 474-481 http://dx.doi.org/10.1111/j.1365-2133.2007.08028.x
6
R. Gallo,F. Drago,S. Paolino,A. Parodi
Rosacea treatments: what's new and what's on the horizon?
Am J Clin Dermatol, 11 (2010), pp. 299-303 http://dx.doi.org/10.2165/11537020-000000000-00000
7
A. Parodi,S. Paolino,A. Greco,F. Drago,C. Mansi,A. Rebora
Small intestinal bacterial overgrowth in rosacea: clinical effectiveness of its eradication
Clin Gastroenterol Hepatol, 6 (2008), pp. 759-764 http://dx.doi.org/10.1016/j.cgh.2008.02.054
8
A.F. Agnoletti,E. DE Col,A. Parodi,I. Schiavetti,V. Savarino,A. Rebora
Etiopathogenesis of rosacea: a prospective study with a three-year follow-up
G Ital Dermatol Venereol, (2016),
9
F. Drago,E. De Col,A.F. Agnoletti,I. Schiavetti,V. Savarino,A. Rebora
The role of small intestinal bacterial overgrowth in rosacea: a 3-year follow-up
J Am Acad Dermatol, 75 (2016), pp. e113-e115 http://dx.doi.org/10.1016/j.jaad.2016.01.059
Corresponding author. (G. Ciccarese giuliaciccarese@libero.it)
Copyright © 2017. Elsevier España, S.L.U. and AEDV
Actas Dermosifiliogr 2018;109:91-2 - Vol. 109 Num.1 DOI: 10.1016/j.adengl.2017.07.015