JPDS
Journal of the Philippine Dermatological Society
Volume 31 Issue 1 • May 2022 • ISSN 2094-201X
Trichoepithelioma (top images) and basal cell carcinoma (bottom images) in a patient
with Brooke-Spiegler syndrome
Teledermatology at a Comparative efficacy and Topical sirolimus for the
tertiary government safety of oral ivermectin, treatment of angiofibromas
hospital in Davao City topical permethrin, and its
during the COVID-19 combination in the treatment in a child with tuberous
pandemic: a retrospective of scabies: a systematic sclerosis complex:
descriptive study literature review first reported case in the
Philippines
Editorial Board 2021-2022
Journal of the Philippine Dermatological Society • Volume 31 Issue 1 • May 2022
EDITOR-IN-CHIEF
Bryan Edgar K. Guevara, MD, FPDS
DEPUTY EDITOR MANAGING EDITOR
Hester Gail Lim Bueser, MD, FPDS Mara P. Evangelista-Huber, MD, FPDS
ASSOCIATE EDITORS
Czarina Chavez, MD, FPDS Elisa Rae Coo, MD, FPDS
Lian Jamisola, MD, FPDS Maria Jasmin J. Jamora, MD, FPDS
Hanna Lucero Orillaza, MD, FPDS Melanie Joy Doria-Ruiz, MD, FPDS
Ana Aurelia M. Santos, MD, FPDS Jennifer Aileen A. Tangtatco, MD, FPDS
Patricia Tinio, MD, FPDS Angeli Eloise E. Torres, MD, DPDS
Emmerson Gale S. Vista, MD, FPDS
SECTION EDITORS
Gisella Adasa, MD, FPDS Joyce C. Castillo, MD, FPDS
Tanya Perez-Chua, MD, FPDS Stephen Lacson, MD, FPDS
Sharon Lim, MD, FPDS Eugenio R. Pipo III, MD, FPDS
Lily Lyralin Laconico Tumalad, MD, FPDS Cybill Dianne C. Uy, MD, FPDS
Mia Angela C. Verzosa, MD, FPDS
SOCIAL MEDIA EDITORS
Terese Monette O. Aquino-Agas, MD, DPDS Jay-V James G. Barit, MD, DPDS
Jarische Frances S. Lao-Ang, MD, DPDS Ana Aurelia M. Santos, MD, FPDS
Erin Jane L. Tababa-Santos, MD, DPDS
Francesca Sumilang Sy-Alvarado, MD, FPDS
EDITORIAL ADVISER
Camille B. Angeles, MD, FPDS
COPYEDITORS LAYOUT ARTIST
Jaryll Gerard L. Ampog Clarence Xlasi D. Ladrero
Rodel C. Roño
EDITORIAL OFFICE
#73 Malakas Street, Diliman, Quezon City 1100 Philippines
(632) 8727 7309 • https://journal.pds.org.ph/
JPDS is indexed in the Western Pacific Rim Index Medicus (WPRIM) and HERDIN.
ISSN: 2094-201X PHILIPPINE COPYRIGHT @ 2014 Philippine Dermatological Society. All rights reserved. No part of this publication may be reproduced, stored, or transmitted in any form or
by any means without prior permission in writing from the copyright holder.
DISCLAIMER
The Philippine Dermatological Society and Editors cannot be held responsible for errors or any consequences arising from the use of information contained in this journal; the views and opinions expressed do not
necessarily reflect those of the Philippine Dermatological Society and Editors, neither does the publication of advertisments constitute any endorsement by the Philippine Dermatological Society and Editors. All
editorial staff are requested to disclose any potential conflict of interest, including current or recent financial relationships with any commercial entity whose products or services may be contained in the journal
content. The competing interests are disclosed in our website.
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X i
Philippine Dermatological Society
OFFICERS AND BOARD DIRECTORS 2021-2022
Journal of the Philippine Dermatological Society • Volume 31 Issue 1 • May 2022
PRESIDENT
Francisco D. Rivera IV, MD, FPDS
VICE PRESIDENT
Noemie Salta Ramos, MD, FPDS
SECRETARY
Roberto Antonio D. Pascual, MD, FPDS
TREASURER
Mary Charmaine G. Castillo, MD, FPDS
IMMEDIATE PAST PRESIDENT
Ma. Purita Paz-Lao, MD, FPDS
DIRECTORS
Christene Pearl F. Arandia, MD, FPDS
Blossom Tian Chan, MD, FPDS
Krisinda Clare Dim-Jamora, MD, FPDS
Lonabel A. Encarnacion, MD, FPDS
Nancy Garcia-Tan, MD, FPDS
Cecilia Roxas Rosete, MD, FPDS
Arnold C. Yu, MD, FPDS
ii J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
Table of Contents
Journal of the Philippine Dermatological Society • Volume 31 Issue 1 • May 2022
ORIGINAL ARTICLES CASE REPORTS
1 33
Teledermatology at a tertiary government hospital Malignant transformation of multiple adnexal
in Davao City during the COVID-19 pandemic: a tumors in a Filipino-American patient with Brooke-
retrospective descriptive study Spiegler Syndrome: a case report
Anna Cristina L. Cuenca, Lalaine R. Visitacion, Jen- Angelie Therese T. Chua, Daisy K. Ismael
Christina Lourdes Q. Segovia
37
7
Primary cutaneous aggressive epidermotropic
Comparative efficacy and safety of oral ivermectin, CD8+ T-cell lymphoma in a 76-year-old Filipino male:
topical permethrin, and its combination in the a case report
treatment of scabies: a systematic literature review Katrina M. Canlas-Estrella, Joshua A. Arcaira, Filomena
Rowena F. Genuino, Maria Christina Filomena R. Batac, Legarda-Montinola, Teresita E. Dumagay
Francis R. Capule, Kimberly Anne G. Ednalino, Fernando
B. Garcia, Jr., Mary Ann J. Ladia, Malaya P. Santos, Ailyn M. 42
Yabes, Maria Stephanie Fay S. Cagayan
Topical sirolimus for the treatment of angiofibromas
20 in a child with tuberous sclerosis complex:
first reported case in the Philippines
Relationship of whole blood zinc levels to acne Angela M. Esguerra, Jarische Frances S. Lao-Ang
severity among Filipinos 18-25 years old: a cross-
sectional comparative study in a tertiary government 46
hospital
Monique Lianne C. Lim-Ang, Ma. Angela M. Lavadia Subungual squamous cell carcinoma of the great toe
presenting as a pyogenic granuloma-like mass in a
26 64-year-old Filipino male: A case report
Sher Claranza O. Liquido, Bernice C. Navarro, Tanya
The economic burden of psoriasis: a cross-sectional Angela Perez Chua, Mae Ramirez Quizon
study in a tertiary hospital in the Philippines
Diandra Aurora R. Zabala, Victoria P. Guillano, Maynie Bambi 50
D. Lugasan
Scrofuloderma and tuberculous gumma
in a young Filipino adult: a rare presentation
of multifocal tuberculosis
Ma. Fatima Lourdes Omangayon, Emmerson Gale S. Vista
54
A case of anti-BP230 antibody-positive
dyshidrosiform bullous pemphigoid secondary to
dipeptidyl peptidase-4 inhibitor in a 65-year-old
Filipino female
Aizlynn Anne J. Robledo, Ma. Jasmin J. Jamora
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X iii
JPDS ORIGINAL ARTICLE
Journal of the Philippine
Dermatological Society
Teledermatology at a tertiary government hospital
in Davao City during the COVID-19 pandemic: a
retrospective descriptive study
Anna Cristina L. Cuenca, MD, DPDS,1 Lalaine R. Visitacion, MD, FPDS,1 Jen-Christina Lourdes Q. Segovia, MD1
ABSTRACT
INTRODUCTION Telemedicine is the practice of remote consultations that utilize computer-mediated communication. Given the visual nature of
dermatology, it is most well-suited to adopt telecommunication practices. This enables remote medical care during public health emergencies
like the current COVID-19 pandemic; limiting the risk of exposure for both patients and doctors alike.
OBJECTIVES This study aimed to describe the demographic and clinical profile of teledermatology patients from April to August 2020. Data were
also compared with face-to-face consultations during the same period in 2019 in order to establish whether telemedicine can be a viable and
reliable substitute to face-to-face consultations during a pandemic.
METHODS We retrospectively analyzed chart data during a 5-month period in 2020; wherein the number of online consultations were observed
to be the highest. We noted demographic and clinical features and compared some of these data to those obtained in the same period in 2019.
RESULTS A total of 1,632 patients were seen via teledermatology in 2020 versus 7,219 face-to-face patients in 2019. Mean age for both groups were
26.59 and 36.89 respectively. Most patients in both years were from Davao. However, there was an increase in consults from other regions in 2020.
Overall, the majority of cases for both periods were non-urgent inflammatory conditions.
CONCLUSION This study showed that providing remote dermatologic care is now possible with the advent of technology even during a pandemic.
Teledermatology may serve as an effective adjunct to traditional consultations.
KEYWORDS telemedicine, dermatology, COVID-19, pandemic
1Department of Dermatology of the INTRODUCTION but is not limited to the “exchange of valid infor-
Southern Philippines Medical Center mation for diagnosis, treatment and prevention
Coronavirus disease 2019 (COVID-19) is an infec- of disease and injuries, research and evaluation,
Corresponding author tious illness caused by the novel severe acute re- and continuing education of health care provid-
Anna Cristina L. Cuenca, MD, DPDS spiratory syndrome coronavirus 2 (SARS-CoV-2). ers. All of these in the interest of advancing the
Despite efforts to halt the rapid rise of infection health of individuals and their communities.”4
Conflict of interest rates, it has since progressed into a pandemic. These terms have minor differences but are im-
None Public health authorities have urged health care portant to recognize as relevant to our study.
facilities to optimize alternative consultation
Source of funding options especially for non-COVID-19 cases. In Teledermatology is the application of tele-
None response to this need, telemedicine, specifically medicine methods in the field of dermatology.
teledermatology, with various studies supporting Dermatologists were encouraged to shift to this
Cite as claims of its efficiency has then been put to the practice because face-to-face dermatological
Cuenca ACL, Visitacion LR, Segovia forefront.1,2 consultations can serve as potential vectors for
JCLQ. Teledermatology at a tertiary disease transmission.5 Studies have shown that
government hospital in Davao City The World Health Organization (WHO) dermatology may be the best-suited field to adopt
during the COVID-19 pandemic: a defines digital health as the use of digital tech- telemedicine because of its “visual character.”1,6,7
retrospective descriptive study. J Phil nologies for health purposes. This encompasses Armstrong and Kwong et al. in 2011 found that
Dermatol Soc. 2022;31(1):1-6. the increasing use of technologies for health ser- the majority of doctors who participated in their
vices.3 Telehealth is the most basic engagement study believed that all skin conditions may be
of eHealth, involving telecommunications and accurately diagnosed by teledermatology. They
virtual technology to deliver health care outside concluded that this system of health care is effi-
of traditional facilities.3 Telemedicine by defini- cient in providing dermatologic care.8 The nature
tion is remote information and communication and effectiveness of teledermatology prompted
technology-mediated healthcare services deliv- some providers to utilize it. This enables patients
ered by healthcare professionals. This includes
1 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
to have access to services without having a risk of exposure in paring charts with information from the database of the medi-
medical facilities.9 cal records department. Data collection forms were signed by
the primary researcher together with the co-author to attest
As many studies attest to telemedicine as an effective and that the data gathered were true. Corrections or modifications
efficient way to provide care during the COVID-19 outbreak, our in the entries were dated, initialed, and rechecked to ascertain
institution officially established our teledermatology services accuracy. Once data collection was completed, a comparison
beginning in April of 2020. This was maximized during the to the census from the previous year was made. All data were
nationwide enhanced community quarantines implemented analyzed by a statistician.
by the Inter Agency Task Force (IATF) for the Management of
Emerging Infectious Diseases.10 VARIABLES AND OUTCOME MEASURES
OBJECTIVES INDEPENDENT VARIABLES
1. Demographic profile - a profile filed in terms of age,
The general objective of this study was to describe the demo-
graphic and clinical profile of patients who sought teleconsulta- sex, and location
tions at the Dermatology Department of a tertiary government 2. Clinical Impression - written diagnosis as found in the
hospital in Davao City from April to August 2020. The specific
objectives of this study were; (1) To describe the following pro- chart
files of patients who availed of the Dermatology Department’s
teledermatology services: age, sex and location; (2) To deter- MAIN OUTCOME
mine the clinical features of these patients in terms of diag- The main outcome of the study included the disposition of
nosis and dispositions (completed consult, admitted, referred the consultations, the improvement measured via self-as-
to or from other departments); (3) To determine the number of sessment of the patient, as well as the analysis of photos
teledermatology consultations and follow-ups done through: a) submitted to the physician through follow-up.
teledermatology consultations only (single consultation only,
no follow-ups done), b) teledermatology consultations requir- STATISTICAL ANALYSES
ing follow-ups; (4) To compare teledermatology consultations This study used descriptive statistics. Continuous data were
seen from April 2020 to August 2020 to face-to-face consulta- analyzed using mean and standard deviation, while categori-
tions from April 2019 to August 2019 in terms of demographic cal data sets were analyzed using frequency rates and percent-
profile, total number of consultations, and top 10 cases of skin ages. Comparative analyses were done through two statistical
problems reported; (5) To determine the outcome of treatments tests: (1) T-test for two proportions to compare the significant
(improved or not improved) of teledermatology consultations difference between two percentages and (2) T-test for two means
upon follow-up. to compare the significant difference between two different
means.
METHODS
ETHICS REVIEW
This descriptive and retrospective study conducted a review of The study was reviewed and approved by the Department of
charts. This included teledermatology patients who consulted Health XI Cluster of Ethics Review Committee.
in between April 2020 through August 2020. The patients who
underwent teleconsultations via the Dermatology Department's PRIVACY AND CONFIDENTIALITY
Facebook, SMS, Viber, and Webex were included in the evalu- In compliance with confidentiality policies to protect research
ation except for those with incomplete demographic data and participants, personal information such as names, contact de-
diagnoses. No face-to-face consultations were done during the tails, and any information that may lead to identification were
study period. During this time, the outpatient department was not used in this study. Moreover, all collected data remained
non-operational because of the pandemic restrictions. The cen- with the researchers only until the completion of the study. All
sus of the outpatient consultations from April 2019 to August data gathered were disposed through drive reformatting for soft
2019 was also taken and reviewed for comparison. copies and burning for hard copies.
All data gathered in this study belonged to the Dermatolo- RESULTS
gy Department of the institution. Records from teledermatolo-
gy consultations from April to August 2020 were gathered, sort- This study examined a total of 9,251 charts. Patients seen from
ed, and scrutinized based on completeness. Demographic data April 1 to August 31 of 2019 amounted to 7,619 while 1,632 were
were collected and encoded on Microsoft Excel. seen from April to August of 2020. Average monthly consulta-
tions were 1,524 for 2019 and 326 for 2020, a 78.6% decrease.
The accuracy, authenticity, consistency, legibility, and
completeness of all information acquired were ensured by com-
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 2
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
A comparative analysis of the demographic profile of pa- The percentage of cases of male patients was higher in 2019
tients who sought face-to-face consultations prior to the pan- while female patients outnumbered males in 2020.
demic, in contrast with virtual consultations during the pan-
demic, showed statistical differences in terms of age, sex, and A statistical difference was noted in the case distribution
location (Table 1). Cases were distributed in the age brackets among the Philippine regions between 2019 and 2020. While
0-18 years old, 19-39 years old, 40-59 years old and 60+ years old data from face-to-face consultations in 2019 showed that most
in both years. In 2019, cases were ranked by number of consul- patients were from the Davao Region, data from telederma-
tations per age bracket in the following decreasing order: 19-39, tology consultations in 2020 showed a wider case distribution
40-59, 0-18 and 60+. In 2020, cases were ranked in the same man- among all Philippine regions. Davao Region had the most cases
ner as follows: 19-39, 0-18, 40-59 and 60+. Relatively younger age while the rest were sparsely distributed among regions from Lu-
groups were recorded to have sought consultations in 2020 than zon to Mindanao.
in 2019. The mean value of both years landed at 26.59 and 36.89,
respectively. However, when cases in both years were grouped The teledermatology cases in this study were categorized
in terms of case distribution by age, no statistical differences under three (3) types: single teledermatology consultations
were noted. without follow-ups (82%), teledermatology consultations that
required face-to-face follow-ups (1%), and teledermatology con-
sultations with teledermatology follow-ups (17%). An average of
Table 1. Demographic profile of patients seen in 2019 and 2020.
Demographic Profile 2019 2020 p-value
26.59±15.732 <0.01
Age (Mean age ± SD, years) 36.89±21.799 356 (21.8%) <0.01
1,011 (61.9%)
0-18 years 1,648 (21.6%) 185 (11.3 %) <0.01
19-39 2,654 (34.8%) 80 (4.9%)
0 (0%)
40-59 1,745 (22.9%)
554 (34.1%)
60 above 1,560 (20.5%) 1,078 (66.1%)
Did not state a 12 (0.2%) 189 (11.6%)
3 (0.2%)
Sex 16 (1%)
3 (0.2%)
Male 3,335 (43.8%) 81 (5%)
164 (10%)
Female 4,284 (56.2%) 11 (0.7%)
16 (1%)
Location 13 (0.8%)
25 (1.5%)
NCR 0 (0%) 12 (0.7%)
13 (0.8%)
CAR 0 (0%) 30 (1.8%)
Region 1 0 (0%) 1,002 (61.4%)
39 (2.4%)
Region 2 0 (0%) 11 (0.7%)
4 (0.2%)
Region 3 0 (0%) 0 (0%)
Region 4-A 0 (0%)
Region 4-B 0 (0%)
Region 5 0 (0%)
Region 6 0 (0%)
Region 7 0 (0%)
Region 8 0 (0%)
Region 9 0 (0%)
Region 10 0 (0%)
Region 11 6,762 (88.8%)
Region 12 0 (0%)
Region 13 0 (0%)
ARMM 0 (0%)
Did not specifyb 857 (11.2%)
a,bAge and location for an indigenous group (Badjao/Bajau) could not be accounted for but not excluded.
3 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
55 follow-ups per month was seen. Among all the cases, the ma- beginning of the COVID-19 pandemic in 2020. Compared to 2019,
jority or 1626 (99.6%) were discharged with prescriptions given, there was a 78.6% decrease in the cases seen. This may be great-
while none required hospitalization. Among the total number ly attributed to the quarantine measures and lockdown proce-
of cases, only one (1) case was a referral from another depart- dures that were implemented throughout the country.10 Despite
ment while 48 (3%) were referred to another service for co-man- the services being remotely available and free of charge, the
agement or further work-up. decline in cases during the 2020 period could also be attribut-
ed to a lack of access to gadgets or to the Internet. Refusal to
In a comparison of top 10 skin diseases treated in 2019 and adapt to online consultation schemes during this time may have
in 2020, results showed a variety of skin conditions. Psoriasis also been a factor, especially for patients 60 years old and above.
vulgaris, tinea, post-inflammatory hyperpigmentation, sebor- This is supported by the findings of Almathami et al.’s system-
rheic dermatitis, scabies, pityriasis versicolor, pityriasis rosea, atic literature review in 2020. The authors noted barriers that
nummular dermatitis/ eczema, verruca vulgaris, and psoriatic influence telemedicine-based consultations such as problems in
arthritis were the top skin diseases treated in 2019. In 2020 the adapting to online consultations (technical issues, willingness
top cases were acne vulgaris, irritant contact dermatitis, acne to adapt), quarantine measures, and foregoing consultations for
scars, Hansen’s Disease, acute urticaria, bite hypersensitivity minor conditions.11
reaction/ papular urticaria, dyshidrotic eczema, herpes zoster,
atopic dermatitis, and lichen simplex chronicus. Most of the Technology is seen as a major roadblock in remote health
cases for both years are non-urgent inflammatory conditions care as it is not accessible to many.12 Results of this study show
(Table 2). that the sudden shift to teledermatology was advantageous to
patients between 19-39 possibly due to more access to technol-
The study was not able to gauge improving or worsening ogy. The same cannot be said for patients outside of that range,
outcomes for single consultations. However, out of the 273 (17%) specifically for patients above 40 due to difficulties adapting to
patients who had teledermatology follow-ups, 85 (31%) reported the platforms.13 Apart from technology, another key factor in
improvement from initial consultation. None reported wors- the measurement of remote health care success is behavior to-
ened conditions. A bulk of the follow-ups were for refill of pre- wards health care. In 2020, the pediatric age group (0-18 years
scriptions. These were for conditions that required prolonged old) came second in terms of number of consultations. This can
management such as acne vulgaris and Hansen’s disease. Over be attributed to parents’ health-seeking behaviors.14 Another
the study period, an average of one (1) to four (4) follow-ups were factor could also be due to the assumed age of the parents. The
done depending on the nature of the disease. Patients treated usual reproductive age was from 15-49 years old which falls into
for irritant contact dermatitis were seen twice on average while those that sought more teledermatology consultations. More-
patients with acne and Hansen’s disease had an average of three over, females sought more teledermatology consultations than
(3) and four (4) consultations respectively. It was also noted that men in the same year, which can be attributed to women’s in-
the rest with status quo conditions followed-up for further work- clination towards health care response.15 The numbers in both
up and management. population groups may be attributed to these health-seeking
behaviors especially since the institution's teledermatology
DISCUSSION consultations were free of charge and made more accessible
through online means.
This study analyzed the demographic and clinical profiles of pa-
tients seen at a government tertiary hospital in Davao City in the While technology can be seen as a roadblock, it can also
be an advantage. Prior to the pandemic, the institution’s face-
Table 2. Top 10 Diseases seen in 2019 and 2020 to-face consultations were mostly accessible only to residents
of the Davao Region. During the outbreak, telehealth consulta-
Top 10 Diseases in 2019 Top 10 Diseases in 2020 tions were encouraged; this was to avoid health and safety risks
among patients and health care workers. With teledermatology
Psoriasis vulgaris Acne vulgaris consultations bridging the gap of inaccessibility, health care be-
came available to a larger population. This may explain the rise
Tinea Irritant contact dermatitis of patients coming from formerly non-serviceable areas. A shift
in the location of patients in 2020 was observed. While almost all
Post inflammatory hyperpigmentation Acne scars the patients resided within Davao Region in 2019, cases were dis-
tributed among the 17 Philippine regions in 2020. However, the
Seborrheic dermatitis Hansen’s disease Davao Region still had the most cases. This may be predictable
as the institution is situated in Davao City. Facebook was one of
Scabies Acute urticaria the most used platforms. It featured page sharing which made
Pityriasis versicolor Bite hypersensitivity reaction
Pityriasis rosea Dyshidrotic eczema
Nummular dermatitis Herpes Zoster
Verruca vulgaris Atopic dermatitis
Psoriatic arthritis Lichen simplex chronicus
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 4
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
the institution visible to patients in Luzon and Visayas. It was likely linked to safety protocols such as wearing of PPEs and
also assumed that word of mouth referrals played a role. Charts frequent disinfection. The age of the patients in 2020 is note-
with narrowed down location showed similar barangays, espe- worthy in this context in that the majority were from relative-
cially in Luzon. The responsiveness of doctors, accessibility via ly younger age groups. This may be attributed to a shortened
multiple platforms, free service, as well as generic medications waiting time, more access to specialists, and free consultations.
being prescribed may have been reasons why patients chose the While teledermatology diagnoses may be challenging due to
institution’s services over other teledermatology providers. a limited visual presentation, instances like these reveal that
teleconsultations may be more convenient for both patients and
As COVID-19 remains to be a threat, many patients may dermatologists. Referrals are reduced but direct consultation is
have opted to forego follow-up consultations especially for con- increased by giving access to specialists. This encourages more
ditions with minor symptoms. It cannot be ruled out that pa- patients with skin conditions to seek medical attention.18
tients without follow-ups may be due to other teledermatology
platforms that may have been preferred more by the patient. CONCLUSION
While the general outcome of the institution’s teledermatology
services cannot be determined with mostly single consultations Findings of the study show that there was an overall decrease in
only, or by the percentage of those who reported improvement, consultations during the pandemic, and that women between
it can be assumed that non-appearance for follow-up consulta- 19-39 years old sought more consultations than any other age
tions mean general improvement or non-worsening conditions and gender group. It also revealed that teledermatology indeed
where patients deemed follow-up consultations to be unneces- made dermatologic care more accessible as there was an influx
sary.1,7 This however does not rule out the possibility of patient of patients outside the institution’s physically serviceable areas.
non-compliance as well as non-improvement Moreover, while Benign inflammatory skin conditions followed by chronic skin
there is a lack of data in terms of outcomes, patients who sought conditions were the main reasons for consultation among pa-
repeat consultations could be attributed to patient satisfaction. tients.
This may prove that teledermatology is an efficient health care
mechanism during the pandemic.16,17 While results of the study currently cannot gauge the suc-
cess of teledermatology, most of the patients reporting improve-
Lastly, several factors contribute to the prevalence of skin ment may prove that the institution's teledermatology platform
conditions in consultation statistics especially with regards to provided appropriate dermatologic care during the pandemic.
medication or treatment-related reasons. Patients with chronic
skin conditions may require multiple follow-up consultations An in-depth analysis of treatment outcomes with a greater
for monitoring or refill of medications, as well as to receive sample size is recommended for future studies. To improve the
in-clinic treatments which may explain the consultation statis- caliber of teledermatology, patient satisfaction surveys compar-
tics in 2019. In 2020, the rise in acne and dermatitis were most ing the benefits and shortcomings of face-to-face versus teleder-
matology consultations may also be investigated.
ACKNOWLEDGMENTS
We would like to thank the staff of the institution for providing us the data used in this study. Also, we are grateful to the members of the
hospital’s dermatology department for their guidance on the direction of our research.
REFERENCES
1. Tensen E, van der Heijden JP, Jaspers MW, Witkamp L. Two Decades of Teledermatology: Current Status and Integration in National
Healthcare Systems. Curr Dermatol Rep. 2016; 5:96-104. doi: 10.1007/s13671-016-0136-7.
2. Flodgren G, Rachas A, Farmer AJ, et.al. Interactive telemedicine: effects on professional practice and health care outcomes. Cochrane
Database Syst Rev. 2015 Sep 7; 2015(9):CD002098. doi: 10.1002/14651858.CD002098.pub2.
3. World Health Organization. Recommendations on Digital Interventions for Health System Strengthening. https://apps.who.int/iris/
bitstream/handlehttps://apps.who.int/iris/bitstream/handle/10665/311941/9789241550505-eng.pdf?ua=1. Published 2019. Accessed 9 July
2020.
4. World Health Organization. Telemedicine: Opportunities and Developments in Member States. World Health Organization. https://www.who.
int/goe/publications/goe_telemedicine_2010.pdf. Published 2010. Accessed 9 July 2020.
5. Kwatra SG, Sweren RJ, Grossberg AL. Dermatology practices as vectors for COVID-19 transmission: A call for immediate cessation of non-
emergent dermatology visits. J Am Acad Dermatol [Internet]. 2020 May 01 [2020 July 11]; 82(5):e179-e180. doi:10.1016/j.jaad.2020.03.037.
6. Warshaw EM, Hillman YJ, Greer NL, et.al. Teledermatology for diagnosis and management of skin conditions: a systematic review. J Am Acad
Dermatol. 2011 Apr; 64(4):759-72. doi: 10.1016/j.jaad.2010.08.026.
7. Giavina-Bianchi M, Santos AP, Cordioli E. The majority of skin lesions in pediatric primary care attention could be managed by
5 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
Teledermatology. PLoS One. 2019 Dec 2; 14(12):e0225479. doi: 10.1371/journal.pone.0225479.
8. Armstrong AW, Kwong MW, Ledo L, et.al. Practice models and challenges in teledermatology: a study of collective experiences from
teledermatologists. PLoS One. 2011; 6(12):e28687. doi: 10.1371/journal.pone.0028687.
9. Lee, I., Kovarik, C., Tejasvi, T., Pizarro, M., and Lipoff, J. Telehealth: Helping your patients and practice survive and thrive during the COVID-19
crisis with rapid quality implementation. J Am Acad Dermatol. 2020; 82(5): 1213-1214. https://doi.org/10.1016/j.jaad.2020.03.052.
10. Interagency Task Force for the management of emerging infectious diseases [Internet]. Philippines: Official gazette; c2020 [cited 2021
October 2]. Available from https://www.officialgazette.gov.ph/downloads/2020/07jul/20200817-IATFRESOLUTION-NO-64.pdf
11. Almathami HKY, Win KT, Vlahu-Gjorgievska E. Barriers and Facilitators That Influence Telemedicine-Based, Real-Time, Online Consultation at
Patients' Homes: Systematic Literature Review. J Med Internet Res. 2020 Feb 20; 22(2):e16407. doi: 10.2196/16407.
12. Hoffman DA. Increasing access to care: telehealth during COVID-19. J Law Biosci. 2020; 7(1):lsaa043. doi:10.1093/jlb/lsaa043.
13. Cimperman M, Brenčič MM, Trkman P, Stanonik Mde L. Older adults' perceptions of home telehealth services. Telemed J E Health. 2013;
19(10):786-90. doi: 10.1089/tmj.2012.0272.
14. Sreeramareddy CT, Shankar RP, Sreekumaran BV, et al. Care seeking behaviour for childhood illness--a questionnaire survey in western
Nepal. BMC International Health and Human Rights. 2006 May; 6:7. DOI: 10.1186/1472-698x-6-7.
15. Thompson AE, Anisimowicz Y, Miedema B, et.al. The influence of gender and other patient characteristics on health care-seeking
behaviour: a QUALICOPC study. BMC Fam Pract. 2016 March; 17:38. doi: 10.1186/s12875-016-0440-0.
16. Elsner P. Teledermatology in the times of COVID-19 - a systematic review. J Dtsch Dermatol Ges. 2020 Aug; 18(8):841-845. doi: 10.1111/ddg.14180.
17. Fluhr JW, Gueguen A, Legoupil D, et.al. Teledermatology in Times of COVID-19 Confinement: Comparing Patients' and Physicians' Satisfaction
by the Standardized Brest Teledermatology Questionnaire. Dermatology. 2021 Feb 10; 237(2):1-6. doi: 10.1159/000514029.
18. Giavina-Bianchi M, Santos AP, Cordioli E. Teledermatology reduces dermatology referrals and improves access to specialists.
EClinicalMedicine. 2020 Nov; 29-30:100641. doi.org/10.1016/j.eclinm.2020.100641.
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 6
JPDS ORIGINAL ARTICLE
Journal of the Philippine
Dermatological Society
Comparative efficacy and safety of oral ivermectin,
topical permethrin, and its combination in the
treatment of scabies: a systematic literature review
Rowena F. Genuino, MD, FPDS,1 Maria Christina Filomena R. Batac, MD, FPDS,2 Francis R. Capule, RPh, MS, PhD,3
Kimberly Anne G. Ednalino, MD,2 Fernando B. Garcia, Jr., PhD,4 Mary Ann J. Ladia, PhD,5 Malaya P. Santos, MD, FPDS,6
Ailyn M. Yabes, PhD,7 Maria Stephanie Fay S. Cagayan, MD, FPOGS, PhD7,8
ABSTRACT
INTRODUCTION Oral ivermectin is an approved first-line option to topical permethrin in Europe and Japan for the treatment of classic scabies,
while combination oral ivermectin and topical permethrin is used in clinical practice for extensive or recurrent cases. There is unclear evidence
on comparative efficacy and safety.
OBJECTIVES To review the evidence on efficacy and safety of oral ivermectin versus topical permethrin or its combination in the treatment of
classic scabies.
METHODS We searched PubMed from January 1, 2016 up to August 7, 2021 for systematic reviews that included RCTs comparing oral ivermectin
versus topical permethrin or its combination in the clinical treatment of scabies. We described the characteristics of included studies, assessed
reporting quality, and summarized results and conclusion.
RESULTS We included five systematic reviews. Permethrin did not differ from oral ivermectin in cure rate at the 3 to 6-week time point but had an
earlier cure at 1–2 weeks. Adverse effects did not significantly differ and were few, mild, and transient with both treatments. The evidence ranged
widely from low to high certainty and mainly came from three moderate-to-high quality systematic reviews. Combination oral ivermectin and top-
ical permethrin was ranked higher in efficacy but lower in safety compared to either drug alone in one moderate validity network meta-analysis.
CONCLUSION There is varying certainty of evidence suggesting comparable efficacy and safety of oral ivermectin versus topical permethrin.
Limited evidence suggest higher efficacy and lower safety of combination oral ivermectin and topical permethrin compared to either drug alone.
An updated systematic review and network meta-analysis is warranted.
KEYWORDS scabies, ivermectin, permethrin, effectiveness, efficacy, safety
1Department of Anatomy, College of Medicine, INTRODUCTION scrapings, or using a high-powered imaging de-
University of the Philippines Manila vice or dermoscopy.9–11 A hypersensitivity reac-
Scabies is a highly prevalent and neglected trop- tion to the mite and its fecal material is respon-
2Department of Dermatology, University of the ical skin disease (skin NTD by World Health Or- sible for the severe itch. The number of mites in
Philippines Manila-Philippine General Hospital ganization),1–3 ranging from 0.2% to 71.4%4 in classic or ordinary scabies in healthy individuals
prevalence especially among young children (be- is usually five or fewer, but may number in the
3Department of Pharmacy, College of Pharmacy, low 6 years)5 and the elderly (> 70 years).6 In the millions in crusted scabies in patients who are
University of the Philippines Manila Philippines, limited community surveys showed immunocompromised (taking steroids or other
4Department of Health Policy and Administration, scabies to be among the top three most common immunosuppressants), transplant patients, with
College of Public Health, University of the skin diseases: ranging from 2.01% (N = 5121, six cancer or diabetes or human immunodeficiency
Philippines Manila leprosy-endemic areas nationwide, 1999-2000)7 virus (HIV), on dialysis, and the elderly.
5Institute of Clinical Epidemiology, National to 24.6% (two urban poor communities in Ma-
Institutes of Health-University of the Philippines nila).8 Scabies ranked 4th among new cases (4%), There was a 45% chance of misdiagnosing
Manila and new and existing cases (4.25%) for all outpa- scabies with other skin conditions (atopic der-
6Department of Pathology, Section of Microbiology tient dermatology consults from selected institu- matitis, dyshidrotic eczema, pyoderma, contact
and Parasitology, St. Luke’s Medical Center tions from 2011–2019 (Philippine Dermatological dermatitis or insect bite reaction) prior to the
College of Medicine-William H. Quasha Memorial Society-Health Information System). current consult.10
7Deparment of Pharmacology and Toxicology,
College of Medicine, University of the Philippines The typical skin lesions of scabies are lin- There is also a delay in the symptoms of skin
Manila ear burrows under the skin and itchy excoriated inflammation and itching until 2–6 weeks after
8Department of Obstetrics and Gynecology, papules and can be confirmed by direct identi- the onset of infestation. The mean duration be-
Philippine General Hospital, University of the fication of mites, eggs, or fecal material, either tween the onset of symptoms and the first con-
Philippines Manila through light microscopic examination of skin sultation of patients with scabies with a derma-
Corresponding author
Rowena F. Genuino, MD, FPDS
Conflict of interest
None
Source of funding
None
Cite as
Genuino RF, Batac MCFR, Capule FR, Ednalino
KAG, Garcia FB Jr, Ladia MAJ, et al.Comparative
efficacy and safety of oral ivermectin, topical
permethrin, and its combination in the treatment
of scabies: a systematic literature review. J Phil
Dermatol Soc. 2022;31(1):7-19.
7 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
tologist was 77.1 days (SD 63.7) (range, 4 to 720 days) in a survey Oral ivermectin blocks a class of ligand-gated chloride ion
in two hospital clinics in Cameroon (N=255). At the first consul- channels in the scabies mite, leading to persistently open chan-
tation with a dermatologist, 74.9% had already tried previous nels. Excessive release of the neurotransmitter gamma-amino-
treatment, such as antibiotics, antifungals, antihistamines or butyric acid (GABA) in the nervous system of the mite leads to its
plant-based medicines.11 Common complications of scabies due death. Due to variable expression of the ligand-gated channels
to scratching include impetigo, which may lead to septicemia depending on the life cycle of the mite, ivermectin is active only
and post-streptococcal immune sequelae such as rheumatic against mobile stages (larva, nymphs and adults) and not the
heart disease and glomerulonephritis.12–14 Infected skin lesions neurologically immature eggs.32 Therefore, it requires a second
should be treated with an appropriate prescription antibiotic dose two weeks after the first dose, or once the eggs have de-
(CDC 2020).15 veloped into adults. In crusted scabies, oral ivermectin is given
more than two doses and is combined with topical scabicides
Scabies is curable using either topical medications, oral and keratolytic creams. Resistance to ivermectin was reported
medications, or a combination of both. The first line of treat- in Australia in two patients with crusted scabies who received
ment often consists of topical neurotoxic insecticidal agents multiple doses.33
(permethrin, ivermectin, malathion, spinosad, lindane, and
benzyl benzoate), leading to paralysis and death of the mites. Adverse events reported in people receiving oral ivermec-
An alternative for pregnant women and small infants is sul- tin in RCTs for classical or uncomplicated scabies included ag-
fur, a topical non-specific irritant agent that eliminates mites gravation of symptoms (including pruritus), irritation, head-
through peeling of the skin. The most commonly recommended ache, nausea, pustular rash, cellulitis, abdominal pain and mild
first-line treatment for classic scabies in most clinical practice diarrhea.34 Rare cases of suspected neurological serious adverse
guidelines and currently used in local practice is topical perme- drug reactions (sADRs) were reported in 18 patients with scabies
thrin (Table 1). It works by blocking sodium channels leading or acarodermatitis after intake of ivermectin.35,36 The mecha-
to delayed depolarization, paralysis, and death of mites and nism responsible for the encephalopathy was believed to be a
eggs. However, topical treatment is challenging since it requires passage of ivermectin through the blood-brain barrier due to
whole body application; thus, expensive and inconvenient, lead- overdose or mutation of transporters/metabolism factors (e.g.,
ing to poor compliance and treatment failure from inadequate polymorphism of MDR1 gene; deficiency in P-glycoproteins).
application.16 In addition, the presence of impetiginized or ec- The safety of oral ivermectin in pregnant/breastfeeding wom-
zematous lesions may preclude its use as topical permethrin en37 and children below 15 kg body weight38 is not yet established
may cause skin irritation. Resistance to permethrin has also and thus, oral ivermectin has limited use for scabies in these
been reported in Paris17 and Austria.18 special populations.
Ivermectin, an old broad-spectrum antiparasitic drug, After the treatment that has effectively killed all mites and
is the only oral scabicide used in mass drug administration in eggs, pruritus and skin lesions may persist within six weeks due
endemic communities19 and FDA-approved for scabies in some to hypersensitivity reaction to the mites and its feces.39 Treat-
European countries, Japan, and Australia is ivermectin, an old ment failure should not be diagnosed before six weeks have
broad-spectrum antiparasitic drug (Table 1). Combination oral elapsed. If itching is still present more than two to four weeks
and topical treatment has also been used not only in crusted sca- after treatment or if new burrows or pimple-like rash lesions
bies, but in recurrent, extensive, or recalcitrant classic scabies continue to appear, retreatment may be necessary.
in vulnerable populations such as those with diabetes mellitus20
and residents in elderly homes.21 Combination oral ivermectin To date, there is no local CPG on scabies management al-
and topical permethrin has been used in a few randomized con- though permethrin 5% cream or lotion, or sulfur 5-10% oint-
trolled trials (RCTs) and showed greater efficacy although ad- ment are commonly used and listed in the Philippine National
verse events were also higher than either drug alone.22,23 Formulary (PNF) (2019) and price index (2021).40–43 Oral ivermec-
tin has only been recently added in the PNF 202142 due to its pur-
Oral ivermectin was first introduced in the 1980s for onchocer- ported role in coronavirus disease 2019 (COVID-19) treatment.44
ciasis, filariasis, and malaria control programs24 and recently has It was approved for compassionate use in COVID-19 for certain
been approved for use in ectoparasitic infections (scabies and pe- hospitals, which required a signed written informed consent for
diculosis) by WHO.25,26 Oral ivermectin is recommended as one of off-label use of medication/s and/or use of investigational drug/s
the first-line treatments for both classic and crusted scabies in only for COVID-19.45
three clinical practice guidelines (CPGs) in the US (2021 CDC STI),27
Europe (2017),28 and Japan (2017).29 Oral ivermectin is approved for There is unclear evidence on the comparative effectiveness
scabies in France (2001), and other European countries followed of oral ivermectin versus topical permethrin or its combination
suit, but not in the USA, UK or the Philippines30,31 where it is only as well as the optimal dosing regimen in the treatment of sca-
approved as an anti-nematodal agent. bies to guide its off-label use in local clinical practice. Thus, this
review aims to summarize the current evidence on the efficacy
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 8
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
Table 1. Pharmacodynamic and pharmacokinetic information for oral ivermectin and topical permethrin in treatment of scabies
Scabicide (Drug Class) Year Developed or Mode of Action Pharmacokinetic Data Recommended Dosage Special Precautions Common Adverse
Introduced Regimen for Classic effects
Scabies
Dermatologic
ORAL IVERMECTIN 1988 (for onchocerciasis), Neurotoxic/Adulticidal Absorption Single oral dose of 200 Do not use in children Pruritus, rash
(Avermectin) 2001 (1st approved in May be increased with a μg/kg body weight in weighing less than 15 kg
France for scabies) Binds to glutamate-gated high-fat meal46 tablet form or in pregnant women. Systemic
chloride ion channels in Fever, myalgia, head-
nerve and muscle cells Distribution May be repeated once Pregnancy (category C). ache47
leading to increased Vd: 3.1 to 3.5 L/kg in after 1–2 weeks. Caution with breastfeed-
permeability to chloride healthy volunteers; mean ing. Caution with severe
ions, and neuromuscular 9.9 L/kg (range: 6.9 to hepatic impairment
paralysis30 15.3 L/kg) in patients
with onchocerciasis; high
concentration in the liver
and adipose tissue; does
not readily cross the
blood-brain barrier47,48
Protein binding
~93% primarily to
albumin47
Metabolism
Hepatic via CYP3A4
(major), CYP2D6 (minor),
and CYP2E1 (minor)
Half-life elimination
18 hours
Time to peak, serum
~4 hours
Excretion
Feces; urine (<1%)49
TOPICAL PERMETHRIN 1986 Neurotoxic/Both ovicidal Absorption Permethrin 5% cream Pregnancy (Category B) Dermatologic
(Synthetic pyrethroid) and adulticidal Negligible systemic applied to all areas of the and lactation Burning, numbness,
absorption body from the neck down stinging, tingling, rash, er-
Disrupts sodium ion influx and washed off after Do not use for infants <2 ythema, pruritus, eczema,
through the nerve cell Excretion 8–14 hrs. months old localized oedema.
membrane channels, 0.5% in urinary excretion
delaying repolarization 168 hrs. post-dose50 May be repeated once Systemic (Accidental
after 1 week toxic ingestion)
Epidermal lesions, sore
throat, nausea, vomiting,
abdominal pain, gastroin-
testinal mucosal irritation,
salivation, respiratory
distress and headaches
in humans51
RCT - Randomized Controlled Trial; CCT - Clinically Controlled Trial; OECD - Organisation for Economic Co-operation and Development; ITS - Internal transcribed spacer sequence analysis.
and safety of oral ivermectin versus topical permethrin or its tematicreview[Filter]) AND (humans[Filter])). We also looked at ref-
combination in the treatment of classic scabies. erence lists and relevant similar articles and citing articles.
METHODS We screened the full reports of relevant records based on
the following eligibility criteria:
We searched MEDLINE (PubMed) from August, 2016 to August 7,
2021 using the following search strategy: (("scabi*"[All Fields] OR We extracted and summarized the characteristics (pa-
"scabies"[MeSH Terms] OR "sarcoptes scabiei"[MeSH Terms] OR tients, intervention, comparator, outcomes, study design). We
"antiscab*"[All Fields]) AND "therapy"[MeSH Subheading]) AND critically appraised the validity of included systematic reviews
((y_5[Filter]) AND (meta-analysis[Filter] OR review[Filter] OR sys- using four criteria (appropriateness of criteria for inclusion of
studies, thoroughness of search for eligible studies, validity as-
9 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
sessment of included studies, and reproducibility of assessments PubMed search and one from a reference list and included five
of the studies) from Dans et al. (2017).52 Systematic reviews were systematic reviews on the efficacy and safety of oral ivermec-
assessed as high validity (4/4 criteria), moderate (3/4), low (2/4), tin versus topical permethrin in the treatment of individuals
and critically low (1/4). We also assessed the quality of reporting with scabies (Figure 1). Upon reading full texts, we merged one
of the review using the 16-item Assessment of Multiple Systematic abridged summary (Rosumeck 2019)54 of an included systematic
Reviews 2 (AMSTAR 2) checklist, rating confidence in the results review (Rosumeck 2018), and excluded two more systematic re-
based on the number of critical flaws/weaknesses as: high, moder- views: one that did not include scabies in its included studies55
ate, low and critically low.53 We collected the data for efficacy and and another that did not have a comparator group.38
safety from the included systematic reviews. We identified limita-
tions and research gaps from the current evidence. CHARACTERISTICS OF INCLUDED SYSTEMATIC REVIEWS
We summarized the characteristics of five included systemat-
RESULTS ic reviews (SR) (Table 2). The primary authors of two SRs were
from Germany, and there was one primary author each from
SEARCH FOR STUDIES Australia, South Africa, and Thailand. One SR was a Cochrane
We screened the titles and abstracts of 72 records from the systematic review (Rosumeck 2018).56 The lowest number of in-
cluded studies was 15 in two reviews (Dhana 2018; Rosumeck
2018), which only compared oral ivermectin and topical per-
methrin, while the highest number was 52 (Thadanipon 2019),57
which compared nine scabicides and placebo/no treatment.
There was an overlap of 30 included studies between two or
more reviews, and a total of 50 unique studies. For data synthe-
sis, three SRs did pairwise meta-analysis while only one SR used
network meta-analysis (NMA) (Thadanipon 2019); one SR only
did qualitative synthesis and did not do meta-analysis due to
clinical heterogeneity (May 2019).58
All SRs included patients with scabies; May et al. (2019) also
included patients with impetigo and fungal skin infections; May
et al. (2019) and Dressler et al. (2016) included studies on both
treatment of individual patients and mass drug administration
in endemic settings. One SR compared five topical (benzyl ben-
zoate, crotamiton, ivermectin, permethrin, and sulfur) and one
oral scabicide (oral ivermectin) (Dressler 2016).59 The largest SR
with network meta-analysis (NMA) by Thadanipon et al. (2019)
compared oral ivermectin, eight other topical scabicides (ben-
zyl benzoate, crotamiton, herbal medicine, ivermectin, lindane,
malathion, permethrin, and sulfur), placebo/no treatment, and
combination oral ivermectin and topical permethrin.57
Figure 1. PRISMA flow diagram QUALITY OF INCLUDED SYSTEMATIC REVIEWS
P – individual patients with classic scabies; I – oral ivermectin, any dose, any regimen; Confidence in the results of the five systematic reviews based
C – topical permethrin or combination oral ivermectin/topical permethrin, any dose/ on the AMSTAR 2 tool rating ranged from high (Rosumeck 2018)
concentration, any regimen; O – cure, itch relief, recurrence, adverse events, quality of to moderate (May 2019) to critically low (Dressler 2016; Dhana
life, other patient-reported outcomes; S – systematic reviews, with or without meta- 2018; Thadanipon 2019) (Table 3). The number of critical flaws
analysis. for the latter three reviews were mostly due to items 2 (adequa-
cy of the literature search) and 15 (assessment of presence and
likely impact of publication bias), while non-critical weakness-
es were due to items 3 (explanation of study design of included
studies), 10 (sources of funding of included studies), 12 (poten-
tial impact of risk of bias on evidence synthesis), and 13 (consid-
eration of risk of bias in interpretation and discussion of review
results) (Appendix 1).
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 10
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
Table 2. Summary of characteristics (participants, interventions comparators, outcomes, study design) of included systematic reviews
Characteristic Thadanipon 2019 May 201965 Rosumeck 201863 Dhana 201867 Dressler 201666
(Australia) (Germany) (South Africa) (Germany)
(Cochrane SR)
Participants Individual patients with Indigenous peoples and Children or adults of both sex- Patients with scabies Patients with scabies, and
scabies populations in resource-limited es with a diagnosis of classical whole populations with high
settings (low, low-middle, scabies, as defined by the prevalence of scabies who
middle-income countries) and study authors received therapeutic and/or
resource-limited populations in preventive treatment
OECD countries with diagno-
sis of impetigo, scabies, crust-
ed scabies, tinea capitis, tinea
corporis or tinea ungiuum; Any
age or sex
Interventions 9 scabicides (benzyl benzoate, Any clinical or public health Topical or systemic ivermectin, Topical or oral ivermectin Topical benzyl benzoate,
crotamiton, herbal medicine, interventions to reduce skin topical permethrin crotamiton, ivermectin, per-
topical/oral ivermectin, lin- infections methrin, and sulfur; Systemic
dane, malathion, permethrin, ivermectin
sulfur, synergized pyrethrins)
or placebo/no treatment
Comparators Any of above interventions Any comparator (including oral Any of above interventions Permethrin Any of above interventions
and topical ivermectin, per-
Excluded: Studies that com- methrin, crotamiton, lindane, Exclusion: Placebo-controlled
pared a single drug in different benzyl benzoate + disulfiram) trials and trials comparing
dosages or formulations different dosage forms
Outcomes Primary Not stated Primary Primary Efficacy and safety
Clinical cure or microscopic/ Complete clearance (outcome Treatment failure (as defined
parasitic cure assessment at 7, 14, and in individual studies, although
30 days’ post-initiation of required that the definition
Secondary treatment) include persistent lesions, new
Persistent itching, Reinfesta- lesions, or confirmation of a
tion, adverse events Secondary live mite)
Number of people retreated
Number of people with at least Secondary
one adverse event Persistence of itch
Number of people withdrawn Adverse effects
from study due to adverse
event
Study Design RCTs Experimental (RCTs, CCTs, RCTs Peer-reviewed RCTs RCTs
before-and-after studies, ITS
analyses) or observational Excluded: case report, letter,
study (cohort and ecological historical article
studies)
Filters Humans English language None as to language or publi- None stated None stated
cation status
Exclusion:
Study which does not provide
sufficient data for pooling after
3 attempts of contacting the
author every 2 weeks
Study published in languages
which reviewers later cannot
translate
Using the critical appraisal criteria from Dans et al. (2017), had a high validity rating (Rosumeck 2018) (Table 3).
the criteria that were most commonly not fulfilled were: thor-
oughness of search and assessment of validity of included stud- EFFICACY AND SAFETY
ies, which were only both addressed in Rosumeck 2018 SR. Four Data on efficacy and safety are summarized in Table 4. For the
SRs were rated to have low to moderate validity while only one three systematic reviews that had pooled analyses, there were
11 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
similar results showing no significant difference in oral iver- points not specified) and showed that oral ivermectin was sig-
mectin versus topical permethrin with RRs for cure rate hover- nificantly less effective than topical permethrin (RR 1.33, 95%
ing around the line of no difference (RR=1.0) especially for the CI 1.04, 1.72; 14 RCTs, N = 1792; I2 = 0%). However, no time points
later time point of measurement (3–6 weeks after treatment). were specified, which means that the effect estimate may have
For the Thadanipon 2019 review, permethrin had a higher cure been pooled from studies that measured the outcome at varying
rate at 1–2 weeks based on the network effect (RR 1.16, 1.05, 1.27) time points. No adverse event outcomes were reported in both
but no significant difference in persistent itching (0.76, 0.49, systematic reviews.
1.17) compared to oral ivermectin.57 At 3–6 weeks, there was
no significant difference between permethrin and oral ivermec- A systematic review by May et al. (2019) on treatment, pre-
tin for cure (RR 1.03, 0.96, 1.11) and composite adverse events vention and public health control of four common skin infections
(RR 1.10, 0.83, 1.48). Based on direct comparisons alone (10 (scabies, crusted scabies, impetigo and fungal skin infections) in
RCTs), adverse events were lower from oral ivermectin (60/642, resource-poor communities (search date not stated) included both
9.3%) than topical permethrin (76/607, 12.5%) but this was in- RCTs and observational studies.58 Based on individual RCTs, lesion
conclusive due to a wide confidence interval (RR 0.84, 95% CI count and pruritus were significantly lower for permethrin at one
0.61, 1.17), while cure rate was slightly lower for oral ivermectin week while clinical cure at four weeks was the same as oral iver-
(525/641, 81.9%) compared to permethrin (523/606, 86%). Rank- mectin (2 RCTs, moderate to high quality evidence). There was su-
ing the interventions using the surface under the cumulative perior symptom relief with permethrin at two weeks, while clinical
ranking curve (SUCRA), combination permethrin plus oral iver- cure was the same as oral ivermectin (1 RCT; low quality evidence).
mectin had the strongest evidence for highest cure at 1-2 weeks However, there was no effect estimates (e.g., relative risk or mean
(SUCRA: 93.4) and 3-6 weeks (SUCRA: 93.1). There was no signif- scores) given to support the results. The review authors concluded
icant difference in persistent itching between permethrin and that there was moderate to high-quality evidence that strongly rec-
oral ivermectin (network RR 0.76, 95% CI 0.49, 1.17). Overall ommends the use of either oral ivermectin or topical permethrin
ranking showed that topical ivermectin had the lowest chance for the treatment of scabies.61–64 Adverse events were not reported,
of persistent itching (SUCRA: 98.4), and synergized pyrethrins although this outcome was specified in the Methods section of the
had the lowest adverse reactions (SUCRA: 98.0). There was no systematic review.
single treatment that ranked highest in all outcomes.
DISCUSSION
The Cochrane systematic review by Rosumeck et al. (2018)
compared oral or topical ivermectin to topical permethrin in 13 SUMMARY OF MAIN FINDINGS
RCTs (N=1456). They concluded that oral ivermectin may be less Overall, the included systematic reviews were consistent in
effective than topical permethrin for complete clearance after showing comparable efficacy and safety between oral ivermec-
one week (ivermectin 43% vs permethrin 65%; RR 0.65, 0.54, tin and topical permethrin at around the 3 to 6-week time point,
0.78; 6 studies, N=613; low certainty evidence) but did not dif- although an earlier cure was seen with permethrin at the 1 or
fer from topical permethrin for cure at three weeks (ivermectin 2-week time point. Adverse events were few, mild, and tran-
68% vs permethrin 74%; RR 0.91, 0.76, 1.08; 5 studies, N = 459; sient; severe itching, secondary bacterial infections, headache
low certainty evidence). Oral ivermectin may not differ from and nausea for oral ivermectin, and erythema, burning and
topical permethrin in number of participants with at least one pruritus with topical permethrin. However, the certainty of evi-
adverse event (ivermectin 5% vs permethrin 4%; RR 1.30 (0.35, dence was ascertained in only three SRs, and had varying levels.
4.83); 4 studies, N = 502; low certainty evidence). Adverse events In two SRs with meta-analyses, the evidence was rated as low to
were few, mild, and did not require withdrawal of drug: severe moderate certainty, mainly due to serious risk of bias, hetero-
itching, secondary bacterial infections, headache and nausea geneity in study characteristics especially variability in dosing
for oral ivermectin, and erythema, burning and pruritus with regimens, and poor reporting. In a third SR without meta-anal-
topical permethrin. ysis that included only low-income settings, evidence from indi-
vidual RCTs was rated as moderate to high.
Two other non-Cochrane reviews by Dressler et al. (2016) (6
RCTs) and Dhana et al. (2018) (15 RCTs, N=2172) compared oral There is limited evidence for efficacy and safety of combi-
ivermectin and topical permethrin for treatment of scabies.59,60 nation oral ivermectin and topical permethrin. In one SR and
Dressler et al. (2016) only did one meta-analysis for reduction network meta-analysis, the combination regimen was ranked as
in lesion count showing no significant difference between per- having superior efficacy but with higher rate of adverse effects
methrin and oral ivermectin (RR 1.07, 95% CI 1.00, 1.15; 2 RCTs, over oral ivermectin or topical permethrin alone. However, the
N = 83; I2 = 0%), and just did a narrative synthesis and stated the SR was appraised to be of low-to-moderate validity with a criti-
range of treatment effects (RRs) for the rest of the comparisons. cally low rating in confidence in its results. The evidence for the
Dhana et al. did one meta-analysis using treatment failure (time combination treatment arm was based on a single 3-arm RCT
and there was no grading of certainty of evidence.
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 12
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
Table 3. Summary of AMSTAR-2 rating and critical appraisal of included systematic reviews
Thadanipon 2019 May 2019 Rosumeck 2018 Dhana 2018 Dressler 2016
(Thailand) (Australia) (Germany) (South Africa) (Germany)
AMSTAR-2 Confidence Rat- Critically low Moderate High Critically low Critically low
ing in Results (Appendix 1) Number of critical flaws: 2
Number of critical flaws: 0 Number of critical flaws: 0 Number of critical flaws: 5 Number of critical flaws: 2
Number on non-critical weak- Number on non-critical weak- Number on non-critical weak- Number on non-critical weak- Number on non-critical weak-
nesses: 4 nesses: 3 nesses: 2 nesses: 4 nesses: 3
Critical Appraisal for Validity Moderate Moderate High Moderate Low
(Painless EBM criteria) (Ap- 2.5/4 2.5/4 4/4 2.5/4 2.0/4
pendix 2)
AMSTAR - A MeaSurement Tool to Assess systematic Reviews; EBM - Evidence-Based Medicine
QUALITY OF SYSTEMATIC REVIEWS European, German, and Japanese. Oral ivermectin also did not
Varying thoroughness of methodological reporting and validity have an approved indication for scabies since it is only approved
resulted in different ratings for confidence in the results from by Health Canada for treating strongyloidiasis and onchocerci-
the five systematic reviews, thereby weakening the collective asis. The Canadian Pediatric Society Position Statement 201567
strength of the evidence. If we were to base our evidence from has recommended topical permethrin as the first line treatment
the highest rated Cochrane systematic review by Rosumeck et to the patients with scabies and their close contacts. In con-
al. (2018), the best available evidence would point to comparable trast, since the Philippine setting is more similar to the Asian
efficacy and safety between oral ivermectin and topical perme- studies included in the reviews, the applicability of the results
thrin, with an earlier cure with permethrin at 1–2 week time may be greater in our setting.
point. However, comparative efficacy and safety between com-
bination oral ivermectin and topical permethrin versus each Our literature review included two additional SRs not found in
drug alone is limited since the only systematic review that pro- the Canadian health technology review: by May et al. (2019), which
vided evidence was of moderate validity and with critically low was specifically on resource-limited settings, and Dressler et al.
confidence in its results. This evidence needs to be confirmed (2016). May et al. (2019) strongly recommended either oral ivermec-
by including more RCTs and conducting an appropriate me- tin or topical permethrin for scabies treatment based on moderate
ta-analysis with grading of certainty of evidence. to high quality evidence (Grade IA). Similarly, the second system-
atic review by Dressler et al. (2016) concluded similar efficacy be-
COMPARISON WITH PREVIOUS LITERATURE REVIEWS tween oral ivermectin or topical permethrin.
Our literature review had three systematic reviews56,57,60 in com-
mon with a 2019 effectiveness review by the Canadian Agency STRENGTHS AND LIMITATIONS OF INCLUDED SYSTEMATIC
for Drugs and Technologies in Health (CADTH) that searched REVIEWS
between January 1, 2014 to April 17, 2019.65 Aside from the three We summarized strengths and limitations of included system-
SRs, the CADTH effectiveness review also included one recent atic reviews in Table 5. In the Thadanipon 2019 et al. (2019) SR/
RCT and three CPGs (2 European28,66 and 1 Japanese29).65 Overall, NMA, it was not explicitly stated how many and which studies
they noted that the trend in efficacy and safety was consistent out of 52 total RCTs contributed indirect evidence to each net-
among the studies. They concluded that oral ivermectin may be work effect.57 It was also noted that they included 13/52 studies
less clinically effective than topical permethrin in the first 1–2 (published 2012 to 2014) comparing various scabicides that were
weeks following treatment but there was no difference at later authored or co-authored by Dr. Goldust from the Department
time points (4 weeks onwards). They also stated that there was of Dermatology, Tabriz University of Medical Sciences, Tabriz,
no difference in adverse events between the two interventions. Iran. This author published eight studies 63,64,68–71 that were sep-
However, they noted that most of the RCTs in the systematic re- arately analyzed and labelled as trials of limited plausibility by
views and evidence base were of limited quality, small sample the systematic review by Dressler et al. in 2016.59 In a published
sizes, with deficiencies in adverse event reporting and consider- letter of concern to the editor of Annals of Parasitology, the fol-
able uncertainty regarding effectiveness results. They conclud- lowing issues were raised by Dressler et al. citing five published
ed that there was lack of applicability in the Canadian treatment studies of Dr. Goldust: 1) reported numbers of patients are of-
setting since most of the studies in the three previous SRs as ten multiples of ten (whether number eligible/enrolled/lost to
well as the RCT were conducted in Asia, while the CPGs were follow up/cured), 2) inconsistencies within each publication.72
Dr. Goldust published an erratum in the same year stating that
13 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
Table 4. Summary of results on efficacy and safety of scabies interventions based on included systematic reviews
Outcome Thadanipon 2019 May 2019 Rosumeck 2018 Dhana 2018 Dressler 2016
Total No. of studies (N) (Thailand) (Australia) (Germany) (South Africa) (Germany)
Cure 52 RCTs (N=9917) 19 RCTs and non-randomized 15 RCTs (N=1896) , analyzed 13 15 RCTs (N=2172) 16 RCTs (N=not stated)
- Oral ivermectin vs permethrin (16 studies (N not stated) on directed RCTs (N=1456) - Oral IVM vs permethrin (14 RCTs) - Permethrin vs oral ivermectin
RCTs, N=1986) clinical treatment of scabies, out of - Oral ivermectin vs permethrin - Topical ivermectin vs permethrin (6 RCTs)
81 studies (mixed skin infections) cream (7 RCTs; N=743) (1 RCT)
Favors permethrin over oral ivermec- - Oral vs topical (11 RCTs) - Oral ivermectin vs permethrin lotion No significant difference between
tin (1-2 wks.) - Topical vs other topical (7 RCTs) (2 RCTs; N=227) No data permethrin and oral ivermectin
Network effect RR - Oral vs topical ivermectin (2 RCTs; RR 1.07 (95% CI 1.00, 1.15); (2
1.16 [95% CI 1.05, 1.27]; P for *No event rates nor treatment effects N=272) RCTs, N=83; I2=0%)
inconsistency = 0.99 provided - Topical ivermectin vs permethrin (1
RCT; N=210)
No difference at 3-6 wks. Lesion count and pruritus were - Diff doses bet oral ivermectin (2
Network RR significantly lower for permethrin at 1 RCTs; N=353)
1.03 [0.96, 1.11]; P for inconsistency week while clinical cure at 4 weeks
= 0.993 was the same as oral ivermectin Favors permethrin cream over oral
(2 RCTs, moderate to high quality ivermectin
Combination permethrin + oral evidence). Week 1
ivermectin had highest probability RR: 0.65 (95% CI 0.54-0.78) (6
of cure at 1-2 weeks (SUCRA: 93.4) Superior symptom relief with per- RCTs, N=613; I2=35% low certainty
over permethrin (81.9) and oral methrin at 2 wks., while clinical cure evidence)
ivermectin (61.3) was the same as oral ivermectin (1 Week 2
RCT; low quality evidence) RR: 0.91 (95% CI 0.76-1.08) (5
Similar trend for 3-6 week cure, RCTs, N=459; I2=61%; low certainty
combination treatment (93.1) over evidence)
permethrin (80.6) and oral ivermectin Week 4
(70.2) (several dose comparisons)
a. 1-dose ivermectin vs 1
application permethrin RR
1.00 (95% CI 0.86-1.16) (1
RCT, N=60; high certainty
evidence
b. 1 to 3 doses ivermectin vs 1
to 3 applications permethrin:
RR 0.92 (95% CI 0.82,,
1.03) (5 RCTs, N=581;
I2=74%; low certainty
evidence) *Variable timing
and no. of retreatment for
non-responders
c. 2 doses ivermectin vs 1
application permethrin RR
0.97 (95% CI 0.83, 1.14)
(1 RCT, N=55; moderate
certainty evidence)
1 dose oral ivermectin vs permethrin
lotion (x 1 application) (1 RCT;
N=120)
Week 1
RR 0.93 (95% CI 0.74, 1.17)
Week 2
RR 1.00 (95% CI 0.78, 1.29)
1-dose oral ivermectin vs permethrin
lotion x 5 consecutive nights (1
RCT, N=107)
Week 1
RR 0.70 (95% CI 0.47, 1.03)
Week 2
RR 0.97 (95% CI 0.81, 1.17)
No significant difference bet. 1
vs 2 doses of oral ivermectin at
week 4
RR 0.97 (95% CI 0.83, 1.14) (1
RCT, N=80)
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 14
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
Persistent itch No significant difference between No data No data No data No data
permethrin and oral ivermectin
Recurrence
Adverse events Network RR 0.76 (95% CI 0.49,
1.17)
Other, specify
Conclusion Lowest probability of persistent No data No data No data No data
itch was with topical ivermectin No data No data
(SUCRA: 98.4), followed by ≥ 1 AE (Week 4) No data
permethrin (SUCRA: 79.2) and Favors permethrin
synergized pyrethrins (SUCRA: RR: 1.30 (95% CI 0.35-4.83)
73.4) (4 RCTs, N=502; low certainty
evidence
Re-infestation was not included in
meta-analyses because a limited
number of studies provided data
regarding this outcome.
No difference bet. permethrin vs
oral ivermectin (3-6 wks.)
Network effect:
RR 1.10 [0.83, 1.48]
Relative ranking No data No data Treatment failure: No data
Oral ivermectin had highest Favors permethrin
safety rank (SUCRA: 63.8), over For the most part, no difference in RR: 1.33 (95% CI 1.04-1.72) (14
permethrin (54.5) and combination efficacy of permethrin compared RCTs; N=1792) (Time point not
oral ivermectin and permethrin to systemic ivermectin. Overall, given)
(28.0) few and mild adverse events.
Confidence in effect estimates
No data was mostly low to moderate. Poor
reporting is a major limitation.
Permethrin has faster cure than Moderate- to high- quality Oral ivermectin is less effective Oral ivermectin and topical
oral ivermectin at 2 wks. evidence supports the use than topical permethrin (Time point permethrin have similar efficacy.
of topical permethrin or not given).
No difference bet oral ivermectin oral ivermectin for scabies
and permethrin for cure and AE treatment (GRADE 1A – Strong All agents have low treatment
(3–6 wks.) recommendation; high quality of failure rates and are well tolerated.
evidence). (No time point given)
Combination permethrin plus oral
ivermectin, topical ivermectin,
and synergized pyrethrins had the
strongest evidence for highest
cure, lowest chance of persistent
itching, and lowest adverse
reactions, respectively.
There was no 1 treatment that
ranked highest in all aspects.
“during seven years, our research group conducted a big and rate pairwise comparisons in several publications is unclear.75
multicenter study on comparing different medications with dif- In the later systematic review by Rosumeck et al. (2018), three
ferent dosage in the treatment of scabies...led to multiple publi- of these studies were excluded for suspicion of flawed data56 fol-
cations in high impact peer reviewed journals.”73 He stated that lowing a unanimous decision at the 2017 annual meeting of the
there were “minor errors in the releasing of study results” and Cochrane Skin Group . A possible option for future systematic
gave corrections in the data for five publications. 63,64,68,69,74 How- reviews is to clarify with the author the original number of par-
ever, the method of splitting the single big multicenter study ticipants randomized to different interventions in the big multi-
with various comparisons (oral ivermectin, permethrin 2.5% center study or include the potentially flawed studies but with a
cream, permethrin 5% cream, permethrin 5% lotion, lindane sensitivity analysis of the effect estimates excluding these stud-
1%, sulfur 10% ointment, malathion, crotamiton 10% cream, ies. There was also no rating of certainty of evidence although
topical ivermectin, benzyl benzoate 2.5% emulsion) into sepa- risk of bias of individual studies were assessed and summarized
15 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
Table 5. Summary of strengths and limitations of included systematic reviews
Thadanipon 201964 May 201965 Rosumeck 201857 Dhana 201861 Dressler 201660
(Thailand) (Australia) (Germany) (South Africa) (Germany)
Strengths Did network meta-analysis, Specific to resource-poor Comprehensive search of 7 Did pairwise meta-analysis for Reported 8 studies separately
with separate networks for dif- countries, results more appli- databases, grey literature, and efficacy outcome due to ‘limited plausibility’
ferent time points for cure; Did cable to Philippines trial registers
subgroup analysis for direct
paired meta-analyses Excluded 3 studies due to
questionable validity
Included combination oral iver- Did separate pairwise me-
mectin and topical permethrin ta-analyses for different time
as one of the interventions points and dosage regimens;
subgroup analyses
Limitations Included 9 studies from group Only included English lan- Rated certainty of evidence Letter to editor only Only searched databases
of authors of studies with guage studies Included 3 studies previously Only did 1 pairwise me-
questionable validity excluded Did not do network meta-anal- excluded or considered ta-analysis due to high clinical
by 2 previous systematic No meta-analysis ysis questionable by previous heterogeneity, and did not rate
reviews systematic reviews certainty of evidence
Did not present treatment No risk of bias assessment
Unclear on number of studies effects (e.g., RRs) within the Lumped together studies with
that contributed indirect narrative synthesis different time points and used
evidence treatment failure outcome,
No adverse event outcomes instead of cure
Did not consider contribution No adverse event outcome
of risk of bias of individual
studies in certainty of evidence
in an appendix. ment. The optimal dosing regimen (whether 1 or 2 doses of oral
The Rosumeck et al. (2018) SR only did pairwise meta-anal- ivermectin) is still unclear. In addition, the evidence comes
from studies with mostly unclear or high risk of bias, thereby,
ysis using direct evidence comparing ivermectin (topical and rated as low to moderate certainty. Furthermore, the impact
oral) to permethrin and found low to moderate certainty of ev- of inclusion of possibly flawed studies in the Thadanipon et al.
idence supporting a faster cure for permethrin, although oral NMA and Dhana et al. SR, should be explored in a sensitivity
ivermectin had comparable efficacy and safety at a later time analysis excluding these studies. The publication of new RCTs
point. Risk of bias assessment was done and was used to rate the since their last search dates in 2017 around four years ago,76–78
certainty of evidence using the GRADE framework. including Philippine RCTs in the local HERDIN database and lo-
cal journals may potentially change the certainty of evidence
Dhana et al. (2018) used treatment failure as the primary and treatment effects and increase applicability of results to our
outcome but did not subgroup according to time points and it is setting. In particular, since permethrin lotion, and not perme-
unclear which time points were included in the meta-analysis thrin cream, is the preparation that is marketed locally, studies
in studies with varying time points. May et al. (2019) gave rec- that used the lotion may have varying results.
ommendations based on evidence rated as low, moderate, and
high, but did not report the actual treatment effects (e.g., rela- CONCLUSION
tive risk, mean difference) for each comparison.
There is varying certainty of evidence suggesting comparable
Dressler et al. (2016) did only one pairwise meta-analysis efficacy and safety of oral ivermectin compared to permethrin
due to clinical heterogeneity and did not rate the certainty of in the treatment of classic scabies. There is limited evidence
evidence based on risk of bias assessments. Eight studies were to suggest higher efficacy and lower safety of combination oral
labelled as having limited plausibility (by Dr. Goldust and col- ivermectin and topical permethrin compared to either drug
leagues) and were not included in the analysis. alone, but of undetermined certainty. Thus there is a need to
conduct a systematic review and network meta-analysis to ad-
In summary, although pooled studies from most system- dress evidence gaps to guide clinical practice, health policy, and
atic reviews showed consistent treatment effects for an earlier future research.
cure for permethrin at (1-week or 1 to 2-week time points), no
significant difference was seen between oral ivermectin and
topical permethrin at a later 3–6 week time point after treat-
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 16
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
REFERENCES
1. Micali G, Lacarrubba F, Verzì AE, Chosidow O, Schwartz RA. Scabies: Advances in Noninvasive Diagnosis. PLoS Negl Trop Dis. 2016;10(6):1-10. doi:10.1371/journal.
pntd.0004691.
2. WHO. Ending the neglect to attain the Sustainable Development Goals. WHO (World Heal Organ. Published online 2020:2. https://apps.who.int/iris/
handle/10665/70809.
3. James SL, Abate D, Abate KH, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 Diseases and Injuries for 195 countries
and territories, 1990-2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018;392(10159):1789-1858. doi:10.1016/S0140-6736(18)32279-7.
4. Romani L, Steer AC, Whitfeld MJ, Kaldor JM. Prevalence of scabies and impetigo worldwide: A systematic review. Lancet Infect Dis. 2015;15(8):960-967. doi:10.1016/
S1473-3099(15)00132-2.
5. Romani L, Marks M, Sokana O, et al. Efficacy of mass drug administration with ivermectin for control of scabies and impetigo, with coadministration of azithromycin:
a single-arm community intervention trial. Lancet Infect Dis. 2019;19(5):510-518. doi:10.1016/S1473-3099(18)30790-4.
6. Zhang W, Zhang Y, Luo L, et al. Trends in prevalence and incidence of scabies from 1990 to 2017: findings from the global Burden of disease study 2017. Emerg
Microbes Infect. 2020;9(1):813-816. doi:10.1080/22221751.2020.1754136.
7. Dofitas B, Ramiro L, Amarillo L, Beringuela A, Fajutrao L. Healthseeking Behavior of Filipinos with Skin Ailments: Focus on Leprosy Prevention and Management
Department of Health (Unpublished Project Report).; 2000.
8. Quijano J, Poa JT, Copuyoc CMG, Chua NSD. A retrospective cross-sectional review on the patterns of dermatological diseases seen in the community skin health
clinics of a local health center, an urban charity hospital, and provincial skin clinics from January to December 2013. St Luke’s Healthc J. 2016;2(1):7-13.
9. Gilson RL CJS [Updated 2020 A 8]. IS [Internet]. TI (FL): SP 2021 J-. A from: https://www. ncbi. nlm. nih. gov/books/NBK544306. Scabies. StatPearls [Internet]. Published
2020. https://www.ncbi.nlm.nih.gov/books/NBK544306/#:~:text=Scabies is a contagious skin condition resulting from the infestation,is
relentless%2C especially at night.
10. Anderson KL, Strowd LC. Epidemiology, diagnosis, and treatment of scabies in a dermatology office. J Am Board Fam Med. 2017;30(1):78-84. doi:10.3122/
jabfm.2017.01.160190.
11. Kouotou EA, Nansseu JR, Sieleunou I, Defo D, Bissek AC NE. Features of human scabies in resource-limited settings: the Cameroon case. BMC Dermatol. 2015;15(12).
12. E ngelman D, Kiang K, Chosidow O, et al. Toward the Global Control of Human Scabies: Introducing the International Alliance for the Control of Scabies. PLoS Negl Trop
Dis. 2013;7(8):5-8. doi:10.1371/journal.pntd.0002167.
13. Thornley S, Marshall R, Jarrett P, Sundborn G, Reynolds E, Schofield G. Scabies is strongly associated with acute rheumatic fever in a cohort study of Auckland
children. J Paediatr Child Health. 2018;54(6):625-632. doi:10.1111/JPC.13851.
14. Marshall CS, Cheng AC, Markey PG, et al. Acute post-streptococcal glomerulonephritis in the Northern Territory of Australia: A review of 16 years data and
comparison with the literature. Am J Trop Med Hyg. 2011;85(4):703-710. doi:10.4269/ajtmh.2011.11-0185.
15. C DC. Scabies. Accessed June 21, 2021. https://www.cdc.gov/parasites/scabies/index.html.
16. La Vincente S, Kearns T, Connors C, Cameron S, Carapetis J, Andrews R. Community management of endemic scabies in remote aboriginal communities of northern
Australia: low treatment uptake and high ongoing acquisition. PLoS Negl Trop Dis. 2009;3(5). doi:10.1371/journal.pntd.0000444.
17. B ouvresse S, Berdjane Z, Bouscaillou JA, Chosidow O, Durand R. Permethrin and malathion resistance in head lice: Results of ex vivo and molecular assays. J Am
Acad Dermatol. 67(6):1143-1150.
18. M eyersburg D, Kaiser A, Bauer JW. “Loss of efficacy of topical 5% permethrin for treating scabies: an Austrian single-center study.” J Dermatolog Treat. 2020;Jun
4(1-4). doi:10.1080/09546634.2020.1774489.
19. R inaldi G, Porter K. Mass drug administration for endemic scabies : a systematic review. 2021;5:1-13.
20. Khan MMU, Ahamed ARS, Islam MA, et al. A Comparative Study of Oral Ivermectin and Topical 5% Permethirn Cream in the Treatment of Scabies in Patient Suffering
from Diabetes Mellitus. Faridpur Med Coll J. 2015;9(2):70-72. doi:10.3329/fmcj.v9i2.25677.
21. Ichikawa M, Tanaka M, Naritomi Y, Furue M. Combined ivermectin and topical therapy significantly reduces treatment time in aged scabietic patients. J Dermatol.
2013;40(4):306-307. doi:10.1111/1346-8138.12070.
22. Wankhade P, Tamboli S, Deshmukh J, Rathode P, Domple V, Vikas D. A Comparative Study of Topical Permethrin, Oral Ivermectin and Combination of Permethrin with
Ivermectin In Patients of Scabies. IOSR J Dent Med Sci e-ISSN. 2016;15(5):67-72. doi:10.9790/0853-1505016772.
23. Kawen A. Scabies complete clearance as a treatment efficacy: in permethrin alone and in combined with oral ivermectin: south Iraq-2019. Int J Pharm Res. 2020;(4).
doi:10.1002/CENTRAL/CN-02158736.
24. C rump A, Omura S. Ivermectin, “Wonder drug” from Japan: The human use perspective. Proc Japan Acad Ser B Phys Biol Sci. 2011;87(2):13-28. doi:10.2183/pjab.87.13.
25. Kircik LH, Rosso JQ Del, Layton AM, Schauber J. Over 25 years of Ivermectin for an Increasing Number of Indications. J Drugs Dermatol. 2016;15(3):325-332.
26. World Health Organization. WHO Expert Committee on the Selection and Use of Essential Medicines: Application for Inclusion of Ivermectin on the WHO Model
List of Essential Medicines (EML) and Model List of Essential Medicines for Children (EMLc) for the Indication of Scabies. https://www.who.int/selection_
medicines/committees/expert/22/applications/s6.6_ivermectin.pdf%0D%0A.
27. W orkowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. Vol 70.; 2021. doi:10.15585/mmwr.rr7004a1.
28. S alavastru CM, Chosidow O, Boffa MJ, Janier M, Tiplica GS. European guideline for the management of scabies. J Eur Acad Dermatology Venereol. 2017;31(8):1248-1253.
doi:10.1111/jdv.14351.
29. Ishii N, Asai T, Asahina A, et al. Guideline for the diagnosis and treatment of scabies in Japan (third edition): Executive Committee of Guideline for the Diagnosis and
Treatment of Scabies. J Dermatol. 2017;44(9):991-1014. doi:10.1111/1346-8138.13896.
30. U S Department of Human Health and Services. CENTER FOR DRUG EVALUATION AND RESEARCH APPROVAL PACKAGE: Ivermectin (Mectizan).; 1996. https://www.
accessdata.fda.gov/drugsatfda_docs/nda/96/050742ap.pdf.
31. Philippine FDA. Oral Ivermectin: Certificate of Product Registration.
32. B ernigaud C, Fernando DD, Lu H, et al. In vitro ovicidal activity of current and under-development scabicides: which treatments kill scabies eggs? Br J Dermatol.
2020;182(2):511-513. doi:10.1111/bjd.18517.
17 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
33. Currie BJ, Harumal P, McKinnon M, Walton SF. First documentation of in vivo and in vitro ivermectin resistance in Sarcoptes scabiei. Clin Infect Dis. 2004;39(1).
doi:10.1086/421776.
34. N ICE. Difficult-to-Treat Scabies: Oral Ivermectin Evidence Summary.; 2014. nice.org.uk/guidance/esuom29.
35. C handler RE. Serious neurological adverse events after ivermectin-do they occur beyond the indication of onchocerciasis? Am J Trop Med Hyg. 2018;98(2):382-388.
doi:10.4269/ajtmh.17-0042.
36. C ampillo JT, Boussinesq M, Bertout S, Faillie JL, Chesnais CB. Serious adverse reactions associated with ivermectin: A systematic pharmacovigilance study in sub-
saharan africa and in the rest of the world. PLoS Negl Trop Dis. 2021;15(4):1-18. doi:10.1371/journal.pntd.0009354.
37. Nicolas P, Maia MF, Bassat Q, et al. Safety of oral ivermectin during pregnancy: a systematic review and meta-analysis. Lancet Glob Heal. 2020;8(1):e92-e100.
doi:10.1016/S2214-109X(19)30453-X.
38. J ittamala P, Monteiro W, Smit MR, et al. A systematic review and an individual patient data meta-analysis of ivermectin use in children weighing less than fifteen
kilograms: Is it time to reconsider the current contraindication? PLoS Negl Trop Dis. 2021;15(3):1-22. doi:10.1371/journal.pntd.0009144.
39. B hat SA, Mounsey KE, Liu X, Walton SF. Host immune responses to the itch mite, Sarcoptes scabiei, in humans. Parasit Vectors. 2017;10(1):385. doi:10.1186/s13071-017-
2320-4.
40. P hilippine Dermatological Society. Scabies. Published 2014. Accessed August 2, 2021. https://pds.org.ph/scabies/.
41. Department of Health, Manila P. Philippine National Formulary 8th Ed.; 2019. https://pharma.doh.gov.ph/the-philippine-national-formulary/.
42. Department of Health Pharmaceutical Division. Philippine National Formulary 8th Edition: Essential Medicines List.; 2021.
43. D epartment of Health Pharmaceutical Division. The Philippine Drug Price Reference Index.; 2021. https://dpri.doh.gov.ph/download/2021DPRI-as-of-
September-15.pdf.
44. JImenez D. Ivermectin and COVID-19: how a cheap antiparasitic became political. Pharmaceutical Technology. Published 2021. Accessed August 25, 2021. https://
www.pharmaceutical-technology.com/features/ivermectin-COVID-19-antiparasitic-political/.
45. K ing-Dominguez R, Lopez C, JP de L, Oyales M. Philippines. In: Ehlers A, Ehlers A, White D, eds. Getting the Deal Through: Life Sciences. Law Business Research Ltd;
2015:79-83.
46. Duthaler U, Suenderhauf C, Karlsson MO, et al. Population pharmacokinetics of oral ivermectin in venous plasma and dried blood spots in healthy volunteers. Br J
Clin Pharmacol. 2019;85(3):626-633. doi:10.1111/bcp.13840.
47. Canga AG, Prieto AMS, Diez Liébana MJ, Martínez NF, Sierra Vega M, García Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans - A mini-review.
AAPS J. 2008;10(1):42-46. doi:10.1208/s12248-007-9000-9.
48. Okonkwo PO, Ogbuokiri JE, Ofoegbu E, Klotz U. Protein binding and ivermectin estimations in patients with onchocerciasis. Clin Pharmacol Ther. 1993;53(4):426-430.
doi:10.1038/clpt.1993.46.
49. I vermectin (systemic): Drug information. UpToDate. Published 2021. Accessed September 11, 2021. https://www.uptodate.com/contents/ivermectin-
systemic-drug-information.
50. Tomalik-Scharte D, Lazar A, Meins J, et al. Dermal absorption of permethrin following topical administration. Eur J. Clin Pharmacol. 2005;61(5-6):399-404. doi:10.1007/
s00228-005-0932-7.
51. Toynton K, Luukinen B, Buhl K, Stone D. Permethrin Technical Fact Sheet. National Pesticide Information Center. Published 2009. Accessed September 11, 2021.
http://npic.orst.edu/factsheets/archive/Permtech.html.
52. Dans A, Dans L, Silvestre M. Painless Evidence-Based Medicine. 2nd ed. Wiley-Blackwell; 2017.
53. S hea BJ, Reeves BC, Wells G, et al. AMSTAR 2: A critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare
interventions, or both. Br Med J. 2017;358:1-9. doi:10.1136/bmj.j4008.
54. R osumeck S, Nast A, Dressler C. Evaluation of Ivermectin vs Permethrin for Treating Scabies — Summary of a Cochrane Review. Published online 2019:24-26.
55. Navarro M, Camprubí D, Requena-Méndez A, et al. Safety of high-dose ivermectin: A systematic review and meta-analysis. J Antimicrob Chemother. 2020;75(4):827-
834. doi:10.1093/jac/dkz524.
56. R osumeck S, Nast A, Dressler C. Ivermectin and permethrin for treating scabies. Cochrane Database Syst Rev. 2018;2018(4). doi:10.1002/14651858.CD012994.
57. Thadanipon K, Anothaisintawee T, Rattanasiri S, Thakkinstian A, Attia J. Efficacy and safety of antiscabietic agents: A systematic review and network meta-analysis
of randomized controlled trials. J Am Acad Dermatol. 2019;80(5):1435-1444. doi:10.1016/j.jaad.2019.01.004.
58. M ay PJ, Tong SYC, Steer AC, et al. Treatment, prevention and public health management of impetigo, scabies, crusted scabies and fungal skin infections in endemic
populations: a systematic review. Trop Med Int Heal. 2019;24(3):280-293. doi:10.1111/tmi.13198.
59. D ressler C, Rosumeck S, Sunderkötter C, Werner RN, Nast A. The Treatment of Scabies: A Systematic Review of Randomized Controlled Trials. Dtsch Arztebl Int.
2016;113(45):757-762. doi:10.3238/arztebl.2016.0757.
60. Dhana A, Yen H, Okhovat JP, Cho E, Keum NN, Khumalo NP. Ivermectin versus permethrin in the treatment of scabies: A systematic review and meta-analysis of
randomized controlled trials. J Am Acad Dermatol. 2018;78(1):194-198. doi:10.1016/j.jaad.2017.09.006.
61. Chhaiya S, Patel V, Dave J, Mehta D. To study cost effectiveness of topical permethrin versus oral ivermectin in patients of uncomplicated scabies. Int J Basic Clin
Pharmacol. 2013;2(6):799. doi:10.5455/2319-2003.ijbcp20131224.
62. S harma R, Singal A. Topical permethrin and oral ivermectin in the management of scabies: A prospective, randomized, double blind, controlled study. Indian J
Dermatol Venereol Leprol. 2011;77(5):581-586. doi:10.4103/0378-6323.84063.
63. G oldust M, Rezaee E, Raghifar R, Hemayat S. Treatment of scabies: the topical ivermectin vs. permethrin 2.5% cream. Ann Parasitol. 2013;59(2):79-84.
64. R anjkesh MR, Naghili B, Goldust M, Rezaee E. The efficacy of permethrin 5% vs. oral ivermectin for the treatment of scabies. Ann Parasitol. 2013;59(4):189-194.
65. C hiu S, Argaez C. Ivermectin for Parasitic Skin Infections of Scabies: A Review of Comparative Clinical Ivermectin for Parasitic Skin Infections of Scabies: A Review
of Comparative Clinical Effectiveness, Cost-Effectiveness, and Guidelines. CADTH Rapid Response Rep Summ with Crit Apprais. Published online 2019:1-35. http://
www.ncbi.nlm.nih.gov/pubmed/31424718.
66. Clinical Effectiveness Group British Association for Sexual Health and HIV. 2016 UK National Guideline on the Management of Scabies.; 2016. https://www.
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 18
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
bashhguidelines.org/media/1137/scabies-2016.pdf.
67. Anna Banerji; Canadian Paediatric Society, First Nations I and MHC. Scabies: CPS position statement. Paediatr Child Heal. 2015;20(7):395-398.
68. Alipour H, Goldust M. Oral Ivermectin Vs 10% Sulfur Ointment. Ann Parasitol. 2015;61(2):79-84.
69. A bolfazl Pourhasan, Mohamad Goldust ER. Treatment of scabies, permethrin 5% cream vs. crotamiton 10% cream. Ann Parasitol. 2013;59(3):143-147.
70. G oldust M, Rezaee E, Raghiafar R. Topical ivermectin versus crotamiton cream 10% for the treatment of scabies. Int J Dermatol. 2014;53(7):904-908. doi:10.1111/
ijd.12447.
71. G oldust M, Rezaee E, Raghifar R. Comparison of oral ivermectin versus crotamiton 10% cream in the treatment of scabies. Cutan Ocul Toxicol. 2014;33(4):333-336. do
i:10.3109/15569527.2013.768258.
72. Dressler C, Rosumeck S, Nast A. Reporting in the clinical trials evaluating scabies treatments. Ann Parasitol. 2016;62(2):153-155. doi:10.17420/ap6202.48.
73. Goldust M. Treatment of scabies, comparing the different medications. Ann Parasitol. 2016;62(3):243. doi:10.17420/ap6203.59.
74. Goldust M, Rezaee E, Raghifar R, Naghavi-Behzad M. Comparison of permethrin 2.5 % cream vs. Tenutex emulsion for the treatment of scabies. Ann Parasitol.
2013;59(1):31-35.
75. S enn SJ. Overstating the evidence - Double counting in meta-analysis and related problems. BMC Med Res Methodol. 2009;9(1):1-7. doi:10.1186/1471-2288-9-10.
76. Rao MA, Raza N, Faheem M, Saleem MA. Comparison Of Efficacy Of Permethrin 5% Cream With Crotamiton 10% Cream In Patients With Scabies. J Ayub Med Coll
Abbottabad. 2019;31(2):230-232.
77. A l Jaff AD, Amin MHM. Comparison the Effectiveness of Sulphur Ointment , Permethrin and Oral Ivermectin In Treatment of Scabies Research Journal of
Pharmaceutical , Biological and Chemical Sciences Comparison the Effectiveness of Sulphur Ointment , Permethrin and Oral Ivermect. Res J Pharm Biol Chem Sci.
2019;9(1):670-676.
78. R Mallya R, Swaroop R, Yashwanth Reddy K, Ghosh A, S Krishn Z. Study of efficacy and cost effectiveness of topical permethrin, benzyl benzoate and oral ivermectin
in the treatment of scabies. IP Indian J Clin Exp Dermatology. 2021;7(1):54-60. doi:10.18231/j.ijced.2021.010.
79. M ay P, Bowen A, Tong S, et al. Protocol for the systematic review of the prevention, treatment and public health management of impetigo, scabies and fungal skin
infections in resource-limited settings. Syst Rev. 2016;5(1):1-8. doi:10.1186/s13643-016-0335-0.
19 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL ARTICLE
Journal of the Philippine
Dermatological Society
Relationship of whole blood zinc levels to acne severity
among Filipinos 18-25 years old: a cross-sectional
comparative study in a tertiary government hospital
Monique Lianne C. Lim-Ang, MD, MBA, DPDS,1 Ma. Angela M. Lavadia, MD, FPDS1
ABSTRACT
INTRODUCTION Acne Vulgaris is one of the most common dermatologic diagnoses in the world. It can persist for years, result in permanent scar-
ring, and have serious adverse effects on psychosocial development.
OBJECTIVES This study aims to determine the relationship between whole blood zinc levels and severity of acne.
METHODS This is a cross-sectional comparative study. Whole blood zinc levels of 30 patients with acne vulgaris divided into mild (n=10), moderate
(n=10), and severe (n=10), and 10 healthy patients were measured. Acne severity was evaluated using the Global Acne Grading System (GAGS).
RESULTS A total of 40 patients participated in this study. The mean whole blood zinc level in acne patients and non-acne patients were 5.03 ± 1.92
mcg/mL and 7.39 ± 0.79 mcg/mL, respectively. The mean zinc level of the controls was significantly higher compared to that of the acne patients
(p=0.0006). Furthermore, mean whole blood zinc level of the patients with severe acne was significantly lower compared to that of the controls,
mild acne and moderate acne (p<0.001). Adjusting for age and sex, there is a significant association between severity of acne vulgaris and blood
zinc levels (p<0.0001). Specifically, the mean blood zinc level of the patients with moderate and severe acne were significantly lower compared to
that of the control group (p=0.019 and p<0.001, respectively).
CONCLUSION Whole blood zinc levels were inversely correlated with acne vulgaris severity in the Filipino population. Further studies are recom-
mended to determine the role of zinc in the pathogenesis of acne and the effects of oral zinc supplementation on acne patients.
KEYWORDS Acne Vulgaris, Whole Blood Zinc Levels, Global Acne Grading System
1Department of Dermatology East INTRODUCTION until after the age of 44.5
Avenue Medical Center Acne can persist for years and result in dis-
Acne vulgaris is a disorder of the pilosebaceous
Corresponding author unit characterized by formation of comedo- figurement and permanent scarring. It can cause
Monique Lianne C. Lim-Ang, MD, MBA, nes, papules, pustules, inflamed nodules, and serious adverse effects on psychosocial devel-
DPDS cysts.1 The four main pathogenic contributors opment, resulting in emotional problems, with-
of acne include follicular hyperkeratinization, drawal from society, and depression.6 Nearly all
Conflict of interest increased sebum production, Cutibacterium adolescents experience different severity levels
None acnes (C. acnes) within the follicle, and inflamma- of acne vulgaris, with moderate to severe levels
tion.1,2 Most common predilection sites are those affecting around 20% of this population.6 In the
Source of funding with hormone-sensitive sebaceous glands such Philippines, high school students were found to
None as the face, neck, chest, upper back, and upper have a mild impairment of quality of life (QOL)
arms.1 Acne vulgaris is the eighth most prev- due to acne, regardless of severity.7
Cite as alent disease in the world, affecting 9.4% of the
Lim-Ang MLC, Lavadia MAM. global population.3 In adults, acne prevalence Safe and effective long-term maintenance
Relationship of whole blood zinc levels ranges from 50 to 54% in females and 40 to 42.5% therapy is necessary to address the chronic and
to acne severity among Filipinos in males.4,5 This disease is commonly misunder- persistent nature of acne.8 In the last three de-
18-25 years old: a cross-sectional stood to primarily affect teenagers. However, a cades, there has been a significant increase in
comparative study in a tertiary large proportion of individuals continue to suffer resistance to antibiotics commonly used to treat
government hospital. J Phil Dermatol from acne or acquire new-onset acne far after acne. This was measured by the increased min-
Soc. 2022;31(1):20-25. their adolescent years.4 Up to 64% of individuals imal inhibitory concentration (MIC) against
have acne persisting into their 20s, and 43% have Cutibacterium acnes (formerly known as Propion-
acne persisting into their 30s.6 Moreover, the ibacterium acnes) for antibiotics such as eryth-
prevalence of acne did not substantially decrease romycin and tetracycline in patients receiving
long-term antibiotic treatment. This increase
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 20
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
was not observed in patients who did not have antibiotic treat- elements in the blood, such as zinc and copper, and correlat-
ment. C. acnes isolates in more recent studies showed resistance ed it to the severity of acne vulgaris. Patients with severe acne
to clindamycin, erythromycin, tetracycline, doxycycline, and had significantly lower levels of zinc.24 A study in Iran suggested
minocycline.8-11 This is a significant international public health that zinc levels may be related to the severity and type of acne
concern because aside from increase in pathogenic C. acnes, lesions, with moderate and severe acne patients having lower
resistance can occur in other bacteria more dangerous than serum zinc levels than mild acne and control patients.25 Another
C. acnes. Given this situation and the complexity of the reper- study of 173 acne patients showed that retinol binding protein
cussions of this trend, it is a challenge to maximize the use of and serum zinc levels were significantly lower in severe acne.26
non-antimicrobial therapy when treating acne.8,12-15 The relative decrease of serum zinc levels in acne patients sug-
gests a role for zinc in the pathogenesis of acne vulgaris. Stud-
The development of a variety of skin disorders, including ies about serum or whole blood zinc levels and its association to
acne, has been linked to oxidative status. Oxidative stress may acne severity in the Philippine setting have not yet been done.
play a major role in the pathogenesis of acne due to the lower Given that acne vulgaris is one of the most common dermato-
plasma levels of the antioxidant enzymes catalase (CAT), super- logic diagnoses in the Philippine population and that there is an
oxide dismutase (SOD), total antioxidant capacity (TAC). Acne increase in cases of antibiotic resistance, studies on other treat-
patients also had a higher level of malondialdehyde (MDA), a ment modalities for acne vulgaris are timely and significant.
marker for oxidative stress.16 Zinc is found in all body tissues
and is an essential element for normal epithelial differentia- OBJECTIVES
tion and development. The conformity, stability, and activity
of more than 200 metalloenzymes are affected by zinc as well The general objective of this study was to determine the rela-
as cell health and proper bodily functions like glandular, re- tionship between whole blood zinc levels and the severity of
productive, immune, and neuropsychiatric processes. In skin, acne vulgaris in Filipino patients 18-25 years old versus normal
it is 5 to 6 times more abundant in the epidermis than in the controls.
dermis. Its antioxidant properties have numerous benefits such
as protection against ultraviolet rays and oxidative damage by The specific objectives were to describe the clinical profile
decreasing reactive oxygen species (ROS) and improvement of of Filipino patients 18-25 years old with acne vulgaris, to deter-
wound healing and prevention of cancer and cardiovascular mine the whole blood zinc levels of acne patients compared to
diseases.17,18 At present, there is paucity of data regarding the controls, and to determine the relationship of the clinical sever-
role of zinc levels in the development or severity of acne vul- ity of acne vulgaris to whole blood zinc levels.
garis. Data on favorable effects of dietary factors such as zinc,
omega‐3 fatty acids, antioxidants, vitamin A, and dietary fiber METHODS
on acne vulgaris are limited especially in the Philippines.
STUDY DESIGN AND SETTING
Zinc deficiency exists both in developed and developing A cross-sectional comparative study design was utilized for this
countries. Several factors may affect serum zinc levels. These study which was conducted from November 2017 to March 2018
include low intake of highly absorbable zinc in fresh foods, high at the Dermatology outpatient clinic of the East Avenue Medical
phytate content of some staple food, pregnancy, lactation, and Center (EAMC). Laboratory services of Hi-Precision Diagnostics
increased demands of physiological processes such as growth were used for measuring whole blood zinc levels.
and sexual maturation.19 Inductively coupled plasma–atomic
emission spectroscopy (ICP-AES) is used for zinc determinations The study was approved by the ethics review board of
in blood and tissue samples, where the electromagnetic radia- EAMC prior to initiation. Informed consent was secured from
tion released by free atoms is used to determine the element.20,21 each participant prior to inclusion in the study. All patients were
When whole blood zinc levels were measured from healthy given proper treatment whether they agreed to participate in
participants in relation to sex and age using atomic absorption the study or not. To ensure confidentiality in data collection, the
spectrophotometry, the mean zinc level obtained in whole hu- investigators assigned a code to replace identifiers such as the
man blood from males was 607.0 ± 105.3 micrograms/100 ml and participant’s name.
585.2 ± 122.9 micrograms/100 ml in females. Males had slightly
higher zinc levels but the difference was not statistically signif- PARTICIPANTS
icant.22 Zinc deficiency starts when zinc levels reach 66 micro- The participants of the study included Filipino patients clini-
grams/dL for non-pregnant females and 70 micrograms/dL for cally diagnosed with acne vulgaris who are 18 to 25 years old,
males older than 9 years old.23 and normal controls in the same age group. Participants were
enrolled from the Dermatology outpatient clinic or Skin Center
A few researches in other countries compared zinc levels in of EAMC. Participants who were excluded from the study were
blood with the severity of acne. A study in Iraq measured trace those who had other chronic dermatoses or systemic disease,
took oral supplements or medications within 3 months prior to
21 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
joining the study, and those who were pregnant or lactating. percentages.
In order to compare the whole blood zinc levels between
OUTCOME MEASURES
The outcome measures were demographics (age and sex), se- cases and controls, independent T-test was used. ANOVA was
verity of acne vulgaris based on Global Acne Grading System used to compare the whole blood zinc levels by acne severity.
(GAGS), and whole blood zinc levels. Multiple linear regression analysis was performed to determine
the association of whole blood zinc levels with acne severity
DATA SOURCES AND MEASUREMENT after controlling for the effects of significant confounding vari-
Acne severity was assessed using the Global Acne Grading Sys- ables. All p-values ≤ 0.05 were considered as significant.
tem (GAGS). The GAGS is an acne severity scale that includes six
locations on the face, chest, and upper back. A factor is provid- RESULTS
ed for each of the 6 locations based on size (forehead = 2, right
cheek = 2, left cheek = 2, nose = 1, chin = 1, chest and upper back CLINICAL PROFILE OF FILIPINO PATIENTS 18-25 YEARS OLD
= 3). Each of the six areas are graded on a scale of 0-4 based on WITH ACNE VULGARIS
the most severe lesion present (no lesion = 0, comedones = 1, A total of 40 patients participated in this study. Among the pa-
papules = 2, pustules = 3, nodules = 4). The local score per loca- tients with acne vulgaris, 10 had mild acne, 10 had moderate
tion is obtained by multiplying the factor with the correspond- acne, and 10 had severe acne. The demographic and clinical
ing score for the most severe lesion. The sum of the local scores profile of the patients are shown in Table 1.
from all locations will result to the global score, with zero as the
lowest and 44 as the highest possible global score. Acne severity The mean age of the patients with acne was 21.63 years
is rated as mild (1-18), moderate (19-30), severe (31-38), and very with a standard deviation of 2.79 years. The youngest patient in
severe (≥39) with corresponding cut-off global scores.27 the group was 18 years old while the oldest patient was 25 years
old. On the other hand, the mean age of the patients without
Twelve milliliters of blood were extracted from each par- acne (i.e., controls) was 23.9 years with a standard deviation of
ticipant with proper aseptic technique. This was properly stored 1.2 years. The youngest patient in the group was 22 years old
in three EDTA tubes, labelled, refrigerated at 15-25°C, and trans- while the oldest patient was 25 years old. 72.5% of the patients in
ported to the laboratory for determination of whole blood zinc both groups were females. There were 22 (73.30%) female acne
levels through ashing acid digestion-inductively coupled plasma patients and 7 (70%) female non-acne patients. The mean GAGS
(ICP) using Shimadzu ICPS-7510, an inductively coupled plasma score of the participants with acne was 23.1 with a standard de-
emission spectrometer. viation of 10.02. The lowest and highest GAGS scores were 3 and
39, respectively.
SAMPLE SIZE
The program used for the computation of minimum sample size WHOLE BLOOD ZINC LEVELS OF ACNE PATIENTS COMPARED
was PASS 2008. Parameters for the computation was obtained TO CONTROLS
from previously published studies. For the one-way ANOVA, a The mean blood zinc level of the non-acne patients was 7.39
minimum of 40 patients (10 for each acne severity: mild, mod- mcg/mL with a standard deviation of 0.79 mcg/mL. The mean
erate and severe acne, and 10 for controls) achieved 95% power
to detect differences among the means versus the alternative Table 1. Demographic and clinical characteristics of study participants
of equal means using an F-test with a significance level of 0.05.
The size of the variation in the means was represented by their Characteristics Cases Controls
standard deviation which was 13.30 mg/dL and the common (n=30) (n=10)
standard deviation within a group was assumed to be 20.00 mg/
dL.24 Mean S.D. Mean S.D.
STATISTICAL METHODS Age (in years) 21.63 2.79 23.9 1.2
All valid data from participants with physical examination and
blood test results were included in the analysis. Missing values GAGS score 23.1 10.02 - -
were not replaced nor estimated during the statistical analysis
of outcome variables. Data was encoded in Microsoft Excel and Frequency Percent Frequency Percent
was converted into a Stata file for further data processing and
analysis. Stata SE version 12 was used for both descriptive and Sex
inferential statistics. Quantitative variables were presented as
mean or median while qualitative variables were presented as Female 22 73.30% 7 70%
Male 8 26.70% 3 30%
Table 2. Mean blood zinc levels (mcg/mL) according to patient group
Group Mean 95% C.I. p-value
Controls (n=10) 7.39 6.82, 7.96 0.0006
Cases (n=30) 5.03 4.31, 5.75
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 22
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
blood zinc level of the acne patients was 5.03 mcg/mL with a Table 3. Mean blood zinc levels (mcg/mL) according to severity of acne vulgaris
standard deviation of 1.92 mcg/mL. The result of the indepen-
dent t-test shows that the mean zinc level of the non-acne pa- Severity of Acne Mean 95% C.I. p-value
tients is significantly higher compared to that of the acne pa-
tients (p=0.0006) (Table 2). Controls (n=10) 7.39 6.82, 7.96
RELATIONSHIP OF THE CLINICAL SEVERITY OF ACNE VUL- Mild (n=10) 6.15 4.97, 7.33 <0.0001
GARIS TO WHOLE BLOOD ZINC LEVELS Moderate (n=10) 5.83 5.54, 6.12
The mean blood zinc level of patients with mild acne was 6.15 Severe (n=10) 3.11 1.91, 4.31
mcg/mL with a standard deviation of 1.65 mcg/mL. The mean
blood zinc level of patients with moderate acne was 5.83 mcg/ Table 4. Comparison of zinc levels (mcg/mL) by severity of acne vulgaris (Bonferroni test)
mL with a standard deviation of 0.41 mcg/mL. The mean blood
zinc level of patients with severe acne was 3.11 mcg/mL with a Row Mean- Control Mild Moderate
standard deviation of 1.68 mcg/mL. Column Mean
The result of the one-way ANOVA shows that the mean Mild -1.24
blood zinc levels significantly varies by severity of acne vulgaris 0.205
(p<0.0001) (Table 3). Specifically, using the Bonferroni test, the
mean zinc level of the patients with severe acne was significant- Moderate -1.56 -0.32
ly lower compared to that of the non-acne patients (p<0.001), pa- 0.053 1.00
tients with mild acne (p<0.001), and patients with moderate acne
(p<0.001). Nevertheless, the mean zinc levels of the patients Severe -4.28 -3.04 -2.72
with mild and moderate acne was not significantly different <0.001 <0.001 <0.001
from that of the non-acne patients (p>0.05) (Table 4).
Table 5. Association between severity of acne vulgaris and blood zinc levels
Adjusting for age and sex, there is a significant associa-
tion between severity of acne vulgaris and blood zinc levels Severity of Acne Coefficient * 95% C.I. p-value
(p<0.0001). Specifically, the mean blood zinc level of the patients
with mild acne was 1.11 mcg/mL lower compared to that of the Controls (n=10) - - -
non-acne patients. Nevertheless, it is not statistically significant
(p=0.071). On the other hand, the mean blood zinc level of the Mild (n=10) -1.11 -2.33, 0.1 0.071
patients with moderate acne was 1.48 mcg/mL lower compared
to that of the control group and it was statistically significant Moderate (n=10) -1.48 -2.7, -0.26 0.019
(p=0.019). Lastly, the mean blood zinc level of the patients with
severe acne was 4.19 mcg/mL lower compared to that of the con- Severe (n=10) -4.19 -5.43, -2.95 <0.001
trol group and it was statistically significant (p<0.001) (Table 5).
*Adjusted for age and sex
DISCUSSION
Similarly, Saleh et al showed that the mean value of serum
This cross-sectional comparative study provided the first evi- zinc significantly decreased in severe acne compared to nor-
dence for the association between whole blood zinc levels and mal controls in the Iraqi population.24 Kaymak et al also found
acne vulgaris in the Filipino population. Findings revealed that that zinc levels were significantly lower in the acne group when
whole blood zinc levels in patients with severe type of acne vul- compared to controls.29 These studies compared acne vulgaris
garis were significantly lower than that of controls, mild, and patients with controls without classifying according to severity.
moderate acne vulgaris patients. Adjusting for age and sex, the
whole blood zinc levels of both severe and moderate types of Mogaddam et al found that the mean serum zinc level of
acne were significantly lower than controls. acne vulgaris patients was lower compared to those in healthy
patients, but it was not statistically significant.25 This may be
A study done by Ozuguz et al showed that serum vitamin due to the participants being mostly classified as having mild
E, vitamin A, and zinc were significantly lower in acne vulgaris acne vulgaris. The participants were composed of 64 mild acne
patients compared to controls. Moreover, patients with severe patients, 32 moderate acne patients, and four (4) severe acne pa-
acne had significantly lower serum vitamin E and zinc levels tients. Mild acne vugaris may have lower serum zinc levels but
compared to controls.28 We had congruent findings in our study are usually not statistically significant when compared to con-
regarding the negative correlation of zinc levels and severity of trols.
acne vulgaris.
Rice is a staple food in the Philippines. It is also known to
have high phytate content, which may reduce the zinc levels in
the blood.19 This study included non-acne participants in order
to be able to limit this possible confounding factor and deter-
mine whether the decrease in whole blood zinc levels is related
to Filipinos in general or may be associated to acne vulgaris and
its severity.
23 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
One of the key factors in the pathogenesis of acne vulgaris to monitor food intake may be done to limit these confounders
is inflammation. Oxidative stress is implicated in acne due to on whole blood zinc levels.
the high levels of malondialdehyde activity and low levels of
antioxidant enzyme activity.16 Low zinc levels in acne vulgaris Conclusion
patients may be related to zinc’s antioxidant and anti-inflamma-
tory role in protecting the body against oxidative damage and In summary, whole blood zinc level was associated with the se-
decreasing reactive oxygen species (ROS).18 verity of acne vulgaris in the Filipino population. Whole blood
zinc levels showed inverse correlation with acne vulgaris se-
Limitations of this study include the unavailability of fac- verity, with lower zinc levels correlated with higher severity of
tors such as the subject’s detailed dietary intake that may affect acne vulgaris. Further studies are needed to determine the role
the zinc levels in blood. The relatively small sample size and of zinc in the pathogenesis of acne vulgaris. Randomized pla-
short duration of the study is also a drawback for this study. Fu- cebo-controlled clinical trials are necessary to determine the
ture trials with longer duration to include larger sample size and effects of oral zinc supplementation on acne vulgaris patients.
REFERENCES
1. Aydemir EH. Acne vulgaris. Turk Pediatri Ars. Mar 2014;49(1):13-6. doi:10.5152/tpa.2014.1943.
2. Toyoda M, Morohashi M. Pathogenesis of acne. Med Electron Microsc. Mar 2001;34(1):29-40. doi:10.1007/s007950100002.
3. T an J, Bhate K. A global perspective on the epidemiology of acne. British Journal of Dermatology. 2015;172(Supp 1):3-12.
4. C ollier CN, Harper JC, Cafardi JA, et al. The prevalence of acne in adults 20 years and older. Journal of the American Academy of
Dermatology. 2008;58:56-59.
5. G oulden V, Stables G, Cunliffe W. Prevalence of facial acne in adults. Journal of the American Academy of Dermatology. 1999;41(4):577-580.
6. Bhate K, Williams H. Epidemiology of acne vulgaris. British Journal of Dermatology. 2013;168(3):474-485.
7. Bernal VA, Sanchez E. A Cross-Sectional Study on the Impact of Acne Vulgaris on the Quality of Life among High School Students in Pasig
City, Philippines. Journal of the Philippine Medical Association. 2016-2017;95(1):1-9.
8. Humphrey S. Antibiotic resistance in acne treatment. Skin Therapy Letter. 2012;17(9):1-3.
9. Leyden JJ, McGinley KJ, Cavalieri S, Webster GF, Mills OH, Kligman AM. Propionibacterium acnes resistance to antibiotics in acne patients. J
Am Acad Dermatol. Jan 1983;8(1):41-5. doi:10.1016/s0190-9622(83)70005-8.
10. Luk NM, Hui M, Lee HC, et al. Antibiotic-resistant Propionibacterium acnes among acne patients in a regional skin centre in Hong Kong. J Eur
Acad Dermatol Venereol. Jan 2013;27(1):31-6. doi:10.1111/j.1468-3083.2011.04351.x.
11. A lkhawaja E, Hammadi S, Abdelmalek M, Mahasneh N, Alkhawaja B, Abdelmalek SM. Antibiotic resistant Cutibacterium acnes among acne
patients in Jordan: a cross sectional study. BMC Dermatol. 11 17 2020;20(1):17. doi:10.1186/s12895-020-00108-9.
12. Cooper AJ. Systematic review of Propionibacterium acnes resistance to systemic antibiotics. Med J Aust. Sep 1998;169(5):259-61.
doi:10.5694/j.1326-5377.1998.tb140250.x.
13. Eady EA, Cove JH, Holland KT, Cunliffe WJ. Erythromycin resistant propionibacteria in antibiotic treated acne patients: association with
therapeutic failure. Br J Dermatol. Jul 1989;121(1):51-7. doi:10.1111/j.1365-2133.1989.tb01399.x.
14. Eady EA, Gloor M, Leyden JJ. Propionibacterium acnes resistance: a worldwide problem. Dermatology. 2003;206(1):54-6. doi:10.1159/000067822.
15. R oss JI, Snelling AM, Carnegie E, et al. Antibiotic-resistant acne: lessons from Europe. Br J Dermatol. Mar 2003;148(3):467-78. doi:10.1046/
j.1365-2133.2003.05067.x.
16. Al-Shobaili H. Oxidants and anti-oxidants status in acne vulgaris patients with varying severity. Annals of clinical and laboratory science.
2014:202-207.
17. Rostan MD EF, DeBuys MD HV, Madey PhD DL. Evidence supporting zinc as an important antioxidant for skin. International Journal of
Dermatology. 2002;
18. Prasad AS. Zinc is an Antioxidant and Anti-Inflammatory Agent: Its Role in Human Health. Frontiers in nutrition. 2014;
19. Marcos JM, Perlas LA, Trio PZ, et al. Zinc Status of Filipinos by Serum Zinc Level. Philippine Journal of Science. 2015;144(2):139-148.
20. Agency for Toxic Substances and Disease Registry. Toxicological Profile for Zinc. August 2005:191-204. https://www.atsdr.cdc.gov/
toxprofiles/tp60-c7.pdf.
21. U niversity of Wroclaw Faculty of Chemistry. Ashing of organic samples and determination of Zn and Fe using ICP-AES method.1-3. http://zd2.
chem.uni.wroc.pl/files/chemistry/22_ENG.pdf.
22. Buxaderas S, Farré-Rovira R. Whole blood and serum zinc levels in relation to sex and age. Revista Espanola De Fisiologia. 1985;41(4):463-470.
23. A khtar S. Zinc status in South Asian populations--an update. J Health Popul Nutr. Jun 2013;31(2):139-49. doi:10.3329/jhpn.v31i2.16378.
24. S aleh BO, Anbar ZN, Majid AY. Serum Trace Elements (Zinc, Copper and Magnesium) Status in Iraqi Patients with Acne Vulgaris:( Case-
Controlled Study). Iraqi Journal of Pharmaceutical Sciences; 2011.
25. Mogaddam MR, Ardabili NS, Maleki N. Correlation between the Severity and Type of Acne Lesions with Serum Zinc Levels in Patients with
Acne Vulgaris. BioMed research international. July 2014:1-6.
26. Michaëlsson G, Vahlquist A, Juhlin L. Serum Zinc and Retinol-Binding protein in Acne. British Journal of Dermatology. 1977;96(3):283-286.
27. Adityan B, Kumari R, Thappa DM. Scoring Systems in Acne Vulgaris. Indian Journal of Dermatology, Venereology and Leprology.
2009;75(75):323-326.
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 24
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
28. Ozuguz P, Kacar SD, Ekiz O, Takci Z, Balta I, Kalkan G. Evaluation of serum vitamins A and E and zinc levels according to the severity of acne
vulgaris. Cutaneous and Ocular Toxicology. 2013;
29. Kaymak Y, Adisen E, Erhan M, Celik B, Gurer MA. Zinc Levels in Patients with Acne Vulgaris. Journal of the Turkish Academy of Dermatology.
2007;1(3).
25 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL ARTICLE
Journal of the Philippine
Dermatological Society
The economic burden of psoriasis: a cross-sectional
study in a tertiary hospital in the Philippines
Diandra Aurora R. Zabala, MD, DPDS,1 Victoria P. Guillano, MD, FPDS,1 Maynie Bambi D. Lugasan, MD, DPDS1
ABSTRACT
INTRODUCTION Costs associated with chronic psoriasis impart a significant economic burden.
OBJECTIVES This study aims to determine the direct and indirect cost of psoriasis patients in a tertiary government hospital in Davao City.
METHODS Plaque-type psoriasis patients who were actively seeking care at the Southern Philippines Medical Center Department of Dermatology
for at least 6 months prior to the study period were included. The participants reported on socioeconomic status, productivity loss and monetary
funding through questionnaires. Work impairment was evaluated using the Work Productivity and Activity Impairment questionnaire and was used
to compute the indirect cost. A 6-month retrospective review of the health information system and medical charts generated the healthcare
resource utilization data as well as the medical data used to compute the direct cost.
RESULTS Among the 43 participants enrolled, 53% had a monthly household income of less than PHP8,000 (USD157) and 27% were unemployed. There
was an overall work impairment of 65.4%, and 55% had experienced a change in employment status due to psoriasis. The mean 6-month direct cost
of psoriasis was PHP22,672.28 ($445). The mean 6-month indirect cost was PHP 26,071.20 ($511) for employment status change and PHP 75,804.30
($1,486) for work impairment. Government agencies provided financial aid for treatment but majority of the costs came from the participants’ own
pockets.
CONCLUSION The economic burden of psoriasis increased substantially due to the indirect cost, which in turn increased remarkably due to work
impairment and employment status change.
KEYWORDS economic burden, psoriasis, absenteeism, presenteeism, cost of psoriasis
1Department of Dermatology of the INTRODUCTION In some studies, severe psoriasis is associated
Southern Philippines Medical Center with a lower probability of employment and has
Psoriasis is a chronic and relapsing inflammato- been reported by some patients to be the sole or
Corresponding author ry skin disease affected by genetic, immunolog- partial cause for unemployment.7,8 Costs result-
Diandra Aurora R. Zabala, MD, DPDS ic and environmental factors.1 According to the ing from impaired productivity and employment
2019 Philippine Dermatological Society - Health status changes directly related to a specific ill-
Conflict of interest Information System (PDS-HIS) data, psoriasis is ness are collectively known as the ‘indirect cost’
None the 4th leading cause for consult among the 11 of illness.9,10
accredited dermatology training institutions in
Source of funding the Philippines.2 According to the data from the In contrast to indirect cost, the ‘direct cost’
None Southern Philippines Medical Center (SPMC) De- of illness is the expense spent for medications,
partment of Dermatology, there were 123 newly laboratory work-up and diagnostic procedures,
Cite as diagnosed cases of psoriasis in 2018. Consul- physical rehabilitation, hospital admissions,
Zabala DAR, Guillano VP, Lugasan tations for both old and new cases of psoriasis consultations, and other health care services.10
MBD. The economic burden of added up to 1,056 consults for the whole of 2018. Direct cost also includes non-healthcare resource
psoriasis: a cross-sectional study in This accounted for 6.28% of the total consults at expenditures such as those spent for transporta-
a tertiary hospital in the Philippines. J the SPMC Department of Dermatology and 0.21% tion to and from the health provider.
Phil Dermatol Soc. 2022;31(1):26-32. of the total consults for the whole outpatient de-
partment. The term ‘cost of illness’ may be used inter-
changeably with ‘the burden of disease.’10 Studies
Psoriasis is prevalent among the work- on the cost of illness provide data that are fun-
ing age group and negatively affects finances damental for planning and financing disease
through reduced work outputs and increased treatment and control programs.11 They influ-
absences from work.3-6 The cost is termed ‘pro- ence policymakers on how an illness should be
ductivity loss’ from the patient perspective and prioritized in the distribution of healthcare re-
‘productivity cost’ from the societal perspective. sources.11,12 They may also be used to evaluate the
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 26
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
efficacy of health policies and programs and compare it to those ployment status due to psoriasis (i.e., retired early, reduced
from other countries.10 Moreover, these studies are also used by work schedule, etc.) and the duration of this change. This was
the World Bank and the World Health Organization to estimate converted into monetary values to calculate the indirect cost us-
of the total burden of a particular disease to society.13 ing the following method by Schaefer et al.7: the local minimum
wage which was PHP396.0016 was divided by the standard eight
Several studies have already been conducted assessing (8) hours of work, then multiplied by the lost productive time
the direct and indirect cost associated with psoriasis in other since the change in employment status (up to a maximum of six
countries as well as their health care utilization profile; how- (6) months).
ever, none from the Philippine setting has been published thus
far. As psoriasis is consistently one of the top leading causes for The second form was the Work Productivity and Activity
consult among the training institutions in the Philippines,2 the Impairment (WPAI) Form – Specific Health Problem question-
information gathered by this study may provide us with a bet- naire (see Appendix 4). This was composed of six (6) questions,
ter understanding of how psoriasis affects the productivity and namely: Q1 – currently employed; Q2 – hours missed due to spe-
finances of the patient and the society. Henceforth, this study cific problem; Q3 – hours missed for other reasons; Q4 – hours
will provide us with a partial insight into the economic burden actually worked; Q5 – the degree (on a scale from 0 to 10) of the
of psoriasis in the Philippines. problem affecting productivity while at work; and, Q6 – the de-
gree (on a scale from 0 to 100) of the problem affecting regu-
METHODOLOGY lar daily activities other than work such as household chores,
shopping, etc.17 Each score was multiplied by 100 to obtain the
This was a cross-sectional study with retrospective review of percentage values. The four (4) domains of absenteeism, presen-
medical data. This study used the prevalence-based approach teeism, overall work impairment, and activity impairment were
of determining the cost of illness. This approach uses data from obtained using the following formulas:18
the total cost of care within a specific time frame and includes
all patients with a specific diagnosis regardless of disease dura- Absenteeism (percent work time missed due to the prob-
tion.13-15 lem) = Q2 / (Q2+Q4)
The study procedures and the questionnaires used were Presenteeism (percent impairment while working due to
all in accord with ethical standards and approved by a research problem) = Q5/10
ethics committee.
Overall Work Impairment = Q2 / (Q2+Q4) + [1- (Q2 / (Q2+Q4))
All psoriasis patients seen at the SPMC Department of x (Q5/10)]
Dermatology from July 2019 to January 2020 were screened for
eligibility. The inclusion criteria were the following: [1] 18-64 Activity Impairment = Q6/10.
years of age; [2] had an initial diagnosis of psoriasis at least six
(6) months prior to enrollment; [3] had moderate to severe (PASI By using the results from the WPAI, the indirect cost from
≥10) plaque type psoriasis upon enrollment or within six (6) work impairment was computed by using the mean absentee-
months prior; [4] had mild psoriasis (PASI <10) treated with pho- ism and presenteeism values, multiplying each of them by the
totherapy or any systemic therapy (e.g., methotrexate, biologic minimum hourly wage to get the total lost wages per week, and
agents) upon or within six (6) months prior to enrollment; and multiplying by the number of work weeks in a 6-month period.
[5] currently undergoing active treatment for psoriasis. This was based on the method by Gupta et al.18
Patients excluded from this study were the following: [1] The third form was the journal of expenses related to the
those with mild psoriasis who did not receive any systemic or diagnosis and treatment of psoriasis (see Appendix 5). This was
phototherapy within the last six (6) months prior to the study; [2] patterned after the Filipino study on the direct medical costs of
with mental or psychiatric illnesses who could not answer the care of adult asthma patients done by Fabian et al.,19 and the
questionnaires; [3] had participated in an experimental study American study on psoriasis by Schaefer et al. using a 4-week
for the treatment of psoriasis within six (6) months prior to patient-recall approach.7 It included a list of all the services, di-
this study; [4] with serious or unstable medical conditions (e.g., agnostics, and medications that the patient acquired during the
Cushing’s syndrome, AIDS, cancer stage 4); [5] with other types last four (4) weeks along with the corresponding cost and the
of cutaneous psoriasis other than plaque psoriasis at the time source of financial funds for each item.
of enrollment (e.g., pustular, erythrodermic, guttate); and [6]
pregnant women who were on maternal leave during the study To determine psoriasis-related health care resource uti-
period. lization (HCRU), a review of the medical charts and the elec-
tronic health information system (HIS) was carried out. This
Three data collection forms were used in this study. The included all outpatient and emergency room consults, hospital
first form was for the patient’s demographic and socioeconom-
ic data (see Appendix 3). This also included the changes in em-
27 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
admissions, laboratory and diagnostic procedures, photothera- Socio-economic Profile, Productivity, and Changes in Em-
py sessions, and medications prescribed within the last six (6) ployment Status
months, based on the methodology of Schaefer et al.7 This also
included the highest PASI and BSA scores in a 6-month period up Seventy-two percent (72%, n=31) of the participants were
until enrollment into the study. currently employed and 42% (n=18) had a regular, full-time job.
A monthly income of less than PHP 8,000.00 was seen in 53%
Data collected from this study was encoded via Microsoft (Table 1). For those who experienced a change in employment
Excel. We used descriptive statistics such as mean and standard status due to psoriasis, it was mostly in the form of a reduced
deviation to express continuous variables, and frequency and work schedule.
percent for categorical/nominal variables. ANOVA was used to
analyze monthly income, work productivity and impairment, Among the participants who were employed, there was a
cost of treatment, cost of diagnosis, and cost of employment 106% mean overall work impairment, which was related more
and work impairment among the three levels of severity. Chi- to impairment while at work (presenteeism of 59%) rather than
square Goodness of Fit test was used for categorical data such absence from work (absenteeism of 23%). Only participants who
as monthly income range and employment status. All statistical reported being employed full time, part time, or self-employed
tests were tested against an alpha of 0.05. provided data for absenteeism, presenteeism, and overall work
impairment. All participants provided data for activity impair-
RESULTS ment (Figure 1).
DEMOGRAPHIC AND CLINICAL PROFILE TREATMENT PATTERNS AND HEALTH CARE UTILIZATION
This study enrolled 43 participants. Of these, 51.2% (n=22) were PROFILE
male and 48.8% (n=21) were female with a mean age of 46.07 There was a mean of 8.88 (±10.02) dermatology outpatient
(±13.96) years and mean illness duration of 8.7 (±7.32) years. consults and 13.67 (±9.10) laboratory examinations in six (6)
The mean age upon the initial diagnosis of psoriasis was 36.37 months. Only one (1) participant from the study group consult-
(±13.8). The mean PASI score and body surface area (BSA) af- ed at the emergency room and was subsequently admitted in the
fected at the time of enrollment was 14.41 (±9.37) and 21.26% hospital (mean 0.02 ±0.15). Participants were prescribed with a
(±19.61%), respectively. mean of 1.80 (±0.79) types of medication for psoriasis. Topical
Table 1. Economic profile of patients (n = 43) PASI <10 PASI 10-20 PASI >20 Overall
(n=13) (n=21) (n=9) (n=43)
Employment Status (n, %)
Full-time 6 (46%) 7 (33%) 5 (56%) 18 (42%)
Part-time 2 (15%) 9 (43%) 2 (22%) 13 (30%)
Housewife 3 (23%) 2 (10%) 2 (22%) 7 (16%)
Retired 0 (0%) 1 (5%) 0 (0%)
Unemployed 2 (15%) 2 (10%) 0 (0%) 1 (2%)
4 (9%)
Occupation (n, %) 1 (8%) 2 (10%) 1 (11%)
Government employee 4 (31%) 6 (29%) 2 (22%) 3 (7%)
Private employee 3 (23%) 8 (38%) 3 (33%) 10 (23%)
Own business 11 (26%)
0 (0%) 0 (0%) 3 (33%)
Monthly Income (n, %) 0 (0%) 0 (0%) 3 (33%) 3 (7%)
> Php 100,000 1 (8%) 2 (10%) 3 (33%) 3 (7%)
Php 50,001-100,000 1 (8%) 0 (0%) 0 (0%) 6 (14%)
Php 30,001-50,000 2 (15%) 5 (24%) 0 (0%) 1 (2%)
Php 15,001-30,000 9 (69%) 14 (67%) 0 (0%) 7 (16%)
Php 8,000-15,000 23 (53%)
< Php 8,000 1 (8%) 0 (0%) 0 (0%)
1 (8%) 0 (0%) 1 (11%) 1 (2%)
Change in employment status due 0 (0%) 1 (5%) 0 (0%) 2 (5%)
to psoriasis (n, %) 3 (23%) 9 (43%) 1 (11%) 1 (2%)
Retired early 9 (69%) 11 (52%) 7 (78%) 13 (30%)
Unemployed 27 (63%)
Disabled 34.00 ± 20.49 37.13 ± 48.52 38.5 ± 33.5
Reduced work schedule 36.52 ± 42.82
None
Duration since change in employ-
ment status in months (mean)
PASI - Psoriasis Area and Severity Index
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 28
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
Figure 1. Work Productivity and Activity Impairment Scores (Mean)
DIRECT COST OF PSORIASIS
Figure 2. Treatment Modality Received During a 6-Month Period The mean direct cost for treatment was PHP22,672.28
(±42,312.22) and the mean direct cost for diagnostic work-up
was PHP2,701.33 (±1,733.24) (Figure 3). The highest reported
cost for treatment was PHP136,216.00 in a participant undergo-
ing biologic therapy.
INDIRECT COST OF PSORIASIS
According to patient-reported changes in employment sta-
tus in a 6-month period due to psoriasis (i.e., decreased work
schedule, early retirement, or unemployment), there was a
mean indirect cost of PHP26,071.20 (±26,085.99), and this was
highest for those with severe psoriasis at PHP30,383.10 (Figure
4). The results did not include data from those who had their
own businesses since their work schedule was neither standard
nor fixed.
The mean indirect cost brought about by work impairment
for the past six (6) months was PHP75,804.30 (Figure 4). This was
largely driven by presenteeism rather than absenteeism for all
groups.
FUNDING SOURCE
The financial aid contributed by the different funding
sources for the past four (4) weeks was mostly based on the par-
ticipants’ self-reported expenses, assisted by the review of med-
ical records and electronic health information system (HIS).
Only participants who chose to solicit from a specific funding
source (e.g., Department of Social Welfare and Development)
and met the criteria required were able to receive financial as-
sistance. All of the participants had out of pocket expenses (Ta-
ble 2).
DISCUSSION
In our study population, psoriasis was first diagnosed at a mean
age of 36, close the WHO global report of 33.20 This shows that
psoriasis is commonly diagnosed in the working age group,
Figure 3. Cost of Treatment and Diagnostic Work-up (in PHP) of Psoriasis During a
6-Month Period
medications were the most used form of treatment among all Figure 4. Mean Indirect Cost (in PHP) of Psoriasis in a 6-Month Period
PASI groups, and biologic therapy was the least used (Figure 2).
29 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
Table 2. Source of Funds for the Direct Cost of Care During the Past Four (4) Weeks sociation between disease severity and treatment costs.29 While
a correlation between disease severity and treatment cost was
Total cost from Range of amounts charged to funding not seen in this study (Figure 3), a direct association between
funding source source biologic agent use and treatment cost was evident. The PASI 10-
20 group used biologics the most (23.81%, n=21) and this group
Source of funds (PHP) also had the highest mean cost of treatment at PHP 28,504.19
±45,850.88 (Figure 3). The nonlinear relationship between dis-
Out of Pocket 332,717.35 Minimum value Maximum value ease severity and treatment cost in this study was mainly due
(PHP) (PHP) to the use of the prevalence-based approach wherein the high-
Philippine Health 0.00 est PASI score within 6 months prior to or upon enrollment was
Insurance Corpora- 150.00 128,221.60 used creating the two (2) following scenarios: (1) the ongoing
tion (PHIC) - - use of biologics for more than six (6) months brought about an
improvement of disease and a low PASI score during the study
Lingap / Malasakit 12,855.00 500.00 3,500.00 period; and (2) participants enrolled upon consultation for dis-
995.00 3,500.00 ease flare after a long time of remission.
CMAP 4,415.00 180.00 1,420.00
The indirect cost due to employment status changes among
Hospital Social 2,947.00 10,000.00 30,000.00 the participants was PHP 26,071.20 ($511) for half a year, or an
Services annual cost of PHP 52,142.40 ($1,022.40). This is comparable to
the results of an American study by Schaefer et al. wherein the
Philippine Charity 50,000.00 indirect cost due to employment status change was $1,090.00.7
Sweepstakes Office On the other hand, the indirect cost from work impairment
(PCSO) among the participants was higher at PHP 75,804.30 ($1,486.00),
or an annual cost of PHP151,608.60 ($2,972.72). Since presentee-
Office of the Mayor/ 11,500.00 2,000.00 6,500.00 ism rather than absenteeism contributed more to the indirect
Congress/ Pres- cost and even amounted to more than the direct cost of treat-
ident ment, decreased productivity not only negatively affects the
patients but the employers as well. This financial impact of
Department of 18,500.00 1,500.00 17,000.00 presenteeism on employers was also found to be true for other
Social Welfare studies that involved a variety of other more common medical
and Development conditions.30-33
(DSWD)
In a Canadian study, an inverse relationship between the
which partially explains the work and productivity impairment employment rate and the severity of psoriasis was demonstrat-
brought about by this disease.7,21-23 ed, and this could have partially explained their finding of a
lower annual income in those with moderate and severe psori-
Topical therapy was still the most used type of medica- asis as compared to those with mild psoriasis.28 In an American
tion among all PASI groups, consistent with the study by Ng et study by Horn et al., more patients with severe psoriasis com-
al. which was conducted in the same tertiary hospital as this pared to mild psoriasis reported that their sole reason for not
study.24 Despite the availability and proven efficacy of biolog- working was due to psoriasis.8 Although no correlation between
ic agents,25-27 only 16.28% of our study population were using the status of employment and severity of psoriasis was found in
these. Other studies that looked into treatment preferences and this study, it is noted that psoriasis—no matter how mild—still
patterns of psoriasis patients found that medication prices, out- affects productivity and overall work performance.
of-pocket costs, and insurance approval were critical factors,5,6
and that biologic agents were more commonly used among Various local government agencies and funding sources
those with larger incomes or those who had full medical insur- were able to assist the participants with the treatment expens-
ance coverage.28 Treatment preferences among the participants es (Table 2). The participants could solicit financial aid from
and reasons for the scarce use of biologics were however outside government agencies if they were able to meet specific criteria
the scope of this study. and submit the required documents. Nonetheless, the highest
maximum value still came from the participants’ own pock-
The mean 6-month cost of treatment was PHP 22,672.28 ets. No insurance company was able to cover for the ongoing
($445, with 1USD equivalent to PHP51 during the study period), treatments of psoriasis. The Philippine Health Insurance Cor-
or an annual cost of PHP45,344.56 ($889.11) when extrapolat- poration (PHIC), for example, was able to cover for the cost of
ed to the number of work weeks per year.18 The mean 6-month biopsy during the initial diagnosis of psoriasis but was not able
cost for diagnostics was PHP2,701.33 ($53) or an annual cost of to contribute towards any of its outpatient treatment expenses.
PHP5,402.66 ($105.93). This shows that treatments rather than
laboratory examinations contribute more to the medical ex-
penses for chronic plaque psoriasis.
A European systematic review of literature on costs asso-
ciated with the management of psoriasis and psoriatic arthritis
across five (5) different countries found that there was a direct as-
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 30
ORIGINAL JPDS
ARTICLE Journal of the Philippine
Dermatological Society
Hence, in our data, no funding came from the PHIC. sent the population of interest.
This study used the prevalence-based approach in deter-
CONCLUSION
mining the cost of illness because the goal was not only to estab-
lish the total cost of psoriasis but also to determine which area Psoriasis is a chronic disease that leads to multiple expenses
of ongoing care contributed to most of the cost. Since the prev- attributed to frequent follow-ups, laboratory examinations and
alence of chronic diseases such as psoriasis is much larger than various treatment regimens. In the setting of a tertiary gov-
the incidence, this would also represent the population better. ernment hospital in the Philippines, the mean 6-month direct
Moreover, this approach is usually used to petition health care cost of psoriasis was PHP22,672.28 ($445.00). Additionally, an
policies and programs especially when policymakers have un- indirect cost of PHP26,071.20 ($511.00) from employment status
derestimated the burden of illness.10,34 change and PHP75,804.30 ($1,486.00) from work impairment
further increased the economic burden. Moreover, the indirect
LIMITATIONS AND RECOMMENDATIONS cost incurred particularly from presenteeism not only negative-
This study only included participants between the ages of ly affects the patient but the employers as well.30-33 Despite the
availability of government agencies that provide financial aid,
18-64; thus, the direct cost of psoriasis only reflects those of the all the participants still had out-of-pocket expenses for treat-
adult and working age group. Using the prevalence-based ap- ment and only less than half of the participants were able re-
proach to determine the costs, only those who were treated at ceive financial aid.
the outpatient department for at least six (6) months and were
relatively actively seeking consult were included. These crite- In our setting wherein the burden of psoriasis is heavy, and
ria excluded those who were newly diagnosed with psoriasis; most patients are expected to shoulder majority of the costs for
hence, this excluded data such as the cost of biopsy and the treatment, perhaps financial assistance from the government
amount shouldered by the PHIC for the biopsy. In addition, the should be made more widely available, accessible, and exten-
prevalence approach cannot precisely compare and determine sive so that personal finances would not limit treatment options.
whether there is truly a direct relationship between the cost and Since the total cost of illness increases remarkably due to the
the severity of psoriasis. For future studies, we recommend the indirect cost, and the indirect cost increases significantly in
following: [1] the inclusion all ages if a more detailed direct cost proportion to the overall work impairment, adequate financial
of disease is desired; [2] the use of a prospective design with the assistance for better treatment outcomes and better disease
inclusion of mild psoriasis patients treated with topical therapy control should lead to enhanced work productivity, a healthy
to determine the relationship between direct cost and disease workforce, and a subsequent lower economic burden of psoria-
severity; [3] and the use of a multicenter study to better repre- sis for the patients and the society.
ACKNOWLEDGMENTS
We would like to acknowledge Dr. Rea Dapiton for her valuable contribution in referring psoriasis patients for enrollment into the study as well
as her constructive suggestions in writing this paper.
REFERENCES
1. Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffell DJ, Wolff K. Fitzpatrick’s Dermatology in General Medicine. 8th ed. New York: McGraw-Hill;
2012.
2. Dizon AB, Pasion CRF, Perez-Chua T, Copuyoc-Sampedro CM, et al. (2020). PDS Top 10 Diseases Based on New and Existing Cases. Skin
Contact: The Official Newsletter of the Philippine Dermatological Society. Available from https://online.anyflip.com/cxek/hcmy/mobile/
index.html.
3. Kurd SK, Troxel AB, Crits-Christoph P, Gelfand JM. The risk of depression, anxiety, and suicidality in patients with psoriasis: a population-
based cohort study. Arch Dermatol. 2010 Aug;146(8):891-5.
4. Lebwohl MG, Kavanaugh A, Armstrong AW, Van Voorhees AS. US Perspectives in the Management of Psoriasis and Psoriatic Arthritis: Patient
and Physician Results from the Population-Based Multinational Assessment of Psoriasis and Psoriatic Arthritis (MAPP) Survey. Am J Clin
Dermatol. 2016 Feb; 17(1):87-97.
5. Alcusky M, Lee S, Lau G, et al. Dermatologist and Patient Preferences in Choosing Treatments for Moderate to Severe Psoriasis. Dermatol
Ther (Heidelb). 2017 Dec; 7(4): 463–483.
6. Kamangar F, Isip L, Bhutani T, Dennis M, Heller MM, Lee ES, Nie H, Liao W. How Psoriasis Patients Perceive, Obtain, and Use Biologic Agents:
Survey from an Academic Medical Center. J Dermatolog Treat. 2013 Feb; 24(1): 13–24.
7. Schaefer CP, Cappelleri JC, Cheng R, Cole JC, Guenthner S, Fowler J, Johnson S, Mamolo C. Health care resource use, productivity, and
costs among patients with moderate to severe plaque psoriasis in the United States. J Am Acad Dermatol. 2015 Oct;73(4):585-593.e3.
8. Horn EJ, Fox KM, Patel V, Chiou CF, Dann F, Lebwohl M. Association of patient-reported psoriasis severity with income and employment. J Am
31 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS ORIGINAL
Journal of the Philippine ARTICLE
Dermatological Society
Acad Dermatol. 2007; 57(6):963-71.
9. Kruntorádová, K., Klimeš, J., Šedová, L., Štolfa, J., Doležal, T., & Petříková, A. (2014). Work Productivity and Costs Related to Patients with
Ankylosing Spondylitis, Rheumatoid Arthritis, and Psoriasis. Value in Health Regional Issues, 4, 100–106.
10. Changik Jo. Cost-of-illness studies: concepts, scopes and methods. Clin Mol Hepatol. 2014 Dec; 20(4): 327–337.
11. R ice DP, Hodgson TA, Kopstein AN. The economic costs of illness: A replication and update. Health Care Financ Rev. 1985 Fall; 7(1): 61–80.
12. C labaugh G, Ward MM. Cost-of-illness studies in the United States: a systematic review of methodologies used for direct cost. Value
Health. 2008 Jan-Feb;11(1):13-21.
13. Byford S, Torgerson DJ, Raftery J. Economic note: Cost of illness studies. BMJ. 2000 May 13; 320(7245): 1335.
14. Corso, Phaedra S.(2016). Cost of illness: the second of a five-part series. Centers for Disease Control and Prevention. Available from:
https://www.cdc.gov/dhdsp/programs/spha/economic_evaluation/docs/podcast_ii.pdf.
15. Mustonen A. Psoriasis Causes Significant Economic Burden to Patients. Dermatol Ther (Heidelb). 2014 Jun; 4(1): 115–124.
16. Beyer V, Wolverton SE. Recent trends in systemic psoriasis treatment costs. Arch Dermatol.2010;146(1):46–54.
17. Reilly MC, Zbrozek AS, Dukes E. The validity and reproducibility of a work productivity and activity impairment measure.
PharmacoEconomics 1993; 4(5):353-365.
18. G upta S, Isherwood G, Jones K, Van Impe K. Productivity loss and resource utilization, and associated indirect and direct costs in
individuals providing care for adults with schizophrenia in the EU5. Clinicoecon Outcomes Res. 2015 Nov 25;7:593-602.
19. Fabian MAM, Concha MEA. Level of bronchial asthma control and direct medical care costs among adult asthma club members: longitudinal
cost of illness study. SPMC J Health Care Serv. 2015;1(1):25¬30.
20. G lobal Report on Psoriasis. (2016) World Health Organization. Available from https://apps.who.int/iris/bitstream/
handle/10665/204417/9789241565189_eng.pdf.psoriasis;jsessionid=54912784D28C9F36ECCD45471AC5775B?sequence=1. Accessed 24 Mar 2019.
21. Puig L, van de Kerkhof PCM, Reich K, Bachelez H, Barker J, Girolomoni G, Paul C. A European subset analysis from the population-based
Multinational Assessment of Psoriasis and Psoriatic Arthritis shows country-specific features: results from psoriasis patients in Spain. J
Eur Acad Dermatol Venereol. 2017 Jul;31(7):1176-1182.
22. Lynde CW, Poulin Y, Guenther L, Jackson C. The burden of psoriasis in Canada: insights from the psoriasis knowledge in Canada (SKIN)
survey. J Cutan Med Surg. 2009 Sep-Oct;13(5):235-52.
23. S trober B, Greenberg JD, Karki C, Mason M, Guo N, Hur P, Zhao Y, Herrera V, Lin F, Lebwohl M. Impact of psoriasis severity on patient-reported
clinical symptoms, health-related quality of life and work productivity among US patients: real-world data from the Corrona Psoriasis
Registry. BMJ Open. 2019 Apr 20;9(4):e027535.
24. N g JN, Guevara BE, Guillano V. Demographic and clinical profiles of adult Filipino patients with psoriasis in Davao City: A cross sectional
study. J Phil Dermatol Soc. 2018; 27(1): 41-63 Levin AA, Gottlieb AB, Au SC. A comparison of psoriasis drug failure rates and reasons for
discontinuation in biologics vs conventional systemic therapies. J Drugs Dermatol. 2014 Jul;13(7):848-53
25. Poulin Y, Papp KA, Wasel NR, Andrew R, Fraquelli E, Bernstein G, Chan D. A Canadian online survey to evaluate awareness and treatment
satisfaction in individuals with moderate to severe plaque psoriasis. Int J Dermatol. 2010 Dec;49(12):1368-75.
26. R onholt K, Iversen L. Old and new biological therapies for psoriasis. Int J Mol Sci. 2017 Nov; 18(11): 2297.
27. Mahler R, Jackson C, Ijacu H. The burden of psoriasis and barriers to refractory care: Results from a Canadian patient survey. J Cutan Med
Surg. 2009 Nov-Dec;13(6):283-93.
28. B urgos-Pol R, Martinez-Sesmero JM, Ventura-Cerda JM, Elias I, Caloto MT, Casado MA. The Cost of Psoriasis and Psoriatic Arthritis in 5
European Countries: A Systematic Review. Actas Dermosifiliogr. 2016 Sep;107(7):577-90.
29. Yoshimoto T, Oka H, Fujii T, Nagata T, Matsudaira K. The economic burden of lost productivity due to presenteeism caused by health
conditions among workers In Japan. J Occup Environ Med. 2020 Oct; 62(10): 883–888.
30. Collins JJ, Baase CM, Sharda CE, et al. The assessment of chronic health conditions on work performance, absence, and total economic
impact for employers. J Occup Environ Med 2005; 47:547–557.
31. Goetzel RZ, Long SR, Ozminkowski RJ, Hawkins K, Wang S, Lynch W. Health, absence, disability, and presenteeism cost estimates of certain
physical and mental health conditions affecting U.S. employers. J Occup Environ Med 2004; 46:398–412.
32. Iverson D, Lewis KL, Caputi P, Knospe S. The cumulative impact and associated costs of multiple health conditions on employee
productivity. J Occup Environ Med 2010; 52:1206–1211.
33. Tarricone, R. (2006). Cost-of-illness analysis. Health Policy, 77(1), 51–63. doi: 10.1016/j.healthpol.2005.07.016.
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 32
JPDS CASE REPORT
Journal of the Philippine
Dermatological Society
Malignant transformation of multiple adnexal tumors
in a Filipino-American patient with Brooke-Spiegler
Syndrome: a case report
Angelie Therese T. Chua, MD,1 Daisy K. Ismael, MD, FPDS1
ABSTRACT
INTRODUCTION Trichoepithelioma is a benign hamartoma which may exhibit similar clinical and histopathological features with
basal cell carcinoma. Since prognosis is dissimilar, differentiating between them is important. Literature reveals fifteen reports
of malignant transformation of multiple trichoepitheliomas into basal cell carcinoma, with none in the local setting. In Brooke-
Spiegler syndrome, the incidence rate of malignant transformation of benign neoplasms has been reported in 5–10 % of patients.
CASE REPORT A 53-year-old Filipino-American female presented with multiple discrete to coalesced, well-defined, skin-colored
to hyperpigmented, smooth, dome-shaped, rubbery papules and nodules on the face since childhood. Throughout the years,
lesions increased in number and size and spread to the scalp, chest, abdomen, back, upper and posterior right thigh. Some de-
veloped ulceration, telangiectasia and pigmentation.
Chest radiography, radiographs of the jaw, whole abdominal ultrasound, cranial CT scan, ophthalmology and otorhinolaryngology
assessments were normal. Based on clinical and histopathologic findings, the final diagnosis was Brooke-Spiegler syndrome
with transformation into basal cell carcinoma. Carbon dioxide (CO2) laser was used to excise large and ulcerated lesions with
good cosmetic results.
CONCLUSION A case of a Filipino-American adult female diagnosed clinically and histologically with Brooke-Spiegler syndrome with
transformation into basal cell carcinoma was presented. Given the similarities in clinical and histopathologic features of tricho-
epithelioma and basal cell carcinoma, accurate diagnosis should be made because of their difference in prognosis. The use of an
acceptable treatment modality such as carbon dioxide (CO2) laser in this case is an important emerging field of study.
KEYWORDS trichoepithelioma, basal cell carcinoma, Brooke-Spiegler syndrome, malignant transformation, carbon dioxide laser
1Department of Dermatology, INTRODUCTION basal cell carcinoma.
University of Santo Tomas
Hospital, Manila Trichoepitheliomas present as benign symmet- CASE REPORT
rical, skin-colored papules, nodules or tumors
Corresponding author commonly on the face, specifically the nasal area A 53-year-old Filipino-American female present-
Angelie Therese T. Chua, MD and nasolabial folds.1 Malignant transformation ed with multiple asymptomatic papules, nod-
rarely occurs, but there have been reports of bas- ules, and tumors over the face, scalp, neck, back,
Conflict of interest al cell carcinomas arising adjacent to trichoepi- chest, abdomen, upper extremities, and posteri-
None theliomas.2 Treatment has been debated due to or right thigh. Lesions developed at eight years
varied results. of age, initially presenting as few asymptomatic
Source of funding skin-colored papules on the nasal grooves mea-
None This case describes a 53-year-old Filipino suring approximately 0.2x0.2 cm. There was
American female who has presented with multi- gradual increase in size and number of papules,
Cite as ple discrete to coalesced, well-defined, skin-col- some evolving into nodules, which spread to the
Chua ATT, Ismael DK. Malignant ored, smooth, dome-shaped, rubbery papules other areas of the face, scalp, neck, back, chest,
transformation of multiple on the face since childhood. Interval history re- abdomen, upper extremities, and posterior right
adnexal tumors in a Filipino- vealed spread of lesions to the scalp, neck, back, thigh. No consultations were done. One year
American patient with Brooke- chest, abdomen, and extremities. Some of the prior to consultation, some of the facial papules
Spiegler Syndrome: a case lesions evolved into nodules and tumors, which evolved into nodules and tumors. Some of the
report. J Phil Dermatol Soc. developed pigmentation, telangiectasia, and ul- lesions developed telangiectasia, pigmentation,
2022;31(1):33-36. ceration. Biopsies showed trichoepithelioma and
33 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS CASE REPORT
Journal of the Philippine
Dermatological Society
Figure 1. A-C. Multiple discrete to coalesced, well-defined, skin-colored to hyperpigmented, smooth-surfaced, dome-shaped, rubbery papules, nodules, and tumors, some with telangiectasia
and ulceration on the face and D. back.
and ulceration; hence, prompting consultation. Figure 2. Dermoscopy of a A. skin-colored nodule on forehead shows B. small, thin, in-focus
Past medical history was unremarkable. She had a nine arborizing vessels amidst an ill-defined shiny white background, while a C. skin-colored nodule
with hyperpigmented areas and telangiectasia on the right cheek shows D. ill-defined blue-gray
pack-years smoking history. None of her known family mem- ovoid nests, flecks of pigment, and telangiectasia.
bers had similar-looking lesions. She has been working as a
street sweeper for thirteen years and previously as a tricycle trichoepithelioma, while the latter revealed basal cell carcino-
driver for eighteen years. In both occupations, she worked out- ma. BerEP4 staining was negative (Figure 3C) for the trichoepi-
doors for prolonged periods without sun protection. thelioma and positive (Figure 3F) for the basal cell carcinoma.
Physical examination revealed multiple discrete to co- Chest radiography, panoramic radiograph of the jaw, whole
alesced, well-defined, skin-colored to hyperpigmented, smooth, abdominal ultrasound, and cranial CT scan were normal. To
dome-shaped, rubbery papules, nodules, and tumors, some with exclude obstruction on other organs, she was referred for oph-
telangiectasia and ulceration on the face (Figure 1A-C), scalp, thalmologic and otorhinolaryngologic examinations, which
neck, back (Figure 1D), chest, abdomen, upper extremities, and
posterior right thigh. The smallest lesion was on the face (0.5 x
0.8 cm) whereas the largest was on the back (10 x 12 cm).
Dermoscopy of a skin-colored nodule on the forehead (Fig-
ure 2A) revealed thin, arborizing vessels amidst an ill-defined
shiny white background (Figure 2B), features suggestive of
trichoepithelioma. Dermoscopy of a skin-colored nodule with
hyperpigmented areas and telangiectasia on the right cheek
(Figure 2C) revealed ill-defined blue-gray ovoid nests and telan-
giectasia (Figure 2D), features consistent with basal cell carci-
noma.
Histologic examination of a small skin-colored papule re-
vealed tumor islands of basaloid cells with a lacelike pattern,
embedded in a fibrous stroma in the dermis (Figure 3A-B). Mi-
crosections of three pigmented ulcerated nodules and tumors
showed asymmetrical tumors islands of atypical basaloid cells
surrounded by retraction artifacts with focal areas of necrosis,
melanin, and melanophages, that are embedded in a fibromyx-
oid stroma (Figure 3D-E). Findings from the former revealed
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 34
CASE REPORT JPDS
Journal of the Philippine
Dermatological Society
Figure 4. Clinical photos at A. baseline, B. 1 week, C. 3 weeks, and D. 16 weeks post-CO2
laser ablation and debulking of ulcerated and friable pigmented lesions
Figure 3. Histology of a skin-colored papule reveals A. tumor islands of basaloid cells omas, especially in long-standing ones, as well as metastasis,
throughout the dermis (H&E stain; 4x) B. lacelike network of basaloid cells embedded have been reported with unknown exact incidence rates.4 Clini-
in a fibrous stroma (H&E stain; 40x), and C. negative BerEP4 staining (40x); Histology cal signs include pain, bleeding, ulceration, and rapid growth.2,5
of hyperpigmented ulcerated nodules and tumors with telangiectasia reveal D. An In Brooke-Spiegler syndrome, malignant transformation of
asymmetrical tumor containing islands of basaloid cells, with focal areas of necrosis pre-existing benign neoplasms has been reported in 5–10% of
surrounded by retraction artifacts (H&E stain; 10x), E. melanin and melanophages within patients.1 Moreover, cases wherein basal cell carcinoma co-ex-
and around the basaloid cells embedded in a fibromyxoid stroma (H&E stain; 10x), and F. isted in adjacent sites and not on pre-existing trichoepithelio-
positive BerEP4 staining (40x). mas have been reported. These have been considered “collision
tumors” wherein the lesions independently developed in the
revealed normal findings. A final diagnosis of Brooke-Spiegler same location.2
syndrome with transformation into basal cell carcinoma was
given. The pigmented and ulcerated lesions were removed and In our patient, some of the skin-colored papules acquired
debulked using ablative CO2 laser with good healing and cos- pigmentation and ulceration, features not seen in trichoepithe-
metic result (Figure 4A-D). She has undergone a total of four lioma. Biopsies of these lesions revealed basal cell carcinoma.
sessions for subsequent removal of new lesions. She has regular All ulcerated lesions were on the face and none were on sun-pro-
follow-up and monitoring for recurrence and metastasis. tected areas. This suggests that some trichoepitheliomas may
have transformed into basal cell carcinomas with chronic sun
DISCUSSION exposure as the inciting factor.
Trichoepitheliomas present as sporadic, skin-colored papules The study of Zaballos et al. showed that on dermoscopy,
appearing in childhood or early adolescence.1,3,4 When present- trichoepitheliomas exhibit thin, in-focus arborizing vessels,
ing as multiple lesions, genetic syndromes must be considered. shiny white areas, blue-gray dots, and yellowish-brown back-
ground. Basal cell carcinomas show leaf-like areas, blue-gray
Brooke-Spiegler syndrome is a genodermatosis, which ovoid nests, brown pigment, branch-like arborizing telangiecta-
presents with various cutaneous neoplasms including trichoep- sia, and spoke-wheel areas.6 These are consistent with the der-
itheliomas, cylindromas, and spiradenomas commonly on the moscopic findings of our patient.
head and neck.1,5 This is caused by mutations in the CYLD gene
on chromosome 16q12-q13, which codes for CYLD. CYLD inacti- Histologically, trichoepitheliomas appear as symmetrical,
vation results in uncontrolled cellular proliferation and devel- well-circumscribed, dermal tumors composed of basaloid cells
opment of adnexal tumors.5 with peripheral palisading, surrounded by fibrous stroma with
clefts between collagen bundles. Characteristic features in-
Rare cases of malignant transformation of trichoepitheli- clude horn cysts and papillary mesenchymal bodies, but their
35 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS CASE REPORT
Journal of the Philippine
Dermatological Society
absence does not rule out trichoepitheliomas.2,4,7 In our patient, tions include increased recurrence, permanent scarring, hy-
some lesions showed features of trichoepithelioma. However, popigmentation, and atrophy. Non-surgical interventions such
biopsies from ulcerated lesions exhibited islands of atypical as 5% imiquimod cream and tretinoin 1% gel have shown favor-
basaloid cells throughout the dermis and into the subcutis, ar- able results.8,9 However, these are not effective for big lesions
tifactual clefts around the basaloid cells, areas of necrosis, and similar to those in our patient.
scattered melanophages. These are characteristic findings of
basal cell carcinoma and not seen in trichoepithelioma. In our patient, ablative CO2 laser was used because of its
minimal side effects and satisfactory cosmetic outcomes.10 Due
Trichoepitheliomas are CD34+/CK20+/CK15+/PHLDA1+/ to the widespread extent of lesions, excision of all lesions was
BerEP4-, while basal cell carcinomas are BerEP4+/CD34-/CK20-/ impossible and could lead to further disfigurement. Therefore,
CK15-/PHLDA1-. Immunohistochemistry is useful in differenti- our treatment goal was to remove and debulk only the ulcerat-
ating between the two entities, but it can distinguish them in ed and friable pigmented lesions. The patient was satisfied with
only in 36% of cases, thus routine histology with clinical cor- the outcome and has undergone several sessions to remove new
relation is still the diagnostic gold standard.7 Small, skin-col- friable lesions.
ored lesions from our patient were negative for BerEP4, while
large hyperpigmented lesions stained positive for BerEP4. This CONCLUSION
denoted that our patient presented with both trichoepithelio-
mas and basal cell carcinomas. A case of malignant transformation of trichoepitheliomas
into basal cell carcinomas in a Filipino-American female with
Treatment of trichoepitheliomas is not routine because Brooke-Spiegler syndrome was presented. Thorough clinical
they are asymptomatic and benign. However, treatment may be and histopathological assessments are necessary to diagnose
indicated for cosmetic purposes or malignancy. For solitary le- malignant transformation so that appropriate management
sions, the treatment of choice is surgical excision with narrow could be instituted. CO2 laser ablation may be used to remove
margins.8,9 For multiple lesions, treatment modalities include ulcerated lesions with satisfactory cosmetic outcomes. Im-
cryosurgery, chemical cauterization,dermabrasion, and others. pingement of lesions on other organs may lead to complications,
However, they have shown varied results. Potential complica- therefore a multi-disciplinary team is warranted.
REFERENCES
1. Kazakov DV. Brooke-Spiegler Syndrome and Phenotypic Variants: An Update. Head Neck Pathol. 2016 Jun;10(2):125-30. DOI: 10.1007/s12105-016-
0705-x.
2. Greywal T, Rubin AG, Jiang B. A rare presentation of basal cell carcinoma arising within trichoepithelioma: a diagnostic challenge. Cureus.
2019 Aug 16;11(8):e5401. DOI: 10.7759/cureus.5401.
3. Kataria U, Agarwal D, Chhillar D. Familial facial disfigurement in multiple familial trichoepithelioma. J Clin Diagn Res. 2013 Dec;7(12):3008-9. DOI:
10.7860/JCDR/2013/6218.3830.
4. Mapar MA, Ranjbari N, Afshar N, Karimzadeh I, Karimzadeh A. Severely disfiguring multiple familial trichoepitheliomas with basal cell carcinoma.
Indian J Dermatol Venereol Leprol. 2014 Jul-Aug;80(4):349-52. DOI: 10.4103/0378-6323.136924.
5. Parren LJMT, Giehl K, van Geel M, Frank J. Phenotype variability in tumor disorders of the skin appendages associated with mutations in the
CYLD gene. Arch Dermatol Res. 2018 Sep;310(7):599-606. DOI: 10.1007/s00403-018-1848-2.
6. Zaballos P, Gómez-Martín I, Martin JM, Bañuls J. Dermoscopy of adnexal tumors. Dermatol Clin. 2018 Oct;36(4):397-412. DOI: 10.1016/j.
det.2018.05.007.
7. du Toit JP, Schneider JW, Visser WI, Jordaan HF. The clinicopathological spectrum of trichoepitheliomas: a retrospective descriptive study.
Int J Dermatol. 2016 Mar;55(3):270-7. DOI: 10.1111/ijd.12855.
8. Hofmann, L., Kraus, S., Brauns, B. Complex surgical therapy of multiple trichoepitheliomas. J Dtsch Dermatol Ges, 2015 May:13(5):457–459.
DOI:10.1111/ddg.12598.
9. Lopiccolo MC, Sage RJ, Kouba, DJ. Comparing ablative fractionated resurfacing, photodynamic therapy and topical imiquimod in the treatment
of trichoblastomas of Brooke-Spiegler syndrome: a case study. Dermatol Surg, 2011 July:37(7): 1047–1050. DOI:10.1111/j.1524 4725.2011.01907.x.
10. Perlas, MCF, Galang, MC, Gabriel, MT, Castillo, AR. Multiple familial trichoepitheliomas: a disfiguring malady successfully treated with carbon
dioxide laser. J Phil Dermatol Soc. 2017 May:26(1), 82-84.
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 36
JPDS CASE REPORT
Journal of the Philippine
Dermatological Society
Primary cutaneous aggressive epidermotropic
CD8+ T-cell lymphoma in a 76-year-old Filipino Male:
a case report
Katrina M. Canlas-Estrella, MD, DPDS,1 Joshua A. Arcaira, MD, DPDS,1
Filomena Legarda-Montinola, MD, FPDS,1 Teresita E. Dumagay, MD, FPCP2
ABSTRACT
INTRODUCTION Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma (PCAECTCL) is a rare subtype of cutaneous
T-cell lymphoma characterized by widely distributed ulcerated lesions, epidermotropic infiltrates of CD8+ cytotoxic T cells, ag-
gressive course, high tendency to spread to extranodal sites, poor response to conventional therapies and unfavorable prog-
nosis.
CASE REPORT We report a 76-year-old Filipino male presenting with eight-month history of erythematous scaly patches evolving
into widespread ulcerated nodules, unresponsive to topical and systemic steroids. Histopathology revealed prominent epider-
motropism and lichenoid infiltrate of atypical lymphocytes. Immunohistochemistry showed positivity for CD3, CD8, Ki67 (5-15%),
CD7, CD2; indeterminate for TIA-1, with high background staining; and was negative for CD20, CD30, CD4, CD5, CD56, granzyme-B,
TdT, Epstein-Barr encoding region in situ hybridization (EBER-ISH), consistent with PCAECTCL. No overt metastasis was detected.
The patient underwent interferon alfa 2B therapy followed by three full cycles of CHOP chemotherapy. Improvement was seen as
thinning of plaques and nodules and re-epithelialization of ulcers however, severe anemia and leukopenia ensued with therapy.
He then succumbed to septic shock secondary to pneumonia during the height of the COVID-19 pandemic.
CONCLUSION This case emphasizes that despite accurate diagnosis, polychemotherapy, and favorable response to therapy, com-
plications may still arise contributing to the poor prognosis and low five-year survival rate of this condition.
KEYWORDS T-cell lymphoma, CD8 positive, neoplasms
1Department of Dermatology, INTRODUCTION occurring in an elderly Filipino male with posi-
Makati Medical Center, Philippines tive response to chemotherapy, but unfortunate-
2Department of Internal Medicine, Primary cutaneous aggressive epidermotropic ly succumbed to pneumonia at the height of the
Makati Medical Center, Philippines CD8+ T-cell lymphoma (PCAECTCL) is a particu- COVID-19 pandemic.
larly rare type of lymphoma known by its bellig-
Corresponding author erence and poor prognostic outcome.1 The pau- CASE REPORT
Joshua A. Arcaira, MD, DPDS city of cases has led to roadblocks in arriving to
its diagnosis. Lack of established criteria render A 76-year-old Filipino male presented with an
Conflict of interest this condition to be in a provisional non-specified eight-month history of generalized, pruritic
None category of the World Health Organization Euro- erythematous patches and scaling. He had a
pean Organization for Research and Treatment background of colon cancer stage I, status post
Source of funding of Cancer (WHO-EORTC).2 hemicolectomy and re-anastomosis, and famil-
None ial history of breast cancer on the maternal side.
PCAECTCL is more commonly seen among No chemotherapy or radiation was administered
Cite as elderly males presenting as generalized papules, post-surgery. He sought consult with a derma-
Canlas-Estrella KM, Arcaira plaques, and nodules that often erode and ulcer- tologist who initially managed him as a case of
JA, Legarda-Montinola F, ate. Histopathology typically shows prominent exfoliative dermatitis but was unresponsive to
Dumagay TE. Primary cutaneous and nodular to diffuse infiltrates of atypical lym- oral and topical steroids. After three (3) months,
aggressive epidermotropic CD8+ phocytes. Immunohistochemical (IHC) profile patches evolved into plaques and nodules, some
T-cell lymphoma in a 76-year-old demonstrates CD3, CD8, CD7, CD45RA, β-F1, and with ulcerations (Figure 1). Likewise, he devel-
Filipino Male: a case report. J Phil TIA-1.3 It remains to be a therapeutic challenge as oped intermittent fever episodes, loss of appe-
Dermatol Soc. 2022;31(1):37-41. most cases achieve a partial response. tite, and generalized body weakness. No palpa-
In this case report, we present PCAECTCL
37 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS CASE REPORT
Journal of the Philippine
Dermatological Society
Figure 1. A-B. Physical examination revealed multiple darkly erythematous to violaceous nodules topped with hemorrhagic crusted erosions on the face, C. trunk and D. extremities. B. With
the largest nodule measuring about 12x10cm on the right cheek. Multiple erythematous to violaceous patches and scaly plaques on the face, trunk, and extremities were also noted.
ble lymph nodes were detected at this time. A single skin punch Figure 2. Histopathology findings revealed an epidermis showing orthokeratosis,
biopsy was done on a nodule on the back which revealed focal acanthosis, with some focal epidermotropic lymphocytes (A. H&E 40X, B. H&E 400X). The
epidermotropism and a heavy lichenoid infiltrate encompass- entire dermoepidermal junction and papillary dermis showed a heavy lichenoid infiltrate
ing the entire dermoepidermal junction and papillary dermis, of atypical lymphocytes (C. H&E 400X) admixed with melanophages. Patchy lymphocytic
composed of medium to large atypical lymphocytes showing infiltrates were present in the reticular dermis surrounding blood vessels, eccrine ducts (D.
pleiomorphism, hyperchromatic nuclei, prominent nucleoli, H&E 400X) and glands.
and several nucleoli. These atypical infiltrates were also present
in the reticular dermis, surrounding blood vessels and adnex- was started on interferon alfa-2B subcutaneous injections three
al structures. No necrosis nor destruction of vessels or follicles (3) times a week for six (6) doses and was subsequently lost to
was seen. The attending dermatopathologist initially signed out follow-up. Minimal improvement was noted. When he returned
the case as a lymphoproliferative disorder warranting a more for consult, he was then started on CHOP (cyclophosphamide,
in-depth work-up. doxorubicin, vincristine, and prednisone) chemotherapy regi-
men with supportive pegylated-GCSF, with the intention of re-
Further IHC staining showed the following profile: posi- assessing for hematopoietic stem cell transplant or novel agents
tive for CD3, CD8, Ki67 (5-15%), CD7, and CD2; indeterminate for after four (4) cycles. He only tolerated three complete cycles of
TIA-1, with high background staining; negative for CD20, CD30, polychemotherapy even though supportive therapy with filgras-
CD4, CD5, CD56, granzyme-B, TdT, and EBER-ISH (Epstein Barr
encoding region- in situ hybridization). With these, a diagnosis
of primary cutaneous aggressive epidermotropic CD8+ positive
T-cell lymphoma was made. An attempt for staging was done
using computed tomography scans of the head, chest, and abdo-
men which revealed non-calcified pleural and subpleural nod-
ules in both upper lobes and prominent axillary lymph nodes.
Elevated lactate dehydrogenase levels were noted. No suspi-
cious lesions were visualized in the brain or visceral organs.
Due to financial constraints, the patient was not able to pursue
further laboratory work-up such as peripheral blood smear to
detect presence of atypical lymphocytes in the bloodstream,
positron emission tomography (PET) scan to evaluate for pos-
sible extranodal metastasis, or lymph node biopsy to check for
nodal involvement.
The patient was placed on narrowband UVB phototherapy
two (2) to three (3) times a week and managed alongside an on-
cologist. Whilst he was still undecided for chemotherapy, he
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 38
CASE REPORT JPDS
Journal of the Philippine
Dermatological Society
Figure 3. A. During his third chemotherapy session, significant improvement in skin lesions were noted, most remarkably on that of his right cheek that markedly decreased in thickness. B-C.Other
skin lesions on the trunk and extremities have become darkly erythematous and ulcers have begun to re-epithelialize.
tim was given. During his 4th cycle, only vincristine was admin- Diagnosis is established through histopathology , where
istered because of severe anemia and leukopenia. Improvement consistent findings are epidermotropism and nodular to diffuse
of skin lesions was noted described as decrease in size, flatten- dermal infiltrates of pleiomorphic atypical lymphocytes, as was
ing of nodules and plaques, and beginning re-epithelialization seen in our patient’s specimen. Immunohistochemistry shows a
of erosions and ulcers (Figure 3). CD8+/CD4- profile, with positivity for CD3, CD45RA, BF1, TIA-1,
but negative for CD30 and CD45RO.4 Although critical to estab-
Unfortunately, despite promising response to therapy, lish positivity to CD8 with negative CD4 profile, it is important to
the patient’s immunocompromised state predisposed him to note that CD8 positivity alone does not always have prognostic
secondary infections and developed pneumonia. However, as value. Some indolent types of CTCL may be CD8+, like CD8+ pag-
this occurred during the height of the pandemic, he was ini- etoid reticulosis (Ketron-Goodman disease), CD8+ mycosis fun-
tially managed as a case of COVID-19 suspect and eventually goides, and anaplastic large cell lymphoma. The impact of CD8+
succumbed to septic shock secondary to pneumonia in immu- on prognosis can be traced to activation of the TH1 pathway in-
nocompromised host. His COVID-19 RT-PCR result came back volving type I interferons. This has been elucidated in biopsy
negative, albeit post-mortem. specimens of viral infections like herpes simplex, where TH1
response results in increased proliferation and recruitment of
DISCUSSION cytotoxic skin-homing lymphocytes.5 In PCAECTCL, this is the
postulated mechanism to which its aggressive nature comes
Primary cutaneous aggressive epidermotropic CD8+ T-cell from. Our patient noted rapid progression over the course of
lymphoma (PCAECTCL) comprises less than 1% of all cases three months, from erythematous patches evolving into eroded
of CTCL.2 Most are elderly males, manifesting clinically with nodules and tumors, and likewise exhibited the CD8+/CD4- pro-
progressive, widespread ulcerated or crusted papules, patches, file. An increased Ki67 proliferation index (at least 20%) is also
plaques, nodules, and tumors. Evolution of lesions do not typ- seen.2 This index correlates with cells in active mitosis, thus de-
ically follow that of mycosis fungoides (patch, plaque, then tu- noting tumor progression. It is used as a marker of prognosis of
mor stages). Oral involvement is a poor prognostic factor but for several human cancers, including melanomas and lymphomas.6
our patient, he had no mucosal lesions. This condition is classi-
fied as a provisional non-distinct entity by WHO-EORTC due to Epidermotrophic T-cell lymphomas encompass a group of
the rarity and variability in clinical presentation.3
39 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS CASE REPORT
Journal of the Philippine
Dermatological Society
rare atypical lymphoid disorders. The closest differential for cy for metastatic spread.9 Other indicators for higher incidence
our case would be a CD8+ phenotype of generalized pagetoid re- of systemic spread identified were angiocentricity and angio-
ticulosis (Ketron-Goodman disease), but this usually starts as a invasion, expression of CD15, and CD7/CD21 phenotypes.1 Our
solitary patch or plaque on the distal extremities as opposed to patient’s specimen exhibited angiocentricity, which could have
our patient who had a generalized presentation. Despite similar likely contributed to the propensity of spread to the pleura and
histopathology, clinical history as well as testing for CD45RA, lymph nodes.
CD45RO, and T-cell receptor stains can help further delineate
this condition but were unfortunately not available. Primary All new patients diagnosed with cutaneous T-cell lympho-
cutaneous anaplastic T-cell lymphomas may also share sim- ma should be overseen by a multi-disciplinary team of a derma-
ilar histology but are strongly CD30-positive, to which our pa- tologist, oncologist, and pathologist to establish the diagnosis,
tient was not, hence that was ruled out. Extranodal NK/T-cell staging, and management plan, as done with our patient. Ex-
lymphoma is commonly seen on the nose, which is spared in amination should include documentation of skin lesions, care-
our patient, and is strongly positive to CD2, CD56, and negative ful palpation of lymph nodes and abdomen to check for visceral
for CD3. Our patient was positive for CD2, but was negative for masses or hepatosplenomegaly. Laboratory work-up should in-
CD56 and conversely positive for CD3, ruling this condition out. clude a complete blood count, CD4/CD8 ratio, check for Sezary
Furthermore, this condition is strongly positive for EBV in situ cells, liver function tests, lactate dehydrogenase, serum urea,
hybridization, which was found to be negative in our patient. electrolytes, computed tomography of chest, abdomen, and
Cutaneous γ/δ (gamma delta)-T cell lymphoma is an aggressive pelvis for staging, lymph node biopsy (if with clinically palpa-
disorder presenting with plaques and tumors on the trunk and ble lymph nodes), and bone marrow aspiration.10 Repeat exam-
upper extremities. It may appear histologically similar to prima- inations may be done if disease progression is suspected. The
ry cutaneous aggressive CD8+ T-cell lymphoma but IHC stains patient is at least T3 since he presented with tumors already,
for this condition would be positive for CD3, CD2, and CD56, although no clinically apparent lymph nodes were palpated on
and negative for CD4 and CD8. Our patient was positive for CD3, physical examination, prominent axillary nodes were seen on
CD2, CD8, and negative for CD56 and CD4, hence that was ruled computed tomography. Due to financial constraints, patient was
out. Ideally, GM3 and TCR-β-F1 immunostains would be positive not able to pursue further laboratory work-up such as peripher-
for this condition but was not available for our patient.7 al blood smear to detect presence of atypical lymphocytes in the
bloodstream, positron emission tomography (PET) scan to eval-
Accurate histopathologic correlation is needed to deter- uate for possible extranodal metastasis, or lymph node biopsy
mine clinical course and response to therapy. To date, there is to check for spread. Multiple skin biopsies can increase chances
no single criterion that is pathognomonic alone for PCAECTCL.3 of clinching the diagnosis, as well as an ellipse or incisional bi-
Submission of multiple simultaneous biopsies from individual opsy, to allow more tissue for examination and immunohisto-
patients can enhance diagnostic accuracy.8 Since our patient chemistry.
initially presented in an erythrodermic state, a biopsy may have
not yet revealed clues towards the diagnosis of lymphoma. In- Although the reported cases of PCAECTCL are few, the
terpretation of biopsy specimens from erythrodermic patients overall prognosis is quite poor, where only 7 of 45 were alive
poses a challenge for pathologists because the microscopic on their latest follow-up.1 An average 5-year survival rate of 18%
manifestations of the underlying condition are subtle. Patients was noted by European cutaneous lymphoma groups.2 Poorer
in erythroderma may have lesions in varying degrees of evolu- outcomes were attributed to rapid metastasis, lower response
tion, timing of doing the biopsy as well as careful selection of rate to chemotherapy, and higher tendency to relapse.
biopsy site and representative lesion are paramount in getting
the highest yield in histopathology. Primary cutaneous aggressive epidermotropic CD8+ T-cell
lymphoma (PCAECTCL) is a persistent therapeutic challenge
PCAECTCL has an increased tendency for systemic spread due to scarcity of reported cases and lack of large randomized
to extracutaneous sites such as the central nervous system, trials. These are indispensable in evaluating various treatment
lungs, and testes. Lymph nodes are usually spared in contrast to regimens, specifically their long-term efficacy. Conventional
classic mycosis fungoides.3 Cases presenting with disseminated therapies for classical CD4+ CTCL are usually ineffective for
ulcerated plaques and nodules at the onset and rapid progres- PCAECTCL (such as topical steroids, UVB, PUVA, local radio-
sion over time has been associated with metastatic spread. Our therapy, and interferon alfa) as these most often target the TH2
patient presented with an already widespread involvement at phenotype. With the paucity of guidelines, the most commonly
the time of consult, and on computed tomography showed sub- used treatment options are adapted from lymphoma protocols,
pleural nodules and prominent axillary nodes which may allude involving polychemotherapy with six (6) to eight (8) courses of
to beginning metastatic spread. Furthermore, it was suggested CHOP or hyper-CVAD (hyper-cyclophosphamide, vincristine,
that patients with CD56 positivity is linked to increased tenden- doxorubicin, and dexamethasone), however, results are unsat-
isfactory and are associated with rapid recurrence.8 The CHOP
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 40
CASE REPORT JPDS
Journal of the Philippine
Dermatological Society
regimen was noted to produce clinical remission in 38% of who received stem cell transplantation following polychemo-
patients with a median response duration of 5 to 41 months.11 therapy, the overall survival rate among patients who received
Our patient was only able to tolerate three (3) complete cycles any type of transplantation (bone marrow or peripheral blood
of CHOP, with the fourth being solely vincristine due to severe origins) was 55.6% at a median follow-up of 24 months.15 Our
immunosuppression. Although there was improvement noted patient was planned to undergo allogenic stem cell transplant
as decrease in redness and thickness of the lesions, he devel- depending on response to his course of polychemotherapy, how-
oped secondary bacterial pneumonia which led to his demise. A ever, he did not survive long enough for reassessment.
favorable response was noted by Gormley (2010) in their patient
who received hyper-CVAD, who just after two (2) cycles achieved CONCLUSION
a dramatic response. After the sixth cycle, the patient was clear
of lesions.12 However, definite conclusions need further evaluation Primary cutaneous aggressive epidermotropic cutaneous T-cell
of efficacy, specifically for long-term remission and 5-year cure lymphoma (PCAECTCL) remains to be a diagnostic and thera-
rates.13 Novel therapies are promising and deliver variable results. A peutic challenge. Early detection and accurate diagnosis are
report by Cyrenne (2017) showed long-term remission in a refracto- key players to attain the best possible outcome for an already
ry case after receiving brentuximab vedotin. This agent is a mono- poorly responsive disease. This case proves that despite accu-
clonal antibody against CD30 antigen and is being explored for cas- rate diagnosis and favorable response to chemotherapy , there
es that fail to respond to conventional therapy. Response rates vary is still a fine line being trudged by both the patient and medical
from 41-56% depending on the CD30 positivity.14 team in providing the appropriate treatment amidst possible
complications. Overall, there are more questions still left unan-
Autologous stem cell transplantation is another promising swered with this debilitating, aggressive, and poorly responsive
treatment option explored for PCAECTCL. In a series of patients disease.
REFERENCES
1. Nofal A, Abdel-Mawla MY, Assaf M, Salah E. (2012). Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: proposed diagnostic criteria
and therapeutic evaluation. J Am Acad Dermatol. 67:748–59.
2. Willemze, R., Cerroni, L., Kempf, W., Berti, E., Facchetti, F., Swerdlow, S. H., & Jaffe, E. S. (2019). The 2018 update of the WHO-EORTC classification for pri-
mary cutaneous lymphomas. Blood, blood–2018–11–881268.
3. Burg G, Kempf W, Cozzio A, Feit J, Willemze R, Jaffe E, Dummer R, Berti E, Cerroni L, Chimenti S, Diaz-Perez J, Grange F, Harris N, Kazakov D, Kerl H, Kurrer
M, Knobler R, Meijer C, Pimpinelli N & Whittaker S. (2005). WHO/EORTC classification of cutaneous lymphomas 2005: histological and molecular aspects.
J Cutan Pathol 32; 647-74.
4. Robson A, Assaf C, Bagot M, Burg G, Calonje E, Castillo C, Cerroni L, Chimenti N, Dechelotte P, Franck F, Geerts M, Gellrich S, Goodlad J, Kempf W, Knobler
R, Massone C, Meijer C, Ortiz P, Petrella T, Pimpinelli N, Roewert J, Russell-Jones R, Santucci M, Steinhoff M, Sterry W, Wechsler J, Whittaker S, Willemze R,
Berti E. (2015). Aggressive epidermotropic cutaneous CD8+ lymphoma: a cutaneous lymphoma with distinct clinical and pathological features. Report
of an EORTC Cutaneous Lymphoma Task Force Workshop. Histopathology. 67(4):425-41. doi: 10.1111/his.12371. Epub 2015 Feb 24.
5. Gormley, RH, Hess, SD, Anand D, Junkins-Hopkins, J, Rook, AH, Kim EJ. (2010). Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. J
Am Acad Dermatol. 62:300-7.
6. Ma, X, Wu, Y, Zhang, T, Song, H, Jv, H, Guo, W, Ren G (2017). Ki67 Proliferation Index as a Histopathological Predictive and Prognostic Parameter of Oral
Mucosal Melanoma in Patients without Distant Metastases. Journal of Cancer, 8(18), 3828-3837.
7. Raghavan, SS & Kim, J. (2018). Histopathologic approach to epidermotropic lymphocytic infiltrates. Clin Cutan Med Surg 37:56-60.
8. Walsh, N. M. G., Prokopetz, R., Tron, V. A., Sawyer, D. M., Kevin Walters, A., Murray, S., & Zip, C. (1994). Histopathology in erythroderma: review of a series of
cases by multiple observers. Journal of Cutaneous Pathology, 21(5), 419–423.
9. Santucci M, Pimpinelli N, Massi D, Kadin ME, Meijer CJ, Muller-Hermelink HK, et al. Cytotoxic/natural killer cell cutaneous lymphomas: report of EORTC
cutaneous lymphoma task force workshop. Cancer 2003;97:610-27.
10. Berti E, Tomasini D, Vermeer MH, Meijer CJ, Alessi E, Willemze R. (1999). Primary cutaneous CD8-positive epidermotropic cytotoxic T-cell lymphomas: a
distinct clinicopathological entity with an aggressive clinical behavior. Am J Pathol 1999; 155:483-492.
11. Scarisbrick, J. J. (2006). Staging and management of cutaneous T-cell lymphoma. Clinical and Experimental Dermatology, 31(2), 181-186.
12. Gormley, RH, Hess, SD, Anand D, Junkins-Hopkins, J, Rook, AH, Kim EJ. (2010). Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma. J
Am Acad Dermatol. 62:300-7.
13. Nofal, A, Abdel-Mawla, MY, Assaf, M, Salah, E, Abd-Elazim, H. (2014). Primary cutaneous aggressive epidermotropic CD8+ T cell lymphoma: a diagnostic
and therapeutic challenge. Int J Dermatol; 53:76-81.
14. Cyrenne, BM, Subtil A, Girardi, M, Foss, F. (2017). Primary cutaneous aggressive epidermotropic cytotoxic CD8+ T-cell lymphoma: long-term remission
after brentuximab vedotin. Int J Dermatol, 56(12), 1448-1450.
15. Cyrenne, BM, Gibson, JF, Subtil, A, Girardi, M, Isufi, I, Seropian, S, Foss, F. (2018). Transplantation in the Treatment of Primary Cutaneous Aggressive Epi-
dermotropic Cyotoxic CD8-positive T-cell Lymphoma. Clinical Lymphoma, Myeloma, & Leukemia, 18(1), e85-e93.
41 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
JPDS CASE REPORT
Journal of the Philippine
Dermatological Society
Topical sirolimus for the treatment of angiofibromas
in a child with tuberous sclerosis complex:
first reported case in the Philippines
Angela M. Esguerra, MD, FPDS,1 Jarische Frances S. Lao-Ang, MD, DPDS1
ABSTRACT
INTRODUCTION Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disorder causing a mutation in the
tumor suppressor genes, TSC1 or TSC2. Loss of function of these genes leads to dysfunction of hamartin and tuberin, resulting
in hamartoma formation. It usually manifests with cutaneous manifestations at childhood. However, it also affects other organ
systems. Based on the Philippine Dermatological Society Health Information System census, there have been 104 cases of TSC
from 2011-2018. Currently, limited data is available regarding the treatment options in the local setting.
CASE REPORT The case involves a 4 year-old boy, with a two year history of flesh-colored to dusky red firm papules on the cen-
trofacial areas and neck. Lesions have been increasing in number since first appearance. He had a normal birth history. Family
history was insignificant. However, delay in expressive speech development was noted. Physical examination revealed multiple
well-defined angiofibromas on centrofacial areas and neck; fibrous cephalic plaque on the left temporal area, and several ash-
leaf spots on the trunk. Periungual and subungual fibromas, confetti macules, shagreen patch and dental pits were absent.
Based on the clinical manifestations, he was diagnosed with TSC. Histopathology of a papule on the chin was consistent with
angiofibroma.
Parents were concerned with the appearance of the lesions and preferred conservative management. Hence, topical sirolimus
0.2% ointment was applied once daily on the angiofibromas for 4 months. Monthly follow-up showed marked improvement, mani-
fested by the decrease in number and by flattening of the lesions.
CONCLUSION To the best of our knowledge, this is the first case report of successful treatment of topical sirolimus for TSC in the
Philippines.
KEYWORDS tuberous sclerosis complex, topical, treatment success, conservative management, hematoma
1Department of Dermatology, St. INTRODUCTION ifestations include ash leaf spots characterized
Luke’s Medical Center, Quezon City as oval-shaped hypopigmented patches, which
Tuberous sclerosis complex (TSC) is a rare geno- were apparent at birth on the lower back and
Corresponding author dermatosis with autosomal dominant inheri- buttocks. He also had a fibrous cephalic plaque,
Jarische Frances S. Lao-Ang, MD, tance. It involves dysfunction of hamartin and soft and flesh-colored, measuring 0.8 x 0.8 cm on
DPDS tuberin secondary to mutation of the TSC1 and the left temporal area. Periungal and subungual
TSC2 gene respectively. Most patients are diag- fibromas, confetti macules, shagreen patch and
Conflict of interest nosed before or at 15 months of age, but adults dental pits were not evident. He had one episode
None can also be affected.1 Dermatologic manifes- of benign febrile seizure when he was 11 months
tations are the usual initial clinical signs. The old, but there was no recurrence. No family
Source of funding lesions in TSC are most often managed through members manifested the same lesions.
None procedures. However, there are emerging topical
management options as well. Based on the 2012 International TSC Guide-
Cite as lines1 patient had definite TSC given that he ful-
Esguerra AM, Lao-Ang JFS. CASE REPORT filled 2 major clinical criteria (presence of angio-
Topical sirolimus for the treatment fibromas or fibrous cephalic plaque and presence
of angiofibromas in a child with The patient is a 4 year-old Filipino male, with a of hypopigmented macules). The skin punch
tuberous sclerosis complex: first 2 year history of firm dusky red to skin-colored biopsy of the papule on the chin was consistent
reported case in the Philippines. J papules on centrofacial areas. Lesions gradually with angiofibromas as well, further supporting
Phil Dermatol Soc. 2022;31(1):42- increased in size and in number, eventually ap- the diagnosis.
45. pearing on the neck. Other significant skin man-
J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 42
CASE REPORT JPDS
Journal of the Philippine
Dermatological Society
Due to an increase in facial angiofibromas, he underwent zure. It presents as infantile spasms with a peak age of 3-7
electrocautery on some facial lesions. However, parents report- months. In the case, the patient had one episode of febrile sei-
ed scar formation and recurrence of lesions.
Figure 1. Skin punch biopsy (H&E x40) A. Epidermis focal parakeratosis overlying basket
At the initial visit to the pediatric dermatologist, he was re- weave stratum corneum, scant spongiosis B. Concentric perivascular and periadnexal
ferred to pediatric neurology, neurodevelopmental service and fibrosis with stellate fibroblasts.
ophthalmology for baseline assessment. Ophthalmologic work-
up revealed normal visual acuity and absence of retinal hamar-
toma. As for neurodevelopmental service, he had normal cogni-
tive development but was noted to have expressive speech delay.
Since parents were concerned with disfigurement, they
opted for conservative management of the angiofibromas. He
underwent 4-month therapy of topical sirolimus 0.2% ointment
applied once daily on the lesions. Slight stinging was noted after
application. Otherwise, there were no other adverse reactions.
Monthly follow-up showed satisfactory results in terms of flat-
tening and of decrease in number.
DISCUSSION
TSC is an autosomal dominant genodermatosis with hamarto-
matous tumors in multiple organ systems. It affects 1 per 6000
to 1000 live births with no gender predilection. Based on the
Philippine Dermatological Society Health Information System
census, there have been 104 cases of TSC from 2011-2018.2
Eighty percent of cases exhibit de novo mutation involving
TSC2 gene encoding tuberin protein while 20% exhibit familial
mutation involving TSC1 gene encoding hamartin protein. The
normal function of the hamartin - tuberin complex is to inhib-
it mTOR signaling cascade, that regulates cell proliferation. In
patients with TSC, mutations lead to a loss of this inhibition,
resulting in upregulation in the mTOR pathway. This increases
cell proliferation, including vascular endothelial growth factors
(VEGF). Ultimately, hamartoma formation is the end result.4 For
the case, the patient has de novo mutation since no one in the
family has the same clinical presentation.
A detailed skin examination is warranted. Lesions usual-
ly start with hypopigmented macules at birth followed by ap-
pearance of facial angiofibromas and shagreen patch at toddler
age, then periungual fibromas at adolescence. This is consistent
with the sequence of appearance of the patient’s lesions.
Based on the recent international TSC consensus,1 TSC can
be diagnosed clinically. A definite diagnosis is fulfilled if the pa-
tient has either a positive genetic mutation or 2 major clinical
features or 1 major and 2 or more minor features. For the case,
the patient has definite TSC since he has 2 major clinical criteria
(presence of angiofibromas or fibrous cephalic plaque and pres-
ence of hypopigmented macules). Skin punch biopsy, though
not required, can be done to further justify TSC. In this case,
histopathologic finding on the chin’s papule was consistent with
angiofibroma (Figure 1).
Since the patient has definite TSC, a multidisciplinary man-
agement is essential since other organ systems can be affected.6
In 79%-90%, the earliest neurologic manifestation is sei-
43 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X
The words you are searching are inside this book. To get more targeted content, please make full-text search by clicking here.
JPDS MAY 2022_A
Discover the best professional documents and content resources in AnyFlip Document Base.
Search