JPDS MAY 2022_A

JPDS CASE REPORT
Journal of the Philippine
Dermatological Society

Table 1. Monitoring of tuberous sclerosis1

Organ System Diagnostic
Skin, and eye Detailed physical exam
Brain Brain MRI ± contrasts, EEG
Heart ECG ; 2D echo

Kidneys Kidney function with GFR, Renal ultrasound

Lungs Pulmonary function test (adults with dyspnea)

zure at 11 months, with no recurrence after. It was assessed as Figure 2. From left to right. Response of patient’s angiofibromas after application of
a benign febrile seizure. Upon current consultation, he was re- topical sirolimus: baseline; at 4 weeks; at 12 weeks and at 16 weeks.
ferred to neurology and neurodevelopment services. Clinically,
he has a normal nervous system. Monitoring is recommended giogenesis by decreasing vascular endothelial growth factors.
by doing baseline electroencephalogram or magnetic reso- There have been numerous reports on the successful use of si-
nance imaging to check for cortical tubers.5 rolimus for angiofibromas in TS. History began in 2008 when
oral sirolimus was given to prevent kidney rejection in a patient
As for the renal system, the most common findings are with TS, who also exhibited improvement of his angiofibromas.
renal cysts in 45% and angiomyolipomas in 80%. These lesions This was followed by formulation of the first topical sirolimus
are benign but are the usual cause of TSC-related mortality due in 2010 showing the same results.9 Based on review of literature,
to renal hemorrhage and renal failure. These can be evaluated topical sirolimus has better response rate in younger patients.
by ultrasonography of the renal system. As for the cardiac sys- Remarkable results were evident by the significant decrease in
tem, the usual lesion is cardiac rhabdomyoma in at least 50% of lesion number and in erythema.
newborns. However, this is detected on prenatal ultrasound. As
for the case, he had a normal prenatal and birth history. Given Since there has been no standardized concentration for
the multiorgan system involvement in TSC, close monitoring is topical sirolimus, a randomized controlled trial was done in Ja-
essential. The international TSC consensus has published the pan to determine the most effective concentration. The study
recommended surveillance and monitoring guideline as listed compared three different sirolimus concentrations (0.05%, 0.1%
in Table 1.1 and 0.2% gel). The result from the trial revealed that the 0.2%
sirolimus was the most optimal concentration.10 The reported
In this case, the major concern was the cosmetic impact of side effect was just local irritation on the application site. Among
the angiofibromas. Various treatment options are available but all reported cases, sirolimus had below level of detection in the
there is still no gold standard at the moment. Based on available blood. Hence, it had minimal systemic absorption.10
literature, physical treatment, laser therapy and topical therapy
have been reported.6 For the case, the patient’s parents agreed to use topical si-
rolimus 0.2% ointment, which was applied once a day over facial
Electrocoagulation is most commonly done. Other physi- angiofibromas. It was compounded by a local pharmacist using
cal therapy includes cryotherapy and radiofrequency ablation. crushed sirolimus tablets incorporated in dimethicone-based
However, the abovementioned physical treatment can lead to ointment. After 16 weeks of therapy, significant improvement
post-inflammatory hyperpigmentation, scar formation and re-
currence. Also, multiple sessions may be required to achieve
favorable results. In the case, the patient had a previous electro-
coagulation session that led to scar formation and recurrence.

With the advent of laser, it was used for its ablative func-
tion in managing angiofibromas. Use of carbon dioxide, and
pulsed dye laser leads to excellent results.7,8 However, scarring
and hyperpigmentation are also the major drawbacks.

Hence, topical therapy offers novel management to facial
angiofibromas. The most recent development is the use of top-
ical sirolimus (also known as rapamycin) which is an mTOR
inhibitor.9 It is a macrolide, originally intended to be used as
an antifungal. Its mechanism in angiofibromas is to regulate
the abnormal increase in mTOR signaling. Also, it inhibits an-

J Phil Dermatol Soc · May 2022 · ISSN 2094-201X 44

CASE REPORT JPDS
Journal of the Philippine
Dermatological Society

was noted. Decrease in the size of the angiofibroma and of the CONCLUSION
cephalic plaque on the left temporal area was noted. However,
scar from the previous electrocurettage did not respond to siro- TSC is a progressive disease. Disease severity varies among indi-
limus (Figure 2). Patient had occasional stinging on the appli- viduals. For the case, the patient has limited cutaneous disease
cation site. No other side effects were noted. Hence, from this hence the prognosis is favorable. Also, the use of topical siroli-
case, topical sirolimus has proven to be an effective treatment mus serves as a treatment option for patients seeking conser-
in improving facial angiofibromas of TSC. vative management. There has been no long-term known com-
plication from its use. This serves to be the first case report in
Recurrence rate upon discontinuation is high and can the Philippines to successfully manage facial angiofibromas in
reach 100%,10 thus many patients are maintained in this med- TSC with topical sirolimus in the best knowledge of the authors.
ication. The longest reported use was at 3 years, with good re- Despite clinical improvement of the facial angiofibromas, the
sponse and no side effects. patient is monitored in a multisystem approach regularly.

REFERENCES

1. Northrup H, Krueger DA; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update:
recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013 Oct;49(4):243-54. DOI:
10.1016/j.pediatrneurol.2013.08.001.

2. Philippine Dermatological Society Health Information System Census 2011-2018.
3. Randle SC. Tuberous Sclerosis Complex: A Review. Pediatr Ann. 2017 Apr 1;46(4):e166-e171. DOI: 10.3928/19382359-20170320-01.
4. Franz DN, Capal JK. mTOR inhibitors in the pharmacologic management of tuberous sclerosis complex and their potential role in other rare

neurodevelopmental disorders. Orphanet J Rare Dis. 2017 Mar 14;12(1):51. DOI: 10.1186/s13023-017-0596-2.
5. Krueger DA, Northrup H; International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and

management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013
Oct;49(4):255-65. DOI: 10.1016/j.pediatrneurol.2013.08.002.
6. Salido-Vallejo R, Garnacho-Saucedo G, Moreno-Giménez JC. Current options for the treatment of facial angiofibromas. Actas Dermosifiliogr.
2014 Jul-Aug;105(6):558-68. English, Spanish. DOI: 10.1016/j.ad.2012.11.020.
7. Sabido, P. E., Ortiz-Policarpio, B. , & Ortiz, J. L.(2013).Tuberous sclerosis complex in a 33-year-old Filipino male: Focus on dermatologic
manifestations and carbon dioxide laser ablation of facial angiofibromas. Journal of the Philippine Dermatological Society, 22(2), 55-59.
8. Papadavid E, Markey A, Bellaney G, Walker NP. Carbon dioxide and pulsed dye laser treatment of angiofibromas in 29 patients with tuberous
sclerosis. Br J Dermatol. 2002 Aug;147(2):337-42. DOI: 10.1046/j.1365-2133.2002.04968.x.
9. Haemel AK, O'Brian AL, Teng JM. Topical rapamycin: a novel approach to facial angiofibromas in tuberous sclerosis. Arch Dermatol. 2010
Jul;146(7):715-8. DOI: 10.1001/archdermatol.2010.125.
10. Wataya-Kaneda M, Nakamura A, Tanaka M, Hayashi M, Matsumoto S, Yamamoto K, Katayama I. Efficacy and Safety of Topical Sirolimus Therapy
for Facial Angiofibromas in the Tuberous Sclerosis Complex : A Randomized Clinical Trial. JAMA Dermatol. 2017 Jan 1;153(1):39-48. DOI: 10.1001/
jamadermatol.2016.3545.

45 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X

JPDS CASE REPORT
Journal of the Philippine
Dermatological Society

Subungual squamous cell carcinoma of the great toe
presenting as a pyogenic granuloma-like mass in a
64-year-old Filipino male: a case report

Sher Claranza O. Liquido, MD,1 Bernice C. Navarro, MD, FPSGS, FPCS,2,3
Tanya Angela Perez Chua, MD, FPDS,1 Mae Ramirez Quizon, MD, FPDS,1,4,5

ABSTRACT

INTRODUCTION Subungual squamous cell carcinoma is rare, though it is the most common primary malignant neoplasm in the
nail unit. Fingernails are more commonly involved than toenails with nonspecific and mild features. Histopathologic presentation
may be difficult to distinguish from other tumors. With this, there is often a delay in diagnosis.

CASE REPORT A 64-year-old male presented with a subungual yellowish granulomatous plaque, eventual dystrophy, and per-
sistent bleeding on the first digit of the right foot of two years’ duration. Initially diagnosed as pyogenic granuloma through skin
punch biopsy, debridement with ungiectomy was done. Upon recurrence, he underwent wide excision with matricectomy, where-
in deeper sections revealed features of basosquamous carcinoma. A positive Epithelial Membrane Antigen and negative BerEP4
staining later confirmed a diagnosis of SCC. Since bone involvement was repeatedly suspected in magnetic resonance imaging
after postoperative radiotherapy, amputation was eventually done.

CONCLUSION We report a case of subungual SCC initially diagnosed as a pyogenic granuloma. Full-thickness biopsy should be done
in persistent nail conditions using special stains to confirm the diagnosis. Surgical treatment or radiotherapy with or without sys-
temic therapy is the first line of treatment for subungual SCC. In cases of bone involvement, amputation may be warranted.

KEYWORDS nail, pyogenic granuloma, squamous cell carcinoma, tumor

1Department of Dermatology, St. INTRODUCTION and was given an oral antibiotic and a topical
Luke’s Medical Center, Quezon antifungal in the form of amorolfine lacquer. Ini-
City and Taguig City Squamous cell carcinoma (SCC) is rare, though it tially, there was an improvement with a decrease
2Institute of Surgery, St. Luke’s is the most common primary malignant neoplasm in discoloration. However, spontaneous bleeding
Medical Center Global City, of the nail unit.1 Fingernails are usually involved recurred. The patient tried applying different
Taguig City and less often toenails with nonspecific and mild solutions composed of benzoic acid with salicylic
3Department of Surgery, Rizal clinical features.2 Histopathologic presentation acid, oak bark extract, essential oils, herbs, and
Medical Center, Pasig City may also be difficult to distinguish from other tea tree oil on top of amorolfine. Despite sting-
4Department of Dermatology, tumors. With this, there is often a delay in the ing pain with every application, he continued for
University of the Philippines- diagnosis.1 two months until he noted edema and erythema
Philippine General Hospital, in the periungual skin, nail dystrophy and loss of
Manila We describe a case of subungual SCC in a middle and distal portion of the nail plate expos-
5Department of Dermatology, Rizal 64-year-old Filipino male, initially presenting as ing a granulomatous nail bed.
Medical Center, Pasig City a pyogenic granuloma on punch biopsy. Later, a
wedge resection biopsy was performed, which The patient was hypertensive, dyslipidemic,
Corresponding author revealed an invasive basosquamous carcinoma. and diabetic, with a family history of leukemia
Sher Claranza O. Liquido, MD Immunohistochemical staining confirmed an on the maternal side. He was a retired military
invasive subungual squamous cell carcinoma. personnel with significant sun exposure, howev-
Conflict of interest er, he denied persistent trauma in the area affect-
None CASE REPORT ed.

Source of funding A 64-year-old male initially presented with yel- A diagnosis of pyogenic granuloma was ini-
None lowish nail discoloration and onycholysis on the tially made, for which he underwent one session
first digit of the right foot of two years duration. of pulsed dye laser (PDL). However, the proce-
Cite as He noted spontaneous bleeding in the area a few dure was discontinued due to intense pain with
Liquido SCO, Navarro BC, Chua months later, hence consulted a dermatologist
TAP, Quizon MR. Subungual
squamous cell carcinoma of
the great toe presenting as a
pyogenic granuloma-like mass
in a 64-year-old Filipino male: a
case report. J Phil Dermatol Soc.
2022;31(1):46-49.

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CASE REPORT JPDS
Journal of the Philippine
Dermatological Society

minimal improvement. A 4-mm skin punch biopsy was then ment of the osseous structure in the terminal phalanx of the
done wherein routine hematoxylin and eosin (H&E) stain re- first digit on the right foot, which was reported to represent a
vealed ectatic blood vessels surrounded by dense lymphohis- neoplastic process with possible osseous infiltration. Howev-
tiocytic and plasma cell infiltrate, supporting the diagnosis of er, as the effect of radiotherapy was expected to extend to two
a pyogenic granuloma. At this point, the lesion presented as a months beyond the last radiotherapy session, a repeat MRI was
well-defined erythematous fleshy plaque with some areas of scheduled. Two months post-radiotherapy, there was neither re-
granulation tissue and discolored dystrophic nail on the distal currence of the fleshy mass, nor pain and bleeding in the affect-
portion of the right great toenail (Figure 1). Unguiectomy and ed digit (Figure 4). Popliteal and inguinal lymphadenopathies
debridement of the nail bed were done. Two weeks later, the le- were not palpable. On repeat MRI, there was regression of the
sion recurred with a further increase in size, pain, and associat- previously noted enhancement; however, there was a develop-
ed bleeding. A wider excision with matricectomy was then done ment of bone marrow edema with minimal enhancement on the
wherein H&E stain initially revealed an invasive basosquamous first digit of the right foot ascribed to a neoplastic process. Due
carcinoma - enlarged atypical basaloid cells in the dermis with to persistent possible osseous involvement on repeat MRI two
peripheral palisading and retraction artefact. Deeper sections months post-radiotherapy, the patient underwent amputation of
showed eosinophilic tumor nests of moderately differentiated the distal phalanx of the right great toe. Histopathologic assess-
keratinocytes with hyperchromatism and nuclear atypia (Fig- ment of the amputated specimen showed clearance of residual
ure 2). Immunohistochemical staining revealed positive Epithe- carcinoma, with chronic inflammation and chronic granulation
lial Membrane Antigen (EMA) (Figure 3) and negative BerEP4, tissue formation.
which confirmed invasive squamous cell carcinoma of the sub-
ungual unit. Work-up for metastases was unremarkable. DISCUSSION

Since the nail unit is a high-risk area, the patient under- Subungual SCC presents with mild nonspecific symptoms and
went postoperative adjuvant radiotherapy, receiving a total tu- an indolent course that is usually misdiagnosed and disregard-
mor dose of 6,000 cGy for 30 days. Two weeks post-radiotherapy, ed. It can present as pain, destruction, or discoloration of the
there was a recurrence of the fleshy plaque on the affected digit. nail plate, hyperkeratosis, erythema, ulceration, periungual or
Magnetic resonance imaging (MRI) showed subtle enhance- subungual mass, or paronychia. In an article by Dijksterhuis

Figure 1. Fleshy plaque with some areas of granulation tissue, and central nail loss and Figure 2. Wide Excision with Matricectomy showing enlarged atypical basaloid cells in the
discoloration of the remaining nail on the periphery of the right great toenail. dermis with peripheral palisading and retraction artefact (H&E: 100x). Inset: Eosinophilic
tumor nests with hyperchromatism and nuclear atypia (yellow arrow) (H&E: 400x).

47 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X

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Journal of the Philippine
Dermatological Society

Figure 3. Positive immunohistochemical staining of the tumor nests (EMA: 40x). Figure 4. No pain, bleeding, or recurrence of the fleshy mass two months post-radiotherapy.

et al. (2018), all 304 cases of SCC in the nail unit reviewed were none of SCC, allowing the separation of the two tumor types.7
initially misdiagnosed before a proper diagnosis was made. It BerEP4 also marks the basaloid component of BSC, allowing the
was misdiagnosed as a chronic infection at 42% and as verruca visualization of a transition zone. On the other hand, EMA labels
vulgaris in 28% of cases.3 In light of its varied clinical manifes- 85-100% of SCC cases and only 2-8% of BCC cases.[8] In our case,
tations, a high index of suspicion and a low threshold for histo- as the specimen from the wide excision and matricectomy was
pathologic examination are vital for making an early diagnosis.4 negative for BerEP4 but positive for EMA (Figure 3), it confirmed
Biopsy techniques for SCC of the nail unit include punch, shave, a squamous cell carcinoma. Accurate determination of the type
and excisional biopsy. Size and depth of the specimen should be of tumor is essential for management, prognostication, and
adequate to provide information that will guide diagnosis and monitoring as tumors have different modes of behavior and
appropriate therapy, such as in aggressive growth patterns.5 metastatic potential.7

In our case, wide excision and matricectomy provided suffi- According to the National Comprehensive Cancer Network
cient specimens for diagnosing malignancy in the deeper sections. (NCCN) guidelines of 2018 which was the most recent available
guideline in place during diagnosis and treatment of the case,
In histopathology, SCC usually consists of nests of cells with localized SCC treatment depends on whether the case is low-
abundant eosinophilic cytoplasm with central keratinization risk or high-risk.9 Any high-risk factor immediately places the
and horn pearl formation, depending on the differentiation patient in the high-risk category.9 Nail involvement is classified
of the tumor.1 SCC may be confused with BCC, such as in the as high-risk with treatment options including surgery or
case of collision tumors, and in differentiating basosquamous radiotherapy with or without systemic therapy.9 Wide excision
carcinoma (BSC) from SCC with basaloid features.6 In our with matricectomy was done with postoperative radiotherapy
patient, aside from showing a moderately differentiated type administered over thirty days. Excision has a 5-year disease-
of squamous cell tumor, basaloid features were also observed free rate of 91% with clear margins.9 However, since margins
with peripheral palisading and retraction artefact from the could not be ascertained in our case due to the fragmented
stroma indicative of BSC. Special stains were then important specimen, radiotherapy with a 5-year cure rate of 90-93% served
in establishing an accurate diagnosis. A study by Beer et al. as an adjuvant, as recommended.9 In cases where there is bone
(2000) showed that BerEP4 and EMA can be used to distinguish involvement, amputation is indicated.10 As osseous infiltration
among BCC, SCC, and BSC. BerEP4 labels most of BCC and

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CASE REPORT JPDS
Journal of the Philippine
Dermatological Society

was repeatedly suspected in the MRI at two months post- years wherein most recurrences develop.9
radiotherapy, amputation was eventually done.
CONCLUSION
Prognosis of nail unit SCC is good if it is recognized early.
Hence, in cases wherein chronic nail conditions fail to respond We report a case of subungual SCC initially diagnosed as a
to conventional treatment, a biopsy should be done since an pyogenic granuloma. Full-thickness biopsy should be done in
underlying malignancy can present as benign nail pathology. persistent nail conditions using special stains to confirm the
Though metastases are rare, subungual SCC tends to quickly diagnosis, as underlying malignancy may present as benign
become more invasive to the bone in up to 20% of cases.10 The nail pathology. Surgical treatment or radiotherapy with or
recurrence rate is also high due to the anatomical difficulty of without systemic therapy is the first line of treatment for
the nail for margins, and pathology is harder to interpret. Long- subungual SCC. In cases of bone involvement, amputation may
term surveillance is needed, especially within the first two be warranted.

REFERENCES

1. Lonsdorf AS, Hadaschik EN. Squamous Cell Carcinoma and Keratoacanthoma. In: Kang S, Amagai M, Bruckner AL, Enk AH, Margolis DJ, McMichael
AJ, Orringer JS, editors. Fitzpatrick's Dermatology in General Medicine. McGraw Hill; 2019. Vol 1; p. 1901-16.

2. Dalle S, Depape L, Phan A, Balme B, Ronger-Savle S, Thomas L. Squamous cell carcinoma of the nail apparatus: clinicopathological study of 35
cases. Br J Dermatol. 2007 May;156(5):871-4. DOI: 10.1111/j.1365-2133.2006.07744.x

3. Dijksterhuis A, Friedeman E, Heijden BVD. Squamous Cell Carcinoma of the Nail Unit: Review of the Literature. J Hand Surg Am. 2018;43(4).
DOI:10.1016/j.jhsa.2018.01.010.

4. Khullar G, Singh S, Saikia UN, Kumar A, Singh MP, Kanwar AJ. Squamous cell carcinoma of the nail fold masquerading as pyogenic granuloma.
Indian J Dermatol Venereol Leprol 2016;82:555-557. DOI: 10.4103/0378-6323.182975.

5. Murad A, Armstrong A, Baum C, Bordeaux JS, Brown M, Busam KJ, et al. Guidelines of care for the management of cutaneous squamous cell
carcinoma. J Am Acad Dermatol. 2018;78:560-78. DOI: 10.1016/j.jaad.2017.10.007.

6. Patterson JW. Tumors of the Epidermis. In: Patterson JW, editor. Weedon's Skin Pathology. Charlottesville, VA: Churchill Livingston; 2016:815-21.
7. Beer TW, Shepherd P, Theaker JM. Ber EP4 and epithelial membrane antigen aid distinction of basal cell, squamous cell and basosquamous

carcinomas of the skin. Histopathology. 2000;37(3):218-23. DOI:10.1046/j.1365-2559.2000.00999.x.
8. Heyderman E, Graham RM, Chapman DV, Richardson TC, Mckee PH. Epithelial markers in primary skin cancer: an immunoperoxidase study of

the distribution of epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA) in 65 primary skin carcinomas. Histopathology.
1984;8(3):423-434. DOI:10.1111/j.1365-2559.1984.tb02354.x.
9. National Comprehensive Cancer Network [Internet]. Squamous Cell Skin Cancer (Version 2.2018) [cited 2020 Jan 6]. Available from: http://
www.nccn.org.
10. Starace M, Alessandrini A, Dika E, Piraccini BM. Squamous cell carcinoma of the nail unit. Dermatol Pract Concept. 2018;8(3):238-44. DOI:10.5826/
dpc.0803a017.

49 J Phil Dermatol Soc · May 2022 · ISSN 2094-201X

JPDS CASE REPORT
Journal of the Philippine
Dermatological Society

Scrofuloderma and tuberculous gumma
in a young Filipino adult: a rare presentation

of multifocal tuberculosis

Ma. Fatima Lourdes Omangayon, MD,1 Emmerson Gale S. Vista, MD, FPDS, FPSVI1

ABSTRACT

INTRODUCTION Cutaneous involvement is relatively uncommon representing a small fraction (1-2%) of the localizations of ex-
trapulmonary tuberculosis. Cutaneous TB presents with several clinical forms, wherein one of the most common is scrofuloder-
ma resulting from the direct extension of a tuberculous focus from a deeper structure such as the lymph node into the overlying
skin. Tuberculous gumma is a rare form which occurs due to hematogenous spread of the TB bacilli. Although presenting with
a wide clinical spectrum, it is believed that the association of different morphologies as well as numerous lesions and sites of
cutaneous TB in a same patient is very rare.

CASE REPORT This is a case of a 20-year-old Filipino male presented with a five-month history of several progressive cutaneous
lesions initially presenting as subcutaneous nodules evolving into well-demarcated suppurative painless ulcers which were un-
responsive to topical antibiotic. Skin punch biopsy from the medial malleolar area of the right foot revealed dilated blood vessels
with a diffuse inflammatory infiltrate of lymphocytes, histiocytes, and few multinucleated giant cells. Clinical and laboratory
findings were consistent with cutaneous tuberculosis. Patient was started on anti-Koch’s treatment regimen and presented an
excellent response to treatment showing resolution of the skin lesions on the neck and forearms and notable regression of the
lesions on the right foot within four (4) months.

CONCLUSION This case serves as a reminder that cutaneous tuberculosis can manifest with a wide spectrum of clinical presen-
tation which can mimic diverse dermatological conditions and may present with high rates of negative or equivocal diagnostic
testing results. This report highlights the importance of a high index of suspicion in the timely diagnosis and management of tuber-
culosis in countries wherein tuberculosis remains a significant health burden such as the Philippines.

KEYWORDS Cutaneous tuberculosis, Scrofuloderma, Tuberculous gumma, Metastatic tuberculous abscess

1Department of Dermatology, INTRODUCTION 334 cases, while tuberculous gumma or meta-
Research Institute for Tropical static tuberculous abscess was the rarest with
Medicine, Muntinlupa City, Metro Tuberculosis is a systemic disease caused by only one (1) reported case from 2011 to 2020.
Manila Mycobacterium tuberculosis which has been rec-
ognized as a major global health problem up Cutaneous tuberculosis comprises a myriad
Corresponding author until this day. In 2020, there was an estimated of clinical presentations creating an extremely
Ma. Fatima Lourdes 10 million cases of active TB. Eight (8) countries challenging situation for dermatologists which
Omangayon, MD accounted for two-thirds of the global total cas- can lead to a delay in the accurate diagnosis and
es, and among the high TB burden countries, the timely management. Reports of this condition
Conflict of interest Philippines ranked 4th accounting for 6% of the presenting as different morphologies with multi-
None cases. It is known to primarily cause pulmonary ple lesions and sites involved in the same patient
infection in immunocompetent patients, how- are rare. Herein, we report a case of multifocal
Source of funding ever, its extrapulmonary involvement has been tuberculosis in a previously healthy young adult
None linked to immunosuppression, HIV infection, male presenting with polymorphic cutaneous le-
malnutrition, and advancing age.1,2 Cutaneous sions, combining scrofuloderma and tuberculous
Cite as involvement is relatively uncommon represent- gumma, in addition to pulmonary involvement.
Omangayon MFL, Vista EGS. ing a small fraction (1-2%) of the localizations of
Scrofuloderma and tuberculous extrapulmonary TB.2 In the Philippine Derma- CASE REPORT
gumma in a young Filipino adult: tological Society - Health Information System
a rare presentation of multifocal registry, scrofuloderma accounted for the most A 20-year-old Filipino male presented with a five-
tuberculosis. J Phil Dermatol common form of cutaneous tuberculosis with month history of several progressive cutaneous
Soc. 2022;31(1):50-53. lesions which were unresponsive to topical an-

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Dermatological Society

Figure 1. A. A subcutaneous nodule with minimal erosions and crusting located on the itary, well-defined, erythematous nodule measuring 2.5 cm x 2.5
left posterior neck. B. Persistent ulceration with purulent discharge and crusting on the cm on the surface of the left posterior neck, along with multiple,
bilateral forearms. C. Multiple nodules with ulceration and draining sinuses located on the well-defined, indurated erythematous nodules with ulcerations
medial aspect of the right foot. covered by cheesy and purulent discharge on the bilateral fore-
arm and medial aspect of the right foot measuring 2.5 cm x 2.5
tibiotic. The patient presented with lesions on multiple sites cm and 8 cm x 5 cm respectively (Figure 1).
which involved the left posterior neck, bilateral forearm, and
medial aspect of the right foot. These lesions have developed as Complete blood count with differential count results were
papules evolving into subcutaneous nodules gradually increas- all within normal limits. HIV test results came back negative.
ing in size and then evolved into well-demarcated suppurative Chest x-ray showed patchy infiltrates on the right lung making
painless ulcers accompanied by swelling of the medial malleo- the impression of pulmonary tuberculosis. Tuberculin purified
lar aspect of the right foot. The patient did not complain of any protein derivative tested negative (less than 5 mm). Acid-fast ba-
other systemic manifestations such as chronic cough, hemopty- cilli microscopy, Mycobacterium and fungal cultures of the skin
sis, fever, night sweats, nausea, vomiting, and joint pains. How- tissue samples were all reported negative.
ever, he had complaints of unintentional weight loss and loss of
appetite. The patient had no previous personal or family history A 4-mm skin punch biopsy was done, obtaining skin tissue
of tuberculosis. There was no reported history of trauma. Sexu- from the medial malleolar area of the right foot, and hematox-
al history was unremarkable. He previously received his Bacille ylin and eosin-stained sections revealed dilated blood vessels
Calmette-Guerin (BCG) vaccination. Similar lesions were not de- with a diffuse inflammatory infiltrate of lymphocytes, histio-
scribed in the family. On physical examination, the patient was cytes, and few multinucleated giant cells (Figure 2). Prominent
generally well, had no other palpable lymphadenopathy, and red blood cell extravasation and fibrosis were seen in the mid to
was underweight with a body mass index of 16.1. Examination lower dermis (Figure 2). A histopathological diagnosis of cuta-
of the pulmonary, cardiovascular, and neuromuscular systems neous tuberculosis was made.
were unremarkable. The cutaneous examination revealed a sol-
A diagnosis of cutaneous tuberculosis probably scrofulo-
derma on the neck and tuberculous gummas on the extremities
was established based on the following parameters: clinical
manifestations, skin tuberculin test, acid-fast smear, histo-
pathological findings, and presence of TB in another organ. The
patient was started on anti-Koch’s treatment regimen as per the
patient’s weight consisting of isoniazid, rifampicin, pyrazin-
amide, and ethambutol for the two (2) months intensive phase,
followed by isoniazid and rifampicin for the continuation
phase. The patient has since been in follow-up and presented an
excellent response to treatment showing clinical improvement
as gain in weight, good appetite, resolution of the skin lesions on
the neck and forearms, and notable regression of the lesions on
the right foot within four (4) months (Figure 3). The anti-tuber-
culosis therapy lasted for a total of six (6) months.

Figure 2. Biopsy from the indurated nodule showing: A. Diffuse pattern of inflammatory infiltrate of lymphocytes (red arrow) and histiocytes (yellow arrow), fibrosis in the mid to lower dermis
(H&E stain, 40x) B. Multinucleated giant cells (red arrow, H&E stain, 100x) C. Dilated blood vessels (blue arrow) and extravasation of red blood cells (red arrow) (H&E stain, 40x)

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Journal of the Philippine
Dermatological Society

Figure 3. Resolution of lesions with residual scarring 4 months after anti-tuberculosis subcutaneous nodules evolving into nontender abscesses with
therapy. ulceration and draining sinus tracts, making them indistin-
guishable from scrofuloderma. This type of cutaneous TB usu-
DISCUSSION ally occurs in undernourished children of low socioeconomic
status and immunocompromised patients, however, its occur-
Tuberculosis is a major health problem in the Philippines. How- rence in immunocompetent hosts is also possible.6 In this case,
ever, even in countries wherein tuberculosis is endemic, cuta- the immunosuppression due to an active pulmonary tuberculo-
neous tuberculosis is still a rare form of extrapulmonary TB sis infection has probably contributed to the onset and evolution
which can manifest with a great range of clinical presentations. of the cutaneous disease. Moreover, the delay in diagnosis and
Its diagnosis is made through a high index of suspicion and fre- treatment of the first localization may have allowed the spread
quently with the use of an extensive diagnostic investigation in- of infection to other sites.
volving cultures and biopsy of the affected skin.
Scrofuloderma and tuberculous gumma are both mul-
It is believed that the association of different morphologies, tibacillary type of cutaneous tuberculosis.7 Although this is
as well as numerous lesions and sites of cutaneous TB in a same the case, their diagnosis is still a challenge owing to the lower
patient, is very rare, making this case riveting. In a series re- sensitivity and specificity of diagnostic methods for cutaneous
ported by Kivanç‐Altunay et al., out of 370 patients with tuber- TB compared to pulmonary TB.8 The overall clinical and histo-
culosis, only 13 (3.51%) had cutaneous TB, and the concern of pathological picture must be taken into account to avoid diag-
polymorphous cutaneous TB was present only in one (1) patient nostic misinterpretation.
presenting as scrofuloderma in association with lupus vulgar-
is.3 Another study by Amraoui et al. reporting seven (7) cases of The importance of treating tuberculous disease as early as
multifocal tuberculosis with cutaneous localization in immuno- possible to prevent morbidity and mortality related to TB can-
competent patients, revealed that none of the patients had an as- not be emphasized enough. For the management of cutaneous
sociation of more than one (1) type of cutaneous tuberculosis.4 tuberculosis, the Anti-Koch’s regimen remains the treatment of
As with our case, a diagnosis of cutaneous tuberculosis— scrof- choice. While some authors have recommended a combination
uloderma on the neck and tuberculous gummas on the extrem- of pharmacologic treatment with surgical excision and debride-
ities was established based on clinical and histopathological ment of all diseased tissue,9 the response to anti-tuberculous
correlation. treatment alone is usually good. As in this case report, the pa-
tient showed excellent response to treatment showing notable
Scrofuloderma, also known as tuberculosis colliquativa regression of lesions within the initial two (2) months of thera-
cutis, results from the direct extension of a tuberculous focus py. Along with that, the patient also received local wound care
from a deeper structure such as the lymph node into the overly- with the use of sucralfate (Cicalfate) cream which could have
ing skin. This usually starts as a painless subcutaneous nodule contributed to the quick recovery. Yen, T. et al. have reported
that would later evolve into an ulcerating lesion with purulent that sucralfate demonstrated in vitro inhibitory activity against
discharge. Commonly affected sites are the neck, chest, and ax- multiple bacterial pathogens including Proteus mirabilis, Pseudo-
illary areas.5 In this patient, the diagnosis of scrofuloderma was monas aeruginosa, Staphylococcus aureus, Staphylococcus pseudin-
made given the typical clinical manifestation and site of predi- termedius, Escherichia coli, and Enterococcus faecalis.10 In addition
lection. to the antimicrobial activity suggested in the study, the authors
also believed that sucralfate is an attractive option for topical
Tuberculous gummas, also known as metastatic tubercu- therapy of superficial pyodermas given its low incidence of tox-
lous abscesses, result from the hematogenous dissemination icity, particularly when applied to the skin. And although no
of Mycobacterium bacilli from an underlying TB focus during standard topical therapy for cutaneous tuberculosis has been
periods of lowered immunity. This condition generally starts as found from related studies, we propose that sucralfate cream
may be used concurrently and possibly has the benefit of im-
proving treatment outcomes.

CONCLUSION

This case serves as a reminder that cutaneous tuberculosis can
manifest with a wide spectrum of clinical presentations which
can mimic diverse dermatological conditions and may present
with high rates of negative or equivocal diagnostic testing re-
sults. This highlights the importance of a high index of suspi-
cion in the timely diagnosis and management of tuberculosis.

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Dermatological Society

REFERENCES

1. Gunal S, Yang Z, Agarwal M, Koroglu M, Arıcı ZK, Durmaz R. Demographic and microbial characteristics of extrapulmonary tuberculosis cases
diagnosed in Malatya, Turkey, 2001–2007. BMC Public Health. 2011;11:154.

2. Khan, A.H., Sulaiman, S.A.S., Laghari, M. et al. Treatment outcomes and risk factors of extra-pulmonary tuberculosis in patients with co-
morbidities. BMC Infect Dis 19, 691 (2019). https://doi.org/10.1186/s12879-019-4312-9.

3. Kivanç-Altunay, I., Baysal, Z., Ekmekçi, T. R., & Köslü, A. (2003). Incidence of cutaneous tuberculosis in patients with organ tuberculosis.
International journal of dermatology, 42(3), 197–200. https://doi.org/10.1046/j.1365-4362.2003.01762.x.

4. Amraoui, N., Krich, S., Meziane, M., Gallouj, S., Abid, H., Elmrini, A., Moumna, K., Harmouch, T., & Mernissi, F. (2015). Cutaneous tuberculosis revealing
multifocal tuberculosis in immunocompetent patients. International journal of mycobacteriology, 4(3), 255–257. https://doi.org/10.1016/j.
ijmyco.2015.05.009.

5. Ganesan, Anuradha & Kumar, Gautham. (2017). Scrofuloderma: A rare cutaneous manifestation of tuberculosis. Journal of Indian Academy of
Oral Medicine and Radiology. 29. 223. 10.4103/jiaomr.jiaomr_33_17.

6. Machan A, Hanafi T, Hjira N, Boui M. Tuberculous gummas: Epidemiological, clinical, bacteriological, immunological, and therapeutic features.
Int J Mycobacteriol. 2018 Jul-Sep;7(3):203-211. doi: 10.4103/ijmy.ijmy_83_18. PMID: 30198497.

7. Khadka P, Koirala S, Thapaliya J. Cutaneous Tuberculosis: Clinicopathologic Arrays and Diagnostic Challenges. Dermatol Res Pract. 2018 Jul
9;2018:7201973. doi: 10.1155/2018/7201973. PMID: 30111996; PMCID: PMC6077618.

8. Santos JB, Figueiredo AR, Ferraz CE, et al. Cutaneous tuberculosis: epidemiologic, etiopathogenic and clinical aspects—part I. An Bras Derma-
tol 2014;89:219-228.

9. Gopalaswamy R, Dusthackeer VNA, Kannayan S, Subbian S. Extrapulmonary Tuberculosis—An Update on the Diagnosis, Treatment and Drug
Resistance. Journal of Respiration. 2021; 1(2):141-164. https://doi.org/10.3390/jor1020015.

10. Yen, T., Boord, M. J., Ghubash, R., & Blondeau, J. M. (2018). A pilot study investigating the in vitro efficacy of sucralfate against common veterinary
cutaneous pathogens. Journal of Small Animal Practice. doi:10.1111/jsap.12902.

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JPDS CASE REPORT
Journal of the Philippine
Dermatological Society

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, MD,1 Ma. Jasmin J. Jamora, MD, FPDS1

ABSTRACT

INTRODUCTION Bullous pemphigoid (BP) is a chronic, relapsing autoimmune blistering disorder commonly found in adults older
than 60 years of age. It is mediated by autoantibodies directed against the hemidesmosomal proteins BP180 and BP230, which
trigger an inflammatory cascade leading to blister formation. BP may present with pruritus, followed by an erythematous plaque
or urticaria, and subsequently by bullae formation with or without mucosal involvement. It develops sporadically but can also be
triggered by ultraviolet light exposure, radiation therapy, and medications such as dipeptidyl peptidase-4 inhibitor (DPP4i). Since
2006, the increasing use of DPP4i (also known as gliptins) for their good safety profile in treating Type II Diabetes Mellitus has led
to a further increase in the incidence of bullous pemphigoid.

CASE REPORT This is a case of a 65-year-old hypertensive and diabetic elderly Filipino female presenting DPP4i (linagliptin)-in-
duced bullous pemphigoid with an atypical dyshidrosiform pattern, negative direct immunofluorescence (DIF), and Enzyme-linked
immunosorbent assay (ELISA) that is negative for anti-BP180 antibodies but positive for anti-BP230 antibodies.

CONCLUSION The increasing use of DPP4i for diabetes mellitus for its good safety profile may be an essential contributing factor to
the increasing incidence of BP in elderly hypertensive and diabetic patients with a simultaneous increasing incidence of atypical BP
presentations such as the dyshidrosiform variant. Inability to recognize these factors carries significant therapeutic implications,
including prolonged multidrug immunosuppression and increased patient morbidity and mortality.

KEYWORDS Bullous pemphigoid, gliptin, ELISA

1Skin and Cancer Foundation, INTRODUCTION incidence of 1.9- to 4.3-fold.2 From 2011 to 2019,
Inc., Pasig City, Metro Manila the Philippine Dermatological Society Health
Bullous pemphigoid (BP) is a chronic, relaps- Information System (PDS-HIS) documented 905
Corresponding author ing, autoimmune blistering disorder common BP cases, of which only 13 were drug-induced,
Aizlynn Anne J. Robledo, MD in adults older than 60 years.1 The incidence and none were DPP4i-induced.6 A 10-year ret-
of classic BP has increased after the Food and rospective prevalence study from 2000 to 2019
Conflict of interest Drug Administration (FDA) approved dipepti- found that 58 (14.6%) out of 397 BP cases were
None dyl peptidase-4 inhibitor (DPP4i) for diabetes DPP4i-associated.7 Although DBP incidence is
mellitus in 2006.2 Due to misdiagnosis of atypi- unknown, retrospective studies have revealed a
Source of funding cal (non-bullous) BP, such as dyshidrosiform BP 3.5 to 45% (median, 28%) incidence.3 Diagnostic
None (DBP), characterized by blisters on the palms dilemmas and delays in treatment were noted
and soles of a patient diagnosed with or sus- due to missed associations of BP with medica-
Cite as pected of having BP, the true incidence of BP is tions such as DPP4i, and an increase in atypical
Robledo AAJ, Jamora MJJ. A unknown.3 BP is characterized by an autoim- BP presentations. To the author’s knowledge,
case of anti-BP230 antibody- mune response against the hemidesmosomal there is still no reported case of anti-BP230 anti-
positive dyshidrosiform bullous proteins BP180 and BP230.1 Anti‐BP230 anti- body-positive dyshidrosiform DPP4i-associated
pemphigoid secondary to body-positive BP accounts for only 5%–8% of BP worldwide and locally.
dipeptidyl peptidase-4 inhibitor all BP cases.4 Direct immunofluorescence (DIF)
in a 65-year-old Filipino can be negative due to improper sampling or CASE REPORT
female. J Phil Dermatol Soc. subthreshold levels of immune complexes.5 The
2022;31(1):54-56. annual cumulative incidence of BP was estimat- A 65-year-old hypertensive, diabetic, Filipino
ed to range from 2.4 to 23 per million in differ- woman presented with pruritus on her right leg
ent populations worldwide, with an increasing four months after empagliflozin plus linagliptin

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JPDS CASE REPORT
Journal of the Philippine
Dermatological Society

Figure 1. Pruritic, erythematous nummular plaque on the anterodistal left leg of a patient Figure 2. A. Multiple pruritic tense tapioca-like vesicles (black arrows) and bullae (white
with dyshidrosiform BP secondary to DPP4i. arrows) on the hand, and B. around a pruritic, erythematous nummular plaque on the
anterodistal left leg of a patient with dyshidrosiform BP secondary to DPP4i.
was started. Four months after, a gradually enlarging (from 2
to 6 cm) pruritic, erythematous, and edematous plaque with zyme-linked immunoassay was negative for anti-BP180 anti-
erosions and serous to purulent discharge (Figure 1) was noted body (2.686 RU/ml; normal value: <20 RU/ml), but positive for
with subsequent appearance of multiple pruritic, tense, tapio- anti-BP230 antibody (>200 RU/ml; normal value <20 RU/ml),
ca-like vesicles and bullae on the hands (Figure 2A) feet, arms, clinching the diagnosis of BP. Currently, the patient occasion-
and legs (Figure 2B). She was diagnosed by a dermatologist ally develops 1 to 2 new lesions that would spontaneously re-
with recalcitrant eczema unresponsive to topical corticoste- solve within the day or after applying clobetasol cream twice
roids, topical and oral antibiotics, and topical antifungal med- a day.
ications. Drug-induced BP was considered, and she was start-
ed on prednisone (20 mg/day, tapered), lymecycline (300 mg/ DISCUSSION
day), cetirizine (20 mg/day), and clobetasol cream (twice a day)
with 90% improvement after three months. Linagliptin was Bullous pemphigoid targets the NC16A domain of BP180 in
discontinued by an endocrinologist as suggested by the derma- approximately 85-90% of cases, and BP230 in about 5-8% of
tologist. Biopsy was done (11 months after empagliflozin plus all BP cases. In contrast to BP180, the pathogenic relevance
linagliptin was started), which revealed subepidermal blister of autoantibodies against BP230 is unclear. Anti-BP230 anti-
formation with eosinophils lining along the dermal-epidermal body-positive BP has a non-inflammatory and milder clinical
junction and surrounding the superficial blood vessels of the
papillary dermis (Figure 3). Direct immunofluorescence (DIF) Figure 3. Subepidermal blister formation with eosinophils (black arrows) lining along the
study was negative for IgG, IgM, IgA, C3, and fibrinogen. En- dermal-epidermal junction and surrounding the superficial blood vessels of the papillary
dermis in a patient with dyshidrosiform BP secondary to DPP4i.

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CASE REPORT JPDS
Journal of the Philippine
Dermatological Society

presentation with a typical initial presentation of edematous linagliptin with about 7-fold increased risk. The pathogenesis
erythemas rather than tense bullae.4,8 In a small percentage is uncertain, but an alteration in the correct cleavage of BP180
of cases, DIF will initially be negative due to either improper resulting in modification of its antigenicity and function was
specimen sampling from lesional skin or a subthreshold quan- postulated as a potential mechanism.2 Studies have shown that
tity of immune complexes on the skin.5 BP was associated with DPP4i-induced BP has a better prognosis with a good response
a 6-44% first-year mortality rate. The causes of mortality can to therapy after drug withdrawal than classic BP.8 DPP4i is pre-
be multifactorial and include heart disease, infection, neuro- ferred for its neutral effects on body weight and good athero-
logic disease, and adverse effects of medications.9 Aside from sclerotic cardiovascular safety compared to other antidiabetic
the classic presentation of tense bullae, BP can also present drugs. A 2021 multicenter retrospective study, which included
with atypical forms, including dyshidrosiform BP, pemphigoid 320 BP cases, revealed that among the cases, 77.5% were id-
vegetans, pemphigoid nodularis, vesicular pemphigoid, large iopathic, 9.7% were potentially drug-induced, and 12.8% had
erosive toxic epidermal necrolysis-like lesions, erythrodermic new medications missed by dermatologists. In addition, 39% of
pemphigoid, and lichen planus pemphigoides.1 Dyshidrosi- the missed cases presented with non-bullous eruptions.10
form BP has been reported in at least 84 cases and is character-
ized by blisters on the palms and soles. Blisters can present on CONCLUSION
both the palms and soles (67%), on the soles (30%), or the palms
only (3%). The diagnosis of this BP subtype is often delayed be- The increasing use of DPP4i for diabetes mellitus for its good
cause it is misdiagnosed as pompholyx or repeatedly treated safety profile may be an essential contributing factor to the in-
for recurrent or persistent dermatitis. Some presented with creasing incidence of BP in elderly hypertensive and diabetic
prodromal symptoms such as eczematous, papular, and urti- patients with a simultaneous increasing incidence of atypi-
carial eruptions prior to the appearance of blisters.8 Bullous cal BP presentations such as the dyshidrosiform variant. An-
pemphigoid can also be triggered by DPP4i. DPP4i is a second ti-BP230 is an important additional serologic marker for BP,
or third-line drug for type 2 diabetes mellitus that has been especially if the anti-BP180 antibody and DIF are negative.
associated with an approximately 3-fold increased risk for Dermatologists must be aware of known BP-associated medi-
BP. The mean latency period between the introduction of the cations and atypical BP presentations, especially in cases with
DPP4i and confirmation of BP is approximately 22.6 months. recalcitrant eczemas. Inability to recognize these factors car-
Among the DPP4i, vildagliptin had the strongest association ries significant therapeutic implications, including prolonged
with an approximately 11-fold increased risk of BP, followed by multidrug immunosuppression and increased patient morbid-
ity and mortality.

REFERENCES

1. Bolognia J, Cerroni L, Schaffer JV. Dermatology. 4th ed. Philadelphia: Elsevier; 2018.
2. Kridin K, Ludwig RJ. The Growing Incidence of Bullous Pemphigoid: Overview and Potential Explanations. Front Med (Lausanne). 2018 Aug

20;5:220. doi: 10.3389/fmed.2018.00220. PMID: 30177969; PMCID: PMC6109638.
3. Cohen PR. Dyshidrosiform Bullous Pemphigoid. Medicina (Kaunas). 2021 Apr 20;57(4):398. doi: 10.3390/medicina57040398. PMID: 33924249; PMCID:

PMC8074754.
4. Fujimoto, M, Imai, Y, Tateishi, C, Yamanishi, K. Anti-BP230 Antibody–positive Bullous Pemphigoid Complicated by Ulcerative Colitis. J Cutan

Immunology and Allergy. 2019 Aug 28;2(5):148-149. doi: 10.1002/cia2.12079.
5. Fudge JG, Crawford RI. Bullous Pemphigoid: A 10-Year Study of Discordant Results on Direct Immunofluorescence. J Cutan Med Surg. 2018 Sep/

Oct;22(5):472-475. doi: 10.1177/1203475418773359. Epub 2018 Apr 22. PMID: 29681159.
6. Philippine Dermatological Society. 2011-2019 Cumulative Number of Cases for Bullous Pemphigoid and Bullous Pemphigoid secondary to DPP-4

inhibitor. Philippine Dermatological Society – Health Information System. 2019. https://pds.org.ph.
7. Kridin K. Dipeptidyl-peptidase IV inhibitors (DPP4i)-associated bullous pemphigoid: Estimating the clinical profile and exploring intraclass

differences. Dermatol Ther. 2020 Jul;33(4):e13790. doi: 10.1111/dth.13790. Epub 2020 Jul 14. PMID: 32506731.
8. Armanious M, AbuHilal M. Gliptin-Induced Bullous Pemphigoid: Canadian Case Series of 10 Patients. J Cutan Med Surg. 2021 Mar-Apr;25(2):163-168.

doi: 10.1177/1203475420972349. Epub 2020 Nov 11. PMID: 33176433.
9. Cortés B, Marazza G, Naldi L, Combescure C, Borradori L; Autoimmune Bullous Disease Swiss Study Group. Mortality of bullous pemphigoid in

Switzerland: a prospective study. Br J Dermatol. 2011 Aug;165(2):368-74. doi: 10.1111/j.1365-2133.2011.10413.x. PMID: 21574978.
10. Molina GE, Yanovsky RL, Wei EX, Chen ST. Missed drug-induced bullous pemphigoid leads to longer immunosuppression than recognized cases:

A 9-year retrospective review. J Am Acad Dermatol. 2020 May;82(5):1255-1258. doi: 10.1016/j.jaad.2019.12.059. Epub 2020 Jan 9. PMID: 31927075.

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Appendix 1

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Appendix 2

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Appendix 5

Journal of the Philippine Dermatological Society • Volume 31 Issue 1 • May 2022