1Department of Dermatology,

Southern Philippines Medical Center,

JP Laurel Ave, Davao City, Philippines Subepidermal blistering disorders (SBD) are diseases associated with antibodies that attack structural proteins
of the skin. Blister formation with widespread distribution is common in these diseases. The diagnosis of SBD
Maria Vinna Nicodemus Crisostomo is established through demonstration of immunoglobulin deposits in the dermoepidermal junction by direct
docmavie_crisostomo@yahoo.com
immunofluorescence microscopy, and the presence of circulating autoantibodies by serology. Systemic
corticosteroids and other immunosuppressive drugs are used to treat SBD. We present the case of a 16­year
Amariz Zarate
Janice Natasha C Ng old female with a 6­week history of intensely pruritic, erythematous plaques with generalized blister formation
on the face, trunk, upper extremities, and inner thighs. We diagnosed the patient as having a subepidermal
15 May 2017 blistering disorder. We placed her on a course of prednisone and azathioprine, which successfully treated her
lesions.
9 October 2018
Keywords. autoimmune disease, bullous pemphigoid, epidermolysis bullosa acquisita, direct
31 August 2018 immunofluorescence, corticosteroids
Crisostomo MVN, Lacuesta­
Gutierrez MPM. Subepidermal
blistering disorder in a 16­year­old
female: case report. SPMC J Health
Care Serv. 2018;4(1):8. consulted a dermatologist who prescribed
http://n2t.net/ark:/76951/jhcs3a9dx4 Subepidermal blistering disorders (SBD) are the topical application of betamethasone
autoimmune disorders of the skin caused by dipropionate + mupirocin ointment twice
© 2018 MVN Crisostomo, et al.
the presence of autoantibodies to the struc- daily on the lesions and oral intake of
tural components of the basement membrane.1 cetirizine 10 mg once a day for 2 weeks.
All dermatologic conditions under this group There was no history of drug intake
histopathologically manifest as blister forma- immediately prior to the onset of the lesions.
tion beneath the epidermis. SBD include the She had no weight loss, easy fatigability, hair
pemphigoid disorders [e.g., pemphigoid ges- loss, photosensitivity, oral ulcers, or joint
tationis, mucous membrane cicatricial pemphi- pains accompanying or preceding the lesions.
goid, bullous pemphigoid (BP)], linear IgA No other family or household members had
bullous dermatosis2 epidermolysis bullosa the same condition. Past medical history was
acquisita (EBA), and anti-p200 pemphigoid.1 unremarkable. She received due vaccinations
These diseases share some clinical features— until she was 1 year old. Development was at
including the presence of pruritic, tense par with age. She had her menarche at 12
blisters—but their differentiation based on years old. She denied any sexual contact.
clinical presentation alone is difficult, hence Dermatologic physical examination re-
the need for laboratory diagnostics such as
direct immunofluorescence (DIF) and antibody
testing.3 There are a number of therapeutic
options, but steroids are the first-line treat-
ment.4 Here, we report the case of a 16-year-
old female who presented with vesicobullous
skin lesions and was managed as having a
subepidermal blistering disorder based on
histopathologic and immunologic findings.

A 16-year-old female was admitted in our

hospital with a six-week history of gen-
eralized, erythematous, pruritic, urticarial
plaques, which gradually progressed to tense
vesicles and bullae on the face, trunk, upper
extremities, and inner aspects of the thighs.
Two weeks prior to admission, the patient

Crisostomo MVN, Lacuesta­Gutierrez MPM. SPMC J Health Care Serv. 2018;4(1):8.

Figure 1 Multiple, erythematous, urticarial plaques and papules, and eroded plaques with purulent discharge on the right axillary area (A) and abdomen (B), topped
with tense vesicles and bullae containing clear fluid.

vealed multiple, erythematous, urticarial plaques anti-BP180 IgG was elevated at 82.43 U/mL
on the face, back, upper extremities and (normal value: < 9 U/mL).
inner thighs. There were multiple, tense Considering the clinical presentation of
bullae containing serous fluid on the trunk, the patient, the DIF findings of linear
axillae, and extremities. The sizes of the deposits of IgG and C3 at the dermoepidermal
bullae ranged from 1-3 cm in diameter. junction, and the presence of autoantibodies
(Figures 1). Eroded plaques with purulent against BP180, we managed the patient as
discharge were also noted. There were no having a subepidermal blistering disorder.
mucosal lesions. Scarring, Nikolsky sign, and
milia formation on or around the lesions
were all absent. The rest of the physical
examination findings were unremarkable. Upon admission, we gave the patient intra-
venous clindamycin 300 mg every 6 hours
and gentamicin 80 mg once a day, both for
The patient’s complete blood counts one week, to cover the infection. Topical
showed leukocytosis (20.09 x 103/µL) and steroid application was continued while
eosinophilia (differential count: 20%). awaiting the final biopsy results. After
Erythrocyte sedimentation rate was normal. establishing the diagnosis of SBD through
ANA and anti-dsDNA levels were negative. DIF, we started the patient on prednisone 50
Chest x-ray findings were within normal mg/day (1 mg/kg/day based on the patient’s
limits. Pregnancy test was negative. Culture weight of 50 kg). After the third day of
and sensitivity of wound discharge showed prednisone, the old lesions did not improve,
no growth of organisms after five days. and new lesions appeared, so we increased
Histopathologic examination of a vesicle the dose to 70 mg/day (1.4 mg/kg/day).
located on the volar aspect of the left After the dose increase, no new vesicles
forearm revealed a subepidermal split with appeared, and the old lesions healed, leaving
neutrophilic infiltrates (Figure 2), consistent only hypopigmented patches. We discharged
with SBD. We sent a sample of perilesional the patient two weeks after admission with
skin from the trunk for (DIF). Results instructions to return for regular follow-up
showed linear deposits of IgG and C3 on consultations.
the basement membrane zone, consistent Starting on the third week of steroid use,
with pemphigoid disorders or epidermolysis we attempted to titrate down the patient’s
bullosa acquisita. (Figure 3). The patient's prednisone. However, on the 9th week, when

Crisostomo MVN, Lacuesta­Gutierrez MPM. SPMC J Health Care Serv. 2018;4(1):8.

 the prednisone dose was 20 mg/day, the
patient developed Cushingoid facies. We SBD are characterized by distinctive blister
added azathioprine starting at 50 mg/day formation due to autoantibodies that target
with the aim to down-titrate the steroid over the structural components of the skin’s base-
the next few weeks. On the 16th week, when ment membrane.1 The presence of auto-
the prednisone dose was 10 mg/day, the antibodies against collagen XVII (BP180),
Cushingoid facies resolved but the patient which is a transmembrane protein structural
developed new vesicles, so we increased the component of the dermoepidermal anchoring
azathioprine dose to 75 mg/day. The patient complex,2 clinically manifests as multiple
did not return for follow-up for a year, but tense blisters with sizes ranging from a few
we came to know upon her return that, millimeters to 3 cm in diameter, as in our
within the year, she eventually discontinued patient.
taking azathioprine, and intermittently took We narrowed down the diagnosis for our
prednisone 10 mg whenever new vesicles patient’s condition based on her clinical
would appear. She returned for follow-up features and laboratory results. We ruled out
because she developed new urticarial plaques pemphigoid gestationis since it is a preg-
and vesicles with generalized distribution. We nancy-associated autoimmune skin disorder,
restarted the patient on prednisone 10 mg/day and we have established at the outset that
and azathioprine 25 mg/day. When the our patient was not pregnant.5 We also ruled
vesicles started to diminish in number, we out cicatricial pemphigoid since the disorder
tapered the prednisone dose over 24 weeks presents with blisters on mucous membranes,
and discontinued azathioprine on the 16th which were not observed in our patient.6
week. In the course of tapering the doses, Likewise, we ruled out linear IgA bullous
there was one episode of appearance of new dermatitis because its characteristic appearance
vesicles, which we were able to control by of urticarial plaques and papules surrounded
increasing the steroid dose to 25 mg and the by “string-of-pearls” blisters was not present
azathioprine dose to 50 mg for 2 months. By in our patient.7 We focused on BP and EBA,
the time we discontinued the prednisone, the since both conditions have similar clinical,
patient’s urticarial plaques and vesicles histologic, and routine immunohistologic
disappeared, and no new lesions developed. features.8

Figure 2 Histopathology of the skin showing basket­weave stratum corneum (A: green arrow) overlying an acanthotic epidermis, with focal intraepidermal
collections of neutrophils (A: red arrow). A subepidermal split filled with neutrophils and red blood cells is also noted (A: yellow arrow). The dermis has superficial
edema, with moderately dense perivascular inflammatory infiltrates composed of neutrophils, lymphocytes and eosinophils (hematoxylin­eosin stain, A: x10 and
B: x40).

Crisostomo MVN, Lacuesta­Gutierrez MPM. SPMC J Health Care Serv. 2018;4(1):8.

 the dermal side.18 However, this examination
was not performed in our patient.
Patients with SBD are commonly treated
with glucocorticoids and immunosuppres-
sants.19 Antihistamines may also be given to
symptomatically treat pruritus. We started
our patient initially on steroids, which
produced only minimal improvement of the
lesions. When we increased the steroid dose,
the lesions healed significantly, but when we
eventually tapered the dose, the lesions
recurred. When our patient developed
Cushingoid facies, which is a known adverse
effect of long-term steroid use, we gave
azathioprine and gradually reduced the
steroid dose. This led to the complete
resolution of the patient’s skin lesions and
Figure 3 Direct immunofluorescence of perilesional skin Cushingoid facies.
(x40) showing linear deposits of IgG and C3 at the Cytotoxic drugs, commonly used as
basement membrane zone (red arrow).
antineoplastic agents, are also known to
suppress the immune system and have been
noted to be effective in the treatment of
Both BP and EBA have female pre- autoimmune diseases.20 Cyclophosphamide, a
dominance and adult age of onset.9 10 BP, cytotoxic chemotherapy drug, has been
which mostly affects the elderly with mean effectively used for BP.21 22 Methotrexate, in
age of onset around 80 years, accounts for combination with oral or topical cortico-
80% of SBD.5 11 It is characterized by gen- steroids, was also reported to be effective in
eralized formation of tense blisters and pru- treating BP and EBA.19 Likewise, intravenous
ritus.3 EBA, on the other hand, is divided immunoglobulin has been used as treatment
into two types: inflammatory and mechano- for bullous autoimmune diseases, especially
bullous.12 The mechanobullous type is seen EBA.23 24 Plasmapheresis, alone or in combi-
in 0.33% of the patients and is characterized nation with cyclophosphamide or azathioprine,
by multiple blisters on trauma-prone areas, is also a viable treatment option, especially
such as the extensor surfaces of the ex- for patients who do not respond to con-
tremities, along with milia formation and ventional therapies.21
scarring.13 The inflammatory type more closely Immediate diagnosis and treatment en-
resembles BP, as it is also characterized by sure good prognosis for patients with SBD,25
pruritus and generalized vesiculobullous but there is a high recurrence rate related to
lesions that affect the trunk, extremities, and down-titration or discontinuation of steroids.26
skin folds.12 13 Our patient presented clinically with the
For our patient’s diagnosis, the presence classic signs of SBD. Recognizing the
of linear deposits of IgG and C3 on the base- severity of the disease, we immediately
ment membrane zone on DIF and elevation initiated an oral steroid regimen, which we
of anti-BP180 pointed towards BP, but we later modified by adding azathioprine to
also strongly considered the inflammatory minimize adverse effects of long-term steroid
type EBA because of its clinical similarities use. Our prompt diagnosis and use of a
with BP. carefully titrated combination of prednisone
In salt-split skin test. the skin biopsy and azathrioprine proved to be effective in
specimen is incubated for 24-72 hours in 1 treating our patient.
mol/L NaCl solution and then split at the
level of the lamina lucida by teasing the
epidermis from the dermis.14-17 This pro- Acknowledgments
cedure differentiates EBA from BP by We would like to thank Dr Jasmin Jamora from the Section of
Dermatology in St Luke’s Medical Center for providing the
determining the location where antibodies immunofluorescence report and images for this case report.
bind to in the split skin.18 In BP, the
antibodies bind to the epidermal side of the Patient consent
split skin, while in EBA, antibodies bind to Obtained

Crisostomo MVN, Lacuesta­Gutierrez MPM. SPMC J Health Care Serv. 2018;4(1):8.

 Reporting guideline used 10. Calonje E, Brenn T, Lazar A. Inherited and autoimmune
CARE Checklist subepidermal blistering diseases. In: Calonje E, Brenn T, Lazar A.
(http://www.care­statement.org/downloads/CAREchecklist­English.pdf) McKee 's Pathology of the skin. 4th ed. New York: Elsevier; 2012.
11. Patterson JW. The vesiculobullous reaction pattern. In:
Article source
Patterson JW. Weedon’s skin pathology. 4th ed. New York:
Submitted
Elsevier Limited; 2016.
Peer review 12. Kim JH, Kim SC. Epidermolysis bullosa acquisita. J Eur Acad
External Dermatol Venereol. 2013 Oct;27(10):1204­13.
13. Ludwig RJ. Clinical presentation, pathogenesis, diagnosis, and
Competing interests treatment of epidermolysis bullosa acquisita. ISRN Dermatol.
None declared 2013; 2013:812029.

Access and license 14. Mohan KH, Pai S, Rao R, Sripathi H, Prabhu S. Techniques of
This is an Open Access article licensed under the Creative immunofluorescence and their significance. Indian J Dermatol
Commons Attribution­NonCommercial 4.0 International License, Venereol Leprol. 2008 Jul­Aug;74(4):415­9.
which allows others to share and adapt the work, provided that 15. Celik G, Atay S. Acquired epidermolysis bullosa and linear
derivative works bear appropriate citation to this original work and immunoglobulin a bullous dermatosis. In: Gonul M, Cakmak S,
are not used for commercial purposes. To view a copy of this editors. Autoimmune bullous diseases. IntechOpen; 2018 May 9.
license, visit http://creativecommons.org/licenses/by­nc/4.0/
16. Gammon WR, Briggaman RA, Inman AO, Queen LL, Wheeler
CE. Differentiating Anti­Lamina Lucida and Anti­Sublamina Densa
antibmz Antibodies by Indirect Immunofluorescence on 1.0 M
Sodium Chloride­Separated Skin. J Investig Dermatol. 1984;
1. Kridin K. Subepidermal autoimmune bullous diseases: 82:139­144.
overview, epidemiology, and associations. Immunologic Research. 17. De A, Rao R, Balachandran C. Salt split technique: a useful
2018; 66(1):6­17. tool in the diagnosis of subepidermal bullous disorders. Indian J
2. Powell AM, Sakuma­Oyama Y, Oyama N, Black MM. Collagen Dermatol. 2010; 55(4):334­6.
XVII/BP180: a collagenous transmembrane protein and 18. Euroimmun. Autoimmune bullous dermatoses [PDF file].
component of the dermoepidermal anchoring complex. Clin Exp Lübeck: Euroimmun AG [cited 2018 Jul 24]. Available from: ht­
Dermatol. 2005 Nov; 30(6):682­7. tps://www.euroimmun.com/documents/Indications/Autoim­
3. Schmidt E, Zillikens D. The diagnosis and treatment of munity/Dermatology/Desmoglein/EA_1490_I_UK_A.pdf.
autoimmune blistering skin diseases. Dtch Arztebl. 2011 Jun; 19. Han A. A practical approach to treating autoimmune bullous
108(23):399­405. disorders with systemic medications. J Clin Aesthet Dermatol.
4. Marinovic B. First line therapy. Nederlands Tijdschrift Voor 2009 May; 2(5):19­28.
Dermatologie En Venereologie. 2013; 23(3). 20. Langford CA, Klippel JH, Balow JE, James SP, Sneller MC.
5. Habif TP. Vesicular and bullous diseases. In: Habif TP. Clinical Use of cytotoxic agents and cyclosporine in the treatment of
Dermatology: A color guide to diagnosis and therapy. 6th ed. New autoimmune disease. Part 1: rheumatologic and renal diseases.
York: Elsevier; 2016. Ann Intern Med. 1998 Jun 15;128(12 Pt 1):1021­8.
6.Billings SD. Dermatoses. In: Goldblum JR, Lamps LW, 21. Culton DA, Diaz LA. Treatment of subepidermal immuno­
McKenney KJ, Myers JL. Rosai and Ackerman’s surgical bullous diseases. Clin Dermatol. 2012 Jan­Feb; 30(1):95­102.
pathology. 11th ed. New York: Elsevier; 2018. 22. Mutasim DF. Therapy of autoimmune bullous diseases. Ther
7. Cunliffe T. Linear IgA disease (syn. chronic bullous disease of Clin Risk Manag. 2007 Mar; 3(1):29­40.
childhood; linear IgA bullous dermatosis). 2014 [cited 2018 August 23. Ruetter A, Luger TA. Efficacy and safety of intravenous
30]. In: Primary Care Dermatology Society [Internet]. immunoglobulin for immune­mediated skin disease: current view.
Rickmansworth: The Primary Care Dermatology Society. Available Am J Clin Dermatol. 2004;5(3):153­60.
from: http://www.pcds.org.uk/clinical­guidance/linear­iga­disease­
24. Mehren CR, Gniadecki R. Epidermolysis bullosa acquisita:
syn.­chronic­bullous­disease­of­childhood­linear­iga­bul.
current diagnosis and therapy. Dermatol Reports. 2011 Oct 5;
8. Valeski JE, Kumar V, Beutner EH, Cartone C, Kasprzyk K. 3(3):e38.
Differentiation of bullous pemphigoid from epidermolysis bullosa 25. Velez AMA, Vasquez­Hincapie DA, Howard MS. Autoimmune
acquisita on frozen skin biopsies. Int J Dermatol. 1992 basement membrane and subepidermal blistering diseases. Our
Jan;31(1):37­41. Dermatol Online. 2013; 4(Suppl. 3):647­662.
9. Fernandes MD, Chiminazzo MD, Tebcherani AJ, Aoki V, 26. Tan SK, Tay YK. Bullous pemphigoid: Profile and outcome in a
Sanchez APG. Inflammatory epidermolysis bullosa acquisita: case series of 100 cases in Singapore. J Dermatol Dermatol Surg
report. An Bras Dermatol. 2009 Apr;84(2):181­184. 2018;22:12­5.

Editor in chief: Alvin S Concha • Issue Editors: Maricarr Pamela M Lacuesta, Mark Anthony Tom • Associate Editors: Seurinane Sean B Española, Aura Rhea D Lanaban, Eugene Lee L Barinaga,
Alex Ivan Junefourth Bolor • Managing Editor: Clarence Xlasi D Ladrero • Assistant Editors: Jaryll Gerard Ampog, Rodel C Roño • Layout Editor: Clarence Xlasi D Ladrero

SPMC JHCS OFFICE Hospital Research Office, Level 1 Outpatient Building, Southern Philippines Medical Center, JP Laurel Avenue, Davao City, Philippines
Landline (+6382) 2272731 loc 4615 • Website http://spmcpapers.com • Email info@spmcpapers.com

Crisostomo MVN, Lacuesta­Gutierrez MPM. SPMC J Health Care Serv. 2018;4(1):8.