Ocular Mucous Membrane Pemphigoid after
Occasional Finding or Predisposing Event?
Luca Fania, MD,1,* Maria I. Giannico, MD,2,* Romina Fasciani, MD,2Anna Zampetti, MD,1
Simone Ambrogio, MD,2Emilio Balestrazzi, MD,2Claudio Feliciani, MD1
characterized by subepithelial detachment resulting from an immunologic reaction against conjunctival basal
membrane zone (BMZ) antigens. Lyell syndrome (LS) is a drug-induced, T cell-mediated, cytotoxic reaction
involving the mucocutaneous areas. Two patients with LS are presented in whom OMMP developed.
Report of 2 cases.
Two male patients, 80 and 60 years old, with persistent corneal ulcerations, corneal melting,
and inflammation some months after an LS episode.
Conjunctival biopsy samples were obtained to perform direct immunofluorescence (DIF) and
histologic analyses. Indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA) also
Main Outcome Measures:
Immunodeposit findings on the conjunctival BMZ obtained by DIF and IIF,
inflammatory infiltration of the corneoconjunctival samples studied by histologic analysis, and autoantibodies of
patient sera directed against BMZ antigens tested by ELISA.
Direct immunofluorescence analyses showed immunoglobulin G and complement 3 component
deposits along the BMZ in a linear pattern. Histologic analysis revealed the presence of eosinophils, neutrophils,
and mast cells with fibrin deposition in the substantia propria of both patients; the data confirmed the clinical
suspicion of OMMP. The IIF and ELISA results were negative.
Chronic eye surface injury associated with LS may promote autoimmunization against ocular
epithelial BMZ antigens, playing a strategic role in the subsequent onset of OMMP. The occurrence of OMMP
after LS could be an occasional finding, or conversely, LS could be an underestimated predisposing factor in the
development of OMMP.
The author(s) have no proprietary or commercial interest in any materials discussed
in this article. Ophthalmology 2012;119:688–693 © 2012 by the American Academy of Ophthalmology.
Ocular mucous membrane pemphigoid (OMMP) is an autoimmune disease involving the eye and
Mucous membrane pemphigoid is an autoimmune disease that
is characterized by vesicles or bullae on mucous membrane
areas, usually leading to scarring. Oral and ocular mucous
membranes are the most affected, followed by nasal, nasopha-
ryngeal, laryngeal, middle ear,anogenital,esophageal,andbron-
chial mucosae and skin (commonly adjacent to orifices). Mucous
membrane pemphigoid belongs to the immune-mediated subep-
ithelial blistering diseases, which also include bullous pemphi-
goid (BP), pemphigoid gestationis, dermatitis herpetiformis,
linear immunoglobulin (Ig) A disease, epidermolysis bullosa
acquisita, and others.1
Ocular mucous membrane pemphigoid (OMMP) is a sub-
group of mucous membrane pemphigoid with exclusive ocular
involvement. Previously named ocular cicatricial pemphigoid,
this bilateral, sight-threatening disease is characterized by pro-
gressive conjunctival cicatrization associated with corneal vas-
cularization and scarring. It generally presents a chronic
course, characterized by periods of activity subsequent to qui-
escent phases.2,3The disease may occur in young or old
patients, but it is more often seen in patients who are in their
seventh decade of life.3Women are much more often affected
by this disease compared with men, at a 6:1 ratio.4Ocular
mucous membrane pemphigoid may be associated with other
autoimmune diseases, such as rheumatoid arthritis, ankylosing
spondylitis, and systemic lupus erythematosus.5,6
Lyell syndrome (LS), also known as toxic epidermal
necrolysis, is a severe adverse drug reaction involving the
mucocutaneous areas. Some data suggest that LS and its
mild form, Stevens-Johnson syndrome (SJS), are provoked
by the inability to detoxify some intermediate drug metab-
olites.7–9This failure leads to an immunologic process in
which these drug metabolites react with human tissue struc-
tures and form antigenic complexes.10,11The authors report
2 consecutive cases of OMMP that developed after LS. This
finding is probably rare but underestimated.
Patients and Methods
The institutional review board of the Catholic University,
Rome, Italy, ruled that approval was not required for this study.
© 2012 by the American Academy of Ophthalmology
Published by Elsevier Inc.
ISSN 0161-6420/12/$–see front matter
Informed consent was obtained from each patient in this series,
and in both cases, this interventional research adhered to the
stipulations presented in the Declaration of Helsinki. A litera-
ture review was conducted to verify whether previous reports of
these findings had been presented. The PubMed and MEDLINE
databases were searched from 1978 to the present, and the
search included the following terms: ocular mucous membrane
pemphigoid, ocular cicatricial pemphigoid, Lyell syndrome,
toxic epidermal necrolysis, basement membrane zone, and di-
Both patients in this study underwent conjunctival biopsies. Direct
immunofluorescence (DIF), indirect immunofluorescence (IIF), and
enzyme-linked immunosorbent assay (ELISA) were performed in
an effort to establish a diagnosis of OMMP. The methods for
conjunctival biopsy and immunofluorescence and the immunoen-
zymatic technique are described below.
The biopsy samples were obtained under injected anesthesia
with 2% Xylocaine without a vasoconstrictor using a scalpel on the
mucosa adjacent to the lesion for DIF testing, and another frag-
ment was taken from the affected mucosa for histologic analysis,
preserved in 10% formaldehyde.
For the DIF analysis, the conjunctival biopsy was laid out in a
plastic cryomold, covered by an optical cutting temperature me-
dium (Tissue Tek, Leica, Italy) and frozen quickly. Four microm-
eters of frozen conjunctival sections were cut in a cryostat, and the
sections were placed on polylysine-coated slides. The slides were
placed in a wet chamber at room temperature, and fluorescein
isothiocyanate conjugated antihuman Igs (1:80 dilution of antihu-
man IgA, IgM, and IgG; DAKO, Glostrup, Denmark) and a 1:80
dilution of antihuman complement 3 (DAKO) were added to the
cross sections. After a 30-minute incubation period, the slides were
washed twice in phosphate-buffered saline for 10 minutes each. To
set up the slides, a fluorescence mounting medium (DAKO) and a
cover glass were used. The slides were read in an epiluminescence
50-watt Zeiss microscope (Zeiss, Arese, Italy) with ?10 and ?40
Indirect immunofluorescence was performed on the oral mu-
cosa using polyclonal rabbit antihuman IgG/fluorescein isothio-
cyanate (FITC) (DAKO). The mucosa sections were incubated
with the patients’ sera for 30 minutes at room temperature. After
3 washes with phosphate-buffered saline, the polyclonal rabbit
antihuman IgG/FITC was added at 1:80 dilution for 30 minutes.
Enzyme-linked immunosorbent assay was performed to detect
the IgG immunoglobulin reactions to some BP proteins—BP180
(NC16a) and BP230 (BP230-N and BP230-C)—in the patients’
sera, using the semiquantitative Mesacup BP180 and BP230
ELISA tests (Medical and Biological Laboratories, Nagoya, Ja-
pan). This test was performed with 1:100 diluted sera in duplicate
wells, according to the manufacturer’s instructions. Enzyme-
linked immunosorbent assay index values were expressed as units
per milliliter of sera (U/ml). Values of more than 9 U/ml were
Patient 1. An 80-year-old white man was referred to the Oph-
thalmology Department of the A. Gemelli Policlinic, Rome, Italy,
in May 2009 for persistent ocular inflammation, burning, bleph-
arospasm, tearing, and photophobia. He had an acute episode of
LS 5 months earlier, secondary to systemic levofloxacin treat-
ment for a urinary tract infection. During that period, extensive
vesiculobullous erosions on the trunk and limbs with hemor-
rhagic crusts on the ocular and oral mucosa developed in the
patient. This life-threatening episode of LS gradually subsided
after intravenous fluids, high doses of corticosteroids (methyl-
prednisolone 60 mg/day intravenously) and intravenous human
Igs (2.5 g/kg daily for 5 days). One month after the onset of the
LS episode, severe conjunctival inflammation developed in the
patient, resulting in trichiasis, corneal ulceration, and scarring
(Fig 1A). The disease led to symblepharon, associated with
ocular pain and progressive loss of vision (Fig 1B). The patient
was treated with topical therapy (0.3% netilmicin and 0.1%
dexamethasone drops twice daily, 1% atropine drops 3 times
daily, 0.15% hyaluronic acid and 0.05% ginkgo biloba extract
drops 4 times daily, 25 000 IU/100 g retinol eye ointment at
bedtime, autoserum eye drops 6 times daily obtained after 4000
cycles/10 minutes centrifugation of 30 ml of the patient’s blood
and stored in a sterile dropper at 4° C; autoserum was not
diluted, but was used at a natural concentration). The patient
also received a low dose of systemic corticosteroids (methyl-
prednisolone 16 mg/day orally) and was submitted to a double-
layer graft of human amniotic membrane (HAM) to reduce
ocular inflammation and to restore the integrity of the corneal
surface. The Eye Bank at San Giovanni Addolorata Hospital,
Rome, Italy, made HAM available for use. Six months after the
LS episode, because of persistent ocular damage, a conjunctival
biopsy was obtained from the lesional area for histologic anal-
ysis and from the perilesional mucosa for DIF. Indirect immu-
nofluorescence and ELISA also were performed. A description
of the findings is reported below. The confirmed diagnosis of
OMMP led the clinicians to continue the topical therapy as
described above and to begin a regimen of intravenous human
Igs (2 g/kg daily for 3 consecutive days) and oral corticoste-
roids (dexamethasone 25 mg/day). The prescribed treatment led
to considerable improvement of the disease.
Patient 2. A 60-year-old white man was hospitalized at the
Dermatology Department of the A. Gemelli Policlinic, Rome,
Italy, in August 2009 for an acute episode of LS after therapy with
allopurinol for gout. An ophthalmologic evaluation was re-
quested because of the onset of painful inflammation in both
eyes. The LS gradually subsided after treatment with high-dose
corticosteroids (methylprednisolone 40 mg/day intravenously),
intravenous human Igs (2.0 g/kg daily for 5 days), and intra-
venous fluid. Two months after the onset of the LS episode, the
patient showed conjunctivitis in the right eye that led to a
corneal neovascularized ulceration and to tarsal fibrosis a few
months later. Topical treatment (antibiotics, corticosteroids,
cycloplegics, autoserum and artificial tears, eye drops or oint-
ments, as described in the first case) provided no benefit to the
clinical symptoms, and he underwent a double-layer graft of
HAM. After 1 week, the HAM was reabsorbed, whereas the
corneal ulceration persisted. Two weeks after the right eye
complication, the left eye was affected by severe bulbar and
tarsal conjunctival inflammation, resulting in fornix foreshort-
ening, symblepharon, deficient tear production, corneal ulcer-
ation, and scarring (Fig 1C). Four months after the LS episode,
a conjunctival biopsy sample was obtained (lesional mucosa for
histologic analysis and perilesional mucosa for DIF) for persis-
tent ocular injury. Indirect immunofluorescence and ELISA also
were performed. The findings of all these analyses are reported
in the Results section.
After the diagnosis of OMMP was made, topical therapy was
continued and systemic therapy (dexamethasone 25 mg/day orally)
was prescribed. The HAM grafts were performed between Novem-
ber 2009 and January 2010 (3 HAM grafts in the right eye
associated with 3 conjunctival plastics and 2 HAM grafts in the left
eye followed by 2 conjunctival plastics). Subsequently, a corneal
patch from sclerocorneal bank donor tissue was required for de-
scemetocele onset in the right eye, followed by partial tarsorrhaphy
Fania et al ? OMMP Pemphigoid after Lyell Syndrome
For both patients, histologic evaluation revealed eosinophils, mast
cells, and rare neutrophils in different amounts, with fibrin deposits
in the conjunctival substantia propria. Intraepithelial inflammatory
cells (neutrophils and lymphocytes) and subepithelial plasma cells
also were detected. The DIF analysis showed IgG (Fig 2A) and
complement 3 deposits (Fig 2B) along the basal membrane zone in
a linear pattern. The data confirmed the diagnosis of OMMP.
Indirect immunofluorescence and ELISA for BP180 and BP230
demonstrated negative results.
Both genetic and environmental factors may play roles in
susceptibility to OMMP and in LS pathogenesis. In 1991,
Chan et al12reported 5 cases of OMMP subsequent to SJS.
Figure 1. A, Slit-lamp photograph of the right eye of patient 1 obtained 1 month after acute episode of Lyell syndrome resolution showing a 2.5?3-mm
paracentral corneal ulceration. B, Slit-lamp photograph of the left eye of patient 1 showing tarsal conjunctival inflammation and scarring. C, Slit-lamp
photograph of the left eye of patient 2 showing neovascularized corneal melting and ulceration. D, Slit-lamp photograph of the right eye of patient 2
showing corneal descemetocele before corneal patch transplantation
Figure 2. A, Direct immunofluorescence from patient 1 showing a linear and continuous deposition of immunoglobulin G at the basal membrane zone
of perilesional conjunctiva. B, Direct immunofluorescence from patient 2 showing a linear and continuous deposition of complement 3 component at the
basal membrane zone of perilesional conjunctiva.
Volume 119, Number 4, April 2012
In 2007, De Rojas et al13reported 1 case of OMMP (con-
firmed by DIF) that developed after LS. The development of
an autoimmune skin disease may be a consequence of
epidermal damage, such as pemphigus after a burn or pem-
phigoid induced by radiotherapy.14,15Some drugs, such as
clonidine, practolol, and topical glaucoma medications
(containing demecarium bromide, echothiophate iodide,
adrenaline, and pilocarpine), may lead to ocular alterations
that are clinically and histologically indistinguishable from
OMMP but generally demonstrate negative results on DIF.
This is called pseudopemphigoid.16,17
With regard to genetic factors, the expression of the
human leukocyte antigen (HLA)-DR4 and HLA-DQB1 al-
leles considerably increases the risk of OMMP.18–21Fur-
thermore, patients affected by LS have an increased inci-
dence of the HLA-B12 allele.22The presence of HLA-
DQB1 even increases the possibility of SJS developing with
ocular complications.23,24For this reason, the high expres-
sion of the HLA-DQB1 allele may play a role in acquired
diseases with ocular involvement because it is expressed
more often in OMMP patients and in patients affected by
SJS with ocular involvement.20,23,24These findings reported
in the literature also were confirmed by the genetic analyses
performed in the 2 present cases, which showed higher
expression of the HLA-A0206, HLA-B12, and HLA-DQB1
alleles in patient 1 and increased expression of the HLA-
B5901, HLA-DQB1, and HLA-DR4 alleles in patient 2.
Ocular mucous membrane pemphigoid is a complex au-
toimmune disorder that is characterized by the presence of
different components of the immune system. Plasma cells,
lymphocytes, neutrophils, eosinophils, mast cells, and
Langerhans’ cells with fibrin deposition in the substantia
propria were found in the conjunctival biopsies of OMMP
patients with active disease.25–27The presence of Langer-
hans’ cells in the conjunctival infiltrate of active OMMP
suggests the hypothesis that antigen-presenting cells may
activate an immunologic reaction to self-antigens that may
develop after epithelial damage. The subsequent activation
of plasma cells and T lymphocytes may lead to an inflam-
matory process, with the production of specific autoantibod-
ies directed against basal membrane zone (BMZ) structures,
as in OMMP.
In cutaneous lesions and in blister fluid from LS patients,
the presence of clusters of differentiation 8 (CD8?) T
lymphocytes that express markers of natural killer cells and
inflammatory cytokines, such as interleukin (IL) 2, IL-5,
IL-6, IL-10, IL-13, IL-18, tumor necrosis factor ?, inter-
feron ?, and Fas ligand, were seen.28–30These CD8? T
lymphocytes are thought to be drug-specific cytotoxic T
cells.31,32Epidermal necrosis depends on the keratinocyte
apoptosis mechanism because of the high expression of
certain cytokines of the tumor necrosis factor family bind-
ing to their death receptors and to the deregulation between
the expression of keratinocyte Fas and its membrane-bound
ligand (Fas ligand).33,34Furthermore, a cell-mediated cyto-
toxic reaction to keratinocytes may be the etiologic trigger
of this disease.35The mechanism by which drugs may cause
this reaction still is not clear, although genetic differences in
patients’ metabolic reactions to drugs may explain why
some patients are much more susceptible to developing LS.8
Histologic analyses performed on the conjunctival sam-
ples from the 2 current patients revealed the presence of
eosinophils, neutrophils, and mast cells in different
amounts, with fibrin deposition in the substantia propria.
Direct immunofluorescence performed on the conjunctival
biopsies of the 2 patients showed a continuous band of IgG
and complement 3 along the BMZ. This linear pattern,
visible on fluorescence microscopy, is indicative of OMMP.
However, the immunofluorescence findings from the tissues
of patients affected by SJS and LS have shown immune
deposits in the dermal vascular structures or, more rarely,
immune deposits on the BMZ in a granular pattern.36,37
The sensitivity of DIF analysis on conjunctival biopsies
for OMMP has been reported to be 60% to 80%. Therefore,
the absence of linear deposits on conjunctival BMZ in DIF
analyses does not exclude OMMP. Repetition of the biop-
sies or further analyses of the patient’s sera are necessary to
validate the diagnosis.38,39Immunoblot analysis identified
in the sera of OMMP patients the presence of IgG autoan-
tibodies against the BP antigens BP230 and BP180 or
against the ?4 integrin subunit, or moreover, IgA autoanti-
bodies against a 45-kDa antigen that has not yet been
The ELISA performed on the sera of the 2 patients
showed no antibodies against BP180 or BP230. Further-
more, IIF using oral mucosa did not detect any deposition
on the BMZ. These negative results could be explained by
the systemic immunosuppressive drugs with which the 2
patients were treated. Chan et al42provided another possible
explanation, which is that in OMMP sera, there are no
antibodies against BP antigens. These findings were con-
firmed by Leonard et al43because they did not detect
antibodies on the epithelial BMZ in IIF using OMMP pa-
tients’ sera. Some authors have concluded that the diagnosis
of OMMP is based on clinical and immunohistopathologic
Guendry et al45reported a higher incidence of ocular
involvement in LS patients with severe skin damage than in
patients with less skin involvement, such as in SJS. The late
ocular sequelae of LS are related to the severity of the
ocular involvement during the acute phase of LS.46Guendry
et al45reported in 2009 that subconjunctival fibrous scarring
was the second most common ocular late complication in 49
patients with LS or SJS. Subconjunctival fibrous scarring is
a typical finding in OMMP. The frequent finding of sub-
conjunctival fibrous scarring in ocular biopsies of patients
with persistent ocular complications after LS or SJS sug-
gests that OMMP after LS or SJS could be an underesti-
mated finding because, in previous reports, DIF, IIF, and
ELISA were not performed.
López-García et al46suggested that ocular involvement
represents the first long-term complication in patients with
LS. The therapy for this complication is based mainly on
topical care (steroids, antibiotics, artificial drops, therapeu-
tic contact lenses) or HAM grafts. Immunosuppressive
treatment is not used because the pathogenesis is still not
well known. Conversely, the use of immunosuppressive
therapy in OMMP is justified by the autoimmunity patho-
genesis of this disease. Long-term ocular complications
developed after SJS or LS should be investigated to deter-
Fania et al ? OMMP Pemphigoid after Lyell Syndrome
mine the correct diagnosis and to administer the appropriate
Although the association between LS or SJS and OMMP
may be coincidental, the authors hypothesize that chronic
eye surface injury associated with LS may represent an
autoimmunologic trigger. It is likely that autoimmunization
against ocular epithelial BMZ antigens that are not normally
present in the immune system plays a critical role in this
process. As suggested by Chan et al,12severe ocular injury
resulting from SJS or LS may promote an autoimmune
phenomenon in which dendritic cells process and present
ocular epithelial BMZ structures to inflammatory cells. This
process may lead to immunologic damage of the conjunc-
tival BMZ, as in OMMP. It is not well known how SJS or
LS that involves the mucocutaneous areas may lead to an
autoimmune disease that affects only the ocular mucosa.
In conclusion, persistent ocular inflammation in patients
affected by LS should prompt clinical suspicion of OMMP.
The authors recommend performing a DIF study on the
conjunctival mucosa in all patients with ocular sequelae
after an LS or SJS episode.
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Footnotes and Financial Disclosures
Originally received: March 22, 2011.
Final revision: September 14, 2011.
Accepted: September 19, 2011.
Available online: December 22, 2011.Manuscript no. 2011-470.
1Department of Dermatology, Universitá del Sacro Cuore, Rome, Italy.
2Department of Ophthalmology, Universitá del Sacro Cuore, Rome,
*Both authors contributed equally as first authors.
Surgeons (ESCRS), September 2010, Paris, France; and the XIX Congress of
“Giornate di dermatologia clinica,” January 2011, Rome, Italy.
The author(s) have no proprietary or commercial interest in any materials
discussed in this article.
Claudio Feliciani, MD, Department of Dermatology, Catholic Univer-
sity of Sacro Cuore, L.go Gemelli 8, 00168 Rome, Italy. E-mail:
Fania et al ? OMMP Pemphigoid after Lyell Syndrome