REVIEW

CURRENT
OPINION Ocular cicatricial pemphigoid
Kaidi Wang, Gerami Seitzman, and John A. Gonzales

Purpose of review
This review offers recommendations for monitoring disease status in ocular cicatricial pemphigoid as well
therapeutic options including local and systemic therapies.
Recent findings
A negative biopsy on direct immunofluorescence does not preclude a diagnosis of OCP. If a patient’s
cicatrization is active and/or progressive, systemic immunosuppression should be commenced.
Summary
OCP is a chronic systemic autoimmune disease that requires systemic immunosuppression.
Keywords
conjunctival cicatrization, keratinization, ocular cicatricial pemphigoid
Downloaded from http://journals.lww.com/co-ophthalmology by BhDMf5ePHKbH4TTImqenVEyMrwFXE1ZVaPFiIrsrumHXoe86039OYCmWfKd+4+6I on 12/03/2018

INTRODUCTION patient presenting with or referred for cicatrizing

Ocular cicatricial pemphigoid (OCP) is a chronic
process and a subset of the systemic autoimmune
inflammatory disease benign mucous membrane
pemphigoid (MMP). Pemphigoid is a blistering dis-
ease characterized by the linear deposition of immu-
noglobulin (Ig) G, IgA, and C3 in the epithelial
basement membrane. Specific target antigens
within the basement membrane may include hemi-
desmosomal proteins, laminins, and collagen. This
antibody/antigen interaction initiates an inflamma-
tory cascade leading to subepithelial blistering.
With MMP, any mucous membrane can be affected
including the trachea, esophagus, vagina, anus, and
urethra. The term OCP is used when there is pre-
dominant involvement of the conjunctiva. Despite
the word ‘benign’ appearing in the name of mucous
membrane pemphigoid, this condition can cause
significant morbidity especially with tracheal and
esophageal involvement. When ocular involvement
is severe, OCP can lead to blindness.
EPIDEMIOLOGY
OCP is a rare disease, occurring in 13 patients out of
105 000 over a 60-year period [1]. OCP typically
affects patients in their 50s to 60s with a female
to male preponderance as high as 3 : 1 [1].
DIFFERENTIAL DIAGNOSIS
Not all cicatrizing conjunctivitis represents OCP.
Before arriving to a premature conclusion that a
conjunctivitis has OCP, one must discuss with the
patient exposures that can cause conjunctival scar-
ring. One should inquire whether thermal and
chemical burns to the eye have occurred in the past,
whether there is a prior history of surgery to the
eyelids, and if the patient has experienced Steven’s
Johnson Syndrome (SJS). The patient may not rec-
ognize the term ‘SJS,’ but would recall if he or she
had experienced a significant inflammatory condi-
tion affecting their skin or mucous membranes in a
severe response to an infection or medication. Addi-
tionally, significant inflammation in postinfectious
conjunctivitis, such as what occurs in epidemic
keratoconjunctivitis mediated by adenovirus, may
not be immediately recognizable to a patient, but
inquiring whether a patient has experienced robust
pink eye may allow one to recall such an important
event. Pseudopemphigoid, drug-induced ocular cic-
atricial pemphigoid or medicamentosa are the terms
used when cicatrization occurs because of toxic
exposure from ocular medications, in particular to
glaucoma eye drops [2].
Francis I. Proctor Foundation, Department of Ophthalmology, University
of California, San Francisco, California, USA
Correspondence to John A. Gonzales, MD, Francis I. Proctor Foundation,
Department of Ophthalmology, University of California, San Francisco,
95 Kirkham Street, San Francisco, CA, USA.
E-mail: john.gonzales@ucsf.edu
Curr Opin Ophthalmol 2018, 29:543–551
DOI:10.1097/ICU.0000000000000517

1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Ocular manifestations of systemic disease
KEY POINTS
 Ocular cicatricial pemphigoid is a subset of benign
mucous membrane pemphigoid featuring
immunoglobulin or complement deposition at the level
of the epithelial basement membrane zone.
 As OCP is a systemic autoimmune condition, systemic
immunosuppression is warranted.
 Monitoring for disease progression and complications
is important to prevent blindness.
ASSESSING THE PATIENT
Proper evaluation for OCP requires a thorough
review of systems, past medical history, and inquiry
of all medication exposures (including nonophthal-
mic). Inquiries into oral, tracheal, skin, vulvar, ure-
thral, or anal lesions should be made. Does the
patient have difficulty swallowing? Are there respi-
ratory issues such as shortness of breath or wheez-
ing? Does the patient have oral blisters or
ulcerations? Have they ever had blisters involving
their labia, vagina, cervix, anus? Is there difficulty
with urination? If skin lesions exist and they are
easily accessible, one should investigate the nature
of such lesions. For example, patients with MMP
may have lesions on the scalp or behind the ears.
These appear as blistering lesions that can later form
scars. Skin lesions in sarcoidosis do not typically
blister and appear more raised and indurated. The
gingiva can also be easily inspected in clinic and
may exhibit extensive atrophy along with a red
appearance. Buccal mucosa may show ulcerative
ulcers and erosions. The ophthalmologist can listen
for stridor during the assessment. This may be a
manifestation of tracheal involvement in MMP
but can also be a feature in sarcoidosis or GPA.
DIAGNOSTIC WORKUP
To rule out other systemic causes of conjunctival
scarring, we typically perform serologic testing for
antineutrophil cytoplasmic antigen (ANCA) and
urinalysis with microscopy (to evaluate for nephrop-
athy) as part of an assessment for ANCA-associated
vasculitidies. We also perform a chest X-ray or a
high-resolution computed tomographic scan when
there is suspicion for sarcoidosis. Additionally, if a
patient manifests constitutional symptoms such as
fevers, unexplained weight loss, malaise, and night
sweats, the possibility for paraneoplastic process
mediating the cicatrizing conjunctivitis should be
considered [3–7]. PET can be used to evaluate for
foci of neoplastic disease in suspected cases of
544 www.co-ophthalmology.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
paraneoplastic disorders. However, after thorough
review of systems and laboratory investigations fail
to disclose another cause, consideration for OCP
should be made.
DIAGNOSIS
Definitive diagnosis of mucous membrane pemphi-
goid requires demonstrating linear deposits of
immunoglobulin or complement at the basement
membrane zone, which will produce a linear hyper-
fluorescence when utilizing direct immunofluores-
cence (DIF). The diagnostic yield of a conjunctival
biopsy will be the highest if it includes an area of
inflamed conjunctiva (as opposed to areas charac-
terized by complete subconjunctival fibrosis). The
greatest challenge with diagnostic biopsies is the
high false negative rate of the test. Despite being
the gold standard for diagnosis, the sensitivity is
variable and frustratingly, the reproducibility of a
positive biopsy from the same patient with known
disease is low. Because of this, there is the frequently
encountered diagnostic dilemma of a patient with
progressive cicatrizing ocular disease whose biopsy
was negative based on DIF. Should such a patient be
disqualified from having a diagnosis of MMP? Ong
&&
et al. [8 ], writing for the Mucous Membrane Pem-
phigoid Study Group found that patients meeting
clinical criteria for ocular MMP, but having negative
biopsy should be considered as having DIF-negative
MMP. Such a designation is important as it can open
the doors for using the same important therapeutic
paradigms used in DIF-positive MMP.
Dr Margolis thoughtfully made a case against
performing biopsies in patients meeting clinical
features of OCP. He argued that after ruling out
other causes of cicatrizing conjunctivitis such as
SJS or medication toxicity, immunosuppression is
required in cases of advancing cicatrizing conjunc-
tivitis regardless of a positive or negative DIF. More-
over, he made the point that patients regardless of
positive of negative DIF should be referred to spe-
cialists (including dermatologists, rheumatologists,
and otolaryngologists) to evaluate for extraocular
involvement of MMP [9]. Although this is a sound
approach, a case can also be made for conjunctival
biopsy, even repeat biopsies when there is a high
suspicion for OCP. Our reasoning is that while DIF
may be negative, other histopathologic inspections
may provide important clues that may be indicative
of other processes. Other conditions associated with
cicatrizing conjunctivitis include the ANCA-associ-
ated vasculitides, sarcoidosis, and paraneoplastic
processes [10,11]. Therefore, when performing biop-
sies, consideration for obtaining large enough speci-
mens so that half may be sent to immunopathology
Volume 29  Number 6  November 2018
 Ocular cicatricial pemphigoid Wang et al.

for DIF and the other half for routine histopatho-
logic processing should be made. Thus, while DIF
may be negative in such cases, identifying granulo-
mas on histopathology is important as this can help
direct specialty referrals or be relevant in treatment
options even when a patient is not manifesting
overt systemic features of vasculitis or sarcoidosis.
As an example, we recently saw a Hispanic
woman with negative past medical history and
diagnostic evaluations (including chest X-ray)
who exhibited progressive cicatrizing conjunctivi-
tis. Her initial conjunctival biopsy was negative on
DIF and histopathology. While she was ANCA neg-
ative, consideration for ANCA-negative vasculitis
was considered. She was started on methotrexate
25 mg p.o. weekly and oral prednisone at 1 mg/kg
daily. However, her cicatrization continued to prog-
ress and she required advancement to pulse intrave-
nous cyclophosphamide therapy. The patient was
noted to have new stridor in our clinic, and a repeat
conjunctival biopsy was pursued. This biopsy dis-
closed characteristic DIF findings of OCP. The DIF
positive sample opened an additional therapeutic
option [anti-tumor necrosis factor (TNF) therapy]
that would not have been considered had we con-
tinued down the route of a vasculitis cause. Another
patient presented with cicatrizing conjunctivitis
and, although DIF was negative, histopathology of
her conjunctiva disclosed granulomas. This patient
was ultimately diagnosed with sarcoidosis (Fig. 1).
DOCUMENTING PROGRESSION
Recognition of OCP progression can be challenging
but is required to assess efficacy of treatment. In the
time of paper charts, detailed drawings of conjunc-
tival involvement were commonplace. However,
even the best artist found difficulty in comparing
one’s prior drawing with possibly new and subtle
areas of progression. With electronic charting
detailed drawings using a computer mouse or tablet
is typically either not feasible or adequate [12–14].
Descriptive text is often used to describe clinical
appearance. The lexicon used varies per observer
and is likely less accurate for comparison than draw-
ings. Handheld external photography utilizing sin-
gle lens reflex (SLR) cameras (CPT Procedure Code
92285) [15,16] is an excellent way to document

FIGURE 1. Photomicrograph of a conjunctival biopsy from a patient with bilateral cicatrizing conjunctivitis. Direct
immunofluorescence was negative, but histopathology revealed a granuloma (within red circle) consistent with sarcoidosis.

1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com 545

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Ocular manifestations of systemic disease
cicatrization. When assessing for progression
changes it is necessary to evaluate for any changes
in the following parameters: forniceal shortening,
subconjunctival scarring, symblepharon, keratiniza-
tion, limbal stem cell dysfunction, and corneal
scarring. Progression of anterior stromal corneal
scarring and limbal stem cell deficiency may occur
independent of forniceal shortening alone and doc-
umenting such features is important.
Measuring inferior fornix depth and progressive
effacement is considered to be a sensitive method
for identifying progression [17]. This was advocated
for initially by Mondino et al. [18]. Reproducibility
of this measurement may be variable depending on
the amount of traction the examiner places on the
inferior lid. Utilizing a photographic system similar
to that described by Foster [19] should be consid-
ered. Additional external photographs with the
patient looking in primary gaze in addition to the
cardinal positions of gaze and everting the superior
and inferior lids provides 11 photographs in total
and can be especially helpful in documenting even
subtle progression over numerous visits (Fig. 2). As
we utilize SLR cameras, the acquisition of external
photographs adds only minimal time to the patient
encounter and does not require that the patient be
put in the queue for slit lamp photographs. At each
visit, the patient is compared with his or her prior
photographs displayed on a computer screen to
evaluate for any new areas of progression. We also
will compare the patient to his/her earlier photos as
FIGURE 2. External photographs taken in cardinal positions of gaze as well as with superior and inferior lids everted.
546 www.co-ophthalmology.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
progression can be very subtle between one visit to
the next. When we identify progression, we then
consider advancing therapy.
DISEASE COURSE AND COMPLICATIONS
Recurrent conjunctivitis in the setting of OCP is not
always indicative of disease progression. Other com-
monly encountered causes of ocular surface inflam-
mation in the setting of OCP include trichiasis,
keratinization, and infection.
Trichiasis is common in OCP as cicatrization
involving the lid margin can lead to lashes abrading
the cornea or the conjunctiva, which can set the
stage for corneal superinfection or conjunctival
injection, respectively.
Chronic inflammation exacerbated by second-
ary aqueous and evaporative tear loss leads to kera-
tinization of the ocular surface. Loss of conjunctival
goblet cells along with abnormal mucosal epithelial
differentiation leads to dessication of the ocular
surface. Normally, there is an abrupt transition from
keratinized stratified squamous epithelium of the
eyelid skin to nonkeratinized mucosal epithelium
of the palpebral conjunctiva, which occurs at the
mucocutaneous junction. However, secondary
aqueous deficiency [20] or evaporative tear loss from
Meibomian gland dysfunction or loss leads to epi-
dermidalization and keratinization of the palpebral
and bulbar conjunctiva. Moreover, chronic inflam-
mation, which can occur in the setting of OCP itself
Volume 29  Number 6  November 2018

or from recurrent infectious conjunctivitis or trichi-
asis can lead to epithelial epidermidalization, char-
acterized by a loss of goblet cells, conversion from
stratified columnar to stratified squamous cells, and
keratinization of the surface cells, replete with rete
ridges and pegs [21]. The keratinized surfaces lack
the wet and reflective appearance that mucosa typi-
cally features and instead appears desiccated and
dull. Such abnormal mucosal epithelial differentia-
tion also frequently occurs in inflammatory condi-
tions including cicatrizing conjunctivitis, Stevens-
Johnson syndrome, and toxic keratoconjunctivitis
[22,23].
In OCP, keratinization and disruption of ocular
surface integrity results in disruption of local
immune function and leads to increased risk of
ocular infections. Patients presenting with new con-
junctival injection should have culture of the con-
junctiva and lids. Typical species that grow include
Staphylococcus aureus and Gram-negative rods. We
consider that OCP patients may be chronically col-
onized with abnormal flora. Even normal flora, such
as Staphylococcus epidermidis, other coagulase nega-
tive Staphylococcus spp. and diphtheroids can cause
conjunctivitis when they exhibit numerous growth
(as opposed to just rare or few colonies on cultures).
Treating patients with topical antibiotic drops
for a week can resolve the conjunctivitis. Close
FIGURE 3. A patient with ocular cicatricial pemphigoid with limbal stem cell deficiency and central corneal perforation
(arrow).
1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Ocular cicatricial pemphigoid Wang et al.
communication with microbiology and requesting
sensitivities is useful.
Limbal stem cell deficiency may occur when
subconjunctival fibrosis involves the region adja-
cent to the basal epithelial layer of the corneal
&
limbus [24 ]. In-vivo confocal microscopy has been
described to identify features of inflammation at the
corneal limbus and demonstrate resolution of
inflammation when immunosuppression has been
&
utilized [24 ].
Corneal perforation occurs in OCP typically
because of corneal superinfection. As noted above,
the compromised ocular surface allows for prolifer-
ation of atypical and aggressive microorganisms
[25]. Chronic corneal epithelial defects may also
result in stromal necrosis and perforation (Fig. 3).
Cornea melts have been described in paraneoplastic
causes of cicatrizing conjunctivitis [4].
TREATMENT
OCP is a systemic disease and requires systemic
treatment. However, local treatment may be consid-
ered as complimentary, but is by no means standard-
of-care. Topical therapy, including all-trans retinoic
acid (ATRA) 0.01–0.1% as either a drop or oint-
ment formulation can be used for keratinization.
ATRA has been shown to inhibit conjunctival
www.co-ophthalmology.com 547
Ocular manifestations of systemic disease
transdifferentiation in animal models and has been
shown to be effective in humans exhibiting kerati-
nization of the conjunctival mucosa or corneal
keratinization [26–28]. N-acetylcysteine 10% eye-
drops may be used if there is a filamentary keratop-
athy. For those exhibiting aqueous deficiency or
decreased tear break up time, artificial tears should
be used. Preservative-free formulations of artificial
tears are ideal to minimize any possible iatrogenic
irritation. Punctal plugs may also be considered to
help patients retain their own tears or lubricating
eye drops longer.
Although high-dose systemic corticosteroids
can manage inflammation in OCP, because of the
chronic nature of the disorder and the long-term
systemic side effects of corticosteroids, long-term
steroid-sparing agents are required. As antimetabo-
lites (such as methotrexate and mycophenolate
mofetil) may take up to 3 months to become thera-
peutic, oral prednisone (or equivalent) at an initial
dose of 1 mg/kg daily, with step-wise dose reduc-
tions, is frequently utilized to manage acute inflam-
mation while awaiting antimetabolite therapy to
become fully therapeutic [29]. The step ladder
approach, similar to what is used for uveitis, can
also be effective in the treatment of OCP [30]. There
are no randomized controlled trials indicating
greater efficacy of one steroid-sparing agent over
another. The antibiotic dapsone is a classic medica-
tion used to treat OCP. Dapsone inhibits folic-acid
synthesis [19] and may be considered for mild dis-
ease. For disease that is moderate-to-severe or that
fails dapsone therapy, antimetabolite therapy
(including methotrexate, mycophenolate mofetil,
and azathioprine) is the next step in management
[31–33].
We agree that a step-ladder approach, which is
similar to what has been utilized for uveitis, can be
used in OCP [30], but may require skipping steps and
advancing to cyclophosphamide or biologic therapy
if the disease is rapidly progressive or switching to
another antimetabolite is felt to be futile. In cases
where failure with one antimetabolite occurs,
switching to another antimetabolite will require
another 3 months to determine full efficacy, so
often prednisone must be restarted to manage any
currently active inflammation. Alternatively, cyclo-
phosphamide or biologic therapy may be pursued.
Cyclophosphamide has been reported to
achieve good remission rates (as high as 91% in a
retrospective cohort study) when oral cyclosporine
2 mg/kg/day in conjunction with prednisone (ini-
tially at a dose of 1 mg/kg/day) were started as first-
line therapy [34]. Because of its rarity, masked
randomized trials do not exist for OCP. However,
from other conditions such as systemic lupus
548 www.co-ophthalmology.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
erythematosus and granulomatosis with polyangii-
tis (GPA), clinical trials have shown that pulse ther-
apy with intravenous cyclophosphamide and anti-
TNF agents (such as infliximab) may be used in OCP
[35]. However, in other causes of cicatrizing con-
junctivitis, anti-TNF agents may not be an appropri-
ate agent. In the case of GPA, for example, anti-TNF
agents are not routinely used. A randomized trial in
which GPA patients were randomized to etanercept
or placebo in addition to their standard-of-care
therapies found that after 6 months, by which time
systemic steroids had been tapered off, there was no
statistically significant difference in remission rates
between the two groups [36]. Whether or not mono-
clonal antibodies that are able to bind multiple
membrane-bound TNFs and induce apoptosis (such
as adalimumab and infliximab) [37,38] may be effec-
tive in GPA remains to be seen. Nevertheless, anti-
TNFs would be avoided in GPA and this makes a case
to perform biopsies as well as check ANCA labs to
identify granulomas consistent with GPA, particu-
larly when there are overlapping features between
GPA and MMP. In short, identifying GPA would
make the use of cyclophosphamide or rituximab
the clear choice, whereas anti-TNF therapy could
be considered in OCP [35].
Combination of intravenous immunoglobulin
(IVIG) and rituximab has been utilized in cases
refractory to cyclophosphamide [39]. IVIG is com-
menced at 2 g/kg per cycle over three equal doses
over 3 days. Rituximab 375 mg/m2 is given intrave-
nous weekly for 8 weeks, then monthly for four
more months. IVIG is administered once a month
until B-cell levels reach a normal percentage of the
complete blood count differential. At that point
IVIG is administered 6 weeks later, increasing the
interval by 2 weeks until the final infusion occurs at
the 16-week interval [40]. The proposed mechanism
of action of this combination therapy involves three
broad phases: B-cell depletion (which occurs in the
first month and is maintained for the first 9
months), then B-cell reconstitution (which occurs
during month 10 through month 24 depending on
when B cells reach 15% of the complete blood cell
count (CBC)), and finally immune restoration (after
month 24) [41].
Occasionally, a patient may fail rituximab,
cyclophosphamide, or both. In these cases, it is
important to explore other options. One of our
patients failed cyclophosphamide and rituximab
&&
and required advancement to bortezomib [42 ].
Bortezomib is a proteasome inhibitor used in treat-
ing multiple myelomas. As OCP is a B-cell mediated
process, the prior identification of OCP by DIF
allowed consideration for the use of bortezomib.
This required interdisciplinary meetings amongst
Volume 29  Number 6  November 2018
 Ocular cicatricial pemphigoid Wang et al.

FIGURE 4. A patient with aggressive and progressive MMP where the ocular disease dictated therapy over oral, respiratory,
and dermatologic disease. At presentation (a and b), both eyes featured conjunctival injection, but both superior eyelids could
be everted. In a year, however (c and d), there was progressive cicatrization involving the inferior lids to a greater degree in
the right eye (c). Moreover, the right eye exhibited corneal neovascularization and the right superior eyelid could no longer
be everted. In another year the right eye (e) has progressed to ankyloblepharon whereas the left eye (f) had less extensive
progression, but progression nonetheless despite cyclophosphamide therapy. The patient received bortezomib, which led to a
remission for over a year, but new progression required restarting bortezomib. The right eye (g) was nearly entirely frozen
with respect to motility and the cornea is entirely keratinized. The left eye (h) showed new symblepharon.

1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved. www.co-ophthalmology.com 549

Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

Ocular manifestations of systemic disease
ophthalmology, rheumatology, hematology, and
dermatology. This patient experienced a remission
of approximately 1 year, before he was noted to
exhibit recurrence of his cicatrization, which
prompted restarting bortezomib (Fig. 4). Addition-
ally, our interdisciplinary meeting had discussed the
use of belimumab, a monoclonal antibody that
targets B-cell activating factor (personal communi-
cation). Again, the diagnosis of OCP was relevant as
hematology and dermatology who were managing
these chemotherapeutic agents required a diagnosis
of a B-cell process to validate their use.
CONCLUSION
Ocular cicatricial pemphigoid is a chronic systemic
autoimmune process and a thorough review of sys-
tems and past medical history can help exclude
other masquerades of cicatrizing conjunctivitis.
Conjunctival biopsy in OCP is frequently negative
and a negative biopsy on DIF does not equate with
ruling out OCP. Advancing and active cicatrization
warrants systemic immunosuppression. If other
masquerades have been ruled out, systemic immu-
nosuppression may proceed without a biopsy. How-
ever, there are occasions where a biopsy may reveal
other non-OCP processes, which may have rele-
vance in directing immunosuppression.
Acknowledgements
We wish to thank Melike Pekmezci, MD, Department of
Pathology, University of California, San Francisco for
provision of the histopathologic photomicrograph used in
Fig. 2.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED
READING
Papers of particular interest, published within the annual period of review, have
been highlighted as:
& of special interest
&& of outstanding interest
1. Bedell AJ. Ocular pemphigus: a clinical presentation of kodachromes. Trans
Am Ophthalmol Soc 1964; 62:109–122.
2. Dart J. Corneal toxicity: the epithelium and stroma in iatrogenic and factitious
disease. Eye (London, England) 2003; 17:886–892.
3. Ahuero AE, Jakobiec FA, Bhat P, et al. Paraneoplastic conjunctival cicatriza-
tion: two different pathogenic types. Ophthalmology 2010; 117:659–664.
4. Gong H, Zhou S, Hu Y, et al. Recurrent corneal melting in the paraneoplastic
pemphigus associated with Castleman’s disease. BMC Ophthalmol 2016;
16:106.
5. Hahn JM, Meisler DM, Lowder CY, et al. Cicatrizing conjunctivitis associated
with paraneoplastic lichen planus. Am J Ophthalmol 2000; 129:98–99.
550 www.co-ophthalmology.com
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
6. Lam S, Stone MS, Goeken JA, et al. Paraneoplastic pemphigus, cicatricial
conjunctivitis, and acanthosis nigricans with pachydermatoglyphy in a patient
with bronchogenic squamous cell carcinoma. Ophthalmology 1992; 99:
108–113.
7. Vroman DT, Breckenridge RR, Solomon KD, et al. Bronchogenic squamous
cell carcinoma presenting as cicatrizing conjunctivitis. Cornea 2006; 25:
611–613.
8. Ong HS, Setterfield JF, Minassian DC, Dart JK. Mucous membrane pemphi-
&& goid with ocular involvement: the clinical phenotype and its relationship to
direct immunofluorescence findings. Ophthalmology 2018; 125:496–504.
This article discusses the pitfall of classifying a patient with a negative DIF who
otherwise meets MMP criteria as having another disease process. Meeting clinical
criteria for MMP warrants immunosuppression.
9. Margolis T. Evidence-based insights into the utility of conjunctival biopsy in
mucous membrane pemphigoid. Ophthalmology 2018; 125:474–475.
10. Miserocchi E, Waheed NK, Baltatzis S, Foster CS. Chronic cicatrizing
conjunctivitis in a patient with ocular cicatricial pemphigoid and fatal Wegener
granulomatosis. Am J Ophthalmol 2001; 132:923–924.
11. O’Donnell JJ Jr, Karakus S, Doroslovacki P, Akpek EK. Sarcoidosis presenting
with cicatrizing conjunctivitis. Optom Vis Sci 2015; 92:e173–e175.
12. Murphy EC, Ferris FL 3rd, O’Donnell WR. An electronic medical records
system for clinical research and the EMR EDC interface. Invest Ophthalmol
Vis Sci 2007; 48:4383–4389.
13. DeBry PW. Considerations for choosing an electronic medical record for an
ophthalmology practice. Arch Ophthalmol 2001; 119:590–596.
14. Nissman SA. Electronic health records. Ophthalmology 2009; 116:
1018–1019.
15. Curtin RE 2nd. External eye photography using 35 mm camera systems.
Journal of ophthalmic nursing & technology 1991; 10:5–14.
16. Sagaties MJ. External eye photography with a single lens reflex camera
system. J Ophthalmic Nurs Technol 1983; 2:94–95.
17. Saw VP, Dart JK, Rauz S, et al. Immunosuppressive therapy for ocular mucous
membrane pemphigoid strategies and outcomes. Ophthalmology 2008;
115:253.e1–261.e1.
18. Mondino BJ, Brown SI. Ocular cicatricial pemphigoid. Ophthalmology 1981;
88:95–100.
19. Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol Soc 1986;
84:527–663.
20. Satchi K, McNab AA. Conjunctival cicatrizing disease presenting with lacrimal
obstruction. Orbit 2016; 35:321–323.
21. L FR, Green WR, Howes EL, et al. Ophthalmic pathology an atlas and
textbook. Vol. 1. Philadelphia: W.B. Saunders Company; 1985.
22. McNamara NA. Molecular mechanisms of keratinizing ocular surface disease.
Optom Vis Sci 2010; 87:233–238.
23. Maumenee AE. Keratinization of the conjunctiva. Trans Am Ophthalmol Soc
1979; 77:133–143.
24. Long Q, Zuo YG, Yang X, et al. Clinical features and in vivo confocal
& microscopy assessment in 12 patients with ocular cicatricial pemphigoid.
Int J Ophthalmol 2016; 9:730–737.
This article discusses the utility of in-vivo confocal microscopy in assessing the
peripheral corneal limbus suggesting a possible additional biomarker in monitoring
disease activity and response to therapy.
25. Ishikawa S, Kato N. A case with corneal perforation due to bacterial concre-
tion derived from lacrimal canaliculitis. Am J Ophthalmol Case Rep 2018;
9:116–118.
26. Tseng SC, Hirst LW, Farazdaghi M, Green WR. Inhibition of conjunctival
transdifferentiation by topical retinoids. Invest Ophthalmol Vis Sci 1987;
28:538–542.
27. Kinoshita S, Friend J, Thoft RA. Biphasic cell proliferation in transdifferentia-
tion of conjunctival to corneal epithelium in rabbits. Invest Ophthalmol Vis Sci
1983; 24:1008–1014.
28. Herbort CP, Zografos L, Zwingli M, Schoeneich M. Topical retinoic acid in
dysplastic and metaplastic keratinization of corneoconjunctival epithelium.
Graefes Arch Clin Exp Ophthalmol 1988; 226:22–26.
29. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of
immunosuppressive drugs in patients with ocular inflammatory disorders:
recommendations of an expert panel. Am J Ophthalmol 2000; 130:
492–513.
30. Dart JK. The 2016 Bowman Lecture Conjunctival curses: scarring conjuncti-
vitis 30 years on. Eye (Lond) 2017; 31:301–332.
31. McCluskey P, Chang JH, Singh R, Wakefield D. Methotrexate therapy for
ocular cicatricial pemphigoid. Ophthalmology 2004; 111:796–801.
32. Hervas Ontiveros A, Salom D, Espana Gregori E, et al. Methotrexate as a
treatment in ocular cicatricial moderate pemphigoid. Arch Soc Esp Oftalmol
2014; 89:447–449.
33. Nottage JM, Hammersmith KM, Murchison AP, et al. Treatment of mucous
membrane pemphigoid with mycophenolate mofetil. Cornea 2013; 32:
810–815.
34. Thorne JE, Woreta FA, Jabs DA, Anhalt GJ. Treatment of ocular mucous
membrane pemphigoid with immunosuppressive drug therapy. Ophthalmol-
ogy 2008; 115:2146.1–2152.e1.
35. Heffernan MP, Bentley DD. Successful treatment of mucous membrane
pemphigoid with infliximab. Arch Dermatol 2006; 142:1268–1270.
Volume 29  Number 6  November 2018

36. Wegener’s Granulomatosis Etanercept Trial (WGET) Research Group.
Etanercept plus standard therapy for Wegener’s granulomatosis. N Engl J
Med 2005; 352:351–361.
37. Kaymakcalan Z, Sakorafas P, Bose S, et al. Comparisons of affinities, avidities,
and complement activation of adalimumab, infliximab, and etanercept in
binding to soluble and membrane tumor necrosis factor. Clin Immunol
2009; 131:308–316.
38. Van den Brande JM, Braat H, van den Brink GR, et al. Infliximab but not
etanercept induces apoptosis in lamina propria T-lymphocytes from patients
with Crohn’s disease. Gastroenterology 2003; 124:1774–1785.
39. Foster CS, Chang PY, Ahmed AR. Combination of rituximab and intravenous
immunoglobulin for recalcitrant ocular cicatricial pemphigoid: a preliminary
report. Ophthalmology 2010; 117:861–869.
1040-8738 Copyright ß 2018 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.
Ocular cicatricial pemphigoid Wang et al.
40. Ahmed AR, Dahl MV. Consensus statement on the use of intravenous
immunoglobulin therapy in the treatment of autoimmune mucocutaneous
blistering diseases. Arch Dermatol 2003; 139:1051–1059.
41. Ahmed AR, Nguyen T, Kaveri S, Spigelman ZS. First line treatment of pemphigus
vulgaris with a novel protocol in patients with contraindications to systemic
corticosteroids and immunosuppressive agents: Preliminary retrospective study
with a seven year follow-up. Int Immunopharmacol 2016; 34:25–31.
42. Saeed L, Schmidt TH, Gensler LS, et al. Successful treatment of mucous
&& membrane pemphigoid with bortezomib. JAAD Case Rep 2018; 4:81–83.
This article describes a recalcitrant case of MMP failing cyclophosphamide and
rituximab monotherapy where the ocular disease drove advancement of therapy to
B-cell-directed therapy with bortezomib, a proteasome inhibitor. The utility of
having a diagnosis of MMP is demonstrated.
www.co-ophthalmology.com 551