Introduction
Mucous membrane pemphigoid (MMP) is one of a group of disorders known as the pemphigoid
diseases. MMP is the third most common autoimmune blistering skin disease in Europe,
after bullous
pemphigoid and pemphigus vulgaris. It is defined by the appearance of autoantibodies
targeting the epithelial basement membrane, predominantly attacking the mucous membranes.
This can affect
all of the mucous membranes in the body. In the course of this disease, approx. 70%
of patients develop ocular involvement with scarring of the conjunctiva [1], [2], [3]. According to a recent international consensus, if the conjunctiva are the sole
targets of the attack, the condition
is referred to as ocular mucous membrane pemphigoid; if other mucous membranes are
also affected at the same time, it is referred to as mucous membrane pemphigoid with
ocular involvement [2].
With an annual incidence of approx. 1 to 2 cases per million and a prevalence of 25
per million population recorded in 2014, MMP is a rare disease [4], [5]. In Germany, with a total population of 83 million, approximately 2,100 patients
are affected overall, with 80 to 170 new cases diagnosed each year. Nevertheless,
this
attack on the conjunctiva represents one of the greatest challenges in the field of
ocular surface diseases. Because the symptoms are initially nonspecific, for example
conjunctival hyperemia,
a burning sensation or a foreign body sensation, MMP is often not diagnosed until
it has reached an advanced stage. In the case of glaucoma patients receiving long-term
topical treatment,
pseudopemphigoid should always be considered as a differential diagnosis [6].
Without adequate treatment, MMP can lead to increasing scar tissue adhesion between
the bulbar conjunctiva and the eyelid (symblepharon or ankyloblepharon), as well as
conjunctival
keratinization. ([Fig. 1]). Subsequently, eyelid malposition and trichiasis can lead to serious complications
such as limbal stem cell deficiency,
neovascularization, and corneal scarring or erosion. It can even lead to corneal perforation
([Fig. 1]) [7]. The progression of MMP
therefore poses a potential threat to visual function; this means that ocular involvement
can have an especially severe impact on the patientʼs quality of life [7], [8]. Treatment is often lengthy and complicated [7]. As a rule, systemic immunosuppressants or immunomodulatory drugs are
required. In the most severe cases, it is often necessary to resort to surgical interventions
such as entropion repair or corneal transplant in order to restore the patientʼs vision
[7]. In Germany to date, there has been no nationwide collection of epidemiological
and clinical data for this disease.
Fig. 1 Slit lamp images showing typical clinical findings for ocular MMP. a Conjunctival keratinization with symblepharon and ankyloblepharon at the lateral
canthus.
b Distinct symblepharon of the lower eyelid with clear shortening of the fornix. c Corneal neovascularization and keratinization with central scarring. d Extensive
corneal ulcer with pronounced scarring of the underlying stroma.
In light of this, we conducted a brief survey on the care situation for MMP patients
and on the approaches used to diagnose and treat ocular MMP and MMP with ocular involvement.
Methods
We designed a survey to investigate the care situation for patients with ocular MMP
and MMP with ocular involvement ([Fig. 2]). In this survey, clinics were
asked whether they provided a specialized outpatient service for this disease, how
many MMP patients they had in total, how many new MMP patients they acquired each
year, what
interdisciplinary clinical collaborations they had established, and which local and/or
systemic therapies they usually used. In April 2020, the survey was sent in paper
form to a total of 44
clinics, including all of the university eye departments, and other potential treatment
centers with patients recruited from different regions.
Fig. 2 Questionnaire.
We used “R”, version 4.0.5 ([7950 Catalina build], R Foundation for Statistical Computing,
2021), to perform a statistical analysis of the results. The descriptive presentation
of the
numerical data includes the mean and standard deviation values as well as the range;
nominal data are presented as percentages, and for ordinal data, the median value
and range are reported.
In order to investigate the degree of correlation in the case of dichotomous variables,
we performed correlation analysis using the phi coefficient, and for variables with
non-normal
distribution we performed correlation analysis using the Spearman correlation coefficient.
Group comparisons for variables with non-normal distribution were performed using
the
Wilcoxon-Mann-Whitney test. P-values ≤ 0.05 were considered statistically significant.
Results
From April 2020 to April 2021, 28 out of 44 response forms were returned (64%) and
analyzed. These 28 clinics reported treating a combined annual average of 27 ± 42
MMP patients (range:
0 – 200), with an average of 3.6 ± 2.2 new patients (range: 0 – 10) each year. This
results in a total cohort of 741 patients, with 101 new patients diagnosed each year.
Of the clinics that took part in the survey, 32% (n = 9) reported that they provide
a specialized outpatient consultation service for MMP. The total number of MMP patients
in the care of
these clinics (49 ± 67) was significantly higher (p = 0.038) than in clinics that
did not provide a specialized outpatient service for MMP (16 ± 23) ([Fig. 3]).
In contrast, the annual number of new MMP patients for the clinics with a specialized
service (4.0 ± 2.7) was not significantly higher than for clinics without a specialized
service
(3.4 ± 1.9) (p = 0.58).
Fig. 3 a Box and whisker plots showing the total number of MMP patients per center, according
to whether or not a specialized service was available. b Box and whisker
plots showing the incidence of MMP patients per ophthalmology center, according to
whether or not a specialized service was available. The median value is indicated
as a continuous line
inside the box. Values greater than 1.5 times the interquartile range were treated
as outliers.
Of all the participating centers, 93% (n = 26) reported collaborating with established
partners from other departments to provide clinical diagnosis. Two clinics reported
that they did not
have any established form of clinical collaboration with other departments. All of
the respondents who collaborated with other departments reported the department in
question to be the
dermatology service available at their location. A further five centers also collaborated
with the rheumatology clinic (17.9%), and two reported collaborating with the department
for internal
medicine (7.1%). 79% of the clinics (n = 22) performed serology and histology diagnostics
in-house. Five clinics (18%) reported sending these to a specialized external autoimmune
laboratory.
Two clinics (7%) did not respond to this question.
A little over half of the centers (57%; n = 16) reported using a standardized treatment
regimen. Clinics providing a specialized outpatient service were not significantly
more likely than
other clinics to use standardized therapy (p = 0.2232). Eight clinics reported that
they did not use a standardized treatment regimen, and four clinics did not provide
information regarding
the therapy they used.
Topical treatment consisted uniformly of artificial tears and anti-inflammatory eyedrops
and ointments. In the group using a standardized treatment regimen, 81.3% (13 of 16)
used topical
glucocorticoids, and seven of these clinics also used topical cyclosporine A. One
clinic treated patients only with topical cyclosporine A as standard, while another
clinic combined
cyclosporine A with tacrolimus. In the group with no standardized treatment regimen
(n = 8), topical glucocorticoids were uniformly the treatment of choice, with six
of these clinics also
using topical cyclosporine A.
Seven clinics gave no response to the question about systemic therapy; of these, three
clinics reported leaving it entirely to the dermatologists to determine this indication.
Among the other
clinics (n = 21), systemic glucocorticoids (66.7%) were most often used, followed
by mycophenolate mofetil and dapsone (57.1%), rituximab (33.3%), azathioprine and
cyclophosphamide (28.6%),
and methotrexate (19.0%). Immunoglobulin was used less frequently (14.3%), followed
by tetracycline, sulfapyridine, and sulfamethoxypyrazine (4.8%) ([Table 1]).
There was a strong correlation (phi coefficient 0.46, p = 0.02 347) between the use
of mycophenolate mofetil and having a standard treatment regimen in place.
Table 1 Reported treatment data.
|
Drug
|
n
|
%
|
|
Topical administration
|
|
Prednisolone + cyclosporine A
|
13
|
54.2
|
|
Prednisolone as monotherapy
|
8
|
33.3
|
|
Cyclosporine A as monotherapy
|
1
|
4.2
|
|
Pimecrolimus
|
1
|
4.2
|
|
Systemic administration
|
|
Methylprednisolone
|
14
|
66.7
|
|
Mycophenolate mofetil
|
12
|
57.1
|
|
Dapsone
|
12
|
57.1
|
|
Rituximab
|
7
|
33.3
|
|
Azathioprine
|
6
|
28.6
|
|
Cyclophosphamide
|
6
|
28.6
|
|
Methotrexate
|
4
|
19.0
|
|
Immunoglobulin
|
3
|
14.3
|
|
Sulfapyridine and sulfamethoxypyrazine
|
1
|
4.8
|
|
Tetracycline
|
1
|
4.8
|
Discussion
In accordance with the international literature, our survey confirms the prevalence
and incidence data reported in other countries [9], [10], [11], [12] which characterize MMP as a rare disease. The results from our survey indicate a
low prevalence and annual
incidence for MMP, with considerable differences sometimes occurring between clinics.
We attribute this disparity to the fact that some clinics recruit patients with ocular
MMP or MMP with
ocular involvement from other regions. Even though MMP is a rare disease, as many
as nine of the German clinics that responded to the survey provide a specialized consultation
service for
patients with ocular involvement. Accordingly, these “centers” accommodate a significantly
higher number of MMP patients.
A diagnosis of MMP can be difficult to confirm. In the case of ocular MMP, a clinical
diagnosis can only be made if the relevant diagnostic tests (biopsy, serology) give
negative results, and
any possible differential diagnoses have been ruled out. However, it is extremely
important both to patients and physicians to be certain about this diagnosis, because
it often leads to
long-term immunosuppressive therapy. In addition, once the diagnosis has been made,
specialists from other disciplines such as dermatology, ENT, or oral surgeons should
be consulted for a
joint assessment in order to reliably rule out other possible causes of lesions.
Interdisciplinary support for treatment planning can be provided by Rheumatology,
and by Dermatology provided that the appropriate expertise is available. Nearly all
of the clinics that took
part in the survey reported collaborating with Dermatology as their primary interdisciplinary
partner, while collaboration with Rheumatology or Internal Medicine was much less
common, even
though skin lesions represent only 25 – 30% of all lesions occurring in affected MMP
patients [7], [13]. Although lesions occur most
frequently (> 85%) in the mucous membranes of the mouth, nose, and larynx [1], [14], no clinics reported working with dental, oral and
maxillofacial, or ENT services; this may be attributable to the fact that symptoms
involving extraocular lesions are minor and tend to have a benign spontaneous course.
Nevertheless, it is
advisable to consult these specialists, because their findings can be of definitive
importance in confirming the diagnosis.
Based on the recently published European guideline, the following measures are recommended
in all cases of ocular MMP or MMP with ocular involvement: biopsy of non-inflamed
conjunctiva and/or
healthy oral mucous membrane with direct immunofluorescence, conventional histopathology
on tissue from conjunctival lesions, and detection of serum autoantibodies. It is
not always possible
to rule out differential diagnoses, such as lichen planus, with certainty [15]. In addition, in the case of a unilateral lesion, performing a biopsy of the
conjunctiva makes it possible to differentiate between MMP and conjunctival intraepithelial
neoplasia. The clinics that participated in the survey were all maximum care providers,
and as such,
they mostly performed diagnostic testing in-house, even though there are autoimmune
laboratories specialized in this field which offer specific diagnostic options based
on their own scientific
focus.
Only half of the clinics surveyed reported using a standardized treatment regimen.
This may be due to the absence of a relevant international consensus. An interdisciplinary
guideline on this
topic has just been published [16]. In principle, it seems useful to take a graduated approach based on whether the
patientʼs inflammatory condition is progressing
or regressing [7], [17]. In the case of persistent inflammation, progression to conjunctival fibrosis and
corneal complications can be
expected. In such cases, it is important to differentiate between immune-mediated
inflammation and other concurrent ocular surface diseases, such as chronic blepharitis
or meibomian gland
dysfunction.
Only 25% of ocular MMP patients do not require systemic immunosuppression. In these
cases, progression of the disease can be minimized by treatment with artificial tears,
topical steroids,
and cyclosporine A (CsA) [7]. However, in such cases it is important to bear in mind the complications that typically
arise with long-term use of steroids (glaucoma
and cataracts). Although available case reports on the use of cyclosporine A show
only variable results [7], [18], half of all clinics
surveyed use it as an adjuvant together with topical steroid treatment; one clinic
even reported using it as the sole topical anti-inflammatory medication. However,
the use of purely topical
anti-inflammatory medication (e.g., tacrolimus) is generally limited to individual
mild cases [19].
Since azathioprine and cyclophosphamide were first used by Foster in 1980, systemic
immunosuppressants have come to be universally considered indispensable for improving
the long-term
prognosis of progressive forms of MMP or in cases of moderate to severe inflammation
[1], [7], [20]. Other
options for systemic therapy include oral dapsone, sulfasalazine, and sulfapyridine
[17]. In all cases, over the course of treatment that can often last for many
years, it is necessary to regularly monitor the patientʼs blood count as well as liver
and kidney function so as to detect any adverse drug effects at an early stage. The
treatment monitoring
forms published by the German Society for Rheumatology can be very useful for this
purpose [21]. However, there is little evidence from clinical studies on this
topic, and the studies that have been published are limited to dapsone and cyclophosphamide.
The same applies in particular for stronger drugs such as mycophenolate mofetil (MMF),
which according to our survey was the most commonly used steroid-sparing immunosuppressant;
this may be
due to the fact that this drug is well tolerated. It was used particularly frequently
in clinics that had an established treatment regimen. In all cases, it is essential
that the patient is
fully informed before starting treatment, not least because of the potentially lethal
complications [17]. Oral or intravenous cyclophosphamide, at times in
combination with intravenous prednisolone, and biologics such as rituximab, or the
significantly more expensive intravenous administration of immunoglobulin [22], [23], [24], tend to be treatments of last resort [21], [25].
Given the generally quite advanced age of this patient cohort, in addition to corneal
complications, cataracts represent another cause of vision loss. Before surgery can
be performed to
restore the patientʼs vision, the inflammatory process first needs to be brought under
control with medication. Corneal neovascularization and a severe tear film deficiency
can significantly
compromise the success of a corneal transplant or a Boston keratoprosthesis. In such
cases, keratoprostheses with biological haptics represent an alternative [26], [27]. Provided that the inflammation is adequately controlled, it is also possible to
successfully restore the patientʼs vision through cataract
surgery; however, reactivation of ocular MMP may lead to renewed loss of vision in
the long term [28].
Despite the low prevalence of MMP, with just over 2,000 cases in Germany, this survey
captured around a third of all MMP cases in the country. According to the literature,
around 70% of
patients with MMP have ocular involvement. The literature also indicates that 20%
of all MMP patients have an exclusively ocular form of the disease [1], [14]. We may assume that there are other patients with ocular involvement in the clinics
that did not respond to the survey, or under the care of other specialist
departments such as dermatology, who so far remain undiagnosed and therefore undertreated.
However, in view of the irreversible and potentially disastrous nature of this disease,
ophthalmologists in Germany ought to be familiar with it as a differential diagnosis,
and should refer patients to a treatment center that has the necessary expertise.
In the future, patients
treated at these centers can be registered in a “German Ocular Pemphigoid Register”;
this is intended to contribute to the prospective collection of clinical, diagnostic,
and therapeutic data
relating to this rare disease, so as to identify possible progression parameters and
thus improve long-term care for these patients.
