CLINICAL SCIENCE
Prospective Study of Ocular Manifestations of Pemphigus and Bullous Pemphigoid Identifies a High Prevalence of Dry Eye Syndrome Jeremy C.K. Tan, BSc(Med), MD,*†‡§ Lien T. Tat, PhD,*†§ Kristy B. Francis, BAppSc(Orth),*†§ Clarisse G. Mendoza, MD,*‡ Dedee F. Murrell, MA, BMBCh, FAAD, FACD, MD,*‡ and Minas T. Coroneo, BSc(Med), MBBS, MSc, MD, MS, FRACS, FRANZCO*†§
Purpose: To study the range of ocular manifestations in an Australian cohort of patients with pemphigus and bullous pemphigoid (BP), including a detailed assessment for dry eye syndrome (DES).
Methods: Twenty-two patients with pemphigus vulgaris, pemphigus foliaceus, and BP were referred for a detailed ophthalmology review between September 2011 and March 2012. Results: A total of 44 eyes of 22 patients with pemphigus vulgaris, pemphigus foliaceus, and BP were examined. Photophobia was the most common symptom reported. The most common ocular signs found in both groups were blepharitis (68.1%), conjunctival hyperemia (22.7%), and limbal broadening (18.2%). In our DES assessment, 92.9% of patients had a reduced Schirmer test score and an abnormal tear break-up time was recorded in 100% of patients. The ocular surface disease index score ranged from 0 to 47.2, with a median score of 10.
Conclusions: The high occurrence of patient-reported ocular symptoms and clinical evidence of dry eye on Schirmer testing and break-up time demonstrate high prevalence of DES in our cohort of pemphigus and BP patients, which is a novel finding. Limbal broadening was another common finding not previously reported. Key Words: pemphigus, bullous pemphigoid, dry eye syndrome, limbal broadening, stem cell (Cornea 2015;34:443–448)
Received for publication August 19, 2014; revision received September 19, 2014; accepted November 2, 2014. Published online ahead of print February 3, 2015. From the *Faculty of Medicine, University of New South Wales, Sydney Australia; †Department of Ophthalmology, Prince of Wales Hospital, Sydney, Australia; ‡Department of Dermatology, St George Hospital, Sydney, Australia; and §Ophthalmic Surgeons, Sydney, Australia. Supported by a grant from the University of New South Wales Independent Learning Programme to J. C. K. Tan to work with D. F. Murrell and M. T. Coroneo. The other authors have no conflicts of interest to disclose. Reprints: Minas T. Coroneo, BSc(Med), MBBS, MSc, MD, MS, FRACS, FRANZCO, University of New South Wales at Prince of Wales Hospital, 2 St Pauls St, Randwick NSW 2031, Sydney, Australia (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cornea Volume 34, Number 4, April 2015
A
utoimmune blistering skin disease (AIBD) is a term used to describe a heterogeneous group of cutaneous and mucosal diseases with significant morbidity and mortality, including pemphigus, bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA), and linear immunoglobulin A bullous dermatosis. A range of ocular manifestations can occur in patients with AIBD because of the underlying blistering disease or as side effects of medications used to treat these diseases. The most common ocular presentation of AIBD is chronic conjunctivitis, which can progress to conjunctival fibrosis and eventually chronic cicatricial conjunctivitis. Cicatrization can lead to severe ocular complications that include symblepharon, fornix foreshortening, entropion, trichiasis, keratopathy, and blindness in certain cases. Pemphigus is a group of autoimmune blistering diseases that are caused by autoantibodies directed against desmosomal proteins that function as intercellular adhesion molecules, resulting in acantholysis and blistering of the skin and mucous membranes. There are 4 major variants of pemphigus, depending on the desmoglein type and epidermal level affected—pemphigus vulgaris (PV), pemphigus foliaceus, paraneoplastic pemphigus, and drug-induced pemphigus. PV is characterized by immunoglobulin G autoantibodies directed against desmoglein 3, which is present in the deep epidermis. In pemphigus foliaceus, autoantibodies are formed against desmoglein 1, present throughout the epidermis.1 The incidence of PV ranges from 0.4 to 1.6 cases per 100,000 individuals, with a greater incidence seen in Ashkenazi Jews.2,3 Affected individuals are typically in their fourth to fifth decades of life. In PV, mucous membranes are usually the first to be affected by the disease. Erosions in the oral cavity are most commonly seen, whereas the conjunctiva, esophagus, and genital areas are less commonly affected. Ocular disease can present with symptoms of ocular irritation, tearing, and foreign body sensation.4–6 A recent study by Akhyani et al reported that ocular involvement was present in 16.5% of their study of 103 patients with PV, with conjunctivitis and erosion of the palpebral conjunctiva being the most common findings.7 Based on a cohort of 167 patients with PV, Daoud et al reported an incidence of ocular involvement of 7%. The authors reported findings of bilateral conjunctivitis and lid margin ulceration. The mean interval between the onset of PV and ocular involvement was 20 www.corneajrnl.com |
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Tan et al
months, and the ocular disease lasted for a mean of 12 months. The authors found that patients had complete recovery and no long-term sequelae due to conjunctival disease.8 There have however been findings of corneal perforation, keratolysis, forniceal foreshortening, and plica semilunaris vegetations in patients with PV reported in the literature.9–11 Another study by Chirinos-Saldana et al reported subconjunctival scarring, symblepharon, trichiasis and entropion, corneal opacities, and ankyloblepharon in their cohort of 15 patients with PV,12 demonstrating the presence of long-term cicatricial changes from ocular disease. Mucous membranes are involved only occasionally in BP, consequently ocular involvement is uncommon. The incidence of ocular involvement is unknown because of lack of large-scale studies examining ocular findings in BP. Ocular manifestations are subtle and may go undetected in the conjunctiva and lid margins. Slit-lamp examination may reveal subepithelial fibrosis with fine linear striae of the tarsus.13,14 Other ocular manifestations reported in the literature include conjunctival scarring, corneal epithelial defects, stromal edema, and corneal opacity.13,14 The aim of this study was to examine the range of ocular manifestations in patients with PV and BP, including the presence of dry eye syndrome (DES).
MATERIALS AND METHODS This study was approved by the local institutional review board in September 2011. From a literature search of past case series and reports describing ocular involvement in AIBD, we created a comprehensive data collection sheet to record the ocular history and examination findings to create a bullous diseases eye score (BDES). Patients with a confirmed diagnosis of pemphigus and BP were recruited from dermatology subspecialty bullous clinics. Diagnosis of patients with pemphigus and BP was confirmed by clinical assessment, histopathology, and direct immunofluorescence of an appropriate skin biopsy specimen, and/or indirect immunofluorescence using patient serum studies. Patients were prospectively referred for comprehensive review by M. T. Coroneo using the BDES between September 2011 and March 2012. A detailed medical history, medication history, and history of any current ocular symptoms, past ocular disease, and procedures was elicited. The history questionnaire component of the BDES, which included a history of the ocular symptoms of itching, tearing, discomfort, photophobia, and mucous discharge was completed with a uniform interviewer (J.C.K.T.). Participants were asked to grade their experience of these symptoms on a scale of 0 to 3, which represented none, mild, moderate, and severe. An ocular surface disease index (OSDI) questionnaire was also administered. The OSDI, developed by the Outcomes Research Group at Allergan, is a 12-item questionnaire designed to provide a rapid assessment of the symptoms of ocular irritation consistent with DES and their impact on vision-related functioning. The OSDI score was calculated according to the following formula: OSDI = [(sum of scores for all questions answered) · 100]/[(total number of questions answered) · 4]. The OSDI is scored on a scale of 0 to 100, with higher scores representing greater disability.
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The visual acuity was measured with a projected Snellen chart adjusted for a 6-m viewing distance. The visual acuity was classified according to the World Health Organization’s definition of visual impairment [grade 0 (6/6 or better), grade 1 (6/9–6/18), grade 2 (6/21–6/48), grade 3 (6/60–6/120), grade 4 (6/150–6/300), grade 5 (worse than 6/300), and grade 6 (No light perception)]. We included 20 components of 3 categories of ocular complications in the slit-lamp examination of the anterior ocular surface. These were classified into eyelid complications—consisting of blepharitis, ectropion, lacrimal duct obstruction, lid retraction, blistering, and trichiasis; conjunctival complications—comprising conjunctival inflammation, conjunctival edema, blepharoconjunctivitis, and symblepharon; and corneal complications—consisting of corneal edema, exposure keratitis, ulceration, scarring, limbal broadening, pannus, opacity, blister, erosion, and neovascularization. Conjunctival inflammation was graded as absent, mild, moderate, or severe. The presence or absence of the other lid, conjunctiva, and cornea findings was recorded. Dry eye was assessed using fluorescein staining, tear break-up time (TBUT), and Schirmer test. Fluorescein staining of the cornea and conjunctiva was administered by touching the inferior fornix with a dry fluorescein strip with the patient looking upward. The slit-lamp biomicroscope was then used to inspect the cornea for punctate staining, and graded as 0 (#2 dots), 1 (.2 but #32 dots), 2 (.32 but #316 dots), or 3 (.316 dots approximately or ulcer/erosion). Dry eye was defined as grade 2 or 3 fluorescein staining. The TBUT was then recorded. This is the time in seconds between the patient’s blink and the appearance of a random dry spot on the cornea. The TBUT was performed 3 times, and the average time was calculated. The test was considered positive if the average TBUT was less than 8 seconds. Schirmer test was performed with a 5- · 35-mm strip of dry filter paper after instillation of anesthetic drops. The length of wetting obtained was graded as normal (grade 0; $15 mm), mild dryness (grade 1; 10–14 mm), moderate dryness (grade 2; 5–9 mm), and severe dryness (grade 3; # 4 mm). Dry eye was defined as Schirmer test grade 2 or 3. Cataract, glaucoma, and retinal diseases were also evaluated, and their presence or absence was recorded.
RESULTS A total of 44 eyes of 22 patients with PV (13 patients), pemphigus foliaceus (2 patients), and BP (7 patients) were included in this study. There were 9 males (41%) and 13 females. Ages ranged from 32 to 87 years with a mean of 63 years. At disease onset, the patients’ age ranged from 25 to 80 years. The mean duration of their blistering disease was 5 years (range, 0–20 years).
Ocular Symptoms and OSDI Seventeen patients (77.3%) complained of at least 1 symptom of dry eye. Photophobia was the most common symptom reported in patients with AIBD (45%) (Table 1). It was also the most common severe symptom reported. Other ocular symptoms reported were tearing (30%), itching (30%), discomfort (27%), and mucous discharge (9.1%). Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Pemphigus, Bullous Pemphigoid and Dry Eye Syndrome
TABLE 1. Prevalence of Self-Reported Ocular Symptoms in Participants Severity Ocular Symptoms PV and pemphigus foliaceus (n = 30 eyes) Itching Tearing Discomfort Photophobia Mucous discharge BP (n = 14 eyes) Itching Tearing Discomfort Photophobia Mucous discharge
Grade 0, n (%)
Grade 1, n (%)
Grade 2, n (%)
Grade 3, n (%)
23 21 22 16 26
(76.7) (70.0) (73.3) (53.3) (86.7)
3 8 7 9 4
(10.0) (26.7) (23.3) (30.0) (13.3)
4 (13.3) 1 (3.3) 1 (3.3) 1 (3.3) 0
0 0 0 4 (13.3) 0
8 10 10 8 14
(57.1) (71.4) (71.4) (57.1) (100)
6 4 4 2
(42.9) (28.6) (28.6) (14.3) 0
0 0 0 4 (28.6) 0
0 0 0 0 0
Twenty patients completed the OSDI questionnaire. The total OSDI score ranged from 0 to 47.2, with a median score of 10. Of these, 13 patients (65%) were graded as normal, 5 patients (25%) had mild ocular surface disease, while 1 patient with pemphigus foliaceus and 1 patient with PV had moderate and severe ocular surface disease.
Visual Acuity Thirteen (59.1%) patients had a visual acuity of at least 6/6 or better. The remaining patients had at visual acuity of at least 6/18 or better.
Assessment of Tear Film A summary of the 3 evaluated components of the tear film assessment in both groups is shown in Table 3. The Schirmer test was performed on 21 patients—1 patient did not undergo the Schirmer test because of intolerance. Severe eye dryness (grade 3, length of wetting # 4 mm) was found in 25 (59.5%) of the 42 eyes tested. Of the remaining eyes, 10 (23.8%) had moderate dryness (grade 2; 5–9 mm), 4 (9.5%) had mild dryness (grade 1; 10–14 mm), and 3 (7.1%) had normal wetting of the filter paper. Overall, 92.9% of patients had an abnormal Schirmer test, 13.6% of patients had significant Fluorescein staining (grade 2 or 3), and 100% of patients had a reduced TBUT average (less than 8 seconds).
DISCUSSION Ocular involvements in pemphigus reported in the literature include conjunctivitis, erosion of palpebral conjunctiva, corneal perforation, keratolysis, corneal opacity, forniceal foreshortening, subconjunctival scarring, symblepharon, trichiasis and entropion, plica semilunaris vegetations, and ankyloblepharon. In BP, subepithelial fibrosis, conjunctival scarring, corneal
TABLE 3. Summary of Results From Tear Film Assessment in Participants Grade Grade 1 Blistering Disease 0 (‡15 mm) (10–14 mm) Schirmer’s test Pemphigus foliaceus (n = 4) PV (n = 24*) BP (n = 14) Total (n = 42*)
Grade 2 (5–9 mm)
Grade 3 (#4 mm)
0
0
0
4
2 1 3 (7.1%)
4 0 4 (9.5%)
4 6 10 (23.8%)
14 7 25 (59.5%)
Ocular Surface Findings Of the 44 eyes, blepharitis was seen in 30 eyes (68.1%). Conjunctival hyperemia was the most common conjunctival finding, observed in 10 eyes (22.7%). Limbal broadening was the commonest corneal complication, seen in 8 eyes (18.2%). Other ocular signs observed were corneal scarring in 6 eyes (13.6%), corneal opacity seen in 3 eyes, conjunctival edema in 2 eyes, symblepharon in 2 eyes, and trichiasis and neovascularization each observed in 1 eye (Table 2).
TABLE 2. Prevalence of Ocular Manifestations in Participants (n = 44 Eyes) Ocular Manifestation Blepharitis Conjunctival hyperemia Limbal broadening Corneal scarring Corneal opacity Conjunctival edema Ectropion Corneal neovascularization
Prevalence 30 10 8 6 3 2 1 1
(68.2) (22.7) (18.2) (13.6) (6.8) (4.5) (2.3) (2.3)
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Blistering Disease Fluorescein staining Pemphigus foliaceus (n = 4) PV (n = 26) BP (n = 14) Total (n = 44)
Grade 0 (#2 Dots)
Grade 1 (.2 but #32 Dots)
Grade 2 (.32 but #316 Dots)
Grade 3 (.316 Dots Approx or Ulcer/Erosion)
0
2
2
0
1
23
2
0
3
9
2
0
4 (9.1)
34 (77.3)
6 (13.6)
0
Blistering Disease Tear break-up time Pemphigus foliaceus (n = 4) PV (n = 26) BP (n = 14) Total (n = 44)
Mean, s
SD
Range
1.2 2.3 2.4 2.3
0.2 0.7 1.0 0.9
1–1.4 1.2–4 1.3–4.8 1–4.8
*One patient with PV could not tolerate the Schirmer test and was excluded.
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epithelial defects, stromal edema, and corneal opacity have been reported. In our cross-sectional study of pemphigus and BP patients, we observed blepharitis, conjunctival hyperemia, conjunctival edema, corneal scarring, corneal opacity, corneal neovascularization, limbal broadening, and DES. Of these complications, the most common ocular signs found were blepharitis (68.1%), conjunctival hyperemia (22.7%), and limbal broadening (18.2%). DES and limbal broadening are novel signs in pemphigus and BP.
Limbal Broadening Limbal broadening was the most common corneal abnormality observed, seen in both eyes of 4 patients (Fig. 1). Three of these patients had PV, and the fourth had BP. The term limbal broadening has been rarely used in the literature, and there is currently no established definition of this ocular sign. Limbal broadening has been described as when the corneal periphery adjacent to the limbus shows marked clouding.15 There have been previous reports documenting this ocular sign in patients with inherited epidermolysis bullosa (EB) in the literature.16 Inherited EB is a group of skin diseases that is characterized by marked mechanical fragility of epithelial tissues and blistering.17 They are caused by mutations in genes that encode for proteins within the epidermis or basement membrane zone. In a case series of 11 patients with the recessive dystrophic form of epidermolysis bullosa (RDEB), McDonnell and Spalton18 reported limbal broadening in 5 patients, where they described observing an “avascular broadening of the superior and inferior limbus.” RDEB is due to defects in the collagen VII gene, leading to defects in the collagen VII protein, the very same protein that is targeted in EBA; McDonnell et al19 also described observing a “pannus-like broadening of the limbus” in 3 of 5 patients with non-Herlitz junctional EB. This form of EB is due to defects in BP180 and collagen XVII, proteins that are targets for BP, linear immunoglobulin A bullous dermatosis, and MMP. There have since been other case reports of EB patients with this interesting ocular manifestation.20
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McCuaig et al21 reported ocular findings observed in a 10-year-old boy with EBA, who had “broadening of the superior limbus” in his right eye, and also “vascularisation of the temporal limbus” in the left eye. This is the only case report in the literature that describes the occurrence of this ocular manifestation in a patient with an autoimmune blistering skin disease. We believe that these descriptions of the phenomenon of limbal broadening in patients with EB and the 1 patient with EBA could possibly be descriptions of early ocular signs of limbal stem cell deficiency (LSCD) or dysfunction. Early slit-lamp microscopy findings of LSCD include flattening of the limbus in the region of the palisades of Vogt.22 The corneal epithelium may also appear hazy and irregular20; however, typically vascularization is a feature. This sign could therefore indicate LSCD in these patients. The corneal epithelium is derived from a subpopulation of stem cells that are located in the corneoscleral limbus of the eye.23 Importantly, ocular MMP is associated with LSCD.24 To the best of our knowledge, there is no report of the occurrence of LSCD in any of the other AIBDs including PV and BP, or in any type of inherited EB in the literature. LSCD leads to ocular symptoms that include redness, irritation, photophobia, and decreased vision. If limbal broadening is indeed an early sign of LSCD, patients with pemphigus and BP with this ocular manifestation will require closer monitoring of their eyes for occurrence or progression of any ocular surface complications. Interestingly, there is also stem cell exhaustion of the skin in the severe forms of EB such as non-Herlitz junctional Epidermolysis Bullosa and recessive dystrophic epidermolysis bullosa, which consequently leads to delayed wound healing and scarring. Of interest is that an immune-mediated limbitis, which may cause partial stem cell deficiency, has been implicated in Graft-versus-host-disease (GVHD).25 We have previously reported 2 cases in which focal stem cell deficiency was evident.26 Furthermore, it has been shown that in GVHD, stem cell populations in the hair parafollicular bulge are preferentially attacked.27 Thus, pemphigus/BP and GVHD may be linked by the observation that DES is common to both and that limbal stem cell involvement is likely.
Dry Eye Syndrome (Keratoconjunctivitis Sicca)
FIGURE 1. Limbal broadening in a patient with PV.
DES or keratoconjunctivitis sicca is a known complication of ocular MMP. We are unaware of previous reports in the literature that describe the association of DES in pemphigus and BP. It is likely that DES is underdiagnosed in this group of conditions as we can find little evidence in the literature regarding this issue. In our cohort of patients with pemphigus and BP, 92.9% had an abnormal Schirmer test and 100% had a reduced TBUT. From results of the Schirmer test, 14 patients (63.6%) had severe dryness (grade 3 dryness; length of filter paper wetting #4 mm). The remaining 7 patients also had some degree of reduced tear production (grade 1 or 2 dryness). Wetting of less than 5 mm indicates a diagnosis of tear deficiency.28 The Schirmer test however has been reported to have low sensitivity but high specificity.29 TBUT measures the stability of the tear film and is reduced in DES.28,30 In this study, we found that all the patients had an
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average TBUT of less than 8 seconds. Patient-reported dry eye symptoms however tend to be more reliable than results from dry eye clinical tests. In our cohort, 77% of our patients complained of at least 1 ocular symptom. The median score by OSDI was 10 of 100, with 31.8% of the patients having at least mild ocular surface disease and in this patient cohort does not appear to reflect disease severity. The high occurrence of patient-reported ocular symptoms and clinical evidence of dry eye on Schirmer test and TBUT therefore demonstrate the high prevalence of dry eye in our cohort of patients with AIBD. It is of interest that the OSDI results would underestimate dry eye prevalence in our patient cohort. The prevalence of dry eye in the Australian general population was estimated to be 16.3% based on a Schirmer test diagnosis,31 although the true prevalence of this condition is unknown because patients often only present for assessment when their condition is moderate to severe. Results of the Schirmer test and TBUT in our patients are consistent with the increased prevalence of DES seen in patients with autoimmune diseases.32 Given that much of the ocular surface and the lacrimal gland are both ectodermally derived, it is possible that there is shared antigenicity and that the lacrimal gland is affected by the same autoimmune process as the skin. Chronic inflammation is also a major component in the pathophysiology of DES33 and apparently the AIBDs. DES is prevalent in our patient cohort, and apart from the associated reduced quality of life34,35 and vision, the underlying disease process may be contributing to the long-term sequelae of conjunctival cicatrization and corneal compromise. Because both DES and the underlying blistering process are associated with chronic inflammation, then from an ocular perspective, reducing this inflammatory process locally with drugs such as topical cyclosporine may provide a new intervention. Our preliminary results in treating DES in a small number of these patients are promising. The rarity of pemphigus and other AIBDs could explain the unfamiliarity of this disease among ophthalmologists, and therefore the lag in detecting DES in these patients. However, the high incidence and the potential for both severe ocular problems in these patients and successful topical intervention suggest that close ophthalmic monitoring is important.
CONCLUSIONS In summary, our study evaluating ocular manifestations in patients with pemphigus and BP has shown that these patients have a high prevalence of DES. Other ocular signs found were blepharitis, conjunctival inflammation, and limbal broadening. With the high prevalence of DES in this population and its negative impact both on the long-term health of the ocular surface and on vision-related quality of life, ophthalmologists should be vigilant in instituting appropriate management early.
ACKNOWLEDGMENTS The authors acknowledge the University of New South Wales Independent Learning Programme grant for J. C. K. Tan to work with D. F. Murrell and M. T. Coroneo. Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pemphigus, Bullous Pemphigoid and Dry Eye Syndrome
REFERENCES 1. Stanley JR, Koulu L, Thivolet C. Distinction between epidermal antigens binding pemphigus vulgaris and pemphigus foliaceus autoantibodies. J Clin Invest. 1984;74:313–320. 2. Pisanti S, Sharav Y, Kaufman E, et al. Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion. Oral Surg Oral Med Oral Pathol. 1974;38:382–387. 3. Simon DG, Krutchkoff D, Kaslow RA, et al. Pemphigus in Hartford County, Connecticut, from 1972 to 1977. Arch Dermatol. 1980;116: 1035–1037. 4. Hodak E, Kremer I, David M, et al. Conjunctival involvement in pemphigus vulgaris: a clinical, histopathological and immunofluorescence study. Br J Dermatol. 1990;123:615–620. 5. Smith RJ, Manche EE, Mondino BJ. Ocular cicatricial pemphigoid and ocular manifestations of pemphigus vulgaris. Int Ophthalmol Clin. 1997; 37:63–75. 6. Merchant S, Weinstein E. Pemphigus vulgaris: the eyes have it. Pediatrics. 2003;112:183–185. 7. Akhyani M, Keshtkar-Jafari A, Chams-Davatchi C, et al. Ocular involvement in pemphigus Vulgaris. J Dermatol. 2014;41:618–621. 8. Daoud YJ, Cervantes R, Foster S, et al. Ocular pemphigus. J Dermatol. 2005;53:585–590. 9. Baykal HE, Pleyer U, Sonnichsen K, et al. Severe eye involvement in pemphigus vulgaris. Ophthalmologe. 1995;92:854–857. 10. Suami M, Kato M, Koide K. Keratolysis in a patient with pemphigus vulgaris. Br J Ophthalmol. 2001;85:1263–1264. 11. Fiore JM, Perry HD, Donnenfeld ED, et al. Pemphigus vulgaris: bilateral plica semilunaris involvement. Cornea. 2011;30:357–359. 12. Frith PA, Venning VA, Wojnarowska F, et al. Conjunctival involvement in cicatricial and bullous pemphigoid: a clinical and immunopathological study. Br J Ophthalmol. 1989;73:52–56. 13. Chirinos-Saldana P, Zuniga-Gonzalez I, Hernandez-Camarena JC, et al. Cicatricial changes in ocular pemphigus. Eye (Lond). 2014;28: 459–465. 14. Kiyokawa C, Fujito S, Mori O, et al. Bullous pemphigoid showing unusual ocular changes. Br J Dermatol. 1998;139:693–696. 15. Stoiber J. “Ophthalmologic aspects of epidermolysis bullosa”. In: Fine JD, Hintner H, eds. Life with Epidermolysis Bullosa (EB). Etiology, Diagnosis, Multidisciplinary Care and Therapy. Wien New York: Springer Verlag GmbH; 2009:136. 16. Fine JD, Johnson LB, Weiner M, et al. Eye involvement in inherited epidermolysis bullosa: experience of the national epidermolysis bullosa registry. Am J Ophthalmol. 2004;138:254–262. 17. Fine JD, Eady RAJ, Bauer EA, et al. The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol. 2008;58:931–950. 18. McDonnell PJ, Spalton DJ. The ocular signs and complications of epidermolysis bullosa. J R Soc Med. 1988;81:576–578. 19. McDonnell PJ, Schofield OMV, Spalton DJ, et al. Eye involvement in junctional epidermolysis bullosa. Arch Ophthalmol. 1989;107:1635– 1637. 20. Matsumoto Y, Dogru M, Tsubota K. Ocular surface findings in Hallopeau-Siemens subtype of dystrophic epidermolysis bullosa: report of a case and literature review. Cornea. 2005;24:474–479. 21. McCuaig CC, Chan LS, Woodley DT, et al. Epidermolysis bullosa acquisita in childhood. Differentiation from hereditary epidermolysis bullosa. Arch Dermatol. 1989;125:944–949. 22. Hatch KM, Dana R. The structure and function of the limbal stem cell and the disease states associated with limbal stem cell deficiency. Int Ophthamol Clin. 2009;49:43–52. 23. Dua HS, Saini JS, Azuara-Blanco A, et al. Limbal stem cell deficiency: concept, aetiology, clinical presentation, diagnosis and management. Indian J Ophthalmol. 2000;48:83–92. 24. Mohammadpour M. Progressive corneal vascularization caused by graftversus-host disease. Cornea. 2007;26:225–226. 25. Osei-Bempong C, Figueiredo FC, Lako M. The limbal epithelium of the eye-a review of limbal stem cell biology, disease and treatment. Bioessays. 2013;35:211–219. 26. Figueira EC, Murrell DF, Coroneo MT. Ophthalmic involvement in inherited epidermolysis bullosa. Dermatol Clin. 2010;28:143.
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27. Sale GE, Beauchamp MD, Akiyama M. Parafollicular bulges, but not hair bulb keratinocytes, are attacked in graft-versus-host disease of human skin. Bone Marrow Transplant. 1994;14:411–413. 28. Bron AJ. Diagnosis of dry eye. Surv Opthalmol. 2001;45:221–226. 29. Farris RL, Gilbard JP, Stuchell RN, et al. Diagnostic tests in keratoconjunctivitis sicca. CLAO J. 1983;9:23–28. 30. Perry HD, Donnenfeld ED. Dry eye diagnosis and management in 2004. Curr Opin Ophthalmol. 2004;15:299–304. 31. McCarty CA, Bansal AK, Livingston PM, et al. The epidemiology of dry eye in Melbourne, Australia. Ophthalmology. 1998;105:1114–1119.
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Prospective Study of Ocular Manifestations of Pemphigus and Bullous Pemphigoid Identifies a High Prevalence of Dry Eye Syndrome Jeremy C.K. Tan, BSc(Med), MD,*†‡§ Lien T. Tat, PhD,*†§ Kristy B. Francis, BAppSc(Orth),*†§ Clarisse G. Mendoza, MD,*‡ Dedee F. Murrell, MA, BMBCh, FAAD, FACD, MD,*‡ and Minas T. Coroneo, BSc(Med), MBBS, MSc, MD, MS, FRACS, FRANZCO*†§
Purpose: To study the range of ocular manifestations in an Australian cohort of patients with pemphigus and bullous pemphigoid (BP), including a detailed assessment for dry eye syndrome (DES).
Methods: Twenty-two patients with pemphigus vulgaris, pemphigus foliaceus, and BP were referred for a detailed ophthalmology review between September 2011 and March 2012. Results: A total of 44 eyes of 22 patients with pemphigus vulgaris, pemphigus foliaceus, and BP were examined. Photophobia was the most common symptom reported. The most common ocular signs found in both groups were blepharitis (68.1%), conjunctival hyperemia (22.7%), and limbal broadening (18.2%). In our DES assessment, 92.9% of patients had a reduced Schirmer test score and an abnormal tear break-up time was recorded in 100% of patients. The ocular surface disease index score ranged from 0 to 47.2, with a median score of 10.
Conclusions: The high occurrence of patient-reported ocular symptoms and clinical evidence of dry eye on Schirmer testing and break-up time demonstrate high prevalence of DES in our cohort of pemphigus and BP patients, which is a novel finding. Limbal broadening was another common finding not previously reported. Key Words: pemphigus, bullous pemphigoid, dry eye syndrome, limbal broadening, stem cell (Cornea 2015;34:443–448)
Received for publication August 19, 2014; revision received September 19, 2014; accepted November 2, 2014. Published online ahead of print February 3, 2015. From the *Faculty of Medicine, University of New South Wales, Sydney Australia; †Department of Ophthalmology, Prince of Wales Hospital, Sydney, Australia; ‡Department of Dermatology, St George Hospital, Sydney, Australia; and §Ophthalmic Surgeons, Sydney, Australia. Supported by a grant from the University of New South Wales Independent Learning Programme to J. C. K. Tan to work with D. F. Murrell and M. T. Coroneo. The other authors have no conflicts of interest to disclose. Reprints: Minas T. Coroneo, BSc(Med), MBBS, MSc, MD, MS, FRACS, FRANZCO, University of New South Wales at Prince of Wales Hospital, 2 St Pauls St, Randwick NSW 2031, Sydney, Australia (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cornea Volume 34, Number 4, April 2015
A
utoimmune blistering skin disease (AIBD) is a term used to describe a heterogeneous group of cutaneous and mucosal diseases with significant morbidity and mortality, including pemphigus, bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA), and linear immunoglobulin A bullous dermatosis. A range of ocular manifestations can occur in patients with AIBD because of the underlying blistering disease or as side effects of medications used to treat these diseases. The most common ocular presentation of AIBD is chronic conjunctivitis, which can progress to conjunctival fibrosis and eventually chronic cicatricial conjunctivitis. Cicatrization can lead to severe ocular complications that include symblepharon, fornix foreshortening, entropion, trichiasis, keratopathy, and blindness in certain cases. Pemphigus is a group of autoimmune blistering diseases that are caused by autoantibodies directed against desmosomal proteins that function as intercellular adhesion molecules, resulting in acantholysis and blistering of the skin and mucous membranes. There are 4 major variants of pemphigus, depending on the desmoglein type and epidermal level affected—pemphigus vulgaris (PV), pemphigus foliaceus, paraneoplastic pemphigus, and drug-induced pemphigus. PV is characterized by immunoglobulin G autoantibodies directed against desmoglein 3, which is present in the deep epidermis. In pemphigus foliaceus, autoantibodies are formed against desmoglein 1, present throughout the epidermis.1 The incidence of PV ranges from 0.4 to 1.6 cases per 100,000 individuals, with a greater incidence seen in Ashkenazi Jews.2,3 Affected individuals are typically in their fourth to fifth decades of life. In PV, mucous membranes are usually the first to be affected by the disease. Erosions in the oral cavity are most commonly seen, whereas the conjunctiva, esophagus, and genital areas are less commonly affected. Ocular disease can present with symptoms of ocular irritation, tearing, and foreign body sensation.4–6 A recent study by Akhyani et al reported that ocular involvement was present in 16.5% of their study of 103 patients with PV, with conjunctivitis and erosion of the palpebral conjunctiva being the most common findings.7 Based on a cohort of 167 patients with PV, Daoud et al reported an incidence of ocular involvement of 7%. The authors reported findings of bilateral conjunctivitis and lid margin ulceration. The mean interval between the onset of PV and ocular involvement was 20 www.corneajrnl.com |
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months, and the ocular disease lasted for a mean of 12 months. The authors found that patients had complete recovery and no long-term sequelae due to conjunctival disease.8 There have however been findings of corneal perforation, keratolysis, forniceal foreshortening, and plica semilunaris vegetations in patients with PV reported in the literature.9–11 Another study by Chirinos-Saldana et al reported subconjunctival scarring, symblepharon, trichiasis and entropion, corneal opacities, and ankyloblepharon in their cohort of 15 patients with PV,12 demonstrating the presence of long-term cicatricial changes from ocular disease. Mucous membranes are involved only occasionally in BP, consequently ocular involvement is uncommon. The incidence of ocular involvement is unknown because of lack of large-scale studies examining ocular findings in BP. Ocular manifestations are subtle and may go undetected in the conjunctiva and lid margins. Slit-lamp examination may reveal subepithelial fibrosis with fine linear striae of the tarsus.13,14 Other ocular manifestations reported in the literature include conjunctival scarring, corneal epithelial defects, stromal edema, and corneal opacity.13,14 The aim of this study was to examine the range of ocular manifestations in patients with PV and BP, including the presence of dry eye syndrome (DES).
MATERIALS AND METHODS This study was approved by the local institutional review board in September 2011. From a literature search of past case series and reports describing ocular involvement in AIBD, we created a comprehensive data collection sheet to record the ocular history and examination findings to create a bullous diseases eye score (BDES). Patients with a confirmed diagnosis of pemphigus and BP were recruited from dermatology subspecialty bullous clinics. Diagnosis of patients with pemphigus and BP was confirmed by clinical assessment, histopathology, and direct immunofluorescence of an appropriate skin biopsy specimen, and/or indirect immunofluorescence using patient serum studies. Patients were prospectively referred for comprehensive review by M. T. Coroneo using the BDES between September 2011 and March 2012. A detailed medical history, medication history, and history of any current ocular symptoms, past ocular disease, and procedures was elicited. The history questionnaire component of the BDES, which included a history of the ocular symptoms of itching, tearing, discomfort, photophobia, and mucous discharge was completed with a uniform interviewer (J.C.K.T.). Participants were asked to grade their experience of these symptoms on a scale of 0 to 3, which represented none, mild, moderate, and severe. An ocular surface disease index (OSDI) questionnaire was also administered. The OSDI, developed by the Outcomes Research Group at Allergan, is a 12-item questionnaire designed to provide a rapid assessment of the symptoms of ocular irritation consistent with DES and their impact on vision-related functioning. The OSDI score was calculated according to the following formula: OSDI = [(sum of scores for all questions answered) · 100]/[(total number of questions answered) · 4]. The OSDI is scored on a scale of 0 to 100, with higher scores representing greater disability.
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The visual acuity was measured with a projected Snellen chart adjusted for a 6-m viewing distance. The visual acuity was classified according to the World Health Organization’s definition of visual impairment [grade 0 (6/6 or better), grade 1 (6/9–6/18), grade 2 (6/21–6/48), grade 3 (6/60–6/120), grade 4 (6/150–6/300), grade 5 (worse than 6/300), and grade 6 (No light perception)]. We included 20 components of 3 categories of ocular complications in the slit-lamp examination of the anterior ocular surface. These were classified into eyelid complications—consisting of blepharitis, ectropion, lacrimal duct obstruction, lid retraction, blistering, and trichiasis; conjunctival complications—comprising conjunctival inflammation, conjunctival edema, blepharoconjunctivitis, and symblepharon; and corneal complications—consisting of corneal edema, exposure keratitis, ulceration, scarring, limbal broadening, pannus, opacity, blister, erosion, and neovascularization. Conjunctival inflammation was graded as absent, mild, moderate, or severe. The presence or absence of the other lid, conjunctiva, and cornea findings was recorded. Dry eye was assessed using fluorescein staining, tear break-up time (TBUT), and Schirmer test. Fluorescein staining of the cornea and conjunctiva was administered by touching the inferior fornix with a dry fluorescein strip with the patient looking upward. The slit-lamp biomicroscope was then used to inspect the cornea for punctate staining, and graded as 0 (#2 dots), 1 (.2 but #32 dots), 2 (.32 but #316 dots), or 3 (.316 dots approximately or ulcer/erosion). Dry eye was defined as grade 2 or 3 fluorescein staining. The TBUT was then recorded. This is the time in seconds between the patient’s blink and the appearance of a random dry spot on the cornea. The TBUT was performed 3 times, and the average time was calculated. The test was considered positive if the average TBUT was less than 8 seconds. Schirmer test was performed with a 5- · 35-mm strip of dry filter paper after instillation of anesthetic drops. The length of wetting obtained was graded as normal (grade 0; $15 mm), mild dryness (grade 1; 10–14 mm), moderate dryness (grade 2; 5–9 mm), and severe dryness (grade 3; # 4 mm). Dry eye was defined as Schirmer test grade 2 or 3. Cataract, glaucoma, and retinal diseases were also evaluated, and their presence or absence was recorded.
RESULTS A total of 44 eyes of 22 patients with PV (13 patients), pemphigus foliaceus (2 patients), and BP (7 patients) were included in this study. There were 9 males (41%) and 13 females. Ages ranged from 32 to 87 years with a mean of 63 years. At disease onset, the patients’ age ranged from 25 to 80 years. The mean duration of their blistering disease was 5 years (range, 0–20 years).
Ocular Symptoms and OSDI Seventeen patients (77.3%) complained of at least 1 symptom of dry eye. Photophobia was the most common symptom reported in patients with AIBD (45%) (Table 1). It was also the most common severe symptom reported. Other ocular symptoms reported were tearing (30%), itching (30%), discomfort (27%), and mucous discharge (9.1%). Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Pemphigus, Bullous Pemphigoid and Dry Eye Syndrome
TABLE 1. Prevalence of Self-Reported Ocular Symptoms in Participants Severity Ocular Symptoms PV and pemphigus foliaceus (n = 30 eyes) Itching Tearing Discomfort Photophobia Mucous discharge BP (n = 14 eyes) Itching Tearing Discomfort Photophobia Mucous discharge
Grade 0, n (%)
Grade 1, n (%)
Grade 2, n (%)
Grade 3, n (%)
23 21 22 16 26
(76.7) (70.0) (73.3) (53.3) (86.7)
3 8 7 9 4
(10.0) (26.7) (23.3) (30.0) (13.3)
4 (13.3) 1 (3.3) 1 (3.3) 1 (3.3) 0
0 0 0 4 (13.3) 0
8 10 10 8 14
(57.1) (71.4) (71.4) (57.1) (100)
6 4 4 2
(42.9) (28.6) (28.6) (14.3) 0
0 0 0 4 (28.6) 0
0 0 0 0 0
Twenty patients completed the OSDI questionnaire. The total OSDI score ranged from 0 to 47.2, with a median score of 10. Of these, 13 patients (65%) were graded as normal, 5 patients (25%) had mild ocular surface disease, while 1 patient with pemphigus foliaceus and 1 patient with PV had moderate and severe ocular surface disease.
Visual Acuity Thirteen (59.1%) patients had a visual acuity of at least 6/6 or better. The remaining patients had at visual acuity of at least 6/18 or better.
Assessment of Tear Film A summary of the 3 evaluated components of the tear film assessment in both groups is shown in Table 3. The Schirmer test was performed on 21 patients—1 patient did not undergo the Schirmer test because of intolerance. Severe eye dryness (grade 3, length of wetting # 4 mm) was found in 25 (59.5%) of the 42 eyes tested. Of the remaining eyes, 10 (23.8%) had moderate dryness (grade 2; 5–9 mm), 4 (9.5%) had mild dryness (grade 1; 10–14 mm), and 3 (7.1%) had normal wetting of the filter paper. Overall, 92.9% of patients had an abnormal Schirmer test, 13.6% of patients had significant Fluorescein staining (grade 2 or 3), and 100% of patients had a reduced TBUT average (less than 8 seconds).
DISCUSSION Ocular involvements in pemphigus reported in the literature include conjunctivitis, erosion of palpebral conjunctiva, corneal perforation, keratolysis, corneal opacity, forniceal foreshortening, subconjunctival scarring, symblepharon, trichiasis and entropion, plica semilunaris vegetations, and ankyloblepharon. In BP, subepithelial fibrosis, conjunctival scarring, corneal
TABLE 3. Summary of Results From Tear Film Assessment in Participants Grade Grade 1 Blistering Disease 0 (‡15 mm) (10–14 mm) Schirmer’s test Pemphigus foliaceus (n = 4) PV (n = 24*) BP (n = 14) Total (n = 42*)
Grade 2 (5–9 mm)
Grade 3 (#4 mm)
0
0
0
4
2 1 3 (7.1%)
4 0 4 (9.5%)
4 6 10 (23.8%)
14 7 25 (59.5%)
Ocular Surface Findings Of the 44 eyes, blepharitis was seen in 30 eyes (68.1%). Conjunctival hyperemia was the most common conjunctival finding, observed in 10 eyes (22.7%). Limbal broadening was the commonest corneal complication, seen in 8 eyes (18.2%). Other ocular signs observed were corneal scarring in 6 eyes (13.6%), corneal opacity seen in 3 eyes, conjunctival edema in 2 eyes, symblepharon in 2 eyes, and trichiasis and neovascularization each observed in 1 eye (Table 2).
TABLE 2. Prevalence of Ocular Manifestations in Participants (n = 44 Eyes) Ocular Manifestation Blepharitis Conjunctival hyperemia Limbal broadening Corneal scarring Corneal opacity Conjunctival edema Ectropion Corneal neovascularization
Prevalence 30 10 8 6 3 2 1 1
(68.2) (22.7) (18.2) (13.6) (6.8) (4.5) (2.3) (2.3)
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Blistering Disease Fluorescein staining Pemphigus foliaceus (n = 4) PV (n = 26) BP (n = 14) Total (n = 44)
Grade 0 (#2 Dots)
Grade 1 (.2 but #32 Dots)
Grade 2 (.32 but #316 Dots)
Grade 3 (.316 Dots Approx or Ulcer/Erosion)
0
2
2
0
1
23
2
0
3
9
2
0
4 (9.1)
34 (77.3)
6 (13.6)
0
Blistering Disease Tear break-up time Pemphigus foliaceus (n = 4) PV (n = 26) BP (n = 14) Total (n = 44)
Mean, s
SD
Range
1.2 2.3 2.4 2.3
0.2 0.7 1.0 0.9
1–1.4 1.2–4 1.3–4.8 1–4.8
*One patient with PV could not tolerate the Schirmer test and was excluded.
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epithelial defects, stromal edema, and corneal opacity have been reported. In our cross-sectional study of pemphigus and BP patients, we observed blepharitis, conjunctival hyperemia, conjunctival edema, corneal scarring, corneal opacity, corneal neovascularization, limbal broadening, and DES. Of these complications, the most common ocular signs found were blepharitis (68.1%), conjunctival hyperemia (22.7%), and limbal broadening (18.2%). DES and limbal broadening are novel signs in pemphigus and BP.
Limbal Broadening Limbal broadening was the most common corneal abnormality observed, seen in both eyes of 4 patients (Fig. 1). Three of these patients had PV, and the fourth had BP. The term limbal broadening has been rarely used in the literature, and there is currently no established definition of this ocular sign. Limbal broadening has been described as when the corneal periphery adjacent to the limbus shows marked clouding.15 There have been previous reports documenting this ocular sign in patients with inherited epidermolysis bullosa (EB) in the literature.16 Inherited EB is a group of skin diseases that is characterized by marked mechanical fragility of epithelial tissues and blistering.17 They are caused by mutations in genes that encode for proteins within the epidermis or basement membrane zone. In a case series of 11 patients with the recessive dystrophic form of epidermolysis bullosa (RDEB), McDonnell and Spalton18 reported limbal broadening in 5 patients, where they described observing an “avascular broadening of the superior and inferior limbus.” RDEB is due to defects in the collagen VII gene, leading to defects in the collagen VII protein, the very same protein that is targeted in EBA; McDonnell et al19 also described observing a “pannus-like broadening of the limbus” in 3 of 5 patients with non-Herlitz junctional EB. This form of EB is due to defects in BP180 and collagen XVII, proteins that are targets for BP, linear immunoglobulin A bullous dermatosis, and MMP. There have since been other case reports of EB patients with this interesting ocular manifestation.20
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McCuaig et al21 reported ocular findings observed in a 10-year-old boy with EBA, who had “broadening of the superior limbus” in his right eye, and also “vascularisation of the temporal limbus” in the left eye. This is the only case report in the literature that describes the occurrence of this ocular manifestation in a patient with an autoimmune blistering skin disease. We believe that these descriptions of the phenomenon of limbal broadening in patients with EB and the 1 patient with EBA could possibly be descriptions of early ocular signs of limbal stem cell deficiency (LSCD) or dysfunction. Early slit-lamp microscopy findings of LSCD include flattening of the limbus in the region of the palisades of Vogt.22 The corneal epithelium may also appear hazy and irregular20; however, typically vascularization is a feature. This sign could therefore indicate LSCD in these patients. The corneal epithelium is derived from a subpopulation of stem cells that are located in the corneoscleral limbus of the eye.23 Importantly, ocular MMP is associated with LSCD.24 To the best of our knowledge, there is no report of the occurrence of LSCD in any of the other AIBDs including PV and BP, or in any type of inherited EB in the literature. LSCD leads to ocular symptoms that include redness, irritation, photophobia, and decreased vision. If limbal broadening is indeed an early sign of LSCD, patients with pemphigus and BP with this ocular manifestation will require closer monitoring of their eyes for occurrence or progression of any ocular surface complications. Interestingly, there is also stem cell exhaustion of the skin in the severe forms of EB such as non-Herlitz junctional Epidermolysis Bullosa and recessive dystrophic epidermolysis bullosa, which consequently leads to delayed wound healing and scarring. Of interest is that an immune-mediated limbitis, which may cause partial stem cell deficiency, has been implicated in Graft-versus-host-disease (GVHD).25 We have previously reported 2 cases in which focal stem cell deficiency was evident.26 Furthermore, it has been shown that in GVHD, stem cell populations in the hair parafollicular bulge are preferentially attacked.27 Thus, pemphigus/BP and GVHD may be linked by the observation that DES is common to both and that limbal stem cell involvement is likely.
Dry Eye Syndrome (Keratoconjunctivitis Sicca)
FIGURE 1. Limbal broadening in a patient with PV.
DES or keratoconjunctivitis sicca is a known complication of ocular MMP. We are unaware of previous reports in the literature that describe the association of DES in pemphigus and BP. It is likely that DES is underdiagnosed in this group of conditions as we can find little evidence in the literature regarding this issue. In our cohort of patients with pemphigus and BP, 92.9% had an abnormal Schirmer test and 100% had a reduced TBUT. From results of the Schirmer test, 14 patients (63.6%) had severe dryness (grade 3 dryness; length of filter paper wetting #4 mm). The remaining 7 patients also had some degree of reduced tear production (grade 1 or 2 dryness). Wetting of less than 5 mm indicates a diagnosis of tear deficiency.28 The Schirmer test however has been reported to have low sensitivity but high specificity.29 TBUT measures the stability of the tear film and is reduced in DES.28,30 In this study, we found that all the patients had an
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average TBUT of less than 8 seconds. Patient-reported dry eye symptoms however tend to be more reliable than results from dry eye clinical tests. In our cohort, 77% of our patients complained of at least 1 ocular symptom. The median score by OSDI was 10 of 100, with 31.8% of the patients having at least mild ocular surface disease and in this patient cohort does not appear to reflect disease severity. The high occurrence of patient-reported ocular symptoms and clinical evidence of dry eye on Schirmer test and TBUT therefore demonstrate the high prevalence of dry eye in our cohort of patients with AIBD. It is of interest that the OSDI results would underestimate dry eye prevalence in our patient cohort. The prevalence of dry eye in the Australian general population was estimated to be 16.3% based on a Schirmer test diagnosis,31 although the true prevalence of this condition is unknown because patients often only present for assessment when their condition is moderate to severe. Results of the Schirmer test and TBUT in our patients are consistent with the increased prevalence of DES seen in patients with autoimmune diseases.32 Given that much of the ocular surface and the lacrimal gland are both ectodermally derived, it is possible that there is shared antigenicity and that the lacrimal gland is affected by the same autoimmune process as the skin. Chronic inflammation is also a major component in the pathophysiology of DES33 and apparently the AIBDs. DES is prevalent in our patient cohort, and apart from the associated reduced quality of life34,35 and vision, the underlying disease process may be contributing to the long-term sequelae of conjunctival cicatrization and corneal compromise. Because both DES and the underlying blistering process are associated with chronic inflammation, then from an ocular perspective, reducing this inflammatory process locally with drugs such as topical cyclosporine may provide a new intervention. Our preliminary results in treating DES in a small number of these patients are promising. The rarity of pemphigus and other AIBDs could explain the unfamiliarity of this disease among ophthalmologists, and therefore the lag in detecting DES in these patients. However, the high incidence and the potential for both severe ocular problems in these patients and successful topical intervention suggest that close ophthalmic monitoring is important.
CONCLUSIONS In summary, our study evaluating ocular manifestations in patients with pemphigus and BP has shown that these patients have a high prevalence of DES. Other ocular signs found were blepharitis, conjunctival inflammation, and limbal broadening. With the high prevalence of DES in this population and its negative impact both on the long-term health of the ocular surface and on vision-related quality of life, ophthalmologists should be vigilant in instituting appropriate management early.
ACKNOWLEDGMENTS The authors acknowledge the University of New South Wales Independent Learning Programme grant for J. C. K. Tan to work with D. F. Murrell and M. T. Coroneo. Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pemphigus, Bullous Pemphigoid and Dry Eye Syndrome
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27. Sale GE, Beauchamp MD, Akiyama M. Parafollicular bulges, but not hair bulb keratinocytes, are attacked in graft-versus-host disease of human skin. Bone Marrow Transplant. 1994;14:411–413. 28. Bron AJ. Diagnosis of dry eye. Surv Opthalmol. 2001;45:221–226. 29. Farris RL, Gilbard JP, Stuchell RN, et al. Diagnostic tests in keratoconjunctivitis sicca. CLAO J. 1983;9:23–28. 30. Perry HD, Donnenfeld ED. Dry eye diagnosis and management in 2004. Curr Opin Ophthalmol. 2004;15:299–304. 31. McCarty CA, Bansal AK, Livingston PM, et al. The epidemiology of dry eye in Melbourne, Australia. Ophthalmology. 1998;105:1114–1119.
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