Journal of Dermatology 2014; 41: 618–621
doi: 10.1111/1346-8138.12447
ORIGINAL ARTICLE
Ocular involvement in pemphigus vulgaris Maryam AKHYANI,1 Alireza KESHTKAR-JAFARI,2 Cheyda CHAMS-DAVATCHI,1 Vahide LAJEVARDI,1 Sara BEIGI,1 Nessa AGHAZADEH,1 Maede RAYATI DAMAVANDI,1 Shabnam ARAMI1 1
Department of Dermatology, Autoimmune Bullous Diseases Research Center, Razi Hospital, and 2Department of Ophthalmology, Farabi Hospital, Tehran University of Medical Sciences, Tehran, Iran
ABSTRACT Pemphigus vulgaris (PV) is an autoimmune disorder affecting the skin and mucous membranes. Ocular involvement in PV has been reported but its prevalence and clinical characteristics are not well defined. This prospective cross-sectional study of 103 PV patients was designed to determine the prevalence, clinical types and epidemiological trends of ocular involvement in a population of Iranian patients with PV. Ocular involvement was present in 17 (16.5%) patients. Conjunctivitis was the most prevalent type of ocular involvement (9/17, 52.9%), followed by erosion of the palpebral conjunctiva (7/17, 41.2%). Erosion of the bulbar conjunctiva was noted in only one patient (5.9%). The most commonly reported symptoms were eye irritation (76.5%) and redness (76.5%). No significant relation was found between ocular involvement and disease activity (partial remission or relapse). Mucoid discharge was significantly more common in patients with conjunctival erosions as compared to patients with conjunctivitis (P = 0.038). We conclude that ocular involvement is not rare in PV; 16.5% of PV patients develop ocular disease independent of the disease activity and extension. Conjunctivitis is the most common type of involvement, however, palpebral conjunctival erosion is more frequent than previously realized.
Key words:
autoimmune blistering diseases, conjunctival erosion, conjunctivitis, pemphigus vulgaris.
INTRODUCTION Pemphigus vulgaris (PV) is an autoimmune disorder characterized by development of flaccid blisters and erosions on otherwise normal skin or mucosal membranes. Although the most frequent mucosal site of involvement has shown to be the oral cavity, ocular surface may also be involved. In 1975, the first report of ocular involvement in PV was released by Bean et al.1 Several case reports and small case series of PV patients with ocular disease have been published since. According to these studies, ocular involvement in PV is considered to be rare, but it is probably underdiagnosed and its frequency appears to be underestimated.2–8 There is still insufficient evidence regarding the true incidence rate of ocular disease in PV as well as its distinct clinical types. This is possibly due to lack of large-scale studies focusing on ocular manifestations of PV. Furthermore, the current case reports and case series merely include patients with significant ocular complaints. Because the ocular symptoms of PV are likely to be mild and non-disturbing, a thorough ophthalmologic examination is often required to detect mild disturbances.4,7
The purpose of this prospective cross-sectional study was to determine the true prevalence of ocular involvement in a population of Iranian patients with PV. We also aimed to study the type, epidemiological trends and clinical associations in patients with ocular disease.
METHODS This study was performed at the Autoimmune Bullous Diseases Research Center, Razi Hospital, Tehran University of Medical Science. All newly or previously diagnosed patients with PV presented to the Autoimmune Bullous Diseases Clinic of Razi Hospital between January 2009 and January 2010 were considered for enrollment. During the study period, each patient was examined once for the presence of ocular pathologies. The diagnosis of PV in patients with compatible clinical features was made based on pathological, and immunohistological criteria (direct immunofluorescence on perilesional skin/ mucosa showing intercellular deposition of immunoglobulin G and/or C3 in the epidermis). A total of 103 consenting patients entered the study. All patients provided a written consent. A thorough ophthalmologic examination (slit lamp examination
Correspondence: Vahide Lajevardi, M.D., Department of Dermatology, Autoimmune Bullous Diseases Research Center, Razi Hospital, Vahdat Eslami Square, Tehran 1199663911, Iran. Email: [email protected] Received 19 December 2012; accepted 27 January 2014.
618
© 2014 Japanese Dermatological Association
Ocular PV
including ocular surface exam, ophthalmoscopy, and assessment of visual acuity) was performed by an experienced ophthalmologist unaware of patients’ identity and clinical characteristics. The diagnosis of conjunctivitis was made based on the presence of conjunctival inflammation and injection with or without discharge. Allergic conjunctivitis was ruled out after taking a thorough history for atopic diathesis, based on lack of severe eyelid pruritus and conjunctival papillary reaction. Absence of follicular and papillary conjunctival reaction made the diagnosis of bacterial conjunctivitis unlikely; however, in case of clinical suspicion Gram stain and bacterial cultures were obtained. Particularly in the presence of conjunctival erosion, evidence of herpetic keratoconjunctivitis such as vesicular blepharitis and dendritic corneal ulcers were carefully sought and ruled out. Anti-desmoglein (Dsg)1 and Dsg3 enzyme-linked immunosorbent assays (ELISA) were performed using MBL kits (Nagoya, Japan) according to the manufacturer’s instructions. Statistical Package for Social Sciences version 17.00 (SPSS, Chicago, IL, USA) was used for statistical analysis. The v2-test, Fisher’s exact test and independent sample Student’s t-test were used when applicable. P < 0.05 was considered to be statistically significant.
RESULTS In total, 103 PV patients, 61 (59.3%) female with a mean age of 44 years, were studied. The most frequent disease type was mucocutaneous (73.8%) followed by cutaneous (13.6%) and mucosa-confined disease (12.6%). Of these patients, 68.9% were in partial remission while 15.5% were in major relapse and another 15.5% in minor relapse. All patients received oral corticosteroids (prednisolone) accompanied by azathioprine in 67%, mycophenolate mofetil in 3.9%, dapsone in 2.9%, cyclophosphamide in 5.8% and i.v. immunoglobulin in 3.9% of patients. Ophthalmic examination revealed that ocular involvement was present in 17 (16.5%) patients. Conjunctivitis was found to be the most prevalent type of ocular involvement (9/17, 52.9%), followed by erosion of the palpebral conjunctiva (7/17, 41.2%) and erosion of the bulbar conjunctiva, which was noted in only one patient (5.9%). Conjunctivitis was bilateral and of mild to moderate severity in all cases (Figs 1,2). However, in two patients the inflammation initially affected the right eye,
Figure 1. Bilateral mild conjunctivitis.
© 2014 Japanese Dermatological Association
Figure 2. Moderate conjunctivitis of the right eye. The patient was in relapse of pemphigus vulgaris with multiple cutaneous and mucosal erosions.
with subsequent involvement of the left. Involvement of the iris, lens, cornea, sclera or retina was not observed in any patient. Visual acuity was not impaired. In eight patients (47.1%), ocular disease occurred after mucocutaneous involvement while in six patients (35.3%) the ocular and mucocutaneous involvement occurred simultaneously. In three patients (17.6%), ocular involvement was the first presentation of PV. The mean time interval between the appearance of ocular and mucocutaneous manifestations was 14.2 8.8 days. The mean duration of ocular involvement was 3.3 2.4 weeks. The most commonly reported symptoms were eye irritation (76.5%) and redness (76.5%), followed by visual complaint (six, 35.3%), pain (six, 35.3%), tearing (five, 29.4%), photophobia (five, 29.4%), eyelid swelling (one, 5.9%) and non-purulent discharge (five, 29.4%). Dsg1 and Dsg3 ELISA were available in 13 patients at the time of diagnosis of ocular disease with mean value of 72.6 (range, 2.6–328) and 216.1 (range 14–348) index value, respectively. Patients with ocular involvement were on average 3 years younger than patients without ocular involvement, but without statistical significance (mean age, 41.3 and 44.4 years, respectively, P = 0.375). No significant relation was found between ocular involvement and disease activity (partial remission or relapse) (Table 1). We did not find any significant relationship between the incidence of ocular signs and localization of cutaneous (head and neck, trunk, extremities and genitalia) or mucosal lesions (oral cavity, pharynx, larynx and genital mucosa). However, the presence of PV lesions in the inguinal region was significantly associated with ocular involvement
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Table 1. Association between disease characteristics and ocular involvement Disease characteristics Disease type Cutaneous (14) Mucosal (13) Mucocutaneous (76) Disease activity Partial remission (71) Minor relapse (16) Major relapse (16) Anatomical localization Head and neck (83) Trunk (84) Extremities (65) Genitalia (32) Inguinal region (45) Oral cavity (86) Pharynx (36) Genital mucosa (10)
Ocular involvement
P-value
0 1 (7.7) 16 (21.1)
0.092
8 (11.4) 5 (31.3) 4 (25)
0.182
16 15 13 7 12 15 4 3
(19.3) (17.9) (20) (21.9) (26.7) (17.4) (11.1) (30)
0.123 0.437 0.211 0.324 0.014 0.565 0.280 0.226
(P = 0.014). The association of self-reported patients’ symptoms with different types of ocular involvement was assessed. We noted that purulent (mucoid) discharge was significantly more common in patients with conjunctival erosions as compared to patients with conjunctivitis (P = 0.038). All patients had a favorable response to systemic steroids, as indicated by PV disease activity (prednisolone; mean initial dose, 37.5 mg), with resolution of ocular signs and symptoms within a mean duration of 10 weeks (range, 4–15). Adjunctively, artificial teardrops were administrated in nine patients and topical steroids in three.
DISCUSSION The present study was designed to estimate the prevalence and characteristics of ocular involvement in a population of Iranian patients with PV. Overall, we found that 16.5% of the patients developed ocular disease. Mild and moderate conjunctivitis was the most frequent type of ocular involvement (52.9%). Nevertheless, more severe ocular involvement appearing as palpebral conjunctival erosion was also commonly observed (41.2%). Erosion of the bulbar conjunctiva was rarely detected. In earlier cohort studies of PV patients in Iran, conjunctival involvement has been reported in 16–26% of patients.9,10 In a study of 167 US PV patients by Daoud et al.,3 biopsy-proven ocular involvement was noted in 7%. These authors have adopted different inclusion criteria and detection methods for ocular involvement. The possibility of genetic propensity for ocular involvement in Iranian patients should be considered; previous studies have shown that the prevalence, age of onset and clinical behavior of pemphigus may be subject to vary depending upon the geographical location and racial backgrounds.11–13 Moreover, the findings of Harman et al.14
620
indicates that the density and distribution of Dsg antigens among Northern European patients differ from individuals with Indian origin. We did not perform conjunctival biopsy in this study because we believe, in accordance with the current evidence, that conjunctival biopsies in PV are less likely to reveal a positive finding as compared to other mucosa and are often not necessary for diagnosing or managing ocular complications. Furthermore, some authors have suggested that conjunctival biopsies should be avoided when biopsy from other sites is available, primarily because the conjunctiva cannot be sutured and is susceptible to bacterial and viral infections.3 The study by Hodak et al.15 revealed positive histopathological findings in only three of the 11 patients with ocular involvement undergoing conjunctival biopsies. This study showed that ocular involvement in PV is not rare. However, compared to other mucosal surfaces such as oral cavity (86/103, 83.4%), the eyes are less frequently involved. Dsg3 is expressed in the basal cells of the conjunctival epithelium, fading in the suprabasal layers. The conjunctiva is also rich in desmoplakin 1 and 2.16,17 The Dsg3 function loss in conjunctiva in most PV patients may be compensated by the presence of other non-Dsg desmosomal proteins.18 Therefore, ocular involvement occurs in a minority of patients. The prominent ocular abnormalities in this study were exclusively localized to the conjunctiva. A novel finding of this study is the high incidence of palpebral conjunctival erosions in ocular PV. Case reports of conjunctival erosions in the setting of PV are present in the published work.3,8,15,19–21 We believe palpebral conjunctival erosion is an underreported and underrecognized complication of PV in the eyes. The deposition of autoantibodies against intercellular adhesion molecules presumably triggers early conjunctival inflammation.6,22 As the disease progresses, the conjunctivitis could be followed by development of fragile vesicles that may rupture and leave erosions on the ocular surface.8 Cornea is an immunologically privileged tissue; therefore, direct immune reaction during autoimmune diseases does not generally occur. Unlike cicatricial pemphigoid, corneal opacities secondary to severe dryness due to tear, aqueous and mucin layer deficiency is not the case in PV.4,6 We noticed that in most patients the ocular symptoms tended to occur simultaneously or after mucocutaneous presentations. A significant minority (17.6%) showed ocular involvement as the first presentation of PV. The exact sequence of manifestations across the course of PV is unknown.3,15 Given that PV may arise primarily from the ocular surface, ophthalmologists are required to become familiar with pemphigus-related abnormalities. Moreover, it is noteworthy that even an isolated conjunctivitis should raise the suspicion of PV, particularly under chronic, unexplained circumstances. Comparable to other studies,15,21,22 we found irritation and redness to be the most frequent ocular symptoms. Notably, more than one-third of patients had visual complaint but ophthalmic examination did not reveal decreased visual acuity. Persistent inflammation and erosion of the eyelids may affect the anatomy of lid margin and the quality of the tear film and cause severe dryness of the eye, leading to poor vision quality. Non-
© 2014 Japanese Dermatological Association
Ocular PV
purulent discharge was the only symptom associated with palpebral conjunctival erosion. Therefore, the presence of mucoid discharge warrants a more careful ophthalmologic examination. Ocular involvement occurs in partial remission, minor and major relapses of PV and is, therefore, not an indicator of more severe disease. Future research is recommended to substantiate and explain the observed association between inguinal and ocular lesions, as well as its practical importance. Our finding supports the idea that prognosis of ocular involvement in PV is favorable;3,15 compared to other mucosal membranes, ocular lesions are often of shorter duration, respond to the conventional systemic therapies for PV, and heal without sequelae. The effect of systemic therapy was not assessed in this study, and it is plausible that the actual prevalence of ocular involvement is underestimated in patients receiving systemic treatments. In conclusion, our study demonstrated that 16.5% of PV patients developed ocular disease independent of their disease activity and extension. The ocular pathologies were entirely confined to conjunctiva with conjunctivitis being the most common involvement (52.9%), closely followed by palpebral conjunctival erosion (41.2%). A multidisciplinary approach with close collaboration of experienced dermatologists and ophthalmologists is needed to better detect and manage ocular pathologies in PV.
CONFLICT OF INTEREST:
None.
REFERENCES 1 Bean SF, Halubar K, Gillett RB. Pemphigus involving the eyes. Arch Dermatol 1975; 111: 1484–1486. 2 Baykal HE, Pleyer U, Sonnichsen K, Thiel HJ, Zierhut M. Severe eye involvement in pemphigus vulgaris. Ophthalmologe 1995; 92: 854– 857. 3 Daoud YJ, Cervantes R, Foster CS, Ahmed AR. Ocular pemphigus. J Am Acad Dermatol 2005; 53: 585–590. 4 Laforest C, Huilgol SC, Casson R, Selva D, Leibovitch I. Autoimmune bullous diseases: ocular manifestations and management. Drugs 2005; 65: 1767–1779. 5 Merchant S, Weinstein M. Pemphigus vulgaris: the eyes have it. Pediatrics 2003; 112 (1): 183–185.
© 2014 Japanese Dermatological Association
6 Baer JC, Hemady RK. Ocular manifestations of systemic immune disease. In: Bosniak S, ed. Principles and Practice of Ophthalmic Plastic and Reconstructive Surgery, Vol. 1. Philadelphia, PA: WB Saunders Company, 1996; 94–119. 7 Camisa C, Meisler DM. Immunobullous diseases with ocular involvement. Dermatol Clin 1992; 10: 555–570. 8 Lifshitz T, Levy J, Cagnano E, Halevy S. Severe conjunctival and eyelid involvement in pemphigus vulgaris. Int Ophthalmol 2004; 25 (2): 73–74. 9 Chams-Davatchi C, Valikhani M, Daneshpazhooh MB et al. Pemphigus: analysis of 1209 cases. Int J Dermatol 2005; 44: 470–476. 10 Esmaili N, Chams-Davatchi C, Valikhani M et al. Pemphigus vulgaris in Iran: a clinical study of 140 cases. Int J Dermatol 2007; 46: 1166– 1170. 11 Alcaide-Martin AJ, Gallardo-Perez MA, Castillo-Munoz R, Mendiola Fernandez MV, Herrera-Ceballos E. Epidemiologic study of 20 cases of pemphigus at Hospital Clinico Universitario Virgen de la Victoria de Malaga, Spain. Actas Dermosifiliogr 2010; 101: 524–533. 12 Asilian A, Yoosefi A, Faghini G. Pemphigus vulgaris in Iran: epidemiology and clinical profile. Skinmed 2006; 5 (2): 69–71. 13 Kanwar AJ, De D. Pemphigus in India. Indian J Dermatol Venereol Leprol 2011; 77 (4): 439–449. 14 Harman KE, Gratian MJ, Bhogal BS, Challacombe SJ, Black MM. A study of desmoglein 1 autoantibodies in pemphigus vulgaris: racial differences in frequency and the association with a more severe phenotype. Br J Dermatol 2000; 143 (2): 343–348. 15 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. 16 Messent AJ, Blissett MJ, Smith GL et al. Expression of a single pair of desmosomal glycoproteins renders the corneal epithelium unique amongst stratified epithelia. Invest Ophthalmol Vis Sci 2000; 41 (1): 8–15. 17 Diebold Y, Calonge M, Enrıquez de Salamanca A et al. Characterization of a spontaneously immortalized cell line (IOBA-NHC) from normal human conjunctiva. Invest Ophthalmol Vis Sci 2003; 44: 4263–4274. 18 Olszewska M, Komor M, Mazur M, Rogozinski T. Response of ocular pemphigus vulgaris to therapy. Case report and review of literature. J Dermatol Case Rep 2008; 2 (1): 1–3. 19 Bianciotto C, Herreras Cantalapiedra JM, Alvarez MA, Mendez Diaz MC. Conjunctival blistering associated with pemphigus vulgaris: report of a case. Arch Soc Esp Oftalmol 2005; 80: 365–368. 20 Brackley R, Pagani JM. Conjunctival erosions associated with pemphigus vulgaris. Optom Vis Sci 2011; 88: 1010–1013. 21 Palleschi GM, Giomi B, Fabbri P. Ocular involvement in pemphigus. Am J Ophthalmol 2007; 144 (1): 149–152. 22 Jackson WB, Gilmore NJ. Ocular immunology: a review (second of two parts). Can J Ophthalmol 1981; 16 (2): 59–65.
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doi: 10.1111/1346-8138.12447
ORIGINAL ARTICLE
Ocular involvement in pemphigus vulgaris Maryam AKHYANI,1 Alireza KESHTKAR-JAFARI,2 Cheyda CHAMS-DAVATCHI,1 Vahide LAJEVARDI,1 Sara BEIGI,1 Nessa AGHAZADEH,1 Maede RAYATI DAMAVANDI,1 Shabnam ARAMI1 1
Department of Dermatology, Autoimmune Bullous Diseases Research Center, Razi Hospital, and 2Department of Ophthalmology, Farabi Hospital, Tehran University of Medical Sciences, Tehran, Iran
ABSTRACT Pemphigus vulgaris (PV) is an autoimmune disorder affecting the skin and mucous membranes. Ocular involvement in PV has been reported but its prevalence and clinical characteristics are not well defined. This prospective cross-sectional study of 103 PV patients was designed to determine the prevalence, clinical types and epidemiological trends of ocular involvement in a population of Iranian patients with PV. Ocular involvement was present in 17 (16.5%) patients. Conjunctivitis was the most prevalent type of ocular involvement (9/17, 52.9%), followed by erosion of the palpebral conjunctiva (7/17, 41.2%). Erosion of the bulbar conjunctiva was noted in only one patient (5.9%). The most commonly reported symptoms were eye irritation (76.5%) and redness (76.5%). No significant relation was found between ocular involvement and disease activity (partial remission or relapse). Mucoid discharge was significantly more common in patients with conjunctival erosions as compared to patients with conjunctivitis (P = 0.038). We conclude that ocular involvement is not rare in PV; 16.5% of PV patients develop ocular disease independent of the disease activity and extension. Conjunctivitis is the most common type of involvement, however, palpebral conjunctival erosion is more frequent than previously realized.
Key words:
autoimmune blistering diseases, conjunctival erosion, conjunctivitis, pemphigus vulgaris.
INTRODUCTION Pemphigus vulgaris (PV) is an autoimmune disorder characterized by development of flaccid blisters and erosions on otherwise normal skin or mucosal membranes. Although the most frequent mucosal site of involvement has shown to be the oral cavity, ocular surface may also be involved. In 1975, the first report of ocular involvement in PV was released by Bean et al.1 Several case reports and small case series of PV patients with ocular disease have been published since. According to these studies, ocular involvement in PV is considered to be rare, but it is probably underdiagnosed and its frequency appears to be underestimated.2–8 There is still insufficient evidence regarding the true incidence rate of ocular disease in PV as well as its distinct clinical types. This is possibly due to lack of large-scale studies focusing on ocular manifestations of PV. Furthermore, the current case reports and case series merely include patients with significant ocular complaints. Because the ocular symptoms of PV are likely to be mild and non-disturbing, a thorough ophthalmologic examination is often required to detect mild disturbances.4,7
The purpose of this prospective cross-sectional study was to determine the true prevalence of ocular involvement in a population of Iranian patients with PV. We also aimed to study the type, epidemiological trends and clinical associations in patients with ocular disease.
METHODS This study was performed at the Autoimmune Bullous Diseases Research Center, Razi Hospital, Tehran University of Medical Science. All newly or previously diagnosed patients with PV presented to the Autoimmune Bullous Diseases Clinic of Razi Hospital between January 2009 and January 2010 were considered for enrollment. During the study period, each patient was examined once for the presence of ocular pathologies. The diagnosis of PV in patients with compatible clinical features was made based on pathological, and immunohistological criteria (direct immunofluorescence on perilesional skin/ mucosa showing intercellular deposition of immunoglobulin G and/or C3 in the epidermis). A total of 103 consenting patients entered the study. All patients provided a written consent. A thorough ophthalmologic examination (slit lamp examination
Correspondence: Vahide Lajevardi, M.D., Department of Dermatology, Autoimmune Bullous Diseases Research Center, Razi Hospital, Vahdat Eslami Square, Tehran 1199663911, Iran. Email: [email protected] Received 19 December 2012; accepted 27 January 2014.
618
© 2014 Japanese Dermatological Association
Ocular PV
including ocular surface exam, ophthalmoscopy, and assessment of visual acuity) was performed by an experienced ophthalmologist unaware of patients’ identity and clinical characteristics. The diagnosis of conjunctivitis was made based on the presence of conjunctival inflammation and injection with or without discharge. Allergic conjunctivitis was ruled out after taking a thorough history for atopic diathesis, based on lack of severe eyelid pruritus and conjunctival papillary reaction. Absence of follicular and papillary conjunctival reaction made the diagnosis of bacterial conjunctivitis unlikely; however, in case of clinical suspicion Gram stain and bacterial cultures were obtained. Particularly in the presence of conjunctival erosion, evidence of herpetic keratoconjunctivitis such as vesicular blepharitis and dendritic corneal ulcers were carefully sought and ruled out. Anti-desmoglein (Dsg)1 and Dsg3 enzyme-linked immunosorbent assays (ELISA) were performed using MBL kits (Nagoya, Japan) according to the manufacturer’s instructions. Statistical Package for Social Sciences version 17.00 (SPSS, Chicago, IL, USA) was used for statistical analysis. The v2-test, Fisher’s exact test and independent sample Student’s t-test were used when applicable. P < 0.05 was considered to be statistically significant.
RESULTS In total, 103 PV patients, 61 (59.3%) female with a mean age of 44 years, were studied. The most frequent disease type was mucocutaneous (73.8%) followed by cutaneous (13.6%) and mucosa-confined disease (12.6%). Of these patients, 68.9% were in partial remission while 15.5% were in major relapse and another 15.5% in minor relapse. All patients received oral corticosteroids (prednisolone) accompanied by azathioprine in 67%, mycophenolate mofetil in 3.9%, dapsone in 2.9%, cyclophosphamide in 5.8% and i.v. immunoglobulin in 3.9% of patients. Ophthalmic examination revealed that ocular involvement was present in 17 (16.5%) patients. Conjunctivitis was found to be the most prevalent type of ocular involvement (9/17, 52.9%), followed by erosion of the palpebral conjunctiva (7/17, 41.2%) and erosion of the bulbar conjunctiva, which was noted in only one patient (5.9%). Conjunctivitis was bilateral and of mild to moderate severity in all cases (Figs 1,2). However, in two patients the inflammation initially affected the right eye,
Figure 1. Bilateral mild conjunctivitis.
© 2014 Japanese Dermatological Association
Figure 2. Moderate conjunctivitis of the right eye. The patient was in relapse of pemphigus vulgaris with multiple cutaneous and mucosal erosions.
with subsequent involvement of the left. Involvement of the iris, lens, cornea, sclera or retina was not observed in any patient. Visual acuity was not impaired. In eight patients (47.1%), ocular disease occurred after mucocutaneous involvement while in six patients (35.3%) the ocular and mucocutaneous involvement occurred simultaneously. In three patients (17.6%), ocular involvement was the first presentation of PV. The mean time interval between the appearance of ocular and mucocutaneous manifestations was 14.2 8.8 days. The mean duration of ocular involvement was 3.3 2.4 weeks. The most commonly reported symptoms were eye irritation (76.5%) and redness (76.5%), followed by visual complaint (six, 35.3%), pain (six, 35.3%), tearing (five, 29.4%), photophobia (five, 29.4%), eyelid swelling (one, 5.9%) and non-purulent discharge (five, 29.4%). Dsg1 and Dsg3 ELISA were available in 13 patients at the time of diagnosis of ocular disease with mean value of 72.6 (range, 2.6–328) and 216.1 (range 14–348) index value, respectively. Patients with ocular involvement were on average 3 years younger than patients without ocular involvement, but without statistical significance (mean age, 41.3 and 44.4 years, respectively, P = 0.375). No significant relation was found between ocular involvement and disease activity (partial remission or relapse) (Table 1). We did not find any significant relationship between the incidence of ocular signs and localization of cutaneous (head and neck, trunk, extremities and genitalia) or mucosal lesions (oral cavity, pharynx, larynx and genital mucosa). However, the presence of PV lesions in the inguinal region was significantly associated with ocular involvement
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Table 1. Association between disease characteristics and ocular involvement Disease characteristics Disease type Cutaneous (14) Mucosal (13) Mucocutaneous (76) Disease activity Partial remission (71) Minor relapse (16) Major relapse (16) Anatomical localization Head and neck (83) Trunk (84) Extremities (65) Genitalia (32) Inguinal region (45) Oral cavity (86) Pharynx (36) Genital mucosa (10)
Ocular involvement
P-value
0 1 (7.7) 16 (21.1)
0.092
8 (11.4) 5 (31.3) 4 (25)
0.182
16 15 13 7 12 15 4 3
(19.3) (17.9) (20) (21.9) (26.7) (17.4) (11.1) (30)
0.123 0.437 0.211 0.324 0.014 0.565 0.280 0.226
(P = 0.014). The association of self-reported patients’ symptoms with different types of ocular involvement was assessed. We noted that purulent (mucoid) discharge was significantly more common in patients with conjunctival erosions as compared to patients with conjunctivitis (P = 0.038). All patients had a favorable response to systemic steroids, as indicated by PV disease activity (prednisolone; mean initial dose, 37.5 mg), with resolution of ocular signs and symptoms within a mean duration of 10 weeks (range, 4–15). Adjunctively, artificial teardrops were administrated in nine patients and topical steroids in three.
DISCUSSION The present study was designed to estimate the prevalence and characteristics of ocular involvement in a population of Iranian patients with PV. Overall, we found that 16.5% of the patients developed ocular disease. Mild and moderate conjunctivitis was the most frequent type of ocular involvement (52.9%). Nevertheless, more severe ocular involvement appearing as palpebral conjunctival erosion was also commonly observed (41.2%). Erosion of the bulbar conjunctiva was rarely detected. In earlier cohort studies of PV patients in Iran, conjunctival involvement has been reported in 16–26% of patients.9,10 In a study of 167 US PV patients by Daoud et al.,3 biopsy-proven ocular involvement was noted in 7%. These authors have adopted different inclusion criteria and detection methods for ocular involvement. The possibility of genetic propensity for ocular involvement in Iranian patients should be considered; previous studies have shown that the prevalence, age of onset and clinical behavior of pemphigus may be subject to vary depending upon the geographical location and racial backgrounds.11–13 Moreover, the findings of Harman et al.14
620
indicates that the density and distribution of Dsg antigens among Northern European patients differ from individuals with Indian origin. We did not perform conjunctival biopsy in this study because we believe, in accordance with the current evidence, that conjunctival biopsies in PV are less likely to reveal a positive finding as compared to other mucosa and are often not necessary for diagnosing or managing ocular complications. Furthermore, some authors have suggested that conjunctival biopsies should be avoided when biopsy from other sites is available, primarily because the conjunctiva cannot be sutured and is susceptible to bacterial and viral infections.3 The study by Hodak et al.15 revealed positive histopathological findings in only three of the 11 patients with ocular involvement undergoing conjunctival biopsies. This study showed that ocular involvement in PV is not rare. However, compared to other mucosal surfaces such as oral cavity (86/103, 83.4%), the eyes are less frequently involved. Dsg3 is expressed in the basal cells of the conjunctival epithelium, fading in the suprabasal layers. The conjunctiva is also rich in desmoplakin 1 and 2.16,17 The Dsg3 function loss in conjunctiva in most PV patients may be compensated by the presence of other non-Dsg desmosomal proteins.18 Therefore, ocular involvement occurs in a minority of patients. The prominent ocular abnormalities in this study were exclusively localized to the conjunctiva. A novel finding of this study is the high incidence of palpebral conjunctival erosions in ocular PV. Case reports of conjunctival erosions in the setting of PV are present in the published work.3,8,15,19–21 We believe palpebral conjunctival erosion is an underreported and underrecognized complication of PV in the eyes. The deposition of autoantibodies against intercellular adhesion molecules presumably triggers early conjunctival inflammation.6,22 As the disease progresses, the conjunctivitis could be followed by development of fragile vesicles that may rupture and leave erosions on the ocular surface.8 Cornea is an immunologically privileged tissue; therefore, direct immune reaction during autoimmune diseases does not generally occur. Unlike cicatricial pemphigoid, corneal opacities secondary to severe dryness due to tear, aqueous and mucin layer deficiency is not the case in PV.4,6 We noticed that in most patients the ocular symptoms tended to occur simultaneously or after mucocutaneous presentations. A significant minority (17.6%) showed ocular involvement as the first presentation of PV. The exact sequence of manifestations across the course of PV is unknown.3,15 Given that PV may arise primarily from the ocular surface, ophthalmologists are required to become familiar with pemphigus-related abnormalities. Moreover, it is noteworthy that even an isolated conjunctivitis should raise the suspicion of PV, particularly under chronic, unexplained circumstances. Comparable to other studies,15,21,22 we found irritation and redness to be the most frequent ocular symptoms. Notably, more than one-third of patients had visual complaint but ophthalmic examination did not reveal decreased visual acuity. Persistent inflammation and erosion of the eyelids may affect the anatomy of lid margin and the quality of the tear film and cause severe dryness of the eye, leading to poor vision quality. Non-
© 2014 Japanese Dermatological Association
Ocular PV
purulent discharge was the only symptom associated with palpebral conjunctival erosion. Therefore, the presence of mucoid discharge warrants a more careful ophthalmologic examination. Ocular involvement occurs in partial remission, minor and major relapses of PV and is, therefore, not an indicator of more severe disease. Future research is recommended to substantiate and explain the observed association between inguinal and ocular lesions, as well as its practical importance. Our finding supports the idea that prognosis of ocular involvement in PV is favorable;3,15 compared to other mucosal membranes, ocular lesions are often of shorter duration, respond to the conventional systemic therapies for PV, and heal without sequelae. The effect of systemic therapy was not assessed in this study, and it is plausible that the actual prevalence of ocular involvement is underestimated in patients receiving systemic treatments. In conclusion, our study demonstrated that 16.5% of PV patients developed ocular disease independent of their disease activity and extension. The ocular pathologies were entirely confined to conjunctiva with conjunctivitis being the most common involvement (52.9%), closely followed by palpebral conjunctival erosion (41.2%). A multidisciplinary approach with close collaboration of experienced dermatologists and ophthalmologists is needed to better detect and manage ocular pathologies in PV.
CONFLICT OF INTEREST:
None.
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© 2014 Japanese Dermatological Association
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