This Article  • Abstract  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on Web of Science (1)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Topic Collections  • External Eye Disease  • Alert me on articles by topic  Social Bookmarking   What's this?

J. James Rowsey, MD; Yolanda Macias-Rodriguez, MD; Chris Cukrowski, DO

Arch Ophthalmol. 2004;122:179-184.

ABSTRACT
Objectives  To describe a method to measure the progression of ocular cicatricial pemphigoid and to compare its facility with traditional methods used to measure the progression of the disease.

Methods  The proposed method consists of measuring (in millimeters) the total relative inferior conjunctival surface available in 3 gaze positions. This method was used to monitor 7 eyes of 4 patients with ocular cicatricial pemphigoid over 2 years. The changes in the conjunctival measurements from baseline were compared with the changes documented by traditional methods.

Results  During the study, 2 eyes remained stable (changes, <3 mm), 2 had a decrease of 10 mm or more, and 3 had a change in measurements between 4 and 9 mm. With the proposed method, we demonstrated the detection of more subtle changes in the conjunctiva of all patients. Patients who had changes between 4 and 9 mm easily underwent staging by the traditional systems when the new technique was used as a reference.

Conclusion  The proposed method offers an objective variable that can be used in consecutive visits to detect subtle progression or disease control in patients with ocular cicatricial pemphigoid.

INTRODUCTION

Jump to Section  • Top  • Introduction  • Methods  • Results  • Comment  • Author information  • References

Ocular cicatricial pemphigoid (OCP) is an acquired autoimmune mucous membrane pemphigoid, type II hypersensitivity reaction, in which the antigen-antibody-complement interaction occurs at the level of the conjunctival epithelial basement membrane zone.^1-3 Bullous pemphigoid 180, laminin 5, and ₄ integrin are the purported antigens located in the transmembrane hemidesmosomal area in the lamina lucida.^3-11

Clinically, OCP is a bilateral disease that is characterized by acute inflammation of the conjunctiva, with redness, blisters, and ulceration of the conjunctiva. Chronic inflammation is associated with subepithelial scarring that leads to fornix shortening.^12-14 More recently, the combined influences of connective tissue growth factor and transforming growth factor ₁ in the cascade of scarring have been demonstrated.¹⁵ This scarring induces eyelid distortion, keratinization of the ocular surface, and eventual ocular fixation causing blindness.^13-16 The progression of pemphigoid may be subtle and variable, despite aggressive immunosuppressive therapy. Minimal changes in the conjunctiva, especially conjunctival shrinkage, fornix shortening, and progressive symblepharon, may elude documentation. Algorithms may not categorize the progressive loss of the conjunctival surface and may miss valuable intervention time.

The proved methods for monitoring changes in patients with OCP are the staging systems described by Tauber and coworkers,¹⁷ Foster,¹⁸ and Mondino and Brown.¹⁹ These methods are invaluable for staging the disease, but do not provide sufficient discriminate information for detecting subtle changes in the conjunctival fornix. The disease can progress undocumented within the same stage in either system. We have developed a method to document nuances of progression that has been helpful for providing earlier intervention whenever the disease becomes more active. This article describes this method and compares its facility with traditional methods used to measure the progression of the disease.

METHODS

Jump to Section  • Top  • Introduction  • Methods  • Results  • Comment  • Author information  • References

A clinical method to measure the amount of conjunctival shrinkage was designed to detect progressive cicatricial changes in the conjunctiva of patients with OCP. It was used in the regular appointments of 4 patients for 2 years. Each patient was informed of the measurement technique being used and the purpose of the measurement. No observer was masked. This method was compared with 2 of the standard methods of staging the disease, described by Tauber et al¹⁷ and Mondino and Brown.¹⁹ The comparison was made to see which methods could document minute changes in the conjunctiva of the patients with OCP between appointments.

PATIENTS

We made the comparison in 4 patients with confirmed OCP (7 eyes). The 4 patients were women, ranging in age from 69 to 77 years. Table 1 shows the clinical summaries of the patients.

View this table: [in this window] [in a new window] Table 1. Clinical Summaries of the Patients*

Measurements and staging were performed at each appointment of these 4 patients, and the changes between each appointment were documented.

NEW METHOD TO MEASURE THE CONJUNCTIVA

The new method consists of measuring (in millimeters) the distance between the lower limbus and the posterior edge of the retracted lower eyelid margin in 3 different gaze positions: looking up, looking up to the right, and looking up to the left. These gaze positions place the examined conjunctiva on stretch at the 5-, 6-, and 7-o'clock positions. Measurements are taken in millimeters of the stretched conjunctiva. The subconjunctival cicatrix allows eyelid traction to pull the eye inferiorly. As the patient looks up, the eyelid is pulled down until the globe first moves due to the traction on the eyelid. A measurement is taken along each direction of gaze (Figure 1, A-D).

View larger version (93K): [in this window] [in a new window] A, Conjunctival stretching measurements in a patient with cicatricial pemphigoid. The measures (in millimeters) are taken in 3 different gaze positions. The 5-o'clock position is demonstrated. B-D, Method to measure the conjunctiva. The measures (in millimeters) are taken from the lower limbus to the posterior edge of the retracted lower eyelid in 3 different gaze positions: 5-o'clock position (B), 6-o'clock position (C), and 7-o'clock position (D). The sum of the 3 measurements (B, 13 mm; C, 10 mm; and D, 13 mm) represents the final value (36 mm). E, Schematic diagram used in the medical records to describe the measurements in 3 gaze positions. This diagram summarizes the measurements in parts B through D.

The result of the sum of the 3 measurements is noted in the medical record at each appointment beside a simple line diagram (Figure 1, E). The normal conjunctiva measurement is approximately 15 mm in each area of the inspection (sum, 45 mm). This is the total "available" conjunctiva.

We compared the apparent conjunctival shrinkage in millimeters with the staging system of Mondino and Brown.¹⁹

THE STAGING SYSTEM OF MONDINO AND BROWN

This method is based on the percentage of conjunctival shrinkage. Stage I of cicatricial pemphigoid shows 25% or less shrinkage of the conjunctival fornices. Stage II of cicatricial pemphigoid shows 25% to 50% conjunctival shrinkage. Stage III of cicatricial pemphigoid shows conjunctival shrinkage of about 75%. The inferior fornix is nearly obliterated; the shallow superior fornix is still present. Stage IV or the end stage of cicatricial pemphigoid shows obliteration of the conjunctival fornices.

THE STAGING SYSTEM OF TAUBER ET AL

This method describes conjunctival destruction and the presence of symblepharon: stage I, chronic conjunctivitis and subepithelial fibrosis; stage II, fornix foreshortening by any degree; stage III, symblepharon by any degree; and stage IV, ankyloblepharon and a frozen globe.

To describe degrees within stages II and III, a indicates 0% to 25%; b, 25% to 50%; c, 50% to 75%; and d, 75% to 100%.

For stage II, a through d describe percentage loss of inferior fornix depth. For stage III, a through d describe percentage of horizontal involvement by symblephara, and describe the number of symblephara counted in each patient.

RESULTS

Jump to Section  • Top  • Introduction  • Methods  • Results  • Comment  • Author information  • References

The results of these 4 patients are congruent with the extant staging systems of Mondino and Brown¹⁹ and Tauber et al.¹⁷

These methods were compared at each appointment. We compared date of service, conjunctival measurement, stages of Tauber et al¹⁷ and Mondino and Brown,¹⁹ time between visits, changes from baseline, and interventions.

We calculated the stage of Tauber et al¹⁷ and Mondino and Brown,¹⁹ based on the difference in millimeters measured at the slitlamp examination. If 100% of the available conjunctiva measures 45 mm in a healthy eye, then 32 mm represents 25% of conjunctival loss; 22 mm, 50% loss; and 11 mm, 75% loss.

In patient 1, minimal shortening was noted at the first visit in each eye. After surgical procedures on the eyelid in both eyes, the right eye showed a shortening of 12 mm in 6 months, and the left eye fornix was reduced after the surgery from 42 to 30 mm (loss of 12 mm). These changes represent progression from stage IIaIIIa(1) to IIbIIIa(1) by Tauber et al¹⁷ or from stage I to II by Mondino and Brown¹⁹ for the right eye, and from stage IIa to IIb by Tauber et al or from stage I to II by Mondino and Brown for the left eye. The treatment with methotrexate was increased to 20 mg/wk, and then reduced to 15 mg/wk (Table 2).

View this table: [in this window] [in a new window] Table 2. Measurements and Changes During the Study in Patient 1

In patient 2, the right eye demonstrated no progression in 9 months, but the left eye demonstrated a minute progression of 2 mm. This 2 mm is within the variation of the measurement technique. By measuring the staging change, the left eye demonstrated progression from stage IIa to IIb (Tauber et al¹⁷) and from stage I to II (Mondino and Brown¹⁹). The eye remained stable throughout the follow-up (Table 3).

View this table: [in this window] [in a new window] Table 3. Measurements and Changes During the Study in Patients 2 Through 4

In patient 3, the right eye progressed from 36 to 32 mm. When the patient was treated with methotrexate, 25 mg/wk, only 4 mm of conjunctival surface was subsequently lost in the follow-up period. This corresponds to a change from stage IIaIIIb(1) to IIbIIIb(1) (Tauber et al¹⁷) and from stage I to II (Mondino and Brown¹⁹) (Table 3).

The left eye progressed from 34 to 30 mm in 17 months, or a decrease from stage IIaIIIb(1) to IIbIIIb(1) (Tauber et al¹⁷) and from stage I to II (Mondino and Brown¹⁹). Immunosuppressive initial treatment was methotrexate, 25 mg/wk; then, cyclosporine, 100 mg/d, was added (Table 3).

Patient 4 demonstrated 30 mm of conjunctiva at the first visit, and after 6 months of treatment with prednisone, in doses from 30 to 40 mg/d, and methotrexate, 10 mg/wk, had an expansion of the conjunctiva to 36 mm. This relaxation of the conjunctiva with treatment is consistent with a regression of scarring from stage IIbIIIa(1) to IIaIIIa(1) by Tauber et al¹⁷ and from stage II to I by Mondino and Brown¹⁹ (Table 3).

COMMENT

Jump to Section  • Top  • Introduction  • Methods  • Results  • Comment  • Author information  • References

Two major therapeutic frustrations confront the clinician treating OCP: the early diagnosis and the determination of progression when the diagnosis is established.^16-22 This potentially blinding disease may be missed in the early stages because of nonspecific patient complaints of redness and irritation and the subtle conjunctival changes of subepithelial fibrosis.^{12, 23} These patient complaints may be treated as different common conjunctival entities for years before the true nature of the problem surfaces with the earliest signs of conjunctival shrinkage.^{20, 23}

The most common mimics of pemphigoid are old acute or current chronic conjunctivitis, chemical injuries, drug toxicities, Sjögren syndrome, and sarcoid.^{13, 24}

A history of severe prior conjunctivitis, corneal scars of old adenovirus, cultures of the conjunctiva, a history of fluids splashed in the eye, and prior drug use, especially for glaucoma, may all help in delineating the cause of conjunctival scarring.^5-31 Treatment modalities, such as oral dapsone,³² topical or systemic corticosteroids,¹⁵ elimination of toxic drugs, immunosuppressive agents,^33-36 or conjunctival reconstruction,³⁷ all hinge on the perspicacity of the clinician in determining progression.

Acute disease activity may lead to rapid progression, whereas slow progression may be associated with minimal conjunctival erythema.^{16, 33} Mondino and Brown³³ noted that 9 (50%) of 18 patients with stage I disease demonstrated progression during a 22-month follow-up period. Unfortunately, the more severe the disease, the greater the tendency to progression. Patients with stage II disease demonstrated a 75% progression rate, and those with stage III disease, a 78% progression rate. This study suggests that the later stages of the disease may progress without careful monitoring and intervention. The advanced staging system of Tauber et al¹⁷ defines more readily the presence of symblephara in addition to fornix depth loss.

We propose a method of measurement that one of us (J.J.R.) has used for the past 6 years to determine if disease progression or stability can be ascertained in the face of a reasonable therapeutic intervention. We have noted that the normal measurement of the inferior conjunctiva is approximately 15 mm in each observed area, for a cumulative total of 45 mm. Patients are first diagnosed as having the disease, however, after conjunctival shrinkage has already occurred. No patient demonstrated a full 45 mm of residual conjunctiva when diagnosed as having pemphigoid.

The proposed technique is useful for comparing the same patient data against previous examination results. A cumulative measurement decrease of more than 3 mm is reasonably consistent with disease progression. The instruction to retract the lower eyelid while the patient is in an upward gaze provides comparable results between observers. Intraobserver and interobserver variations have not been addressed in this analysis. Measurement errors between examinations may occur if a different retraction pressure is applied to the lower eyelid. The end point of first globe movement on eyelid retraction is the best standardized technique for providing consistent measurements. It is reasonably easy to stage the disease by the published methods, once the progression (in millimeters) is documented. The millimeter measurement is more readily compared than even a serial photographic comparison. It is easy to document a linear 45-mm cicatrization to 33 mm, all in stage IIa of the disease (0%-25% loss). Similarly, cumulative loss of the conjunctival total from 32 to 22 mm is more readily appreciated than determining if any progression has occurred within stage IIb (25%-50% loss). We have documented the independent addition of symblephara at each visit on the medical record, but have noted that this progressive shortening is normally documented as an extension of the subepithelial fibrosis already being measured. Horizontal shortening of the eyelid seems to be reflected in the simultaneous vertical conjunctival fibrosis being measured. We were intrigued that some disease regression appeared with heavy treatment, as in patient 4. Previous observers have not suggested disease regression with expansion of the conjunctival surface with aggressive intervention. We are unable to determine if this is truly relaxation and expansion of the conjunctiva or decreased orbicularis spasm with eyelid retraction when the disease remits. By using this technique, we were able to classify our patients more readily than by the system of either Tauber et al¹⁷ or Mondino and Brown,¹⁹ and were able to ascertain subtle progression between stages. Validation of the technique with a larger series of patients with OCP is warranted. We submit this proposed simplified technique for others to consider in these difficult therapeutic decisions.

In conclusion, a new method of measuring conjunctival progressive fibrosis in patients with OCP is proposed. Four patients demonstrated changes in conjunctival cicatrization during a 2-year period. Use of this method demonstrates subtle progression of pemphigoid.

AUTHOR INFORMATION

Jump to Section  • Top  • Introduction  • Methods  • Results  • Comment  • Author information  • References

Corresponding author and reprints: J. James Rowsey, MD, Department of Cornea and External Diseases, St Luke's Cataract and Laser Institute, 43309 US Hwy 19 N, PO Box 5000, Tarpon Springs, FL 34688-5000 (e-mail: jrowsey{at}tampabay.rr.com).

Submitted for publication March 21, 2003; final revision received October 8, 2003; accepted October 14, 2003.

We thank Mark Erickson, Department of Photography, St Luke's Cataract and Laser Institute (www.jirehdesign.com), for providing the illustrations.

From the Department of Cornea and External Diseases, St Luke's Cataract and Laser Institute, Tarpon Springs, Fla (Drs Rowsey and Cukrowski); and the Department of Ophthalmology, Instituto Tecnológico y de Estudios Superiores de Monterrey, Monterrey, N. L. Mexico (Dr Macias-Rodriguez). The authors have no relevant financial interest in this article.

REFERENCES

Jump to Section  • Top  • Introduction  • Methods  • Results  • Comment  • Author information  • References

1. Giuri S. Ocular cicatricial pemphigoid [in Romanian]. Oftalmologia. 1999;47:13-21. PUBMED 2. Zillikens D. Acquired skin disease of hemidesmosomes. J Dermatol Sci. 1999;20:134-154. FULL TEXT | ISI | PUBMED 3. Chan LS. Human skin basement membrane in health and in autoimmune diseases. Front Biosci. 1997;2:D343-D352. PUBMED 4. Kumari S, Bhol KC, Simmons RK, et al. Identification of ocular cicatricial pemphigoid antibody binding site(s) in human 4 integrin. Invest Ophthalmol Vis Sci. 2001;42:379-385. FREE FULL TEXT 5. Egan CA, Yancey KB. The clinical and immunopathological manifestations of anti-epiligrin cicatricial pemphigoid, a recently defined subepithelial autoimmune blistering disease. Eur J Dermatol. 2000;10:585-589. ISI | PUBMED 6. Leverkus M, Schmidt E, Lazarova Z, Brocker EB, Yancey KB, Zillikens D. Antiepiligrin cicatricial pemphigoid: an underdiagnosed entity within the spectrum of scarring autoimmune subepidermal bullous diseases? Arch Dermatol. 1999;135:1091-1098. FREE FULL TEXT 7. Zillikens D. BP180 as the common autoantigen in blistering diseases with different clinical phenotypes. Keio J Med. 2002;51:21-28. PUBMED 8. Kromminga A, Sitaru C, Meyer J, et al. Cicatricial pemphigoid differs from bullous pemphigoid and pemphigoid gestationis regarding the fine specificity of autoantibodies to the BP180 NC16A domain. J Dermatol Sci. 2002;28:68-75. FULL TEXT | ISI | PUBMED 9. Kirtschig G. Autoantigens of cicatricial pemphigoid and their pathogenetic significance [in German]. Hautarzt. 1998;49:818-825. FULL TEXT | ISI | PUBMED 10. Lazarova Z, Hsu R, Yee C, Yancey KB. Antiepiligrin cicatricial pemphigoid represents an autoimmune response to subunits present in laminin 5 (₃₃₂). Br J Dermatol. 1998;139:791-797. FULL TEXT | ISI | PUBMED 11. Fujimoto W, Toi Y, Okazaki F, Lazarova Z, Yancey KB, Arata J. Anti-epiligrin cicatricial pemphigoid with IgG autoantibodies to the beta and gamma subunits of laminin 5. J Am Acad Dermatol. 1999;40:637-639. FULL TEXT | ISI | PUBMED 12. Mondino BJ, Manthey R. Dermatological diseases and the peripheral cornea. Int Ophthalmol Clin. 1986;26:121-136. FULL TEXT | ISI | PUBMED 13. Mondino BJ, Bartly J, Hovanesian J, Pleyer U. Bullous diseases of the skin and mucous membranes. In: Duane, eds. Clinical Ophthalmology [book on CD-ROM]. Vol 4. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001:chap 12. 14. Mondino BJ. Cicatricial pemphigoid and erythema multiforme. Ophthalmology. 1990;97:939-952. ISI | PUBMED 15. Razzaque MS, Foster CS, Ahmed AR. Role of connective tissue growth factor in the pathogenesis of conjunctival scarring in ocular cicatricial pemphigoid. Invest Ophthalmol Vis Sci. 2003;44:1998-2003. FREE FULL TEXT 16. Mondino BJ, Brown SI, Lempert S, Jenkins MS. The acute manifestations of ocular cicatricial pemphigoid: diagnosis and treatment. Ophthalmology. 1979;86:543-555. ISI | PUBMED 17. Tauber J, Jabbur N, Foster CS. Improved detection of disease progression in ocular cicatricial pemphigoid. Cornea. 1992;11:446-451. ISI | PUBMED 18. Foster CS. Cicatricial pemphigoid. Trans Am Ophthalmol Soc. 1986;84:527-663. PUBMED 19. Mondino BJ, Brown SI. Ocular cicatricial pemphigoid. Ophthalmology. 1981;88:95-100. ISI | PUBMED 20. Holsclaw DS. Ocular cicatricial pemphigoid. Int Ophthalmol Clin. 1998;38:89-106. FULL TEXT | ISI | PUBMED 21. Messmer EM, Hintschich CR, Partscht K, Messer G, Kampik A. Ocular cicatricial pemphigoid: retrospective analysis of risk factors and complications [in German]. Ophthalmologe. 2000;97:113-120. FULL TEXT | ISI | PUBMED 22. Elder MJ, Bernauer W, Leonard J, Dart JK. Progression of disease in ocular cicatricial pemphigoid. Br J Ophthalmol. 1996;80:292-296. FREE FULL TEXT 23. Baier G, Zillikens D. Cicatricial pemphigoid—an important differential diagnosis in inflammatory mucous membrane changes [in German]. Laryngorhinootologie. 1999;78:632-637. FULL TEXT | PUBMED 24. Flach A. Symblepharon in sarcoidosis. Am J Ophthalmol. 1978;85:210-214. ISI | PUBMED 25. Darougar S, Quinlan MP, Gibson JA, Jones BR. Epidemic keratoconjunctivitis and chronic papillary conjunctivitis in London due to adenovirus type 19. Br J Ophthalmol. 1977;61:76-85. FREE FULL TEXT 26. Bialy-Golan A, Brenner S. Penicillamine-induced bullous dermatoses. J Am Acad Dermatol. 1996;35(pt 1):732-742. FULL TEXT | ISI | PUBMED 27. Lass JH, Thoft RA, Dohlman CH. Idoxuridine-induced conjunctival cicatrization. Arch Ophthalmol. 1983;101:747-750. FREE FULL TEXT 28. Patten JT, Cavanagh HD, Allansmith MR. Induced ocular pseudopemphigoid. Am J Ophthalmol. 1976;82:272-276. ISI | PUBMED 29. Kubo M, Sakuraba T, Arai Y, Nakazawa M. A case of suspected drug-induced ocular pemphigoid [in Japanese]. Nippon Ganka Gakkai Zasshi. 2001;105:189-192. PUBMED 30. Pouliquen Y, Patey A, Foster CS, Goichot L, Savoldelli M. Drug-induced cicatricial pemphigoid affecting the conjunctiva: light and electron microscopic features. Ophthalmology. 1986;93:775-783. ISI | PUBMED 31. Fiore PM, Jacobs IH, Goldberg DB. Drug-induced pemphigoid: a spectrum of diseases. Arch Ophthalmol. 1987;105:1660-1663. FREE FULL TEXT 32. Rogers RS 3rd, Seehafer JR, Perry HO. Treatment of cicatricial (benign mucous membrane) pemphigoid with dapsone. J Am Acad Dermatol. 1982;6:215-223. ISI | PUBMED 33. Mondino BJ, Brown SI. Immunosuppressive therapy in ocular cicatricial pemphigoid. Am J Ophthalmol. 1983;96:453-459. ISI | PUBMED 34. Tauber J, Sainz de la Maza M, Foster CS. Systemic chemotherapy for ocular cicatricial pemphigoid. Cornea. 1991;10:185-195. FULL TEXT | ISI | PUBMED 35. Elder MJ, Lightman S, Dart JK. Role of cyclophosphamide and high dose steroid in ocular cicatricial pemphigoid. Br J Ophthalmol. 1995;79:264-266. FREE FULL TEXT 36. Bohn J, Jonsson S, Holst R. Successful treatment of recalcitrant cicatricial pemphigoid with a combination of plasma exchange and cyclophosphamide. Br J Dermatol. 1999;141:536-540. FULL TEXT | ISI | PUBMED 37. Trigui A, Kammoun B, Ghodhbane M, Fourati M, Mseddi M, Chaabouni M. Penetrating keratoplasty in ocular cicatricial pemphigoid [in French]. J Fr Ophtalmol. 2002;25:48-51. ISI | PUBMED

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    Twitter     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Development of ocular disease in patients with mucous membrane pemphigoid involving the oral mucosa
Higgins et al.
Br J Ophthalmol 2006;90:964-967.
ABSTRACT | FULL TEXT