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 deEstudios Superiores de Monterrey, Monterrey, N. L. Mexico(Dr Macias-Rodriguez). The authors have no relevant financial interest inthis article.
To describe a method to measure the progression of ocular cicatricialpemphigoid and to compare its facility with traditional methods used to measurethe progression of the disease.
The proposed method consists of measuring (in millimeters) the totalrelative inferior conjunctival surface available in 3 gaze positions. Thismethod was used to monitor 7 eyes of 4 patients with ocular cicatricial pemphigoidover 2 years. The changes in the conjunctival measurements from baseline werecompared with the changes documented by traditional methods.
During the study, 2 eyes remained stable (changes, <3 mm), 2 hada decrease of 10 mm or more, and 3 had a change in measurements between 4and 9 mm. With the proposed method, we demonstrated the detection of moresubtle changes in the conjunctiva of all patients. Patients who had changesbetween 4 and 9 mm easily underwent staging by the traditional systems whenthe new technique was used as a reference.
The proposed method offers an objective variable that can be used inconsecutive visits to detect subtle progression or disease control in patientswith ocular cicatricial pemphigoid.
Ocular cicatricial pemphigoid (OCP) is an acquired autoimmune mucousmembrane pemphigoid, type II hypersensitivity reaction, in which the antigen-antibody-complementinteraction occurs at the level of the conjunctival epithelial basement membranezone.1- 3 Bullouspemphigoid 180, laminin 5, and β4 integrin are the purportedantigens located in the transmembrane hemidesmosomal area in the lamina lucida.3- 11
Clinically, OCP is a bilateral disease that is characterized by acuteinflammation of the conjunctiva, with redness, blisters, and ulceration ofthe conjunctiva. Chronic inflammation is associated with subepithelial scarringthat leads to fornix shortening.12- 14 Morerecently, the combined influences of connective tissue growth factor and transforminggrowth factor β1 in the cascade of scarring have been demonstrated.15 This scarring induces eyelid distortion, keratinizationof the ocular surface, and eventual ocular fixation causing blindness.13- 16 Theprogression of pemphigoid may be subtle and variable, despite aggressive immunosuppressivetherapy. 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 surfaceand may miss valuable intervention time.
The proved methods for monitoring changes in patients with OCP are thestaging systems described by Tauber and coworkers,17 Foster,18 and Mondino and Brown.19 Thesemethods are invaluable for staging the disease, but do not provide sufficientdiscriminate information for detecting subtle changes in the conjunctivalfornix. The disease can progress undocumented within the same stage in eithersystem. We have developed a method to document nuances of progression thathas been helpful for providing earlier intervention whenever the disease becomesmore active. This article describes this method and compares its facilitywith traditional methods used to measure the progression of the disease.
A clinical method to measure the amount of conjunctival shrinkage wasdesigned to detect progressive cicatricial changes in the conjunctiva of patientswith 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 thepurpose of the measurement. No observer was masked. This method was comparedwith 2 of the standard methods of staging the disease, described by Tauberet al17 and Mondino and Brown.19 Thecomparison was made to see which methods could document minute changes inthe conjunctiva of the patients with OCP between appointments.
We made the comparison in 4 patients with confirmed OCP (7 eyes). The4 patients were women, ranging in age from 69 to 77 years. Table 1 shows the clinical summaries of the patients.
Measurements and staging were performed at each appointment of these4 patients, and the changes between each appointment were documented.
The new method consists of measuring (in millimeters) the distance betweenthe lower limbus and the posterior edge of the retracted lower eyelid marginin 3 different gaze positions: looking up, looking up to the right, and lookingup to the left. These gaze positions place the examined conjunctiva on stretchat the 5-, 6-, and 7-o'clock positions. Measurements are taken in millimetersof the stretched conjunctiva. The subconjunctival cicatrix allows eyelid tractionto pull the eye inferiorly. As the patient looks up, the eyelid is pulleddown until the globe first moves due to the traction on the eyelid. A measurementis taken along each direction of gaze (Figure1, A-D).
A, Conjunctival stretching measurements in a patient with cicatricialpemphigoid. 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 posterioredge of the retracted lower eyelid in 3 different gaze positions: 5-o'clockposition (B), 6-o'clock position (C), and 7-o'clock position (D). The sumof the 3 measurements (B, 13 mm; C, 10 mm; and D, 13 mm) represents the finalvalue (36 mm). E, Schematic diagram used in the medical records to describethe measurements in 3 gaze positions. This diagram summarizes the measurementsin parts B through D.
The result of the sum of the 3 measurements is noted in the medicalrecord at each appointment beside a simple line diagram (Figure 1, E). The normal conjunctiva measurement is approximately15 mm in each area of the inspection (sum, 45 mm). This is the total "available"conjunctiva.
We compared the apparent conjunctival shrinkage in millimeters withthe staging system of Mondino and Brown.19
This method is based on the percentage of conjunctival shrinkage. StageI of cicatricial pemphigoid shows 25% or less shrinkage of the conjunctivalfornices. Stage II of cicatricial pemphigoid shows 25% to 50% conjunctivalshrinkage. Stage III of cicatricial pemphigoid shows conjunctival shrinkageof about 75%. The inferior fornix is nearly obliterated; the shallow superiorfornix is still present. Stage IV or the end stage of cicatricial pemphigoidshows obliteration of the conjunctival fornices.
This method describes conjunctival destruction and the presence of symblepharon:stage I, chronic conjunctivitis and subepithelial fibrosis; stage II, fornixforeshortening by any degree; stage III, symblepharon by any degree; and stageIV, 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 fornixdepth. For stage III, a through d describe percentage of horizontal involvementby symblephara, and describe the number of symblephara counted in each patient.
The results of these 4 patients are congruent with the extant stagingsystems of Mondino and Brown19 and Tauber etal.17
These methods were compared at each appointment. We compared date ofservice, conjunctival measurement, stages of Tauber et al17 andMondino and Brown,19 time between visits, changesfrom baseline, and interventions.
We calculated the stage of Tauber et al17 andMondino and Brown,19 based on the differencein millimeters measured at the slitlamp examination. If 100% of the availableconjunctiva measures 45 mm in a healthy eye, then 32 mm represents 25% ofconjunctival loss; 22 mm, 50% loss; and 11 mm, 75% loss.
In patient 1, minimal shortening was noted at the first visit in eacheye. After surgical procedures on the eyelid in both eyes, the right eye showeda shortening of 12 mm in 6 months, and the left eye fornix was reduced afterthe surgery from 42 to 30 mm (loss of 12 mm). These changes represent progressionfrom stage IIaIIIa(1) to IIbIIIa(1) by Tauber et al17 orfrom stage I to II by Mondino and Brown19 forthe right eye, and from stage IIa to IIb by Tauber et al or from stage I toII by Mondino and Brown for the left eye. The treatment with methotrexatewas increased to 20 mg/wk, and then reduced to 15 mg/wk (Table 2).
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 withinthe 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).
In patient 3, the right eye progressed from 36 to 32 mm. When the patientwas treated with methotrexate, 25 mg/wk, only 4 mm of conjunctival surfacewas subsequently lost in the follow-up period. This corresponds to a changefrom 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 decreasefrom 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, andafter 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 regressionof scarring from stage IIbIIIa(1) to IIaIIIa(1) by Tauber et al17 andfrom stage II to I by Mondino and Brown19 (Table 3).
Two major therapeutic frustrations confront the clinician treating OCP:the early diagnosis and the determination of progression when the diagnosisis established.16- 22 Thispotentially blinding disease may be missed in the early stages because ofnonspecific patient complaints of redness and irritation and the subtle conjunctivalchanges of subepithelial fibrosis.12,23 Thesepatient complaints may be treated as different common conjunctival entitiesfor years before the true nature of the problem surfaces with the earliestsigns of conjunctival shrinkage.20,23
The most common mimics of pemphigoid are old acute or current chronicconjunctivitis, 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, andprior drug use, especially for glaucoma, may all help in delineating the causeof conjunctival scarring.5- 31 Treatmentmodalities, such as oral dapsone,32 topicalor systemic corticosteroids,15 eliminationof toxic drugs, immunosuppressive agents,33- 36 orconjunctival reconstruction,37 all hinge onthe perspicacity of the clinician in determining progression.
Acute disease activity may lead to rapid progression, whereas slow progressionmay be associated with minimal conjunctival erythema.16,33 Mondinoand Brown33 noted that 9 (50%) of 18 patientswith stage I disease demonstrated progression during a 22-month follow-upperiod. Unfortunately, the more severe the disease, the greater the tendencyto progression. Patients with stage II disease demonstrated a 75% progressionrate, and those with stage III disease, a 78% progression rate. This studysuggests that the later stages of the disease may progress without carefulmonitoring and intervention. The advanced staging system of Tauber et al17 defines more readily the presence of symblepharain addition to fornix depth loss.
We propose a method of measurement that one of us (J.J.R.) has usedfor the past 6 years to determine if disease progression or stability canbe ascertained in the face of a reasonable therapeutic intervention. We havenoted that the normal measurement of the inferior conjunctiva is approximately15 mm in each observed area, for a cumulative total of 45 mm. Patients arefirst diagnosed as having the disease, however, after conjunctival shrinkagehas already occurred. No patient demonstrated a full 45 mm of residual conjunctivawhen diagnosed as having pemphigoid.
The proposed technique is useful for comparing the same patient dataagainst previous examination results. A cumulative measurement decrease ofmore than 3 mm is reasonably consistent with disease progression. The instructionto retract the lower eyelid while the patient is in an upward gaze providescomparable results between observers. Intraobserver and interobserver variationshave not been addressed in this analysis. Measurement errors between examinationsmay 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 standardizedtechnique for providing consistent measurements. It is reasonably easy tostage the disease by the published methods, once the progression (in millimeters)is documented. The millimeter measurement is more readily compared than evena serial photographic comparison. It is easy to document a linear 45-mm cicatrizationto 33 mm, all in stage IIa of the disease (0%-25% loss). Similarly, cumulativeloss of the conjunctival total from 32 to 22 mm is more readily appreciatedthan determining if any progression has occurred within stage IIb (25%-50%loss). We have documented the independent addition of symblephara at eachvisit on the medical record, but have noted that this progressive shorteningis normally documented as an extension of the subepithelial fibrosis alreadybeing measured. Horizontal shortening of the eyelid seems to be reflectedin the simultaneous vertical conjunctival fibrosis being measured. We wereintrigued that some disease regression appeared with heavy treatment, as inpatient 4. Previous observers have not suggested disease regression with expansionof the conjunctival surface with aggressive intervention. We are unable todetermine if this is truly relaxation and expansion of the conjunctiva ordecreased orbicularis spasm with eyelid retraction when the disease remits.By using this technique, we were able to classify our patients more readilythan by the system of either Tauber et al17 orMondino and Brown,19 and were able to ascertainsubtle progression between stages. Validation of the technique with a largerseries of patients with OCP is warranted. We submit this proposed simplifiedtechnique for others to consider in these difficult therapeutic decisions.
In conclusion, a new method of measuring conjunctival progressive fibrosisin patients with OCP is proposed. Four patients demonstrated changes in conjunctivalcicatrization during a 2-year period. Use of this method demonstrates subtleprogression of pemphigoid.
Corresponding author and reprints: J. James Rowsey, MD, Departmentof Cornea and External Diseases, St Luke's Cataract and Laser Institute, 43309US Hwy 19 N, PO Box 5000, Tarpon Springs, FL 34688-5000 (e-mail: firstname.lastname@example.org).
Submitted for publication March 21, 2003; final revision received October8, 2003; accepted October 14, 2003.
We thank Mark Erickson, Department of Photography, St Luke's Cataractand Laser Institute (www.jirehdesign.com), for providing the illustrations.
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