`Therapy for Keratoconjunctivitis Sicca in
`Sjo¨gren Syndrome
`
`Peter Marsh, MD, Stephen C. Pflugfelder, MD
`
`Objective: To review the efficacy and side effects of topical nonpreserved corticosteroid therapy for
`treatment of severe keratoconjunctivitis associated with Sjo¨ gren syndrome.
`Design: Retrospective, noncomparative case series.
`Participants: Twenty-one patients with Sjo¨ gren syndrome–associated keratoconjunctivitis sicca and annoy-
`ing ocular irritation.
`Intervention: Treatment with topical nonpreserved methylprednisolone sodium succinate.
`Main Outcome Measures: Symptom severity, frequency of instillation of artificial tears, corneal fluorescein
`staining scores, resolution of filamentary keratitis, steroid-related side effects.
`Results: Before starting methylprednisolone therapy, all patients were experiencing moderate-to-severe eye
`irritation despite prior punctal occlusion in most cases and frequent use of nonpreserved artificial tears by all.
`After 2 weeks of topical application, three to four times per day, moderate (43%) or complete (57%) relief of
`irritation symptoms was experienced by all patients and no complications were observed. An average decrease
`in corneal fluorescein scores of 2.6 6 0.5 points (on a 12-point scale) was observed, and filamentary keratitis
`resolved in all ten eyes with this condition. Therapy was stopped after 2 weeks in eight patients, and six of these
`patients reported that their symptoms remained at a tolerable level for weeks to months. Lower dose steroid
`therapy was continued in the remaining patients, whose symptoms worsened after attempted weaning. Com-
`plications of corticosteroid therapy in patients receiving prolonged therapy included increased intraocular
`pressure in one patient at 3 months, worsening of pre-existing posterior subcapsular cataracts in one patient at
`6 months, and formation of posterior subcapsular cataracts in another patient at 6 months.
`Conclusions: These findings indicate that topical nonpreserved methylprednisolone is an effective treatment
`option for patients suffering from severe keratoconjunctivitis sicca who continue to experience bothersome eye
`irritation despite maximum aqueous enhancement therapies. They also suggest that inflammation is a key
`pathogenic factor in this condition. Careful monitoring is essential in dry eye patients treated with corticosteroids
`for more than 2 weeks because steroid-related complications (increased intraocular pressure and cataract
`formation) were observed after several months of therapy in this series. Because of the chronic nature of this
`disease and the likelihood of patients developing steroid-related complications with their long-term use, topical
`nonpreserved methylprednisolone therapy appears to be most appropriate for short-term “pulse” treatment of
`exacerbations of keratoconjunctivitis sicca. Ophthalmology 1999;106:811– 816
`
`Ocular irritation is often associated with deficiencies of one
`or more of the constituents of the tear film.1 Among the
`different types of dry eye, aqueous tear deficiency resulting
`from lacrimal gland secretory dysfunction is associated with
`the greatest ocular discomfort and leads to ocular surface
`disease, termed keratoconjunctivitis sicca.1,2
`
`Originally received: May 5, 1998.
`Manuscript no. 98235.
`Revision accepted: November 25, 1998.
`From the Ocular Surface and Tear Center, Bascom Palmer Eye Institute,
`Department of Ophthalmology, University of Miami School of Medicine,
`Miami, Florida.
`A coauthor (SCP) and the University of Miami School of Medicine have
`jointly filed a patent for nonpreserved steroid therapy for dry eye.
`Reprint requests to Stephen C. Pflugfelder, MD, Bascom Palmer Eye
`Institute, 900 NW 17th Street, Miami, FL 33136.
`
`Aqueous enhancement therapies, including artificial tears
`and punctal occlusion, are currently the mainstay of therapy
`for patients with irritation due to aqueous tear deficiency.3
`These treatments may decrease irritation symptoms and
`improve ocular surface disease in many patients, particu-
`larly those with mild disease. In contrast, patients with
`severe keratoconjunctivitis sicca, as typically seen in
`Sjo¨gren syndrome, often complain of annoying irritation,
`photophobia, and intolerance to sustained visual effort de-
`spite maximum use of aqueous-enhancing therapies. These
`patients may also experience acute exacerbations of this
`condition, such as filamentary keratitis, that produce dis-
`abling symptoms.
`The mechanism by which aqueous tear deficiency leads
`to ocular surface disease has been proposed to be secondary
`to increased tear osmolarity, desiccation of surface epithe-
`lium, and to a poorly lubricated ocular surface.4 There is
`
`811
`
`MYLAN - EXHIBIT 1052
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
`
`
`
`Ophthalmology Volume 106, Number 4, April 1999
`
`increasing evidence that inflammation may be an important
`factor in the pathogenesis of keratoconjunctivitis sicca.
`Squamous metaplasia, a pathogenic condition of reduced
`mucus production by the conjunctival epithelium, is more
`severe in the systemic autoimmune disease Sjo¨gren syn-
`drome than other forms of aqueous tear deficiency.2 Inflam-
`matory cell infiltration, consisting predominantly of T lym-
`phocytes, has been reported to occur in the conjunctiva of
`patients with Sjo¨gren syndrome.5–7 Further, abnormally in-
`creased expression of inflammatory cytokines such as inter-
`leukin-6 (IL-6) and upregulation of the cell surface immune
`adhesion molecules, human leukocyte antigen-DR (HLA-
`DR) and intercellular adhesion molecule-1 (ICAM-1), in the
`conjunctival epithelium have been reported to occur in
`Sjo¨gren syndrome.2,8,9
`Based on these immunopathologic findings, we began
`treating patients with Sjo¨gren syndrome and keratoconjunc-
`tivitis sicca who were experiencing severe and disabling
`symptoms that were unresponsive to aqueous enhancement
`therapy with a topical nonpreserved corticosteroid solution.
`Here we report the results of a retrospective review of the
`safety and efficacy of this therapy in 21 such patients with
`Sjo¨gren syndrome. The results indicate that topically ap-
`plied corticosteroids are a very effective therapy for the
`symptoms and ocular surface disease seen in these patients.
`Side effects were rare, but when present were those typi-
`cally associated with topical steroid therapy (ocular hyper-
`tension and cataracts).
`
`Patients and Methods
`
`After approval by the University of Miami Institutional Review
`Board, the medical records of all patients treated by one physician
`(SCP) with topical corticosteroid solution for aqueous tear defi-
`ciency associated with Sjo¨gren syndrome were reviewed. All pa-
`tients had the diagnosis of either primary or secondary Sjo¨gren
`syndrome. Criteria used for the diagnosis of primary Sjo¨gren
`syndrome were those used previously2 and included all of the
`following: 5-minute Schirmer test without anesthesia less than or
`equal to 5-mm strip wetting, interpalpebral conjunctival and cor-
`neal rose bengal and/or fluorescein staining, presence of one or
`more serum autoantibodies (rheumatoid factor $ 1:160, antinu-
`clear antibody $ 1:160, Sjo¨gren syndrome antibody A [SS-A] or
`Sjo¨gren syndrome antibody B [SS-B]), xerostomia, and absence of
`a connective tissue disease. Those diagnosed as having secondary
`Sjo¨gren syndrome met the above criteria for aqueous tear defi-
`ciency, ocular surface changes, and xerostomia but had been
`diagnosed as having either rheumatoid arthritis, systemic lupus
`erythematosus, or juvenile rheumatoid arthritis by a rheumatolo-
`gist.
`Records were reviewed to determine the nature and severity of
`symptoms patients experienced both before and after treatment.
`Change in symptoms was graded as no change, 11 (irritation
`symptoms decreased, but still present), 21 (irritation symptoms
`barely noticeable or absent most of the time), and 31 (complete
`resolution of irritation symptoms). The type and frequency of
`topical medications used before methylprednisolone treatment
`were noted, as well as any change in the frequency of “as needed”
`medications (e.g., artificial tears) during or after treatment with
`topical corticosteroid. In cases in which this information was not
`clearly presented in the chart, patients were contacted by tele-
`
`812
`
`phone, and their history and symptomatic response were reviewed.
`Patients were also asked how long their irritation symptoms re-
`mained tolerable after stopping corticosteroid therapy.
`Corneal fluorescein staining was graded from 0 (none) to 12
`(most severe) by one physician (SCP) for each eye before and
`throughout the use of methylprednisolone according to a previ-
`ously reported scoring system that has been routinely used for all
`patients evaluated by the investigator since 1992.1
`Patients were initially treated with the corticosteroid methyl-
`prednisolone. A topical solution of this steroid was prepared by the
`pharmacy of the Bascom Palmer Eye Institute by diluting intrave-
`nous methylprednisolone sodium succinate in nonpreserved sterile
`normal saline solution to final concentrations of 0.1% to 1%.
`Patients were dispensed bottles containing 5 ml of the steroid
`solution and were instructed to keep it refrigerated and to discard
`it after 3 weeks.
`Initial therapy consisted of 1% methylprednisolone three to
`four times a day for 2 weeks. Patients were re-evaluated at that
`time, and based on their symptoms, the methylprednisolone solu-
`tion was either stopped or was continued at a lower frequency
`(usually one drop per day) or dose (0.1%– 0.5%). Two patients
`were changed from methylprednisolone to 1% hydroxymethylpro-
`gesterone (HMS; Allergan, Irvine, CA) and one was switched to
`0.1% fluorometholone (FML; Allergan, Irvine, CA) to reduce
`corticosteroid-related side effects. Any change in symptoms or
`ocular surface disease after this change of medication was noted.
`
`Results
`
`Between December 1994 and June 1996, 21 patients were placed
`on topical nonpreserved methylprednisolone for treatment of the
`irritation symptoms or filamentary keratitis associated with pri-
`mary or secondary Sjo¨gren syndrome keratoconjunctivitis sicca.
`Diagnosis, demographic data, prior therapy, change in symptoms
`and corneal fluorescein staining score after 2 weeks of therapy,
`duration of therapy, and complications are presented in Table 1.
`Nineteen of the 21 patients were women. Ages ranged from 31
`to 79 years (mean, 59 years). Primary Sjo¨gren syndrome was
`diagnosed in 17 of the 21 patients. Of the four patients diagnosed
`with secondary Sjo¨gren syndrome, two had rheumatoid arthritis,
`one had systemic lupus erythematosus, and one had juvenile rheu-
`matoid arthritis.
`All patients were using nonpreserved topical lubricants (tears
`or ointments) before starting methylprednisolone. One patient was
`using topical vitamin A ointment, and one patient was using oral
`cyclosporin A. Two patients (cases 1 and 9 in Table 1) had been
`previously treated with preservative-containing corticosteroid
`preparations with some, but not complete relief of symptoms.
`All patients reported improvement in irritation symptoms after
`2 weeks of methylprednisolone therapy. Moderate improvement in
`symptoms was noted in 43% of patients (9 of 21), and 57% (12 of
`21) of the patients experienced complete relief of their ocular
`irritation. One patient experienced mild discomfort after instilling
`the medication. Therapy was stopped after 2 weeks in eight pa-
`tients who had complete relief of their symptoms. Six of these
`patients reported that their symptoms remained at a tolerable level
`with use of artificial tears for periods ranging from 2 weeks to 6
`months.
`The change in corneal fluorescein staining scores after 2 weeks
`of therapy is presented in Table 1. A mean decrease in corneal
`fluorescein scores of 2.6 6 0.5 points (on a 12-point scale) was
`observed. Fluorescein staining scores decreased by at least 3 points
`in 30 (71%) of the 42 eyes, 7 eyes (17%) had a decrease in staining
`of 2 points, and 5 eyes (12%) had a decrease of 1 point. In addition
`
`
`
`Marsh and Pflugfelder z Steroid Therapy for Dry Eye
`
`Table 1. Clinical Features of Steroid-treated Sjo¨gren Syndrome Patients
`
`Patient
`No.
`
`Age
`(yrs)/
`Gender
`
`Cause of ATD
`
`Prior Therapy*
`
`73 /F
`48 /F
`50 /F
`66 /F
`
`Bion, Inflamase Forte
`Primary SS
`Hypotears PF
`Primary SS
`Secondary SS (RA) Bion
`Primary SS
`Hypotears PF
`
`Therapeutic Response
`after 2 Weeks
`Ocular Surface
`Disease‡
`
`Symptoms†
`31
`31
`21
`31
`
`Right Eye
`31
`31(*)
`11
`31
`
`Left Eye
`31
`31(*)
`31
`31(*)
`
`21
`
`21
`
`21
`
`21
`31
`31
`21
`
`31
`31
`
`31
`31
`31
`21
`31
`21
`21
`31
`
`21
`
`21
`
`11
`
`31
`31
`31(*)
`31
`
`31
`11
`
`31
`31
`31
`31
`31
`31(*)
`11
`31(*)
`
`21
`
`21
`
`31(*)
`
`21
`31
`31(*)
`31
`
`21
`31
`
`31
`31
`31
`31
`21
`31(*)
`11
`31(*)
`
`Treatment
`Duration§
`
`Complications|
`
`2 wks
`6 wks
`6 mos
`2 wks
`
`2 mos,
`3 wks
`3 wks
`
`Increased IOP at 3 mos
`History of ocular HTN, switched
`to FML to minimize rise in
`IOP
`
`7 mos Worsening of pre-existing PSC
`OU at 6 mos
`
`4 wks
`52 wks
`2 wks
`5 mos
`
`2 wks
`5 wks
`
`2 wks
`3 wks
`2 wks
`6 wks
`2 wks
`5 wks
`9 wks
`2 wks
`
`Early PSC at 6 mos, HMS started
`
`Switched to HMS but stopped
`due to burning
`
`Burning and discharge with MP
`
`1
`2
`3
`4
`
`5
`
`6
`
`7
`
`8
`9
`10
`11
`
`12
`13
`
`14
`15
`16
`17
`18
`19
`20
`21
`
`45 /M Primary SS
`
`53 /M Primary SS
`
`67 /F
`
`69 /F
`36 /F
`65 /F
`53 /F
`
`62 /F
`68 /F
`
`79 /F
`70 /F
`31 /F
`67 /F
`62 /F
`49 /F
`55 /F
`64 /F
`
`Celluvisc, oral CSA, oral
`Bromhexine
`Secondary SS (RA) Hypotears PF, 10%
`acetylcysteine drops,
`Refresh plus
`Refresh plus, Refresh PM
`ointment
`Hypotears PF
`Primary SS
`Secondary SS (JRA) Pred Forte, Aquasite
`Primary SS
`Bion, Refresh plus
`Primary SS
`0.01% transretinoic acid
`ointment, Refresh plus
`Refresh plus
`Refresh plus, Bion
`
`Primary SS
`Primary SS
`
`Refresh plus, Bion
`Primary SS
`Bion
`Primary SS
`HMS, Bion, Refresh
`Primary SS
`Bion
`Primary SS
`Secondary SS (SLE) Refresh Plus
`Primary SS
`Refresh plus, Bion
`Primary SS
`Bion
`Primary SS
`Refresh Plus
`
`SS 5 Sjo¨gren syndrome; PSC 5 posterior subcapsular cataract; IOP 5 intraocular pressure; HTN 5 hypertension; ATD 5 aqueous tear deficiency.
`* BION Tears (hydroxylpropylmethylcellulose, dextran 70; Alcon Laboratories, Ft. Worth, TX), Inflamase Forte (1% prednisolone phosphate, CIBA
`Vision Corp, Duluth, GA), Hypotears PF (polyvinyl alcohol, PEG-400, dextrose, CIBA Vision Corp), Celluvisc (1% carboxymethylcellulose, Allergan,
`Inc, Irvine, CA), CSA 5 2% cyclosporin emulsion, Refresh Plus (0.5% carboxymethylcellulose, Allergan), Refresh PM (mineral oil, petrolatum and
`lanolin alcohol, Allergan, Inc), Pred Forte (1% prednisolone acetate, Allergan, Inc), FML (0.1% fluorometholone, Allergan), Aquasite (polycarbophil,
`PEG-400, dextran 70, CIBA Vision), HMS (1% hydroxymethylprogesterone, Allergan, Inc, Irvine, CA), MP 5 methylprednisolone.
`† 11 5 slight improvement; 21 5 moderate improvement; 31 5 complete relief.
`‡ 0 5 no change; decrease in corneal fluorescein staining score by one point 5 11; 2 points 5 21; 3 points or resolution of filamentary keratitis 5 31;
`(*) 5 resolution of filamentary keratitis.
`§ Duration of treatment at the time of the last follow-up examination.
`\ Complications at the time of the last follow-up examination.
`
`to a decrease in the intensity of fluorescein staining, a change in the
`pattern of staining from diffuse punctate staining to localized
`blotches, as demonstrated in Figure 1, was often observed. Fila-
`mentary keratitis resolved in all ten eyes with this condition (Fig
`2). All patients reported a decrease in the use of topical lubricants
`while on methylprednisolone, in many cases from 10 to 15 times
`per day to once or twice per day.
`Treatment duration ranged from 2 weeks to 1 year (mean, 9.1
`weeks). In those patients still using the medication, the dose of
`methylprednisolone at the time of last evaluation ranged from
`0.5% once a day to 1% twice a day. No complications were
`observed after 2 weeks of therapy. Complications that were likely
`to be related to more prolonged treatment included elevated in-
`traocular pressure and cataracts. Intraocular pressure increased
`from the high teens to 23 mmHg in the right eye and to 24 mmHg
`in the left eye of one patient (case 3, Table 1) after 3 months of
`
`therapy. Once the dose of methylprednisolone was tapered to 0.5%
`twice daily, the intraocular pressure returned to the high teens.
`Pre-existing posterior subcapsular cataracts in one patient (case 7,
`Table 1) worsened after 6 months of therapy. Another patient (case
`9, Table 1) developed minimal posterior subcapsular cataracts in
`both eyes that were noted after 6 months of therapy. The patient
`was using 0.5% methylprednisolone once or twice a day at the time
`the cataracts were noted. The patient stated that she could not
`function off of the steroid, and the methylprednisolone was
`changed to hydroxymethylprogesterone (HMS) once a day. A
`follow-up examination 6 months after switching to hydroxymeth-
`ylprogesterone revealed a distance visual acuity was 20/20 in each
`eye and no change in the cataracts.
`Three patients were changed from methylprednisolone to less
`potent topical corticosteroids. One patient (case 4, Table 1) was
`switched to fluorometholone 0.1% once or twice daily because of
`
`813
`
`
`
`Ophthalmology Volume 106, Number 4, April 1999
`
`Figure 1. Patient 10. A decrease in area of fluorescein staining and change
`in staining pattern from a diffuse punctate exposure zone to blotches was
`observed (Table 1) after 2 weeks of nonpreserved methylprednisolone
`therapy. This was representative of the therapeutic response in most
`patients.
`
`a history of steroid-responsive elevated intraocular pressure. One
`patient (case 9, Table 1) was switched to HMS 1% twice daily at
`first evidence of cataract formation. This dose controlled the pa-
`tient’s ocular irritation over 6 months of follow-up. Another pa-
`tient (case 13, Table 1) was changed from methylprednisolone to
`HMS 1% to reduce the likelihood of steroid-induced complica-
`tions, although she had no evidence of complications at that time.
`This patient had marked improvement in symptoms and ocular
`surface disease after 5 weeks of methylprednisolone treatment.
`After 1 month of using HMS 1% 1 to 2 times a day, she com-
`plained that the drop felt “thick” and clouded her vision. This
`medication was discontinued and the patient’s ocular surface dis-
`ease and symptoms were stable when they were re-evaluated 5
`months later. No cases of infectious keratitis, corneal epithelial
`defects, or sterile corneal thinning were observed throughout the
`follow-up period.
`
`Discussion
`
`This retrospective review of our preliminary experience
`with the use of nonpreserved topical methylprednisolone
`
`Figure 2. Patient 11. Two weeks of methylprednisolone reduced cornea
`punctate epitheliopathy, adherent mucus, and filaments in both eyes
`(Table 1).
`
`814
`
`
`
`Marsh and Pflugfelder z Steroid Therapy for Dry Eye
`
`indicates that topically applied corticosteroid produces rapid
`and dramatic improvement in ocular irritation symptoms
`and the keratoconjunctivitis sicca that develops in aqueous
`tear deficiency occurring in Sjo¨gren syndrome. This therapy
`was used in a group of patients that had constant annoying
`and occasionally disabling irritation symptoms despite max-
`imal aqueous enhancement therapy. It was offered to pa-
`tients to improve the quality of their lives and to allow them
`to perform their daily activities in a more normal fashion.
`All patients reported improvement in irritation symptoms
`within several days of starting steroid therapy, and improve-
`ment in keratoconjunctivitis sicca was clearly evident by the
`2-week follow-up visit. One shortcoming of this study is
`that symptomatic response to therapy was based on a ret-
`rospective review of records rather than completion of a
`formal symptom survey. In most cases in this series, the
`effect of the steroid therapy on irritation symptoms and
`daily function was clearly documented at the 2-week fol-
`low-up visit, and a numeric value in the four-point symptom
`grading scheme that was used could be assigned without
`difficulty. After the 2-week “pulse” of topical methylpred-
`nisolone, the steroid was either stopped or patients were
`switched to a lower concentration of this medication and
`were instructed to taper their dosing frequency. In some
`cases, the medication was stopped after several additional
`weeks while other patients required prolonged low-dose
`therapy to control their irritation symptoms, under close
`monitoring for steroid-related complications.
`It is interesting that irritation symptoms remained at a
`tolerable level in many patients for weeks to months after
`the steroid was stopped. This suggests that steroids may
`decrease or eliminate the factors that cause irritation in
`keratoconjunctivitis sicca and that they are efficacious for
`treatment of acute exacerbations of this condition. No com-
`plications were observed at the 2-week follow-up examina-
`tion that was performed in all patients. Steroid-related com-
`plications were observed in three patients
`receiving
`prolonged topical steroid therapy. These included ocular
`hypertension in one patient after 3 months and posterior
`subcapsular cataracts in two patients after 6 months of
`treatment.
`Keratoconjunctivitis sicca and Sjo¨gren syndrome are es-
`tablished risk factors for microbial keratitis and sterile cor-
`neal ulceration.4 Neither of these corneal complications was
`observed in this series. Because of their immunosuppressive
`effects, corticosteroids could potentially increase the risk
`for developing microbial keratitis or worsen this condition if
`it should develop during therapy. Corticosteroids also sup-
`press corneal wound healing, and they could inhibit healing
`of sterile corneal ulcers.10 Therefore, they should not be
`used in patients with keratoconjunctivitis who have corneal
`epithelial defects, stromal thinning, or stromal infiltrates.
`Because of the chronic nature of Sjo¨gren syndrome ker-
`atoconjunctivitis and the likelihood of patients developing
`steroid-related complications with their long-term use, it
`appears that topical nonpreserved methylprednisolone is
`most appropriate for short-term pulse therapy of acute dis-
`ease exacerbations. Longer term corticosteroid therapy
`should be reserved only for patients with aqueous tear
`deficiency who have disabling irritation symptoms or ocular
`
`surface disease (such as filamentary keratitis) that decreases
`their visual acuity and their ability to function. These pa-
`tients need to be informed of the risks of therapy and to be
`evaluated at frequent intervals to look for signs of steroid-
`related complications.
`The unparalleled anti-inflammatory efficacy of cortico-
`steroids has prompted the investigation of regimens for
`treatment of systemic inflammatory diseases that minimize
`systemic side effects.11–13 Strategies intended to minimize
`complications of systemic steroid therapy have included the
`use of lower doses for rheumatoid arthritis and enteric-
`coated “site-specific” preparations that facilitate delivery of
`the medication to the diseased intestinal mucosa, and min-
`imize systemic absorption, in Crohn disease.11–13 The im-
`proved quality of life and reduced end-organ damage re-
`ported in these clinical trials were thought to outweigh the
`minimal corticosteroid-related side effects that were ob-
`served.11–13
`Other steroid moieties with less potential to cause ocular
`toxicity than methylprednisolone sodium succinate may
`also prove to be useful for therapy of keratoconjunctivitis
`sicca. Methylprednisolone was used in our dry eye patients
`because it could be prepared as a nonpreserved aqueous
`preparation to avoid the well-documented toxicity associ-
`ated with benzalkonium chloride, the preservative in all
`commercially available ophthalmic steroids.14,15 Further-
`more, methylprednisolone has proven efficacy for pulse
`intravenous therapy of systemic and ocular inflammatory
`diseases.16 Several of our patients continued to experience
`improvement in their irritation symptoms after they were
`switched to fluorometholone or hydroxymethylprogester-
`one, two topical corticosteroids that have a lower reported
`propensity to raise intraocular pressure than prednisolo-
`ne.17,18 Because of their lower potential for complications,
`these less toxic steroids appear to be viable options if they
`are formulated without preservatives. Another agent that
`could be considered is loteprednol etabonate, a corticoste-
`roid that is reported to have greater specificity for ocular
`surface epithelial cells, reduced intraocular activity, and a
`lower propensity to raise intraocular pressure.19
`The findings in our study suggest that ocular surface
`inflammation plays an important pathogenic role in the
`ocular irritation and ocular surface disease that develop in
`aqueous tear deficiency. This is further supported by the
`improvement in irritation symptoms and ocular surface dis-
`ease that have been observed from topical therapy with the
`immunosuppressive agent cyclosporin A.20 Indeed, immu-
`nopathologic studies show evidence of immune activation
`of the conjunctival epithelium in Sjo¨gren syndrome. Com-
`pared with normal eyes, a significantly greater percentage of
`conjunctival epithelial cells from patients with Sjo¨gren syn-
`drome express the immune adhesion molecules, HLA class
`II and ICAM-1 antigens.8,9 Furthermore, significantly ele-
`vated concentrations of messenger RNAs (mRNAs) encod-
`ing the inflammatory cytokines tumor necrosis factor-a,
`interleukin-1a, and IL-6 have been found in the conjuncti-
`val epithelium of patients with Sjo¨gren syndrome compared
`to normal control subjects.8,21 Corticosteroids decrease both
`production and release of these inflammatory cytokines,22,23
`and inhibition of their production and release has been
`
`815
`
`
`
`Ophthalmology Volume 106, Number 4, April 1999
`
`postulated as one of the mechanisms by which corticoste-
`roids suppress the inflammatory response.24 Future studies
`may determine whether the clinical improvement in kera-
`toconjunctivitis sicca observed with topical corticosteroid
`therapy is correlated with a decrease in cytokine production
`by cells on the ocular surface.
`In summary, this preliminary clinical series indicates that
`topical corticosteroid therapy is efficacious for the treatment
`of severe aqueous tear deficiency that is refractory to lubri-
`cant therapy without preservatives and punctal occlusion.
`Future clinical trials appear to be warranted to determine the
`optimum corticosteroid agent and the concentration and
`dosing frequency of steroid that will minimize steroid-
`related ocular complications.
`
`References
`
`1. Pflugfelder SC, Tseng SCG, Sanabria O, et al. Evaluation of
`subjective assessments and objective diagnostic tests for di-
`agnosing tear-film disorders known to cause ocular irritation.
`Cornea 1998;17:38 –56.
`2. Pflugfelder SC, Tseng SCG, Yoshino K, et al. Correlation of
`goblet cell density and mucosal epithelial membrane mucin
`expression with rose bengal staining in patients with ocular
`irritation. Ophthalmology 1997;104:223–35.
`3. American Academy of Ophthalmology. Blepharitis and the
`Dry Eye in the Adult. Preferred Practice Pattern. San Fran-
`cisco, CA: American Academy of Ophthalmology, 1991.
`4. Murillo–Lopez F, Pflugfelder SC. Dry Eye. In: Krachmer JH,
`Mannis MJ, Holland EJ, eds. Cornea. St. Louis: Mosby, 1997;
`V. 1, Chap. 56.
`5. Raphael M, Bellefqih S, Piette J Ch, et al. Conjunctival biopsy
`in Sjo¨gren’s syndrome: correlations between histological and
`immunohistochemical features. Histopathology 1988;13:191–
`202.
`6. Power WJ, Mullaney P, Farrell M, Collum LM. Effect of
`topical cyclosporin A on conjunctival T cells in patients with
`secondary Sjo¨gren’s syndrome. Cornea 1993;12:507–11.
`7. Pflugfelder SC, Huang AJW, Feuer W, et al. Conjunctival
`cytologic features of primary Sjogren’s syndrome. Ophthal-
`mology 1990;97:985–91.
`8. Jones DT, Monroy D, Ji Z, et al. Sjo¨gren’s syndrome: cytokine
`and Epstein–Barr viral gene expression within the conjuncti-
`val epithelium. Invest Ophthalmol Vis Sci 1994;35:3493–504.
`9. Baudouin C, Brignole F, Becquet F, et al. Flow cytometry in
`impression cytology specimens. A new method for evaluation
`of conjunctival
`inflammation. Invest Ophthalmol Vis Sci
`1997;38:1458 – 64.
`
`10. McCarey BE, Napalkov JA, Pippen PA, et al. Corneal wound
`healing strength with topical antiinflammatory drugs. Cornea
`1995;14:290 – 4.
`11. Breedveld FC. New perspectives on treating rheumatoid ar-
`thritis [editorial]. N Engl J Med 1995;333:183– 4.
`12. Kirwan JR. The effect of glucocorticoids on joint destruction
`in rheumatoid arthritis. The Arthritis and Rheumatism Council
`Low-Dose Glucocorticoid Study Group. N Engl J Med 1995;
`333:142– 6.
`13. Greenburg GR, Feagan BG, Martin F, et al. Oral budes-
`onide for active Crohn’s disease. N Engl J Med 1994;331:
`836 – 41.
`14. Ichijima H, Petroll WM, Jester JV, Cavanagh HD. Confocal
`microscopic studies of living rabbit cornea treated with ben-
`zalkonium chloride. Cornea 1992;11:221–5.
`15. Ubels JL, McCartney MD, Lantz WK, et al. Effects of
`preservative-free artificial tear solutions on corneal epithe-
`lial structure and function. Arch Ophthalmol 1995;113:
`371– 8.
`16. McCluskey P, Wakefield D. Intravenous pulse methylpred-
`nisolone in scleritis. Arch Ophthalmol 1987;105:793–7.
`17. Cantrill HL, Palmberg P, Zink HA, et al. Comparison of in
`vitro potency of corticosteroids with ability to raise intraocular
`pressure. Am J Ophthalmol 1975;79:1012–7.
`18. Mindel JS, Tavitian HO, Smith H, Jr, Walker EC. Compara-
`tive ocular pressure elevation by medrysone, fluorometholone,
`and dexamethasone phosphate. Arch Ophthalmol 1980;98:
`1577– 8.
`19. Friedlaender MH, Howes J. A double-masked, placebo-con-
`trolled evaluation of the efficacy and safety of loteprednol
`etabonate in the treatment of giant papillary conjunctivitis.
`Am J Ophthalmol 1997;123:455– 64.
`20. Gunduz K, Ozdemir O. Topical cyclosporin treatment of ker-
`atoconjunctivitis sicca in secondary Sjo¨gren’s syndrome. Acta
`Ophthalmol (Copenh) 1994;72:438 – 42.
`21. Jones DT, Monroy D, Ji Z, Pflugfelder SC. Alterations of
`ocular surface gene expression in Sjogren’s syndrome. Adv
`Exp Med Biol 1998;438:533– 6.
`22. Lee SW, Tsou AP, Chan H, et al. Glucocorticoids selectively
`inhibit the transcription of interleukin 1B gene and decrease
`the stability of interleukin 1bmRNA. Proc Natl Acad Sci U S
`A 1988;85:1204 – 8.
`23. Zanker B, Walz G, Wieder KJ, Strom TB. Evidence that
`glucocorticosteroids block expression of the human inter-
`leukin-6 gene by accessory cells. Transplantation 1990;49:
`183–5.
`24. Chrousos GP. The hypothalmic–pituitary–adrenal axis and
`immune-mediated inflammation. N Engl J Med 1995;332:
`1351– 62. (HMS; Allergan, Irvine, CA)
`
`816
`
`