Ocular Rosacea
`Patient Characteristics and Follow..-up
`
`Esen Karamursel Akpek, MD, 1 Amyna Merchant, MD/ Vakur Pinar, MD,l,2
`C. Stephen Foster, MD 1
`
`Purpose: The purpose of this report is to review the presenting symptoms and
`signs, treatment regimens used, complications encountered, and outcome in a cohort of
`patients with ocular rosacea.
`Methods: The medical records of 131 patients with a diagnosis of ocular rosacea
`were reviewed retrospectively. Data were entered in a tabulated form, and a descriptive
`analysis was performed.
`Results: The age range at presentation was between 23 and 85 years (mean, 56
`years). Cutaneous manifestations of rosacea were present in 112 of the patients at their
`first visit. The most common presenting symptoms were foreign body sensation and
`burning, and the most common signs were telangiectasia and irregularity of lid margins,
`and meibomian gland dysfunction. Thirteen patients had decreased visual acuity at the
`time of presentation due to corneal complications. Six of these patients required penetrat(cid:173)
`ing keratoplasty during the course of their disease. Seven patients had severe cicatrizing
`conjunctivitis at the time of referral. One hundred thirteen patients were treated with oral
`tetracycline derivatives. Seven patients were left with visual acuity less than 20/400, and
`one patient underwent enucleation for corneal perforation and endophthalmitis.
`Conclusions: Ocular rosacea is a common disease involving the skin and the eyes.
`It is widely underdiagnosed by many ophthalmologists despite the blinding potential.
`Successful therapy requires a multidisciplinary approach.
`Ophthalmology 1997; 104:1863-1867
`
`Acne rosacea is a common chronic skin disease character(cid:173)
`ized by persistent erythema, telangiectases, papules, and
`pustules in the flush areas of the face and neck. The
`typical feature of the advanced stage of the disease is the
`rhinophyma caused by sebaceous gland hypertrophy. 1
`Ocular involvement (ocular rosacea) is reported in 3%2
`to 58% 3 of cases depending on the series. The severity
`of the ocular signs ranges from mild blepharoconjunctivi-
`
`Originally received: December 9, 1996.
`Revision accepted: May 13, 1997.
`'Department of Immunology, Massachusetts Eye and Ear Infirmary,
`243 Charles Street, Boston, Massachusetts.
`2 Department of Ophthalmology, Dokuz Ey1u1 University, Izmir, Tur(cid:173)
`key.
`Presented at The Castroviejo Cornea Society Meeting, Chicago, Illinois,
`October 1996.
`Address correspondence to C. Stephen Foster, MD, Immunology Ser(cid:173)
`vice, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston,
`MA 02114.
`
`tis to vision-impairing corneal involvement such as neo(cid:173)
`vascularization, thinning, and, in rare instances, perfora(cid:173)
`tion.4
`The etiopathogenesis of ocular rosacea is not yet clear.
`Rufli and Btichner5 attributed the skin lesions to a cell(cid:173)
`mediated immune response to Demodex folliculorum be(cid:173)
`cause inflammatory infiltrates, mainly helper-inducer T
`cells, were found around these sites. Brown and Shahi(cid:173)
`nian6 showed immunoglobulin and C3 deposition in the
`epithelium and the basement membrane of patients with
`severe ocular rosacea. Hoang-Xuan et aC concluded that
`the mechanism involved in rosacea conjunctival inflam(cid:173)
`mation resembled a type-IV hypersensitivity reaction by
`studying the histology-immunopathology of conjunctival
`biopsy specimens from patients with the diagnosis of ocu(cid:173)
`lar rosacea.
`This report describes the patient demographics, pre(cid:173)
`senting symptoms and signs, treatment regimens used,
`complications encountered, and outcome in a cohort of
`patients with ocular rosacea who were treated throughout
`
`1863
`
`MYLAN - EXHIBIT 1062
`Mylan Pharmaceuticals Inc. et al. v. Allergan, Inc.
`IPR2016-01127, -01128, -01129, -01130, -01131, & -01132
`
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`

`Ophthalmology Volume 104, Number 11, November 1997
`
`Table 1. Patient Characteristics at the Initial
`Examination
`
`Patient Characteristic
`
`No. of patients
`Male/female
`Race
`Mean age at onset ( yrs)
`No. of patients <30 yrs
`Facial rosacea
`Previous diagnosis of rosacea
`
`Value
`
`131
`75/56
`White
`56 (23-85)
`10
`112
`12
`
`their follow-up at the Massachusetts Eye and Ear Infir(cid:173)
`mary Immunology Department.
`
`Patients and Methods
`
`The medical records of 131 patients who were admitted
`to the Immunology Service at the Massachusetts Eye and
`Ear Infirmary with a diagnosis of ocular rosacea were
`reviewed. The diagnosis of rosacea was based on the
`findings of telangiectasia of the nose and face and one or
`more of the following: hypertrophic sebaceous glands,
`papules, pustules, and erythema of the flush areas of the
`face. 8 Records were entered in a tabulated form, and a
`descriptive analysis was performed to determine the pa(cid:173)
`tient characteristics retrospectively.
`
`Results
`
`Fifty-six (43%) of the 131 patients were women and 75
`(57%) were men. The age range at presentation was be(cid:173)
`tween 23 and 85 years (mean, 56 years). Ten patients
`were younger than 30 years of age. None of the patients
`were black (Table 1).
`Most patients presented with a chief reported problem
`of foreign body sensation, pain, burning, or redness. U su(cid:173)
`ally both eyes were affected simultaneously, but occasion(cid:173)
`ally alternate involvement was noted.
`Thirteen patients had an initial reported problem of
`decreased visual acuity due to the corneal complications;
`12 were referred due to the cicatrizing conjunctivitis to
`rule out ocular cicatricial pemphigoid, 5 were referred for
`further treatment of ocular rosacea, 2 for recurrent chala(cid:173)
`zia, and 1 for recurrent episcleritis.
`Facial skin rosacea was present in 112 of the patients at
`their first visit. In most of these patients, the dermatologic
`findings were not so pronounced so as to make the diagno(cid:173)
`sis obvious to even a casual observer. Indeed, only 12 of
`the patients were diagnosed previously with acne rosacea.
`In 1 I patients, the skin manifestations developed later,
`and in 8 patients, only mild skin changes were noted
`during a follow-up period of 2 to 40 months (mean, 13
`months). The age range of these eight patients was 31 to
`84 years (mean, 47 years).
`The patients' ocular findings were confined mainly to
`
`1864
`
`the eyelids, conjunctiva, and cornea (Table 2). The most
`common finding was telangiectasia and irregularity of
`the lid margins, which occurred in 106 patients (81 %).
`Meibomian gland dysfunction that is stagnation of the
`expressible sebum from the meibomian duct orifices were
`encountered in 103 patients (78% ), and 86 patients (65%)
`had blepharitis with varying degrees of erythema, edema,
`scale, and scurf formation of the eyelid skin along with
`meibomian gland dysfunction. Fourteen patients were af(cid:173)
`fected by chalazia at the time of the initial examination.
`Conjunctival hyperemia, mostly confined to the bulbar
`conjunctiva, was noted in 59 patients (45% ). Seven of
`the 12 patients having signs of cicatrizing conjunctivitis
`had either fornix foreshortening, symblepharon, or entro(cid:173)
`pion and trichiasis at the time of their referral. None of the
`conjunctival biopsy specimens showed immunoreactant
`deposition at the epithelial basement membrane zone on
`immunohistochemical analysis. The histopathologic char(cid:173)
`acteristics of the biopsy specimen showed a conjunctival
`granuloma in one patient who had a bulbar conjunctival
`mass and chronic diffuse granulomatous inflammation in
`the others. One patient had phlyctenular conjunctivitis.
`Episcleritis was seen in 11 patients, scleritis in 1 pa(cid:173)
`tient, and iritis developed in 3 patients sometime during
`the course of their disease.
`Thirty-four patients had keratoconjunctivitis sicca con(cid:173)
`firmed by Schirmer test with topical anesthesia. After
`instillation of a drop of topical anesthetic (0.5% propara(cid:173)
`caine) and removal of tears in the lower cul-de-sac by
`tissue paper capillary attraction, aqueous tear production
`was measured by the extent of wetting the standard
`Schirmer paper strip at the end of 5 minutes. Less than
`5 mm was considered as deficient "basal" aqueous tear
`production. These patients were treated with preservative(cid:173)
`free artificial tears.
`
`Table 2. Ocular Findings of Patients with Rosacea
`
`Sign
`
`Total no. of patients
`Telangiectasia and irregularity of
`lid margins
`Meibomian gland dysfunction
`Blepharitis
`Conjunctival hyperemia
`Keratoconjunctivitis sicca
`Stromal keratitis with peripheral
`neovascularization
`Superficial punctate keratitis
`Chalazia
`Cicatrizing conjunctivitis
`Episcleritis
`Recurrent epithelial erosion
`Corneal ulcer
`Iritis
`Scleritis
`Conjunctival granuloma
`Phlyctenular conjunctivitis
`
`No.(%) of
`Patients
`
`131
`
`106 (81)
`103 (78)
`86 (65)
`59 (45)
`34 (26)
`
`21 (16)
`20 (15)
`14 (10)
`12 (9)
`11 (8)
`7 (5)
`7 (5)
`3 (2)
`1 (0.7)
`1 (0.7)
`1 (0.7)
`
`

`

`Akpek et al · Ocular Rosacea Characteristics
`
`A spectrum of corneal findings was documented in 54
`patients. Superficial punctate keratopathy, usually con(cid:173)
`fined to the inferior half of the cornea, affected 20 pa(cid:173)
`tients. Mild-to-severe stromal keratitis with peripheral
`vascularization was seen in 21 patients. Three of these
`patients had peripheral corneal thinning in the inferior
`half of the cornea and one patient had descemetocele
`formation. One of the patients with stromal keratitis had
`Salzmann's nodular degeneration develop, and another
`patient had peripheral corneal thinning. Two patients
`showed improvement and increased visual acuities after
`oral tetracycline therapy.
`Intermittent pain on awakening with characteristic
`signs of recurrent erosion, discrete areas of epithelial ele(cid:173)
`vations, epithelial erosions, and subepithelial opacities
`was present in six patients. Seven patients had a corneal
`ulcer develop, two of whom had a corneal perforation.
`Stromal puncture was performed for one patient with re(cid:173)
`current corneal erosion syndrome, and a bandage contact
`lens was applied to a patient with a corneal ulcer. The
`vision improved in both patients with these treatment
`methods.
`Thirteen patients with corneal complications had sig(cid:173)
`nificantly decreased visual acuity at the time of presenta(cid:173)
`tion; 6 required penetrating keratoplasty. During a follow(cid:173)
`up period of 1 to 8 years (mean, 4 years), three of the
`grafts remained clear and three failed because of immune
`rejection. Two patients needed repeat keratoplasties, but
`those grafts failed as well.
`One patient (56-year-old white male) with a history of
`herpetic keratouveitis had a corneal perforation of the
`right eye. The patient had no cutaneous manifestations of
`rosacea at the time of his examination. He underwent
`penetrating keratoplasty two times and the graft failed
`each time. A year later, the classical rosacea facies devel(cid:173)
`oped and the patient was treated with oral doxycycline.
`But the patient was an alcohol abuser and he had a compli(cid:173)
`ance problem with treatment and follow-up visits to the
`clinic. Three years after his initial clinical presentation,
`the cornea perforated, and the patient underwent enucle(cid:173)
`ation because of endophthalmitis. The left eye of the pa(cid:173)
`tient with extreme meibomian gland dysfunction, blepha(cid:173)
`ritis, and superficial punctate keratitis improved and re(cid:173)
`mained stable on doxycycline for a period of 12 years.
`Treatment with oral tetracycline derivatives was insti(cid:173)
`tuted in 113 patients (86% ). The usual starting dose for
`the tetracycline was 250 mg four times a day, and for the
`doxycycline, the starting dose was 100 mg once daily.
`After a period of remission of 3 to 6 months, the antibiot(cid:173)
`ics were tapered and then discontinued. Patients with
`sight-threatening complications were kept on a low-dose
`maintenance treatment indefinitely to prevent recurrence.
`Two patients did not respond to both tetracycline and
`doxycycline. The remaining patients responded well and
`showed dramatic improvement in their symptoms or signs
`or both. The response time varied from 2 to 6 weeks.
`Thirty-three patients (25%) reported adverse effects; the
`most common effects were nausea ( 171113, 15%) and
`photosensitivity (8/113, 7% ). One patient reported chest
`pain, and one had difficulty swallowing. Genital yeast
`
`infection occurred in only 2 ( 4%) of the 48 female patients
`while they still were receiving the antibiotics.
`Seven patients who had advanced cicatrizing conjunc(cid:173)
`tivitis findings had no further complications develop and
`remained stable receiving oral tetracycline without evi(cid:173)
`dence of further conjunctival cicatrization.
`Among the 47 patients with a follow-up period of 3
`or more years (range, 3-16 years), 6 patients were left
`with visual acuity of 20/400 or less. This was because of
`opaque corneal grafts (performed for severe complica(cid:173)
`tions due to rosacea itself in three patients and for pseu(cid:173)
`dophakic bullous keratopathy in three patients). One pa(cid:173)
`tient was left with no light perception (the patient who
`underwent enucleation).
`
`Discussion
`
`Duke-Elder9 described ocular rosacea as a common and
`frequently undiagnosed disease. Skin involvement in ro(cid:173)
`sacea is characterized by erythema, telangiectasia, pap(cid:173)
`ules, pustules, and sebaceous gland hypertrophy. The le(cid:173)
`sions are reported to be distributed only in the flush areas,
`including cheeks, forehead, nose, chin, and the ''V'' of
`the neck. Rosacea is distinguished from acne vulgaris by
`the absence of comedones and by its confinement to flush
`areas. Acne vulgaris commonly involves the back and
`chest as well as the face. 4
`The age range most common for patients with rosacea,
`as reported in the dermatologic literature, is 40 to 50
`years?· 10 In a series of 47 patients with ocular rosacea,
`the decade of peak prevalence was 51 to 60 years. 11 In
`our study, the mean age was 56 years, and only 10 of
`the 131 patients were younger than 30 years of age; the
`youngest was 26.
`Rosacea without ocular involvement was reported to
`involve women twice as often as men, 12
`13 but cases with
`"
`ocular manifestations are about evenly divided between
`the sexes. In our study, there was a small male preponder(cid:173)
`ance (M/F: 1.3/1).
`There are no data on the variation in prevalence of
`rosacea among races. There is a widespread clinical im(cid:173)
`pression that rosacea mainly affects fair-skinned people
`of northern European descent. Dermatologists, however,
`accept the existence of rosacea in blacks, although the
`14 In our study, none of the patients
`condition is rare.3
`•
`were black.
`Facial rosacea was evident at the initial visit in 112
`patients (85% ). Eleven other patients had obvious rosacea
`facies develop some time during the course of their dis(cid:173)
`ease. Eight patients had only few telangiectasias and mild
`erythema. We attributed this to the young age range of
`the patients (mean, 47) and to the relatively short follow(cid:173)
`up period (mean, 13 months).
`Ocular manifestations of rosacea can be attributed to
`acne rosacea with certainty when there is simultaneous
`involvement of the facial skin. Therefore, the ophthalmol(cid:173)
`ogist should perform a careful dermatologic inspection of
`the face and be familiar with the variable presentation of
`facial rosacea to make the diagnosis. However, the skin
`
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`
`

`

`Ophthalmology Volume 104, Number 11, November 1997
`
`lesions required to confirm a suspicion of ocular rosacea
`need not be severe.4 In fact, only 10% (121112) of our
`patients with facial rosacea had been diagnosed else(cid:173)
`where. However, 15% of our patients (19/131) had ocular
`rosacea without the skin lesions. In such cases, because
`there is no specific test available to distinguish rosacea
`from other causes of ocular inflammation, consultation
`with a dermatologist is invaluable. Browning and Proia4
`suggest that response to a therapeutic trial of oral tetracy- .
`cline may be helpful in confirming a tentative diagnosis.
`The most common symptoms of ocular rosacea are
`nonspecific and include a foreign body, gritty, or dry
`sensation, burning, tearing, or redness. Frequently, the
`symptoms are out of proportion to the minimal eye find(cid:173)
`ings,8 and this has been our impression as well.
`The ocular manifestations of rosacea range from minor
`to severe. Blepharitis, conjunctival injection, tearing,
`burning, recurrent chalazia, corneal vascularization and
`scarring, corneal and scleral perforation, episcleritis, and
`iritis have been reported to occur in rosacea.2·3·8·12·15- 17
`The most common findings in our study were lid margin
`telangiectasia in 106 patients (81 %), meibomian gland
`dysfunction in 103 patients (78%), and blepharitis in 86
`patients (65%).
`Conjunctival involvement in ocular rosacea usually is
`in the form of a mild hyperemia, especially of the bulbar
`conjunctiva. Although rosacea is listed among the causes
`of cicatrizing conjunctivitis, it is infrequent. Seven of our
`patients were referred for diagnosis and further treatment
`of their advanced cicatrizing conjunctivitis. We also noted
`conjunctival granuloma (one patient) and phlyctenular
`conjunctivitis (one patient) among our patients. Conjunc(cid:173)
`tival granuloma in rosacea has been reported previously,
`and it has been recommended that rosacea be included in
`the differential diagnosis of conjunctival granulomas. 18
`Lempert et al19 found that 57% of patients older than
`19 years of age scheduled for chalazion excision had
`rosacea. We found that only 2 of the 14 patients who
`had recurrent chalazia were taking oral tetracycline for
`diagnosed rosacea.
`Corneal involvement is, of course, the sight-threaten(cid:173)
`ing problem in rosacea. The most common manifestation
`is superficial punctate keratitis, usually in the inferior half
`of the cornea. Peripheral nodular epithelial elevations,
`map-like changes, fingerprints, epithelial microcysts, ker(cid:173)
`atitis with neovascularization, and corneal thinning have
`been described. 8 Corneal involvement in varying degrees
`was noted in 54 patients (41 %) among our study group.
`Thirteen patients had significantly reduced visual acuity
`at the time of initial presentation. Six of these patients
`required penetrating keratoplasty (two of the patients were
`regrafted) and three did not respond despite aggressive
`treatment. Patients with rosacea who require penetrating
`keratoplasty are reported to be more prone to graft rejec(cid:173)
`tion than are other patients, because of the corneal vascu(cid:173)
`larization.4
`Keratoconjunctivitis sicca has been described in pa(cid:173)
`tients with acne rosacea,20'21 but no clear explanation was
`hypothesized for this association. In the study carried out
`by Zengin et al,22 the tear film breakup time in patients
`
`with meibomian gland dysfunction was found to be de(cid:173)
`creased significantly compared with that of those patients
`without meibomian gland dysfunction ( dermatologic ro(cid:173)
`sacea). Because meibomian gland expression did not im(cid:173)
`prove the tear film breakup time, but oral tetracycline did,
`Zengin et al22 concluded that the tear film breakup time
`abnormality in ocular rosacea was caused by an abnormal
`lipid composition. Because neither meibomian gland dys(cid:173)
`function nor tetracycline therapy had a beneficial effect
`on decreased tear secretion, they recommended the use
`of artificial tears in addition to oral tetracycline. 11 We
`found decreased tear production, confirmed by Schirmer's
`test with anesthesia, in 34 patients. These patients were
`provided with lid hygiene, artificial tears, and oral tetracy(cid:173)
`cline. Three patients required inferior puncta! plug inser(cid:173)
`tion. All 34 patients improved with these treatment meth(cid:173)
`ods.
`Episcleritis and scleritis also have been reported to
`occur in patients with rosacea.2'16 Episcleritis was quite
`common (8%) among our patients, and one patient had
`scleritis.
`Because most of the patients with rosacea have meibo(cid:173)
`mian gland dysfunction and blepharitis, a continuing regi(cid:173)
`men of eyelid hygiene with warm compresses and meibo(cid:173)
`mian gland expression is important. The patient is in(cid:173)
`structed to warm the eye lids with cloths soaked in warm(cid:173)
`to-hot water to liquefy the solidified sebum in the meibo(cid:173)
`mian ducts and to dilate the ducts. The patient then is
`instructed to massage the lids to mechanically force the
`sebum and debris from the plugged or stagnant ducts.
`The patient's goal is to massage down on the upper lid
`and up on the lower lid to express stagnant sebum from
`the ducts and to clean the bases of the eyelashes and the
`lid margins, not just the eyelid skin. Antibiotics effective
`against staphylococci such as bacitracin and erythromycin
`may be useful in controlling bacterial overgrowth.
`The conventional management of chalazia and sties,
`including warm compresses and incision with curettage,
`may help speed the resolution of these lesions while tetra(cid:173)
`cycline is taking effect. Topical steroid therapy can be
`useful in managing iritis, keratitis, and episcleritis of ocu(cid:173)
`lar rosacea. However, close follow-up and the lowest con(cid:173)
`centration of the steroid that is effective are strongly rec(cid:173)
`ommended because patients with rosacea are prone to
`rapid corneal melting with higher corticosteroid concen(cid:173)
`trations. 23
`Frucht-Pery et al24 compared the effects of tetracy(cid:173)
`cline and doxycycline on the subjective symptoms of ro(cid:173)
`sacea. They reported that tetracycline alleviates the symp(cid:173)
`toms faster, but doxycycline causes less gastrointestinal
`side effects and is easier with which to comply. In our
`study, we noted relatively more side effects with doxycy(cid:173)
`cline than with tetracycline. Among 17 patients having
`nausea, 12 were taking doxycycline, and of the 8 patients
`with photosensitivity, 6 were taking doxycycline. In addi(cid:173)
`tion, two female patients experienced a fungal genital
`tract infection while taking doxycycline therapy. Two pa(cid:173)
`tients did not respond to any of the oral tetracyclines and
`were advised to continue with aggressive lid hygiene.
`Topical metronidazole, a broad-spectrum antibiotic and
`
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`
`

`

`Akpek et al · Ocular Rosacea Characteristics
`
`antiparasitic agent, was reported to be highly effective in
`treating the facial rosacea. 25 However, it currently is not
`available in an ophthalmic preparation to be used directly
`on the lids or in the eye, and whether controlling the
`facial skin findings has any effects on the ocular manifes(cid:173)
`tations is not certain. Although in vitro evaluation of the
`effects of metronidazole on rabbit corneal epithelial cells
`showed that it was quite safe at low doses, 26 clinical safety
`and efficacy studies need to be done to determine whether
`topical metronidazole is useful for the treatment of ocular
`rosacea.
`In summary, acne rosacea is a common disease of
`unknown cause and protean manifestations. Although the
`minor manifestations are more prevalent than the major
`ones, acne rosacea is a potentially blinding disease. There
`is no specific test for the disease, and none of the findings
`of ocular rosacea are specific. It is underdiagnosed by
`ophthalmologists who do not carefully examine the face
`of the patient, because the skin lesions required to confirm
`a suspicion of ocular rosacea need not be severe. The
`treatment of rosacea is multifaceted and prolonged, re(cid:173)
`quiring high patient compliance.
`
`References
`
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