Accepted Manuscript Treatment of Blepharitis: Recent Clinical Trials Stephen Pflugfelder, MD Paul Karpecki, OD Victor L. Perez, MD PII:
S1542-0124(14)00126-8
DOI:
10.1016/j.jtos.2014.05.005
Reference:
JTOS 102
To appear in:
Ocular Surface
Received Date: 21 February 2014 Revised Date:
16 May 2014
Accepted Date: 16 May 2014
Please cite this article as: Pflugfelder S, Karpecki P, Perez VL, Treatment of Blepharitis: Recent Clinical Trials, Ocular Surface (2014), doi: 10.1016/j.jtos.2014.05.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
SECTION: Clinical Practice, John E. Sutphin, MD, Editor
RI PT
TITLE: Treatment of Blepharitis: Recent Clinical Trials Authors: Stephen Pflugfelder, MD,1 Paul Karpecki, OD,2 and Victor L. Perez, MD3 SHORT TITLE: TREATMENT OF BLEPHARITIS/Pflugelder et al
Footnotes
SC
Accepted for publication May 2014.
From 1Baylor College of Medicine, Houston, TX, 2Kentucky Center for Vision, Lexington, KY,
M AN U
and 3Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
Editorial assistance was funded by Bausch + Lomb. The authors retained full control of manuscript content.
The authors have no financial or proprietary interest in any concept or product discussed in this article.
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Single-copy reprint requests to: Stephen Pflugfelder, MD (address below). Corresponding author: Stephen Pflugfelder, MD, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, 6565 Fannin, NC-205, Houston, Texas 77030 USA.
EP
Tel: 713-798-6100. Fax: 713-798-4231. E-mail: [email protected]
AC C
KEY WORDS antibiotics, bacteria, blepharitis, corticosteroids, cyclosporine, inflammation, meibomian gland dysfunction
1
ACCEPTED MANUSCRIPT
ABSTRACT Blepharitis is a chronic inflammatory disease of the eyelids that is frequently encountered in clinical practice. The etiology of the disorder is complex and not fully understood, but the general consensus is that bacteria and inflammation contribute to the pathology. Blepharitis can be classified into anterior blepharitis, involving the anterior lid margin and eyelashes, and
RI PT
posterior blepharitis, characterized by dysfunction of the meibomian glands. Long-term
management of symptoms may include daily eyelid cleansing routines and the use of therapeutic agents that reduce infection and inflammation. A cure is not possible in most cases, and subjective symptoms may persist even when a clinical assessment of signs indicates that the condition has
SC
improved. There are no established guidelines regarding therapeutic regimens, but recent clinical trials have shown that antibiotics and topical corticosteroids can produce significant improvement
M AN U
in signs and symptoms of blepharitis. Fixed combinations of a topical antibiotic and a corticosteroid offer an effective and convenient treatment modality that addresses both infectious and inflammatory components of the disease. Further clinical trials are needed to determine optimal therapies for managing blepharitis.
AC C
EP
TE D
KEY WORDS antibiotics, blepharitis, corticosteroids, cyclosporine A, infecction, inflammation
2
ACCEPTED MANUSCRIPT
II.
EP AC C
IV.
TE D
M AN U
III.
Introduction A. Incidence and Prevalence B. Classification C. Clinical Characteristics D. Etiology Overview of Current Treatments A. Lid Hygiene B. Pharmaceutical Interventions 1. Antibiotics 2. Steroids C. Other Review of Recent Clinical Trials A. Selection of Studies for Inclusion B. Findings of Clinical Trials 1. Dietary Supplementation 2. Topical Antibiotics a. Azithromycin b. Fluoroquinolones c. Aminoglycosides d. Conclusion 3. Topical Antibiotic/Steroid Combinations 4. Oral Antibiotics 5. Topical Cyclosporine Summary and Conclusions
SC
I.
RI PT
Outline
3
ACCEPTED MANUSCRIPT
I.
Introduction Blepharitis, a chronic inflammatory condition of the eyelid margin, is one of the most
common ocular disorders seen by ophthalmic practitioners.1,2 While generally not sightsuperficial keratopathy, corneal neovascularization, or ulceration.3
SC
A. Incidence and Prevalence
RI PT
threatening, blepharitis can induce permanent eyelid margin alterations and even vision loss from
Blepharitis affects all age and ethnic groups.2,3 While children can develop blepharitis,
M AN U
onset is typically during middle age.1 Although blepharitis is commonly encountered in clinical practice, its true incidence and prevalence in the general population has not been well documented apart from some regional studies. In one survey, ophthalmologists and optometrists in the United States reported that 37% to 47% of their patients had evidence of blepharitis.2 A recent crosssectional study in Spain based on a randomly selected sampling population reported rates of asymptomatic and symptomatic meibomian gland dysfunction (a condition closely linked with
B. Classification
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posterior blepharitis) of 21.9% and 8.6% of individuals, respectively.4
Various classification systems have been used to categorize blepharitis over the years, and
EP
some controversy remains with regard to blepharitis terminology. The most recent American Academy of Ophthalmology (AAO) Preferred Practice Patterns on blepharitis classifies the condition according to anatomic location.1 Anterior blepharitis affects the base of the eyelashes
AC C
and follicles and includes the traditional classifications of staphylococcal and seborrheic blepharitis. Posterior blepharitis involves the posterior lid margin (segment that contacts the cornea and bulbar conjunctiva) and has a range of potential etiologies, the primary cause being meibomian gland dysfunction (MGD). MGD is characterized by functional abnormalities of the meibomian glands and altered secretion of meibum, which plays an important role in slowing the evaporation of tear film; this change in protective function leaves the eye susceptible to surface damage and discomfort.3 Other causative factors in posterior blepharitis include infectious (herpes simplex, varicella zoster) and inflammatory conditions (e.g., meibomitis, atopic
4
ACCEPTED MANUSCRIPT
blepharoconjunctivitis, graft vs host disease, chalazia). To further complicate the classification of blepharitis, it is common for patients to have a mixture of anterior and posterior lid margin disease.1,5
RI PT
C. Clinical Characteristics Figure 1 illustrates various presentations of blepharitis. While the clinical features of the blepharitis categories can overlap, certain signs and symptoms are more commonly associated with particular subtypes.1 Patients with staphylococcal (anterior) blepharitis frequently exhibit eyelash
SC
loss and/or misdirection, signs that are rarely seen with other types of blepharitis. Other signs of staphylococcal blepharitis can include eyelid ulceration (severe cases), eyelid scarring, hordeolum, mild- to-moderate conjunctival injection, corneal changes (erosions, infiltrates, scarring,
M AN U
neovascularization and pannus, thinning, phlyctenules), and matted, hard scales/collarettes. Seborrheic (anterior) blepharitis is often accompanied by seborrheic dermatitis, with ocular findings typified by oily or greasy eyelid deposits, mild conjunctival injection, and inferior punctate epithelial erosions. Eyelash changes are rare.
Posterior blepharitis/MGD, often associated with rosacea, typically features plugging or
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displacement of the ductal openings, dilated and telangiectatic lid margin blood vessels, and decreased lipid secretion with foamy tears. Chalazia may be a cause or consequence of MGD. Eyelash misdirection and eyelid scarring can occur in long-standing posterior blepharitis, and corneal changes can include inferior punctate epithelial erosions, marginal infiltrates, scarring,
EP
neovascularization and pannus, and ulceration.
Aqueous tear deficiency is a frequent finding in all types of blepharitis.1 Cases of suspected
AC C
Demodex blepharitis are often associated with rosacea and individuals over the age of 70, but can affect any patient.6 The presentation is characterized by chronic inflammation of the base of the lashes and eyelid margins, a clear ”sleeve” or scurf surrounding the base of the lashes with significant debris, irregular eyelid margins, madarosis, and symptoms of itching and irritation.6,7
D.
Etiology The underlying causes of blepharitis and associated inflammation are not fully understood
5
ACCEPTED MANUSCRIPT
but probably involve several pathogenic mechanisms. Chronic low-grade bacterial infection is a likely factor in some cases, with effects mediated through bacterial toxins, direct tissue invasion, and inflammation stimulated by bacterial components.5,8 Normal, or commensal, bacteria may be present in excess, a different species may
RI PT
be colonizing, and/or there may be an imbalance of the species that normally colonize the eyelids.1 Demodex mites may play a role in some cases of anterior and posterior blepharitis,
although the association has not been firmly established because Demodex can also be found in asymptomatic patients.5,9 The infestation and waste produced by the mites has been theorized to
SC
cause follicle and gland blockage, as well as to trigger an inflammatory response.3 A recent metaanalysis of the association between Demodex infestation and blepharitis based on 13 published
M AN U
case-control series (2098 subjects with blepharitis; 2643 controls) reported a pooled odds ratio from random effect models of 4.89 (95% confidence interval, 3.00-7.97), suggesting that examination for Demodex mites is warranted when conventional blepharitis treatment is ineffective.10
Environmental factors may contribute to the pathogenesis of blepharitis. Ocular exposure to air pollution has been linked with an increase in blepharitis cases.11 Additionally, exposure to a
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drafty, low humidity environment, similar to that of air-conditioned offices, was found to increase concentrations of certain inflammatory factors in tears that could affect health of the lid margins.12 Blepharitis can also be associated with systemic diseases, such as rosacea, seborrheic dermatitis,
Overview of Current Treatments
AC C
II.
EP
atopic dermatitis, and graft vs host disease.3,5
Blepharitis is a chronic condition with frequent exacerbation. Currently, standard therapy is directed at control of symptoms and inflammatory signs, and patients should be counseled that cure is not likely.
There are no FDA-approved products specifically studied and indicated for blepharitis, nor are there definitive treatment recommendations for chronic blepharitis, although the International Workshop on Meibomian Gland Dysfunction published guidelines in 2011 which include a
6
ACCEPTED MANUSCRIPT
treatment algorithm.3 A recent Cochrane review evaluated 34 chronic blepharitis intervention studies and found no strong evidence to suggest that any of the studied treatments resulted in a cure.3 The latest Preferred Practice Pattern (PPP) on blepharitis from the AAO suggests the following to be helpful: warm compresses, eyelid hygiene, antibiotics (topical and/or systemic),
A.
RI PT
and topical anti-inflammatory agents (e.g., corticosteroids, cyclosporine).1
Lid Hygiene
SC
Lid hygiene (warm compresses, eyelid scrubs) has been shown to produce symptomatic benefit3 and should be considered in the patient’s regular routine to reduce and manage symptom
M AN U
recurrence. In posterior blepharitis/MGD, topical lubricants such as artificial tears are recommended for dry eye symptoms, based on growing experience with their benefits in evaporative dry eye.13-15 If Demodex infestation is suspected, the hygiene regimen should include a weekly scrub with 50% tea-tree oil solution, and a daily scrub with tea-tree shampoo for 6 weeks should be considered. In one study, this regimen was found to be effective in a subset of patients with Demodex mite infection who had not responded to conventional treatment.16 Oral ivermectin
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has been shown to reduce the number of Demodex organisms and improve signs and symptoms in patients with refractory posterior blepharitis and confirmed pre-treatment presence of the mites in
B.
EP
lash samples.9,17
Pharmaceutical Interventions
AC C
Pharmaceutical interventions can lessen the bacterial load, reducing inflammation and improving meibomian gland function.2
1. Antibiotics
For anterior blepharitis, topical antibiotics have been found useful for symptomatic relief and effective in eradicating bacteria from the eyelid margins.3 Topical ointments such as bacitracin or erythromycin may be applied to the eyelid margins one or more times daily or before bed for 7
7
ACCEPTED MANUSCRIPT
days or longer, depending on response to treatment. Data published within the past 10 years suggest an increase in methicillin-resistant S. aureus (MRSA) among ocular isolates in general, and in blepharoconjunctivitis cases specifically.18 In a cross-sectional study of 915 ocular isolates collected between 1998 and 2006, the proportion of MRSA isolates increased during that
RI PT
timeframe from 4.1% to 16.7%.18 Among patients with ocular MRSA infection, 78.0% had a diagnosis of blepharoconjunctivitis. These trends may warrant the use of ocular antibacterials having relatively higher activity against MRSA, such as besifloxacin and trimethoprim.19-21
SC
Oral antibiotics such as tetracyclines (tetracycline, doxycycline, minocycline) or
macrolides (erythromycin, azithromycin) are recommended for patients with MGD not controlled with eyelid hygiene or patients with associated rosacea.1 In such cases, the oral antibiotics are used
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in large part for their anti-inflammatory and lipid-regulating properties.13 Treatment can be tailored to response, and therapy can be started and stopped as needed. The tetracyclines and related drugs have several well-documented side effects, including photosensitization, gastrointestinal upset, and vaginitis. Tetracyclines should not be given to pregnant or nursing women, children under 10 years
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of age, and patients sensitive to this class of drugs.1
2. Steroids
Short courses of topical steroids have been found beneficial for symptomatic relief in cases with clinically significant ocular inflammation.3 Corticosteroid drops or ointment can be applied
EP
several times daily to the eyelids or ocular surface until the inflammation is reduced. These agents can be tapered over time and gradually discontinued, then reintroduced as needed. The minimally
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effective dose with the shortest duration of use should be used to reduce the risk of increased intraocular pressure (IOP) and cataracts. Corticosteroids with a decreased risk of IOP elevation and cataract formation (e.g., loteprednol etabonate [LE]22) or limited ocular penetration (e.g., fluoromethalone) are preferable.1 Topical combinations of an antibiotic and corticosteroid such as tobramycin/dexamethasone or tobramycin/loteprednol have been shown to significantly improve signs and symptoms of blepharitis.3 Topical application of the calcineurin inhibitor, cyclosporine has also been reported to have efficacy for treating signs and symptoms of posterior blepharitis. Consistent with its immunomodulatory/anti-inflammatory activity, treatment of posterior blepharitis/meibomian gland 8
ACCEPTED MANUSCRIPT
disease for 3 months with cyclosporine resulted in significantly greater improvement in eyelid margin inflammatory signs, including injection and vascular telangiectasia, than the comparator group -- artificial tears23,24 or tobramycin/dexamethasone.25
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C. Other
Changes in the meibomian glands and tear film may contribute to the cascade of inflammation and infection that leads to chronic blepharitis. Increased intake of essential fatty acids (EFAs) was
SC
recommended by the International Workshop on MGD for cases of mild-to-severe MGD.13 Recently, intraductal meibomian gland probing was reported to provide rapid and lasting symptom
III.
Review of Recent Clinical Trials A. Selection of Studies for Inclusion
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relief in a case series of patients with obstructive MGD.26
The medical literature was searched to identify recent human studies on the treatment of blepharitis. PubMed was searched for English-language clinical studies published during the past
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decade (2003-2013) using the search terms blepharitis treatment, meibomian gland dysfunction treatment, and blepharokeratoconjunctivitis treatment. Studies were included only if they involved pharmaceutical treatments that are commercially available in a broad international market. Investigations of procedural interventions (e.g., thermodynamic techniques) are not reviewed here.
1)
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The search initially identified 48 unique citations. Of these, 31 were excluded because: Treatment used was obscure, regionally marketed products or non-commercially
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available products (tea tree oil eyelid scrub, bibrocathol, diquafosol, sea buckthorn oil, topical N-acetylcysteine).
2)
Primary diagnosis was not blepharitis (dry eye, graft-vs-host disease, glaucoma, feline eosinophilic keratitis, infectious keratitis, inflammatory bowel disease, atopic keratoconjunctivitis, cystic fibrosis, Sjögren syndrome).
3)
Treatment involved procedural interventions (e.g., thermal treatments).
9
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As an additional search measure, BIOSIS was searched for the same time interval for any
B.
Findings of Clinical Trials
1.
Dietary Supplementation
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relevant yet unpublished data presented at medical/scientific meetings in abstract or poster form.
Supplementation with EFAs has been postulated to change the composition of tear film
SC
secretions from the meibomian glands and improve tear stability.27 Modulating inflammation is another mechanism by which EFAs may impact dry eye. Ocular surface inflammation contributes
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to the irritation symptoms and ocular surface disease that can develop in dry eye, while the Ω-6 fatty acid gamma-linolenic acid (GLA) and the Ω-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA, DHA) produce anti-inflammatory activity.27 Recent clinical studies have demonstrated measurable benefits from oral supplementation with EFAs (Ω-3 FAs from fish oil and Ω-6 FAs from GLA derived via Black Currant Seed oil) in improving dry eye symptoms and ocular comfort in non-blepharitis conditions, such as dry eye syndrome,28,29 contact lens-
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associated dry eye,30 keratoconjunctivitis sicca,31,32 and Sjögren syndrome.33 These studies administered GLA-containing oils alone or in combination with EPA and DHA. Two randomized studies investigated dietary supplementation with EFAs in patients with
EP
MGD and/or blepharitis.
In a randomized, placebo-controlled, masked trial,27 Mascai assigned 38 patients with MGD and blepharitis to supplementation with oral Ω-3 FAs (two 1000-mg flaxseed oil capsules)
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or control olive oil capsules, each given three times daily (TID). Among subjects who completed 1 year of treatment (flaxseed oil group, n=14; control group, n=16), the flaxseed oil group demonstrated 36% and 31% reductions in Ω-6 to Ω-3 FA ratios in plasma and RBCs, respectively, with while no such changes were observed in the control group. Subjects completed the 12-item Ocular Surface Disease Index (OSDI) every 3 months for 1 year, with possible total scores ranging from 0 (normal eye) to 100 (severe dry eye). In the flaxseed oil group, significant decreases (improvements) from baseline were observed in OSDI overall score (-11.6; P=.02), environmental triggers (-16.7; P=.04), and ocular symptoms (-19.1; P=.02). In the control group, only ocular
10
ACCEPTED MANUSCRIPT
symptoms were significantly improved from baseline (-9.5; P
S1542-0124(14)00126-8
DOI:
10.1016/j.jtos.2014.05.005
Reference:
JTOS 102
To appear in:
Ocular Surface
Received Date: 21 February 2014 Revised Date:
16 May 2014
Accepted Date: 16 May 2014
Please cite this article as: Pflugfelder S, Karpecki P, Perez VL, Treatment of Blepharitis: Recent Clinical Trials, Ocular Surface (2014), doi: 10.1016/j.jtos.2014.05.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
SECTION: Clinical Practice, John E. Sutphin, MD, Editor
RI PT
TITLE: Treatment of Blepharitis: Recent Clinical Trials Authors: Stephen Pflugfelder, MD,1 Paul Karpecki, OD,2 and Victor L. Perez, MD3 SHORT TITLE: TREATMENT OF BLEPHARITIS/Pflugelder et al
Footnotes
SC
Accepted for publication May 2014.
From 1Baylor College of Medicine, Houston, TX, 2Kentucky Center for Vision, Lexington, KY,
M AN U
and 3Bascom Palmer Eye Institute, University of Miami Miller School of Medicine, Miami, FL, USA.
Editorial assistance was funded by Bausch + Lomb. The authors retained full control of manuscript content.
The authors have no financial or proprietary interest in any concept or product discussed in this article.
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Single-copy reprint requests to: Stephen Pflugfelder, MD (address below). Corresponding author: Stephen Pflugfelder, MD, Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, 6565 Fannin, NC-205, Houston, Texas 77030 USA.
EP
Tel: 713-798-6100. Fax: 713-798-4231. E-mail: [email protected]
AC C
KEY WORDS antibiotics, bacteria, blepharitis, corticosteroids, cyclosporine, inflammation, meibomian gland dysfunction
1
ACCEPTED MANUSCRIPT
ABSTRACT Blepharitis is a chronic inflammatory disease of the eyelids that is frequently encountered in clinical practice. The etiology of the disorder is complex and not fully understood, but the general consensus is that bacteria and inflammation contribute to the pathology. Blepharitis can be classified into anterior blepharitis, involving the anterior lid margin and eyelashes, and
RI PT
posterior blepharitis, characterized by dysfunction of the meibomian glands. Long-term
management of symptoms may include daily eyelid cleansing routines and the use of therapeutic agents that reduce infection and inflammation. A cure is not possible in most cases, and subjective symptoms may persist even when a clinical assessment of signs indicates that the condition has
SC
improved. There are no established guidelines regarding therapeutic regimens, but recent clinical trials have shown that antibiotics and topical corticosteroids can produce significant improvement
M AN U
in signs and symptoms of blepharitis. Fixed combinations of a topical antibiotic and a corticosteroid offer an effective and convenient treatment modality that addresses both infectious and inflammatory components of the disease. Further clinical trials are needed to determine optimal therapies for managing blepharitis.
AC C
EP
TE D
KEY WORDS antibiotics, blepharitis, corticosteroids, cyclosporine A, infecction, inflammation
2
ACCEPTED MANUSCRIPT
II.
EP AC C
IV.
TE D
M AN U
III.
Introduction A. Incidence and Prevalence B. Classification C. Clinical Characteristics D. Etiology Overview of Current Treatments A. Lid Hygiene B. Pharmaceutical Interventions 1. Antibiotics 2. Steroids C. Other Review of Recent Clinical Trials A. Selection of Studies for Inclusion B. Findings of Clinical Trials 1. Dietary Supplementation 2. Topical Antibiotics a. Azithromycin b. Fluoroquinolones c. Aminoglycosides d. Conclusion 3. Topical Antibiotic/Steroid Combinations 4. Oral Antibiotics 5. Topical Cyclosporine Summary and Conclusions
SC
I.
RI PT
Outline
3
ACCEPTED MANUSCRIPT
I.
Introduction Blepharitis, a chronic inflammatory condition of the eyelid margin, is one of the most
common ocular disorders seen by ophthalmic practitioners.1,2 While generally not sightsuperficial keratopathy, corneal neovascularization, or ulceration.3
SC
A. Incidence and Prevalence
RI PT
threatening, blepharitis can induce permanent eyelid margin alterations and even vision loss from
Blepharitis affects all age and ethnic groups.2,3 While children can develop blepharitis,
M AN U
onset is typically during middle age.1 Although blepharitis is commonly encountered in clinical practice, its true incidence and prevalence in the general population has not been well documented apart from some regional studies. In one survey, ophthalmologists and optometrists in the United States reported that 37% to 47% of their patients had evidence of blepharitis.2 A recent crosssectional study in Spain based on a randomly selected sampling population reported rates of asymptomatic and symptomatic meibomian gland dysfunction (a condition closely linked with
B. Classification
TE D
posterior blepharitis) of 21.9% and 8.6% of individuals, respectively.4
Various classification systems have been used to categorize blepharitis over the years, and
EP
some controversy remains with regard to blepharitis terminology. The most recent American Academy of Ophthalmology (AAO) Preferred Practice Patterns on blepharitis classifies the condition according to anatomic location.1 Anterior blepharitis affects the base of the eyelashes
AC C
and follicles and includes the traditional classifications of staphylococcal and seborrheic blepharitis. Posterior blepharitis involves the posterior lid margin (segment that contacts the cornea and bulbar conjunctiva) and has a range of potential etiologies, the primary cause being meibomian gland dysfunction (MGD). MGD is characterized by functional abnormalities of the meibomian glands and altered secretion of meibum, which plays an important role in slowing the evaporation of tear film; this change in protective function leaves the eye susceptible to surface damage and discomfort.3 Other causative factors in posterior blepharitis include infectious (herpes simplex, varicella zoster) and inflammatory conditions (e.g., meibomitis, atopic
4
ACCEPTED MANUSCRIPT
blepharoconjunctivitis, graft vs host disease, chalazia). To further complicate the classification of blepharitis, it is common for patients to have a mixture of anterior and posterior lid margin disease.1,5
RI PT
C. Clinical Characteristics Figure 1 illustrates various presentations of blepharitis. While the clinical features of the blepharitis categories can overlap, certain signs and symptoms are more commonly associated with particular subtypes.1 Patients with staphylococcal (anterior) blepharitis frequently exhibit eyelash
SC
loss and/or misdirection, signs that are rarely seen with other types of blepharitis. Other signs of staphylococcal blepharitis can include eyelid ulceration (severe cases), eyelid scarring, hordeolum, mild- to-moderate conjunctival injection, corneal changes (erosions, infiltrates, scarring,
M AN U
neovascularization and pannus, thinning, phlyctenules), and matted, hard scales/collarettes. Seborrheic (anterior) blepharitis is often accompanied by seborrheic dermatitis, with ocular findings typified by oily or greasy eyelid deposits, mild conjunctival injection, and inferior punctate epithelial erosions. Eyelash changes are rare.
Posterior blepharitis/MGD, often associated with rosacea, typically features plugging or
TE D
displacement of the ductal openings, dilated and telangiectatic lid margin blood vessels, and decreased lipid secretion with foamy tears. Chalazia may be a cause or consequence of MGD. Eyelash misdirection and eyelid scarring can occur in long-standing posterior blepharitis, and corneal changes can include inferior punctate epithelial erosions, marginal infiltrates, scarring,
EP
neovascularization and pannus, and ulceration.
Aqueous tear deficiency is a frequent finding in all types of blepharitis.1 Cases of suspected
AC C
Demodex blepharitis are often associated with rosacea and individuals over the age of 70, but can affect any patient.6 The presentation is characterized by chronic inflammation of the base of the lashes and eyelid margins, a clear ”sleeve” or scurf surrounding the base of the lashes with significant debris, irregular eyelid margins, madarosis, and symptoms of itching and irritation.6,7
D.
Etiology The underlying causes of blepharitis and associated inflammation are not fully understood
5
ACCEPTED MANUSCRIPT
but probably involve several pathogenic mechanisms. Chronic low-grade bacterial infection is a likely factor in some cases, with effects mediated through bacterial toxins, direct tissue invasion, and inflammation stimulated by bacterial components.5,8 Normal, or commensal, bacteria may be present in excess, a different species may
RI PT
be colonizing, and/or there may be an imbalance of the species that normally colonize the eyelids.1 Demodex mites may play a role in some cases of anterior and posterior blepharitis,
although the association has not been firmly established because Demodex can also be found in asymptomatic patients.5,9 The infestation and waste produced by the mites has been theorized to
SC
cause follicle and gland blockage, as well as to trigger an inflammatory response.3 A recent metaanalysis of the association between Demodex infestation and blepharitis based on 13 published
M AN U
case-control series (2098 subjects with blepharitis; 2643 controls) reported a pooled odds ratio from random effect models of 4.89 (95% confidence interval, 3.00-7.97), suggesting that examination for Demodex mites is warranted when conventional blepharitis treatment is ineffective.10
Environmental factors may contribute to the pathogenesis of blepharitis. Ocular exposure to air pollution has been linked with an increase in blepharitis cases.11 Additionally, exposure to a
TE D
drafty, low humidity environment, similar to that of air-conditioned offices, was found to increase concentrations of certain inflammatory factors in tears that could affect health of the lid margins.12 Blepharitis can also be associated with systemic diseases, such as rosacea, seborrheic dermatitis,
Overview of Current Treatments
AC C
II.
EP
atopic dermatitis, and graft vs host disease.3,5
Blepharitis is a chronic condition with frequent exacerbation. Currently, standard therapy is directed at control of symptoms and inflammatory signs, and patients should be counseled that cure is not likely.
There are no FDA-approved products specifically studied and indicated for blepharitis, nor are there definitive treatment recommendations for chronic blepharitis, although the International Workshop on Meibomian Gland Dysfunction published guidelines in 2011 which include a
6
ACCEPTED MANUSCRIPT
treatment algorithm.3 A recent Cochrane review evaluated 34 chronic blepharitis intervention studies and found no strong evidence to suggest that any of the studied treatments resulted in a cure.3 The latest Preferred Practice Pattern (PPP) on blepharitis from the AAO suggests the following to be helpful: warm compresses, eyelid hygiene, antibiotics (topical and/or systemic),
A.
RI PT
and topical anti-inflammatory agents (e.g., corticosteroids, cyclosporine).1
Lid Hygiene
SC
Lid hygiene (warm compresses, eyelid scrubs) has been shown to produce symptomatic benefit3 and should be considered in the patient’s regular routine to reduce and manage symptom
M AN U
recurrence. In posterior blepharitis/MGD, topical lubricants such as artificial tears are recommended for dry eye symptoms, based on growing experience with their benefits in evaporative dry eye.13-15 If Demodex infestation is suspected, the hygiene regimen should include a weekly scrub with 50% tea-tree oil solution, and a daily scrub with tea-tree shampoo for 6 weeks should be considered. In one study, this regimen was found to be effective in a subset of patients with Demodex mite infection who had not responded to conventional treatment.16 Oral ivermectin
TE D
has been shown to reduce the number of Demodex organisms and improve signs and symptoms in patients with refractory posterior blepharitis and confirmed pre-treatment presence of the mites in
B.
EP
lash samples.9,17
Pharmaceutical Interventions
AC C
Pharmaceutical interventions can lessen the bacterial load, reducing inflammation and improving meibomian gland function.2
1. Antibiotics
For anterior blepharitis, topical antibiotics have been found useful for symptomatic relief and effective in eradicating bacteria from the eyelid margins.3 Topical ointments such as bacitracin or erythromycin may be applied to the eyelid margins one or more times daily or before bed for 7
7
ACCEPTED MANUSCRIPT
days or longer, depending on response to treatment. Data published within the past 10 years suggest an increase in methicillin-resistant S. aureus (MRSA) among ocular isolates in general, and in blepharoconjunctivitis cases specifically.18 In a cross-sectional study of 915 ocular isolates collected between 1998 and 2006, the proportion of MRSA isolates increased during that
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timeframe from 4.1% to 16.7%.18 Among patients with ocular MRSA infection, 78.0% had a diagnosis of blepharoconjunctivitis. These trends may warrant the use of ocular antibacterials having relatively higher activity against MRSA, such as besifloxacin and trimethoprim.19-21
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Oral antibiotics such as tetracyclines (tetracycline, doxycycline, minocycline) or
macrolides (erythromycin, azithromycin) are recommended for patients with MGD not controlled with eyelid hygiene or patients with associated rosacea.1 In such cases, the oral antibiotics are used
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in large part for their anti-inflammatory and lipid-regulating properties.13 Treatment can be tailored to response, and therapy can be started and stopped as needed. The tetracyclines and related drugs have several well-documented side effects, including photosensitization, gastrointestinal upset, and vaginitis. Tetracyclines should not be given to pregnant or nursing women, children under 10 years
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of age, and patients sensitive to this class of drugs.1
2. Steroids
Short courses of topical steroids have been found beneficial for symptomatic relief in cases with clinically significant ocular inflammation.3 Corticosteroid drops or ointment can be applied
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several times daily to the eyelids or ocular surface until the inflammation is reduced. These agents can be tapered over time and gradually discontinued, then reintroduced as needed. The minimally
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effective dose with the shortest duration of use should be used to reduce the risk of increased intraocular pressure (IOP) and cataracts. Corticosteroids with a decreased risk of IOP elevation and cataract formation (e.g., loteprednol etabonate [LE]22) or limited ocular penetration (e.g., fluoromethalone) are preferable.1 Topical combinations of an antibiotic and corticosteroid such as tobramycin/dexamethasone or tobramycin/loteprednol have been shown to significantly improve signs and symptoms of blepharitis.3 Topical application of the calcineurin inhibitor, cyclosporine has also been reported to have efficacy for treating signs and symptoms of posterior blepharitis. Consistent with its immunomodulatory/anti-inflammatory activity, treatment of posterior blepharitis/meibomian gland 8
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disease for 3 months with cyclosporine resulted in significantly greater improvement in eyelid margin inflammatory signs, including injection and vascular telangiectasia, than the comparator group -- artificial tears23,24 or tobramycin/dexamethasone.25
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C. Other
Changes in the meibomian glands and tear film may contribute to the cascade of inflammation and infection that leads to chronic blepharitis. Increased intake of essential fatty acids (EFAs) was
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recommended by the International Workshop on MGD for cases of mild-to-severe MGD.13 Recently, intraductal meibomian gland probing was reported to provide rapid and lasting symptom
III.
Review of Recent Clinical Trials A. Selection of Studies for Inclusion
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relief in a case series of patients with obstructive MGD.26
The medical literature was searched to identify recent human studies on the treatment of blepharitis. PubMed was searched for English-language clinical studies published during the past
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decade (2003-2013) using the search terms blepharitis treatment, meibomian gland dysfunction treatment, and blepharokeratoconjunctivitis treatment. Studies were included only if they involved pharmaceutical treatments that are commercially available in a broad international market. Investigations of procedural interventions (e.g., thermodynamic techniques) are not reviewed here.
1)
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The search initially identified 48 unique citations. Of these, 31 were excluded because: Treatment used was obscure, regionally marketed products or non-commercially
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available products (tea tree oil eyelid scrub, bibrocathol, diquafosol, sea buckthorn oil, topical N-acetylcysteine).
2)
Primary diagnosis was not blepharitis (dry eye, graft-vs-host disease, glaucoma, feline eosinophilic keratitis, infectious keratitis, inflammatory bowel disease, atopic keratoconjunctivitis, cystic fibrosis, Sjögren syndrome).
3)
Treatment involved procedural interventions (e.g., thermal treatments).
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As an additional search measure, BIOSIS was searched for the same time interval for any
B.
Findings of Clinical Trials
1.
Dietary Supplementation
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relevant yet unpublished data presented at medical/scientific meetings in abstract or poster form.
Supplementation with EFAs has been postulated to change the composition of tear film
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secretions from the meibomian glands and improve tear stability.27 Modulating inflammation is another mechanism by which EFAs may impact dry eye. Ocular surface inflammation contributes
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to the irritation symptoms and ocular surface disease that can develop in dry eye, while the Ω-6 fatty acid gamma-linolenic acid (GLA) and the Ω-3 fatty acids eicosapentaenoic and docosahexaenoic acid (EPA, DHA) produce anti-inflammatory activity.27 Recent clinical studies have demonstrated measurable benefits from oral supplementation with EFAs (Ω-3 FAs from fish oil and Ω-6 FAs from GLA derived via Black Currant Seed oil) in improving dry eye symptoms and ocular comfort in non-blepharitis conditions, such as dry eye syndrome,28,29 contact lens-
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associated dry eye,30 keratoconjunctivitis sicca,31,32 and Sjögren syndrome.33 These studies administered GLA-containing oils alone or in combination with EPA and DHA. Two randomized studies investigated dietary supplementation with EFAs in patients with
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MGD and/or blepharitis.
In a randomized, placebo-controlled, masked trial,27 Mascai assigned 38 patients with MGD and blepharitis to supplementation with oral Ω-3 FAs (two 1000-mg flaxseed oil capsules)
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or control olive oil capsules, each given three times daily (TID). Among subjects who completed 1 year of treatment (flaxseed oil group, n=14; control group, n=16), the flaxseed oil group demonstrated 36% and 31% reductions in Ω-6 to Ω-3 FA ratios in plasma and RBCs, respectively, with while no such changes were observed in the control group. Subjects completed the 12-item Ocular Surface Disease Index (OSDI) every 3 months for 1 year, with possible total scores ranging from 0 (normal eye) to 100 (severe dry eye). In the flaxseed oil group, significant decreases (improvements) from baseline were observed in OSDI overall score (-11.6; P=.02), environmental triggers (-16.7; P=.04), and ocular symptoms (-19.1; P=.02). In the control group, only ocular
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symptoms were significantly improved from baseline (-9.5; P
