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Articles  |   March 2011
The International Workshop on Meibomian Gland Dysfunction: Report of the Clinical Trials Subcommittee
Author Affiliations & Notes
  • Penny A. Asbell
    From the Department of Ophthalmology, Mount Sinai Medical Center, New York, New York;
  • Fiona J. Stapleton
    the School of Optometry and Vision Science, University of New South Wales, Sydney, New South Wales, Australia;
  • Kerstin Wickström
    Läkemedelsverket, Medical Products Agency, Uppsala, Sweden;
  • Esen K. Akpek
    The Wilmer Eye Institute, Johns Hopkins Hospital, Baltimore, Maryland;
  • Pasquale Aragona
    the Department of Surgical Specialties, Section of Opthalmology, University of Messina, Messina, Italy;
  • Reza Dana
    Schepens Eye Research Institute, Boston, Massachusetts;
  • Michael A. Lemp
    Georgetown University, Washington, DC; and
  • Kelly K. Nichols
    the School of Optometry, Ohio State University, Columbus, Ohio.
  • Corresponding author: Kelly K. Nichols, College of Optometry, 338 W. 10th Avenue, Ohio State University, Columbus, OH 43210-1280; knichols@optometry.osu.edu
Investigative Ophthalmology & Visual Science March 2011, Vol.52, 2065-2085. doi:10.1167/iovs.10-6997h
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      Penny A. Asbell, Fiona J. Stapleton, Kerstin Wickström, Esen K. Akpek, Pasquale Aragona, Reza Dana, Michael A. Lemp, Kelly K. Nichols; The International Workshop on Meibomian Gland Dysfunction: Report of the Clinical Trials Subcommittee. Invest. Ophthalmol. Vis. Sci. 2011;52(4):2065-2085. doi: 10.1167/iovs.10-6997h.

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The objective of this subcommittee was to summarize the evidence in clinical trials on meibomian gland dysfunction (MGD) and to use this information to make recommendations for best-practice clinical trial design for this condition. 
We conducted a PubMed and Medline literature review (through the end of 2009) to identify treatment or observational trials. Our search terms were those commonly used interchangeably with MGD, including (in addition to MGD) posterior blepharitis, meibomian gland disease, and tarsal gland disease. The level of evidence for each study was classified (Table 1) according to American Academy of Ophthalmology (AAO) Classification Scheme. In short, level I evidence includes evidence obtained from at least one properly conducted, well-designed randomized controlled trial. It could include meta-analyses of randomized controlled trials. Level II includes evidence obtained from well-designed controlled trials without randomization, well-designed cohort or case–control analytic studies, preferably from more than one clinical center or from multiple-time series with or without the intervention. Level III includes evidence obtained from descriptive studies, case reports, or reports of expert committees/organizations (e.g., panel consensus with external peer review). Additional information on levels of evidence is found in Table 1 of The Report on Management and Therapy. In some cases, the trial designs were not sufficiently described to have more than a tentative grading. Further, recent publications (August 2009 and later) were purposely excluded from Table 1
Table 1.
 
Evidence Levels of Eligible Trials (in Chronological Order)
Table 1.
 
Evidence Levels of Eligible Trials (in Chronological Order)
Evidence Level* Publications (n) References†
I 3 Yoo et al. 26
Perry et al. 17
Schechter et al. 21
I–II 2 Goto et al. 8
Rubin and Rao 20
II 8 Paugh et al. 16
Yalcin et al. 25
Olson et al. 15
Romero et al. 19
Pinna et al. 18
Luchs 10
Souchier et al. 24
Matsumoto et al. 12
II–III 1 Mori et al. 14
III 12 Dougherty et al. 4
Epstein and Putterman 5
Song et al. 23
Meisler et al. 13
Goto et al. 6
Goto et al. 7
Shine et al. 22
Albietz and Lenton 1
Cetinkaya et al. 3
Matsumoto et al. 11
Blackie et al. 2
Ishida et al. 9
Articles were reviewed according to the key components that are necessary for protocol design in determining safety and efficacy of a new treatment: objectives, trial design and methodology, patient group, inclusion criteria, exclusion criteria, outcome measures, treatment, and statistical considerations. We also evaluated clinical trials that had been registered at ClinicalTrials.gov if they included a summary of key trial design features. Further, a summary of key design features of the registered trials plus recommendations for future trials are suggested. 
The review and summary were also based on the committee's personal expertise, including experience in clinical trials in ocular disease and in MGD. The initial search was performed in March 2009 and updated in July 2009. Twenty-six eligible papers 1 26 were identified and reviewed. 
During the review, committee members found that the study investigators in the published papers often had not been explicit in describing their methods. As a result, the members, who conducted their reviews independently of one another, often interpreted the available data differently. The various interpretations are included in this summary. 
Few publications qualify as well-designed randomized controlled trials. Aside from the three studies graded level I, there are additional trials that were randomized and controlled. Some were open-label with very small sample sizes and seemed to be lacking information on the statistical planning of the study. We expect that these smaller open-label studies will continue to provide information that will lead to larger placebo-controlled double-masked randomized clinical trials. 
Key Topics to Be Addressed
Trial Objectives
Overview and Results.
A summary of key trial objectives and design for the 26 studies 1 26 reviewed is detailed in Table 2. Of the 26 published articles, 25 reported the use of a treatment for MGD. Of those 25, 24 were considered interventional studies. Twenty-two (84.6%) of the 26 studies had as their objective the assessment of efficacy of a therapeutic approach. Of the 26, 9 (34.6%) were noncomparative. Of the remaining studies, most compared the treatment approach of interest with a traditional or palliative treatment, such as use of hot compresses or artificial tears, whereas several studies used a nontreatment control group for comparison. 
Table 2.
 
Study Design and Descriptive Features
Table 2.
 
Study Design and Descriptive Features
Ref. First Author Evidence Level Title Journal/Year Treatment Interventional Efficacy Assessed? Comparative? Treatment Protocol Duration Prospective/Retrospective Randomized Masked Placebo or Control Subject Group (n, Group) Age Range
17 Perry HD I Efficacy of commercially available topical cyclosporine A 0.05% in the treatment of meibomian gland dysfunction Cornea. 2006 Feb;25(2):171–175 Y Y Y Y Topical 0.05% cyclosporin versus artificial tears 3 months Prospective Y Y-double Y n = 33 enrolled, n = 16 (12 completed) treatment (Tx), n = 17 (14 completed) placebo 18 and older, average age, not given
21 Schechter BA I Efficacy of topical cyclosporine for the treatment of ocular rosacea Adv Ther. 2009;26(6):651–659 Y Y Y Y Topical 0.05% cyclosporine versus artificial tears 3 months Prospective Y Y-double Y n = 37, n = 21 Tx, n = 16 placebo 18 and older, average age, ∼72.6 y
26 Yoo SE I The effect of low-dose doxycycline therapy in chronic meibomian gland dysfunction Korean J Ophthalmol. 2005;19(4):258–263 Y Y Y Y Systemic doxycycline 200 or 20 mg twice a day or placebo 1 month Prospective Y Y-patient Y n = 150 enrolled (n = 139 completed), n = 50 high dose, n = 50 low dose, n = 50 placebo 18 and older, average age, ∼47.2 y
8 Goto E I–II Low-concentration homogenized castor oil eye drops for noninflamed obstructive meibomian gland dysfunction Ophthalmology. 2002;109(11):2030–2035 Y Y Y Y Castor oil eye drop versus artificial tears 2 week washout, 1 month Prospective, cross-over Y Y-double Y n = 20, 10 per group 18 and older, average age, 52.1 y
20 Rubin M I–II Efficacy of topical cyclosporin 0.05% in the treatment of posterior blepharitis J Ocul Pharmacol Ther 2006;22:47–53 Y Y Y Y Topical 0.05% cyclosporin versus topical 0.3% tobramycin/0.1% dexamethasone 3 months Prospective Y N N n = 30, 15 per group 18 and older, average age, ∼51 y
10 Luchs J II Efficacy of topical azithromycin ophthalmic solution 1% in the treatment of posterior blepharitis. Adv Ther. 2008;25:858–870 Y Y Y Y Topical azithromycin 1% and hot compresses versus hot compresses alone 2 weeks Prospective Y N Y n = 21, n = 11 Tx and n = 10 placebo 18 and older, average age, 63.7 y
12 Matsumoto Y II The evaluation of the treatment response in obstructive meibomian gland disease by in vivo laser confocal microscopy Graefes Arch Clin Exp Ophthalmol. 2009;247(6):821–829 Y Y Y Y Lid hygiene, topical nonpreserved artificial tears, and 0.1% sodium hyaluronate eye drops, topical 0.5% levofloxacin, topical 0.1% fluorometholone, oral minocycline 100 mg twice a day versus lid hygiene, topical nonpreserved artificial tears and 0.1% sodium hyaluronate drops 12 weeks Prospective N N Y n = 27, n = 16 Tx, n = 11 control 18 and older, average age, ∼65 y
15 Olson MC II Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction Eye Contact Lens. 2003;29(2):96–99 Y Y Y Y Heated compress over experimental eye versus room temperature compress over control eye 5, 15, 30 minutes following application (same day) Prospective Y (contralateral eye) N Y n = 20 range, 26–59 y
16 Paugh JR II Meibomian therapy in problematic contact lens wear Optom Vis Sci. 1990;67(11):803–806 Y Y Y Y Lid hygiene, warm compresses twice daily for 2 weeks in one eye 2 weeks Prospective Y (contralateral eye) Y-examiner Y n = 21 range, 22–33 y
18 Pinna A II Effect of oral linoleic and gamma-linolenic acid on meibomian gland dysfunction Cornea. 2007;26(3):260–264 Y Y Y Y Oral linoleic acid and γ-linolenic acid once daily versus eyelid hygiene (warm eyelid compresses, eyelid massage, and eyelid margin scrubbing) versus both treatments 6 months Prospective Y Y-examiner Y n = 57 (49 completed), 19 per group 18 and older, average age, 50 y
19 Romero JM II Conservative treatment of meibomian gland dysfunction Eye Contact Lens. 2004;30(1):14–19 Y Y Y Y Lid hygiene, warm saline soaks, and non-preserved AT four times per day for 2 weeks and then twice per day for 4 weeks 6 weeks Prospective N Y-photo grader N n = 37 enrolled (26 completed) 18 and older, average age, 57 y
24 Souchier M II Changes in meibomian fatty acids and clinical signs in patients with meibomian gland dysfunction after minocycline treatment Br J Ophthalmol. 92(6):819–822 Y Y Y Y Lid hygiene versus oral minocycline 50 mg (patients nonresponsive to compress therapy received minocycline) 8 weeks Prospective N N Y n = 20 patients, 10 per group 18 and older, average age, 66 y
25 Yalcin E II N-acetylcysteine in chronic blepharitis Cornea. 2002;21:164–168 Y Y Y Y Topical steroid, topical antibiotic, artificial tears, warm compress, and oral n-acetylcysteine versus topical steroid, topical antibiotic, artificial tears, warm compress 3 months Prospective N N Y n = 40, n = 22 Tx, n = 18 control 18 and older, average age, ∼43 y
14 Mori A II–III Disposable eyelid-warming device for the treatment of meibomian gland dysfunction Jpn J Ophthalmol. 203;47(6):578–586 Y Y Y Y Application of Eye Warmer lid warming device versus untreated control 2 weeks Prospective N N (only interferometry grader was masked) Y n = 25 (17 treated, 8 untreated) 18 and older, average age, 53.6 y
1 Albietz JM III Effect of antibacterial honey on the ocular flora in tear deficiency and meibomian gland disease Cornea. 2006;25:1012–1019 Y Y N N Topical antibacterial honey 3 months Prospective N N Y n = 84 (49 completed), of those enrolled 15 MGD and 20 MGD with tear deficiency 18 and older, average age, ∼59 y
2 Blackie CA III Inner eyelid surface temperature as a function of warm compress methodology Optom Vis Sci. 2008;85(8):675–683 Y Y N Y External heat (warm compresses in several different ways) Same day study Same day study Y (contralateral eye) N Y n = 32 normal patients, group A (n = 10), B (n = 10) and C (n = 12) 18 and older, average age, 34.7 y
3 Cetinkaya A III Pediatric ocular acne rosacea: long-term treatment with systemic antibiotics Am J Ophthalmol. 2006;142(5):816–821 Y (case series) Y Y N Four pediatric cases: oral erythromycin or oral doxycycline in combination with topical methyl prednisolone and tobramycin 12–36 months Retrospective case series N N N n = 4 range, 4–12 y
4 Dougherty JM III The role of tetracycline in chronic blepharitis. Inhibition of lipase production in staphylococci Invest Ophthalmol Vis Sci. 1991;32(11):2970–2975 Y (clinical samples, no direct patient treatment) N N N Tetracycline solution incubated with tetracycline-sensitive strains (Staphylococcus epidermidis and Staphylococcus Aureus) and tetracycline-resistant strains (S. Epidermidis and S. Aureus) 24 hours Retrospective, sample collection N N N MKC n = 2 samples (isolates), Staphylococcus blepharitis, 2 samples (isolates) Not defined
5 Epstein GA III Combined excision and drainage with intralesional corticosteroid injection in the treatment of chronic chalazia Arch Ophthalmol. 1988;106(4):514–516 Y Y Y Y Initial warm eyelid soaks for chronic chalazia, eyelid cleaning, topical antibiotic-steroid combination. If no improvement within 2 weeks, surgical excision versus surgical excision and intratarsal injection of triamcinolone 6 weeks Initially retrospective, second part prospective N N N n = 298, first 146 patients: 88 surgery only, 58 surgery and steroids in combination. Additionally 152 patients with combined treatment. range, 6–88 y, most >50 y
6 Goto E III Improvement of tear stability following warm compression in patients with meibomian gland dysfunction Adv Exp Med Biol. 2002;506:1149–1152 Y Y Y N Warm compress therapy with a warm steam eye cup device applied for 5 minutes Same day study Same day study N N N n = 6 18 and older, average age, 45.8 y
7 Goto E III Treatment of non-inflamed obstructive meibomian gland dysfunction by an infrared warm compression device Br J Ophthalmol, 2002;86(12):1403–1407 Y Y Y N Infrared warm compression device 2 weeks Prospective N N N n = 37 18 and older, average age, ∼55 y
9 Ishida R III Tear film with “Orgahexa EyeMasks” in patients with meibomian gland dysfunction Optom Vis Sci. 2008;85(8):684–691 Y Y Y N Orgahexa EyeMask eye warmer mask 2 weeks Prospective N N Y n = 42, n = 20 Tx, n = 22 control 18 and older, average age, 54.5 y
11 Matsumoto Y III Efficacy of a new warm moist air device on tear functions of patients with simple meibomian gland dysfunction Cornea. 200625(6):644–650 Y Y Y Y Steam warmer four times daily versus traditional warm compresses twice daily 2 weeks Prospective N N Y n = 35, n = 15 MGD, n = 20 control 18 and older, average age, ∼58.8 y
13 Meisler DM III Oral erythromycin treatment for childhood blepharokeratitis J AAPOS. 2000;4(6):379–380 Y (case series) Y Y N Oral erythromycin, varying dose starting at 30 to 250 mg twice daily, depending on severity of disease, lid scrubbing twice a day Up to 12 months Prospective case series N N N n = 5 range, 4–9 y
22 Shine WE III Minocycline effect on meibomian gland lipids in meibomianitis patients Exp Eye Res. 2003;76(4):417–420 Y Y Y N Oral minocycline 50 mg/daily for 2 weeks followed by 100 mg/daily 3 months on Tx, 3 months off Tx Prospective N N N n = 10 N/A
23 Song CH III Enhanced secretory group II PLA2 activity in the tears of chronic blepharitis patients Invest Ophthalmol Vis Sci. 1999;40(11):2744–2748 7N N N N No treatment, normal tear PLA2 compared with blepharitis including MGD Same day study Same day study N N N n = 46, chronic blepharitis n = 36, controls n = 10 range, 30–40 y
Trial Design and Methodology
Overview and Results.
The MGD clinical studies primarily comprised trials with fewer than 40 participants and were of short (<3 months) duration. Although most were prospective, fewer than half used a randomized controlled design, and only three were double-masked. 
Twenty-four (92.3%) of the reviewed studies were interventional. Only one of those evaluated a surgical intervention, two evaluated a medical device, and the remainder assessed the efficacy of a supplement, drug intervention, or warm-compress therapy. 
The majority of the trials (21/26, 80.8%) had a prospective component; some of the studies also reported a preliminary retrospective evaluation. Of the 26 studies reviewed, 16 used either a control group (e.g., normal/healthy group) or a placebo group, whereas 7 were controlled but the control groups were not uniformly well defined. Important design factors such as washout periods and management of concurrent treatments were often not mentioned or clearly detailed. Ten (38.5%) of the studies were classified as randomized: Seven were randomized between groups and three by eye (contralateral eye receiving a different therapy). Descriptions of the method of randomization were omitted in all but one study. For example, it was unclear who performed the randomization or how randomization was performed. Only three (11.5%) of the studies were double-masked, whereas examiner or photography/interferometry grading masking was used in an additional five studies. 
Comments.
In general, although a significant majority of the studies included herein were prospective, there has been a dearth of prospective, randomized double-masked trials in the area of MGD. The studies have tended to be small and of short duration. Randomization techniques, inclusion and exclusion criteria, and clear choices for allowed or disallowed concurrent treatments have been mostly lacking. Adoption of more rigorous approaches to study design and biostatistical methods (including a clear approach on how to handle various endpoints) is a requirement for more definitive trial results in this area. 
Patient Group
Overview and Results.
Various definitions of MGD have been used in past clinical trials or observational studies, but such trials typically discuss selection of patients with chronic lid disease and use the terms posterior blepharitis or MGD, sometimes in association with anterior lid disease, including seborrhea. A concise description of definitions can be found in the Report on Definition and Classification. 
Most of the studies evaluated herein included adults older than 18 years, with the average age of the subjects approximately 50 to 60 years. Two studies evaluated children (4–12 years old), and the age of the sample was not reported in two studies (Table 2). Clinical testing for entry in the study or as an outcome was described in 23 of the 26 studies reviewed (Table 3). Of the 26 studies, 13 (50.0%) included symptoms as an entry criterion, diagnostic criterion, or an outcome. The symptoms described are those primarily associated with dry eye disease; only one (3.8%) study specifically examined MGD symptoms in the presence and absence of dry eye disease. 
Table 3.
 
Clinical Characteristics and Symptoms Assessed as Either Entry Criteria or Outcomes
Table 3.
 
Clinical Characteristics and Symptoms Assessed as Either Entry Criteria or Outcomes
Ref. First Author Evidence Level Title Clinical Testing Described/Performed Symptoms Transillumination (Obstruction and Dropout) MG Obstruction MG Secretions Interferometry Eyelid Temperature Lid Debris Lid Edema/Thickening Irregular Lid Lid Hyperemia/Erythema Lid Telangiectasia Conjunctival Papillae/Hyperemia TFBUT Corneal Staining Schirmer's Test Contact Lens Wear Acne Rosacea
17 Perry HD I Efficacy of commercially available topical cyclosporine A 0.05% in the treatment of meibomian gland dysfunction Yes Yes Yes (plugging) Yes Yes Yes Yes
21 Schechter BA I Efficacy of topical cyclosporine for the treatment of ocular rosacea Yes Yes Yes Yes Yes Yes Yes Yes
26 Yoo SE I The effect of low-dose doxycycline therapy in chronic meibomian gland dysfunction Yes Yes Yes Yes
8 Goto E I–II Low-concentration homogenized castor oil eye drops for noninflamed obstructive meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes Yes Yes
20 Rubin M I–II Efficacy of topical cyclosporin 0.05% in the treatment of posterior blepharitis Yes Yes Yes Yes Yes Yes Yes
10 Luchs J II Efficacy of topical azithromycin ophthalmic solution 1% in the treatment of posterior blepharitis. Yes Yes Yes Yes Yes Yes Yes
12 Matsumoto Y II The evaluation of the treatment response in obstructive meibomian gland disease by in vivo laser confocal microscopy Yes Yes Yes Yes Yes Yes Yes
15 Olson MC II Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction Yes Yes Yes Yes Yes Yes
16 Paugh JR II Meibomian therapy in problematic contact lens wear Yes Yes Yes Yes Yes Yes
18 Pinna A II Effect of oral linoleic and gamma-linolenic acid on meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes Yes Yes
19 Romero JM II Conservative treatment of meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes Yes Yes
24 Souchier M II Changes in meibomian fatty acids and clinical signs in patients with meibomian gland dysfunction after minocycline treatment Yes Yes Yes Yes Yes Yes Yes
25 Yalcin E II N-acetylcysteine in chronic blepharitis Yes Yes Yes
14 Mori A II–III Disposable eyelid-warming device for the treatment of meibomian gland dysfunction Yes Yes Yes Yes Yes
1 Albietz JM III Effect of antibacterial honey on the ocular flora in tear deficiency and meibomian gland disease Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
2 Blackie CA III Inner eyelid surface temperature as a function of warm compress methodology Yes
3 Cetinkaya A III Pediatric ocular acne rosacea: long-term treatment with systemic antibiotics Yes Yes Yes Yes Yes Yes
4 Dougherty JM III The role of tetracycline in chronic blepharitis. Inhibition of lipase production in staphylococci No
5 Epstein GA III Combined excision and drainage with intralesional corticosteroid injection in the treatment of chronic chalazia
6 Goto E III Improvement of tear stability following warm compression in patients with meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes
7 Goto E III Treatment of non-inflamed obstructive meibomian gland dysfunction by an infrared warm compression device Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
9 Ishida R III Tear film with “Orgahexa EyeMasks” in patients with meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes
11 Matsumoto Y III Efficacy of a new warm moist air device on tear functions of patients with simple meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes
13 Meisler DM III Oral erythromycin treatment for childhood blepharokeratitis Yes Yes Yes Yes
22 Shine WE III Minocycline effect on meibomian gland lipids in meibomianitis patients Yes Yes Yes
23 Song CH III Enhanced secretory group II PLA2 activity in the tears of chronic blepharitis patients No
Total (n) 24 13 8 12 14 5 3 1 7 4 7 6 3 14 15 11 2 3
% (of 26) 92.3% 50.0% 30.8% 46.2% 53.8% 19.2% 11.5% 3.8% 26.9% 14.4% 26.9% 23.1% 11.5% 53.8% 57.7% 42.3% 7.7% 11.5%
MGD was clinically defined most frequently through the evaluation of meibomian gland obstruction and/or gland dropout and abnormal gland secretions. Of the 26 papers, 12 (46.2%) reported meibomian gland obstruction, 14 (53.8%) contained assessments of secretions, and 8 (30.8%) involved transillumination of the glands or meibography. Descriptions of lid abnormalities including erythema, irregularity of lid margins, lid margin thickening, and/or telangiectasia were included in 10 (38.5%) studies. Four (15.3%) papers specifically eliminated patients with evidence of lid inflammation, but did not define the symptom further. 
It was of interest to note that tests typically performed in dry eye clinical trials, such as fluorescein tear break-up time (FTBUT), conjunctival and corneal staining, and Schirmer's test, were included in only approximately 5% of the studies in defining the MGD subjects. Most studies, however, did evaluate these signs at baseline and in follow-up visits, and such signs were often used as outcome measures (Table 3). FTBUT was the most frequently reported clinical test in the studies evaluated (14/26, 53.8%). 
Nearly all studies excluded subjects who had recent eye surgery or were current contact lens (CL) wearers, except for one study on MGD in association with CL intolerance and one study in which contact lens wear was allowed. Three studies specifically targeted MGD with concurrent skin disease, such as acne rosacea. 
Comments.
In summary, past MGD clinical trials did not have a uniform way of defining the study population, although symptoms and changes in the lid, especially plugging and abnormal secretions, were the most common clinical characteristics used to define the clinical sample of patients. Of note, dry eye disease was not typically either specifically included or excluded in selecting patients other than in selecting subjects with symptoms. Signs of dry eye disease were not generally used as selection criteria, although they were frequently included in the study design as outcome measures. 
Inclusion Criteria
Overview.
In approximately half of the identified studies, adult patients with a known history of MGD (12/26, 46.1%) or chronic blepharitis were enrolled, whereas specific eyelid findings were reported as entry qualifications for others. In three of the studies, the patients had to have clinical evidence of facial acne rosacea to be included. A previously established classification system was used in three studies, 27 whereas in the remaining studies, no specific published criteria were routinely used. Several studies reported no specific inclusion criteria other than a diagnosis of MGD or posterior blepharitis. How these diagnoses were determined was not disclosed. A list of the details related to inclusion in the 26 studies can be seen in Tables 4 and 5
Table 4.
 
Inclusion and Exclusion Criteria
Table 4.
 
Inclusion and Exclusion Criteria
Ref. First Author Evidence Level Title Inclusion Criteria Exclusion Criteria
17 Perry HD I Efficacy of Commercially Available Topical Cyclosporine A 0.05% in the Treatment of Meibomian Gland Dysfunction Adult patients with slit lamp diagnosis of meibomian gland dysfunction, with an OSDI score of >12. Contact lens wear, active ocular disease other than blepharitis, surgery within past 3 months, active ocular allergy, used isotretinoin within the past 6 months, or have autoimmune disease requiring treatment.
21 Schechter BA I Efficacy of Topical Cyclosporine for the Treatment of Ocular Rosacea Adult patients with rosacea-associated eyelid and corneal changes. Eyelid defects, lagophthalmos, active ingredient sensitivity, pregnant/nursing mothers.
26 Yoo SE I The Effect of Low-Dose Doxycycline Therapy in Chronic Meibomian Gland Dysfunction Adult patients with newly diagnosed chronic meibomian gland dysfunction with grade 2 or worse meibomian gland destruction or meibomian gland orifice obstruction, and whose symptoms failed to improve despite warm compression, lid massage, lid scrub, and topical eye drops or ointment therapy for more than 2 months. Topical therapy within 2 weeks before the beginning of the study.
8 Goto E I–II Low-Concentration Homogenized Castor Oil Eye Drops for Noninflamed Obstructive Meibomian Gland Dysfunction Consecutive series of adult MGD patients nonresponsive to conventional therapy, which could include lid hygiene and topical artificial tears, antibiotics (oral/topical), and/or corticosteroids. Anterior blepharitis of more than moderate severity, infectious conjunctivitis, MGD with acute inflammation, seborrheic MGD. No patients wore CLs; unclear if this was an exclusion criterion.
20 Rubin M I–II Efficacy of Topical Cyclosporin 0.05% in the Treatment of Posterior Blepharitis Consecutive adult patients presenting with posterior blepharitis defined as lid erythema and MG telangiectasia. Current punctal plugs, doxycycline, steroids, women of childbearing age with no contraception.
10 Luchs J II Efficacy of Topical Azithromycin Ophthalmic Solution 1% in the Treatment of Posterior Blepharitis Adult patients with a diagnosis of poster blepharitis by a qualified ophthalmologist; patients must have a grade of at least 2 of lid redness/swelling and gland plugging. Eyelid structural abnormalities, active inflammation, fungal or viral infection, ocular surgery in the past 90 days, including LASIK or glaucoma surgery.
12 Matsumoto Y II The Evaluation of the Treatment Response in Obstructive Meibomian Gland Disease by in Vivo Laser Confocal Microscopy Consecutive adult patients with severe obstructive MGD associated with lid inflammation. History of Sjögren's syndrome; Stevens-Johnson syndrome; chemical, thermal, or radiation injury; or any ocular surgery or procedure that would create an ocular surface problem. History of contact lens use.
15 Olson MC II Increase in Tear Film Lipid Layer Thickness Following Treatment with Warm Compresses in Patients with Meibomian Gland Dysfunction Consecutive adult patients with symptoms of ocular dryness were enrolled with the following criteria: (1) subjective dry eye status determined by a score of ≥6 on dry eye symptoms questionnaire; (2) meibomian gland obstruction determined by SLE; (3) TFLLT baseline of ≤90 nm; as well as fluorescein tear breakup time and Schirmer results of ≤10 mm/5 min. Exclusions were not defined other than evidence of ocular disease.
16 Paugh JR II Meibomian Therapy in Problematic Contact Lens Wear Consecutive adult contact lens wearers with (1) minimal or transient symptoms of dryness, (2) cloudy or absent MG secretions, and (3) CL intolerance not related to lens or solution parameters. History of ocular trauma or surgery, use of tear-influencing medications, systemic connective tissue disease, ocular conditions (blepharitis, meibomitis, or any anterior segment disease), contact lens intolerance due to poor lens fit, deposits, care system hypersensitivity.
18 Pinna A II Effect of Oral Linoleic and Gamma-Linolenic Acid on Meibomian Gland Dysfunction Group 4 and 5 of McCulley Classification system for MGD (McCulley et al. Classification of chronic blepharitis. 27 Infectious keratoconjunctivitis, inflammatory disease unrelated to MGD, Schirmer I test result <10 mm/5 min, concomitant ocular disease, previous ocular surgery, alterations of the lacrimal drainage system, concomitant topical ophthalmic medic ations, topical ophthalmic steroids taken during the 4 weeks before the study; treatment with systemic drugs affecting.
19 Romero JM II Conservative Treatment of Meibomian Gland Dysfunction Adult patients with (1) a chief complaint of MGD (ocular discomfort assessed by questionnaire) and (2) diagnosis of MGD with two or more of the following: redness or thickening of the lid margin, telangiectasia, reduced or no secretions, poor quality secretions, gland capping. Current use of treatments for blepharitis, current use of topical or systemic steroids, topical or systemic antibiotics, or topical or systemic antimetabolites, history of contact lens wear, history of eyelid surgery, presence of any ocular disease provoking dry eye syndrome and
24 Souchier M II Changes in Meibomian Fatty Acids and Clinical Signs in Patients with Meibomian Gland Dysfunction after Minocycline Treatment Adult patients with chronic posterior blepharitis defined by redness, thickening, or irregularity of the lid margin, telangiectasia, reduced or no secretions, poor-quality secretions, gland capping, and/or MG metaplasia. Smokers, contact lens wearers, and diabetic patients.
25 Yalcin E II N-Acetylcysteine in Chronic Blepharitis Adult clinic patients with chronic posterior blepharitis. Eye disorders that could affect the ocular surface (e.g. infectious conjunctivitis), excessive meibomian lipid secretion, ≤10 mm by Schirmer II, and contact lens use.
14 Mori A II–III Disposable Eyelid-Warming Device for the Treatment of Meibomian Gland Dysfunction Short term efficacy study: adult patients with TBUT ≤5 s and dry eye symptoms. Therapeutic study: adult patients with TBUT ≤5 s, MGD (not defined), and dry eye symptoms. Exclusions were not defined.
1 Albietz JM III Effect of Antibacterial Honey on the Ocular Flora in Tear Deficiency and Meibomian Gland Disease Consecutive adult dry eye patients subsequently classified into four groups: non-Sjögren's tear deficienc y, Sjögren's tear deficiency, MGD (posterior lid margin thickening, irregularity, telangiectasia, gland loss, plugging and capping, and abnormal MG secretions), and MGD plus tear deficiency. Contact lens wear, eye surgery, punctal occlusion, and use of eye drops other than artificial tears within the past 3 months, ocular infection, pregnancy/nursing, changes in systemic medications altering the tear film, uncontrolled systemic disease.
2 Blackie CA III Inner Eyelid Surface Temperature as a Function of Warm Compress Methodology Healthy adult individuals. Ocular adnexal disease that would interfere with warm compress application.
3 Cetinkaya A III Pediatric Ocular Acne Rosacea: Long-Term Treatment with Systemic Antibiotics Rosacea patients younger than 12 years of age, with or without obvious skin involvement, who were having active inflammation with ocular discomfort, photophobia, and red eyes, despite topical steroid, antibiotic or Exclusions were not defined.
4 Dougherty JM III The Role of Tetracycline in Chronic Blepharitis: Inhibition of Lipase Production in Staphylococci Isolates from patients with meibomian keratoconjunctivitis and staphylococcal blepharitis; patients not clinically defined. Exclusions were not defined.
5 Epstein GA III Combined Excision and Drainage with Intralesional Corticosteroid Injection in the Treatment of Chronic Chalazia Adult and pediatric patients undergoing surgical excision of chronic chalazia; patients not clinically defined. Exclusions were not defined.
6 Goto E III Improvement of Tear Stability Following Warm Compression in Patients with Meibomian Gland Dysfunction Consecutive adult patients with noninflamed obstructive MGD. Anterior blepharitis of more than moderate severity, infectious conjunctivitis, MGD with acute inflammation, meibomitis, seborrheic MGD.
7 Goto E III Treatment of Non-Inflamed Obstructive Meibomian Gland Dysfunction by an Infrared Warm Compression Device Consecutive adult patients with MGD unresponsive to conventional treatment, which could include lid hygiene and topical artificial tears, antibiotics (oral/topical) and/or corticosteroids. Anterior blepharitis of moderate or greater severity, infectious conjunctivitis, occluded punctum, contact lens wear, best corrected acuity <1.0 logMAR, “obvious” eyelid skin abnormalities (atopic dermatitis).
9 Ishida R III Tear Film with “Orgahexa EyeMasks” in Patients with Meibomian Gland Dysfunction Adult patients with simple MGD defined as (1) occluded MG orifices, (2) cloudy secretions, (3) keratinization and/or mucocutaneous junction displacement, and (4) noninflamed lid margins. Exclusions were not defined.
11 Matsumoto Y III Efficacy of a New Warm Moist Air Device on Tear Functions of Patients with Simple Meibomian Gland Dysfunction Adult patients with simple MGD defined as (1) occluded MG orifices, (2) cloudy secretions, (3) keratinization and/or mucocutaneous junction displacement, and (4) noninflamed lid margins. Exclusions were not defined.
13 Meisler DM III Oral Erythromycin Treatment For Childhood Blepharokeratitis Children with chronic lid margin inflammation (lid redness and thickening). Exclusions were not defined.
22 Shine WE III Minocycline Effect on Meibomian Gland Lipids in Meibomianitis Patients Patients were selected based on clinical appearance and categorized as having acne rosacea with or without meibomianitis, or seborrheic blepharitis alone. 27 Exclusions were not defined.
23 Song CH III Enhanced Secretory Group II PLA2 Activity in the Tears of Chronic Blepharitis Patients Adult patients with the presence of one or more of the signs and symptoms of blepharitis for more than 6 months, categorized into six blepharitis groups. 27 Exclusions were not defined.
Table 5.
 
List and Frequency of Reported Criteria (All Studies Represented)
Table 5.
 
List and Frequency of Reported Criteria (All Studies Represented)
A. Inclusion Criteria Frequency (%)
Age of Participants
Adult patients 22/26 (84.6)
Pediatric patients 2/26 (2.7)
Adult and pediatric patients 1/26 (3.8)
Not mentioned 1/26 (3.8)
Symptomatology
Ocular Surface Disease Index questionnaire 1/26 (3.8)
Symptoms fail to improve with conventional therapy 3/26 (11.5)
Discomfort or foreign body sensation 2/26 (7.7)
Eye redness 1/26 (3.8)
Photophobia 1/26 (3.8)
Ocular dryness 3/26 (11.5)
Contact lens intolerance 1/26 (3.8)
Ocular Symptoms Scale 1/26 (3.8)
Lid Margin Findings
Previous or current diagnosis of MGD or posterior blepharitis 12/26 (46.1)
Posterior lid margin erythema or hyperemia 5/26 (19.2)
Eyelid edema 1/26 (3.8)
Lid margin thickening or irregularity 4/26 (15.4)
Meibomian gland orifice plugging 8/26 (30.8)
Cloudy, yellow, or frothy meibomian gland secretions 5/26 (19.2)
Lid margin telangiectasia 4/26 (15.4)
Meibomian gland capping 3/26 (11.5)
Meibomian gland loss/destruction 5/26 (19.2)
Chalazia 1/26 (3.8)
Eyelid inflammation (not defined) 2/26 (7.7)
Eyelid noninflammation 2/26 (7.7)
Ocular Surface Findings
Rosacea-associated eyelid and corneal changes 3/26 (11.5)
Tear Film Findings
Tear interferometry 1/26 (3.8)
TBUT<10 seconds 1/26 (3.8)
TBUT<5 seconds 1/26 (3.8)
Schirmer's test <10 seconds 1/26 (3.8)
Existing Classification Scheme
McCulley Classification system for MGD 27 2/26 (7.7)
B. Exclusion criteria 1,2,6 8,10,12,14 21,24,26 Frequency (%)
Contact lenses use 10/17 (58.8)
History of ocular surgery 7/17 (41.2)
Eye disorders affecting the ocular surface 6/17 (35.3)
Meibomitis, seborrheic MGD, and excessive meibomian lipid secretion 4/17 (27.5)
Topical medical therapy (of any kind) 4/17 (27.5)
Infectious conjunctivitis 4/17 (27.5)
Systemic diseases affecting the ocular surface 4/17 (27.5)
Topical or systemic steroids use 3/17 (17.6)
Active ocular disease 3/17 (17.6)
Pregnancy or childbearing age without contraception 3/17 (17.6)
Stevens-Johnson syndrome 3/17 (17.6)
Chemical, thermal, or radiation injury 3/17 (17.6)
Decreased reflex tearing (<10 mm/5 min Schirmer test result) 2/17 (11.8)
Diabetes 2/17 (11.8)
Current treatment for blepharitis 2/17 (11.8)
Topical or systemic antibiotics 2/17 (11.8)
Alteration of lacrimal drainage system 2/17 (11.8)
Drugs affecting tearing 2/17 (11.8)
Sjögren's syndrome 2/17 (11.8)
MGD with acute inflammation 2/17 (11.8)
Anterior blepharitis with more than moderate severity 2/17 (11.8)
Active ocular allergy 2/17 (11.8)
Inflammatory diseases unrelated to MGD 2/17 (11.8)
Ocular adnexal pathology interfering with warm compress application 2/17 (11.8)
Lid structural abnormality 2/17 (11.8)
Topical or systemic antimetabolites 1/17 (5.9)
Eyelid surgery 1/17 (5.9)
Use of isotretinoin within the past 6 months 1/17 (5.9)
Autoimmune disease requiring treatment 1/17 (5.9)
Smokers 1/17 (5.9)
Punctal plugs 1/17 (5.9)
Anterior chamber inflammation 1/17 (5.9)
Glaucoma 1/17 (5.9)
Anterior segment diseases 1/17 (5.9)
Best corrected visual acuity <1.0 logMAR 1/17 (5.9)
Lid skin disease 1/17 (5.9)
Cicatricial conjunctival diseases 1/17 (5.9)
Sensitivity to study medication 1/17 (5.9)
Results.
In most of the studies, adult patients between 18 and 70 years of age with chronic signs and symptoms of blepharitis or MGD were enrolled. In three of the studies (two prospective and one retrospective case series), children were included. The age of the participants was not mentioned in two studies. In three studies, treatment with warm compresses and lid scrubbing had to fail for the patient to be included. 
Several parameters were used, including symptomatology, lid margin, and ocular surface findings by slit lamp examination and dry eye findings, as follows:
  •  
    Symptomatology. No specific MGD questionnaire has been developed or validated to date. Only seven studies (7/26, 26.9%) used single or multiple patient symptoms or questionnaires specifically as inclusion factors, whereas three studies cited failure of conventional therapy. (It is unclear how failure was assessed; some examples of therapy were provided.) Published studies generally report on main symptom types: discomfort, visual disturbance, and ocular appearance. The main symptoms reported by patients in questionnaires or interviews in the studies assessed included dryness (6/26, 23.1%) and discomfort or foreign body sensation (6/26, 23.1%). These symptoms were usually graded subjectively as mild, moderate, or severe. Few studies applied questionnaires (mostly questionnaires used in dry eye studies) at entry into as well as exit from the study, but in general they did not require a certain level of symptomatology as a specific entry criterion.
  •  
    Lid margin findings. Lid margin signs are the most frequently reported inclusion criteria. Signs included posterior lid margin erythema/hyperemia, lid margin thickening/irregularity, meibomian gland orifice plugging, turbidity of meibomian gland secretions, lid margin telangiectasia, and meibomian gland plugging. Signs were mainly graded as mild, moderate, or severe. Meibomian gland plugging was the single most common lid margin finding to be used as an inclusion criterion (8/26, 30.8%).
  •  
    Ocular surface findings. Findings included, but were not limited to, corneal infiltrates, neovascularization, bulbar conjunctival hyperemia, and tarsal conjunctival papillae. Studies that involved patients with ocular rosacea listed ocular surface findings as inclusion criteria.
  •  
    Dry eye findings. It is notable that dry eye signs were inclusion criteria in several of the papers. They were used either to define groups or as an indicator of tear film stability. Dry eye signs included a low tear film breakup time (TFBUT), presence and degree of corneal staining using fluorescein, presence and degree of conjunctival staining as determined with rose bengal or lissamine green, and Schirmer's test for measuring aqueous tear production and flow.
Comments.
Except for the lid margin findings determined by slit lamp examination, there seemed to be no specific and consistent inclusion criteria for blepharitis or MGD, which are different from the criteria commonly used in dry eye studies. This deficiency is perhaps not unexpected, as the overlap between MGD and dry eye has yet to be fully understood. In general, symptoms associated with MGD may be related to altered tear film stability and evaporative dry eye. The most commonly used inclusion criteria in MGD studies to date are symptoms of discomfort/foreign body sensation and signs of meibomian gland plugging, expressibility of the meibomian glands, and quality of gland secretions. 
Exclusion Criteria
Overview.
The exclusion criteria are reported in 17 (65.4%) studies (Tables 4, 5B). The exclusion criteria varied according to the objectives of each trial and the sample of patients included. It is therefore possible to classify the papers in four different types, divided according to the purpose of the trial, the terminology used by the authors, and the patients included:
  1.  
    Obstructive meibomian gland dysfunction (nine papers)
  2.  
    Posterior blepharitis (six papers)
  3.  
    Seborrhea with secondary meibomianitis (one paper)
  4.  
    Meibomian therapy in CL wearers (one paper).
Furthermore, it is possible to classify the exclusion criteria reported into three different categories: (1) ocular disease-related, (2) iatrogenic, and (3) systemic disease-related. 
Results.
The 26 papers were reviewed for exclusion criteria, and in the 17 papers that included a description of exclusion criteria, 39 distinct criteria were reported. The most frequently were CL use (10/17, 58.8%), history of ocular surgery (7/17, 41.2%), and eye disorders affecting the ocular surface (6/17, 35.3%). The entire list of exclusion criteria and their frequency of citation is shown in Table 5B. 
Considering the different goals of the studies included and the terminology used by the authors the exclusion criteria can be grouped as follows:
  1.  
    Papers about obstructive MGD treatment. In this group, three studies included patients with noninflamed obstructive MGD, one included patients with obstructive MGD and lid inflammation, three included MGD patients, and two described “simple” MGD. Seven studies evaluated different types of warm compress and lid hygiene for treatment of MGD. In these, the exclusion criteria were anterior blepharitis of more than moderate severity; infectious conjunctivitis; meibomitis; seborrheic MGD, and excessive meibomian lipid secretion; ocular adnexal pathology interfering with warm compress application; CL use; diabetes; current use of treatments for blepharitis; eyelid surgery; presence of dry eye conditions other than MGD; history of Stevens-Johnson syndrome; chemical, thermal and radiation injury; topical drugs; and surgery or procedures that might create ocular surface problems.
  2.  
    Papers about posterior blepharitis (a term often used synonymously with MGD in the literature). This group included six studies that evaluated the effect of different types of antibiotic and anti-inflammatory pharmacologic treatment of posterior blepharitis. All patients had, to some extent, an inflammatory condition. The exclusion criteria in this group of studies were topical therapy within 2 weeks before the beginning of the study, systemic treatments with other antibiotic or anti-inflammatory agents, plugs, CL wear, active ocular diseases other than blepharitis, lid abnormalities, fungal or viral infections, ocular surface surgery or other inflammatory ocular surface diseases such as Sjögren's syndrome and Steven-Johnson syndrome, and thermal, chemical, or radiation injury.
  3.  
    Seborrhea with secondary meibomianitis. One study is included in this group, a trial studying the effect of the ω-6 fatty acid γ-linolenic acid on MGD patients. The reported exclusion criteria were infectious keratoconjunctivitis; inflammatory disease unrelated to MGD; Schirmer I test <10 mm/5 minutes; concomitant ocular pathologies; a history of ocular surgery; alterations of the lacrimal drainage system; concomitant topical ophthalmic medications; topical ophthalmic steroids taken during the 4 weeks before the study; treatment with systemic drugs affecting tearing, pregnancy, or diabetes; and other systemic, neurologic, or dermatologic disorders affecting the health of the ocular surface.
  4.  
    Meibomian therapy in CL wearers. The single paper in this group discussed the treatment of MGD in CL wearers. The exclusion criteria in this article were a history of ocular trauma or surgery; use of tear-influencing medication (e.g., antihistamine, antianxiety, anticholinergic); systemic connective tissue disease; ocular conditions such as blepharitis, meibomianitis, and any anterior segment disease; CL intolerance related to lens fit; the presence of deposits; and known care system hypersensitivity or toxicity.
The 39 exclusion criteria can be divided into three categories: (1) ocular disease–related, (2) iatrogenic, or (3) systemic disease-related. Table 6 describes the systemic disease–related exclusion criteria. 
  1.  
    Exclusion criteria concerning the presence or history of ocular disease was the most frequently reported (20/39 criteria; 51.3%). Among these, three (7.7%) criteria described the presence of meibomian gland dysfunction, defined by the authors as seborrhea and/or acute or chronic meibomitis. These three exclusion criteria were reported in four papers regarding the treatment of obstructive MGD and in one paper about MGD therapy in CL wearers.
  2.  
    Exclusion criteria related to iatrogenic events was the second most common category, with 13 of 39 exclusion criteria (33.3%) falling in this category. Among these, medical therapy, surgical therapy, use of CLs or punctal plugs, and smoking are included.
  3.  
    The last group of exclusion criteria refers to the presence of systemic diseases, pregnancy or being of childbearing age without contraception, and known sensitivity to study drugs. This group of exclusion criteria included 6 of the 39 criteria identified (15.4%).
Table 6.
 
Categories of 39 Exclusion Criteria in 17 Studies*
Table 6.
 
Categories of 39 Exclusion Criteria in 17 Studies*
Frequency (%)
Ocular Diseases (20/39; 51.3%)
Eye disorders that affect the ocular surface 6/17 (35.3)
Meibomitis, seborrheic MGD, and excessive meibomian lipid secretion* 4/17 (23.5)
Infectious conjunctivitis 4/17 (23.5)
Active ocular disease 3/17 (17.6)
Stevens-Johnson syndrome 3/17 (17.6)
Meibomitis and seborrheic MGD† 3/17 (17.6)
Highly decreased reflex tearing <10 mm 2/17 (11.8)
MGD with acute inflammation† 2/17 (11.8)
Anterior blepharitis of more than moderate severity 2/17 (11.8)
Active ocular allergy 2/17 (11.8)
Inflammatory diseases unrelated to MGD 2/17 (11.8)
Ocular adnexal pathology interfering with warm compress application 2/17 (11.8)
Lid structural abnormality 2/17 (11.8)
Alteration of lacrimal drainage system 2/17 (11.8)
Anterior chamber inflammation 1/17 (5.9)
Glaucoma 1/17 (5.9)
Anterior segment diseases 1/17 (5.9)
Best corrected visual acuity <1.0 logMAR 1/17 (5.9)
Cicatricial conjunctival diseases 1/17 (5.9)
Lid skin disease 1/17 (5.9)
Iatrogenic (13/39; 33.3%)
Contact lens use 10/17 (58.8)
Ocular surgery 7/17 (41.2)
Topical medical therapy (of any kind) 4/17 (23.5)
Topical or systemic steroids 3/17 (17.6)
Chemical, thermal, radiation injury 3/17 (17.6)
Current treatment for blepharitis 2/17 (11.8)
Topical or systemic antibiotics 2/17 (11.8)
Drugs affecting tearing 2/17 (11.8)
Topical OD systemic antimetabolites 1/17 (5.9)
Eyelid surgery 1/17 (5.9)
Use of isotretinoin within the past 6 month 1/17 (5.9)
Smoking 1/17 (5.9)
Plugs 1/17 (5.9)
Systemic Diseases (6/39; 15.4%)
Systemic, neurologic, dermatologic diseases affecting ocular surface 4/17 (23.5)
Pregnancy/child bearing age without contraception 3/17 (17.6)
Diabetes 2/17 (11.8)
Sjögren's syndrome 2/17 (11.8)
Autoimmune disease requiring treatment 1/17 (5.9)
Sensitivity to study medication 1/17 (5.9)
Comments.
Inclusion and exclusion criteria define the patient sample of all types of studies. In studies of MGD, it is crucial to state how MGD is diagnosed, use consistent terminology, and carefully define clinical characteristics. Dividing exclusion criteria into three categories (ocular disease-related, iatrogenic, and systemic disease-related) can help in producing a logical list of eligible and ineligible subjects, suitable for each trial. Further consistency in entry and exclusion criteria in clinical trials related to MGD is needed. 
Outcome Measures (Endpoints): Primary and Secondary
Overview.
Many of the studies we evaluated were relatively small in sample size and were exploratory in nature. Therefore, several clinical variables were regarded as outcome variables, without identifying specific primary and secondary outcomes. The outcomes, therefore, can be grouped on the basis of clinical appearance. The main clinical characteristics can be categorized as follows:
  •  
    Symptoms (dry eye or blepharitis) and visual disturbance (fluctuation)
  •  
    Eyelid assessment (lid margin injection/hyperemia, blocked meibomian glands, debris on lashes, tarsal and lid margin telangiectasia, and edema)
  •  
    Tear film parameters (TFBUT, interferometry, aqueous production, and osmolarity)
  •  
    Ocular surface involvement (corneal and conjunctival staining)
  •  
    Inflammation of the ocular surface (injection)
  •  
    Abnormal meibum (expressibility, quantity, and quality)
  •  
    Bacterial involvement.
Defining the characteristics in this manner allows the outcome measures to be better contextualized, given the diversity of the disease. The individual papers were categorized according to the characteristics, and the main outcome measures are described in Table 7. All relevant studies independent of their level of evidence were included. 
Table 7.
 
Clinical and Symptom Outcomes
Table 7.
 
Clinical and Symptom Outcomes
Ref. First Author Eyelids Meibomian Glands Inflammation Ocular Surface Microbial Tear Symptoms Other
Lid Margin Appearance Lid Margin Injection/Erythema/Redness Tarsal Telangiectasia Edema Debris Inflammatory Cell Density Temperature Papillary Hypertrophy Expression/Secretion Destruction (Meibography) Obstruction/Plugging Meibum Composition Improvement Recurrence Conjunctival Hyperemia Conjunctival Papillae Conjunctival Staining Corneal Staining Corneal Neovascularization Change In Flora Lipase Production (In Vitro) Bacterial Growth Inhibition (In Vitro) TBUT Schirmer I (w/wo Anesthesia) Mucous Fern Test Evaporation Rate Lipid Layer Interference Pattern/Thickness Lysozyme Levels or PLA2 Type Activity Foam (Tear Meniscus) General Ocular Face Scores Progression of Post-Surgical Healing Overall Disease Improvement Safety
17 Perry HD Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes w a Yes
21 Schechter BA Yes Yes Yes Yes w a Yes
26 Yoo SE Yes Yes Yes Yes wo a Yes
8 Goto E Yes Yes Yes Yes Yes Yes Yes
20 Rubin M Yes Yes Yes Yes Yes Yes Yes
10 Luchs J Yes Yes Yes Yes Yes Yes Yes
12 Matsumoto Y Yes Yes Yes Yes Yes Yes Yes Yes Yes wo a Yes
15 Olson MC Yes
16 Paugh JR Yes
18 Pinna A Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes (OSDI)
19 Romero JM Yes Yes Yes
24 Souchier M Yes Yes Yes Yes
25 Yalcin E Yes Yes Yes
14 Mori A Yes Yes Yes Yes
1 Albietz JM Yes
2 Blackie CA Yes
3 Cetinkaya A Yes Yes Yes
4 Dougherty JM Yes Yes Yes
5 Epstein GA Yes Yes Yes Yes Yes Yes
6 Goto E
7 Goto E Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
9 Ishida R Yes Yes Yes Yes Yes wo a Yes Yes
11 Matsumoto Y Yes Yes Yes Yes Yes wo a Yes Yes
13 Meisler DM Yes Yes
22 Shine WE Yes
23 Song CH Yes
In these studies, it can be assumed that all types of MGD are more or less chronic, although chronicity was not explicitly described in all cases (none were described as acute). Future studies may include more specific terminology on the basis of the terminology proposed in the Report on Definition and Classification. 
Results.
While several outcome measures were used, a likely reflection of the diversity of the disease, the methods used to grade change varied. In general, there appeared to be no distinction between primary and secondary endpoints. In studies in which scales were defined, categorical or ordinal scales were often used (e.g., yes/no; graded 0–4; or none, mild, moderate, or severe). 
The changes in outcome measures can be summarized as follows:
  •  
    Symptoms (improvement in total ocular symptom score, specific dry eye symptoms, reduction of visual fluctuation, and increase in comfortable CL wearing time)
  •  
    Eyelid assessment (reduction in graded severity)
  •  
    Tear film parameters (increased aqueous production TBUT and improvement in tear lipid layer interference)
  •  
    Ocular surface involvement (reduction in graded severity of staining)
  •  
    Inflammation of the ocular surface (reduction in graded severity injection)
  •  
    Abnormal meibum (improved expressibility, quantity, and quality)
  •  
    Bacterial involvement (reduction of bacterial load)
  •  
    Improvement/reduction of the recurrence of inflammation (chronic lid margin, corneal, and chronic granulomatous disease).
The most frequently reported outcome measures in the 26 papers included ocular symptoms (14, 53.8%), TBUT (14, 53.8%), meibomian gland secretion and expression (9, 34.6%), Schirmer I (10, 38.5%), corneal staining (8, 30.8%), meibomian gland obstruction (6, 23.1%), eyelids (5, 19.2%), and lipid layer interference (5, 19.2%). 
Outcome measures associated with signs and symptoms of dry eye and not necessarily specific to MGD were used in most of the publications. Parameters related to evaluation of the eyelids have been more frequently used in recent years, and direct assessments of the glands have increasingly been used as outcome measures in the more recent papers. 
There were no major differences in the choice of outcome measures when the evaluation was limited to papers of evidence level I or II. 
Comment.
The importance of signs and symptoms of dry eye appears evident in the outcome measures described in the literature. Specific symptom surveys for MGD as well as uniform grading of eyelid margin findings are needed. It is somewhat surprising that the different outcome measures selected in different trials appeared not to be associated with the different manifestations of MGD, but instead were evenly distributed, independent of how the disease was expressed. 
Treatment
Overview.
Twenty-three of the 26 eligible studies had sufficient information to be assessed under the following categories (Table 2):
  •  
    Treatment type (pharmacological, homeopathic, surgical, and external)
  •  
    Dose regimen
  •  
    Concurrent treatment
  •  
    Control treatment
  •  
    Duration
  •  
    Washout
  •  
    Follow-up.
Results.
Pharmacologic test treatments used in 11 (42.3%) of the 26 studies included systemic or topical macrolide antibiotics (3, 11.5%), systemic tetracyclines (4, 15.4%, in one case with topical prednisolone and tobramycin), and topical anti-inflammatory/immunosuppressive drugs (4, 15.4%). Homeopathic test treatments were used in three (11.5%) of the studies, including two with topical agents (honey or oil drop) and one with a systemic agent (linoleic acid). External treatments were reported in nine (34.6%) studies, including heat (warm compresses or a warming device) in seven (26.9%), lid hygiene in one (3.8%), and both treatments in one (3.8%). 
Systemic treatments were almost invariably used twice daily. Dose regimens for tetracyclines ranged from 20 to 200 mg of doxycycline twice daily, 50 mg daily or 50 mg twice daily of minocycline, or 30 to 350 mg of erythromycin twice daily. 
Concurrent treatment was continued or instituted in 10 trials. Artificial tears were used in nine trials and lid therapy in five, of which four used only lid hygiene. One study allowed whatever treatment in use 1 month before the trial to continue to be used throughout the trial. Most did not disclose whether concurrent treatment was continued. 
Nine studies used some form of treatment in the control group. Lid hygiene was the most frequent treatment in the control group (three studies); one study used heat, one used conventional eye masks, and one used warm towels. Control groups were assigned to artificial tears in three studies; one of those studies also used lid hygiene. One study involved a placebo control for systemic doxycycline. 
A single application was used in four eyelid heat trials. Three devices were tested using one 10-minute application and then a 2-week trial. Including this trial, there were seven trials involving 2-week treatments. The other most common length for a trial was 3 months (six studies). There were four trials of treatments lasting 2 weeks to 3 months and three trials with treatment lasting longer than 3 months. 
No washout period (run-in period) was observed in the majority (n = 17) of the trials. Artificial tears were prescribed for the washout in two trials (specified for 2 weeks in one of these). One study discontinued the use of systemic doxycycline for 2 weeks before the study's start. No topical therapy was specified before two of the trials, with trial duration of 2 weeks one and of 3 months in the other. In the 3-month washout trial, artificial tears were allowed to be used, but no punctual occlusion or CL use was permitted. 
To standardize treatment, some studies required all subjects to use lid scrubbing and artificial tears at entry. Standardizing treatment for lid disease may help decrease confounding variables when evaluating a new treatment. Using standard treatment for 2 to 4 weeks before randomizing subjects may help eliminate the placebo responders and provide better baseline information. 
Five studies included a follow-up (to rule out relapse) after 2 to 3 months. 
Comment.
Most trials lacked a washout period and did not check for relapse; half allowed concurrent use of other treatments and a third allowed treatment in the control group. There was a large variability between duration of studies, but pharmacological trials tended to be of longer duration and were more likely to have a follow-up period than those using external factors and were more likely to have a follow-up period. 
Statistical Considerations
Overview and Results.
There were a limited number of well-conducted, randomized controlled trials available for statistical review. None of these studies gave much detail related to the calculation of effect size, power, or required sample size. There was limited information on how missing data—for example, loss to follow-up and exclusion due to noncompliance—were handled. 
Additional Clinical Trials
Additional ongoing clinical trials from ClinicalTrials.gov were retrieved with the search term meibomian. The relevant ones are listed in Table 8
Table 8.
 
Relevant Registered Clinical Trials
Table 8.
 
Relevant Registered Clinical Trials
Condition Title Interventions Status Outcome Comment
MGD A Single-Center, Double-Masked, Randomized, Vehicle Controlled Study to Evaluate the Safety and Efficacy of Testosterone 0.03% Ophthalmic Solution Compared to Vehicle for the Treatment of MGD Testosterone ophthalmic solution vs. vehicle R Primary: MG secretion (128 days) Secondary: comfort (128 days) Phase II, enrollment by invitation only
MGD Efficacy of 0.05% Cyclosporine Ophthalmic Emulsion Compare with Tear in MGD 0.05% cyclosporine eye drop R Primary: NTBUT (0,1,2,3 month) Phase IV
Secondary: OSDI score, TBUT, fluorescein/rose bengal staining, MG (0,1,2,3 month)
Blepharitis Lipids of the Human Tear Film and Their Effect on Tear Stability Doxycycline; essential fatty acid; azithromycin R Primary: inflammation of eyelid (2 months) Phase IV
Secondary: character of MG secretion (2 months)
Dry eye syndrome A Prospective Clinical Study Assessing the Effects of Tetracycline Antibiotic on Tear Film and Tear Lipid Composition within a Population of Patients Diagnosed with Blepharitis and Dry Eye Disease Condition Tetracycline: doxycycl ine analog T Primary: evaporimetry; fluorophotometry; MG expression and lipid analysis
Secondary: Schirmer's, TBUT, bacteriology, transillumination and meibography
Blepharitis A Placebo-Controlled Double-Masked Clinical Assessment Study of Essential Fatty Acid Supplement and Its Effect on Patients with Apparent Aqueous-Deficient Dry Eye Syndrome Condition Essential fatty acid supplement R Primary: lipid bio chemistry changes Phase IV
Secondary: evaporimetry and fluorophotometry
Posterior blepharitis Topical IL-1-Ra for Treatment of Posterior Blepharitis 2.5% IL-1Ra, Placebo; 5% IL-1Ra R Primary: MG secretion/quality, TBUT, cornea and conjunctival staining, and OSDI questionnaire (12 weeks) Phase I/II
Secondary: MG occlusion, Schirmer with and without anesthesia. (12 weeks)
KCS Efficacy and Safety Study of Nutritional Supplements for Treatments of Dry Eye Condition Dietary supplement: Hydroeye; vs. inactive capsule R Primary: Schirmer, OSDI, TBUT, corneal staining (screening at weeks 4, 12, and 24) Signs of MGD were inclusion criteria
Secondary: Corneal topography, MGD, facial expression subjective scale, artificial tear usage, HLA-DR staining of impression cytology (screening, at weeks 12 and 24)
Blepharitis meibomitis; dry eye Treatment of Patients With Blepharitis and Facial Rosacea Doxycycline vs. placebo R Primary: Change in OSDI, bulbar conjunctival hyperemia (baseline to end of study) Phase II
Secondary: Change in Schirmer result, TBUT, meibum character/fluidity, MG inspissation (baseline to end of study)
Comments.
Several of the ongoing clinical trials are randomized double-masked placebo-controlled studies with well-defined primary and secondary outcome measures. Results from these trials may add to the list of clinical trials on MGD with a high evidence grades. At the time of this compilation, however, none of those studies had published results. 
Necessary MGD Trial Design Improvements
Decisions concerning the design of future trials should be based on available data from reliable studies published in peer-reviewed journals. Such studies should be prospective randomized double-masked (when possible) and controlled with a sufficiently large MGD sample. 
To date, very few trials have met those stringent criteria, although as already noted, several are under way. It is unknown when, if ever, the results of those ongoing trials will be published. 
Objectives
Although generic clinical trial design recommendations are available, design recommendations specific to MGD should include trials with well-defined objectives. Those objectives should be clearly stated and allow for concise and specific questions to be answered. Important and basic questions to address in MGD are:
  •  
    Is there an association between MGD and dry eye disease? Can we distinguish between MGD and dry eye disease? How? Our review of past clinical trials of MGD suggests that there is no clear consensus. Some researchers include subjects with dry eyes, others exclude them, and still others fail to evaluate dry eye status altogether. Given the current lack of sufficient reliable data, answers to this question can only be tentative; no conclusive recommendations are possible. MGD appears to be clinically associated with alterations in the quality and quantity of lipids secreted by the meibomian glands, which contribute to the preocular tear film. Many clinicians believe MGD is the most common cause of evaporative dry eye and that there is considerable overlap in the occurrence of MGD and aqueous-deficient dry eye states, both demonstrating typical signs and symptoms suggestive of dry eye disease. Studies that evaluate the possible role of MGD in aqueous deficiency, possibly through creating an inflammatory state on the ocular surface, would also be welcome.
  •  
    Given that there is considerable uncertainty between MGD and dry eye disease, trials that evaluate the association between MGD and dry eye would be beneficial, as would observational trials that assess the natural history of MGD. Of special value would be a standardized symptom questionnaire that could distinguish MGD lid disease from dry eye disease.
  •  
    Developing alternative or indirect ways of assessing and testing MGD would also be desirable. Accurate, repeatable measures of symptoms are of obvious value as outcome measures and are directly relevant to the patient's health. Quantitative measures of disease may also be useful, especially if it can be shown that reversal improves long-term health. Examples include osmolarity, interferometry, high resolution OCT, tests that can measure visual function and interblink visual acuity decay, and techniques that identify differences in the meibum. To learn how to use such tools, researchers need standardized video and/or web-based training. Clinical studies demonstrating the correlation between the results of these tests and clinical findings, such as symptoms or signs, should be executed first.
Design
The most desirable clinical trials would be prospective, randomized, controlled, and double-masked, if possible. Considerations important in good clinical trial design should be incorporated into any MGD trial (e.g., Guidelines from International Conference on Harmonization [ICH] E6 Good Clinical Practice: Consolidated Guidance, 28 ICH topic E8 General Consideration of Clinical Trials; 29 ICH topic E9 Statistical Principles for Clinical Trials 30 ; and E10 topic Choice of Control Group and Related Issues in Clinical Trials, 31 see www.ich.org). Other types of designs, such as epidemiologic or registry studies, entail other considerations. 
Selection of Subjects and Inclusion/Exclusion Criteria
Past MGD clinical trials did not have a uniform way of defining the study population, although symptoms and changes in the lid, especially plugging and abnormal secretions, were the most common clinical characteristics that were selected. Of note, dry eye disease was not usually specifically included or excluded in selecting patients, other than in subject recruitment based on symptoms. Signs of dry eye disease were uncommonly used as selection criteria but were often assessed to determine improvement. Future studies should carefully consider inclusion of tests for dry eye disease. 
Clearly, the clinical trial study population must be rigorously defined. A robust classification system for MGD is important; however, in an interventional clinical trial, a system should be based on accessible and validated objective and/or subjective clinical signs and symptoms that are relevant to ocular surface health and are responsive to intervention. Noninterventional, exploratory therapeutic, or mechanistic studies may involve additional measurements (biomarkers or clinical signs) not feasible in a large population, according to the trial objective. Such studies may involve testing procedures that do not translate to a multicenter clinical trial or to more generalized patient care. 
A consistent, standardized classification system is important in measuring the effects of intervention, in establishing natural history, and in defining inclusion and exclusion criteria. Two approaches can be taken when grading or classifying patients: grading of individual clinical characteristics or classification based on global severity. Individual grading is discussed in the Report on Diagnosis, whereas the Report on Management and Therapy utilizes a clinical-staging approach to determining disease according to a uniform grading methodology and not exclusively by tear and ocular surface characteristics. Development of such a consistent grading and evaluation methodology across all research in MGD would facilitate comparisons between studies. 
To emphasize continuity between graders and examiners, a training program for researchers both for diagnosis and grading could be developed, perhaps using web-based delivery. Such a training program may assist in ensuring concordance between investigators and improve data quality. It might also include reading centers such as those used in other vision-related studies (i.e., those of the retina, glaucoma, and keratoconus). 
An important aspect in MGD may be ethnicity. Ethnic differences may influence the choice of study population, as it may affect the study medication's safety, efficacy, dosage and dose regimen. Since epidemiologic data indicate a substantially higher prevalence of MGD in people of Asian descent, one must consider that both extrinsic (e.g., culture, including diet and medical practice) and intrinsic (e.g., genetic polymorphism; ICH E5: Ethnic Factors in the Acceptability of Foreign Clinical Data) 32 factors have a potential to influence the outcome of a clinical trial. The ability to generalize results will also reflect the homogeneity (or lack thereof) of the study population. 
Appropriate inclusion and exclusion criteria are essential to ensuring the integrity of the trial. Previously published clinical studies have not adequately identified clinically relevant and specific inclusion criteria for MGD that differ from those for dry eye disease. In general, the use of CLs has been a major reason for excluding subjects from trials, followed by exclusion criteria related to general ocular surface conditions or past surgery. In early phases of drug development, the inclusion and exclusion criteria may be very stringent, to maximize the chance of observing specific clinical effects of interest. These restrictive criteria may result in selection of a sample from a very narrow subgroup of the total patient population for which a treatment may eventually be indicated. However, in later confirmatory trials, subjects should more closely mirror the target population. The inclusion and exclusion criteria should be relaxed as much as possible to allow researchers the ability to suggest generalizations for routine patient care. 
Selection of the Control Group
Control groups have one major purpose: to allow discrimination of patient outcomes (for example, changes in symptoms, signs, or other morbidity) caused by the test treatment from outcomes caused by other factors, such as the natural progression of the disease, observer or patient expectations, or other treatment. Therefore, the choice of control group is always a critical decision in designing a clinical trial. 
In most cases, the primary choice is to use a concurrent control group. The test and control groups should be similar with regard to all baseline and on-treatment variables that could influence outcome, except for the study treatment. In MGD, such baseline factors could be related to age, ethnicity, systemic disease, concurrent medication, and environmental factors, to cite just a few examples. Randomization reduces potential bias between the experimental and the control group. To further minimize the risk of bias, the study should be double-masked, so that both the subject and the examiner are unaware of the medication versus placebo assignment. When double-masking is not possible, which may be the case in MGD if, for example, lid scrubbing is part of one treatment regimen (the examiner could remain masked), efforts to identify which outcome measures can be masked to an independent evaluator should be made as well as efforts to minimize subject discussion related to the therapy. 
Currently there is no well-defined, accepted standard of care in the treatment of MGD. Therefore, careful discussion with regulatory agencies may be needed for study design issues such as a control paradigm. In the absence of an established standard of care, it is important to define the control or comparator treatment—for example, placebo control (vehicle) and/or lid hygiene. 
Although choosing a comparator in a superiority trial in MGD may be straightforward, in a noninferiority trial for MGD, there is no established treatment with which to compare. Further, a clinically relevant noninferiority margin of error or range has to be determined. Other types of studies may include a crossover design. In such a case, it would be critical to address whether there is interference between treatments and what would define a suitable washout period. In any clinical trial in MGD, it is critical to address potential confounders, such as the effects of concurrent treatment (in the current literature, the most common concurrent treatments include lid hygiene and artificial tear substitutes), washout of current treatment, and treatment during the run-in phase of a study. Standard operating procedures to manage these situations should be clearly defined in the study protocol. 
Duration of the Trial
In MGD, there has been a large variability in the duration of the studies reviewed. Pharmacologic trials tended to be of longer duration than those assessing other nonpharmacological factors and were more likely to include a follow-up period after treatment discontinuation. As in any clinical trial, the treatment duration must be sufficiently long to obtain the desired outcome. A follow-up period to address recurrence after treatment termination would be desirable. In pharmacologic treatment trials, the trial duration should correspond with the proposed clinical care treatment duration to adequately address any safety issues that the treatment regimen might create in a real-world setting. 
Sample Size
The power of the study, calculated on the basis of the primary outcome measure in a study—for example 80% (generally accepted as the recommended minimum value)—is the ability of a test to detect an effect, if any. 33 For example, if a previous trial has demonstrated a clinically meaningful decrease in corneal staining, evaporation, or tear osmolarity with a certain treatment, such data would be used to calculate the number of patients needed to achieve (at least), with the desired probability, a similar magnitude of effect in the planned trial. Necessary components in calculating statistical power include effect size, variability, sample size, and significance level. 34 Given that there is limited published information available to assist with sample size or power estimates in MGD trials, the calculations are likely to be based on preliminary and/or uncertain data and information. Data from exploratory or early-phase studies continue to be needed. Presently, data comparing specific characteristics in normal and diseased subjects should be used to assist in obtaining data on a potential effect of a treatment and therefore in calculating sample size. An interim check (on masked data) to adjust the sample size may also be useful, but must be performed with extreme caution and is best suited in pilot work. A revised sample size may then be calculated by using suitably modified assumptions (ICH E9). 30 When estimating a sample size, additional subjects should be included to compensate for withdrawal or loss to follow-up. These additional subjects are especially important in longer term trials or trials with complicated or noxious therapies in which a higher withdrawal rate is expected. A sufficient sample size is also needed to appropriately address the safety of an intervention (ICH E1). 35  
Outcome Measures
Primary outcome measures or endpoints, as well as secondary outcome measures or endpoints, should be clearly defined in MGD trials. The selected outcome measures should provide the most clinically relevant and convincing evidence directly related to the objectives of the trial. Generally, the primary endpoint is one that demonstrates a clear quantitative measure of benefit. In MGD, the choice of outcome measures related to efficacy of an intervention would probably be dependent on the classification and severity of disease. The classification recommended by the Definition and Classification Subcommittee is based on pathophysiological changes in which the main categories are low- and high-delivery states. Consequently, in a low-delivery state such as an obstructive condition, a reasonable endpoint could include assessment of lid margin inflammation and/or gland obstruction. Likewise, disease severity or disease progression may be variables of interest. MGD severity staging, such as the scheme found in the Report on Management and Therapy, may include several clinical characteristics within a disease severity stage and could be used in clinical trials, but may lack the sensitivity of an individual grading scheme for a unique clinical test. Therefore, outcome measures have to be carefully selected to address the hypothesis of the proposed study. 
In many of the past clinical trials, outcome measures have reflected ocular surface rather than lid signs (tear status and ocular surface staining). Such measures may reflect the concurrence of MGD and dry eye disease, especially in evaporative dry eye disease, in which lipid abnormalities are thought to lead to changes in tear film stability. 36 In such conditions, typical signs of dry eye disease (TBUT, vital staining of the cornea and conjunctiva, and Schirmer's test result) would be appropriate outcome measures for MGD. In addition, as discussed in the Report on Diagnosis, in the evaporative dry eye state, significant differences in tear turnover rate, evaporation, and osmolarity may be seen between evaporative dry eye and normal subjects. The use of such clinical endpoints is promising, but must have further evaluation. Accordingly, MGD trials should include adequate information about tear film parameters (typically included in the description of tear-deficient states), in addition to descriptions that delineate the extent of the lid margin disease. Endpoints associated with lid findings may be selected as primary or as important secondary outcome measures and graded using a uniform grading methodology. Of note, it is unclear whether existing grading scales reflect linear progression in severity, and efficacy may therefore be difficult to demonstrate for more severe disease. 
As in dry eye disease, it would also be essential to evaluate treatment effects on symptoms specific to MGD but also including foreign body sensation or irritation; itching; burning, swollen eyelids; a feeling of dryness; excessive tearing; and a crust on the eye lashes, especially in the morning. These symptoms are very similar to those reported in dry eye disease. To better define and evaluate patient symptoms in MGD, a specific and validated questionnaire specific to MGD is highly desirable, not only to differentiate between dry eye and MGD, if possible, but also to address a response to treatment. The use of electronic symptom diaries may improve real-time data collection, data quality, and accuracy. 
Depending on the etiology, manifestation, and severity of the disease, additional outcome measures such as tear and ocular surface characteristics may be highly relevant endpoints. The clinical value of commonly used endpoints such as (but not limited to) changes in lipid layer interference pattern, meibum expressibility, quality and composition, and tear evaporation rate should have further evaluation. 
Surrogate Endpoints and Biomarkers
Besides moving science forward, the use of surrogate endpoints or biomarkers has potential benefits during drug development. For example, data may be obtained sooner or by more uncomplicated and less invasive methods and may be ethically preferable or less costly. However, in MGD, there is no information on the specificity or sensitivity of biomarkers, let alone knowledge about how they may change in response to therapy. From a regulatory perspective, the use of surrogate endpoints or biomarkers in clinical trials depends on which weight these are given and what claims would be associated with data relying on such endpoints. In exploratory trials during earlier development of a drug, a surrogate endpoint or biomarker may be used as a secondary, or even as a primary, endpoint. A surrogate endpoint could, for example, be used to obtain a proof of concept, to aid in dose selection, to give support on a mechanism of action, or for subgroup characterization. Also in confirmatory trials, surrogate endpoints or biomarkers may be included. Regulators are often liberal, or even encouraging, when such endpoints are used during early development or as exploratory endpoints in a confirmatory study. Again, it depends on which weight the results associated with these endpoints will be given. If, on the other hand, a surrogate is to be used as a primary endpoint, the link to and relevance of a clinical outcome, or an outcome that matters for the patient (short or long-term) must be established. Surrogate endpoints must be validated by using clinical trial data, with both the surrogate and true endpoint in a representative patient sample. In such validation, the following guidelines should be considered. The surrogate endpoint or biomarker should be:
  •  
    Mechanistically plausible
  •  
    Able to predict clinical outcome (earlier, or in parallel with the “true outcome”)
  •  
    Able to measure efficacy, severity, and safety
  •  
    Able to change with intervention and to predict an effect of treatment on a clinical outcome
  •  
    Standardized and reproducible between investigators and clinical trial centers.
Methods of Minimizing Bias
In MGD, specific considerations should be given to masking, compliance to study treatment, washin/washout, concurrent treatment, and methods for handling missing data. The latter could be critical and should be handled differently; for example, based on whether the condition is expected to progress or improve during the study period without treatment or whether discontinuations are due to adverse effects of an active treatment. 
Treatment
Treatment duration must be clearly defined. Most past clinical trials in MGD have lacked a washout period and did not monitor relapse after the study's end. Other studies allowed concurrent use of other treatment or treatment in the control group. Omitting washout or allowing concurrent medication may affect the ability to perform a robust efficacy or safety evaluation. If no confounding effects are suspected with a certain concurrent treatment, allowed (as well as not allowed) medications should nevertheless be predefined and monitored, and any potential effects on the study outcome should be identified. 
Adherence to Study Protocol
Adherence to some management measures, including the use of lid scrubbing and hygiene, may be difficult to maintain. When such measures are included in a trial, it is critical that adherence be monitored with patient diaries. In addition, it may be wise to increase the sample size of the study, since a higher dropout may be expected. 
Assay Sensitivity
Given that limited information is available on the magnitude of treatment effects in previous clinical trials in MGD, additional information would be of value before confirmatory therapeutic studies are performed that have a high probability of showing the desired outcome. Such information includes the magnitude of clinically relevant effect or noninferiority margins and which magnitude of a placebo response to expect. 
Modifications of the Protocol
As previously discussed, interim analyses to assist in adjusting the sample size may be useful. In earlier phases of clinical development in MGD, an adaptive study design involving design modifications based on the results of an interim analysis may also be used to speed up the process of drug development or to allocate resources more efficiently without lowering scientific and regulatory standards. Assay sensitivity is especially essential during noninferiority trials, so that the trial data are not compromised. In such a trial, one way to ensure this would be to include a placebo group as a third arm. 
Statistical Plan
As in any clinical trial, the principal features of the eventual statistical analysis of the data should be predefined and described in the statistical section of the protocol, for example, methodology for handling missing data, perhaps due to loss to follow up, noncompliance, or withdrawal due to adverse events. The ICH Topic E9, Statistical Principles for Clinical Trials, 30 should be considered. 
Future studies would be well served by more clearly defining the study population, especially if a multicenter trial is planned. Including evaluation for dry eye disease will help in defining its association with MGD disease and determining the effect of treatment on signs and symptoms associated with dry eye disease. 
Summary
We suggest the following main priorities in future clinical trials in MGD:
  •  
    Natural history of MGD
  •  
    The association between MGD and dry eye disease
  •  
    A specific and validated questionnaire for symptoms of MGD
  •  
    Standardized grading for lid and other signs in MGD
  •  
    Feasibility and clinical value of lipidomic and protein inflammatory mediators
  •  
    Validation of surrogate clinical outcomes related to MGD.
Footnotes
 Supported by the Tear Film and Ocular Surface Society (TFOS: http://www.tearfilm.org): individual author support is listed in the Appendix of the Introduction.
Footnotes
 Disclosure: Each Workshop Participant's disclosure data can be found in the Appendix of the Introduction.
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Goto E Shimazaki J Monden Y . Low-concentration homogenized castor oil eye drops for noninflamed obstructive meibomian gland dysfunction. Ophthalmology. 2002;109:2030–2035. [CrossRef] [PubMed]
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Table 1.
 
Evidence Levels of Eligible Trials (in Chronological Order)
Table 1.
 
Evidence Levels of Eligible Trials (in Chronological Order)
Evidence Level* Publications (n) References†
I 3 Yoo et al. 26
Perry et al. 17
Schechter et al. 21
I–II 2 Goto et al. 8
Rubin and Rao 20
II 8 Paugh et al. 16
Yalcin et al. 25
Olson et al. 15
Romero et al. 19
Pinna et al. 18
Luchs 10
Souchier et al. 24
Matsumoto et al. 12
II–III 1 Mori et al. 14
III 12 Dougherty et al. 4
Epstein and Putterman 5
Song et al. 23
Meisler et al. 13
Goto et al. 6
Goto et al. 7
Shine et al. 22
Albietz and Lenton 1
Cetinkaya et al. 3
Matsumoto et al. 11
Blackie et al. 2
Ishida et al. 9
Table 2.
 
Study Design and Descriptive Features
Table 2.
 
Study Design and Descriptive Features
Ref. First Author Evidence Level Title Journal/Year Treatment Interventional Efficacy Assessed? Comparative? Treatment Protocol Duration Prospective/Retrospective Randomized Masked Placebo or Control Subject Group (n, Group) Age Range
17 Perry HD I Efficacy of commercially available topical cyclosporine A 0.05% in the treatment of meibomian gland dysfunction Cornea. 2006 Feb;25(2):171–175 Y Y Y Y Topical 0.05% cyclosporin versus artificial tears 3 months Prospective Y Y-double Y n = 33 enrolled, n = 16 (12 completed) treatment (Tx), n = 17 (14 completed) placebo 18 and older, average age, not given
21 Schechter BA I Efficacy of topical cyclosporine for the treatment of ocular rosacea Adv Ther. 2009;26(6):651–659 Y Y Y Y Topical 0.05% cyclosporine versus artificial tears 3 months Prospective Y Y-double Y n = 37, n = 21 Tx, n = 16 placebo 18 and older, average age, ∼72.6 y
26 Yoo SE I The effect of low-dose doxycycline therapy in chronic meibomian gland dysfunction Korean J Ophthalmol. 2005;19(4):258–263 Y Y Y Y Systemic doxycycline 200 or 20 mg twice a day or placebo 1 month Prospective Y Y-patient Y n = 150 enrolled (n = 139 completed), n = 50 high dose, n = 50 low dose, n = 50 placebo 18 and older, average age, ∼47.2 y
8 Goto E I–II Low-concentration homogenized castor oil eye drops for noninflamed obstructive meibomian gland dysfunction Ophthalmology. 2002;109(11):2030–2035 Y Y Y Y Castor oil eye drop versus artificial tears 2 week washout, 1 month Prospective, cross-over Y Y-double Y n = 20, 10 per group 18 and older, average age, 52.1 y
20 Rubin M I–II Efficacy of topical cyclosporin 0.05% in the treatment of posterior blepharitis J Ocul Pharmacol Ther 2006;22:47–53 Y Y Y Y Topical 0.05% cyclosporin versus topical 0.3% tobramycin/0.1% dexamethasone 3 months Prospective Y N N n = 30, 15 per group 18 and older, average age, ∼51 y
10 Luchs J II Efficacy of topical azithromycin ophthalmic solution 1% in the treatment of posterior blepharitis. Adv Ther. 2008;25:858–870 Y Y Y Y Topical azithromycin 1% and hot compresses versus hot compresses alone 2 weeks Prospective Y N Y n = 21, n = 11 Tx and n = 10 placebo 18 and older, average age, 63.7 y
12 Matsumoto Y II The evaluation of the treatment response in obstructive meibomian gland disease by in vivo laser confocal microscopy Graefes Arch Clin Exp Ophthalmol. 2009;247(6):821–829 Y Y Y Y Lid hygiene, topical nonpreserved artificial tears, and 0.1% sodium hyaluronate eye drops, topical 0.5% levofloxacin, topical 0.1% fluorometholone, oral minocycline 100 mg twice a day versus lid hygiene, topical nonpreserved artificial tears and 0.1% sodium hyaluronate drops 12 weeks Prospective N N Y n = 27, n = 16 Tx, n = 11 control 18 and older, average age, ∼65 y
15 Olson MC II Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction Eye Contact Lens. 2003;29(2):96–99 Y Y Y Y Heated compress over experimental eye versus room temperature compress over control eye 5, 15, 30 minutes following application (same day) Prospective Y (contralateral eye) N Y n = 20 range, 26–59 y
16 Paugh JR II Meibomian therapy in problematic contact lens wear Optom Vis Sci. 1990;67(11):803–806 Y Y Y Y Lid hygiene, warm compresses twice daily for 2 weeks in one eye 2 weeks Prospective Y (contralateral eye) Y-examiner Y n = 21 range, 22–33 y
18 Pinna A II Effect of oral linoleic and gamma-linolenic acid on meibomian gland dysfunction Cornea. 2007;26(3):260–264 Y Y Y Y Oral linoleic acid and γ-linolenic acid once daily versus eyelid hygiene (warm eyelid compresses, eyelid massage, and eyelid margin scrubbing) versus both treatments 6 months Prospective Y Y-examiner Y n = 57 (49 completed), 19 per group 18 and older, average age, 50 y
19 Romero JM II Conservative treatment of meibomian gland dysfunction Eye Contact Lens. 2004;30(1):14–19 Y Y Y Y Lid hygiene, warm saline soaks, and non-preserved AT four times per day for 2 weeks and then twice per day for 4 weeks 6 weeks Prospective N Y-photo grader N n = 37 enrolled (26 completed) 18 and older, average age, 57 y
24 Souchier M II Changes in meibomian fatty acids and clinical signs in patients with meibomian gland dysfunction after minocycline treatment Br J Ophthalmol. 92(6):819–822 Y Y Y Y Lid hygiene versus oral minocycline 50 mg (patients nonresponsive to compress therapy received minocycline) 8 weeks Prospective N N Y n = 20 patients, 10 per group 18 and older, average age, 66 y
25 Yalcin E II N-acetylcysteine in chronic blepharitis Cornea. 2002;21:164–168 Y Y Y Y Topical steroid, topical antibiotic, artificial tears, warm compress, and oral n-acetylcysteine versus topical steroid, topical antibiotic, artificial tears, warm compress 3 months Prospective N N Y n = 40, n = 22 Tx, n = 18 control 18 and older, average age, ∼43 y
14 Mori A II–III Disposable eyelid-warming device for the treatment of meibomian gland dysfunction Jpn J Ophthalmol. 203;47(6):578–586 Y Y Y Y Application of Eye Warmer lid warming device versus untreated control 2 weeks Prospective N N (only interferometry grader was masked) Y n = 25 (17 treated, 8 untreated) 18 and older, average age, 53.6 y
1 Albietz JM III Effect of antibacterial honey on the ocular flora in tear deficiency and meibomian gland disease Cornea. 2006;25:1012–1019 Y Y N N Topical antibacterial honey 3 months Prospective N N Y n = 84 (49 completed), of those enrolled 15 MGD and 20 MGD with tear deficiency 18 and older, average age, ∼59 y
2 Blackie CA III Inner eyelid surface temperature as a function of warm compress methodology Optom Vis Sci. 2008;85(8):675–683 Y Y N Y External heat (warm compresses in several different ways) Same day study Same day study Y (contralateral eye) N Y n = 32 normal patients, group A (n = 10), B (n = 10) and C (n = 12) 18 and older, average age, 34.7 y
3 Cetinkaya A III Pediatric ocular acne rosacea: long-term treatment with systemic antibiotics Am J Ophthalmol. 2006;142(5):816–821 Y (case series) Y Y N Four pediatric cases: oral erythromycin or oral doxycycline in combination with topical methyl prednisolone and tobramycin 12–36 months Retrospective case series N N N n = 4 range, 4–12 y
4 Dougherty JM III The role of tetracycline in chronic blepharitis. Inhibition of lipase production in staphylococci Invest Ophthalmol Vis Sci. 1991;32(11):2970–2975 Y (clinical samples, no direct patient treatment) N N N Tetracycline solution incubated with tetracycline-sensitive strains (Staphylococcus epidermidis and Staphylococcus Aureus) and tetracycline-resistant strains (S. Epidermidis and S. Aureus) 24 hours Retrospective, sample collection N N N MKC n = 2 samples (isolates), Staphylococcus blepharitis, 2 samples (isolates) Not defined
5 Epstein GA III Combined excision and drainage with intralesional corticosteroid injection in the treatment of chronic chalazia Arch Ophthalmol. 1988;106(4):514–516 Y Y Y Y Initial warm eyelid soaks for chronic chalazia, eyelid cleaning, topical antibiotic-steroid combination. If no improvement within 2 weeks, surgical excision versus surgical excision and intratarsal injection of triamcinolone 6 weeks Initially retrospective, second part prospective N N N n = 298, first 146 patients: 88 surgery only, 58 surgery and steroids in combination. Additionally 152 patients with combined treatment. range, 6–88 y, most >50 y
6 Goto E III Improvement of tear stability following warm compression in patients with meibomian gland dysfunction Adv Exp Med Biol. 2002;506:1149–1152 Y Y Y N Warm compress therapy with a warm steam eye cup device applied for 5 minutes Same day study Same day study N N N n = 6 18 and older, average age, 45.8 y
7 Goto E III Treatment of non-inflamed obstructive meibomian gland dysfunction by an infrared warm compression device Br J Ophthalmol, 2002;86(12):1403–1407 Y Y Y N Infrared warm compression device 2 weeks Prospective N N N n = 37 18 and older, average age, ∼55 y
9 Ishida R III Tear film with “Orgahexa EyeMasks” in patients with meibomian gland dysfunction Optom Vis Sci. 2008;85(8):684–691 Y Y Y N Orgahexa EyeMask eye warmer mask 2 weeks Prospective N N Y n = 42, n = 20 Tx, n = 22 control 18 and older, average age, 54.5 y
11 Matsumoto Y III Efficacy of a new warm moist air device on tear functions of patients with simple meibomian gland dysfunction Cornea. 200625(6):644–650 Y Y Y Y Steam warmer four times daily versus traditional warm compresses twice daily 2 weeks Prospective N N Y n = 35, n = 15 MGD, n = 20 control 18 and older, average age, ∼58.8 y
13 Meisler DM III Oral erythromycin treatment for childhood blepharokeratitis J AAPOS. 2000;4(6):379–380 Y (case series) Y Y N Oral erythromycin, varying dose starting at 30 to 250 mg twice daily, depending on severity of disease, lid scrubbing twice a day Up to 12 months Prospective case series N N N n = 5 range, 4–9 y
22 Shine WE III Minocycline effect on meibomian gland lipids in meibomianitis patients Exp Eye Res. 2003;76(4):417–420 Y Y Y N Oral minocycline 50 mg/daily for 2 weeks followed by 100 mg/daily 3 months on Tx, 3 months off Tx Prospective N N N n = 10 N/A
23 Song CH III Enhanced secretory group II PLA2 activity in the tears of chronic blepharitis patients Invest Ophthalmol Vis Sci. 1999;40(11):2744–2748 7N N N N No treatment, normal tear PLA2 compared with blepharitis including MGD Same day study Same day study N N N n = 46, chronic blepharitis n = 36, controls n = 10 range, 30–40 y
Table 3.
 
Clinical Characteristics and Symptoms Assessed as Either Entry Criteria or Outcomes
Table 3.
 
Clinical Characteristics and Symptoms Assessed as Either Entry Criteria or Outcomes
Ref. First Author Evidence Level Title Clinical Testing Described/Performed Symptoms Transillumination (Obstruction and Dropout) MG Obstruction MG Secretions Interferometry Eyelid Temperature Lid Debris Lid Edema/Thickening Irregular Lid Lid Hyperemia/Erythema Lid Telangiectasia Conjunctival Papillae/Hyperemia TFBUT Corneal Staining Schirmer's Test Contact Lens Wear Acne Rosacea
17 Perry HD I Efficacy of commercially available topical cyclosporine A 0.05% in the treatment of meibomian gland dysfunction Yes Yes Yes (plugging) Yes Yes Yes Yes
21 Schechter BA I Efficacy of topical cyclosporine for the treatment of ocular rosacea Yes Yes Yes Yes Yes Yes Yes Yes
26 Yoo SE I The effect of low-dose doxycycline therapy in chronic meibomian gland dysfunction Yes Yes Yes Yes
8 Goto E I–II Low-concentration homogenized castor oil eye drops for noninflamed obstructive meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes Yes Yes
20 Rubin M I–II Efficacy of topical cyclosporin 0.05% in the treatment of posterior blepharitis Yes Yes Yes Yes Yes Yes Yes
10 Luchs J II Efficacy of topical azithromycin ophthalmic solution 1% in the treatment of posterior blepharitis. Yes Yes Yes Yes Yes Yes Yes
12 Matsumoto Y II The evaluation of the treatment response in obstructive meibomian gland disease by in vivo laser confocal microscopy Yes Yes Yes Yes Yes Yes Yes
15 Olson MC II Increase in tear film lipid layer thickness following treatment with warm compresses in patients with meibomian gland dysfunction Yes Yes Yes Yes Yes Yes
16 Paugh JR II Meibomian therapy in problematic contact lens wear Yes Yes Yes Yes Yes Yes
18 Pinna A II Effect of oral linoleic and gamma-linolenic acid on meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes Yes Yes
19 Romero JM II Conservative treatment of meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes Yes Yes
24 Souchier M II Changes in meibomian fatty acids and clinical signs in patients with meibomian gland dysfunction after minocycline treatment Yes Yes Yes Yes Yes Yes Yes
25 Yalcin E II N-acetylcysteine in chronic blepharitis Yes Yes Yes
14 Mori A II–III Disposable eyelid-warming device for the treatment of meibomian gland dysfunction Yes Yes Yes Yes Yes
1 Albietz JM III Effect of antibacterial honey on the ocular flora in tear deficiency and meibomian gland disease Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
2 Blackie CA III Inner eyelid surface temperature as a function of warm compress methodology Yes
3 Cetinkaya A III Pediatric ocular acne rosacea: long-term treatment with systemic antibiotics Yes Yes Yes Yes Yes Yes
4 Dougherty JM III The role of tetracycline in chronic blepharitis. Inhibition of lipase production in staphylococci No
5 Epstein GA III Combined excision and drainage with intralesional corticosteroid injection in the treatment of chronic chalazia
6 Goto E III Improvement of tear stability following warm compression in patients with meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes
7 Goto E III Treatment of non-inflamed obstructive meibomian gland dysfunction by an infrared warm compression device Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
9 Ishida R III Tear film with “Orgahexa EyeMasks” in patients with meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes
11 Matsumoto Y III Efficacy of a new warm moist air device on tear functions of patients with simple meibomian gland dysfunction Yes Yes Yes Yes Yes Yes Yes
13 Meisler DM III Oral erythromycin treatment for childhood blepharokeratitis Yes Yes Yes Yes
22 Shine WE III Minocycline effect on meibomian gland lipids in meibomianitis patients Yes Yes Yes
23 Song CH III Enhanced secretory group II PLA2 activity in the tears of chronic blepharitis patients No
Total (n) 24 13 8 12 14 5 3 1 7 4 7 6 3 14 15 11 2 3
% (of 26) 92.3% 50.0% 30.8% 46.2% 53.8% 19.2% 11.5% 3.8% 26.9% 14.4% 26.9% 23.1% 11.5% 53.8% 57.7% 42.3% 7.7% 11.5%
Table 4.
 
Inclusion and Exclusion Criteria
Table 4.
 
Inclusion and Exclusion Criteria
Ref. First Author Evidence Level Title Inclusion Criteria Exclusion Criteria
17 Perry HD I Efficacy of Commercially Available Topical Cyclosporine A 0.05% in the Treatment of Meibomian Gland Dysfunction Adult patients with slit lamp diagnosis of meibomian gland dysfunction, with an OSDI score of >12. Contact lens wear, active ocular disease other than blepharitis, surgery within past 3 months, active ocular allergy, used isotretinoin within the past 6 months, or have autoimmune disease requiring treatment.
21 Schechter BA I Efficacy of Topical Cyclosporine for the Treatment of Ocular Rosacea Adult patients with rosacea-associated eyelid and corneal changes. Eyelid defects, lagophthalmos, active ingredient sensitivity, pregnant/nursing mothers.
26 Yoo SE I The Effect of Low-Dose Doxycycline Therapy in Chronic Meibomian Gland Dysfunction Adult patients with newly diagnosed chronic meibomian gland dysfunction with grade 2 or worse meibomian gland destruction or meibomian gland orifice obstruction, and whose symptoms failed to improve despite warm compression, lid massage, lid scrub, and topical eye drops or ointment therapy for more than 2 months. Topical therapy within 2 weeks before the beginning of the study.
8 Goto E I–II Low-Concentration Homogenized Castor Oil Eye Drops for Noninflamed Obstructive Meibomian Gland Dysfunction Consecutive series of adult MGD patients nonresponsive to conventional therapy, which could include lid hygiene and topical artificial tears, antibiotics (oral/topical), and/or corticosteroids. Anterior blepharitis of more than moderate severity, infectious conjunctivitis, MGD with acute inflammation, seborrheic MGD. No patients wore CLs; unclear if this was an exclusion criterion.
20 Rubin M I–II Efficacy of Topical Cyclosporin 0.05% in the Treatment of Posterior Blepharitis Consecutive adult patients presenting with posterior blepharitis defined as lid erythema and MG telangiectasia. Current punctal plugs, doxycycline, steroids, women of childbearing age with no contraception.
10 Luchs J II Efficacy of Topical Azithromycin Ophthalmic Solution 1% in the Treatment of Posterior Blepharitis Adult patients with a diagnosis of poster blepharitis by a qualified ophthalmologist; patients must have a grade of at least 2 of lid redness/swelling and gland plugging. Eyelid structural abnormalities, active inflammation, fungal or viral infection, ocular surgery in the past 90 days, including LASIK or glaucoma surgery.
12 Matsumoto Y II The Evaluation of the Treatment Response in Obstructive Meibomian Gland Disease by in Vivo Laser Confocal Microscopy Consecutive adult patients with severe obstructive MGD associated with lid inflammation. History of Sjögren's syndrome; Stevens-Johnson syndrome; chemical, thermal, or radiation injury; or any ocular surgery or procedure that would create an ocular surface problem. History of contact lens use.
15 Olson MC II Increase in Tear Film Lipid Layer Thickness Following Treatment with Warm Compresses in Patients with Meibomian Gland Dysfunction Consecutive adult patients with symptoms of ocular dryness were enrolled with the following criteria: (1) subjective dry eye status determined by a score of ≥6 on dry eye symptoms questionnaire; (2) meibomian gland obstruction determined by SLE; (3) TFLLT baseline of ≤90 nm; as well as fluorescein tear breakup time and Schirmer results of ≤10 mm/5 min. Exclusions were not defined other than evidence of ocular disease.
16 Paugh JR II Meibomian Therapy in Problematic Contact Lens Wear Consecutive adult contact lens wearers with (1) minimal or transient symptoms of dryness, (2) cloudy or absent MG secretions, and (3) CL intolerance not related to lens or solution parameters. History of ocular trauma or surgery, use of tear-influencing medications, systemic connective tissue disease, ocular conditions (blepharitis, meibomitis, or any anterior segment disease), contact lens intolerance due to poor lens fit, deposits, care system hypersensitivity.
18 Pinna A II Effect of Oral Linoleic and Gamma-Linolenic Acid on Meibomian Gland Dysfunction Group 4 and 5 of McCulley Classification system for MGD (McCulley et al. Classification of chronic blepharitis. 27 Infectious keratoconjunctivitis, inflammatory disease unrelated to MGD, Schirmer I test result <10 mm/5 min, concomitant ocular disease, previous ocular surgery, alterations of the lacrimal drainage system, concomitant topical ophthalmic medic ations, topical ophthalmic steroids taken during the 4 weeks before the study; treatment with systemic drugs affecting.
19 Romero JM II Conservative Treatment of Meibomian Gland Dysfunction Adult patients with (1) a chief complaint of MGD (ocular discomfort assessed by questionnaire) and (2) diagnosis of MGD with two or more of the following: redness or thickening of the lid margin, telangiectasia, reduced or no secretions, poor quality secretions, gland capping. Current use of treatments for blepharitis, current use of topical or systemic steroids, topical or systemic antibiotics, or topical or systemic antimetabolites, history of contact lens wear, history of eyelid surgery, presence of any ocular disease provoking dry eye syndrome and
24 Souchier M II Changes in Meibomian Fatty Acids and Clinical Signs in Patients with Meibomian Gland Dysfunction after Minocycline Treatment Adult patients with chronic posterior blepharitis defined by redness, thickening, or irregularity of the lid margin, telangiectasia, reduced or no secretions, poor-quality secretions, gland capping, and/or MG metaplasia. Smokers, contact lens wearers, and diabetic patients.
25 Yalcin E II N-Acetylcysteine in Chronic Blepharitis Adult clinic patients with chronic posterior blepharitis. Eye disorders that could affect the ocular surface (e.g. infectious conjunctivitis), excessive meibomian lipid secretion, ≤10 mm by Schirmer II, and contact lens use.
14 Mori A II–III Disposable Eyelid-Warming Device for the Treatment of Meibomian Gland Dysfunction Short term efficacy study: adult patients with TBUT ≤5 s and dry eye symptoms. Therapeutic study: adult patients with TBUT ≤5 s, MGD (not defined), and dry eye symptoms. Exclusions were not defined.
1 Albietz JM III Effect of Antibacterial Honey on the Ocular Flora in Tear Deficiency and Meibomian Gland Disease Consecutive adult dry eye patients subsequently classified into four groups: non-Sjögren's tear deficienc y, Sjögren's tear deficiency, MGD (posterior lid margin thickening, irregularity, telangiectasia, gland loss, plugging and capping, and abnormal MG secretions), and MGD plus tear deficiency. Contact lens wear, eye surgery, punctal occlusion, and use of eye drops other than artificial tears within the past 3 months, ocular infection, pregnancy/nursing, changes in systemic medications altering the tear film, uncontrolled systemic disease.
2 Blackie CA III Inner Eyelid Surface Temperature as a Function of Warm Compress Methodology Healthy adult individuals. Ocular adnexal disease that would interfere with warm compress application.
3 Cetinkaya A III Pediatric Ocular Acne Rosacea: Long-Term Treatment with Systemic Antibiotics Rosacea patients younger than 12 years of age, with or without obvious skin involvement, who were having active inflammation with ocular discomfort, photophobia, and red eyes, despite topical steroid, antibiotic or Exclusions were not defined.
4 Dougherty JM III The Role of Tetracycline in Chronic Blepharitis: Inhibition of Lipase Production in Staphylococci Isolates from patients with meibomian keratoconjunctivitis and staphylococcal blepharitis; patients not clinically defined. Exclusions were not defined.
5 Epstein GA III Combined Excision and Drainage with Intralesional Corticosteroid Injection in the Treatment of Chronic Chalazia Adult and pediatric patients undergoing surgical excision of chronic chalazia; patients not clinically defined. Exclusions were not defined.
6 Goto E III Improvement of Tear Stability Following Warm Compression in Patients with Meibomian Gland Dysfunction Consecutive adult patients with noninflamed obstructive MGD. Anterior blepharitis of more than moderate severity, infectious conjunctivitis, MGD with acute inflammation, meibomitis, seborrheic MGD.
7 Goto E III Treatment of Non-Inflamed Obstructive Meibomian Gland Dysfunction by an Infrared Warm Compression Device Consecutive adult patients with MGD unresponsive to conventional treatment, which could include lid hygiene and topical artificial tears, antibiotics (oral/topical) and/or corticosteroids. Anterior blepharitis of moderate or greater severity, infectious conjunctivitis, occluded punctum, contact lens wear, best corrected acuity <1.0 logMAR, “obvious” eyelid skin abnormalities (atopic dermatitis).
9 Ishida R III Tear Film with “Orgahexa EyeMasks” in Patients with Meibomian Gland Dysfunction Adult patients with simple MGD defined as (1) occluded MG orifices, (2) cloudy secretions, (3) keratinization and/or mucocutaneous junction displacement, and (4) noninflamed lid margins. Exclusions were not defined.
11 Matsumoto Y III Efficacy of a New Warm Moist Air Device on Tear Functions of Patients with Simple Meibomian Gland Dysfunction Adult patients with simple MGD defined as (1) occluded MG orifices, (2) cloudy secretions, (3) keratinization and/or mucocutaneous junction displacement, and (4) noninflamed lid margins. Exclusions were not defined.
13 Meisler DM III Oral Erythromycin Treatment For Childhood Blepharokeratitis Children with chronic lid margin inflammation (lid redness and thickening). Exclusions were not defined.
22 Shine WE III Minocycline Effect on Meibomian Gland Lipids in Meibomianitis Patients Patients were selected based on clinical appearance and categorized as having acne rosacea with or without meibomianitis, or seborrheic blepharitis alone. 27 Exclusions were not defined.
23 Song CH III Enhanced Secretory Group II PLA2 Activity in the Tears of Chronic Blepharitis Patients Adult patients with the presence of one or more of the signs and symptoms of blepharitis for more than 6 months, categorized into six blepharitis groups. 27 Exclusions were not defined.
Table 5.
 
List and Frequency of Reported Criteria (All Studies Represented)
Table 5.
 
List and Frequency of Reported Criteria (All Studies Represented)
A. Inclusion Criteria Frequency (%)
Age of Participants
Adult patients 22/26 (84.6)
Pediatric patients 2/26 (2.7)
Adult and pediatric patients 1/26 (3.8)
Not mentioned 1/26 (3.8)
Symptomatology
Ocular Surface Disease Index questionnaire 1/26 (3.8)
Symptoms fail to improve with conventional therapy 3/26 (11.5)
Discomfort or foreign body sensation 2/26 (7.7)
Eye redness 1/26 (3.8)
Photophobia 1/26 (3.8)
Ocular dryness 3/26 (11.5)
Contact lens intolerance 1/26 (3.8)
Ocular Symptoms Scale 1/26 (3.8)
Lid Margin Findings
Previous or current diagnosis of MGD or posterior blepharitis 12/26 (46.1)
Posterior lid margin erythema or hyperemia 5/26 (19.2)
Eyelid edema 1/26 (3.8)
Lid margin thickening or irregularity 4/26 (15.4)
Meibomian gland orifice plugging 8/26 (30.8)
Cloudy, yellow, or frothy meibomian gland secretions 5/26 (19.2)
Lid margin telangiectasia 4/26 (15.4)
Meibomian gland capping 3/26 (11.5)
Meibomian gland loss/destruction 5/26 (19.2)
Chalazia 1/26 (3.8)
Eyelid inflammation (not defined) 2/26 (7.7)
Eyelid noninflammation 2/26 (7.7)
Ocular Surface Findings
Rosacea-associated eyelid and corneal changes 3/26 (11.5)
Tear Film Findings
Tear interferometry 1/26 (3.8)
TBUT<10 seconds 1/26 (3.8)
TBUT<5 seconds 1/26 (3.8)
Schirmer's test <10 seconds 1/26 (3.8)
Existing Classification Scheme
McCulley Classification system for MGD 27 2/26 (7.7)
B. Exclusion criteria 1,2,6 8,10,12,14 21,24,26 Frequency (%)
Contact lenses use 10/17 (58.8)
History of ocular surgery 7/17 (41.2)
Eye disorders affecting the ocular surface 6/17 (35.3)
Meibomitis, seborrheic MGD, and excessive meibomian lipid secretion 4/17 (27.5)
Topical medical therapy (of any kind) 4/17 (27.5)
Infectious conjunctivitis 4/17 (27.5)
Systemic diseases affecting the ocular surface 4/17 (27.5)
Topical or systemic steroids use 3/17 (17.6)
Active ocular disease 3/17 (17.6)
Pregnancy or childbearing age without contraception 3/17 (17.6)
Stevens-Johnson syndrome 3/17 (17.6)
Chemical, thermal, or radiation injury 3/17 (17.6)
Decreased reflex tearing (<10 mm/5 min Schirmer test result) 2/17 (11.8)
Diabetes 2/17 (11.8)
Current treatment for blepharitis 2/17 (11.8)
Topical or systemic antibiotics 2/17 (11.8)
Alteration of lacrimal drainage system 2/17 (11.8)
Drugs affecting tearing 2/17 (11.8)
Sjögren's syndrome 2/17 (11.8)
MGD with acute inflammation 2/17 (11.8)
Anterior blepharitis with more than moderate severity 2/17 (11.8)
Active ocular allergy 2/17 (11.8)
Inflammatory diseases unrelated to MGD 2/17 (11.8)
Ocular adnexal pathology interfering with warm compress application 2/17 (11.8)
Lid structural abnormality 2/17 (11.8)
Topical or systemic antimetabolites 1/17 (5.9)
Eyelid surgery 1/17 (5.9)
Use of isotretinoin within the past 6 months 1/17 (5.9)
Autoimmune disease requiring treatment 1/17 (5.9)
Smokers 1/17 (5.9)
Punctal plugs 1/17 (5.9)
Anterior chamber inflammation 1/17 (5.9)
Glaucoma 1/17 (5.9)
Anterior segment diseases 1/17 (5.9)
Best corrected visual acuity <1.0 logMAR 1/17 (5.9)
Lid skin disease 1/17 (5.9)
Cicatricial conjunctival diseases 1/17 (5.9)
Sensitivity to study medication 1/17 (5.9)
Table 6.
 
Categories of 39 Exclusion Criteria in 17 Studies*
Table 6.
 
Categories of 39 Exclusion Criteria in 17 Studies*
Frequency (%)
Ocular Diseases (20/39; 51.3%)
Eye disorders that affect the ocular surface 6/17 (35.3)
Meibomitis, seborrheic MGD, and excessive meibomian lipid secretion* 4/17 (23.5)
Infectious conjunctivitis 4/17 (23.5)
Active ocular disease 3/17 (17.6)
Stevens-Johnson syndrome 3/17 (17.6)
Meibomitis and seborrheic MGD† 3/17 (17.6)
Highly decreased reflex tearing <10 mm 2/17 (11.8)
MGD with acute inflammation† 2/17 (11.8)
Anterior blepharitis of more than moderate severity 2/17 (11.8)
Active ocular allergy 2/17 (11.8)
Inflammatory diseases unrelated to MGD 2/17 (11.8)
Ocular adnexal pathology interfering with warm compress application 2/17 (11.8)
Lid structural abnormality 2/17 (11.8)
Alteration of lacrimal drainage system 2/17 (11.8)
Anterior chamber inflammation 1/17 (5.9)
Glaucoma 1/17 (5.9)
Anterior segment diseases 1/17 (5.9)
Best corrected visual acuity <1.0 logMAR 1/17 (5.9)
Cicatricial conjunctival diseases 1/17 (5.9)
Lid skin disease 1/17 (5.9)
Iatrogenic (13/39; 33.3%)
Contact lens use 10/17 (58.8)
Ocular surgery 7/17 (41.2)
Topical medical therapy (of any kind) 4/17 (23.5)
Topical or systemic steroids 3/17 (17.6)
Chemical, thermal, radiation injury 3/17 (17.6)
Current treatment for blepharitis 2/17 (11.8)
Topical or systemic antibiotics 2/17 (11.8)
Drugs affecting tearing 2/17 (11.8)
Topical OD systemic antimetabolites 1/17 (5.9)
Eyelid surgery 1/17 (5.9)
Use of isotretinoin within the past 6 month 1/17 (5.9)
Smoking 1/17 (5.9)
Plugs 1/17 (5.9)
Systemic Diseases (6/39; 15.4%)
Systemic, neurologic, dermatologic diseases affecting ocular surface 4/17 (23.5)
Pregnancy/child bearing age without contraception 3/17 (17.6)
Diabetes 2/17 (11.8)
Sjögren's syndrome 2/17 (11.8)
Autoimmune disease requiring treatment 1/17 (5.9)
Sensitivity to study medication 1/17 (5.9)
Table 7.
 
Clinical and Symptom Outcomes
Table 7.
 
Clinical and Symptom Outcomes
Ref. First Author Eyelids Meibomian Glands Inflammation Ocular Surface Microbial Tear Symptoms Other
Lid Margin Appearance Lid Margin Injection/Erythema/Redness Tarsal Telangiectasia Edema Debris Inflammatory Cell Density Temperature Papillary Hypertrophy Expression/Secretion Destruction (Meibography) Obstruction/Plugging Meibum Composition Improvement Recurrence Conjunctival Hyperemia Conjunctival Papillae Conjunctival Staining Corneal Staining Corneal Neovascularization Change In Flora Lipase Production (In Vitro) Bacterial Growth Inhibition (In Vitro) TBUT Schirmer I (w/wo Anesthesia) Mucous Fern Test Evaporation Rate Lipid Layer Interference Pattern/Thickness Lysozyme Levels or PLA2 Type Activity Foam (Tear Meniscus) General Ocular Face Scores Progression of Post-Surgical Healing Overall Disease Improvement Safety
17 Perry HD Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes w a Yes
21 Schechter BA Yes Yes Yes Yes w a Yes
26 Yoo SE Yes Yes Yes Yes wo a Yes
8 Goto E Yes Yes Yes Yes Yes Yes Yes
20 Rubin M Yes Yes Yes Yes Yes Yes Yes
10 Luchs J Yes Yes Yes Yes Yes Yes Yes
12 Matsumoto Y Yes Yes Yes Yes Yes Yes Yes Yes Yes wo a Yes
15 Olson MC Yes
16 Paugh JR Yes
18 Pinna A Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes (OSDI)
19 Romero JM Yes Yes Yes
24 Souchier M Yes Yes Yes Yes
25 Yalcin E Yes Yes Yes
14 Mori A Yes Yes Yes Yes
1 Albietz JM Yes
2 Blackie CA Yes
3 Cetinkaya A Yes Yes Yes
4 Dougherty JM Yes Yes Yes
5 Epstein GA Yes Yes Yes Yes Yes Yes
6 Goto E
7 Goto E Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
9 Ishida R Yes Yes Yes Yes Yes wo a Yes Yes
11 Matsumoto Y Yes Yes Yes Yes Yes wo a Yes Yes
13 Meisler DM Yes Yes
22 Shine WE Yes
23 Song CH Yes
Table 8.
 
Relevant Registered Clinical Trials
Table 8.
 
Relevant Registered Clinical Trials
Condition Title Interventions Status Outcome Comment
MGD A Single-Center, Double-Masked, Randomized, Vehicle Controlled Study to Evaluate the Safety and Efficacy of Testosterone 0.03% Ophthalmic Solution Compared to Vehicle for the Treatment of MGD Testosterone ophthalmic solution vs. vehicle R Primary: MG secretion (128 days) Secondary: comfort (128 days) Phase II, enrollment by invitation only
MGD Efficacy of 0.05% Cyclosporine Ophthalmic Emulsion Compare with Tear in MGD 0.05% cyclosporine eye drop R Primary: NTBUT (0,1,2,3 month) Phase IV
Secondary: OSDI score, TBUT, fluorescein/rose bengal staining, MG (0,1,2,3 month)
Blepharitis Lipids of the Human Tear Film and Their Effect on Tear Stability Doxycycline; essential fatty acid; azithromycin R Primary: inflammation of eyelid (2 months) Phase IV
Secondary: character of MG secretion (2 months)
Dry eye syndrome A Prospective Clinical Study Assessing the Effects of Tetracycline Antibiotic on Tear Film and Tear Lipid Composition within a Population of Patients Diagnosed with Blepharitis and Dry Eye Disease Condition Tetracycline: doxycycl ine analog T Primary: evaporimetry; fluorophotometry; MG expression and lipid analysis
Secondary: Schirmer's, TBUT, bacteriology, transillumination and meibography
Blepharitis A Placebo-Controlled Double-Masked Clinical Assessment Study of Essential Fatty Acid Supplement and Its Effect on Patients with Apparent Aqueous-Deficient Dry Eye Syndrome Condition Essential fatty acid supplement R Primary: lipid bio chemistry changes Phase IV
Secondary: evaporimetry and fluorophotometry
Posterior blepharitis Topical IL-1-Ra for Treatment of Posterior Blepharitis 2.5% IL-1Ra, Placebo; 5% IL-1Ra R Primary: MG secretion/quality, TBUT, cornea and conjunctival staining, and OSDI questionnaire (12 weeks) Phase I/II
Secondary: MG occlusion, Schirmer with and without anesthesia. (12 weeks)
KCS Efficacy and Safety Study of Nutritional Supplements for Treatments of Dry Eye Condition Dietary supplement: Hydroeye; vs. inactive capsule R Primary: Schirmer, OSDI, TBUT, corneal staining (screening at weeks 4, 12, and 24) Signs of MGD were inclusion criteria
Secondary: Corneal topography, MGD, facial expression subjective scale, artificial tear usage, HLA-DR staining of impression cytology (screening, at weeks 12 and 24)
Blepharitis meibomitis; dry eye Treatment of Patients With Blepharitis and Facial Rosacea Doxycycline vs. placebo R Primary: Change in OSDI, bulbar conjunctival hyperemia (baseline to end of study) Phase II
Secondary: Change in Schirmer result, TBUT, meibum character/fluidity, MG inspissation (baseline to end of study)
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