Characteristics of included studies [ordered by study ID]

Adenis 1996a
Methods	Study design: randomized, parallel-group study Conditions included: acute conjunctivitis or acute or chronic blepharitis Enrollment: 77 participants randomized; 21 with chronic blepharitis Exclusions and loss to follow-up: 38 participants who were either culture-negative on day 0 or did not complete follow-up were excluded from the efficacy analyses Study follow-up: 7 days
Participants	Country: France Age: mean 52.8 ± 22.8 years (range 6 to 93 years) Gender: 37 men and 40 women Inclusion criteria: 1) at least 1 year of age, 2) clinical evidence of bacterial acute conjunctivitis or acute or chronic blepharitis Exclusion criteria: 1) allergic to ciprofloxacin, fusidic acid, or components of either formulation; 2) treatment with topical or systemic antimicrobial agents or steroids in the last 48 hours; 3) pregnant or not using adequate birth control methods
Interventions	Ciprofloxacin (n = 39; 7 with chronic blepharitis; 21 culture-positive on day 0): 0.3% ciprofloxacin ophthalmic solution, starting with 2 drops every 2 hours for the first 48 hours and followed by 2 drops every 4 hours from days 2 to 6; eyelid margin scrub with 2 drops of ciprofloxacin during treatment period Fusidic acid (n = 38; 14 with chronic blepharitis; 18 culture-positive on day 0): 1% fusidic acid gel, 1 drop applied twice a day to the conjunctival sac
Outcomes	Primary outcomes: 1) efficacy of interventions (in participants who were culture-positive on day 0): bacteriologic response to treatment between day 7 and day 0 (eradication, reduction, persistence, or proliferation); change in clinical sign and symptom scores; patient’s response to treatment (cured, improved, unchanged, or worsened) 2) safety of interventions (in all participants): clinical adverse events Measurements taken at baseline and day 7 Unit of analysis: microbiologic outcomes were based on the eye having the least response to treatment, overall signs and symptoms were based on the average of both eyes in cases of bilateral infections, and safety data were reported descriptively for all eyes
Notes	Study dates: not reported Funding source: Alcon Laboratories Inc., USA Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Reported as an open study.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Reported as an open study.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Reported as an open study.
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed.
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Combined results for participants with conjunctivitis or acute or chronic blepharitis. Even with randomization there was an imbalance between treatment groups with respect to diagnosis Funded by the pharmaceutical industry.
Akyol-Salman 2010
Methods	Study design: randomized, parallel-group study Conditions included: MGD (posterior blepharitis) Enrollment: 20 participants randomized Exclusions and loss to follow-up: none Study follow-up: 1 month
Participants	Country: Turkey Age: mean 40 years Gender: 12 men and 8 women Inclusion criteria: 1) thickening or irregularity of the eye lid margins; 2) erythema of posterior lid margin; 3) dilation of blood vessels and telangiectasis around the glandular orifices; 4) reduced or no expulsion of normally thin, oily secretions on digital pressure; 5) expulsion of large amounts of cloudy, turbid, foamy, granular, or semi-solid secretion on digital pressure; 6) and capping of meibomian gland orifices Exclusion criteria: 1) systemic abnormalities, 2) previous ocular surgery, 3) intraocular pathology, 4) history of allergic reaction to the drugs, 5) current use of therapies for MGD
Interventions	NAC (n = 10): 5% NAC ophthalmic solution 4 times daily Control (n = 10): preservative-free artificial tear 4 times daily All participants applied lid hygiene with a solution (Blepharoshampoo) once daily
Outcomes	Primary outcomes: 1) decrease in severity of inflammatory symptoms 2) change in mean ocular symptoms (ocular burning, itching, foreign body sensation, and intermittent filmy or blurred vision) 3) tear function: Schirmer test and fluorescein BUT Safety outcomes: elevated IOP and allergic reactions Measurements taken at baseline and 1 month Unit of analysis: the individual (mean of both eyes)
Notes	Study dates: not reported Funding source: not reported Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“A random-number generator assigned patients to a treatment group. Odd numbers were assigned to the NAC group, and even numbers were assigned to the preservative-free artificial tear group.”
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Masking of participants was not reported.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Masking of healthcare providers was not reported.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	“All patients were examined by the same masked investigator at 1 day and 1 month.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed.
Selective reporting (reporting bias)	High risk	Results for changes in the severity of inflammatory symptoms were not reported
Other bias	Low risk
Aragones 1973
Methods	Study design: randomized, parallel-group study Conditions included: infectious blepharitis Enrollment: 30 patients hospitalized at the Lapeer State Home and Training School, Michigan, USA Exclusions and loss to follow-up: none Study follow-up: not specified
Participants	Country: USA Age: not specified Gender: not specified Inclusion criteria: 1) clinically diagnosed blepharitis with an infectious component sensitive to sulfacetamide, 2) associated inflammation
Interventions	Prednisolone/sulfacetamide (n = 15): 10% sodium sulfacetamide plus 0.2% prednisolone acetate suspension, 3 drops in each eye 4 times daily Sulfacetamide alone (n = 15): 10% sodium sulfacetamide, 3 drops in each eye 4 times daily All participants: nurses administered the eyedrops without removing the excess from the eyelids; no concurrent antibiotics or steroids were given
Outcomes	Primary outcomes: 1) subjective efficacy of interventions: overall response to treatment (excellent, good, no change, worse); rate of therapeutic effect (rapid, normal, slow) 2) objective efficacy of interventions: changes in clinical signs and symptoms Secondary outcomes: 1) bacteriologic eradication rates 2) clinical adverse events Measurements taken at baseline and daily until completion of treatment Unit of analysis: the individual
Notes	Study dates: not reported Funding source: Allergan Pharmaceuticals, USA Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A randomized numbering technique was used.
Allocation concealment (selection bias)	Low risk	Identical opaque white plastic dropper bottles filled with solutions of similar appearance were prepared
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Participants were masked to treatment group by the use of identically prepared solutions that were administered by nurses
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	Reported as a double-blind study; medications were serially dispensed to each participant from the supply of masked containers
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	Reported as a double-blind study; medications were serially dispensed to each participant from the supply of masked containers
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed as there were no exclusions or losses to follow-up
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Funded by the pharmaceutical industry.
Behrens-Baumann 2006
Methods	Study design: randomized, placebo-controlled study Conditions included: blepharitis Enrollment: 203 participants enrolled at 14 medical practices Exclusions and loss to follow-up: 6 participants, 3 from each group, did not complete at least 1 follow-up exam and were excluded from the analyses Study follow-up: 2 weeks
Participants	Country: Germany Age: median 66 years (range 18 to 89 years) Gender: 87 men and 116 women Inclusion criteria: 1) at least 18 years of age, 2) a blepharitis summary score of at least 12 Exclusion criteria: 1) antibiotic therapy was indicated, 2) cases of resistant blepharitis, 3) unusual eyelid anatomy (independent of the blepharitis), 4) surgical intervention in the eye within the last 90 days, 5) severe KCS (dry-eye syndrome), 6) allergic ocular illnesses, 7) allergies to components of the test medication, 8) heavy systemic dysfunction judged by the treating doctor, 9) rheumatoid arthritis/spondylitis, 10) anamnesis of malignant illnesses within the last 5 years
Interventions	Bibrocathol (n =103): bibrocathol (Noviform) 5% ointment Placebo (n =100): vehicle ointment All participants: applied a 5-mm long ribbon of ointment on the upper and lower eyelid up to the eyelid edge after eyelid hygiene 3 times daily
Outcomes	Primary outcomes: 1) change in blepharitis summary score at 2 weeks 2) change in objective signs at 2 weeks 3) change in subjective symptoms at 2 weeks 4) adverse effects Measurements taken 2 days before baseline, at baseline, and days 7 and 14 Unit of analysis: the individual
Notes	Study dates: not reported Funding source: Novartis Pharma GmbH, Nuremberg Declarations of interest: 1 study author affiliated with Novartis Pharma GmbH, Nuremberg and 1 study author affiliated with IMEREM Institute for Medical Research Management and Biometrics GmbH, Nuremberg Publication language: German
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomization was carried out by the sponsor of the study in blocks of 4
Allocation concealment (selection bias)	Low risk	Participants were allocated to treatment groups at the baseline visit, which occurred 2 days after study enrollment
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	The participants were masked to treatment groups and a placebo ointment was used. The medication for both treatment groups was identical concerning packaging, inscription, tube, and size
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	A masked investigator graded the ocular findings at the initial visit, at each follow-up visit, and at the conclusion of the treatment period
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	A masked investigator graded the ocular findings at the initial visit, at each follow-up visit, and at the conclusion of the treatment period
Incomplete outcome data (attrition bias) All outcomes	High risk	6 participants who were randomized to receive treatment, but did not complete at least 1 follow-up were excluded from the analyses
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Funded by the pharmaceutical industry and 2 study authors affiliated with industry
Bloom 1994
Methods	Study design: randomized, parallel-group study Conditions included: blepharitis and blepharoconjunctivitis Enrollment: 464 participants from multiple, international specialist eye centers Exclusions and loss to follow-up: 220 participants who were culture-negative on day 0 and did not complete follow-up were excluded from the efficacy analyses Study follow-up: 7 days
Participants	Countries: Europe and North America Age: mean 61 years (range 18 to 80 years) Gender: 217 men and 247 women Inclusion criteria: patients with blepharitis or blepharoconjunctivitis with presumed bacterial origin Exclusion criteria: 1) history of allergy to components of medications, 2) treatment with an antimicrobial agent or steroid in previous 48 hours, 3) pregnancy, 4) refusal to stop wearing contact lenses during study period, 5) meibomian disease, 6) frank marginal ulceration or severe pseudomembranous conjunctivitis
Interventions	Ciprofloxacin (n = 230): 0.3% ciprofloxacin eyedrops, starting with 1 or 2 drops every 2 hours for the first 48 hours and followed by 2 drops every 4 hours from days 2 to 6 Tobramycin (n = 234): 0.3% tobramycin eyedrops, starting with 1 or 2 drops every 2 hours for the first 48 hours and followed by 2 drops every 4 hours from days 2 to 6 All participants: nightly lid scrubs
Outcomes	Primary outcomes: 1) change in clinical assessment (cured, better, unchanged, worse) 2) changes in clinical signs and symptoms 3) change in bacteriologic assessment (eradication, reduction, persistence, proliferation) 4) clinical adverse events Measurements taken at baseline and day 7 Unit of analysis: the individual, using the worse eye in cases of bilateral disease
Notes	Study dates: not reported Funding source: not reported Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Unclear risk	Reported as double-masked, but details of masking not reported
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Unclear risk	Reported as double-masked, but details of masking not reported
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Unclear risk	Reported as double-masked, but details of masking not reported
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed.
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Included participants with blepharitis or blepharoconjunctivitis
Collum 1984
Methods	Study design: randomized, placebo-controlled study Conditions included: chronic blepharitis Enrollment: 40 participants Exclusions and loss to follow-up: 2 participants, 1 from each group, were lost to follow-up Study follow-up: 4 weeks during the time of receiving treatment
Participants	Country: Ireland (or UK not specified) Age: not reported Gender: not reported Inclusion criteria: history of blepharitis for at least 2 years Exclusion criteria: 1) other eye pathology, 2) use of concurrent steroids or antihistamines
Interventions	DSCG (n = 20): 4% disodium cromoglycate ointment (Opticrom) 4 times daily for 4 weeks Placebo (n = 20): placebo ointment of yellow paraffin and acetylated lanolin 4 times daily for 4 weeks All participants: lid scrub performed at initial visit
Outcomes	Primary outcomes: 1) clinical assessment of signs and symptoms at 4 weeks 2) change in bacterial cultures at 4 weeks 3) adverse effects 4) patients’ and clinicians opinions of treatment 5) skin testing for common allergens Measurements taken at baseline and weekly for 4 weeks Unit of analysis: the individual
Notes	Study dates: not reported Funding source: not reported Declarations of interest: 1 of the authors affiliated with Fisons Pharmaceuticals, Loughborough, UK Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Reported as double-masked and used placebo for control group
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Unclear risk	Reported as double-masked, but details of masking not reported
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Unclear risk	Reported as double-masked, but details of masking not reported
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed.
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	1 of the authors affiliated with pharmaceutical industry.
Donshik 1983
Methods	Study design: randomized, placebo-controlled study Conditions included: chronic staphylococcal blepharoconjunctivitis Enrollment: 100 participants Exclusions and loss to follow-up: 3 participants were lost to follow-up, 18 participants were excluded from the efficacy analyses Study follow-up: 2 weeks
Participants	Country: USA Age: range 20 to 94 years Gender: 41 men and 56 women (as reported) Inclusion criteria: 1) chronic staphylococcal blepharoconjunctivitis (at least 1 previous episode of acute blepharoconjunctivitis or at least 1 month’s duration of the present eye complaint); 2) scores of 2 or more for conjunctival or lid hyperemia or both, and a total score of at least 5 for all signs; 3) staphylococcal infection sensitive to gentamicin Exclusion criteria: 1) use of topical or systemic corticosteroids, antihistamines, or decongestants within 24 hours; 2) known allergies to the study medications; 3) patients with viral infections, fulminant corneal ulcers, uveitis, endophthalmitis, orbital cellulitis, fungal infections, glaucoma, foreign body, postoperative infections, contact lens or other forms of mechanical irritation, trauma, and chemical conjunctivitis
Interventions	Combination (n = 25): 0.3% gentamicin sulfate and 0.1% betamethasone phosphate ophthalmic solution, 1 drop 4 times daily for 2 weeks Betamethasone (n = 25): 0.1% betamethasone phosphate ophthalmic solution, 1 drop 4 times daily for 2 weeks Gentamicin (n = 25): 0.3% gentamicin sulfate (Garamycin) ophthalmic solution, 1 drop 4 times daily for 2 weeks Placebo (n = 25): sterile vehicle placebo solution, 1 drop 4 times daily for 2 weeks Participants were not allowed to use concomitant topical medications (eye shampoos, tear replacement agents, etc.) or oral or other systemic medications with known effects on the eye; warm compresses, lid hygiene with water, and oral analgesics were allowed
Outcomes	Primary outcomes: 1) improvement of signs and symptoms at 2 weeks 2) change in bacterial cultures at 2 weeks 3) adverse reactions 4) compliance with treatment Measurements taken at baseline, days 3 to 4, days 7 to 8, and days 14 to 15 Unit of analysis: the eye with the most severe signs
Notes	Study dates: not reported Funding source: not reported Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Assignment of treatment numbers to the 4 groups was randomized equally between groups
Allocation concealment (selection bias)	Low risk	Treatment numbers were assigned pending culture results.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Study was double-masked and identical packages were used for all solutions, which had similar appearance, color, and consistency
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	Study was double-masked and used treatment numbers on identically packaged bottles
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	Study was double-masked and used treatment numbers on identically packaged bottles
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed.
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Included participants with blepharoconjunctivitis.
Friedland 2011
Methods	Study design: randomized, intra-individual comparative study Conditions included: MGD (posterior blepharitis) Enrollment: 14 participants Exclusions and loss to follow-up: 2 participants were not included in final analyses Study follow-up: 3 months
Participants	Country: USA Age: mean 54.2 years (range 37 to 72 years) Gender: 4 men and 10 women Inclusion criteria: 1) age 18 years or older; 2) written informed consent; 3) willingness and ability to return for all study visits; 4) history of self-reported dry eye symptoms for 3 months prior to study; 5) need for regular use of artificial tears, lubricants, or rewetting drops; 6) previous diagnosis of moderate-to-severe dry eye; 7) meibomian gland obstruction Exclusion criteria: 1) history of recent ocular surgery, ocular trauma, or herpetic keratitis within 3 months of study; 2) chronic or recurrent ocular inflammation; 3) active ocular inflammation or infection; 4) lid surface abnormalities that affect lid function in either eye; 5) grade 3 or 4 meibomitis, and/or blepharitis on a scale of 0 to 4; 6) dry eye related to Steven-Johnson syndrome, Riley Day syndrome, sarcoidosis, leukemia, ocular trauma, or chemical burns; 7) women who were pregnant, nursing, or not using adequate birth control; 8) patients who had changed the dosing of systemic or ophthalmic medication in past 30 days of study; 9) use of topical or systemic medications known to cause ocular dryness; 10) use of another investigational device or agent within 30 days of study
Interventions	Automated device (n = 14): TearScience® automated treatment device for 12 minutes; the lid warmer rests on sclera and heats the meibomian glands of the upper and lower eyelids, the eye cup rests on the closed eyelids and massages the eyelids to express the meibomian glands of the upper and lower eyelids Automated device and manual expression (n = 14): TearScience® automated treatment device for 12 minutes followed by heating and manual expression of individual meibomian glands by clinician All eyes received 2 drops of topical anesthetic prior to device insertion; eyes were treated sequentially, not simultaneously
Outcomes	Primary outcomes: 1) meibomian gland assessment (meibomian gland secretion score and number of meibomian glands yielding liquid secretion across lower eyelid) 2) objective dry eye tests (tear BUT and corneal fluorescein staining) 3) subjective dry eye symptoms (SPEED, OSDI) 4) ocular health examination (anterior segment and retina evaluation, IOP) 5) discomfort/pain evaluation during and after treatment Measurements taken at baseline, 1 day, 1 week, 1 month, and 3 months Unit of analysis: each eye of each participant (intracomparative)
Notes	Study dates: June 2008 Funding source: Korb Associates (Boston, MA, USA) and TearScience (Morrisville, NC, USA) Declarations of interest: study authors consultants and/or employees of TearScience Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Selection of eyes to receive or not receive manual expression was described as random. It was not clear what method of randomization was used
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Participants could not be masked to treatment groups.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Study providers could not be masked to treatment groups.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Outcome assessors were not masked (open study).
Incomplete outcome data (attrition bias) All outcomes	High risk	2 participants who missed follow-up visits were not included in the analysis
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	High risk	The study was funded by the company producing the treatment intervention and the study authors were consultants and/or employees of the company producing the treatment intervention
Goldberg 1960
Methods	Study design: parallel-group study (participants with unilateral disease) and intra-individual comparative study (participants with bilateral disease) Conditions included: inflammatory and/or infectious eye diseases Enrollment: 185 participants (39 participants had bilateral disease); 27 with blepharoconjunctivitis Exclusions and loss to follow-up: none reported Study follow-up: 2 to 40 days (majority were treated between 3 to 14 days)
Participants	Country: USA Age: range 11 to 78 years Gender: 98 men and 87 women Inclusion criteria: variety of inflammatory and/or infectious conditions in the eye for which topical therapy was given
Interventions	Triamcinolone acetonide: Preparation #1 (n = 82 participants with unilateral disease; 19 participants with bilateral disease): 1 mg/cc triamcinolone acetonide sodium hemisuccinate eyedrops Preparation #2 (n = 36 participants with unilateral disease; 19 participants with bilateral disease): 1 mg/cc triamcinolone acetonide dipotassium phosphate eyedrops Triamcinolone acetonide plus antibiotics: Preparation #1 (n = 4 participants with unilateral disease; 20 participants with bilateral disease): 1 mg/cc triamcinolone acetonide sodium hemisuccinate, 2.5 mg/cc neomycin sulfate and 0.25 mg/cc gramicidin eyedrops Preparation #2 (n = 24 participants with unilateral disease; 20 participants with bilateral disease): 1 mg/cc triamcinolone acetonide dipotassium phosphate, 2.5 mg/cc neomycin sulfate and 0.25 mg/cc gramicidin eyedrops 1 drop of ophthalmic solution was administrated according to whatever dosage schedule was prescribed in the individual case; other medications or therapeutic measures were used as needed
Outcomes	Primary outcomes: 1) clinical improvement (changes in the symptoms and inflammatory clinical findings) at the end of the treatment period 2) adverse reactions Measurements taken at the end of the treatment period Unit of analysis: the individual for participants with unilateral disease and the eye for participants with bilateral disease (intracomparative)
Notes	Study dates: not reported Funding source: The Squibb Institute for Medical Research, USA Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Randomization was not reported.
Allocation concealment (selection bias)	High risk	The assignment scheme for unilateral disease participants was not reported. It was not reported how treatment groups for bilateral disease participants were determined
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Study interventions were prepared differently by the participant. Triamcinolone acetonide sodium hemisuccinate was provided in powder form and reconstituted immediately before use. Triamcinolone acetonide dipotassium phosphate was provided in ready-to-use form.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Study investigators prescribed the dosage for individual cases
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Masking of outcome assessors was not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	Intent to treat analysis was followed.
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	High risk	Included participants with various inflammatory and/or infectious conditions, not limited to blepharitis It was unclear if the study intended for 2 types of preparations to be used from the beginning, or if the second preparation was added after the trial began since it was easier to administer. It was also not clear why the dosage was prescribed on an individual basis and what effect this may have had on the results
Goto 2002
Methods	Study design: randomized, placebo-controlled cross-over study Conditions included: noninflamed obstructive MGD Enrollment: 20 participants (40 eyes) Exclusions and loss to follow-up: none reported Study follow-up: 6 weeks
Participants	Country: Japan Age: mean 52.1 ± 11.0 years Gender: 7 men and 13 women Inclusion criteria: patients with MGD who had not improved sufficiently with conventional treatments such as eye lid hygiene, topical therapy with artificial tear, antibiotics, and corticosteroids or systemic antibiotics Exclusion criteria: eyes with anterior blepharitis of more than moderate severity, infectious conjunctivitis, MGD with acute inflammation, eyes with excessive expression of meibum (seborrheic MGD)
Interventions	Homogenized oil drops: 2% castor oil, 5% polyoxyethylene castor oil, 0.3% sodium chloride, 0.15% potassium chloride, and 0.5% boric acid emulsion Placebo drops: normal saline solution Drops were instilled 6 times daily for weeks; participants used a preservative-free artificial tear for 2 weeks (wash-out) before receiving either oil or placebo drops for 2 weeks, then switching for 2 more weeks
Outcomes	Primary outcomes: 1) change in symptoms (face score) 2) tear interference grading (1 to 5) 3) tear evaporation rates 4) fluorescein score (0 to 9) and rose bengal score (0 to 9) 5) tear BUT 6) meibomian gland orifice obstruction (0 to 3) Secondary outcomes: 1) adverse events 2) stability of emulsion Measurements taken at baseline and weeks 2, 4, and 6 Unit of analysis: each eye of each participant
Notes	Study dates: not reported Funding source: Japanese Ministry of Education and Science; Medical School Faculty and Alumni Grants of Keio University, Japan; Hightech Research Centerat Tokyo Dental College; and Nihon Tenganyaku Kenkyusho Co. Ltd., Japan Declarations of interest: 2 study authors and 1 funding source applied for a patent on the eyedrops tested in this study Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Treatment groups were randomly divided by a co-author. It was not clear what method of randomization was used
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	“Blinding among participants … were performed entirely by protocol.”
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	“Blinding among … persons performing the intervention… were performed entirely by protocol.”
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	“Blindingamong… outcome assessors were performed entirely by protocol.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed.
Selective reporting (reporting bias)	High risk	Results at baseline in placebo group were not reported.
Other bias	Unclear risk	Funded by the pharmaceutical industry; company and study authors have patent pending on study intervention Potential carry-over in cross-over phases. Data were presented by eyes rather than by the unit of randomization, which was the individual
Hyndiuk 1990
Methods	Study design: randomized, placebo-controlled study Conditions included: bacterial blepharitis Enrollment: 58 participants Exclusions and loss to follow-up: 19 participants were excluded from the study (6 due to low initial bacterial counts, 5 due to noncompliance, 5 lost to follow-up, and 3 due to adverse reactions) Study follow-up: 7 days
Participants	Country: USA Age: not reported Gender: not reported Inclusion criteria: biomicroscopic evidence of blepharitis Exclusion criteria: 1) other inflammatory pathology of the eye, 2) use of topical medication in previous 72 hours
Interventions	Mercuric oxide (n = 19): 1 % mercuric oxide (yellow) ophthalmic ointment applied twice daily to the eyelid margin for 10 days Placebo (n = 20): anhydrous ointment base without active ingredient applied twice daily to the eyelid margin for 10 days
Outcomes	Primary outcomes: 1) improvement of clinical score and signs at 1 week 2) change in bacterial colonies at 1 week 3) adverse reactions 4) compliance with treatment Measurements taken at baseline (day 1), day 3, and day 7 Unit of analysis: the individual
Notes	Study dates: not reported Funding source: Commerce Drug Co., Inc.; National Institutes of Health; and Research to Prevent Blindness, Inc Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Used placebo ointment so participants were unaware which treatment they received
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	Used randomly coded ointments bottles.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	Used randomly coded ointments bottles.
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed for 19 excluded participants.
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Funded by the pharmaceutical industry.
Ishida 2008
Methods	Study design: controlled clinical trial Conditions included: MGD (posterior blepharitis) Enrollment: 20 participants Exclusions and loss to follow-up: none Study follow-up: 2 weeks
Participants	Country: Japan Age: mean 54.5 years Gender: 8 men and 12 women Inclusion criteria: patients with simple MGD including 1) occluded meibomian gland orifices, 2) cloudy or inspissated glandular secretion with lack of clear meibum secretion after applying moderate pressure, 3) presence of keratinization or displacement of the mucocutaneous junction Exclusion criteria: 1) inflammatory lid disease, 2) history or clinical findings of cicatricial eyelid and conjunctival diseases, 3) excessive meibomian lipid secretion (seborrheic MGD)
Interventions	Orgahexa eye warmer (n = 10): eye mask made of carbon fiber (body heat warms the fiber, which releases far-infrared radiation to warm the mask); masks were applied for 10 minutes in the short-term study and overnight during sleeping for 2 weeks in the long-term study Conventional eye warmer (n = 10): eye mask; masks were applied for 10 minutes in the short-term study and overnight during sleeping for 2 weeks in the long-term study No topical medication were used during the study
Outcomes	Primary outcome: efficacy of warming device after 2 weeks measured by 1) eyelid temperature 2) slit lamp examinations 3) tear BUT 4) Schirmer test 5) vital staining 6) tear film lipid layer interferometry 7) dry-eye symptoms Measurements taken at baseline, 10 minutes, and 2 weeks Unit of analysis: the individual (right eyes only)
Notes	Study dates: not reported Funding source: Therath Medico, Tokyo, Japan supplied the Orgahexa fiber masks Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Reported as a “prospective unmasked nonrandomized study.” The allocation was not described
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Unclear risk	It was reported that “patients did not know which type of mask they were using in this study,” however, the study authors noted that the two masks being studied “had obvious design and appearance differences.”
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Healthcare providers were not masked.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Outcome assessors were not masked. “The type of eye warmer used was masked to the statistician (MK) performing the analyses.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed. “All patients completed both short- and long-term trials wearing the masks successfully during sleep.”
Selective reporting (reporting bias)	Low risk	Results were reported for outcomes described in the methods section of the report
Other bias	Unclear risk	Orgahexa eye warmers were provided by industry.
Jackson 1982
Methods	Study design: randomized, placebo-controlled study Conditions included: symptomatic infective blepharitis or blepharoconjunctivitis Enrollment: 46 participants from 2 study centers Exclusions and loss to follow-up: 3 participants were lost to follow-up Study follow-up: 14 days
Participants	Country: Canada Age: mean 48 years Gender: 23 men and 23 women Inclusion criteria: 1) symptomatic infective marginal blepharitis or blepharoconjunctivitis with a total symptom/sign score between 5 and 25 and significant growth at 24 hours of S. epidermidis or S. aureus, 2) at least 12 years of age Exclusion criteria: 1) recent therapy, 2) contraindication for topical steroid therapy, 3) signs of associated KCS
Interventions	Combination (n = 15): 0.3% gentamicin sulfate and 0.1% betamethasone sodium phosphate (Garasone) ointment applied to the lid margin and gently rubbed into the lashes 3 times daily for 2 weeks Gentamicin (n = 15): 0.3% gentamicin sulfate (Garamycin) ointment applied to the lid margin and gently rubbed into the lashes 3 times daily for 2 weeks Placebo (n = 16): placebo ointment of mineral oil and white petroleum applied to the lid margin and gently rubbed into the lashes 3 times daily for 2 weeks Participants were asked to clean the lid margin before reapplying ointment
Outcomes	Primary outcomes: 1) improvement of signs and symptoms at 2 weeks 2) change in bacterial cultures at 2 weeks 3) adverse reactions Measurements taken at baseline, day 7, and day 14 Unit of analysis: the individual
Notes	Study dates: not reported Funding source: Schering Canada Inc. Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was done by the company, Schering Canada (personal communication with study author)
Allocation concealment (selection bias)	Low risk	Participants were assigned to receive gentamicin-betamethasone, gentamicin, or placebo by opening a sealed envelope that contained the coded study drug number (personal communication with study author)
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Used placebo ointment and coded bottles so participants were unaware which treatment they received
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	Used coded ointment bottles.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	Used coded ointment bottles.
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed for 3 participants lost to follow-up
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Funded by the pharmaceutical industry. Included participants with blepharoconjunctivitis.
Key 1996
Methods	Study design: intra-individual comparative study Conditions included: chronic blepharitis Enrollment: 26 participants Exclusions and loss to follow-up: 1 participant was lost to follow-up Study follow-up: 4 months with limited 3-month extension
Participants	Country: USA Age: mean 37 years Gender: 7 men and 19 women Inclusion criteria: preference for contact lenses wears with concomitant symptoms and signs of blepharitis
Interventions	OCuSoft (n = 26): lid scrub with the OCuSoft pad on the right eye in the morning and evening Neutrogena (n = 26): lid scrub with Neutrogena bar soap on the left eye in the morning and evening Baby shampoo (n = 10): as part of study extension, 10 participants replaced Neutrogena lid scrubs in the left eye with diluted Johnson’s baby shampoo All participants were instructed to minimize use of ocular cosmetics and to keep their scalp, facial skin, and eyebrows clean; all antibiotic medications were discontinued; participants were encouraged to continue wearing contact lenses
Outcomes	Primary outcomes: 1) change in symptom rankings at 4 months by clinician 2) change in sign rankings at 4 months by slit lamp examination 3) patient rankings of effectiveness and ease of use Measurements taken at baseline, 6 weeks, and 4 months; and at 7 months for extension period Unit of analysis: each eye of each participant (intracomparative)
Notes	Study dates: not reported Funding source: not reported Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	High risk	No randomization; right versus left eyes.
Allocation concealment (selection bias)	High risk	Treatments were allocated by assigning the right and left eyes to receive lid scrubs with OCuSoft or Neutrogena, respectively
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Participants could not be masked to treatment groups.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Allocation of right eyes and left eyes was known.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Allocation of right eyes and left eyes was known.
Incomplete outcome data (attrition bias) All outcomes	High risk	Intent to treat analysis was not followed for 1 participant who did not complete follow-up
Selective reporting (reporting bias)	High risk	Changes in signs and symptoms were not reported by treatment group
Other bias	Unclear risk	In the recruitment process, every effort was made to enroll participants wearing contact lenses: 8 participants wore soft contact lenses, 12 wore rigid gas permeable contact lenses, and 6 did not wear contact lenses
Laibovitz 1991
Methods	Study design: placebo-controlled study Conditions included: blepharitis Enrollment: number of participants not reported Exclusions and loss to follow-up: not reported Study follow-up: not reported
Participants	Age: not reported Gender: not reported Inclusion criteria: blepharitis
Interventions	Tetracycline: 1% tetracycline ointment Placebo: placebo ointment
Outcomes	Primary outcome: efficacy of treatment determined by quantitative cultures, clinical evaluations, and patient questionnaires Measurements taken before and after treatment Unit of analysis: the individual
Notes	Study dates: not reported Funding source: not reported Declarations of interest: not reported This study was reported in abstract form only; no other associated publications have been identified
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Randomization was not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Unclear risk	Reported as double-masked, but details of masking not reported
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Unclear risk	Reported as double-masked, but details of masking not reported
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Unclear risk	Reported as double-masked, but details of masking not reported
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Description of participants, methods, and exclusions and losses to follow-up were not reported in the abstract
Selective reporting (reporting bias)	Unclear risk	Primary and secondary outcomes were not clearly specified in the abstract
Other bias	Unclear risk	Study reported in abstract form only, no peer reviewed publications were available
Luchs 2008
Methods	Study design: randomized, parallel-group, open-label study Conditions included: posterior blepharitis Enrollment: 21 participants at 1 study center Exclusions and loss to follow-up: 1 participant who discontinued treatment was excluded Study follow-up: 14 days
Participants	Country: USA Age: mean 63.7 ± 16.13 years (range 28 to 85 years) Gender: 9 men and 11 women (as reported) Inclusion criteria: 1) diagnosis of posterior blepharitis by a qualified ophthalmologist, 2) sign severity score of at least 2 for either redness or swelling of the eyelid margin, 3) sign severity score of at least 2 for either eyelid debris or plugging of the meibomian gland, 4) best corrected visual acuity in both eyes of at least +0.7 Exclusion criteria: 1) lid structural abnormalities; 2) inflammation, active structural change, or both in the iris or anterior chamber; 3) suspected ocular fungal or viral infection; 4) penetrating intraocular surgery in the past 90 days; 5) ocular surface surgery within the past year; 6) history of herpes keratitis; 7) known hypersensitivity to azithromycin or other macrolide antibiotic; 8) glaucoma; 9) pregnant or lactating women
Interventions	Azithromycin (n = 10): topical azithromycin ophthalmic solution 1%, starting with 1 drop twice daily for 2 days and followed by once daily for the next 12 days, plus warm compresses Compress (n = 11): warm compresses alone Compresses were applied to each eye for 5 to 10 minutes twice daily for 14 days Restrictions for topical and systemic medications were enforced prior to and during the study period; unpreserved tear substitutes were allowed; use of contact lenses and eyelid scrubs were discontinued during the study period
Outcomes	Primary outcomes: 1) change in severity of 5 clinical signs (eyelid debris, eyelid redness, eyelid swelling, meibomian gland plugging, and quality of meibomian gland secretion) at 14 days 2) patients’ rating of overall symptom relief at 14 days 3) ocular safety/adverse events Measurements taken at baseline and day 14 Unit of analysis: each eye of each participant (both eyes were included for all participants)
Notes	Study dates: not reported Funding source: Inspire Pharmaceuticals, Inc., USA Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer-generated randomization was used.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Participants could not be masked to treatment groups.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	“While the study was not masked, while examining the patients, I did not have access to the patients chart, nor did I inquire as to which group the patients belonged to. One of my research coordinators was always present to ensure that I was as ”blinded“ as possible as to which group patients fell into. Not a truly masked study, but I did my best.” (personal communication with study author)
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	“While the study was not masked, while examining the patients, I did not have access to the patients chart, nor did I inquire as to which group the patients belonged to. One of my research coordinators was always present to ensure that I was as ”blinded“ as possible as to which group patients fell into. Not a truly masked study, but I did my best.” (personal communication with study author)
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed for 1 participant who discontinued treatment
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Funded by the pharmaceutical industry. Data were presented by eyes rather than by the unit of randomization, which was the individual
Macsai 2008
Methods	Study design: randomized, placebo-controlled study Conditions included: MGD (posterior blepharitis) Enrollment: 38 participants Exclusions and loss to follow-up: 1 participant was excluded due to diagnosis of Sjogren syndrome and 7 participants were lost to follow-up Study follow-up: 1 year
Participants	Country: USA Age: mean 50 years Gender: 6 men and 32 women Inclusion criteria: 1) patients with moderate-to-severe chronic blepharitis and simple obstructive meibomian gland disease, onset > 3 months’ duration; 2) 18 years or older Exclusion criteria: 1) pregnant or nursing, 2) not willing to comply with study procedures, 3) taking aspirin or COX-2 inhibitors regularly, 4) on anticoagulant therapy or having blood disorder, 5) preexisting ocular disease, 6) long-term use of nonsteroidal antiinflammatory agents or COX-2 inhibitors, 7) use of dietary fatty acid supplementation 1 month prior to study
Interventions	Omega-3 supplement (36 eyes, 18 participants): two 1000 mg flaxseed oil capsules (55% omega-3 fatty acid, 15% omega-6 fatty acid, and 19% omega-9 fatty acid) 3 times a day for 1 year Placebo (40 eyes, 20 participants): 2 olive oil capsules 3 times a day for 1 year Use of artificial tears was allowed during study period; all participants continued daily lid hygiene with dilute baby shampoo
Outcomes	Primary outcomes (at 1 year): 1) change in tear BUT 2) change in meibum quality score (meibum color and character scores) 3) change in patient symptoms (overall OSDI score) Secondary outcomes: 1) Schirmer score (under anesthesia) 2) fluorescein and rose bengal surface staining 3) meibomian gland health (appearance and number of gland orifices, quality of meibum) Measurements taken at baseline and months 3, 6, 9, and 12 Unit of analysis: each eye of each participant
Notes	Study dates: not reported Funding source: Pearl Vision Foundation (Dallas, TX, USA); Research for the Prevention of Blindness, Inc. (USA); Ophthalmology Research Fund, Evanston Northwestern Healthcare (USA); and Natrol Corporation (Chatsworth, CA, USA) provided the supplement and placebo capsules Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“Subject numbers were pre-assigned to the control or study group with the aid of the random number generator in Microsoft Excel.”
Allocation concealment (selection bias)	Unclear risk	It is unclear how and when the “subject numbers were preassigned.”
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	“Subjects were masked to the contents of the oil capsule” and “capsules were made to look alike as much as possible and were coded by content.”
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	“The list was not incorporated into any documentation, and only research staff members not involved in patient care had access to these assignments.”
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	“The list was not incorporated into any documentation, and only research staff members not involved in patient care had access to these assignments.”
Incomplete outcome data (attrition bias) All outcomes	Low risk	“An intent-to-treat analysis has been done by assuming that patients lost to follow-up had no change.”
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	High risk	Data were presented by eyes rather than by the unit of randomization, which was the individual Supplements were provided by industry.
Matsumoto 2006
Methods	Study design: controlled clinical trial Conditions included: simple MGD (posterior blepharitis) Enrollment: 20 participants Exclusions and loss to follow-up: none Study follow-up: 2 weeks
Participants	Country: Japan Age: mean 65 years (range 48 to 75 years) Gender: 3 men and 17 women Inclusion criteria: 1) the presence of plugging of the meibomian gland orifices, 2) cloudy or inspissated glandular secretion with lack of clear meibum secretion after the application of moderate digital pressure on the tarsus of the upper and lower eye lid Exclusion criteria: 1) displacement or keratinization of the mucocutaneous junction, 2) inflammatory lid disease or inflammatory skin disorders, 3) history or clinical findings of cicatricial eye lid and conjunctival diseases, 4) excessive meibomian lipid secretion (seborrheic MGD)
Interventions	Warm moist air (n = 10): warm moist air device applied to the eyes for 10 minutes twice a day for 2 weeks; device was set to 60 °C to maintain constant warm moist air Warm compress control (n = 10): towels heated and wetted with 60 °C water applied to the eyes for 10 minutes twice a day for 2 weeks
Outcomes	Primary outcome: effectiveness of warm moist air device after 2 weeks on TFLLT and ocular surface health measured by changes in the following, 1) symptom scores 2) tear BUT 3) fluorescein score 4) rose bengal score Measurements taken at baseline and week 2 Unit of analysis: the individual
Notes	Study dates: not reported Funding source: not reported Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	High risk	No randomization; the assignment was consecutive such that if a participant with MGD was eligible to the study the participant was assigned number 1 and received air device treatment where the next coming participant was number 2 and was allocated to the warm compress group (personal communication with study author)
Allocation concealment (selection bias)	High risk	Allocation was not concealed, participants were assigned alternately to treatment groups
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Participants could not be masked to differences in treatment groups
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Masking of physicians was not done; “Physician in charge thus knew which device the patients received” (personal communication with study author)
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Participants were not masked, thus patient-reported outcomes for symptoms were not masked. Masking of clinical outcome assessors was not done
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed.
Selective reporting (reporting bias)	Low risk	Results of treatment effects for all outcomes were reported.
Other bias	Low risk
More 1968
Methods	Study design: placebo-controlled, cross-over study Conditions included: chronic or recurrent blepharitis Enrollment: 13 participants Exclusions and loss to follow-up: none Study follow-up: 8 weeks
Participants	Country: UK Age: mean 40.8 ± 23.9 years (range 9 to 75 years) Gender: not reported Inclusion criteria: participants with chronic or recurrent blepharitis
Interventions	Penotrane (n = 6): 0.033% penotrane lotion in a Lissapol and glycerin base and 0.033% penotrane hydroxymethylcellulose gel (Octrane) Placebo (n = 7): lotion base and gel base without Penotrane Participants were instructed to scrub or wipe their lid margins with tissue soaked in the lotion and then to squeeze the gel along the intermarginal strip and lower conjunctival fornix 3 times daily for 4 weeks After 4 weeks of using initial treatment, participants switched to alternate treatment for another 4 weeks
Outcomes	Primary outcomes: 1) changes in signs and symptoms after treatment periods 2) change in conjunctival cultures after treatment periods 3) adverse reactions Measurements taken at baseline, and weeks 4 and 8 Unit of analysis: the individual
Notes	Study dates: not reported Funding source: Ward Blenkinsop and Co. Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Allocation to treatment group was not randomized; determined by even or odd birth date
Allocation concealment (selection bias)	High risk	Allocation to treatment group determined by even or odd birth date
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Active and inert preparations were identified by letters “A” or “B” and their true identity remained unknown until the conclusion of the trial
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	Active and inert preparations were identified by letters “A” or “B” and their true identity remained unknown until the conclusion of the trial
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	Active and inert preparations were identified by letters “A” or “B” and their true identity remained unknown until the conclusion of the trial
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed.
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Medication was provided by industry. Potential carry-over in cross-over phases.
Mori 2003
Methods	Study design: RCT Conditions included: MGD (posterior blepharitis) Enrollment: 25 participants Exclusions and loss to follow-up: none Study follow-up: 2 weeks
Participants	Country: Japan Age: 53 years (range 26 to 78) Gender: 2 men and 23 women Inclusion criteria: patients with 1) MGD (defined as the absence of visible gland structure or the presence of obstruction of meibomian gland orifices), 2) tear BUT ≤ 5 seconds in both eyes, 3) dry eye symptoms Exclusion criteria: 1) eye disorders affecting the ocular surface such as infectious conjunctivitis, allergic diseases, autoimmune diseases, and collagen diseases; 2) contact lens wear; 3) excessive meibomian lipid secretion (seborrheic MGD); 4) reflex tear production ≤ 10 mm by Schirmer II test (nasal stimulation)
Interventions	Eye warmer (n = 17): disposable eyelid warming device heated by the oxidation of iron contained inside the mask, applied for 5 minutes once a day for 2 weeks Control (n = 8): untreated
Outcomes	Primary outcome: therapeutic efficacy of warming device after 2 weeks measured by 1) tear film lipid layer interference patterns 2) tear BUT 3) meibomian gland secretion 4) dry-eye symptoms Measurements taken at baseline and week 2 Unit of analysis: the individual
Notes	Study dates: not reported Funding source: Kao Corporation, Japan Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was not reported in publication, but a “computer automatically assigned the participants to two groups” (email communication with study author)
Allocation concealment (selection bias)	Low risk	Method of allocation concealment not reported in publication, but “the allocation assignment was conducted by the third person who specialized in computer” (email communication with study author).
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Participants could not be masked to differences in treatment groups
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	The study examinations and measurements were done by a masked observer
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	The outcomes for dry eye symptoms were participant reported and therefore not masked
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed.
Selective reporting (reporting bias)	High risk	Results of treatment effects for all outcomes were not reported
Other bias	Unclear risk	Funded by industry.
Nelson 1990
Methods	Study design: randomized, placebo-controlled study Conditions included: seborrheic and mixed seborrheic/staphylococcal blepharitis Enrollment: 40 participants Exclusions and loss to follow-up: 3 participants were withdrawn during the study; participants who did not attend a follow-up appointment were excluded from the analysis for that time period Study follow-up: 9 weeks
Participants	Country: UK Age: mean 50.5 years (range 20 to 80 years) Gender: 19 men and 21 women Inclusion criteria: patients with seborrheic and mixed seborrheic/staphylococcal blepharitis not currently receiving treatment Exclusion criteria: 1) use of topical or systemic antibiotics or anti-inflammatory drugs, 2) significant active corneal disease, 3) contact lens wearers, 4) potential pregnancy, 5) known allergy to imidazole antifungals
Interventions	Ketoconazole (n = 20): 2% ketoconazole cream for 5 weeks Placebo (n = 20): lanolin base only cream for 5 weeks All participants used lid hygiene, using cotton buds moistened with Johnson and Johnson baby shampoo, prior to applying cream; lid hygiene was used for 9 weeks
Outcomes	Primary outcomes: 1) change in symptoms using a VAS 2) change in yeast counts 3) change in clinical features 4) bacterial growth or reduction Measurements taken at baseline, and weekly for 9 weeks Unit of analysis: the individual
Notes	Study dates: not reported Funding source: not reported Declarations of interest: 1 of the authors affiliated with Janssen Pharmaceutical Ltd Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Random number tables were used (personal communication with study author)
Allocation concealment (selection bias)	Low risk	Allocation was concealed by use of coded, identically packaged treatment bottles (personal communication with study author)
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Study was double-masked and a placebo treatment was used.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	Study was double-masked and a placebo treatment was used.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	Study was double-masked and a placebo treatment was used.
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed for participants excluded or lost to follow-up
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	1 of the authors affiliated with pharmaceutical industry.
Nguyen 1990
Methods	Study design: parallel-group study Conditions included: blepharitis Enrollment: 29 participants at 22 study centers Exclusions and loss to follow-up: none reported Study follow-up: 7 days
Participants	Country: not reported Age: not reported Gender: not reported Inclusion criteria: patients with symptoms (such as itching, tearing, foreign body sensation) or signs (such as discharge, papillary response, conjunctival hyperemia) of blepharitis
Interventions	Ciprofloxacin (n = 14): ciprofloxacin ophthalmic solution Tobramycin (n = 15): Tobrex® ophthalmic solution (3 mg tobramycin base per mL, preserved with 0.01% (m/v) benzalkonium chloride) Participants applied 1 drop of solution every 2 hours for the first 48 hours, then every 4 hours for the next 4 days; lid scrubs using a cotton swab with the solution were also done nightly
Outcomes	Primary outcomes: 1) patient reported changes in symptoms on day 7 2) clinician evaluated changes in signs and symptoms on day 7 3) bacteriologic cultures on days 0 and 7 4) Patient reported side effects during treatment Measurements taken at baseline and day 7 Unit of analysis: the individual
Notes	Study dates: not reported Funding source: not reported Declarations of interest: not reported This study was reported in abstract form only, no other associated publications have been identified
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Randomization was not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Participants were given masked solution bottles.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Masking was not reported for the physicians.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Masking was not reported for outcome assessors.
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	Description of participants, methods, and exclusions and losses to follow-up were not reported in the abstract
Selective reporting (reporting bias)	High risk	Primary and secondary outcomes were not clearly specified in the abstract. Results for participant reported changes in symptoms were not reported
Other bias	Unclear risk	Study reported in abstract form only, no peer reviewed publications were available
Olson 2003
Methods	Study design: randomized, intra-individual comparative study Conditions included: MGD (posterior blepharitis) Enrollment: 20 participants Exclusions and loss to follow-up: none Study follow-up: 30 minutes during therapy and 5 minutes post-therapy
Participants	Country: USA Age: range 26 to 59 years Gender: 3 men and 17 women Inclusion criteria: patients with a principle complaint of ocular dryness including 1) subjective dry eye score of 6 or more, 2) meibomian gland obstruction determined by biomicroscopic examination of the eyelid margin, 3) baseline TFLLT of ≤ 90 nm determined by interferometry, 4) fluorescein BUT of ≤ 10 s determined by the Dry Eye Test, 5) Schirmer test ≤ 10 mm performed under topical ocular anesthesia, 6) no evidence of other ocular pathology
Interventions	Warm compresses (20 eyes): white cotton napkins saturated with tap water and warmed to 40 °C; applied to closed eyelids for 30 minutes Control compresses (20 eyes): white cotton napkins saturated with tap water and left at room temperature; applied to closed eyelids for 30 minutes During the 30-minute therapy session fresh compresses were applied to each eye every 2 minutes to maintain the proper temperature; participants were instructed to not close their eyelids tightly and to apply the compresses with gentle pressure
Outcomes	Primary outcomes: changes in TFLLT during and after therapy Measurements taken at baseline, at 5, 15, and 30 minutes during therapy, and 5 minutes post-therapy Unit of analysis: each eye of each participant (intra-comparative)
Notes	Study dates: not reported Funding source: Ocular Research of Boston, Inc., USA Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Participants could not be masked to differences in treatment groups
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Physicians could not be masked to differences in treatment groups
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Outcome assessors could not be masked to treatment groups since measurements were taken during the interventions
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed.
Selective reporting (reporting bias)	Low risk	Results were reported for the primary outcome at all follow-up times
Other bias	Low risk
Perry 2006
Methods	Study design: randomized, placebo-controlled study Conditions included: MGD (posterior blepharitis) Enrollment: 33 participants Exclusions and loss to follow-up: 7 participants were excluded due to noncompliance or discomfort with treatment (4 in the cyclosporine group and 3 in the placebo group) Study follow-up: 3 months
Participants	Country: USA Age: not reported Gender: not reported Inclusion criteria: 1) at least 18 years of age, 2) slit-lamp diagnosis of MGD, 3) score of 12 or greater on the patient Ocular Symptoms Scale, 4) ability to understand and give signed informed consent, 5) willing and able to cooperate with study requirements, 6) use of reliable contraception if of childbearing potential Exclusion criteria: 1) use of contact lenses within 30 days of study; 2) active ocular disease, excluding glaucoma, or infections other than blepharitis; 3) ocular surgery within past 3 months; 4) active ocular allergies; 5) use of isotretinoin within past 6 months; 6) autoimmune disease requiring systemic treatment; 7) unwilling or unable to discontinue use of certain medications during or 30 days prior to study; 8) history of hypersensitivity to oral cyclosporine A; 9) pregnant or nursing or not using reliable contraception
Interventions	Cyclosporine A (n = 16): topical 0.05% cyclosporine A, 1 drop instilled in each eye twice a day for 3 months Placebo (n = 17): Refresh Plus preservative-free artificial tears, 1 drop instilled in each eye twice a day for 3 months The use of artificial tears was discouraged, but allowed during the study; participants who were practicing lid hygiene prior to the study were allowed to continue; participants not practicing lid hygiene prior to the study were encouraged, but not required, to practice lid hygiene using warm saline soaks
Outcomes	Primary outcomes: 1) total ocular symptoms score 2) number of meibomian gland inclusions 3) fluorescein staining scores 4) tear BUT 5) lissamine green staining 6) Schirmer scores Measurements taken at baseline, and monthly for 3 months Unit of analysis: the worse eye of each participant
Notes	Study dates: not reported Funding source: Allergan, Inc. Declarations of interest: 2 study authors consultants for Allergan, Inc Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Microsoft Excel software was used to randomize participants to treatment groups
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Both the participants and the investigators were masked as to which participants were receiving cyclosporine and which were receiving placebo
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	Both the participants and the investigators were masked as to which participants were receiving cyclosporine and which were receiving placebo
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	Both the participants and the investigators were masked as to which participants were receiving cyclosporine and which were receiving placebo
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed for the 7 excluded participants
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Funded by the pharmaceutical industry and 2 study authors affiliated with industry
Pinna 2007
Methods	Study design: randomized, parallel-group study Conditions included: MGD (posterior blepharitis) Enrollment: 57 participants Exclusions and loss to follow-up: 8 participants were lost to follow-up Study follow-up: 180 days
Participants	Country: Italy Age: mean 50 ± 16 years (range 18 to 82 years) Gender: 27 men and 30 women Inclusion criteria: participants with diagnosis of MGD (classified as seborrheic with meibomian seborrhea or seborrheic with secondary meibomitis) Exclusion criteria: 1) infectious keratoconjunctivitis or inflammatory disease unrelated to MGD; 2) Schirmer I test < 10 mm/5 min; 3) concomitant ocular pathologies; 4) previous ocular surgery; 5) alterations of the lachrymal drainage system; 6) concomitant topical ophthalmic medications; 7) topical steroids taken during previous 4 weeks; 8) treatment with systemic drugs affecting tearing; 9) pregnancy; 10) diabetes or other systemic, neurologic, or dermatologic disorders affecting the health of the ocular surface
Interventions	Group A (n = 19): oral linoleic acid (28.5 mg) and γ-linolenic acid (15 mg) once daily for 180 days Group B (n = 19): eyelid hygiene consisting of warm eyelid compresses, eyelid massage, and eyelid margin scrubbing once daily for 180 days Group C (n = 19): groups A and B combined for 180 days All participants were instructed to follow their usual diet
Outcomes	Primary outcomes: 1) change in symptoms score 2) change in clinical signs 3) corneal fluorescein staining 4) foam collection in the tear meniscus Measurements taken at baseline, and days 60 and 180 Unit of analysis: the worse eye of each participant at baseline, if equal then the right eye was used
Notes	Study dates: not reported Funding source: not reported Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The participants were randomly divided into 3 treatment groups of 19. The random sequence was computer-generated (personal communication with study author)
Allocation concealment (selection bias)	High risk	Allocation was not concealed (personal communication with study author)
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Participants could not be masked to treatment groups.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	Healthcare providers were masked to treatment groups.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	Outcome assessors were masked to treatment groups.
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed for 8 participants lost to follow-up
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Low risk
Rubin 2006
Methods	Study design: randomized, parallel-group study Conditions included: posterior blepharitis Enrollment: 30 participants Exclusions and loss to follow-up: 6 participants, 3 in each group, were lost to follow-up Study follow-up: 3 months
Participants	Country: USA Age: mean 51 years Gender: 11 men and 19 women Inclusion criteria: 1) patients with posterior blepharitis (presence of posterior lid erythema and meibomian gland telangiectasia), 2) previous use of traditional therapies without adequate symptom relief Exclusion criteria: 1) treatment with punctual occlusion, oral doxycycline, steroid-containing drops, or ointments; 2) uncontrolled systemic disease; 3) contraindication to the study medications; 4) women who were pregnant, lactating, planning pregnancy, or not using reliable birth control
Interventions	Cyclosporine (n = 63): topical 0.05% cyclosporine ophthalmic emulsion (Restasis), 1 drop applied every 12 hours Tobramycin/dexamethasone (n = 62): 0.3% tobramycin/0.1% dexamethasone ophthalmic solution, 1 drop applied every 12 hours
Outcomes	Primary outcomes: 1) change in Schirmer’s scores 2) change in tear BUT 3) improvement in clinical health 4) improvement in symptoms Measurements taken at baseline and every 2 weeks for 3 months Unit of analysis: the individual (average of both eyes)
Notes	Study dates: not reported Funding source: Allergan, Inc. and Research to Prevent Blindness Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Masking was not reported for participants.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	The study did not have masked observers.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	The study did not have masked observers.
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed for 6 participants lost to follow-up
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Funded by the pharmaceutical industry.
Seal 1995
Methods	Study design: randomized, partial cross-over study Conditions included: chronic blepharitis with and without associated rosacea Enrollment: 61 participants Exclusions and loss to follow-up: 18 participants were excluded or lost to follow-up Study follow-up: 8 months
Participants	Country: UK Age: not reported Gender: not reported Inclusion criteria: patients with chronic blepharitis Exclusion criteria: 1) known hypersensitivity to fusidic acid, oxytetracycline, or benzalkonium chloride; 2) simultaneous wearing of contact lenses; 3) pregnant or nursing or having childbearing potential; 4) concurrent use of prescribed anti-infective drugs; 5) other ophthalmic complications; 6) severe renal impairment
Interventions	Fusidic acid (n = 18): topical 1% fusidic acid in a carbomer gel made isotonic by adding mannitol, buffered to pH 5.5, and preserved plus placebo tablet every 12 hours Oxytetracycline (n = 22): oral 250 mg oxytetracycline tablet plus placebo gel every 12 hours Combination (n = 34): both topical fusidic acid and oral oxytetracycline every 12 hours Placebo (n = 61): placebo gel and placebo tablet every 12 hours Study was divided into four 2-month periods: 1) all participants received placebo gel and tablets, 2) 50% randomized to receive combination and 50% to receive either fusidic acid gel and placebo tablet or placebo gel and oxytetracycline tablet, 3) all participants received placebo gel and tablets, 4) participants who previously received combination were randomized to receive either fusidic acid gel and placebo tablet or placebo gel and oxytetracycline tablet and the remaining participants received combination
Outcomes	Primary outcomes: 1) patients’ subjective improvement of symptoms 2) investigators’ assessment of improvement of signs Measurements taken at baseline, and every 2 months for 8 months Unit of analysis: the individual
Notes	Study dates: not reported Funding source: not reported Declarations of interest: 1 study author affiliated with Leo Laboratories Ltd. (Bucks, UK) Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization was done by the pharmacy.
Allocation concealment (selection bias)	Low risk	The pharmacist distributed the study medications after participants were enrolled
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Drugs were dispensed every 2 months to participants by the pharmacy so that they were unaware whether they were entering the placebo or active treatment phase
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	Active treatment and combination assignments were masked by use of placebos and pharmacy distribution
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	Active treatment and combination assignments were masked by use of placebos and pharmacy distribution
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed.
Selective reporting (reporting bias)	High risk	Results were not reported for the end of each treatment phase
Other bias	Unclear risk	1 of the authors affiliated with industry. Placebo periods (1 and 3) were not parallel with active treatment periods (2 and 4)
Shulman 1982
Methods	Study design: randomized, placebo-controlled study Conditions included: chronic staphylococcal blepharoconjunctivitis Enrollment: 87 participants were enrolled, 71 were eligible for efficacy analyses Exclusions and loss to follow-up: 2 participants were lost to follow-up Study follow-up: 14 days
Participants	Country: USA Age: range 10 to 86 years Gender: 36 men and 51 women Inclusion criteria: 1) patients with staphylococcal blepharoconjunctivitis with at least 1 prior episode, or duration of symptoms for at least 1 month; 2) signs and symptoms score of 2 for conjunctival, lid, or both hyperemia and a total score of no less than 5 for all other signs; 3) staphylococcal infection sensitive to gentamicin Exclusion criteria: 1) patients receiving topical or systemic antimicrobials, corticosteroids, antihistamines, or decongestants within 24 hours of enrollment; 2) glaucoma patients requiring concomitant topical medications; 3) history of allergy to any study medications; 4) any eye diseases contraindicated to topical corticosteroids
Interventions	Combination (n = 18): 0.3% gentamicin sulfate and 0.1% betamethasone phosphate ointment applied to the lid margin and gently rubbed into the lashes 3 times daily for 2 weeks Gentamicin (n = 19): 0.3% gentamicin sulfate (Garamycin) ointment applied to the lid margin and gently rubbed into the lashes 3 times daily for 2 weeks Betamethasone (n = 16): 0.1% betamethasone phosphate ointment applied to the lid margin and gently rubbed into the lashes 3 times daily for 2 weeks Placebo (n = 18): vehicle ointment applied to the lid margin and gently rubbed into the lashes 3 times daily for 2 weeks All participants: use of eye shampoos or tear replacement agents was not permitted; ancillary therapeutic measures (i.e. warm compresses, water for lid hygiene, lid scrubs, oral analgesics) were allowed; systemic medications known to affect the eye were not allowed
Outcomes	Primary outcomes: 1) clinical improvement of signs at 2 weeks 2) change in bacterial cultures at 2 weeks 3) adverse reactions Measurements taken at baseline, days 3 to 4, 7 to 8, and 14 to 15 Unit of analysis: the eye of each participant with the most severe signs at enrollment
Notes	Study dates: not reported Funding source: not reported Declarations of interest: 2 study authors from the Schering Corporation (New Jersey, USA) Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomization of treatment numbers was in groups of 4 equally divided between the 4 treatment groups
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported. “I recall that I would give out unmarked samples and would record the clinical response” (email communication with study author)
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	All ointments were packaged identically and labeled with treatment numbers and dosage only
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	All ointments were packaged identically and labeled with treatment numbers and dosage only
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	All ointments were packaged identically and labeled with treatment numbers and dosage only
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed for 2 participants lost to follow-up
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	2 study authors affiliated with industry. Included participants with blepharoconjunctivitis, not limited to blepharitis
Sore 2002
Methods	Study design: parallel-group study Conditions included: blepharitis Enrollment: 60 participants Exclusions and loss to follow-up: 1 participant excluded or lost to follow-up Study follow-up: 29 days
Participants	Country: France Age: not reported Gender: 3 men and 56 women (as reported) Inclusion criteria: patients with seborrheic blepharitis, and/or anterior blepharitis, and/or posterior blepharitis with conjunctival irritation
Interventions	Zinc sulfate (n = 30): isotonic 0.1% zinc sulfate solution Thermal water (n = 30): natural selenium-rich thermal water (La Roche-Posay) 1 solution impregnated compress applied to each eye twice a day for 4 weeks; no eye makeup throughout study
Outcomes	Primary outcomes: 1) ocular safety and clinical tolerance 2) biologic markers of inflammation in the lachrymal film and microbial flora of palpebral edge and meibomian glands Measurements taken at baseline and day 29 Unit of analysis: not reported (both eyes were treated)
Notes	Study dates: not reported Funding source: not reported Declarations of interest: authors affiliated with La Roche-Posay Pharmaceutical Laboratories and Laboratoire Péritesco, France Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	High risk	Randomization was not reported; “volunteers were divided into two groups”
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Masking not reported.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Masking not reported.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Masking not reported.
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed; 1 participant excluded or lost to follow-up
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Authors affiliated with pharmaceutical industry. Unit of analysis was not reported.
Wasserman 1989
Methods	Study design: randomized, parallel-group study Conditions included: chronic blepharitis Enrollment: 20 participants enrolled Exclusions and loss to follow-up: none reported Study follow-up: 10 days, duration of protocol treatment
Participants	Country: USA Age: not reported Gender: not reported Inclusion criteria: patients with subjective and objective complaints of blepharitis
Interventions	Protocol 1 (n = 7): daily lid hygiene with commercial eye makeup remover, application of adrenocorticosteroid ointment (fluorometholone 0.1%) to lid margin twice daily, followed by placement of lyophilized collagen eye pads for 20 minutes for 10 days Protocol 2 (n = 7): daily lid hygiene with commercial eye makeup remover and application of adrenocorticosteroid ointment (fluorometholone 0.1%) to lid margin twice daily for 10 days Protocol 3 (n = 6): daily lid hygiene with 1:2 dilution of baby shampoo and application of adrenocorticosteroid ointment (fluorometholone 0.1%) to lid margin twice daily for 10 days
Outcomes	Primary outcomes: 1) mean change in signs and symptoms at day 10 2) change in bacterial cultures at day 10 Measurements taken at baseline and day 10 Unit of analysis: the individual
Notes	Study dates: not reported Funding source: not reported Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Participants could not be masked to differences in treatment groups
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Masking not reported.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Masking not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed.
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Low risk
White 2008
Methods	Study design: randomized, parallel-group study Conditions included: blepharokeratoconjunctivitis Enrollment: 276 participants from 17 centers (280 were screened) Exclusions and loss to follow-up: 13 participants withdrew from the study Study follow-up: 14 days
Participants	Countries: USA Age: mean 55 years (range 18 to 89 years) Gender: 105 men and 168 women (gender for 3 participants not reported) Inclusion criteria: 1) 18 years of age or older, 2) clinical diagnosis of blepharokeratoconjunctivitis in at least 1 eye, 3) willing to comply with all treatment and follow-up procedures and able to self-administer the drug, 4) informed consent, 5) women of childbearing age who were sexually inactive or using accepted birth control methods, 6) willing to discontinue contact lens use for duration of study and pinhole Snellen visual acuity equal or better than 20/40 in both eyes Exclusion criteria: 1) nursing or pregnant; 2) significant systemic disease; 3) known hypersensitivity to study drugs or their components; 4) contraindications to tobramycin or ocular corticosteroids; 5) use of systemic or topical ophthalmic non-steroidal anti-inflammatory agents, analgesics, or antihistamines; 6) use of topical ophthalmic medications within 2 hours of enrollment; 7) use of systemic or topical ophthalmic antibiotic agents within 72 hours of enrollment; 8) use of systemic or topical ophthalmic corticosteroid agents within 7 days of enrollment; 9) use of systemic or topical ophthalmic mast cell stabilizers within 14 days of enrollment; 10) use of topical ophthalmic immunosuppressant agents within 30 days of enrollment; 11) suspected preseptal cellulitis, dacryocystitis, or any other disease that could interfere with the safety and efficacy evaluations of the study drugs; 12) participation in other trials within 30 days prior to study entry; 13) ocular surgery in either eye within past 3 months
Interventions	LE/T (n = 138): combination 0.5% loteprednol etabonate and 0.3% tobramycin ophthalmic suspension (Zylet®), 1 or 2 drops 4 times a day for 14 days DM/T (n = 138): combination 0.3% dexamethasone and 0.1% tobramycin ophthalmic suspension (Tobradex®), 1 or 2 drops 4 times a day for 14 days
Outcomes	Primary outcomes: 1) change from baseline in signs (blepharitis, conjunctivitis, and keratitis) and symptoms (itchiness, foreign body sensation, blurred vision, light sensitivity, painful or sore eyes, and burning) composite score at day 15 Secondary outcomes: 1) percentage of eyes cured or not cured at each visit based on the investigators’ global clinical assessment (cured, improved, not changed, worsened) 2) change from baseline in signs and symptoms composite score at days 3 and 7 3) change from baseline to each visit in signs composite score and symptoms composite score 4) change from baseline to each visit in blepharitis signs composite score, conjunctivitis signs composite score, and keratitis signs composite score 5) change from baseline to each visit in individual signs and symptoms Safety outcomes: visual acuity, biomicroscopy findings, IOP measurements, and adverse events were assessed at each visit Measurements taken at baseline (day 1) and days 3, 7, and 15 Unit of analysis: the individual, using the worse eye in cases of bilateral disease or the right eye if eyes were equal
Notes	Study dates: January 2007 to June 2007 Funding source: Bausch & Lomb, Inc (makers of Zylet®) Declarations of interest: 2 study authors employees of Bausch & Lomb, Inc Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	“The randomization code was developed by an independent statistician prior to study enrollment using a computer random number generator…”
Allocation concealment (selection bias)	Low risk	Once randomized, subject kit boxes “were to be assigned to sites sequentially”; bottles of the study drugs “were packaged in identical subject kit boxes.”
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Participants were not masked to treatment.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	The study investigators were masked to treatment groups (“investigator-masked” study)
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	The study investigators were masked to treatment groups (“investigator-masked” study)
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	13 participants withdrew from the study: 4 withdrew consent (1 in the LE/T group and 3 in the DM/T group), 2 had adverse events (both in LE/T group), and 7 related to use of disallowed medications and subject ineligibility (3 in LE/T group and 4 in DM/T group). 3 participants were excluded from the ITT analysis due to missing data for all study follow-up visits
Selective reporting (reporting bias)	Low risk	Primary and secondary outcomes specified in the methods section and in the clinical trial registration were reported
Other bias	Unclear risk	The study was funded by the company producing a treatment intervention and 2 study authors were employees of the company producing the treatment intervention Included participants with blepharokeratoconjunctivitis, not limited to blepharitis
Wong 1956
Methods	Study design: randomized, parallel-group study Conditions included: marginal blepharitis Enrollment: 60 participants Exclusions and loss to follow-up: clinical data were not reported for 1 participant in the selenium group Study follow-up: 6 weeks, including 4 weeks during the time of treatment and 2 weeks after completion of treatment
Participants	Country: USA Age: median 20.5 years (range 2.5 to 86 years) Gender: 29 men and 30 women (as reported) Inclusion criteria: patients with marginal blepharitis
Interventions	Selenium (n = 39): selenium sulfide 0.5% ophthalmic ointment Control (n = 21): ammoniated mercury 0.5% ophthalmic ointment All participants instructed to cleanse lids with warm water and cotton swab prior to applying ointment twice a day for 4 weeks
Outcomes	Primary outcomes: 1) clinical improvement assessed by physician at 6 weeks 2) bacteriology and mycology of marginal blepharitis 3) adverse reactions Measurements taken at baseline and weekly for 6 weeks Unit of analysis: the eye (117 eyes from 59 participants)
Notes	Study dates: not reported Funding source: Medical Fluid Research Fund (Yale University, USA) Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	All drugs were identified by code symbol only.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	All clinical observers were without knowledge of the nature of the drug used by each participant and all drugs were identified by code symbol only
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	Low risk	All clinical observers were without knowledge of the nature of the drug used by each participant and all drugs were identified by code symbol only
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed.
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Unclear risk	Data were presented by eyes rather than by the unit of randomization, which was the individual
Yalçin 2002
Methods	Study design: randomized, parallel-group study Conditions included: chronic posterior blepharitis Enrollment: 40 participants Exclusions and loss to follow-up: none reported Study follow-up: 4 months
Participants	Country: Turkey Age: mean 43 years Gender: 12 men and 28 women Inclusion criteria: patients with chronic posterior blepharitis visiting SSK Okmeydani Education Hospital’s Eye Clinic
Interventions	Therapy group (43 eyes of 22 participants): 100 mg oral NAC 3 times a day for 8 weeks, plus control treatment Control group (36 eyes of 18 participants): topical steroids (prednisone acetate) and antibiotics (tobramycin sulfate) 4 times daily for 4 weeks, plus warm compresses twice daily for 2 months and artificial tears (polyvidone) 4 times daily for 3 months
Outcomes	Primary outcomes: 1) Schirmer-1 test increase rate between groups 2) fluorescein BUT increase rate between groups 3) mucus fern test increase rate between groups 4) adverse events Measurements taken at baseline and weekly for 4 months Unit of analysis: the individual (average of both eyes)
Notes	Study dates: not reported Funding source: not reported Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	High risk	Participants could not be masked to differences in treatment groups
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	High risk	Masking not reported.
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Masking not reported.
Incomplete outcome data (attrition bias) All outcomes	Low risk	ITT analysis was followed.
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Low risk
Yoo 2005
Methods	Study design: randomized, parallel-group study Conditions included: chronic MGD Enrollment: 150 participants Exclusions and loss to follow-up: 11 participants lost to follow-up or stopped medication due to side effects Study follow-up: 1 month
Participants	Country: Korea Age: mean 47.2 ± 12.36 years Gender: 55 men and 95 women Inclusion criteria: 1) patients newly diagnosed with chronic MGD with grade 2 or worse meibomian gland destruction or meibomian gland orifice obstruction; 2) symptoms failed to improve despite warm compression, lid massage, lid scrub, and topical eyedrops or ointment therapy for more than 2 months
Interventions	High dose (n = 50): 200 mg systemic doxycycline monohydrate twice a day Low dose (n = 50): 20 mg systemic doxycycline hyclate twice a day Placebo (n = 50): placebo pill twice a day All topical therapy was stopped at least 2 weeks prior to beginning study medication
Outcomes	Primary outcomes: 1) change in tear BUT 2) change in Schirmer test results 3) change in signs and symptoms 4) adverse events Measurements taken at baseline and 1 month Unit of analysis: the individual (average of both eyes)
Notes	Study dates: January to December 2003 Funding source: not reported Declarations of interest: none reported Publication language: English
Risk of bias
Bias	Authors’ judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	Method of randomization not reported.
Allocation concealment (selection bias)	Unclear risk	Method of allocation concealment not reported.
Masking (performance bias and detection bias) Were participants masked to treatment group?	Low risk	Participants were masked to medication and treatment group.
Masking (performance bias and detection bias) Were healthcare providers masked to treatment group?	Low risk	Baseline exams were conducted prior to randomization. Nurses dispensing the medication were masked to treatment groups
Masking (performance bias and detection bias) Were outcome assessors masked to treatment group?	High risk	Masking of outcome assessors not reported.
Incomplete outcome data (attrition bias) All outcomes	High risk	ITT analysis was not followed; 11 participants were excluded or lost to follow-up
Selective reporting (reporting bias)	Low risk	Results were reported for primary and secondary outcomes.
Other bias	Low risk

BUT: breakup time

COX: cyclo-oxygenase

DM/T: dexamethasone + tobramycin

IOP: intraocular pressure

ITT: intention to treat

KCS: keratoconjunctivitis sicca

LE/T: loteprednol etabonate + tobramycin

MGD: meibomian gland dysfunction

NAC: N-acetylcysteine

OSDI: Ocular Surface Disease Index

SPEED: Standard Patient Evaluation of Eye Dryness questionnaire

TFLLT: tear-film lipid layer thickness

VAS: visual analog scale