1. Delay in Symptom Resolution After Thermal Pulsation System Treatment for Meibomian Gland Dysfunction in Dry-Eye Disease Delay in Symptom Resolution After Thermal Pulsation System Treatment for Meibomian Gland Dysfunction in Dry-Eye Disease Jack V. Greiner, M.S., D.O., Ph.D. Paula J. Oliver, A.S. Mikhail Salganik, Ph.D. The Schepens Eye Research Institute Massachusetts Eye and Ear Infirmary Harvard Medical School The Boston Ocular Surface Center E-mail: Jack_Greiner@meei.harvard.edu None of the Authors have a Financial Interest to Disclose

2. Delay in Symptom Resolution After Treatment of Dry Eye Diseases Secondary to Meibomian Gland Dysfunction (MGD) Simultaneous warming of the meibomian glands and meibomian gland expression accomplished by the non-pharmacologic technology of the LipiFlow thermal pulsation system (LTPS) treatment results in a more prompt improvement in meibomian gland dysfunction (MGD) and dry eye symptoms (e.g. ≤ 1month 1-3 ), than the conventional use of these techniques individually. 1 Lane, Dubiner, Epstein, Ernest, Greiner: Cornea 2012;31(4):396-404. 2 Greiner: Curr Eye Res 2012;37(4):272-278. 3 Greiner: J Clin Experiment Ophthalmol 2013;41:524-530.

3. Delay in Symptom Resolution After Treatment of Dry Eye Disease Secondary to Meibomian Gland Dysfunction (MGD) In some cases, however, it was noted that the significant improvement in meibomian gland secretion (MGS) score at 1 month post-LTPS treatment was not associated with a corresponding improvement in symptoms as might have been expected. The basis of this disconnect between improvement in signs and symptoms is unclear.

4. Purpose To explore this variability in the time-line of improvement in signs and symptoms of dry eye disease secondary to MGD after a single 12-minute thermal pulsation system (LTPS) treatment.

5. Methods LTPS treatment was conducted on moderate to severe MGD patients (n=68) in a prospective, single-center, open-label randomized clinical trial. Inclusion criteria required a validated Standard Patient Evaluation for Eye Dryness (SPEED) questionnaire score of ≥6 and meibomian gland secretion (MGS) score of ≤20.

6. Signs and Symptoms Evaluated Signs were measured using tear film breakup time (TFBUT) and MGS scores at Baseline pre-LTPS and at 1 and 3 months post-LTPS. Symptoms were measured using SPEED and Ocular Surface Disease Index (OSDI) questionnaire scores at Baseline pre-LTPS and 1 and 3 months post-LTPS.

7. Tear Film Break-up Time Tear film break-up time (TFBUT) was measured 3 consecutive times using a stop-watch (sec) following instillation of fluorescein using the DET test 1,2 at Baseline pre-LPST and 1 and 3 months post-LPST 1 Korb, Greiner, Herman: Cornea 2001;20:811-815. 2 Abdul-Fattah, Bhargava, Korb, Glonek, Finnemore, Greiner: Optom Vis Sci 2002;79:435-438.

8. Meibomian Gland Secretion (MGS) Scores These scores were obtained using a meibomian gland evaluator (MGE).

9. Meibomian Gland Evaluator (MGE) MGE-mediated meibomian gland assessment is standardized 1 by allowing quantification of the force used to diagnose meibomian gland obstruction and dysfunction. The skin is applanated with the MGE with a constant force of approximately 1.2 gm/mm 2 pressure. 1 Horley DW, Korb DR: US Patent 3411364, November 19, 1968.

10. 5 consecutive nasal glands Nose Gland Evaluator 5 consecutive temporal glands Lower Eyelid Margin Lower Punctum 5 consecutive central glands Standardization of the Meibomian Gland Secretion Score Standardization of the Meibomian Gland Secretion Score Five meibomian glands are evaluated for each of 3 sections of the lower eyelid (temporal, central, and nasal).

11. Meibomian Gland Secretion Score to Determine Severity & Monitor Treatment Considering the grading scale the maximum possible number of meibomian glands yielding liquid secretion per eyelid =15, while the maximum possible secretion quality score = 45. GRADE SECRETION CHARACTERISTICS 0 No secretion 1 Inspissated solid secretion (toothpaste consistency) 2 Cloudy liquid secretion 3 Clear liquid secretion

12. Grading Meibomian Gland Secretions No Secretion [score 0] Inspissated Solid Secretion (Toothpaste Consistency) [score 1] Cloudy Liquid Secretion [score 2] Clear Liquid Secretion [score 3]

13. Symptoms Analyzed by Two Validated Questionnaires Ocular Surface Disease Index (OSDI) Standard Patient Evaluation of Eye Dryness (SPEED)

15. Measurement of Symptom Scores using the SPEED Questionnaire Symptoms were measured using the validated SPEED questionnaire 1,2 at Baseline pre-LPST) and 1 and 3 months post-LPST. 1 Korb, Herman, Greiner et al: Eye Contact Lens 2005;31:2-8. 2 Ngo, Ping, Kier, et al: Cornea 2013:32:1204-1210.

16. Standard Patient Evaluation of Eye Dryness (SPEED) Questionnaire Evaluates the frequency and severity of dry eye symptoms over the past 3 months. A SPEED symptom score of ≥6 should be considered for treatment.

17. Results At both the 1 and 3 month time points, all 68 patients had improved signs of TFBUT (p<0.01) and MGS scores (p<0.001) compared to Baseline values. At 1 month, 9% (n=6) of these same patients were still symptomatic as measured by SPEED (p<0.05) and OSDI (p<0.05) questionnaire scores. At 3 months, 3% (n=2) of these same patients remained symptomatic based on SPEED and OSDI questionnaire scores.

18. Conclusion Symptomatic relief may lag behind clinically- evident improvement in signs in a subset of patients post-LTPS treatment, suggesting that a ≥3 month time point may be more informative when evaluating the success of this procedure and framing patients’ expectations prior to the procedure itself. This delay in symptomatic relief may be a reflection of the multifactorial nature of dry eye disease itself in that some patients may have multiple factors that contribute to their symptomatic experience that are not immediately relieved by resolving the MGD.

19. Delay in Symptom Resolution after Thermal Pulsation System Treatment for Meibomian Gland Dysfunction in Dry-Eye Disease Delay in Symptom Resolution after Thermal Pulsation System Treatment for Meibomian Gland Dysfunction in Dry-Eye Disease Jack V. Greiner, M.S., D.O., Ph.D. Paula J. Oliver, A.S. Mikhail Salganik, Ph.D. The Schepens Eye Research Institute Massachusetts Eye and Ear Infirmary Harvard Medical School The Boston Ocular Surface Center E-mail: Jack_Greiner@meei.harvard.edu