Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Disclosures • K. Nichols TFOS Ocular Surface Research Update Kelly K. Nichols, OD, MPH, PhD FERV Professor University of Houston College of Optometry Chair, TFOS International Meibomian Gland Workshop TFOS Governing Board Member WHAT WAS STATE OF THE ART IN DRY EYE © 2007? WHAT HAS HAPPENED SINCE? What’s New? • Research support – Paid consultant to: • Alcon • Allergan • B+L • Celtic/ Resolvyx • Eleven Biotherapeutics • Forest • InSite • Ista • SARcode • TearLab – CL Tear Film Lab (OSU) • Alcon • CIBA • Inspire • TearLab • Pfizer • Vistakon – National Eye Institute • R01 EY015519 (PI) • R01 EY017951 (Co-I) • R34 EY017626 (Co-I) Updated Dry Eye Definition “Dry eye is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.” MGD Contributes to Dry Eye • Growing awareness of link between blepharitis (esp. MGD) and dry eye – Lemp et al report • Younger people are more prone than older people to blepharitis (contrary to dogma) • ECPs report 37-47% of patients have blepharitis • Blepharitis management paradigms are shifting… – from antibiotic ointment and warm compress therapy – to prescription therapy for anterior and posterior blepharitis DEWS Definition and classification report. Ocular Surface 2007 1 A call for change— Epidemiology • In the 2007 DEWS report three goals were presented: – Summarize the epidemiology of DED • Prevalence • Incidence • Natural history – Review risk factors for DED – Review existing questionnaires for DED Evaluating “change” Since DEWS 2007… 1096 articles with keyword “dry eye” published • PubMED searches for existing literature using key words “DRY EYE,” “PREVALENCE,” and “Incidence” • Review of clinicaltrials.gov • Review of surveys utilized in clinical trials Population-based studies of DED Global Prevalence of Dry Eye-2011 Singapore Malay Sumatra 8 Studies Range 5-30% Taiwan Tibet Beijing Mongoiia Japanese High School Students Japanese VDT users 16 Studies Range 5-55% US Women's Health Study US Male Physicians Melbourne Blue Mountains (AUS) Beaver Dam (US) Maryland USA Spain 0% 10% 20% 30% 40% 50% 60% 2 What’s New? Prevalence of DED, by Age Women and Men • Dry Eye Epidemiology – Schaumberg et al report men have increasing dry eye with age • 3.90% among men aged 50 to 54 years • 7.67% among men 80 years and older • Additional male risk factors: – hypertension, benign prostatic hyperplasia, and antidepressant use Number of Americans with DED Incidence of Dry Eye • Data from the largest US studies (≥50 y) • Beaver Dam Eye Study – Women’s Health Study – Physicians’ Health Study Severe Symptoms 1.09 Diagnosed Women Men 0.78 2.21 Severe Sx or Dx 1.37 3.23 0 1 – 13.3% developed dry eye over 5 years – 21.6% developed dry eye over 10 years (Moss, 2008) – Higher incidence in older ages • But effect of age relatively modest magnitude 1.62 2 3 4 5 6 Number Affected (Millions) – No difference by sex at 5 years – Incidence was greater in women (25.0%) than men (17.2%, p < 0.001) at 10 years (Moss, 2008) What’s New? Natural history of dry eye • 10-year incidence data • Minimal to no studies of progression • Progression between severity groups (ITF/ Delphi) in a non-treatment group has been assessed in one small-scale study and is a concept warranting further investigation – Moss et al report dry eye incidence of 21.6% • Risk factors: – age – female gender – poorer self-rated health – antidepressant or oral steroid use – thyroid disease untreated with hormone Rao SN. Topical cyclosporine 0.05% for the preven9on of dry eye disease progression. J Ocul Pharmacol Ther. 2010 Apr;26(2):157-‐64. 3 Goal 2. Risk Factors for DED 2007 Risk factors for DED (Moss et al, 2008) • Increased incidence was associated with: – Age – Female gender – Poorer self-rated health – Antidepressant or oral steroid use, and – Thyroid disease untreated with hormone. • It was lower for those: – Using angiotensin-converting enzyme inhibitors or a – Sedentary lifestyle. Moss SE, Klein R, Klein BE. Long-‐term incidence of dry eye in an older popula9on. Optom Vis Sci. 2008 Aug;85(8):668-‐74. Risk factors for men (new data) Systemic co-morbidities • Benign prostatic hyperplasia • Ischaemic heart disease (OR = 1.36) • Hyperlipidaemia (OR = 1.68) • Peripheral vascular disorders (OR = 1.57) • Migraines (OR = 1.76) • Myasthenia gravis (OR = 2.85) • RA (OR = 2.86) • Systemic lupus (OR = 3.98) • Pulmonary circulation disorders (OR = 1.37), – OR=1.26, CI=1.09 to 1.44 • Hypertension – OR=1.28, CI=1.12 to 1.45 • Medications to treat BPH – OR=1.35, CI=1.01 to 1.80 • Antidepressant medications – OR=1.90, CI=1.39 to 2.61 Schaumberg DA, Dana R, Buring JE, Sullivan DA. Arch Ophthalmol. 2009 Jun;127(6):763-‐8. Goal 3. Review questionnaires • Diabetes with complications (OR = 1.31) • Hypothyroidism (OR = 1.94) • Liver diseases (OR =1.71) • Heptic ulcers (OR = 1.76) • Hepatitis B (OR = 1.64), • Depression (OR = 2.11) • Psychoses (OR = 1.87) • Solid tumors without metastasis (OR = 1.41) Wang TJ, Wang IJ, Hu CC, Lin HC. Comorbidi9es of dry eye disease: a na9onwide popula9on-‐based study. Acta Ophthalmol. 2010 Aug 31. [Epub ahead of print] Since DEWS… 211 registered DRY EYE trials • Identify purpose of questionnaire: screening, clinical, epidemiologic studies • Assess available data on validation, reproducibility, and responsiveness 4 Since DEWS… 76 Currently active trials Clinicaltrials.gov: Summary 2010 Primary outcome (s) OSDI (n=13) or other Sx Staining Schirmer TBUT 19 13 6 4 IntervenBonal ObservaBonal 48 9 I II III IV Not listed 3 12 6 16 20 Oral Topical Surgical or other 5 39 4 Industry University/Government 39 18 Design Phase IntervenBons (n=48) Sponsor Dry eye surveys • OSDI ocular surface disease severity ratings across the scale (0-100) have been reported:1 – Normal 0-12, Mild 13-22, Moderate 23-32, and Severe 33-100, and a 7 unit change was noted as clinically significant; sub-scale analysis may also have importance • The DEQ-5 comprises:2 – Frequency of watery eyes (r=0.48), discomfort (r=0.41), and dryness (r=0.35), and late day (PM) intensity of discomfort and dryness (r=0.42, 0.36) all significantly correlated to SA-Sev (p<0.01) 1. Miller KL et al. Minimal Clinically Important Difference for the Ocular Surface Disease Index. Arch Ophthalmol. 2010;128(1):94-‐101. 2. Chalmers RL, Begley CG, Caffery B. Valida9on of the 5-‐Item Dry Eye Ques9onnaire (DEQ-‐5): Discrimina9on across self-‐assessed severity and aqueous tear deficient dry eye diagnoses. Cont Lens Anterior Eye. 2010 Apr;33(2):55-‐60. Surveys: ocular comfort • The Ocular Comfort Index (OCI) uses Rasch analysis to produce estimates on a linear interval scale.3 • The OCI measure exhibited a positive correlation with the OSDI score (p < 0.0001) and a negative correlation with TBUT (p < 0.0001) and was able to detect improvement in symptoms of dry eye in individuals before and after treatment (P < 0.0001) Johnson ME, Murphy PJ. Measurement of ocular surface irrita9on on a linear interval scale with the ocular comfort index. Invest Ophthalmol Vis Sci. 2007 Oct;48(10):4451-‐8. Diagnosis • Dr. Nichols, is there a new, easy, inexpensive, and accurate way to diagnosis dry eye (maybe something a technician could do)? – Sorry, not yet… – Newer diagnostic tools are not ready for the “average” clinic • Technology intensive and expensive – Osmometers – Tearscope – OCT – Fluorophotometry 5 Mechanism of action for therapeutics • Stimulation of natural tear constituents • Inhibition of inflammation of the ocular surface • Stabilization of the tear film • Decreasing tear osmolarity But first, Dx….Grading Scheme Osmolarity in Diagnosis & Grading of Dry Eye Summary—Advancing Epi • Advances have been made in the global prevalence assessment (~17% total; ~30% Asia) of dry eye as a symptom-based disease • New 10-year incidence data (21%) and risk factor assessment (antidepressants, Asian race, systemic comorbidities) refines our existing knowledge base • Further research regarding Natural History, the ability of newer surveys to monitor change (DEQ short version, OCI),and the impact of MGD on dry eye is needed. Diagnosis Osmolarity Severity Analysis 6 Summary—from TearLab Treatments • Osmolarity is the best single test for DED – – – – – – Highest correla9on to disease severity Quan9ta9ve, Objec9ve Operator Independent Test (reduces need for training) No site-‐to-‐site varia9on Rapid (< 30 seconds for 2 eyes) Most sensi9ve test for discrimina9ng small changes • DiagnosBc Cutoff > 308 mOsms/L – PPV = 85% • Suggested inclusion criteria for clinical trials • Hierarchical options based on severity The preferred treatment for mild dry eye patients, ASK about symptoms at every visit – One eye > 328 mOsms/L – Opposite eye > 316 mOsms/L Level 1 Treatments What’s New? • Environmental and dietary modifications • Essential Fatty Acids – Essential Fatty Acids • Recommended in principle, no dosing given – Environmental Considerations • Avoid desiccating stresses – Low humidity, air conditioning drafts • Computer users – Take breaks, lower monitor below eye level to limit lid aperture • Use humidifier – Kokke et al report omega-6 (300 mg γ-linolenic acid/ d) improve symptoms and tear meniscus height in contact lens wearers – Macsai reports omega-3 (3.3 g α-linolenic acid/d) improves symptoms and decreases saturated fat in meibum – Call for RCT in literature • Which is better, or is it a combination? – Rashid et al report topical form improves dry eye in mice What’s New? What’s New? • Environment • Education (Jackson) – Guillon et al report that contact lens wear is associated with greater evaporation of the tear film and this effect lasts for at least 24 hours after lens removal – Blink rate reduced with long sessions of… • Reading • TV watching • Computer – Use ATs if engaging in one of these activities – Avoid hot, windy, low-humidity, high altitude areas if possible 7 Level 1 Treatments What’s New? • Elimination of offending systemic medications • A related note – Avoid systemic anticholinergics • Antihistamines, antidepressants – Leung et al and Rossi et al report ocular surface disease is common in glaucoma and increases with each BAK-preserved glaucoma drop used – Glaucoma field moves toward recommendation of non-BAK medications and concomitant preservative-free AT use What’s New? Level 1 Treatments • Acupuncture • Artificial tear substitutes, gels/ointments – Lee et al used a meta-anaylsis approach to suggest that acupuncture is a least a good as artificial tears for TBUT, Schirmer, and staining – A significant part of report – New tears with LIPID targeting MGD Artificial Tears Artificial Tear Preservatives • AT use can improve symptoms, but they persist • A beneficial effect of ATs on the health of the ocular surface has not been proven • Main variables in composition: • “Single most critical advance in the treatment of dry eye came with the elimination of preservatives, such as benzalkonium chloride (BAK)...” • …”the absence of preservatives is of more critical importance than the particular polymeric agent”… – Preservative type – Electrolyte concentration – Osmolarity – Viscosity agent – Lipid – Unfortunately, non-preserved solutions do not improve the surface inflammation 8 Artificial Tear Preservatives Electrolyte composition • Report gave special consideration to “vanishing” preservatives • Most useful ones… – Sodium chlorite • Degrades upon exposure to UV light – Potassium to maintain corneal thickness – Bicarbonate to help recovery of epithelial barrier function and maintain mucin layer – Sodium perborate • Degrades on contact with tear film Osmolarity Viscosity Agent • Dry eye patients have high tear osmolarity • Influence contact time • Can provide protection by hydrating the gel-forming mucin and bind to epithelium • Lower molecular weight agents minimize blur and lash crusting – Results in cellular morphology changes and is proinflammatory • Hypotonic tears may reduce swelling in dysfunctional cells – HP-guar – Castor oil – Mineral oil Artificial Tear Summary What’s New? • So which one is best? • “Vanishing” Preservatives – Available studies suggest a variety of preparations can help signs and symptoms – No preparation is superior to another • Symptoms and inflammation remain – Preservative-free preparations are generally better tolerated – Consider lipid containing products with MGD – Epstein et al report that sodium perborate causes at least some tissue damage – Yamazaki et al report that glaucoma patients who were switched to SofZia-preserved travaprost from latanoprost had a decrease in SPK 9 MGD IN CL WEARERS Disease Pathway What’s New? • Viscosity Agent – Uchiyama et al report RCT where HP-guar has a longer residence time than saline – Wang et al report randomized trial comparing HP-guar gel versus carbomer gel • Both improved signs and symptoms, slight edge to carbomer group – In meta-analysis, Doughty et al report treatment can help about 25%, but with no difference between carbomer gels and hyaluronic acid (HA) products What’s New? What’s New? • Osmolarity • Ocular Inserts – Suzuki et al report tear osmolarity is correlated with DEWS severity scale – Bernelli et al report artificial tears lower osmolarity up to 10 points after instillation – Koffler et al report hydroxypropyl cellulose inserts improve signs and symptoms of dry eye beyond habitual treatment and are generally tolerated – Consider for Sjogren’s patients • Blurred vision most common problem • Sterile, preservative-free, Rx only • Extends duration of treatment • Low rate (2.5%) of adverse events Level 1 Treatments Rapidheatpacks.com • Eye lid therapy – No details given in DEWS report – MGD workshop report 10 What’s New? Ocular Ointments and Gels • Eyelid therapy • Ointments do not need preservatives because the mineral oil or petrolatum base do not support bacterial growth • Consider gels with carbomers – Blackie et al recommend warm compress regimen • Heat compress to 104° F • Maintain good contact • Have multiple warm compresses ready, switch prn • Perform for at least 4 minutes • AKA Acrylic acid polymers – Longer retention time, less blurring • Recommendations to avoid products with: – Lanolin – irritation, delayed corneal healing – Parbens – a poorly tolerated preservative – Petrolatum base – visual blurring Level 2 Treatments • Topical Anti-Inflammatory Therapy – Cyclosporin A Emulsion • Improves symptoms, staining, and Schirmer values • Increases Goblet Cell density • Decreases IL-6, T-cells, and apoptotic markers – Pimecrolimus – Tacrolimus – Androgen (testosterone) • Improve symptoms, meibum quality, TBUT, lipid layer thickness What’s New? Level 2 Treatments • Topical Anti-Inflammatory Therapy • Anti-Inflammatory Therapy • Kim et al report Vitamin A is as effective as cyclosporine in treating signs and symptoms of dry eye and recommend it as a adjunct therapy to artificial tears • Foulks et al report topical azithromycin can improve evaporative dry eye by restoring the disordered lipids in MGD • Still under development – Corticosteroids • Quite effective in reducing ocular surface symptoms and inflammation – Loteprednol etabonate, fluoromethalone, methyprednisone, etc. • Inherent Hazards – IOP rise, Cataract – Androgen, Pimocrolimus,Tacrolimus » Used by some corneal specialists (ex keratoplasty, cicatricial pemphigoid) 11 What’s New? Level 2 Treatments • Topical anti-inflammatory • Tetracyclines for MGD, rosacea – Steroidal burst for a few weeks, then transition to non-steroidal treatment • Cyclosporine is still the only FDA approved Rx for dry eye – Pavesio et al recommend treatment of dry eye with loteprednol because its ester quality is likely safer than the more common ketone form of ocular steroids – Antibacterial • Less lipolytic exoenzymes and lipase production – Anti-inflammatory • Decrease MMPs, collagenase, TNF-α, IL-1, etc. – Anti-angiogenic • Potential for less benign vessel formation in rosacea – 20 mg of doxycycline per day may be enough to treat MGD Level 2 Treatments What’s New? • Punctal Plugs • Punctal Plugs – Objective and subjective improvements for a variety of ocular surface diseases – About 75% of dry eye patients report improved symptoms – May interfere with normal feedback mechanism and temporarily decrease tear production – Chen et al report similar improvements in signs and symptoms when plugs are placed in either the upper or lower puncta – Burgess et al report equivalent efficacy of SmartPlugs versus standard silicone plugs Level 2 Treatments What’s New? • Topical Secretogogues • Topical Secretogogues – Were under various stages of drug development – P2Y2 agonist • Diquafosol improves aqueous and mucous secretion – Still under development • Many failing to make endpoints so far • Ecabet sodium had positive results in Phase 2b study and may go to Phase 3 trial in 2010 – Mucous secretion stimulants • Rebamipide, gefarnate, ecabet sodium – MUC-1 Stimulant • 15(S)-HETE 12 Level 2 Treatments What’s New? • Oral Secretogogues • Oral Dry Eye Treatment – Pilocarpine can improve ocular problems in Sjogen Syndrome patients but has side effects (esp. excessive sweating) – Cevimeline has been reported to improve symptoms and increase tear production with less side effects – Avni et al report a Phase 2 study where an experimental A3 adenosine receptor agonist improves staining, TBUT, and tear meniscus height • An anti-inflammatory agent that down regulates a host of inflammatory mediators (ex. autoreactive T cells, TNF-α) – Chang et al report a small, but measurable, improvement in signs and symptoms with 3 months of oral uridine (like topical Diquafosol) Level 2 Treatments • Moisture Chamber Spectacles – Poorly documented in the literature – Reports of special spectacles increasing the periocular humidity – Not very popular • Because an easy alternative is contact lenses?? 7eye.co m Level 3 Treatments What’s New? • Autologous Serum • Serum Eye Drops – Concentrations of 20-50% can decrease staining and relieve symptoms better than habitual eye drops Patients with Schirmer scores ≤5mm/5min. AND central corneal staining are level III – Kojima et al report a RCT where autologous serum eye drops are more effective than artificial tears – Yoon et al report umbilical cord serum is more effective than autologous serum in relieving signs and symptoms 13 Level 3 Treatments Level 3 Treatments • Contact Lenses • Permanent punctal occlusion – Used in severe dry eye • Ex. large diameter / scleral lenses – Can improve vision and comfort – Can health persistent epithelial defects – Overnight wear an option but brings added risk in a dry eye patient – Little detail in report – Used as alternative to semi-permanent punctal plugs Level 4 Treatments • Beyond scope of this talk • Systemic anti-inflammatory agents • Surgery – Lid surgery, tarsorrhaphy – Transplantation of mucus membrane, salivary gland, or amniotic membrane transplantation Thank you for your attention! [email protected] 14