Ocular Surface Biomarkers and Inflammation A. J. Bron Nuffield - PowerPoint PPT Presentation

Ocular Surface Biomarkers and Inflammation A. J. Bron Nuffield Laboratory of Ophthalmology Oxford EMA 27/28 th October Image -freedoncurrent.com

Biomarkers in Inflammation • Scope • Biomarker Technologies • Definition of a biomarker • Monitoring - Candidates • Applications • Diagnosis – Bioinformatics • Risk factors v Screening • Duration of trials • Ocular Phenotypes • Conclusions • Measuring Symptoms • Signs v Symptoms • Sampling variables

Scope •Prenatal screening: • Huntingdon mutation in •Neonatal screening HD – endocrine and metabolic • Serum anti-citrullinated disorders, lysosomal storage peptide plus RhF in dis. Rheumatoid arthritis •Adult diagnosis diagnosis (PPV 100%) •Alzheimer’s diagnosis: • Prediction of morbidity/ –CSF: A β and τ ; FDG-PET mortality in end stage scan renal failure. •HER2 –efficacy of HER2 blockade in treatment of metastatic breast cancer

Definition and Applications • Predicting Risk • A disease- • Screening associated • Diagnosis parameter • Scaling severity • Discriminates • Monitoring progress • Predicting response to affected from therapy unaffected • Determining prognosis • Understanding disease mechanism

Prediction of dry eye in at-risk groups? • Contact lens wear • Isotretinoin therapy -MGD • LASIK -Refractive laser surgery – dry eye or LINE • Chronic topical preservatives - in glaucoma therapy • Bone marrow transplantation – G v H disease • Connective tissue disease - 2°rheumatoid Sjögren • Postmenopausal estrogen therapy • Meds: antihistamines • Androgen deficiency or receptor blockade

Is a strong risk factor of use in screening:? • The relative odds for the association of cholesterol (RO 1-5 ) with Ischaemic Heart Disease ≅ 2.7 • This gives a DR 5 ≅ 15% which is poor for a screening test DR 5 = Detection Rate at a False Positive rate of 5% Wald et al. BMJ 1999; 319

Odds ratios and Detection Rates • Emerging Risk Factors Collaboration: CRP and CHD Kaptoge et al 2010 – Odds ratio 3 • Rotterdam Coronary Calcification Study: CC and CHD Vliegenthart et al. 2005 – Relative risk 8.3 • Atherosclerosis Risk in the Community: HbA1C- DM and CHD Selvin et al. 2010 – Odds = 103.5 [for Diabetes] See Wald and Morris 2011 Arch Intern Med 2011; 171 : www.wolfson.gmul.ac.uk/rsc/

Odds ratios and Detection Rates • Emerging Risk Factors Collaboration: CRP and CHD Kaptoge et al 2010 – Odds ratio 3 – DR 5 = 9% • Rotterdam Coronary Calcification Study: CC and CHD Vliegenthart et al. 2005 – Relative risk 8.3 • Atherosclerosis Risk in the Community: HbA1C- DM and CHD Selvin et al. 2010 – Odds = 103.5 [for Diabetes] Wald and Morris 2011: www.wolfson.gmul.ac.uk/rsc/

Odds ratios and Detection Rates • Emerging Risk Factors Collaboration: CRP and CHD Kaptoge et al 2010 – Odds ratio 3 – DR 5 = 9% • Rotterdam Coronary Calcification Study: CC and CHD Vliegenthart et al. 2005 – Relative risk 8.3 – DR 5 = 22% • Atherosclerosis Risk in the Community: HbA1C- DM and CHD Selvin et al. 2010 – Odds = 103.5 [for Diabetes] Wald and Morris 2011: www.wolfson.gmul.ac.uk/rsc/

Odds ratios and Detection Rates • Emerging Risk Factors Collaboration: CRP and CHD Kaptoge et al 2010 – Odds ratio 3 – DR 5 = 9% • Rotterdam Coronary Calcification Study: CC and CHD Vliegenthart et al. 2005 – Relative risk 8.3 – DR 5 = 22% • Atherosclerosis Risk in the Community: HbA1C- DM and CHD Selvin et al. 2010 – Odds = 103.5 [for Diabetes] Wald and Morris 2011: – DR 5 = 32% www.wolfson.gmul.ac.uk/rsc/

Screening for Downs and Neural Tube Defect US - Nuchal translucency in Downs • 2-step integrated test for Downs • 1 st Trimester –nuchal translucency and serum pregnancy- associated plasma protein A • 2 nd Trimester - AFP, Serum AFP raised in NTD hCG, unconjugated Nearly all NTD pregnancies can estriol, and Inhibin-A be identified by AFP screening. Risk result in 2 nd tr. • DR 5 = 91% spina bifida • DR 2 = 90% Wald 2010 Valuable diagnostic tests may take time to

Global Phenotypes features DRY EYE Symptoms + Hyperosmolarity + Tear Instability + Surface stain + Tear allergy markers negative

Global Phenotypes features DRY EYE Symptoms + > 20 OSDI Hyperosmolarity + ≥ 316 mOsm/l Tear Instability + BUT ≤ 10 s Surface stain + ≥ 3 or 4 VB Tear allergy markers negative

Phenotypes DRY EYE - aqueous deficient Symptoms + > 20 OSDI Hyperosmolarity + ≥ 316 mOsm/l Schirmer +ve MGD –ve Tear Instability + ≤ 5 mm BUT ≤ 10 s negative MGD surrogates Meniscus radius Meniscus height Surface stain + Tear clearance ≥ 3 or 4 VB Tear EGF Tear Lysozyme Tear Lactoferrin Tear allergy markers negative

Phenotypes DRY EYE - aqueous deficient Symptoms + > 20 OSDI Hyperosmolarity + ≥ 316 mOsm/l Schirmer +ve MGD –ve Tear Instability + ≤ 5 mm BUT ≤ 10 s negative MGD surrogates Meniscus radius Meniscus height Surface stain + Tear clearance ≥ 3 or 4 VB Tear EGF Tear Lysozyme Tear Lactoferrin Tear allergy markers negative

Phenotypes DRY EYE Evaporative Symptoms + > 20 OSDI Hyperosmolarity + ≥ 316 mOsm/l MGD + Schirmer Tear Instability + >5 mm MGD signs + BUT ≤ 10 s ↑ evaporation TFLL changes - negative LG Meibum change Surface stain + surrogates tear Calgranulin ≥ 3 or 4 VB Tear allergy markers negative

Phenotypes DYSFUNCTIONAL TEAR SYNDROME Symptoms + > 20 OSDI Hyperosmolarity + ≥ 316 mOsm/l Schirmer MGD + Tear Instability + Lack of expressable < 10 mm BUT ≤ 7 s meibum ≥ 75% of glands Surface stain + 2 or more of: Acinar atrophy ≥ 3 or 4 VB Orifice metaplasia Vascular dilatation at posterior lid margin Tear allergy markers negative

Endpoints – Signs versus Symptoms symptoms in dry eye symptoms in dry eye � Soreness, irritation � Frequency � Gritty, scratchy � Timing � Burning, stinging � Intensity � Itching � Dryness � Provocations: � Low humidity-AC � Tired eyes. � Airflow – windy day � Fumes - smoke � Light Sensitivity, � Visual Change eg D E Q– Begley et al 2002

Symptom Name # of Author questio Measurement ns Schaumberg et al. Womens 3 2003 Health • In dry eye, whose major Sjögren 3 Vitali et al. 2002 feature is symptoms, Consensus there is no surrogate for Schein 6 Schein et al. 1997 symptom measurement McMonnies and Ho McMonnies 12 1986 • Validated OSDI 12 Schiffman et al. 2000 Questionnaires are SPEED 12 Korb et al. 2005 available Doughty et al. 1997 CANDEES 13 • Biomarkers whose Begley et al. 2002 DEQ 21 levels correlate with NEI-VFQ 25 OCULAR 31 Johnson Murphy symptom severity are of 2007 COMFORT interest because they INDEX may be closer to IDEEL 57 Rajagopalan et al. 2005 symptom mechanisms

Symptom / Sign correlation is often poor • Goren 1988 • Enriquez de Salamanca 2010 • Begley 2003 • Nichols 2004 • No correlation with global scores: • Saleh 2006 • Some scattered corrlns • Moore 2009 with individual CKs. • Fuentes-Paez 2011

Symptom sources in dry eye � Hyperosmolarity � Diffuse: meniscus sample � Focal: tear film break up [Ocular Protection Index - BUT/Blink interval]. 1 � Reduced lubrication � frictional drag: loss of glycocalyx and goblet cell mucin � lid wiper epitheliopathy. 2 [Shearing between lids and globe during blinks and eye movements] � Conjunctivochalasis � Inflammatory mediators [Prostanoids, cytokines, neurokinins, neuromediators] � Ocular surface damage [Alterred nerve excitability 3 ; neuropathic firing 4 ] 1. Ousler et al. 2008 2. Korb et al 2005 3. dePaiva and Pflugfelder 2004 4. Belmonte, Gallar 2011 .

Symptom sources - are dependent on are dependent on- - - Corneal sensory fibres – Polymodal nociceptors – Cold fibres 1 Muller et al. 2005 • Physiological De Paiva Pflugfeldedr 2004 – Surface stress - increased stimuli – increased excitability • Neuropathic firing – cold fibres 1 Lid margin sensory fibres? 1. Belmonte Gallar IOVS 2011, Vol. 52, 3888

the source of symptoms in dry eye Innervation of the Eye Sensitivity varies over the lids • Many sources of symptoms • Lack of a powerful and ocular surface association between a whose relative contribution conjunctiva biomarker and dry eye may change with stage of symptoms at diagnosis disease. should not discourage its • Current symptoms may cornea use to track the efficacy of a 64% reflect the cumulative effect of 6.0 drug, several causes. Bulbar • particularly where it reflects conjunctiva • Studies needed to identify a causal hypothesis or could lid/MGD specific symptoms tarsus provide proof of principle of Lid margin drug action Lid margin mucosa Sensitivity of Lid margin mucosa Lid margin skin Lawrenson and Ruskell 1993; as high as Cornea McGowan et al 1994