Los Angeles Classification: Development, validation and accumulated experience John Dent Chair, International Working Group for the Classification of Oesophagitis

Important challenges addressed during development of a novel severity grading system for reflux esophagitis The name of the classification? How to develop and validate? How many grades of severity? What endoscopic findings are reliable indicators of reflux esophagitis? Criteria and methods for severity assessment? How to make it simple and memorable?

The name of the classification?

Why the Los Angeles Classification? First presented at a symposium at the 1994 Los Angeles World Congress

How to develop and validate?

Development of criteria (1) Discussion, discussion, discussion on multiple occasions by a small international working group Testing of approaches on a bank of still endoscopic pictures of esophagitis

Development of criteria (2) The first publication from the group describes the development of the Los Angeles Classification criteria by assessment of stored still images 1996 – The endoscopic assessment of esophagitis – A progress report on observer agreement. Armstrong D, Bennett JR, Blum AL, Dent J, de Dombal FT, Galmiche J-P, Lundell L, Margulies M, Richter JE, Spechler SJ, Tytgat GNJ, Wallin L. Gastroenterology 111:85-92 1996

Limited image quality handicapped the development of the Los Angeles Classification Still photographs from fibre optic endoscopes were the only option for the first study Images had very limited resolution and brightness Could not capture all relevant findings in a single frame

Major outcomes of development study (1) Assessment of radial extent of mucosal breaks shown to be more reliable and so adopted as the main severity criterion Endoscopic judgment of length of mucosal breaks greater than a few mm shown to be unreliable 1 cm D Armstrong et al., Gastroenterology 1996;111:85-92

Major outcomes of development study (2) Folds best demonstrated by partial deflation of the esophagus Mucosal folds were found to be the best landmarks for determination of radial extent 1 cm D Armstrong et al., Gastroenterology 1996;111:85-92

How many grades of severity?

Three or four severity grades? Hotly debated within the group Majority of members eventually supported four grades believing: these would be clinically relevant criteria for four grades possible

What endoscopic findings are reliable indicators of reflux esophagitis?

Minimal endoscopic changes for the diagnosis of reflux esophagitis? Literature review and the working group’s assessments indicate minimal changes cannot be scored reliably with standard endoscopes

Minimal endoscopic changes for the diagnosis of reflux esophagitis? The working group is currently investigating the utility of newer endoscopic technologies for recognition of minimal changes

How to handle use of the words “erosion” and “ulceration”? Still on the topic of minimum endoscopic criteria for reflux esophagitis How to handle use of the words “erosion” and “ulceration”? The Los Angeles Group eventually decided to avoid them, using “mucosal break” to include erosion and ulceration, and not to use ulceration as measure of severity Why? – because the group’s studies showed that endoscopic differentiation of erosion and ulceration could not be made with consistent reliability

Definition of a mucosal break “An area of slough or erythema with a sharp line of demarcation from adjacent normal mucosa”

Criteria and methods for severity assessment?

The Los Angeles Classification was designed to only grade severity of esophagitis Thus, the only logical criterion is an estimation of extent of mucosal breaks Complications of esophagitis such as stricture and Barrett’s Esophagus are not reliable measures of severity of esophagitis, so should not be used for assessment of its severity

Final approach to grading the extent of esophagitis Rely primarily on radial extent, using mucosal folds as landmarks The two milder grades are distinguished by: mucosal breaks not extending between two or more mucosal folds axial extent of mucosal breaks differentiates between these grades The two most severe grades are defined by: mucosal breaks extending between two or more mucosal folds radial extent of mucosal folds differentiates between these grades

Los Angeles Classification of reflux esophagitis LA grade A LA grade B One (or more) mucosal break no longer than 5 mm, that does not extend between the tops of two mucosal folds One (or more) mucosal break more than 5 mm long, that does not extend between the tops of two mucosal folds 1 cm 1 cm LA grade C LA grade D One (or more) mucosal break that is continuous between the tops of two or more mucosal folds, but which involves less than 75% of the circumference One (or more) mucosal break which involves at least 75% of the esophageal circumference 1 cm 1 cm Lundell et al., Gut 45:172-180 (1999)

How to make it simple and memorable?

Keeping it simple and memorable This was helped by: Building criteria around longitudinal mucosal folds Minimizing numerical judgments on axial and radial extent Giving the four grades the letters A-D as a code for severity grade

Validation study of criteria

Validation of criteria through grading of endoscopic video clips by external assessors and by pathophysiological correlates The second publication from the group is the definitive description of the Los Angeles Classification 1999 – Endoscopic assessment of oesophagitis: clinical and functional correlates and further validation of the Los Angeles Classification Lundell LR, Dent J, Bennett JR, Armstrong D, Galmiche J-P, Johnson F, Hongo, M, Richter JE, Spechler SJ, Tytgat GNJ, Wallin L. Gut 45:172-180 1999

Inter-observer agreement on presence of individual measures of severity of esophagitis Kappa value is measure of agreement: 0.0 = only chance agreement; 0.4 = just acceptable; 1.0 = perfect agreement The level of agreement was probably reduced by endoscopic image degradation through recording & copying of video clips 0.6 0.5 Kappa value median and interquartile range 0.4 0.3 0.2 0.1 Mucosal break present ≥2 mucosal breaks continued to the top of mucosal folds Mucosal break involving ≥2 folds being continuous between folds Radial extension (0-25%) of the circumference 0.0 Lundell et al., Gut 45:172-180 (1999)

Correlates with measurements of gastro-esophageal reflux

24 hour esophageal acid exposure according to LA grade Gradation of acid exposure by LA grade 20 n=10 % Time Esophageal pH<4.0 16 n=50 n=9 12 n=50 8 n=40 4 Non-erosive reflux disease A B C D LA grade Johnsson et al., Scand J Gastroenterol 33:15-20 (1998)

LA grades C and D predict high levels of nocturnal acid exposure Day-time LA grades C and D identify patients with high levels of nocturnal acid reflux Night-time 70 n=8 n=7 60 50 % Time Esophageal pH<4.0 (median) 40 30 20 n=10 n=12 10 n=20 Normal A B C D LA grade Adachi et al., J Gastroenterol & Hepatol 16:1191-1196 (2001)

Other methodological evaluations outside the IWGCO

Levels of interobserver agreement on endoscopic grading of reflux esophagitis with three grading systems Nine endoscopists scored video recordings of the esophagus in 60 patients with and without reflux esophagitis according to the 3 systems 1.0 Excellent Endoscopist experience 0.8 High (n=3) Good Moderate (n=3) 0.6 Kappa Value Minimal (n=3) Moderate 0.4 Fair 0.2 Poor Random * Two severity grades for both erosions and ulcer Los Angeles Muse Erosions* Muse Ulcer* Savary- Miller Agreement Level Rath et al., Gastrointest Endosc 60; 44-49 (2004)

Additional methodological research into the Los Angeles Classification Pandolfino et al. Comparison of inter- and intraobserver consistency for grading of esophagitis by expert and trainee endoscopists. Gastrointest Endosc 56:639-643 (2002) Kusano et al. Numerical modification of the Los Angeles Classification of gastroesophageal reflux disease fails to decrease observer variation. Dig Endosc 16:9-11 (2004)

Patterns of adoption of the LA Classification in recent years

The LA Classification is now used most widely A review of all relevant publications (n=306) in which reflux esophagitis was formally graded from 2003–2006 inclusive Others 2% More than one 1% Hetzel-Dent 5% Savary Miller Los Angeles 36% 56% Savary-Miller and Hetzel-Dent classifications include modifications

% studies using LA Classification The uptake of the LA Classification has been greatest outside Europe and North America Data for published studies 2003–2006 inclusive 100 80 79% 60 % studies using LA Classification 46% 40 40% 20 Year of publication Europe (n=139) North America (n=50) Rest of World (n=117) Number of published studies

Adoption of the LA Classification is increasing 100 80 73% 62% 60 % studies using LA Classification 52% 40 38% 20 Year of publication 2003 (n=86) 2004 (n=67) 2005 (n=89) 2006 (n=64) Number of published studies

Other studies in which use of the Los Angeles Classification has been important Nakase et al. Relationship between asthma and gastro-oesophageal reflux: significance of endoscopic grade… J Gastroenterol & Hepatol 14:715–722 (1999) Inamori et al. Clinical characteristics of Japanese reflux esophagitis patients as determined by Los Angeles classification. J Gastroenterol & Hepatol 17:172–176 (2003) Okamoto et al. Clinical Symptoms in endoscopic reflux esophagitis: evaluation in 8031 patients. Dig Dis Sci 48:2237-2241 (2003) Sasaki et al. Long-term observation of reflux oesophagitis developing after Helicobacter pylori eradication therapy. Aliment Pharmacol Ther 17:1529–1534 (2003) Lin et al. Limited value of typical gastro-esophageal reflux disease symptoms to screen for erosive esophagitis in Taiwanese. J Formos Med Assoc 102:299-304 (2003) El-Serag et al. Gastro-esophageal reflux among different racial groups in the United States. Gastroenterology 126:1692-1699 (2004) Ishiki et al. Helicobacter pylori eradication improves pre-existing reflux esophagitis in patients with duodenal ulcer disease. Clin Gastroenterol & Hepatol 2:474-479 (2004) Johnson and Fennerty. Heartburn severity underestimates erosive esophagitis severity in elderly patients with gastro-esophageal reflux disease. Gastroenterology 126:660-664 (2004)

The Los Angeles Classification since 1994 A now huge experience indicates that this is the best system available for diagnosis and grading of the severity of reflux esophagitis J Dent, on behalf of IWGCO Members, on basis of literature review and survey data in process of publication

Conclusions – The Los Angeles Classification The subgrouping of patients into LA grades A-D is clinically relevant Hundreds of endoscopists around the world have shown that they can learn and use the classification Outcomes from multiple studies can now be pooled to explore factors possibly relevant to reflux esophagitis severity LA grading should be useful for guiding clinical management strategies, but this needs more formal research