Call for standardized definitions of osteoarthritis and risk stratification for clinical trials and clinical use

Abstract

Osteoarthritis (OA) is a heterogeneous disorder. The goals of this review are (1) To stimulate use of standardized nomenclature for OA that could serve as building blocks for describing OA and defining OA phenotypes, in short to provide unifying disease concepts for a heterogeneous disorder; and (2) To stimulate establishment of ROAD (Risk of OA Development) and ROAP (Risk of OA Progression) tools analogous to the FRAX™ instrument for predicting risk of fracture in osteoporosis; and (3) To stimulate formulation of tools for identifying disease in its early preradiographic and/or molecular stages - REDI (Reliable Early Disease Identification). Consensus around more sensitive and specific diagnostic criteria for OA could spur development of disease modifying therapies for this entity that has proved so recalcitrant to date. We fully acknowledge that as we move forward, we expect to develop more sophisticated definitions, terminology and tools.

Keywords: Anatomy; Biomarkers; Criteria; Definition; Osteoarthritis; Physiology.

Conflict of interest statement

Conflicts of Interest

Virginia Byers Kraus -- Has received salary support through NIH grants PO1 AR050245 and AG028716; lecture/consultancy fees from Merrimack Pharmaceuticals, Flexion Therapeutics, Bioiberica and Abbott. She is an Associate Editor of Osteoarthritis & Cartilage.

Francisco J Blanco -- has received Grants (Clinical Trials, conferences, advisor and publications) from: Abbvie, Amgen, Bioiberica, Bristol Mayer, Celgene, Celltrion, Cellerix, Grunenthal, Gebro Pharma, Lilly, MSD, Merck Serono, Pfizer, Pierre-Fabra, Roche, Sanofi, Servier and UCB.

Martin Englund – has received honorarium for lectures in a course in clinical epidemiology from Pfizer and for a lecture in knee OA from Össur.

Morten Karsdal - is a full time employee of Nordic Bioscience, a company engaged in biomarker and medicinal product research and development.

Stefan Lohmander -- Relevant financial activities outside the submitted work include consultancy for Abbvie, Flexion, Galapagos, Medivir, MerckSerono, Teijin, Össur. Employment as Editor-in-Chief of Osteoarthritis and Cartilage.

Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Figures

Figure 1. Relationships of disease and illness components

We posit that the disease may be manifest by a prolonged period of isolated musculoskeletal tissue abnormalities at a molecular and clinically silent level (molecular). Further, the molecular abnormalities could precede the anatomic and physiologic level organ system disease and illness manifestations by years or even decades. In addition, abnormalities of two domains or all in combination could be imagined (depicted by arrows and the ring connecting the components).

Figure 2. Taxonomy of Osteoarthritis (OA)

We propose a new ‘taxonomy of OA’ based on the standardized nomenclature of disease (made up of molecular, anatomic and physiologic components, domains or disease elements) and illness (panel A). As illustrated here, a clinical threshold would be anticipated that would result in the transition from disease to illness. This taxonomy anticipates the development of composite indices of OA (arrow) that by analogy to the Disease Activity Score (DAS) in rheumatoid arthritis, would encompass all three-disease domains (molecular, anatomic and physiologic) and illness that could be useful for clinical evaluation and trials. Varying weights might be ascribed to the different elements in the composite score (illustrated by the terms lower and higher within the arrow). Osteoarthritis specific examples for each domain are included in panel B.

Figure 3. Stages of Osteoarthritis incorporating the new taxonomy

Three stages can be imagined -- a no disease/no illness stage, a subclinical stage (with disease manifestations only) and a clinical stage (with illness manifestations). The goal at the predisease stage is to promote health through education on healthy lifestyle choices and specific prevention against the inception of disease by modifying risk factors in a favorable direction. The goal at the subclinical stage is to be able to make a presymptomatic diagnosis to prevent its progression to symptomatic disease and thereby prevent illness and associated disability. The goal at the clinical stage is to provide treatment in an effort to prevent its progression to disability; this includes maximizing the remaining capabilities and functions via pain management, symptom control, stress relief, disease management, rehabilitation and risk reduction. (Levels of prevention adapted from Katz et al. [79]).

Figure 4. Disease versus illness

The tissue functional threshold for establishment of a clinical symptomatic disease differs by organ system. The horizontal dashed lines depict the transition from disease to illness for different diseases. The threshold is relatively high in heart, liver and kidney disease but anticipated to be relatively low for the transition of joint disease to illness (symptoms, disability and joint failure). It is possible that the threshold will vary according to type of joint disease. Both the kidney and liver have a large “functional reserve”. This contributes to their being silent killer diseases [80], in which asymptomatic late stage disease suddenly becomes clinically apparent with a possibly fatal outcome for some patients [63]. AMI=acute myocardial infarction due to coronary heart disease.