Phenotype More Important Than Disease Stage in Knee Osteoarthritis

By Brian Hoyle

BOSTON -- November 18, 2014 -- Disease phenotypes rather than disease status are driving disease progression in osteoarthritis (OA) of the knee, according to results of a post hoc analysis of over 2,200 subjects presented at the 2014 Annual Scientific Meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP).

“The criteria that are diagnostic and prognostic in large cohort studies for OA -- such as weight and pain -- are not prognostic for progression in randomised clinical trials, most likely because of the short duration (2 years) versus long term cohorts,” explained lead investigator Morten Asser Karsdal, PhD, Nordic Bioscience A/S, Herlev, Denmark, presenting here on November 16. “A combination of markers and criteria were able to select the patients that progress by identifying 3 different OA phenotypes -- bone, cartilage, and synovial -- which clearly need different interventions,” he added.

OA does not progress uniformly. The heterogeneity of the disease is reflected in the various routes of progression that occur in about half of patients with OA. Furthermore, the speed of progression can differ. The aim of this study was to identify key characteristics for disease progression.

Dr. Karsdal and colleagues focused on the discovery and development of disease biomarkers. The team analysed 2 double-blind trials (NCT00486434 and NCT00704847) involving 2,206 subjects treated for painful OA of the knee using salmon calcitonin. The team examined Kellgren-Lawrence (KL) scores of the severity of knee OA, joint-space width, pain and function scores determined using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) questionnaire, body mass index (BMI), and demographics.

Comparison of affected and unaffected knees at baseline revealed comparable mean joint-space index values in knees with no radiographic evidence of OA and knees in which joint-space narrowing was doubtful. As the severity of knee OA increased (i.e., KL-2, -3, and -4), the difference in mean joint-space narrowing between affected and unaffected knees became significantly different. For example, in knees rated KL-2 and -3, the mean joint space in unaffected knees (3.32 ± 0.03 mm) was significantly narrower than in knees with OA (3.42 ± 0.02 mm) (P < .001). The KL scores were positively and significantly correlated with the WOMAC pain score and total WOMAC score, despite the variability in KL scores in the subjects, which is reflective of the heterogeneity of OA and the varying pain tolerances of the subjects.

OA progression was evident in only about 1 third of subjects. Of those, the change was minimal in over half the subjects. Nonetheless, the mean joint-space narrowing at 2 years in the unaffected and affected knees (0.25 ± 0.02 vs 0.32 ± 0.02 mm) was significantly different (P < .01). Patients with symptomatic OA at baseline progressed significantly faster than patients with asymptomatic disease.

When patients were stratified in quartiles of WOMAC pain and BMI, and WOMAC pain and KL scores, however, WOMAC pain quartile 3 (11 to 15) was associated with greater progression of OA than subjects in quartile 2 (6 to 10) and quartile 4 (16 to 20), suggesting that phenotypes other than the state of the disease drive OA progression.

“This dataset is ideally suited for identification of different phenotypes of OA, and biomarkers associated with those,” wrote the researchers in the poster. “The data…clearly describe significant associations between KL-score, joint-space narrowing, pain, and BMI in patients with symptomatic knee OA,” they concluded.

[Presentation title: OA Phenotypes Rather Than Disease Stage Drive Structural Progression – Identification of Structural Progressors from 2 Phase III Randomized Clinical studies with Symptomatic Knee OA. Abstract 222]
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