Osteoarthritis: Towards a progressive APPROACH

Abstract

Osteoarthritis is a progressive degenerative joint disease. There is increasing evidence that osteoarthritis is a disease of the whole joint, including multiple joint tissues, with an important role for synovial inflammation. Therefore, an ideal disease modifying osteoarthritis drug (so-called DMOAD) should have chondroprotective, anti-inflammatory, and analgesic effects. Currently, no such drug exists. Recently, a fusion protein of Interleukin-4 and Interleukin-10 was developed, the IL4-10 FP. In vitro, the IL4-10 FP showed chondroprotective and anti-inflammatory effects. In two in vivo animal models, the IL4-10 FP showed chondroprotective and analgesic effects. These results indicate the DMOAD potential of the IL4-10 FP. Since no DMOADs are available for osteoarthritis, current treatment is mainly focused on relief of symptoms. However, the underlying mechanisms leading to clinical symptoms differ between patients. In development of new treatments, the distinction between these different phenotypes, with different characteristics and origin, is not sufficiently acknowledged. This explains the mostly disappointing results of new approaches, because these ‘one size fits all’ approaches are not realistic. To increase the chance for success in future clinical trials, a different approach is needed. The APPROACH cohort study will contribute to the identification of multiple phenotypes of osteoarthritis in several ways. Firstly, using machine learning, patients were selected with a high chance to show (fast) disease progression. This is important because to proof that a new treatment stops or slows down disease progression, you have to make sure that you select patients who actually progress without treatment. Secondly, APPROACH combined not only multiple conventional but also new disease markers to monitor the disease and with that define different phenotypes. One of these new markers is motion analysis using the GaitSmart® system. GaitSmart® gives additional information on someone’s disease status, next to radiographs and patient reported outcome measures. In addition, GaitSmart® combines evaluation of self-reported and performance-based physical function and is able to detect short term changes in performance-based physical function. One of the possible phenotypes of osteoarthritis identified in this thesis are patients where a neuropathic pain component plays a role. Compared to patients without a neuropathic pain component, matched for knee pain and general pain, patients with a neuropathic pain component have less radiographic damage in their index knee (the joint on which selection was based) but a worse physical function. This might be explained by osteoarthritis in other joints, however, despite higher pain levels in other joint throughout the body, there was no difference in radiographic damage in these other joints. This indicates that in patients with a neuropathic pain component, pain and loss of function are not always a direct result of local joint damage. This implies that these patients might not benefit from the ‘one-size-fits-all’ approach using conventional analgesics (treating nociceptive pain) or total joint replacement (where the damages tissue is removed). Eventually, the APPROACH database provides the possibility to identify more phenotypes of osteoarthritis, and with that be of help to develop a new approach, focused on more personalized treatments for patients with osteoarthritis.