Tissue structure damage in late-stage knee osteoarthritis: medication, markers, and disease modification before replacement surgery

Abstract

The aim of this thesis is to gain more insight in the characteristics of end-stage osteoarthritic patients who are about to undergo total knee replacement surgery. Their use of medication, potential markers of actual characteristics of joint damage and inflammation, and effects of potential disease modification by drugs were studied. For this purpose, a clinical trial was performed with patients with end-stage knee osteoarthritis. While on the waiting list for total knee replacement surgery, patients were randomized to receive pharmacological treatment for four to six weeks prior to joint replacement surgery. At the moment of surgery cartilage and synovial tissue were harvested for detailed macroscopic, microscopic, and biochemical evaluation. Clinical effects of medication before surgery and clinical effects of surgery itself were evaluated by use of questionnaires. It appeared that most patients on the waiting list for total knee replacement surgery experience significant levels of pain and limitations due to their disease. But surprisingly, the majority of the patients on the waiting list did not take adequate pain medication. When patients were asked one and a half year after total knee replacement surgery whether they would have undergone the treatment again with the present (post-treatment) knowledge, it was revealed that 13% of the treated patients would not have undergone the treatment if they knew the clinical outcome beforehand.Radiographs also appear to be good indicators for the actual severity of joint damage in contrast to clinical characteristics and should be taken into account when selecting patients for joint replacement surgery. Adipokine levels were all clearly higher compared to controls without any radiographic sign of cartilage damage, also after adjustment for gender, age, and BMI. In the OA population clear relations with age were found for adiponectin and resistin and with BMI for leptin and adiponectin. No associations were found between serum levels of adipokines and cartilage damage whereas a marginal positive association was found with synovial inflammation. Supporting an important role of adipokines in osteoarthritis, but the mechanism remains to be elucidated. In a pilot study the effects of celecoxib compared to a frequently used conventional NSAID indomethacin was investigated. The result of this pilot study was the basis for a larger prospective, randomized, observer blinded clinical trial. The promising effect of the earlier study could however not be confirmed by this randomized, observer blinded clinical trial. In conclusion, celecoxib appears to have less clear disease modifying osteoarthritic drug (DMOAD) properties as originally supposed. This thesis demonstrates that end-stage knee osteoarthritis patients are very different in their demographic, radiographic, and actual joint tissue characteristics. It also demonstrates that part of the patients undergoing total knee replacement surgery could have delayed their surgery if they had used adequate pharmacological therapy and proper selection based on radiographic damage. Celecoxib might be treatment of choice although DMOAD activity is not unambiguously proven.