Progression Of Joint Space Narrowing Research Articles

Recommendations for the use of new methods to assess the efficacy of disease-modifying drugs in the treatment of osteoarthritis

Background: Recent innovations in the pharmaceutical drug discovery environment have generated new chemical entities with the potential to become disease modifying drugs for osteoarthritis (DMOAD’s). Regulatory agencies acknowledge that such compounds may be granted a DMOAD indication, providing they demonstrate that they can slow down disease progression; progression would be calibrated by a surrogate for structural change, by measuring joint space narrowing (JSN) on plain X-rays with the caveat that this delayed JSN translate into a clinical benefit for the patient. Recently, new technology has been developed to detect a structural change of the OA joint earlier than conventional X-rays. Objective: The Group for the Respect of Ethics and Excellence in Science (GREES) organized a working party to assess whether these new technologies may be used as surrogates to plain x-rays for assessment of DMOADs. Methods: GREES includes academic scientists, members of regulatory authorities and representatives from the pharmaceutical industry. After an extensive search of the international literature, from 1980 to 2002, two experts meetings were organized to prepare a resource document for regulatory authorities. This document includes recommendations for a possible update of guidelines for the registration of new chemical entities in osteoarthritis. Results: Magnetic resonance imaging (MRI) is now used to measure parameters of cartilage morphology and integrity in OA patients. While some data are encouraging, correlation between short-term changes in cartilage structure observed with MRI and long-term radiographic or clinical changes are needed. Hence, the GREES suggests that MRI maybe used as an outcome in phase II studies, but that further data is needed before accepting MRI as a primary end-point in phase III clinical trials. Biochemical markers of bone and cartilage remodelling are being tested to predict OA and measure disease progression. Recently published data are promising but validation as surrogate end-points for OA disease progression requires additional study. The GREES suggests that biochemical markers remain limited to ‘proof of concept’ studies or as secondary end-points in phase II and III clinical trials. However, the GREES emphasizes the importance of acquiring additional information on biochemical markers in order to help better understand the mode of action of drugs to be used in OA. Regulatory agencies consider that evidence of improvement in clinical outcomes is critical for approval of DMOAD. Time to total joint replacement surgery is probably the most relevant clinical end-point for the evaluation of efficacy of a DMOAD. However, at this time, time to surgery can not be used in clinical trials because of bias by non disease-related factors like patient willingness for surgery or economic factors. At this stage, it appears that DMOAD should demonstrate a significant difference compared to placebo. Benefit should be measured by 3 co-primary end-points: JSN, pain and function. Secondary end-points should include the percentage of patients who are ‘responder’ (or ‘failure’). The definition of a ‘failure’ patient would be someone with progression of JSN>0.5 mm over a period of 2–3 years or who has a significant worsening in pain and/or function, based on validated cut-off values. The definition of the clinically relevant cut-off points for pain and function must be based on data evaluating the natural history of the disease (epidemiological cohorts or placebo groups from long-term studies). These cut-offs points should reflect a high propensity, for an individual patient, to later require joint replacement. Conclusion: GREES has outlined a set of guidelines for the development of a DMOAD for OA. Although these guidelines are subject to change as new information becomes available, the information above is based on the present knowledge in the field with the addition of expert opinion.

How do we best measure the clinical benefit of a structure-modifying osteoarthritis drug?

Rationale The aim of the treatment of osteoarthritis (OA) is to improve symptoms and function; ideally, treatment would also prevent the structural progression of the disease. The targets of structure-modifying OA drugs (STMOADs) can be one of the various lesions of OA, including cartilage destruction, osteophytes, bone sclerosis, cysts, and bone attrition. However, prevention of cartilage destruction (chondroprotection) is currently accepted as the most promising target of STMOADs. The possibility of preventing progression of cartilage damage has been demonstrated in various animal models of OA. Chondroprotection is now being investigated in human OA. Several trials are in progress, and two positive studies have already been reported 1,2 . The goal of these initial trials was mainly to demonstrate that a reduction of the natural progression of OA joint space narrowing is possible in humans. Today, chondroprotection is no longer considered a myth, and the questions now are whether STMOADs provide a clinical benefit for the patient and how to evaluate that benefit. These new and relevant questions are difficult to answer. Can we expect a clinical benefit from STMOADs? Drugs evaluated for a structure-modifying effect may or may not also have symptomatic effects in the short term. STMOADs with a symptomatic effect can be expected to lead to clinical improvement in the OA patient in the long term. Evaluation of the clinical benefit of STMOADs could be possible with the tools presently used for the assessment of symptom-modifying drugs in OA. The clinical benefit that can be expected from a drug without known symptomatic effects but with a structuremodifying effect and how to measure that clinical benefit are as yet unknown. An effective STMOAD is not expected to induce a repair of the structural lesions of OA, but it is expected to stop or decrease their progression. Such a structural effect in the long term might result in symptom improvement or might only prevent a progression of symptoms. It also might have no clinical effect, since symptoms and lesions are poorly correlated in OA patients. The time required to demonstrate the clinical benefit of a STMOAD is unknown. It is possible that there may be a long delay (several years) between the beginning of STMOAD efficacy and the realization of any clinical benefit. The extent of clinical benefit could be related to the degree of effectiveness of the STMOAD. If this were true, the delay in clinical benefit could be very long for drugs able to only partially reduce the structural progression of the disease. Finally, the clinical benefit of a STMOAD might be missed by our usual tools and could require new methods of evaluation.

A ONE‐YEAR, RANDOMISED, PLACEBO (SALINE) CONTROLLED CLINICAL TRIAL OF 500–730 KDA SODIUM HYALURONATE (HYALGAN®) ON THE RADIOLOGICAL CHANGE IN OSTEOARTHRITIS OF THE KNEE

SUMMARYThe primary objective of this study was to investigate structural changes, as measured by joint space narrowing (JSN), within the knee joint during treatment with intra‐articular sodium hyaluronate (HA) of molecular weight 500–730 kDa in patients with osteoarthritis (OA) of the knee. Patients received a weekly intra‐articular injection of either 20 mg2/ml HA or a 2 ml vehicle placebo (saline) for three weeks. This course was repeated twice more at four‐monthly intervals. Concomitant treatment with analgesics or NSAIDs was allowed. The primary efficacy measure was the reduction in mean joint space width (JSW) of the medial compartment at 52 weeks. A total of 408 patients were randomised and 319 completed the one‐year study (HA: n=160, placebo: n=159); 273 of the 319 were included in the primary analysis. Analysis of variance on these 273 patients did not show a statistically significant difference between the two treatment groups. However, there was a significant difference in response to treatment in terms of the baseline JSW (p=0.01), indicating that outcome of treatment may depend on‐baseline JSW. Therefore, a subgroup analysis by baseline JSW was conducted. This compared patients with a JSW >4.6 mm with those with a JSW <4.6 mm. In those with radiologically milder disease at baseline and receiving HA, the JSN was significantly reduced compared with placebo (p=0.02). In patients with radiologically more severe disease there was no difference in JSN between the two treatments. Although, in this one‐year study, no overall treatment effect was seen, those with radiologically milder disease at baseline had less progression of joint space narrowing when treated with HA.

Quantitative assessment of joint space width with an electronic caliper

The progression of joint space narrowing (JSN) is considered to be the best available marker of osteoarthritis (OA) progression. Several techniques have been proposed for the measurement of joint space at its narrowest point in OA of the hips and knees.Objective To evaluate the properties of the technique using an electronic caliper for the measurement of JSN in OA patients.Design We used an electronic caliper to measure joint space width (JSW) for hips on 100 plain radiographs. JSW was measured in the vertical position at the center of the femoral head. Femoral head diameter was also determined to correct for variations due to differences in magnification of digitized X-rays. All films were read twice by each of two rheumatologists (one junior, one senior) and two radiologists (one junior, one senior). Intraclass correlation coefficients and their 95% confidence intervals were calculated.Results Detailed results are given for right hips (38 with OA, 18 inflammatory, 44 normal); very similar results were obtained for left hips. For JSW, the intraclass correlation coefficient was between 0.96 and 0.99 for intraobserver reliability. The level of reliability was similar for analysis of the diameter of the femoral head (R:0.84 to 0.98) and for the ratio of these two measurements (0.96 to 0.99). The most reliable measurements were those made by the senior radiologist, followed by those made by the two rheumatologists. In assessments of interobserver reliability for the measurement of JSW, R varied from 0.91 to 0.96 for the first reading and from 0.88 to 0.96 for the second reading. For the measurement of femoral head diameter, R varied from 0.86 to 0.96 for the first reading and from 0.74 to 0.96 for the second reading.Conclusion The electronic caliper technique is an accurate method for measuring JSW in the hip. This technique seems to be reproducible, is simple, and could be used for routine evaluation. Further validation is required, with the measurement of serial X-rays from the same patients. Copyright 2002 OsteoArthritis Research Society International. Published by Elsevier Science Ltd. All rights reserved.

Tissue inhibitor of metalloprotease-1 (TIMP-1) serum level may predict progression of hip osteoarthritis

Objective To determine the predictive value of serum levels of TIMP-1 and hyaluronic acid in a 1 year prospective study in hip osteoarthritis (OA).Methods Twenty-nine patients with OA of the hip were enrolled in a 1-year prospective study (median follow-up, 13 months). Biochemical analysis was used to assess TIMP-1 and hyaluronic acid at entry and at the end of the study. Radiographic evaluation with an assisted computed program was performed to calculate progression of joint space narrowing. Statistical tests served to determine correlations between observed serum levels and radiograph joint space narrowing.Results Among the 29 patients, 10 showed joint space narrowing greater than 0.6mm per year. The initial concentration of TIMP-1 as well as delta value of variation in serum levels of TIMP-1 (difference between TIMP-1 concentration at entry and at the end) correlated with the progression of joint space narrowing. A cut-off value of 600ng/ml of TIMP-1 allowed the patients who progressed slowly from those who progressed more rapidly. Hyaluronic acid serum level was not predictive of evolution.Conclusion TIMP-1 serum level may serve to predict the evolution of patients with hip OA.

Quantitative measurement of joint space narrowing progression in hip osteoarthritis: a longitudinal retrospective study of patients treated by total hip arthroplasty.

To evaluate the rate of progression of radiological joint space narrowing (JSN) in patients operated on for hip osteoarthritis (OA) and to determine its predictive factors. retrospective longitudinal trial of 61 patients who underwent total hip arthroplasty (THA) for hip OA (69 operated hips). Mean follow-up 81.2 +/- 9.9 months. Collected data: (1) standing frontal radiographs of the pelvis from diagnosis to surgery (246 films) for morphological evaluation and quantitative measurement of joint space width (JSW) (computerized reading of digitized X-rays); (2) demographic data (sex, age, body mass index, smoking status, professional and sporting activities, family history of OA); (3) clinical data (age at onset-diagnosis and THA, drug consumption, time from diagnosis to permanent disability, OA at other joints, previous THA of the contralateral hip). multivariate analysis. The yearly mean narrowing (YMN) of MeanJSW was 0.43 +/- 0.43 mm/yr (median 0.29, range 0.03-2.55). YMN correlated inversely with joint space width at operation and follow-up duration, and was increased in atrophic OA (r = 0.71). The time between diagnosis and THA correlated with JSW at diagnosis, and was inversely correlated with age at onset and YMN. It was longer in patients with hypertrophic OA (r = 0.69). Rapid progression of JSN, older age and absence of osteophytes appear to be the main factors leading to THA.

Prediction of the progression of joint space narrowing in osteoarthritis of the knee by bone scintigraphy.

To test the hypothesis that bone scintigraphy will predict the outcome of osteoarthritis (OA) of the knee joint. Ninety four patients (65 women, 29 men; mean age 64.2 years) with established OA of one or both knee joints were examined in 1986, when radiographs and bone scan images (early and late phase) were also obtained. The patients were recalled, re-examined, and had further radiographs taken in 1991. Paired entry and outcome radiographs were read by a single observer, blinded to date order and other data. Scan findings and other entry variables were related to outcome. Progression of OA of the knee was defined as an operation on the knee or a decrease in the tibiofemoral joint space of 2 mm or more. Over the five year study period 10 patients died and nine were lost to follow up. Fifteen had an operation on one or both knees (22 knees). Of the remaining 120 knees (60 patients) analysed radiographically, 14 (12%) had progressed in the manner defined. Of 32 knees with severe scan abnormalities, 28 (88%) showed progression, whereas none of the 55 knees with no scan abnormality at entry progressed. The strong negative predictive power of scintigraphy could not be accounted for by disease severity or any combination of entry variables. Pain severity predicted a subsequent operation, but age, sex, symptom duration, and obesity had no predictive value. Scintigraphy predicts subsequent loss of joint space in patients with established OA of the knee joint. This is the first description of a powerful predictor of change in this disease. The finding suggests that the activity of the subchondral bone may determine loss of cartilage.

Rate of progression of joint space narrowing in osteoarthritis of the knee

Rate of progression of joint space narrowing in osteoarthritis of the knee