Summary Objective Total joint replacement has been proposed as an endpoint in disease modifying osteoarthritis drug (DMOAD) randomized clinical trials (RCTs); however, disparities have generated ...concerns regarding this outcome. A combined Osteoarthritis Research Society International (OARSI)/Outcome Measures in Rheumatology (OMERACT) initiative was launched in 2004 to develop a composite index ‘virtual total joint replacement’ (VJR) as a surrogate outcome for osteoarthritis (OA) progression in DMOAD RCTs. Our objective was to evaluate the prevalence of patients fulfilling different thresholds of sustained pain, reduced function, and X-ray change in existing DMOAD RCTs. Design Post hoc analysis of summary data from the placebo arm of eight DMOAD RCTs. Results Eight OA RCTs representing 1379 patients were included. Pain was assessed by WOMAC and/or VAS and function by WOMAC and/or Lequesne. Among six knee and two hip studies, 248 (22%) and 132 (51%) patients respectively had X-ray progression decrease joint space width (JSW) ≥0.5 mm. The prevalence of patients fulfilling clinical and radiographic criteria was highest ( n = 163, 12%) in the least stringent scenario (pain + function ≥80 at ≥2 visits); with few patients ( n = 129, 2%) in the most stringent scenario (pain + function ≥80 at ≥4 visits). Using these prevalence data, a sample size of 352–2144 per group would be needed to demonstrate a 50% difference between groups. Conclusions The prevalence of patients with sustained symptomatic OA of at least a moderate degree with X-ray progression is low. Even using lenient criteria to define VJR, large patient numbers would be required to detect differences between groups in DMOAD RCTs. Investigation of the optimal cutoff threshold and combination of symptoms and radiographic change should be pursued.
Summary Background Joint space width (JSW) evaluated in millimeters on plain X-rays is the currently optimal recognized technique to evaluate osteoarthritis (OA) structural progression. Data obtained ...can be presented at the group level (e.g., mean ± standard deviation of the changes). Such presentation makes difficult the interpretation of the clinical relevance of the reported results. Therefore, a presentation at the individual level (e.g., % progressors) seems more attractive but requires to determining a cut-off. Several methodologies have been proposed to define cut-offs in JSW: arbitrary chosen cut-off, cut-off based on the validity to predict a relevant end-point such as the requirement of total articular replacement or cut-off based on the measurement error such as smallest detectable difference (SDD). Objectives The objective of this OARSI–OMERACT initiative was to define a cut-off evaluated in millimeters on plain X-rays above which a change in JSW could be considered as relevant in patients with hip and knee OA. Methods The first step consisted in a systematic literature research performed using Medline database up to July 2007 to obtain all manuscripts published between 1990 and 2007 reporting a cut-off value in JSW evaluated in millimeters at either the knee or hip level. The second step consisted in a consensus based on the best knowledge of the 11 experts with the support of the available evidence. Results Among the 506 articles selected by the search, 47 articles reported cut-off of JSW in millimeters. There was a broad heterogeneity in cut-off values, whatever the methodologies or the OA localization considered (e.g., from 0.12 to 0.84 mm and from 0.22 to 0.78 mm for Knee (seven studies) and hip (seven studies), respectively when considering the data obtained based on the reliability). Based on the data extracted in the literature, the expert committee proposed a definition of relevant change in JSW based on plain X-rays, on an absolute change of JSW in millimeters and on the measurement error e.g., calculation of the SDD using the Bland and Altman technique. The results of the analysis of JSW should be expressed in terms of a dichotomous variable (e.g., progressors yes/no): a patient with a change in JSW during the study over such SDD will fulfill the definition of “progressor”. Moreover, the pilot study aimed at evaluating the measurement error should be designed to reflect the different characteristics of the primary study in which the analysis of the radiological findings will be based on (patient's characteristics, centers characteristics, readers). Conclusion This initiative based on both an Evidence Based Medicine (Systematic Literature Research) and Expert Opinion approach resulted in a proposal of definition of relevant radiological progression in OA to be used as end-point in clinical trials and also recommendations on the conduct of the reliability study allowing such definition.
Summary Objective The objective of this work was to compare the measurement properties of three categorical X-ray scoring methods of knee osteoarthritis (OA), both on semiflexed and extended views. ...Methods In data obtained from trials and cohorts, X-rays were graded using Kellgren and Lawrence (KL), the OA Research Society International (OARSI) joint space narrowing score, and measurement of joint space width (JSW). JSW was analyzed as a categorical variable. Construct validity was assessed through logistic regression between X-ray stages and Western Ontario and McMaster Universities OA Index. Inter-observer reliability was assessed in 50 subjects for extended views by weighted kappa. Intra-observer reliability and sensitivity to change were assessed separately for extended and semiflexed views in 50 patients who had both views performed, over a 30-month interval, by weighted kappa and standardized response mean (SRM). Results Extended views were available from three trials and two cohorts (1759 X-rays), including one trial in which both extended and semiflexed views (antero-posterior) were obtained. Correlation with clinical parameters was low for the three scoring methods, except for the single community-based cohort. Inter-rater reliability was higher for categorical JSW in extended views (kappa, 0.86 vs 0.56 and 0.48 for KL and OARSI, respectively). Intra-rater reliability was higher for categorical JSW, both in extended views (0.83 vs 0.61 and 0.71) and in semiflexed views (0.89 vs 0.50 and 0.67). Sensitivity to change was also higher for categorical JSW, particularly in semiflexed views (SRM, 0.49 vs 0.22 and 0.34). Conclusion These results indicate categorical JSW, in particular on semiflexed views, may be the preferred method to evaluate structural severity in knee OA clinical trials.
Summary Objective To estimate the extent to which varus malalignment, a source of abnormal intra-articular stresses in the medial tibiofemoral compartment and risk factor for progression of knee ...osteoarthritis (OA), may have diminished the structure-modifying benefit of doxycycline in knee OA. Methods Post hoc treatment group comparisons from a randomized, placebo-controlled trial of the effect of doxycycline (100 mg, twice daily) on medial joint space narrowing (JSN) in subgroups of varus and non-varus OA knees. Subjects ( N = 379 with X-ray follow-up) were obese 45–64-year-old women with unilateral knee OA at baseline. JSN was measured manually in semiflexed anteroposterior (AP) radiographs acquired with standardized fluoroscopic positioning. The anatomic-axis angle (AAA) was measured in each baseline radiograph and transformed to an estimate of the mechanical-axis angle (MAAest ) using a validated regression equation. Knees with MAAest < 178° were classified as varus. Results In our original comparison with placebo, doxycycline slowed the rate of medial JSN in OA knees by 38% at 16 months and by 33% at 30 months. Among non-varus OA knees, 16-month JSN in the doxycycline group was 44% slower than in the placebo group (0.09 vs 0.16 mm/year, P = 0.080), and 39% slower at month 30 (0.10 vs 0.17 mm/year, P = 0.026). JSN in varus knees (0.20–0.27 mm/year) was more rapid than in non-varus knees ( P = 0.083) and unaffected by doxycycline. Conclusion Varus malalignment negated the slowing of structural progression of medial-compartment OA by doxycycline. To our knowledge, this is the first report documenting that static varus angulation can negate a pharmacologic structure-modifying effect.
Summary Objective To ascertain the contribution of articular cartilage morphometry and meniscal position on MRI to joint space width (JSW) measured in the Lyon schuss radiograph of the knee. Design ...62 obese women with knee OA and 99 non-obese female controls (mean age 56.6 years) were imaged using 3 T MRI and coronal water excitation spoiled gradient echo sequences. Segmentation of femorotibial cartilage morphology and regional morphometric analysis was performed using custom software. Meniscal position was measured quantitatively in sagittal and coronal planes. Minimum space width (mJSW) was measured in the Lyon Schuss knee radiograph; Kellgren and Lawrence grades (KLG) were assigned on standing anteroposterior knee films. The relative contribution of regional cartilage thickness and meniscal position to mJSW was assessed initially in univariate models and subsequently with multivariable modelling. Results 65% of the variation in mJSW was explained by regional cartilage thickness measures, different KLG and meniscal coverage. Of these measures the medial tibia cartilage thickness measures and central region of the central medial femur (ccMF) play a consistent role in variations in mJSW observed across all KLG. Further ccMF and the addition of percent meniscal coverage to this model explains the remaining differences in mean mJSW found between those subjects with definite joint space narrowing (KLG3) and those without OA. Conclusion The variation in radiographic mJSW is best described by five regional cartilage thickness measures and percent meniscal coverage. The magnitude of each measures contribution differs according to radiographic severity with more variability explained by cartilage thickness of ccMF cartilage thickness and percent meniscal coverage with more severe disease.
Objective:The Lyon Schuss (LS) and fixed flexion (FF) views of the knee are superior to a conventional standing anteroposterior view in evaluating joint space narrowing (JSN) in osteoarthritis (OA). ...Both position the knee identically but only the LS aligns the medial tibial plateau (MTP) with the x-ray beam fluoroscopically. The present study provides the first head-to-head comparison of the LS and FF views.Methods:At baseline and 12 months, 62 OA and 99 control knees were imaged twice on the same day with LS and FF views. Minimum joint space width (mJSW) was measured by computer and MTP alignment was assessed from the distance between anterior and posterior margins of the MTP (intermargin distance, IMD). Reproducibility of measurements of mJSW and sensitivity to change were evaluated.Results:In normal knees, JSW did not vary over 12 months with either view. In OA knees, 12-month mJSN was 0.22 (0.43) mm with the LS view and −0.01 (0.46) mm with the FF view (p = 0.0002 and p = 0.92, respectively). Mean IMD was only half as large in LS as in FF views (0.9 (0.5) mm vs 1.9 (1.2) mm, p<0.0001).Conclusions:LS and FF radiographs offer similar reproducibility in JSW measurement. However, presumably due to its superiority in aligning the MTP, the LS view is much more sensitive to JSN in OA knees.
Summary Objective To identify subregional differences in femorotibial cartilage morphology between healthy controls and women with different grades of radiographic knee osteoarthritis (OA). Design ...158 women aged ≥40 years were studied. Weight-bearing extended anterior-posterior (AP) and Lyon schuss radiographs were obtained and the Kellgren Lawrence grade (KLG) determined. 97 women had a body mass index (BMI) ≤ 28, no symptoms, and were AP KLG0. 61 women had a BMI ≥ 30, symptoms in the target knee, and mild (KLG2 = 31) to moderate (KLG3 = 30) medial femorotibial radiographic OA in the AP views. Coronal spoiled gradient echo water excitation sequences were acquired at 3.0 Tesla. Total plate and regional measures of cartilage morphology of the weight-bearing femorotibial joint were quantified. Results KLG2 participants displayed, on average, thicker cartilage than healthy controls in the medial femorotibial compartment (particularly anterior subregion of the medial tibia (MT) and peripheral external, internal subregions of the medial femur), and in the lateral femur. KLG3 participants displayed significantly thinner cartilage than KLG0 participants in the medial weight-bearing femur (central subregion), in the external subregion of the MT, and in the internal subregion of the lateral tibia. These differences were generally unaffected when possible effects of demographic covariates were considered. Conclusions The results indicate that in femorotibial OA regional cartilage thickening and thinning may occur, dependent on the (radiographic) disease status of the joint. These changes appear to display a heterogeneous spatial pattern, where certain subregions are more strongly affected than others.
Summary Objective This study evaluated the longitudinal performance of a modified Lyon schuss (LS) knee examination in the detection of radiographic joint space narrowing (JSN) in knees with ...osteoarthritis (OA). The modified LS exam entails two to four iterative acquisitions with empirically adjusted angulation of the X-ray beam to achieve superimposition of the anterior and posterior margins of the medial tibial plateau (MTP), a marker of parallel radioanatomic alignment that the original LS exam achieves with fluoroscopically guided beam angulation. Methods Seventy-four obese women with symptomatic knee OA underwent LS and fixed-flexion (FF, caudal 10° beam angulation) X-ray exams at baseline and 1 year later. For 47 subjects, beam angulation for both LS exams was guided by fluoroscopy. For 27 subjects, the modified LS exam was performed at one or both times. Modified and original LS procedures were evaluated relative to concurrent FF radiographs with respect to the inter-margin distance (IMD) at the MTP midpoint (quality and reproducibility of alignment) and sensitivity to JSN. Results Compared to FF radiographs, modified LS radiographs afforded a smaller mean IMD at baseline (0.89 vs 2.06 mm, P = 0.002), more reproducible IMD (mean change = 0.49 vs 0.91 mm, P = 0.007) and more rapid JSN (mean = 0.25 vs 0.02 mm/yr, P = 0.005). These differences paralleled those observed between original LS and FF procedures with respect to baseline alignment (0.96 vs 1.94 mm, P < 0.001), reproducibility of alignment (0.49 vs 1.00 mm, P < 0.001) and sensitivity to JSN (0.16 vs −0.01 mm/yr, P = 0.007). Conclusion In clinical centers where the absence of fluoroscopy equipment precludes use of the original LS protocol, a modified procedure employing iterative, empirical adjustment of the beam angle to achieve parallel radioanatomic alignment with the MTP affords a degree of superiority over the FF protocol with respect to quality and reproducibility of positioning and sensitivity to JSN in OA knees similar to that of the original.
Summary
Sepsis is characterized by a severe systemic inflammatory response to infection that is associated with high morbidity and mortality despite optimal care. Invariant natural killer T (iNK T) ...cells are potent regulatory lymphocytes that can produce pro‐ and/or anti‐inflammatory cytokines, thus shaping the course and nature of immune responses; however, little is known about their role in sepsis. We demonstrate here that patients with sepsis/severe sepsis have significantly elevated proportions of iNK T cells in their peripheral blood (as a percentage of their circulating T cells) compared to non‐septic patients. We therefore investigated the role of iNK T cells in a mouse model of intra‐abdominal sepsis (IAS). Our data show that iNK T cells are pathogenic in IAS, and that T helper type 2 (Th2) polarization of iNK T cells using the synthetic glycolipid OCH significantly reduces mortality from IAS. This reduction in mortality is associated with the systemic elevation of the anti‐inflammatory cytokine interleukin (IL)‐13 and reduction of several proinflammatory cytokines within the spleen, notably interleukin (IL)‐17. Finally, we show that treatment of sepsis with OCH in mice is accompanied by significantly reduced apoptosis of splenic T and B lymphocytes and macrophages, but not natural killer cells. We propose that modulation of iNK T cell responses towards a Th2 phenotype may be an effective therapeutic strategy in early sepsis.
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