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Objective: To evaluate intraarticular onabotulinumtoxinA 400 U and 200 U in reducing symptoms of knee osteoarthritis (OA) in patients with nociceptive pain., Design: A multicenter, double-blind, randomized, placebo-controlled study was conducted in adults with knee OA and a painDETECT questionnaire score of ≤12 (indicating nociceptive pain). Patients were randomized to receive intraarticular onabotulinumtoxinA 400 U or 200 U or placebo (saline) in the study knee on a 1:1:2 ratio and were followed-up for 24 weeks posttreatment. The primary efficacy measure was the daily average numeric rating scale pain score for the study knee over 7 days at week 8. Secondary efficacy measures included the Western Ontario and McMaster Universities Osteoarthritis Index pain and physical function scores, the patient global impression of change score and the 7-day average worst pain score., Results: Of the 176 enrolled patients, 158 completed the study. The daily average pain score was reduced by approximately two points for all treatments (week 8); the reduction was sustained throughout follow-up, with no significant between-group difference between onabotulinumtoxinA and placebo (both doses: 0.22 [95% confidence interval (CI): -0.33, 0.76]; 400 U: 0.42 [95% CI: -0.26, 1.10]; 200 U: -0.03 [95% CI: -0.70, 0.64]). Similar results were found for all secondary efficacy measures. Treatment-related adverse events occurred in 3.4% of the pooled onabotulinumtoxinA group and placebo group; none were serious., Conclusions: There were no significant differences between onabotulinumtoxinA and placebo in reducing average pain score at week 8 compared with baseline in patients with knee OA. No safety concerns were identified. CLINICALTRIALS., Gov Identifier: NCT02230956., (Copyright © 2018. Published by Elsevier Ltd.)

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 > or =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)< or =28, no symptoms, and were AP KLG0. 61 women had a BMI> or =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.

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 degrees 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.

Objective: Quantitative MRI (qMRI) of cartilage morphology is a promising tool for disease-modifying osteoarthritis drug (DMOAD) development. Recent studies at single sites have indicated that measurements at 3.0 Tesla (T) are more reproducible (precise) than those at 1.5 T. Precision errors and stability in multicentre studies with imaging equipment from various vendors have, however, not yet been evaluated., Methods: A total of 158 female participants (97 Kellgren and Lawrence grade (KLG) 0, 31 KLG 2 and 30 KLG 3) were imaged at 7 clinical centres using Siemens Magnetom Trio and GE Signa Excite magnets. Double oblique coronal acquisitions were obtained at baseline and at 3 months, using water excitation spoiled gradient echo sequences (1.0x0.31x0.31 mm3 resolution). Segmentation of femorotibial cartilage morphology was performed using proprietary software (Chondrometrics GmbH, Ainring, Germany)., Results: The precision error (root mean square coefficient of variation (RMS CV)%) for cartilage thickness/volume measurements ranged from 2.1%/2.4% (medial tibia) to 2.9%/3.3% (lateral weight-bearing femoral condyle) across all participants. No significant differences in precision errors were observed between KLGs, imaging sites, or scanner manufacturers/types. Mean differences between baseline and 3 months ranged from <0.1% (non-significant) in the medial to 0.94% (p<0.01) in the lateral femorotibial compartment, and were 0.33% (p<0.02) for the total femorotibial subchondral bone area., Conclusions: qMRI performed at 3.0 T provides highly reproducible measurements of cartilage morphology in multicentre clinical trials with equipment from different vendors. The technology thus appears sufficiently robust to be recommended for large-scale multicentre trials.

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.

Although treatments for osteoarthritis of the knee are often directed at relieving pain, pain may cause patients to alter how they perform activities to decrease the loads on the joints. The knee-adduction moment is a major determinant of the load distribution between the medial and lateral plateaus. Therefore, the interrelationship between pain and the external knee-adduction moment during walking may be especially important for understanding mechanical factors related to the progression of medial tibiofemoral osteoarthritis. Fifty-three subjects with symptomatic radiographic evidence of osteoarthritis of the knee were studied. These subjects were a subset of those enrolled in a double-blind study in which gait analysis and radiographic and clinical evaluations were performed after a 2-week washout of anti-inflammatory and analgesic treatment. The subjects then took a nonsteroidal anti-inflammatory drug, acetaminophen, or placebo for 2 weeks, and the gait and clinical evaluations were repeated. The change in the peak external adduction moment between the two evaluations was inversely correlated with the change in pain (R = 0.48, p < 0.001) and was significantly different between those whose pain increased (n = 7), decreased (n = 18), or remained unchanged (n = 28) (p = 0.009). Those with increased pain had a significant decrease in the peak external adduction (p = 0.005) and flexion moments (p = 0.023). In contrast, the subjects with decreased pain tended to have an increase in the peak external adduction moment (p = 0.095) and had a significant increase in the peak external extension moment (p = 0.017). The subjects whose pain was unchanged had no significant change in the peak external adduction (p = 0.757), flexion (p = 0.234), or extension (p = 0.465) moments. Thus, decreases in pain among patients with medial tibiofemoral osteoarthritis were related to increased loading of the degenerative portion of the joints. Additional long-term prospective studies are needed to determine whether increased loading during walking actually results in accelerated progression of the disease.

Objective: The adduction moment at the knee during gait is the primary determinant of medial-to-lateral load distribution. If the adduction moment contributes to progression of osteoarthritis (OA), then patients with advanced medial tibiofemoral OA should have higher adduction moments. The present study was undertaken to investigate the hypothesis that the adduction moment normalized for weight and height is associated with medial tibiofemoral OA disease severity after controlling for age, sex, and pain level, and to examine the correlation of serum hyaluronan (HA) level with disease severity and with the adduction moment in a subset of patients., Methods: Fifty-four patients with medial tibiofemoral OA underwent gait analysis and radiographic evaluation. Disease severity was assessed using the Kellgren-Lawrence (K-L) grade and medial joint space width. In a subset of 23 patients with available sera, HA was quantified by sandwich enzyme-linked immunosorbent assay. Pearson correlations, a random effects model, and multivariate regression models were used., Results: The adduction moment correlated with the K-L grade in the left and right knees (r = 0.68 and r = 0.60, respectively), and with joint space width in the left and right knees (r = -0.45 and r = -0.47, respectively). The relationship persisted after controlling for age, sex, and severity of pain. The partial correlation between K-L grade and adduction moment was 0.71 in the left knees and 0.61 in the right knees. For every 1.0-unit increase in adduction moment, there was a 0.63-mm decrease in joint space width. In the subset of patients in whom serum HA levels were measured, HA levels correlated with medial joint space width (r = -0.55), but not with the adduction moment., Conclusion: There is a significant relationship between the adduction moment and OA disease severity. Serum HA levels correlate with joint space width but not with the adduction moment. Longitudinal studies will be necessary to determine the contribution of the adduction moment, and its contribution in conjunction with metabolic markers, to progression of medial tibiofemoral OA.

Treatment of patients with OA of the knee should be individualized and tailored to the severity of the symptoms. In individuals with mild symptomatic OA, treatment may be limited to patient education, physical and occupational therapy and other nonpharmacologic modalities, and pharmacologic therapy including non-opioid oral and topical analgesics. In patients who are unresponsive to this treatment regimen, the use of NSAIDs in addition to nonpharmacologic therapy is appropriate unless medically contraindicated. Judicious use of intraarticular steroid injections has a role either as monotherapy or an adjunct to systemic therapy in patients with knee OA who have symptomatic effusions. The role of joint lavage and arthroscopic debridement in patients with OA of the knee who are unresponsive to conservative medical therapy needs further study, and these procedures cannot be routinely recommended for all patients at this time. Patients with severe symptomatic OA of the knee require an aggressive approach to decreasing pain, increasing mobility, and decreasing functional impairment; such patients may benefit from orthopedic consultation and evaluation for osteotomy or total joint arthroplasty.

Objective: To determine whether the use of a nonsteroidal antiinflammatory drug (NSAID) in patients with painful osteoarthritis (OA) of the knee would result in alterations in specific biomechanical parameters of gait., Methods: Eighteen patients with symptomatic knee OA and varus knee deformity underwent initial clinical evaluation for pain and activities of daily living, and assessment of parameters of gait utilizing a well-described computerized system. All patients were then treated with piroxicam at 20 mg once daily, and clinical and gait analyses were repeated after 4 weeks., Results: Fifteen of the 18 patients studied had a significant increase in the knee adduction moment after treatment. In the group as a whole there was a significant increase in knee adduction moment (mean percent body weight times height [%BWTH] 4.11 pretreatment versus 4.57 after 4 weeks of treatment; P < 0.01) and maximum quadriceps moment (mean %BWTH 2.13 pretreatment, 2.62 posttreatment; P < 0.01), as well as changes in other gait parameters that might be expected to be altered as a result of relief of pain. Sixteen of 18 patients experienced symptomatic relief, with a significant reduction in pain in the group as a whole after 4 weeks (P < 0.001)., Conclusion: NSAID treatment in patients with knee OA results in a reduction in symptomatic pain and an increase in loading of the knee. Whether the increased loading is due to the analgesic effects of the treatment is unknown, but if so, the development of agents capable of relieving pain while reducing loads at the knee may be desirable.

We examined the relationship between serum and synovial fluid (SF) levels of antigenic keratan sulfate (KS) and the clinical, laboratory, and radiologic features of disease in 125 well-characterized patients with knee osteoarthritis (OA). KS was quantified by enzyme-linked immunosorbent assay, using an antibody specific for a highly sulfated epitope on KS chains; the results were calculated as equivalents of an international standard of KS from human costal cartilage. The mean level of serum KS (393 ng/ml) was significantly higher than those previously reported for populations of adults without OA. There was a wide scatter of serum KS values (range 156-912 ng/ml), with little correlation with clinical or radiologic features. Men had significantly higher levels than women (456 +/- 135 ng/ml versus 368 +/- 110 ng/ml, mean +/- SD), and there was a statistically significant but weak association with indicators of polyarticular involvement (number of symptomatic joints, Heberden's nodes, hip symptoms) in women. Despite the wide scatter of results in the population as a whole, individual levels of KS were stable for up to 4 consecutive years in the 9 patients studied. Levels of KS were much higher in SF (n = 25) than in serum, but the two were not correlated. There was an inverse correlation between radiographic evidence of cartilage loss and the level of KS in SF. The large variations in serum KS values suggest that this measure may not be of diagnostic significance among populations of patients.(ABSTRACT TRUNCATED AT 250 WORDS)