A comprehensive care management program to prevent chronic obstructive pulmonary disease hospitalizations: a randomized, controlled trial.

BACKGROUND: Improving a patient's ability to self-monitor and manage changes in chronic obstructive pulmonary disease (COPD) symptoms may improve outcomes. OBJECTIVE: To determine the efficacy of a comprehensive care management program (CCMP) in reducing the risk for COPD hospitalization. DESIGN: A randomized, controlled trial comparing CCMP with guideline-based usual care. (ClinicalTrials.gov registration number: NCT00395083) SETTING: 20 Veterans Affairs hospital-based outpatient clinics. PARTICIPANTS: Patients hospitalized for COPD in the past year. INTERVENTION: The CCMP included COPD education during 4 individual sessions and 1 group session, an action plan for identification and treatment of exacerbations, and scheduled proactive telephone calls for case management. Patients in both the intervention and usual care groups received a COPD informational booklet; their primary care providers received a copy of COPD guidelines and were advised to manage their patients according to these guidelines. Patients were randomly assigned, stratifying by site based on random, permuted blocks of variable size. MEASUREMENTS: The primary outcome was time to first COPD hospitalization. Staff blinded to study group performed telephone-based assessment of COPD exacerbations and hospitalizations, and all hospitalizations were blindly adjudicated. Secondary outcomes included non-COPD health care use, all-cause mortality, health-related quality of life, patient satisfaction, disease knowledge, and self-efficacy. RESULTS: Of the eligible patients, 209 were randomly assigned to the intervention group and 217 to the usual care group. Citing serious safety concerns, the data monitoring committee terminated the intervention before the trial's planned completion after 426 (44%) of the planned total of 960 patients were enrolled. Mean follow-up was 250 days. When the study was stopped, the 1-year cumulative incidence of COPD-related hospitalization was 27% in the intervention group and 24% in the usual care group (hazard ratio, 1.13 [95% CI, 0.70 to 1.80]; P= 0.62). There were 28 deaths from all causes in the intervention group versus 10 in the usual care group (hazard ratio, 3.00 [CI, 1.46 to 6.17]; P= 0.003). Cause could be assigned in 27 (71%) deaths. Deaths due to COPD accounted for the largest difference: 10 in the intervention group versus 3 in the usual care group (hazard ratio, 3.60 [CI, 0.99 to 13.08]; P= 0.053). LIMITATIONS: Available data could not fully explain the excess mortality in the intervention group. Ability to assess the quality of the educational sessions provided by the case managers was limited. CONCLUSION: A CCMP in patients with severe COPD had not decreased COPD-related hospitalizations when the trial was stopped prematurely. The CCMP was associated with unanticipated excess mortality, results that differ markedly from similar previous trials. A data monitoring committee should be considered in the design of clinical trials involving behavioral interventions.

Experience with a placebo-controlled randomized clinical trial of a disease-modifying drug for osteoarthritis: the doxycycline trial.

Little effort has gone into the development of more effective analgesics for osteoarthritic pain. Efforts to improve symptomatic therapy for osteoarthritis have been deflected or diluted by a decision to pursue the development of disease-modifying OA drugs (DMOADs). These agents' main mechanism of action is directed not at the relief of joint pain but at slowing the progression of structural damage. This article describes the results of a recent randomized placebo-controlled designed to examine the DMOAD effect in humans of the tetracycline antibiotic doxycycline, and reviews the experience gained from other recent DMOAD trials in humans.

Is knee radiography useful for studying the efficacy of a disease-modifying osteoarthritis drug in humans?

Recent research on the radiographic imaging of knee OA has helped clarify the features of imaging protocols that contribute to accurate representation of disease severity--specifically, the thickness of articular cartilage--and to sensitive detection of disease progression. The absence of standards for reproducible positioning of the knee in the conventional standing AP view obscures the true rate and variability of JSN in knee OA. Moreover, the standing AP view is susceptible to systematic bias insofar as longitudinal changes in knee pain might lead to over- or underestimation of radiographic JSW depending on the direction of change in pain. More recent protocols for standardized knee radiography have been designed to achieve reproducible alignment of the medical tibial plateau and x-ray beam. As a group these protocols permit measurement of tibiofemoral JSW with remarkable precision--the sine qua non of sensitivity to change--however, only limited longitudinal data is available to permit a direct evaluation of the suitability of these protocols for use in clinical DMOAD trials. Longitudinal studies published to date suggest that fluoroscopic positioning methods are superior to nonfluoroscopic methods with respect to reproducing the position of the knee in serial examinations performed several years apart. Fluoroscopic methods also appear to be superior with respect to achieving parallel alignment of the medial tibial plateau and x-ray beam in serial radiographs, a positioning marker strongly associated with sensitive detection of JSN in knee OA. It is important to note that while the various standardization protocols described in this article perform with great success in short-term demonstrations of the reproducibility of positioning and radiographic JSW, differences clearly exist between protocols in the quality of performance over intervals relevant to clinical DMOAD trials. Over intervals of 2 to 3 years, changes in patient characteristics (e.g., severity of knee pain, body weight, load bearing, varus--valgus deformity) and uncontrollable events related to radiography (e.g., technologist turnover, equipment upgrades) have ample opportunity to affect the technical quality of a radiological knee examination. It is difficult, therefore, to conclude whether or not an apparent difference with respect to sensitivity to OA progression between specific radiographic protocols, implemented in separate locations with different cohorts, reflects a robust difference in technical quality or uncontrollable patient variables and events. The most informative recent studies have provided the results of head-to-head longitudinal comparisons of alternative standardization protocols or conventional examination methods performed concurrently in the same subjects [20,22]. Additional comparative studies of this nature are needed, however, to fully characterize the strengths and weaknesses of currently available alternatives in a way that will permit generalizable conclusions regarding the best radiographic methods for multicenter DMOAD trials.

Research to encourage exercise for fibromyalgia (REEF): use of motivational interviewing, outcomes from a randomized-controlled trial.

OBJECTIVES: Regular exercise is associated with important benefits in patients with fibromyalgia (FM). Unfortunately, long-term maintenance of exercise after a structured program is rare. The present study tested the efficacy of Motivational Interviewing (MI) to promote exercise and improve symptoms in patients with FM. METHODS: A total of 216 patients with FM were randomized to 6 MI sessions (n=107) or an equal number of FM self-management lessons (education control/EC, n=109). Co-primary endpoints were an increase of 30 minutes in moderate-vigorous physical activity and improvement in the Fibromyalgia Impact Questionnaire (FIQ)-Physical Impairment score, assessed at pretreatment, posttreatment, and 3-month and 6-month follow-up. Secondary outcomes included clinically meaningful improvements in FIQ score, pain severity ratings, and a 6-minute walk test. RESULTS: There were no significant treatment group differences in either co-primary endpoint at 6-month follow-up. However, more MI participants than controls exhibited meaningful improvements in FIQ score at 6-month follow-up (62.9% vs. 49.5%, P=0.06). Compared with EC participants, MI participants also displayed a larger increment in their 6-minute walk test (43.9 vs. 24.8 m, P=0.03). In addition, MI was superior to EC in increasing the number of hours of physical activity immediately postintervention and in reducing pain severity both immediately after the intervention and at 3-month follow-up. CONCLUSIONS: Despite a lack of benefits on long-term outcome, MI seems to have short-term benefits with respect to self-report physical activity and clinical outcomes. This is the first study in FM that explicitly addresses exercise maintenance as a primary aim.

Malalignment and subchondral bone turnover in contralateral knees of overweight/obese women with unilateral osteoarthritis: implications for bilateral disease.

OBJECTIVE: To explore whether the risk of incident tibiofemoral (TF) osteoarthritis (OA) in the radiographically normal contralateral knee of overweight/obese women with unilateral knee OA is mediated by malalignment and/or preceded by increased turnover of subchondral bone. METHODS: We used data of post hoc analyses from a randomized controlled trial. Cross-sectional analyses evaluated the baseline association between frontal plane alignment and bone turnover in the medial TF compartment in 78 radiographically normal contralateral knees. Longitudinal analyses ascertained whether incident radiographic OA (TF osteophyte formation within 30 months) was associated with malalignment and/or increased bone turnover at baseline. Alignment subcategories (varus/neutral/valgus) were based on the anatomic axis angle. (99m)Tc-methylene diphosphonate uptake in a late-phase bone scan was quantified in regions of interest in the medial tibia (MT) and medial femur (MF) and adjusted for uptake in a reference segment of the ipsilateral tibial shaft (TS). RESULTS: MF and MT uptake in varus contralateral knees was 50-55% greater than in the TS. Adjusted MT uptake in varus contralateral knees was significantly greater than that in neutral and valgus contralateral knees (mean 1.55 versus 1.38 and 1.43, respectively; P < 0.05). Among 69 contralateral knees followed longitudinally, 22 (32%) developed TF OA. Varus angulation was associated with a marginally significant increase in the odds of incident OA (adjusted odds ratio 3.98, P = 0.067). CONCLUSION: While the small sample size limited our ability to detect statistically significant risk factors, these data suggest that the risk of developing bilateral TF OA in overweight/obese women may be mediated by varus malalignment.

Association of nociceptive responsivity with clinical pain and the moderating effect of depression.

UNLABELLED: The role of central sensitization (CS) in clinical pain reported by FMS patients is unclear. In this report, we sought to establish evidence of a prospective association between clinical pain and an objective measure of spinal nociception (nociceptive flexion reflex [NFR] threshold) and explore whether depression moderates this relationship. We collected measures that included the NFR threshold (in the range of 0-60 milliamperes (mA); a lower threshold represents greater nociceptive responsivity) and clinical variables (ie, Fibromyalgia Impact Questionnaire (FIQ)-total, FIQ-pain, depression and current pain intensity) at 3 time points (baseline, weeks 6 and 12). Using linear mixed effects models, clinical variables were treated as time-varying covariates. Across time, current pain intensity [estimate -1.79 mA (.8), P = .03] and the presence of depression [estimate -6.30 mA (3.2), P = .059] were significantly associated with NFR threshold. The interaction of current pain intensity and depression was also significantly associated with NFR threshold. Specifically, the relationship between current pain intensity and NFR threshold was present in the nondepressed group but not in the depressed group (estimate -3.9 versus .07, P = .01). Both FIQ-total and FIQ-pain were not associated with NFR threshold. In conclusion, higher level of clinical pain intensity correlated with greater nociceptive responsivity, and that depression moderated this association. PERSPECTIVE: Given that clinical pain correlated with nociceptive responsiveness, our findings support the mechanistic role of CS in fibromyalgia. If replicated in larger studies, NFR threshold may serve as a biomarker of clinical pain in nondepressed fibromyalgia patients. Also, our results may have future implication for treatment of FMS with and without comorbid depression.

OARSI/OMERACT initiative to define states of severity and indication for joint replacement in hip and knee osteoarthritis. An OMERACT 10 Special Interest Group.

OBJECTIVE: To define pain and physical function cutpoints that would, coupled with structural severity, define a surrogate measure of "need for joint replacement surgery," for use as an outcome measure for potential structure-modifying interventions for osteoarthritis (OA). METHODS: New scores were developed for pain and physical function in knee and hip OA. A cross-sectional international study in 1909 patients was conducted to define data-driven cutpoints corresponding to the orthopedic surgeons' indication for joint replacement. A post hoc analysis of 8 randomized clinical trials (1379 patients) evaluated the prevalence and validity of cutpoints, among patients with symptomatic hip/knee OA. RESULTS: In the international cross-sectional study, there was substantial overlap in symptom levels between patients with and patients without indication for joint replacement; indeed, it was not possible to determine cutpoints for pain and function defining this indication. The post hoc analysis of trial data showed that the prevalence of cases that combined radiological progression, high level of pain, and high degree of function impairment was low (2%-12%). The most discriminatory cutpoint to define an indication for joint replacement was found to be [pain (0-100) + physical function (0-100) > 80]. CONCLUSION: These results do not support a specific level of pain or function that defines an indication for joint replacement. However, a tentative cutpoint for pain and physical function levels is proposed for further evaluation. Potentially, this symptom level, coupled with radiographic progression, could be used to define "nonresponders" to disease-modifying drugs in OA clinical trials.

Risk factors for early radiographic changes of tibiofemoral osteoarthritis.

OBJECTIVE: To evaluate the risk factors for early radiographic changes of knee osteoarthritis. SUBJECTS: (n = 114) with unilateral or bilateral grade 0-1 knee osteoarthritis underwent x ray examination of the knees (semiflexed anteroposterior view) and assessment with the Western Ontario and McMaster Universities (WOMAC) Osteoarthritis Index at baseline and 30 months later. Severity of joint space narrowing (JSN) and osteophytosis were graded in randomly ordered serial radiographs by two readers, blinded to the sequence of the films, using standard pictorial atlases. RESULTS: The odds of an initial appearance of radiographic features of knee osteoarthritis at month 30 were more than threefold greater in African Americans than in whites (osteophytosis: odds ratio (OR) 3.30, 95% confidence interval (CI) 1.04 to 10.54; JSN: OR 3.49, 95% CI 1.16 to 10.68). In addition, the appearance of osteophytosis was positively related to baseline stiffness (OR 1.91/2.1 points on the 2-10 WOMAC scale, 95% CI 1.29 to 2.82). CONCLUSIONS: The distinction between incident and established, but early, radiographic knee osteoarthritis is difficult because of the limits to which all possible evidence of the disease can be ruled out in a conventional baseline knee radiograph. Nonetheless, our finding that African Americans were at greater risk of early osteophytosis and JSN than other subjects differs from the results of our previous analysis of risk factors for progressive knee osteoarthritis in the same subjects. The development of osteophytes also was associated with joint stiffness. Future investigations should focus on the systemic and local influences that these ostensible risk factors represent.

Urinary TIINE concentrations in a randomized controlled trial of doxycycline in knee osteoarthritis: implications of the lack of association between TIINE levels and joint space narrowing.

OBJECTIVE: To use the collagenase cleavage site neoepitope, TIINE, a marker of type II collagen breakdown in cartilage, to analyze the mechanism underlying the slowing of joint space narrowing (JSN) in patients with knee osteoarthritis treated with doxycycline. METHODS: The creatinine-adjusted urinary TIINE concentration was determined at baseline and every 6 months thereafter in a subset of patients who completed a 30-month randomized, placebo-controlled study of the effect of doxycycline on radiographic progression of JSN. The subset was selected a priori to permit comparison of 60 radiographic progressors with 60 radiographic nonprogressors. JSN was determined in highly standardized, semiflexed anteroposterior images. RESULTS: The coefficient of variation of TIINE concentrations over the 5 study visits was 30%. At the 5 semiannual followup visits, the mean TIINE concentration for doxycycline-treated patients was higher than that for the placebo group. In both treatment groups, the correlation between TIINE levels and JSN in the index knee was weak (for doxycycline, r(2) = 0.06, P = 0.08; for placebo, r(2) = 0.06, P = 0.05). CONCLUSION: High variability from visit to visit limits the sensitivity of the TIINE assay for detecting changes in individual patients and restricts its utility to group comparisons. The increase in TIINE concentration with treatment indicates that inhibition of collagenase-mediated breakdown of type II collagen in articular cartilage is unlikely to have accounted for the observed reduction of JSN in the index knees of patients in the doxycycline treatment group.

Acetaminophen, like conventional NSAIDs, may reduce synovitis in osteoarthritic knees.

OBJECTIVE: To determine the extent to which treatment of patients with symptomatic knee osteoarthritis (OA) with non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (ACET) reduces total effusion volume and synovial tissue volume, as quantified by magnetic resonance imaging (MRI). METHODS: Sequential pilot studies used subjects whose knee OA was treated with NSAIDs (n=10) or with ACET or=15 of 25 on the Western Ontario and McMaster Universities' pain scale underwent l.5T MRI. Effusion was quantified in axial short tau inversion recovery images; to measure synovial tissue volume, fat-suppressed T1-weighted axial images were obtained 3 min after i.v. injection of gadolinium contrast. After the initial MRI examination, patients resumed their customary pain medications until the severity of knee pain returned to baseline, when pain was again measured and the MRI was repeated. RESULTS: Pain severity after washout was similar in subjects taking ACET and NSAIDs. Reinstitution of ACET resulted in a 50% decrease in the mean of pain scores (P=1.7 x 10(-12)) that was comparable with that seen after the reinstitution of NSAID (49%, P=6.0 x 10(-7)). The mean total effusion volume measured during the flare of knee pain induced by the withdrawal of the two drugs was comparable (ACET 16.9 ml, NSAID 16.2 ml; P=0.884). Significant decreases in mean total effusion volume were observed after reinstitution of both ACET (-4.5 ml, P=0.009) and NSAID (-3.3 ml, P=0.013); the difference between drugs was not significant. Analyses of synovial volume yielded similar results. CONCLUSION: While uncontrolled and derived from small samples, these data suggest that ACET may have a significant anti-inflammatory effect in patients with knee OA, comparable with that achieved with NSAIDs, possibly through an effect on neurogenic inflammation. Joint pain is the clinical feature of OA that most often leads the affected individual to seek medical attention. Because many patients with OA improve symptomatically with the use of NSAIDs, it has been widely assumed that the pain of OA is due to synovial inflammation. However, the origins of OA pain are numerous and may vary from patient to patient and, within the same subject, from visit to visit. Although the articular cartilage is usually the site of the most obvious pathological changes in this disease, it is aneural and, therefore, is not the source of joint pain. However, in addition to the synovium, the subchondral bone, joint capsule, osteophytes, menisci, ligaments, periarticular tendons, entheses and bursae all contain nociceptive nerve endings, stimulation of which by chemical or physical mediators may be a basis for OA pain.

Effects of strength training on the incidence and progression of knee osteoarthritis.

OBJECTIVE: Quadriceps weakness is a risk factor for incident knee osteoarthritis (OA). We describe a randomized controlled trial of effects of lower-extremity strength training on incidence and progression of knee OA. METHODS: A total of 221 older adults (mean age 69 years) were stratified by sex, presence of radiographic knee OA, and severity of knee pain, and were randomized to strength training (ST) or range-of-motion (ROM) exercises. Subjects exercised 3 times per week (twice at a fitness facility, once at home) for 12 weeks, followed by transition to home-based exercise after 12 months. Assessments of isokinetic lower-extremity strength and highly standardized knee radiographs were obtained at baseline and 30 months. RESULTS: Subjects in both groups lost lower-extremity strength over 30 months; however, the rate of loss was slower with ST than with ROM. Compared with ROM, ST decreased the mean rate of joint space narrowing (JSN) in osteoarthritic knees by 26% (P = not significant). However, the difference between ST and ROM groups with respect to frequency of knee OA progression in JSN consensus ratings was marginally significant (18% versus 28%; P = 0.094). In knees that were radiographically normal at baseline, JSN >0.50 mm was more common in ST than in ROM (34% versus 19%; P = 0.038). Incident JSN was unrelated to exercise adherence or changes in quadriceps strength or knee pain. CONCLUSION: The ST group retained more strength and exhibited less frequent progressive JSN over 30 months than the ROM group. The increase in incident JSN >0.50 mm in ST is unexplained and requires confirmation.

Associations between joint space narrowing and molecular markers of collagen and proteoglycan turnover in patients with knee osteoarthritis.

OBJECTIVE: We examined whether plasma concentrations of biomarkers of the collagenase cleavage of type II collagen (C2C), types I and II collagens (C1,2C), type II collagen synthesis (CPII), proteoglycan aggrecan turnover (CS846), and the ratio C2C:CPII would distinguish subjects with progressive radiographic osteoarthritis (OA) from those with stable disease. METHODS: Subjects were 120 obese middle-aged women with unilateral knee OA who participated in a 30-month clinical trial of structure modification with doxycycline, in which a standardized semiflexed anteroposterior view of the knee was obtained at baseline, 16 months, and 30 months. Subjects were selected from a larger sample to permit a priori comparisons between 60 OA progressors and 60 nonprogressors, as defined by joint space narrowing (JSN) in the medial tibiofemoral compartment. Each group contained 30 subjects who exhibited clinically significant increases in knee pain over 30 months and 30 who did not. Plasma samples were obtained every 6 months for determination of C2C, CPII, CS846, and C1,2C. RESULTS: None of the biomarkers was a significant predictor of progression of JSN. Over the interval from baseline to 16 months, the mean and the maximum of the intercurrent CS846 values were significantly associated with JSN (i.e., 0.12-0.14 mm of JSN per SD decrease in mean or maximum CS846; p < 0.01). The mean of serial CS846 levels was related to JSN also during the interval between months 16 and 30. CONCLUSION: Markers of type II collagen synthesis/degradation and of proteoglycan aggrecan turnover were not predictive of JSN in knee OA in this pilot study. However, serial concentrations of proteoglycan aggrecan epitope CS846 were associated with JSN during both the intervals studied.

Use of the plasma stromelysin (matrix metalloproteinase 3) concentration to predict joint space narrowing in knee osteoarthritis.

OBJECTIVE: To determine whether baseline or serial plasma concentrations of stromelysin (matrix metalloproteinase 3 [MMP-3]) protein might distinguish subjects with progressive radiographic knee osteoarthritis (OA) from those with stable disease. METHODS: Subjects were 120 women with unilateral knee OA who participated in a 30-month randomized, placebo-controlled trial of structure modification with doxycycline. Anteroposterior views of both knees in a semiflexed position were obtained at baseline, 16 months, and 30 months. Subjects were selected to obtain comparisons of plasma MMP-3 levels between 60 progressors (21 taking doxycycline, 39 taking placebo) and 60 nonprogressors (30 taking doxycycline, 30 taking placebo) with respect to medial joint space narrowing (JSN) in the index knee. Each group consisted of 30 subjects who exhibited significant increases in knee pain. Blood samples were obtained semiannually for MMP-3 assay. RESULTS: Subjects in the placebo group whose MMP-3 concentration was in the upper tertile of the baseline distribution showed a 4-fold increase in the odds of progression of JSN as compared with the lower tertile (odds ratio 4.12, P = 0.037). Baseline MMP-3 levels were unrelated to knee pain. The within-subject mean of serial MMP-3 concentrations was associated with concurrent JSN in the placebo group over the 0-16-month interval (b = 0.18 mm/SD increase in the mean MMP-3, P < 0.01) and over the 16-30-month interval (b = 0.15, P < 0.05). Similar evidence of concurrent validity was found in the placebo group for the maximum of intercurrent MMP-3 values. CONCLUSION: The baseline MMP-3 level was a significant predictor of JSN in this pilot study. Moreover, serial plasma MMP-3 levels reflected concurrent JSN in the placebo group over the 30-month period of observation.

Severity of joint pain and Kellgren-Lawrence grade at baseline are better predictors of joint space narrowing than bone scintigraphy in obese women with knee osteoarthritis.

OBJECTIVE: To compare the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a baseline late-phase bone scan and assessments of the radiographic and symptomatic severity of knee osteoarthritis (OA) at baseline as predictors of loss of articular cartilage thickness, as reflected in joint space narrowing (JSN) in the medial tibiofemoral compartment. METHODS: Subjects (174 obese women, 45-64 yrs of age, with unilateral knee OA) were a subset of a larger cohort who participated in a placebo controlled trial of a disease modifying OA drug. Uptake of technetium medronate (99mTc-MDP) in anteroposterior (AP) and lateral views of a late-phase bone scan was measured at baseline in a region of interest drawn around the medial tibia, and was adjusted for (i.e., expressed as a ratio to) uptake in a reference segment of the tibial shaft, which served as an internal standard. Each subject underwent a fluoroscopically standardized radiographic examination of the knees (semiflexed AP view) and a pain assessment with the WOMAC OA Index at baseline, 16 months, and 30 months. RESULTS: Controlling for baseline joint space width and treatment group, multiple linear regression models showed that the adjusted 99mTc-MDP uptake at baseline was a significant predictor of joint space narrowing (JSN) in the index knee at 16 months (b = 0.180, p = 0.015) and 30 months (b = 0.221, p = 0.049). In the contralateral knee, uptake was only a marginally significant predictor of JSN at 30 months (b = 0.246, p = 0.083). Uptake in the upper and middle tertiles of the distribution predicted subjects who would exhibit JSN >/= 0.50 mm within 16 months with 65% sensitivity (PPV 23%) and 36% specificity (NPV 77%). In contrast, a prediction rule based solely on the presence of Kellgren-Lawrence grade 3 OA severity and greater than median WOMAC Pain score identified progressors with 65% sensitivity (PPV 48%) and 79% specificity (NPV 88%). CONCLUSION: Although the level of adjusted 99mTc-MDP uptake was significantly associated with JSN in knees with established radiographic OA, baseline bone scintigraphy is inferior to the radiographic severity of OA and knee pain (alone or in combination) as a predictor of loss of articular cartilage in subjects with knee OA.

Effects of doxycycline on progression of osteoarthritis: results of a randomized, placebo-controlled, double-blind trial.

OBJECTIVE: To confirm preclinical data suggesting that doxycycline can slow the progression of osteoarthritis (OA). The primary outcome measure was joint space narrowing (JSN) in the medial tibiofemoral compartment. METHODS: In this placebo-controlled trial, obese women (n = 431) ages 45-64 years with unilateral radiographic knee OA were randomly assigned to receive 30 months of treatment with 100 mg doxycycline or placebo twice a day. Tibiofemoral JSN was measured manually in fluoroscopically standardized radiographic examinations performed at baseline, 16 months, and 30 months. Severity of joint pain was recorded at 6-month intervals. RESULTS: Seventy-one percent of all randomized subjects completed the trial. Radiographs were obtained from 85% of all randomized subjects at 30 months. Adherence to the dosing regimen was 91.8% among subjects who completed the study per protocol. After 16 months of treatment, the mean +/- SD loss of joint space width in the index knee in the doxycycline group was 40% less than that in the placebo group (0.15 +/- 0.42 mm versus 0.24 +/- 0.54 mm); after 30 months, it was 33% less (0.30 +/- 0.60 mm versus 0.45 +/- 0.70 mm). Doxycycline did not reduce the mean severity of joint pain, although pain scores in both treatment groups were low at baseline and remained low throughout the trial, suggesting the presence of a floor effect. However, the frequency of followup visits at which the subject reported a > or = 20% increase in pain in the index knee, relative to the previous visit, was reduced among those receiving doxycycline. In contrast, doxycycline did not have an effect on either JSN or pain in the contralateral knee. In both treatment groups, subjects who reported a > or = 20% increase in knee pain at the majority of their followup visits had more rapid JSN than those whose pain did not increase. CONCLUSION: Doxycycline slowed the rate of JSN in knees with established OA. Its lack of effect on JSN in the contralateral knee suggests that pathogenetic mechanisms in that joint were different from those in the index knee.

Imaging and osteoarthritis: what is the predictive value?

Recent protocols for standardized knee radiography, which attempts to image the knee with reproducible, parallel alignment of the medial tibial plateau and radiograph beam, possess many theoretic advantages. As a group, they permit measurement of tibiofemoral joint space width with remarkable precision--the sine qua non of sensitive detection of change. However, only limited longitudinal data are available in peer-reviewed publications to permit a direct evaluation of the suitability of these protocols for use in multicenter clinical trials and studies of biomarkers of osteoarthritis (OA) progression. Longitudinal data from several National Institutes of Health-supported studies of OA progression, as reflected in radiographs acquired with high levels of standardization for radioanatomic positioning of the knee, should be available in the next several years. Alternatively, data from the placebo groups of several industry-supported phase III trials of purported disease-modifying OA drugs, which were terminated prematurely because of adverse events or lack of efficacy, may be made available for rapid analysis regarding the performance of current standardization protocols with respect to their sensitivity to disease progression.

Detection of radiographic joint space narrowing in subjects with knee osteoarthritis: longitudinal comparison of the metatarsophalangeal and semiflexed anteroposterior views.

OBJECTIVE: Although recent protocols for standardized knee radiography afford highly reproducible radioanatomic alignment of the joint and measurement of joint space width (JSW) in repeat radiographs acquired on the same day, the sensitivity of these techniques to joint space narrowing (JSN) over time in subjects with knee osteoarthritis (OA) is unknown. The present study was undertaken to compare the metatarsophalangeal (MTP) view and the semiflexed anteroposterior (AP) view with respect to sensitivity to JSN in knee OA. METHODS: In 49 subjects with definite knee OA, 2 MTP radiographs and 1 semiflexed AP radiograph were obtained at baseline. Each examination was repeated 14 months later. In MTP views, minimum JSW and the distance between the anterior and posterior margins of the medial tibial plateau (intermargin distance [IMD], an indicator of parallel alignment of the tibial plateau and the x-ray beam) were measured with a pair of calipers and a magnifying lens fitted with a graticule. JSW in semiflexed AP views was measured by digital image analysis. RESULTS: The mean of within-knee standard deviations of JSW in the baseline MTP examinations (n = 52 OA knees) was 0.24 mm (coefficient of variation 5.8%). Although IMDs in the 2 baseline MTP views were very highly correlated (+0.88), IMDs in the serial examinations were only moderately correlated (+0.45). Serial MTP views showed a small increase in mean JSW over 14 months that was not significantly greater than zero (mean +/- SD +0.09 +/- 0.66 mm; P not significant). In contrast, concurrent semiflexed AP examinations showed a marginally significant decrease in mean JSW (-0.09 +/- 0.31 mm; P = 0.10). CONCLUSION: These results demonstrate that evidence of the short-term reproducibility of a radiographic protocol is an insufficient basis on which to predict the quality of its longitudinal performance.

Pitfalls in the accurate measurement of joint space narrowing in semiflexed, anteroposterior radiographic imaging of the knee.

OBJECTIVE: Computerized measurement of changes in joint space width (JSW) on serial radiographs of the knee in the semiflexed, anteroposterior (SF-AP) view has been used recently as a primary outcome measure in clinical trials of disease-modifying osteoarthritis drugs (DMOADs). In the use of fluoroscopy to achieve reproducible alignment of the medial tibial plateau and x-ray beam, the SF-AP radiographic protocol affords greater sensitivity in the detection of joint space narrowing (JSN) than that achieved by conventional radiographic positioning techniques. However, the utility of the SF-AP view is compromised by the variation in x-ray penetration in each examination, which may confound the correction of the automated measurement of JSW for the radiographic magnification inherent in an AP view of the knee. A recent DMOAD trial using the SF-AP protocol showed an improbable increase in JSW of > or =0.50 mm (i.e., greater than the measurement error). The present report provides an analysis of this problem, and the study aim was to demonstrate that substitution of the automated estimates of JSW with precise manual measurements can markedly reduce the problem attributable to radiographic magnification. METHODS: SF-AP radiographs were obtained at baseline and at 16 months and 30 months thereafter from subjects enrolled in a 6-center DMOAD trial. For each examination, a 6.35-mm steel ball was affixed to the skin over the head of the fibula to permit estimation of the percentage of radiographic magnification (%Mag) and correction of JSW measurements. Measurements of the minimum interbone distance (IBD) in the medial tibiofemoral compartment and the %Mag were obtained by an automated method (edge detection) and manually. Combinations of automated and manual measurements of the IBD and %Mag in estimates of magnification-corrected JSW were compared with respect to their reproducibility, agreement, and sensitivity to JSN. RESULTS: With fully automated measurements, variations in x-ray penetration in analog radiographs and edge enhancement in digital radiographs resulted in the computer "seeing" a metal ball whose diameter was artifactually reduced, resulting in an inflated measurement of JSW. Use of manual measurement of the IBD and %Mag largely eliminated these problems and reduced, from 16% to 2%, the frequency of knees exhibiting an increase in JSW > or =0.50 mm. In 14 of the 15 knees in which a significant increase in JSW was noted with the manual method, this increase in JSW could be explained by the development of significant lateral compartment narrowing during the study or poor alignment of the medial plateau. CONCLUSION: Although automated and manual methods of JSW measurement of the knee in the SF-AP view possess comparable intrareader reproducibility, the manual method is less susceptible to technical factors that affect the correction of raw JSW estimates for radiographic magnification. Until we can identify practical, effective solutions to these technical problems, use of any radiographic protocol involving AP imaging of the knee in a DMOAD trial must be viewed with caution.

Knee pain reduces joint space width in conventional standing anteroposterior radiographs of osteoarthritic knees.

OBJECTIVE: A suspected, but heretofore undemonstrated, limitation of the conventional weight-bearing anteroposterior (AP) knee radiograph, in which the joint is imaged in extension, for studies of progression of osteoarthritis (OA) is that changes in knee pain may affect extension, thereby altering the apparent thickness of the articular cartilage. The present study was undertaken to examine the effect of changes in knee pain of varying magnitudes on radiographic joint space width (JSW) in the weight-bearing extended and the semiflexed AP views, in which radioanatomic positioning of the knee was carefully standardized by fluoroscopy. METHODS: Fifteen patients with knee OA underwent a washout of their analgesic/nonsteroidal antiinflammatory drug (NSAID) agents (duration 5 half-lives), after which standing AP and semiflexed AP knee radiographs of both knees were obtained. Examinations were repeated 1-12 weeks later (median 4.5 weeks, mean 6.0 weeks), after resumption of analgesic/NSAID therapy. Knee pain was measured with the pain subscale of the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index (Likert scale). JSW was measured with a pair of calipers and a magnifying lens. Mixed model analyses of variance were used to test the significance of changes in pain and JSW within and between 2 groups of knees with mild-to-moderate radiographic severity of OA: (a) "flaring knees," in which the patient rated standing knee pain as severe or extreme after the washout and in which pain decreased to any degree after resumption of analgesics and/or NSAIDs (n = 12) and (b) "nonflaring knees," in which standing knee pain was absent, mild, or moderate after the washout or did not decrease after resumption of treatment (n = 15). RESULTS: After reinstitution of treatment, WOMAC pain scores decreased significantly in both flaring and nonflaring knees (-44%; P < 0.0001 and -18%; P < 0.01, respectively). After adjustment for the within-subject correlation between knees, mean JSW (+/-SEM) in the extended view of the flaring OA knee increased significantly from the first to second examination (0.20 +/- 0.06 mm; P = 0.005). In contrast, the change in adjusted mean JSW in the extended view of the nonflaring OA knee was negligible (-0.04 +/- 0.04 mm) and significantly smaller than that observed in flaring knees (P < 0.01). Mean JSW in the semiflexed AP view was unaffected by the severity or responsiveness of standing knee pain in flaring and nonflaring OA knees. CONCLUSION: JSW in weight-bearing extended-view radiographs of highly symptomatic OA knees can be altered significantly by changes in joint pain. In clinical trials and in epidemiologic studies of OA progression that use this radiographic technique, longitudinal variations in pain may confound changes in the apparent thickness of the articular cartilage.