Christine E. Chaisson

The association of bone marrow lesions with pain in knee osteoarthritis.

Knee osteoarthritis affects 11% to 15% of the U.S. population 65 years of age or older (1) and is a leading cause of disability in the elderly. The major source of disability and care seeking for patients with osteoarthritis is pain in the knee (2). The cause of knee pain in patients with osteoarthritis is unclear. Osteoarthritis has been considered a disease whose characteristic pathologic feature is loss of hyaline articular cartilage, but that tissue contains no pain fibers. Pain fibers are present in several other structures, however, that are often affected by pathologic processes in knee osteoarthritis, including the joint capsule, ligaments in and around the knee joint, the outer third of the meniscus, and possibly the synovium (although for this last tissue, evidence is conflicting [3, 4]). In addition, bone in the periosteum and bone marrow is richly innervated with nociceptive fibers and represents a potential source of pain in patients with knee osteoarthritis. In athletes and younger adults who do not have osteoarthritis, traumatic knee injuries produce high-signal lesions in the medullary space extending to subcortical bone according to T2-weighted magnetic resonance imaging (MRI). These lesions are thought to represent contusions within the bone marrow and have been correlated with the occurrence of pain in athletes (5). Bone marrow lesions that are similar in appearance to those contusions have been noted (6) in patients with knee osteoarthritis, but their association with the occurrence of pain in this disease is unknown. The treatment of pain in osteoarthritis has been frustrating, in part because the target of therapy is unclear. Creamer and colleagues (7) injected intra-articular anesthetic into joints and found that only 6 of 10 persons with painful osteoarthritis had pain relief. This suggests that in some patients, pain originates from extraarticular, noncapsular sources, one of the most likely of which is bone. If pain in some patients does emanate from bone, this finding would have important therapeutic implications and suggests that for these patients, anti-inflammatory treatments targeted at synovitis or intra-articular drainage to relieve capsular distention would be ineffective. We sought to evaluate whether persons with knee pain and osteoarthritis were more often affected by bone marrow lesions than similarly aged persons without knee pain, many of whom also had radiographic knee osteoarthritis. We tested whether pain in the knee was associated with the presence of bone marrow lesions after adjustment for the severity of radiographic osteoarthritis. In addition, among persons with symptomatic knee osteoarthritis, we evaluated whether the severity of their pain was associated with the presence of these lesions. Methods Patient Selection The minimum age for entry into the study was 45 years for men and 50 years for women. The entry age for women was chosen to lessen the chance of inadvertently obtaining radiographs in pregnant women. Male participants were drawn from the Veterans Health Study (VHS), a prospective observational study of health outcomes in 2425 veterans (8). Participants in the VHS were recruited from all men receiving ambulatory care between August 1993 and March 1996 at four Veterans Administration system facilities in the Boston area. Veterans who indicated that they could not read, were identified as unable to answer questions by an accompanying proxy, were disoriented, or did not complete the screening questionnaire were ineligible. A random sample of eligible respondents was contacted by telephone and recruited for the VHS. Of the 4137 patients who were telephoned, 2425 (59%) participated in the VHS. Participant age ranged from 22 to 91 years (mean, 62.4 years). The VHS was designed to be representative of users of ambulatory care in the Veterans Administration system. Compared with all utilizers of the Veterans Administration health care system, the sample underrepresented patients with less education or limitations in literacy or cognitive functioning. Patients in the VHS had lower functional status scores on the physical and mental health components of the Short Form-36 survey (a measure of health status) and had more comorbid conditions (8) than do men 45 years of age or older in the general U.S. population. Male participants were also drawn separately from Veteran Affairs clinics and from the community. Female participants were drawn from clinics at Boston Medical Center and the Veterans Affairs Medical Center; from advertisements in local newspapers; and from a study of women veterans, the Veterans Administration Womens Health Project (n = 719), that was designed to describe the health status of female veterans using ambulatory health care services. The human studies committee and the institutional review board approved protocols. Informed consent was obtained from all participants. All participants were surveyed about knee symptoms. They were asked two questions: Do you have pain, aching, or stiffness in one or both knees on most days? and Has a doctor ever told you that you have knee arthritis? For persons interested in participating in our study of knee pain and osteoarthritis, we conducted a follow-up interview in which those who answered yes to both questions were asked about other types of arthritis that could cause knee symptoms. If no other forms of arthritis were identified in the interview, the person was eligible for recruitment as a participant with knee pain (which we characterize here as knee symptoms). Figure 1 is a flow diagram of the source of participants. Of our male participants, 151 came from the Veterans Health Study, 76 came from Veterans Administration ambulatory clinics, and 8 came from the community. Of our female participants, 18 came from the Veterans Administration Womens Health Project, 9 came from ambulatory clinics, and 89 came from the community. Figure 1. Sources of study participants. We recruited participants from the VHS and the Veterans Administration Womens Health Project without knee pain from among those who answered no to both of the above screening questions (Figure 1). We also asked participants to evaluate the severity of pain in each knee, which they scored by using a 100-mm visual analogue scale (generating a score of 0 [no pain] to 100 [most severe pain possible]). Participants also filled out the WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) questionnaire (9), a validated instrument that assesses knee pain and disability during various activities; we analyzed their WOMAC pain subscale score. Radiographic Evaluation All participants underwent weight-bearing posteroanterior radiography by using the protocol of Buckland-Wright (10 and weight-bearing skyline [9] and weight-bearing lateral radiography (11). For the posteroanterior view, the knee was positioned and radiographed under fluoroscopy so that the anterior and posterior medial tibial plateaus were superimposed; this was done to optimize measurement of joint space. Radiographs were read for the presence of definite osteophytes and other features by one radiologist using an atlas. If a definite osteophyte was present in a knee (including the patella) on any one of the three views, the knee was characterized as having osteoarthritis regardless of whether the participant experienced symptoms. This definition of radiographic disease has been recommended by other investigators (22). On the basis of responses to the screening questions, we defined a knee as symptomatic if the participant stated that he or she had pain or aching in that knee on most days. This definition of symptomatic osteoarthritis meets American College of Rheumatology criteria (12). We identified too few symptomatic persons without a radiographic osteophyte to include them as a separate study group (n = 4) and therefore excluded them; we also excluded 16 participants without knee pain whose radiographs showed no osteophytes. Kellgren and Lawrence grades have been developed for the anteroposterior (posteroanterior) view. We therefore assigned Kellgren and Lawrence grades (0 to 4) on this view only. In addition, we read posteroanterior, skyline, and lateral radiographic views and scored them for individual radiographic featuresosteophytes (scale of 0 to 3), joint space narrowing (scale of 0 to 3), cysts (scale of 0 to 1), and sclerosis (scale of 0 to 3)by using the Framingham Osteoarthritis Study atlas (13). The reproducibility of readings of these features and of the Kellgren and Lawrence scale is reported elsewhere (14). Magnetic Resonance Imaging Each person with knee pain underwent MRI of the more symptomatic knee. For persons without knee pain, the dominant knee was selected for imaging. All studies were performed on a General Electric Signa 1.5-Tesla MRI system (GE Medical Systems, Milwaukee, Wisconsin) using a phased-array knee coil. A positioning device for the ankle and knee was used to ensure uniformity between patients. Coronal, sagittal, and axial images were obtained in each participant. Coronal spin-echo fat-saturated proton-density and T2-weighted fat-saturated images (repetition time, 2200 ms; echo time, 20/80 ms) with a slice thickness of 3 mm, a 1-mm interslice gap, 1 excitation, a field of view of 11 to 12 cm, and a matrix of 256 128 pixels were obtained. To evaluate bone marrow lesions on MRI, we used coronal spin-echo T2-weighted fat-saturated images. Each femur and tibia was divided into medial, central, and lateral quadrants, resulting in six potential sites of lesions in each knee. We defined bone marrow lesions as discrete areas of increased signal adjacent to the subcortical bone in either the femur or the tibia, and we scored each bone marrow lesion from 0 to 3 on the basis of lesion size (Figure 2). Lesions with a score of at least 1 were considered definite bone marrow lesions, and lesions with a score of at least 2 were considered larg

Surgery versus Physical Therapy for a Meniscal Tear and Osteoarthritis

BACKGROUND Whether arthroscopic partial meniscectomy for symptomatic patients with a meniscal tear and knee osteoarthritis results in better functional outcomes than nonoperative therapy is uncertain. METHODS We conducted a multicenter, randomized, controlled trial involving symptomatic patients 45 years of age or older with a meniscal tear and evidence of mild-to-moderate osteoarthritis on imaging. We randomly assigned 351 patients to surgery and postoperative physical therapy or to a standardized physical-therapy regimen (with the option to cross over to surgery at the discretion of the patient and surgeon). The patients were evaluated at 6 and 12 months. The primary outcome was the difference between the groups with respect to the change in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) physical-function score (ranging from 0 to 100, with higher scores indicating more severe symptoms) 6 months after randomization. RESULTS In the intention-to-treat analysis, the mean improvement in the WOMAC score after 6 months was 20.9 points (95% confidence interval [CI], 17.9 to 23.9) in the surgical group and 18.5 (95% CI, 15.6 to 21.5) in the physical-therapy group (mean difference, 2.4 points; 95% CI, -1.8 to 6.5). At 6 months, 51 active participants in the study who were assigned to physical therapy alone (30%) had undergone surgery, and 9 patients assigned to surgery (6%) had not undergone surgery. The results at 12 months were similar to those at 6 months. The frequency of adverse events did not differ significantly between the groups. CONCLUSIONS In the intention-to-treat analysis, we did not find significant differences between the study groups in functional improvement 6 months after randomization; however, 30% of the patients who were assigned to physical therapy alone underwent surgery within 6 months. (Funded by the National Institute of Arthritis and Musculoskeletal and Skin Diseases; METEOR ClinicalTrials.gov number, NCT00597012.).

Evidence for a Mendelian gene in a segregation analysis of generalized radiographic osteoarthritis the Framingham Study

OBJECTIVE To investigate the inheritance of generalized osteoarthritis (OA). METHODS OA was identified on hand and knee radiographs obtained from members of the Framingham Study cohort (the parents) in 1967-1970 and 1992-1993, and from their adult children in the Framingham Offspring Study in 1993-1994. All hand and knee radiographs evaluated for OA were graded using the Kellgren and Lawrence (K/L) scale. A measure of generalized OA was defined as the count of the number of hand and knee joints affected, as determined by the proportion of joints with a K/L grade > or =2. The OA count, treated as a continuous variable, was adjusted for age, body mass index, and a measure of physical activity for each joint area (hand or knee). Calculations were made separately for each generation and each sex, and correlations were analyzed against the standardized residual of OA. Segregation analysis was used to test whether OA aggregated in families, and if its transmission fit a Mendelian pattern. RESULTS A total of 337 nuclear families with 2 parents and at least 1 biologic offspring were studied. In parents, the mean age was 61.2 years at the time of hand radiographs and 72.8 years at the time of knee radiographs, which were mostly obtained at a later examination. The mean age at the time of radiographs in offspring was 53.9 years. Using standardized residuals, parent-offspring and sibling-sibling correlations ranged from 0.115 to 0.306. In segregation analyses, models testing the hypotheses of no familial aggregation, no familial transmission, or a Mendelian gene alone were all rejected (P < 0.001 for each of these models). The best-fitting models were mixed models with a Mendelian mode of inheritance and a residual multifactorial component. The Mendelian recessive model provided the best fit. CONCLUSION These analyses support a significant genetic contribution to OA, with evidence for a major recessive gene and a multifactorial component, representing either polygenic or environmental factors.

Trail Making Test Errors in Normal Aging, Mild Cognitive Impairment, and Dementia

The objective of the present study was to provide normative data for Trail Making Test (TMT) time to completion and performance errors among cognitively normal older adults, and to examine TMT error rates in conjunction with time scores for pre-clinical and clinical Alzheimers disease (AD) diagnostic decision-making. A sample of 526 individuals was classified into three diagnostic groups (normal controls, N=269; mild cognitive impairment, MCI, N=200; AD, N=57) by a multidisciplinary consensus conference. Results indicated that performance differed among the three groups for TMT A and B time scores as well as TMT B error rate. Diagnostic classification accuracy (i.e., sensitivity, specificity, and positive and negative predictive powers) is described for various combinations of the diagnostic groups. The findings show that TMT B time and errors are independently meaningful scores, and both therefore have clinical utility in assessing individuals referred for dementia evaluations.

Screening and brief intervention for drug use in primary care: the ASPIRE randomized clinical trial.

IMPORTANCE The United States has invested substantially in screening and brief intervention for illicit drug use and prescription drug misuse, based in part on evidence of efficacy for unhealthy alcohol use. However, it is not a recommended universal preventive service in primary care because of lack of evidence of efficacy. OBJECTIVE To test the efficacy of 2 brief counseling interventions for unhealthy drug use (any illicit drug use or prescription drug misuse)-a brief negotiated interview (BNI) and an adaptation of motivational interviewing (MOTIV)-compared with no brief intervention. DESIGN, SETTING, AND PARTICIPANTS This 3-group randomized trial took place at an urban hospital-based primary care internal medicine practice; 528 adult primary care patients with drug use (Alcohol, Smoking, and Substance Involvement Screening Test [ASSIST] substance-specific scores of ≥4) were identified by screening between June 2009 and January 2012 in Boston, Massachusetts. INTERVENTIONS Two interventions were tested: the BNI is a 10- to 15-minute structured interview conducted by health educators; the MOTIV is a 30- to 45-minute intervention based on motivational interviewing with a 20- to 30-minute booster conducted by masters-level counselors. All study participants received a written list of substance use disorder treatment and mutual help resources. MAIN OUTCOMES AND MEASURES Primary outcome was number of days of use in the past 30 days of the self-identified main drug as determined by a validated calendar method at 6 months. Secondary outcomes included other self-reported measures of drug use, drug use according to hair testing, ASSIST scores (severity), drug use consequences, unsafe sex, mutual help meeting attendance, and health care utilization. RESULTS At baseline, 63% of participants reported their main drug was marijuana, 19% cocaine, and 17% opioids. At 6 months, 98% completed follow-up. Mean adjusted number of days using the main drug at 6 months was 12 for no brief intervention vs 11 for the BNI group (incidence rate ratio [IRR], 0.97; 95% CI, 0.77-1.22) and 12 for the MOTIV group (IRR, 1.05; 95% CI, 0.84-1.32; P = .81 for both comparisons vs no brief intervention). There were also no significant effects of BNI or MOTIV on any other outcome or in analyses stratified by main drug or drug use severity. CONCLUSIONS AND RELEVANCE Brief intervention did not have efficacy for decreasing unhealthy drug use in primary care patients identified by screening. These results do not support widespread implementation of illicit drug use and prescription drug misuse screening and brief intervention. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00876941.

Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: The Framingham study

OBJECTIVE To examine whether estrogen replacement therapy (ERT) prevents worsening of radiographic knee osteoarthritis (OA) in elderly women. METHODS A total of 551 women ages 63-91 years (mean age 71) in the Framingham Study were followed up from biennial examination 18 (1983-1985) to examination 22 (1992-1993). Data on postmenopausal ERT were obtained every 2 years. Subjects were classified into 3 groups according to their estrogen use at biennial examination 18: never users (n = 349), past users (n = 162), and current users (n = 40). Women received anteroposterior weight-bearing knee radiographs at examinations 18 and 22. Using the Kellgren and Lawrence criteria, global radiographic knee OA was assessed, (grade range 0-4) and individual radiographic features, such as osteophytes and joint space narrowing, were scored from 0 to 3. Worsening was defined as either development of radiographic OA that was not present at baseline (incident OA) or progression of baseline radiographic OA by > or =1 Kellgren and Lawrence grade (progressive OA). Potential confounding factors included age, body mass index, weight change, smoking, knee injury, physical activity level, and bone mineral density at the femoral neck. RESULTS During 8 years of followup, 17.4% of knee radiographic scores worsened by 1 grade and 5.8% by 2 or 3 grades among never users of ERT. Among current estrogen users, only 11.7% of knee radiographic scores worsened by 1 grade and none worsened by more than 1 grade. After adjusting for age and other potential confounding factors, the relative risk of incident radiographic knee OA in comparison with never users of estrogen was 0.8 (95% confidence interval [95% CI] 0.5-1.4) in past users and 0.4 (95% CI 0.1-3.0) in current users. Current use of estrogen also showed a trend toward decreased risk of progressive knee OA compared with never use (odds ratio [OR] 0.5, 95% CI 0.1-2.9). When both incident and progressive radiographic knee OA cases were combined, current ERT use had a 60% decreased risk compared with never use (OR 0.4, 95% CI 0.1-1.5). CONCLUSION This is the first prospective cohort study to examine the effects of ERT on radiographic knee OA. The results indicate that current use of ERT had a moderate, but not statistically significant, protective effect against worsening of radiographic knee OA among elderly white women. These findings corroborate those of cross-sectional studies and point further to a potential benefit of female hormones in OA.

2 Understanding the relationship between body weight and osteoarthritis

Overweight people are at high risk of developing knee osteoarthritis (OA) and may also be at increased risk of hand and hip OA. Furthermore, being overweight accelerates disease progression in knee OA. While the increased joint stress accompanying obesity may explain the strong linkage between obesity and knee OA risk, it does not necessarily explain why obese people have a high risk of disease in the hand nor why obese women are at higher comparative risk of knee disease than obese men. Unfortunately, studies of metabolic factors linked to obesity have not provided an explanation for these findings. There are a paucity of data on weight loss as a treatment for OA, but preliminary information suggests it is especially effective in knee disease and that even small amounts of weight reduction may have favourable effects.

Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football

Importance Players of American football may be at increased risk of long-term neurological conditions, particularly chronic traumatic encephalopathy (CTE). Objective To determine the neuropathological and clinical features of deceased football players with CTE. Design, Setting, and Participants Case series of 202 football players whose brains were donated for research. Neuropathological evaluations and retrospective telephone clinical assessments (including head trauma history) with informants were performed blinded. Online questionnaires ascertained athletic and military history. Exposures Participation in American football at any level of play. Main Outcomes and Measures Neuropathological diagnoses of neurodegenerative diseases, including CTE, based on defined diagnostic criteria; CTE neuropathological severity (stages I to IV or dichotomized into mild [stages I and II] and severe [stages III and IV]); informant-reported athletic history and, for players who died in 2014 or later, clinical presentation, including behavior, mood, and cognitive symptoms and dementia. Results Among 202 deceased former football players (median age at death, 66 years [interquartile range, 47-76 years]), CTE was neuropathologically diagnosed in 177 players (87%; median age at death, 67 years [interquartile range, 52-77 years]; mean years of football participation, 15.1 [SD, 5.2]), including 0 of 2 pre–high school, 3 of 14 high school (21%), 48 of 53 college (91%), 9 of 14 semiprofessional (64%), 7 of 8 Canadian Football League (88%), and 110 of 111 National Football League (99%) players. Neuropathological severity of CTE was distributed across the highest level of play, with all 3 former high school players having mild pathology and the majority of former college (27 [56%]), semiprofessional (5 [56%]), and professional (101 [86%]) players having severe pathology. Among 27 participants with mild CTE pathology, 26 (96%) had behavioral or mood symptoms or both, 23 (85%) had cognitive symptoms, and 9 (33%) had signs of dementia. Among 84 participants with severe CTE pathology, 75 (89%) had behavioral or mood symptoms or both, 80 (95%) had cognitive symptoms, and 71 (85%) had signs of dementia. Conclusions and Relevance In a convenience sample of deceased football players who donated their brains for research, a high proportion had neuropathological evidence of CTE, suggesting that CTE may be related to prior participation in football.

Grip strength and the risk of developing radiographic hand osteoarthritis: Results from the Framingham study

OBJECTIVE In knees, quadriceps strength may protect against osteoarthritis (OA). Muscle activity is a major determinant of forces at the hand joints, and grip is a common task during which high muscle forces are sustained, especially at the proximal hand joints (metacarpophalangeal [MCP] joints and thumb base). This longitudinal study of radiographic hand OA examined the association between incident OA at different hand joints and maximal grip strength. METHODS Four hand joint groups were studied: distal interphalangeal (DIP), proximal interphalangeal (PIP), MCP, and the base of the thumb (carpometacarpal and scaphotrapezial combined). Subjects were members of the Framingham OA Study who had a baseline radiograph in 1967-1969 and a followup radiograph in 1992-1993 (mean followup 24 years) and had no prevalent radiographic OA in any hand joint at baseline. Incident disease was defined as development of OA defined as a modified Kellgren/Lawrence grade of > or =2. Grip strength was measured in kilograms by dynamometer in 1958-1961 and again in 1960-1963, and the 2 measures were averaged and divided into sex-specific tertiles. Joint-based analysis was performed by adjusting for age, physical activity, and occupational category using the lowest grip strength tertile as the referent. RESULTS Baseline and followup radiographs were obtained from 746 subjects. Of these, 453 subjects with no prevalent OA at baseline were eligible for analysis. In men, higher maximal grip strength was associated with an increased risk of OA in the PIP (highest tertile odds ratio [OR] 2.8 compared with lowest tertile, 95% confidence interval [95% CI] 1.2-6.7), MCP (highest tertile OR 2.9, 95% CI 1.1-7.4), and thumb base joints (highest tertile OR 2.8, 95% CI 1.1-7.4). In women, there was increased risk of OA in the MCP joints (highest tertile OR 2.7, 95% CI 1.1-6.4). CONCLUSION Men with high maximal grip strength are at increased risk for the development of OA in the PIP, MCP, and thumb base joints, and women, in the MCP joints. No association was found between maximal grip strength and incident OA in the DIP joints of men or women.

Cherry consumption and decreased risk of recurrent gout attacks

OBJECTIVE To study the relationship between cherry intake and the risk of recurrent gout attacks among individuals with gout. METHODS We conducted a case-crossover study to examine the associations of a set of putative risk factors with recurrent gout attacks. Individuals with gout were prospectively recruited and followed up online for 1 year. Participants were asked to provide the following information regarding gout attacks: the onset date of the gout attack, symptoms and signs, medications (including antigout medications), and exposure to potential risk factors (including daily intake of cherries and cherry extract) during the 2-day period prior to the gout attack. We assessed the same exposure information over 2-day control periods. We estimated the risk of recurrent gout attacks related to cherry intake using conditional logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS Our study included 633 individuals with gout. Cherry intake over a 2-day period was associated with a 35% lower risk of gout attacks compared with no intake (multivariate OR 0.65 [95% CI 0.50-0.85]). Cherry extract intake showed a similar inverse association (multivariate OR 0.55 [95% CI 0.30-0.98]). The effect of cherry intake persisted across subgroups stratified by sex, obesity status, purine intake, alcohol use, diuretic use, and use of antigout medications. When cherry intake was combined with allopurinol use, the risk of gout attacks was 75% lower than during periods without either exposure (OR 0.25 [95% CI 0.15-0.42]). CONCLUSION These findings suggest that cherry intake is associated with a lower risk of gout attacks.