Allan C. Gelber

Joint Injury in Young Adults and Risk for Subsequent Knee and Hip Osteoarthritis

Osteoarthritis is a major contributor to functional impairment and reduced independence in older adults (1-4). It is the leading cause of arthritis in the United States, affecting an estimated 21 million persons (5), and has substantial economic impact (6, 7). History of an injury to a joint, particularly at the knee and hip, is associated with an increased risk for osteoarthritis in cross-sectional and casecontrol studies (8-11). Such studies, however, may overestimate this relation because persons with symptomatic osteoarthritis may be more likely to recall a past injury or to interpret early symptoms of osteoarthritis as indicative of joint injury. A prospective cohort study can address this weakness by determining exposure status before the outcome develops. To date, prospective studies have examined the relation between history of joint injury and osteoarthritis in middle-aged persons and senior citizens (12, 13), but not in young adults. However, many athletic injuries occur in high school and college. In addition, joint trauma may be a more common cause of osteoarthritis than has been previously recognized (14). We performed a prospective cohort study of 1321 young adults to examine the risk for knee and hip osteoarthritis associated with joint injury during young adult life. Methods Study Participants The Johns Hopkins Precursors Study was designed by the late Caroline Bedell Thomas, MD, to identify precursors of the aging process (15). A total of 1337 medical students, members of the graduating classes of 1948 through 1964 at the Johns Hopkins University School of Medicine in Baltimore, Maryland, enrolled in the study. The cohort was 91% male and 97% white; the mean age was 22 years. At entry, participants underwent a standard history and examination, including assessment of musculoskeletal disorders, history of trauma, level of physical activity, and measurement of weight and height. Body mass index was calculated as weight in kilograms divided by height in meters squared. In addition, participants were asked to categorize their level of physical training during the past month as none, little, moderate, or much, as described elsewhere (16). Since graduation, participants have been followed prospectively with annual self-administered questionnaires to detect incident disease and to update risk factor status over time. At the time that baseline data were collected, it was not customary to obtain informed consent. After establishment of the Joint Committee on Clinical Investigation at Johns Hopkins, the follow-up protocol was reviewed and approved. Assessment of Injury Injury was defined as a report of trauma to the knee or hip joint, including internal derangement and fracture. During the baseline assessment, knee and hip injuries that occurred before graduation from medical school and the year of their occurrence were recorded. Postgraduation injuries were assessed by annual morbidity questionnaires. During every 5-year follow-up period, at least 86% of the living participants responded at least once to the questionnaires. Injuries were assigned diagnosis codes according to the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) (17). Diagnoses included torn meniscus (code 836.2); torn knee ligament (code 844.9); tibial fracture (code 823.8); femoral fracture (code 821.01); fibular fracture (code 823.81); patellar fracture (code 822); broken leg, site not otherwise specified (code 827.0); knee injury, not otherwise specified (code 959.7); gunshot wound (code 891); hemarthrosis (code 844.9); shin splints (code 844.9); and hip dislocation (code 836.5). Incidence of Osteoarthritis The methods used to determine osteoarthritis incidence in this cohort have been described elsewhere (18). Briefly, all participants were mailed annual morbidity questionnaires. Before 1985, respondents were queried about the development of physical and musculoskeletal disorders. Since 1985, follow-up morbidity questionnaires have contained the specific question, Have you ever had arthritis? and have asked those who respond affirmatively to provide the type of arthritis, year of onset, and treatment received. An event of osteoarthritis was defined as the self-report of osteoarthritis or degenerative arthritis in response to the questionnaire. The incidence date was determined by the reported year of osteoarthritis onset. Two rheumatologists reviewed each report of osteoarthritis, assigned ICD-9-CM codes (17) to the most specific arthritis site reported by the respondent, and excluded inflammatory arthritides. For this analysis, only osteoarthritis at the knee (code 715.96) and hip (code 715.95) were included as outcomes. In 1995, all surviving participants who had previously reported osteoarthritis were mailed a more detailed questionnaire. They were asked, Have you had pain in or around the knee, including back of the knee, on most days for at least 1 month? and Have you had pain in or around either hip joint, including the buttock, groin, and side of upper thigh, on most days for at least 1 month? These symptom-related questions were used to screen for knee and hip osteoarthritis, respectively, in the National Health and Nutrition Examination Survey (NHANES) (19). Respondents were also asked whether they had undergone radiographic evaluation of their knees and hips and whether radiography revealed osteophytes, joint space narrowing, subchondral cysts, or bony sclerosis (the radiographic hallmarks of osteoarthritis) (20). Statistical Analysis The association between baseline characteristics and injury status was assessed by using the Student t-test for continuous variables and the chi-square test for categorical variables. These data are presented both for the entire cohort and separately by sex. Injury was the independent variable in the survival analysis; age was the time variable. Knee and hip osteoarthritis were examined as separate outcomes. The relation of a joint injury at baseline to the incidence of osteoarthritis was examined by using KaplanMeier analysis (21). The log-rank statistic was used to test whether the cumulative incidence of osteoarthritis differed according to injury status at cohort entry (22). In addition, Cox proportional-hazards analysis was used to estimate the independent risk for osteoarthritis associated with a joint injury. Cox models were constructed for injury status at cohort entry and over follow-up, modeled as a time-dependent covariate. We adjusted for age at graduation, sex, body mass index, and level of physical activity, each of which was determined at baseline, to evaluate for possible confounding. In this cohort, body mass index at enrollment was more predictive of future osteoarthritis than average or most recent body mass index during follow-up (18). These analyses were performed for all reported events of knee and hip osteoarthritis and for cases confirmed by both characteristic symptoms and radiographic findings. Hazard ratios are reported as relative risks with 95% CIs. Statistical significance was defined as an level equal to 0.05 using a two-tailed test. We conducted a sensitivity analysis to assess the potential effect of an omitted covariate on the association between joint injury and subsequent osteoarthritis. Role of the Funding Sources The funding sources did not have a role in the collection, analysis, or interpretation of the data or in the decision to submit the study for publication. Results At graduation from medical school, the average age of the 1216 men and 121 women in the cohort was 26 years. Our analysis is based on events reported through 30 November 1995 and represents a median follow-up of 36 years. Information at baseline or during follow-up was available for 1321 participants, who form the basis of our longitudinal analysis. At the end of follow-up in 1995, the mean age of the cohort SD was 61.4 8.9 years. Overall, 141 participants had a joint injury (knee alone [n =111], hip alone [n =16], or injuries at both sites [n =14]) before or after graduation. Table 1 shows the baseline characteristics of the cohort according to injury status at the end of follow-up. Proportions of men and women with joint injury were similar (P >0.2, chi-square test). Participants were generally lean, 49% were physically active, and 54% smoked cigarettes. Men who had a joint injury were heavier at baseline than men who were injury-free, but both groups of men were similar in age, level of physical activity, and smoking status. Women with injury were, on average, 2 years older at baseline than those without injury. Table 1. Baseline Characteristics of 1321 Men and Women according to Joint Injury at Cohort Entry or during Follow-up At baseline, 47 men (3.9%) reported a knee injury and 12 men (1.0%) reported a hip injury. The mean age at which the injuries occurred was 16 years. Knee injuries included 10 tibial fractures, 3 fibular fractures, 4 femoral fractures, 2 patellar fractures, and 9 otherwise unspecified leg fractures. In addition, 8 men incurred trauma resulting in torn knee cartilage, 2 had torn knee ligaments, 2 had knee injuries resulting from gunshot wounds, 1 had traumatic hemarthrosis, 1 had joint dislocation, 1 had shin splints, and 4 had otherwise unspecified knee injuries. Of men with a knee injury, 4 reported that they were injured while playing football, 2 each reported that they were injured while playing basketball or participating in athletics, and 1 each reported that he was injured while horseback riding, bicycling, skiing, playing volleyball, wrestling, playing baseball, or playing tennis. Knee trauma also resulted from motor vehicle accidents (n =3) and falls (n =2). At baseline, 4 of the 121 women (3.3%) had a history of knee injuries and 1 (0.8%) had a history of hip injuries. Sixty-two men and 7 women developed knee osteoarthritis, and 27 men and 5 women developed hip osteoarthritis. The mean SD ages at onset of knee

Abdominal adiposity in rheumatoid arthritis: Association with cardiometabolic risk factors and disease characteristics

OBJECTIVE Abdominal adiposity, especially visceral adiposity, is emerging as a recognized cardiometabolic risk factor. This study was undertaken to investigate how abdominal fat is distributed in rheumatoid arthritis (RA), and its RA-related determinants. METHODS Men and women with RA were compared with non-RA controls from the Multi-Ethnic Study of Atherosclerosis. Participants underwent anthropometric studies and quantification of visceral and subcutaneous fat areas (VFA and SFA) using abdominal computed tomography. RESULTS A total of 131 RA patients were compared with 121 controls. Despite similar body mass index and waist circumference between the RA and control groups, the adjusted mean VFA was 45 cm2 higher (+51%) in male RA patients versus male controls (P = 0.005), but did not significantly differ by RA status in women. The adjusted mean SFA was 119 cm2 higher (+68%) in female RA patients versus female controls (P < 0.001), but did not significantly differ by RA status in men. Elevated VFA (≥75th percentile) was associated with a significantly higher adjusted probability of having an elevated fasting glucose level, hypertension, or meeting the composite definition of the metabolic syndrome in the RA group compared with controls. Within the RA group, rheumatoid factor seropositivity and higher cumulative prednisone exposure were significantly associated with a higher mean adjusted VFA. Higher C-reactive protein levels and lower Sharp/van der Heijde scores were significantly associated with both VFA and SFA. CONCLUSION The distribution of abdominal fat differs significantly by RA status. Higher VFA in men with RA, and the more potent association of VFA with cardiometabolic risk factors in men and women with RA, may contribute to cardiovascular risk in RA populations.

Coronary arterial calcification in rheumatoid arthritis: comparison with the Multi-Ethnic Study of Atherosclerosis

IntroductionAlthough cardiovascular morbidity and mortality are increased in rheumatoid arthritis, little is known about the burden of subclinical coronary atherosclerosis in these patients.MethodsUsing computed tomography, coronary artery calcification was measured in 195 men and women with rheumatoid arthritis aged 45 to 84 years without clinical cardiovascular disease and compared with 1,073 controls without rheumatoid arthritis enrolled in the Baltimore cohort of the Multi-Ethnic Study of Atherosclerosis.ResultsThe prevalence of coronary calcification (Agatston score > 0) was significantly higher in men, but not women, with rheumatoid arthritis after adjusting for sociodemographic and cardiovascular risk factors (prevalence ratio = 1.19; P = 0.012). Among participants with prevalent calcification, those with rheumatoid arthritis had adjusted mean Agatston scores 53 units higher than controls (P = 0.002); a difference greater for men than women (P for interaction = 0.017). In all analyses, serum IL-6 attenuated the association between rheumatoid arthritis and coronary calcification, suggesting its role as a potential mediator of enhanced atherosclerosis. Notably, increasing severity of rheumatoid arthritis was associated with a higher prevalence and extent of coronary calcification among both men and women with rheumatoid arthritis, and for all age categories. The largest percentage difference in coronary arterial calcification between rheumatoid arthritis patients and their nonrheumatoid arthritis counterparts was observed in the youngest age category.ConclusionsIncreasing rheumatoid arthritis disease severity was associated with a higher prevalence and greater extent of coronary artery calcification, potentially mediated through an atherogenic effect of chronic systemic inflammation. Gender and age differences in association with coronary calcification suggest that preventive measures should be emphasized in men with rheumatoid arthritis, and considered even in younger rheumatoid arthritis patients with low levels of traditional cardiovascular risk factors.

Prevalence of traditional modifiable cardiovascular risk factors in patients with rheumatoid arthritis: comparison with control subjects from the multi-ethnic study of atherosclerosis.

OBJECTIVE Despite the recognized risk of accelerated atherosclerosis in patients with rheumatoid arthritis (RA), little is known about cardiovascular risk management in contemporary cohorts of these patients. We tested the hypotheses that major modifiable cardiovascular risk factors were more frequent and rates of treatment, detection, and control were lower in patients with RA than in non-RA controls. METHODS The prevalence of hypertension, diabetes, elevated low-density lipoprotein (LDL) cholesterol, elevated body mass index, smoking, moderate-high 10-year cardiovascular risk and the rates of underdiagnosis, therapeutic treatment, and recommended management were compared in 197 RA patients and 274 frequency-matched control subjects, and their associations with clinical characteristics were examined. RESULTS Eighty percent of RA patients and 81% of control subjects had at least 1 modifiable traditional cardiovascular risk factor. Hypertension was more prevalent in the RA group (57%) than in controls [42%, P = 0.001]. There were no statistically significant differences in the frequency of diabetes, elevated body mass index, smoking, intermediate-high 10-year coronary heart disease risk, or elevated LDL in patients with RA versus controls. Rates of newly identified diabetes, hypertension, and hyperlipidemia were similar in RA patients versus controls. Rates of therapeutic interventions were low in both groups but their use was associated with well-controlled blood pressure (OR = 4.55, 95% CI: 1.70, 12.19) and lipid levels (OR = 9.90, 95% CI: 3.30, 29.67). CONCLUSIONS Hypertension is more common in RA than in controls. Other traditional cardiovascular risk factors are highly prevalent, underdiagnosed, and poorly controlled in patients with RA, as well as controls.

Ascertainment of collagen vascular disease in patients presenting with interstitial lung disease

INTRODUCTION Previous studies of interstitial lung disease (ILD) suggest that prognosis and therapeutic response are influenced by the presence of underlying collagen vascular disease (CVD). Yet, what proportion of patients presenting with ILD have CVD is largely unknown. We sought to determine the frequency of a new CVD diagnosis in an ILD referral population. MATERIALS/PATIENTS AND METHODS We retrospectively studied 114 consecutive patients evaluated at the Johns Hopkins Interstitial Lung Disease Clinic for the development of CVD. RESULTS In this retrospective cohort, nearly one-third of the 114 patients with confirmed ILD satisfied published criteria for a CVD diagnosis. Seventeen (15%) patients were diagnosed with a new CVD as a direct consequence of their ILD evaluation. Patients with new CVD diagnosis were younger than those without new CVD diagnosis: 51.4years (95% CI 45-58years) and 60years (95% CI 57-63), respectively (p=0.01). Moreover, an ANA>or=1:640 (p=0.03) and elevated levels of creatine phosphokinase (CPK) or aldolase (p<0.001) were associated with a new CVD diagnosis. CONCLUSIONS Unrecognized collagen vascular disease may be more common than previously appreciated among patients referred with ILD. High titer ANA and an elevated CPK or aldolase are associated with a CVD diagnosis in this referral population.

Longitudinal predictors of progression of carotid atherosclerosis in rheumatoid arthritis

OBJECTIVE To explore predictors of change in measures of carotid atherosclerosis among rheumatoid arthritis (RA) patients without known cardiovascular disease (CVD) at baseline. METHODS RA patients underwent carotid ultrasonography at 2 time points separated by a mean ± SD of 3.2 ± 0.3 years. The associations of baseline and average patient characteristics with the average yearly change in the mean maximal intima-media thickness (IMT) of the common carotid artery (CCA) and the internal carotid artery (ICAs) and with incident or progressive plaque in the ICA/carotid bulb, were explored. RESULTS Among the 158 RA patients, the maximal CCA-IMT increased in 82% (median 16 μm/year; P < 0.001) and the maximal ICA-IMT increased in 70% (median 25 μm/year; P < 0.001). Incident plaque was observed in 14% of those without plaque at baseline (incidence rate 4.2 per 100 person-years [95% confidence interval 1.6, 6.8]). Plaque progression was observed in 5% of those with plaque at baseline. Among RA predictors, the adjusted average yearly change in the maximal CCA-IMT was significantly greater in patients with earlier RA than in those with disease of longer duration. Those taking tumor necrosis factor (TNF) inhibitors at baseline had a 37% lower adjusted rate of progression in the maximal CCA-IMT compared with nonusers (14 μm/year versus 22 μm/year; P = 0.026). For the maximal ICA-IMT, cumulative prednisone exposure was associated with progression after adjustment (1.2 μm/year per gm [95% confidence interval 0.1, 2.4]) and was lower in patients who were prescribed statins concomitant with prednisone. Higher swollen joint counts and higher average C-reactive protein levels were both associated with incident or progressive plaque, primarily in patients with elevated CVD risk at baseline based on the Framingham Risk Score. CONCLUSION These prospective data provide evidence that inflammation is a contributor to the progression of subclinical atherosclerosis in RA and that it is potentially modified favorably by TNF inhibitors and detrimentally by glucocorticoids.

Left ventricular structure and function in patients with rheumatoid arthritis, as assessed by cardiac magnetic resonance imaging

OBJECTIVE Heart failure is a major contributor to cardiovascular morbidity and mortality in patients with rheumatoid arthritis (RA), but little is known about myocardial structure and function in this population. This study was undertaken to assess the factors associated with progression to heart failure in patients with RA. METHODS With the use of cardiac magnetic resonance imaging, measures of myocardial structure and function were assessed in men and women with RA enrolled in the Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis study, a cohort study of subclinical cardiovascular disease in patients with RA, in comparison with non-RA control subjects from a cohort enrolled in the Baltimore Multi-Ethnic Study of Atherosclerosis. RESULTS Measures of myocardial structure and function were compared between 75 patients with RA and 225 frequency-matched controls. After adjustment for confounders, the mean left ventricular mass was found to be 26 gm lower in patients with RA compared with controls (P < 0.001), an 18% difference. In addition, the mean left ventricular ejection fraction, cardiac output, and stroke volume were modestly lower in the RA group compared with controls. The mean left ventricular end systolic and end diastolic volumes did not differ between the groups. In patients with RA, higher levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies and current use of biologic agents, but not other measures of disease activity or severity, were associated with significantly lower adjusted mean values for the left ventricular mass, end diastolic volume, and stroke volume, but not with ejection fraction. The combined associations of anti-CCP antibody level and biologic agent use with myocardial measures were additive, without evidence of interaction. CONCLUSION These findings suggest that the progression to heart failure in RA may occur through reduced myocardial mass rather than hypertrophy. Both modifiable and nonmodifiable factors may contribute to lower levels of left ventricular mass and volume.

Reliability and Sensitivity of the Self-report of Physician-diagnosed Gout in the Campaign Against Cancer and Heart Disease and the Atherosclerosis Risk in the Community Cohorts

Objective. Gout is often defined by self-report in epidemiologic studies. Yet the validity of self-reported gout is uncertain. We evaluated the reliability and sensitivity of the self-report of physician-diagnosed gout in the Campaign Against Cancer and Heart Disease (CLUE II) and the Atherosclerosis Risk in the Community (ARIC) cohorts. Methods. The CLUE II cohort comprises 12,912 individuals who self-reported gout status on either the 2000, 2003, or 2007 questionnaires. We calculated reliability as the percentage of participants reporting having gout on more than 1 questionnaire using Cohen’s κ statistic. The ARIC cohort comprises 11,506 individuals who self-reported gout status at visit 4. We considered a hospital discharge diagnosis of gout or use of a gout-specific medication as the standard against which to calculate the sensitivity of self-reported, physician-diagnosed gout. Results. Of the 437 CLUE II participants who self-reported physician-diagnosed gout in 2000, and subsequently answered the 2003 questionnaire, 75% reported gout in 2003 (κ = 0.73). Of the 271 participants who reported gout in 2000, 73% again reported gout at the 2007 followup questionnaire (κ = 0.63). In ARIC, 196 participants met the definition for gout prior to visit 4 and self-reported their gout status at visit 4. The sensitivity of a self-report of physician-diagnosed gout was 84%. Accuracy was similar across sex and race subgroups, but differed across hyperuricemia and education strata. Conclusion. These 2 population-based US cohorts suggest that self-report of physician-diagnosed gout has good reliability and sensitivity. Thus, self-report of a physician diagnosis of gout is appropriate for epidemiologic studies.

Effect of Oral Vitamin C Supplementation on Serum Uric Acid: A Meta-analysis of Randomized Controlled Trials

To assess the effect of vitamin C supplementation on serum uric acid (SUA) by pooling the findings from published randomized controlled trials (RCTs).

The DNA mismatch repair enzyme PMS1 is a myositis-specific autoantigen.

OBJECTIVE The specificity of the autoantibody response in different autoimmune diseases makes autoantibodies useful for diagnostic purposes. It also focuses attention on tissue- and event-specific circumstances that may select unique molecules for an autoimmune response in specific diseases. Defining additional phenotype-specific autoantibodies may identify such circumstances. This study was undertaken to investigate the disease specificity of PMS1, an autoantigen previously identified in some sera from patients with myositis. METHODS We used immunoprecipitation analysis to determine the frequency of autoantibodies to PMS1 in sera from patients with myositis, systemic lupus erythematosus, or scleroderma and from healthy controls. Additional antigens recognized by PMS1-positive sera were further characterized in terms of their susceptibility to cleavage by apoptotic proteases. RESULTS PMS1, a DNA mismatch repair enzyme, was identified as a myositis-specific autoantigen. Autoantibodies to PMS1 were found in 4 of 53 patients with autoimmune myositis (7.5%), but in no sera from 94 patients with other systemic autoimmune diseases (P = 0.016). Additional mismatch repair enzymes (PMS2, MLH1) were targeted, apparently independently. Sera recognizing PMS1 also recognized several other proteins involved in DNA repair and remodeling, including poly(ADP-ribose) polymerase, DNA-dependent protein kinase, and Mi-2. All of these autoantigens were efficiently cleaved by granzyme B, generating unique fragments not observed during other forms of cell death. CONCLUSION PMS1 autoantibodies are myositis specific. The striking correlation between an immune response to a group of granzyme B substrates (functioning in DNA repair and remodeling) and the myositis phenotype strongly implies that tissue- and event-specific biochemical events play a role in selecting these molecules for an autoimmune response. Understanding the role of granzyme B cleavage in this response is an important priority.