Showing papers by "Marc C. Hochberg published in 2018"

Genome-wide meta-analysis of 158,000 individuals of European ancestry identifies three loci associated with chronic back pain.

Abstract: Back pain is the #1 cause of years lived with disability worldwide, yet surprisingly little is known regarding the biology underlying this symptom. We conducted a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). Adults of European ancestry were included from 15 cohorts in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and from the UK Biobank interim data release. CBP cases were defined as those reporting back pain present for ≥3–6 months; non-cases were included as comparisons (“controls”). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p<5×10−8. Suggestive (p<5×10−7) and genome-wide significant (p<5×10−8) variants were carried forward for replication or further investigation in the remaining UK Biobank participants not included in the discovery sample. The discovery sample comprised 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p = 7.2×10−10). This was subsequently replicated in 283,752 UK Biobank participants not included in the discovery sample, including 50,915 cases (OR 1.06, p = 5.3×10−11), and exceeded genome-wide significance in joint meta-analysis (OR 1.07, p = 4.5×10−19). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p = 4.4×10−13), and an intronic variant, rs4384683, in DCC (OR 0.97, p = 2.4×10−10). In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP (SOX5). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis (CCDC26/GSDMC and DCC).

Dynamic Effects of Depressive Symptoms on Osteoarthritis Knee Pain

Abstract: Objective To estimate the dynamic causal effects of depressive symptoms on osteoarthritis (OA) knee pain. Methods Marginal structural models were used to examine dynamic associations between depressive symptoms and pain over 48 months among older adults (n = 2,287) with radiographic knee OA (Kellgren/Lawrence grade 2 or 3) in the Osteoarthritis Initiative. Depressive symptoms at each annual visit were assessed (threshold ≥16) using the Center for Epidemiologic Studies Depression Scale. OA knee pain was measured using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale, rescaled to range from 0 to 100. Results Depressive symptoms at each visit were generally not associated with greater OA knee pain at subsequent time points. Causal mean differences in WOMAC pain score comparing depressed to nondepressed patients ranged from 1.78 (95% confidence interval [95% CI] −0.73, 4.30) to 2.58 (95% CI 0.23, 4.93) within the first and fourth years, and the depressive symptoms by time interaction were not statistically significant (P = 0.94). However, there was a statistically significant dose-response relationship between the persistence of depressive symptoms and OA knee pain severity (P = 0.002). Causal mean differences in WOMAC pain score comparing depressed to nondepressed patients were 0.89 (95% CI −0.17, 1.96) for 1 visit with depressive symptoms, 2.35 (95% CI 0.64, 4.06) for 2 visits with depressive symptoms, and 3.57 (95% CI 0.43, 6.71) for 3 visits with depressive symptoms. Conclusion The causal effect of depressive symptoms on OA knee pain does not change over time, but pain severity significantly increases with the persistence of depressed mood.

Genome-wide Meta-analysis of 158,000 Individuals of European Ancestry Identifies Three Loci Associated with Chronic Back Pain

Abstract: OBJECTIVES: To conduct a genome-wide association study (GWAS) meta-analysis of chronic back pain (CBP). METHODS: Adults of European ancestry were included from 16 cohorts in Europe and North America. CBP cases were defined as those reporting back pain present for >3-6 months; non-cases were included as comparisons (9controls9). Each cohort conducted genotyping using commercially available arrays followed by imputation. GWAS used logistic regression models with additive genetic effects, adjusting for age, sex, study-specific covariates, and population substructure. The threshold for genome-wide significance in the fixed-effect inverse-variance weighted meta-analysis was p -8 . Suggestive (p -7 ) and genome-wide significant (p -8 ) variants were carried forward for replication or further investigation in an independent sample. RESULTS: The discovery sample was comprised of 158,025 individuals, including 29,531 CBP cases. A genome-wide significant association was found for the intronic variant rs12310519 in SOX5 (OR 1.08, p=7.2x10 -10 ). This was subsequently replicated in an independent sample of 283,752 subjects, including 50,915 cases (OR 1.06, p=5.3x10 -11 ), and exceeded genome-wide significance in joint meta-analysis (OR=1.07, p=4.5x10 -19 ). We found suggestive associations at three other loci in the discovery sample, two of which exceeded genome-wide significance in joint meta-analysis: an intergenic variant, rs7833174, located between CCDC26 and GSDMC (OR 1.05, p=4.4x10 -13 ), and an intronic variant, rs4384683, in DCC (OR 0.97, p=2.4x10 -10 ). DISCUSSION: In this first reported meta-analysis of GWAS for CBP, we identified and replicated a genetic locus associated with CBP ( SOX5 ). We also identified 2 other loci that reached genome-wide significance in a 2-stage joint meta-analysis ( CCDC26/GSDMC and DCC ).

Running does not increase symptoms or structural progression in people with knee osteoarthritis: data from the osteoarthritis initiative.

Abstract: Higher levels of moderate to vigorous physical activity improve all-cause mortality and cardiovascular events. However, the effect of running, a moderate to vigorous activity, in those with knee osteoarthritis (OA), a common arthritis that occurs with aging, a high-risk group for mortality and cardiovascular events, is unclear. Therefore, we aimed to evaluate the association of self-selected running on OA symptom and structure progression in people with knee OA. This nested cohort study within the Osteoarthritis Initiative (OAI) (2004–2014) included those at least 50 years old with OA in at least one knee. Runners were defined using a self-administered questionnaire at the 96-month visit. At baseline and 48-months, symptoms were assessed and radiographs were scored for Kellgren-Lawrence (KL) grade (2–4) and medial Joint Space Narrowing (JSN) score (0–3). We evaluated the association of self-selected running with outcomes: KL worsening, medial JSN worsening, new knee pain, and improved knee pain over 48 months, adjusting for baseline age, sex, body mass index (BMI), KL score, contralateral KL score, contralateral knee pain, and injury. If data were not available at the 48-month visit, then they were imputed from the 36-month visit. One thousand two hundred three participants had a mean age of 63.2 (7.9) years, BMI of 29.5 (4.6) kg/m2, 45.3% male, and 11.5% runners. Data from 8% of participants required imputation. Adjusted odds ratios for KL grade worsening and new frequent knee pain were 0.9 (0.6–1.3) and 0.9 (0.6–1.6) respectively. Adjusted odds ratio for frequent knee pain resolution was 1.7 (1.0–2.8). Among individuals 50 years old and older with knee OA, self-selected running is associated with improved knee pain and not with worsening knee pain or radiographically defined structural progression. Therefore, self-selected running, which is likely influenced by knee symptoms and may result in lower intensity and shorter duration sessions of exercise, need not be discouraged in people with knee OA.

Abatacept for the treatment of adults with psoriatic arthritis: patient selection and perspectives.

Abstract: Psoriatic arthritis (PsA) is a heterogeneous disease with several clinical subtypes including peripheral arthritis, dactylitis, enthesitis, nail disease, and axial arthritis. Nonsteroidal anti-inflammatory drugs, glucocorticoids, and conventional disease-modifying agents are used as first line in the treatment of active PsA. For moderate-to-severe PsA failing conventional therapy, antitumor necrosis factor inhibitors have historically been the drugs of choice. In recent years, novel interleukin-23/interleukin-17 pathway targets such as ustekinumab and secukinumab, and phosphodiesterase-4 inhibitor apremilast have been approved for use in the United States and Europe. Two sets of recommendations for the management of PsA were published in 2016 with consideration for these newer therapies. Since then, the results from a Phase III randomized controlled trial demonstrated that abatacept has efficacy in the treatment of PsA. Abatacept, a cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4)-Ig human fusion protein, acts to prevent naive T-cell activation through the inhibition of the critical CD28 co-stimulatory signal. In the 2017 Active Psoriatic Arthritis Randomized Trial (ASTRAEA), 424 participants were randomized 1:1 to receive subcutaneous abatacept 125 mg weekly versus placebo. At week 24, 39.4% of those who received abatacept achieved a minimum of 20% improvement in the American College of Rheumatology (ACR) response compared to 22.3% in the placebo arm, a statistically significant finding (P<0.001). The 2011 Phase II study published by Mease et al demonstrated statistically significant improvements in the ACR20 response by week 169 in participants treated with intravenous abatacept 10 mg/kg (48%) and 30/10 mg/kg (42%) when compared with placebo (19%). This article reviews the data supporting the efficacy of abatacept in the management of PsA and attempts to place this agent in the context of other biologic disease-modifying antirheumatic drugs and targeted small molecules used in the treatment of patients with PsA.

Examining Differences in Recovery Outcomes between Male and Female Hip Fracture Patients: Design and Baseline Results of a Prospective Cohort Study from the Baltimore Hip Studies

Abstract: Incidence of hip fractures in men is expected to increase, yet little is known about consequences of hip fracture in men compared to women. It is important to investigate differences at time of fracture using the newest technologies and methodology regarding metabolic, physiologic, neuromuscular, functional, and clinical outcomes, with attention to design issues for recruiting frail older adults across numerous settings. To determine whether at least moderately-sized sex differences exist across several key outcomes after a hip fracture. This prospective cohort study (Baltimore Hip Studies 7th cohort [BHS-7]) was designed to include equal numbers of male and female hip fracture patients to assess sex differences across various outcomes post-hip fracture. Participants were recruited from eight hospitals in the Baltimore metropolitan area within 15 days of admission and were assessed at baseline, 2, 6 and 12 months post-admission. Assessments included questionnaire, functional performance evaluation, cognitive testing, measures of body composition, and phlebotomy. Of 1709 hip fracture patients screened from May 2006 through June 2011, 917 (54%) were eligible and 39% (n=362) provided informed consent. The final analytic sample was 339 (168 men and 171 women). At time of fracture, men were sicker (mean Charlson score= 2.4 vs. 1.6; p<0.001) and had worse cognition (3MS score= 82.3 vs. 86.2; p<0.05), and prior to fracture were less likely to be on bisphosphonates (8% vs. 39%; p<0.001) and less physically active (2426 kilocalories/week vs. 3625; p<0.001). This paper provides the study design and methodology for recruiting and assessing hip fracture patients and evidence of baseline and pre-injury sex differences which may affect eventual recovery one year later.

Persistence of depressive symptoms and gait speed recovery in older adults after hip fracture.

Abstract: Objective Depression after hip fracture in older adults is associated with worse physical performance; however, depressive symptoms are dynamic, fluctuating during the recovery period. The study aim was to determine how the persistence of depressive symptoms over time cumulatively affects the recovery of physical performance. Methods Marginal structural models estimated the cumulative effect of persistence of depressive symptoms on gait speed during hip fracture recovery among older adults (n = 284) enrolled in the Baltimore Hip Studies 7th cohort. Depressive symptoms at baseline and at 2-month and 6-month postadmission for hip fracture were evaluated by using the Center for Epidemiological Studies Depression Scale, and persistence of symptoms was assessed as a time-averaged severity lagged to standardized 3 m gait speed at 2, 6, and 12 months. Results A 1-unit increase in time-averaged Center for Epidemiological Studies Depression score was associated with a mean difference in gait speed of -0.0076 standard deviations (95% confidence interval [CI]: -0.0184, 0.0032; P = .166). The association was largest in magnitude from baseline to 6 months: -0.0144 standard deviations (95% CI: -0.0303, 0.0015; P = 0.076). Associations for the other time intervals were smaller: -0.0028 standard deviations (95% CI: -0.0138, 0.0083; P = .621) at 2 months and -0.0121 standard deviations (95% CI: -0.0324, 0.0082; P = .238) at 12 months. Conclusion Although not statistically significant, the magnitude of the numerical estimates suggests that expressing more depressive symptoms during the first 6 months after hip fracture has a meaningful impact on functional recovery.

Identification of pain categories associated with change in pain in patients receiving placebo: data from two phase 3 randomized clinical trials in symptomatic knee osteoarthritis

Abstract: Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinical characteristics and pain categories particularly associated with this phenomenon is needed. The purpose of this post-hoc analysis was to investigate clinical characteristics and pain categories and their association with radiographic progression and placebo pain reduction (PPR) in OA patients as measured the Western Ontario and McMasters Arthritis (WOMAC). Pooled data from the placebo groups of two phase III randomized clinical trials in patients with knee OA followed for 2 years were analyzed. Differences between individual sub-scores and pain categories of weight-bearing and non-weight bearing pain over time were assessed. Selected patient baseline characteristics were assessed for association with PPR. Association between pain categories and radiographic progression was analyzed. The reduction of pain in placebo-treated patients was significantly higher in the composite of questions related to weight-bearing pain compared to non-weight-bearing pain of the target knee. Baseline BMI, age and JSW were not associated with pain change. Pain reduction was higher in the Target knee, compared to the Non-Target knee at all corresponding time-points. A very weak correlation was found between weight-bearing pain and progression in the non-target knee. These results indicate that the reduction in pain in patients treated with placebo is significantly different between pain categories, as weight-bearing pain was significantly more reduced compared to non-weight-bearing pain. Further research in pain categories in OA is warranted. NCT00486434 (trial 1) and NCT00704847 (trial 2)

Older men who sustain a hip fracture experience greater declines in bone mineral density at the contralateral hip than non-fractured comparators.

Abstract: Men experience declining bone mineral density (BMD) after hip fracture; however, changes attributable to fracture are unknown. This study evaluated the excess BMD decline attributable to hip fracture among older men. Older men with hip fracture experienced accelerated BMD declines and are at an increased risk of secondary fractures. The objective was to determine whether bone mineral density (BMD) changes in men after hip fracture exceed that expected with aging. Two cohorts were used: Baltimore Hip Studies 7th cohort (BHS-7) and Baltimore Men’s Osteoporosis Study (MOST). BHS-7 recruited older adults (N = 339) hospitalized for hip fracture; assessments occurred within 22 days of admission and at 2, 6, and 12 months follow-up. MOST enrolled age-eligible men (N = 694) from population-based listings; data were collected at a baseline visit and a second visit that occurred between 10 and 31 months later. The combined sample (n = 452) consisted of Caucasian men from BHS-7 (n = 89) and MOST (n = 363) with ≥ 2 dual-energy X-ray absorptiometry scans and overlapping ranges of age, height, and weight. Mixed-effect models estimated rates of BMD change, and generalized linear models evaluated differences in annual bone loss at the total hip and femoral neck between cohorts. Adjusted changes in total hip and femoral neck BMD were − 4.16% (95% CI, − 4.87 to − 3.46%) and − 4.90% (95% CI, − 5.88 to − 3.92%) in BHS-7 participants; − 1.57% (95% CI, − 2.19 to − 0.96%) and − 0.99% (95% CI, − 1.88 to − 0.10%) in MOST participants; and statistically significant (P < 0.001) between-group differences in change were − 2.59% (95% CI, − 3.26 to − 1.91%) and − 3.91% (95% CI, − 4.83 to − 2.98%), respectively. Hip fracture in older men is associated with accelerated BMD declines at the non-fractured hip that are greater than those expected during aging, and pharmacological interventions in this population to prevent secondary fractures may be warranted.

Soluble Tumor Necrosis Factor Alpha Receptor 1, Bone Resorption, and Bone Mineral Density in the Year Following Hip Fractures: The Baltimore Hip Studies.

Abstract: Although inflammation is known to influence bone turnover and bone mineral density (BMD), less is known about role of soluble tumor necrosis factor alpha receptor 1 (sTNFα-R1) in changes in bone turnover and BMD in the year after hip fracture. We studied 245 persons (117 men and 128 women) from the Baltimore Hip Studies. Bone turnover markers of resorption (carboxy-terminal type I collagen cross-links [CTX-I]) and formation (amino-terminal propeptide type I collagen [P1NP]), BMD of the contralateral hip, and sTNFα-R1 were measured within 15 days of hospitalization and 2, 6, and 12 months later. Latent class growth modeling was used to determine sTNFα-R1 trajectories. Weighted generalized estimating equations were used to examine the association of sTNFα-R1 trajectories with serum levels of CTX-I and P1NP and BMD; standardized beta coefficients (βˆ) are reported. Higher baseline sTNFα-R1 was significantly associated with a greater rate of CTX-I change (βˆ = 0.26, p = 0.004). Four distinct sTNFα-R1 trajectories were identified. The two groups with higher sTNFα-R1 levels during the year following fracture had faster increasing levels of CTX-I compared to the group with lowest sTNFα-R1 levels (men: group 3: βˆ = 0.76, p = 0.02; group 4: βˆ = 1.4, p < 0.001; women: group 3; βˆ = 0.67, p = 0.02; group 4: βˆ = 1.3, p = 0.004). Men in the highest sTNFα-R1 group had a greater decline in BMD compared to the lowest sTNFα-R1 group (2-month βˆ = -0.01, p = 0.01; 6-month: βˆ = -0.09, p = 0.001; 12-months: βˆ = -0.1, p < 0.001). An increasing rate of CTX-I was associated with a steeper decline in total hip BMD in those within higher sTNFα-R1 trajectory groups (p < 0.001). CTX-I was significantly increased with sTNFα-R1 in both sexes. CTX-I and the highest sTNFα-R1 trajectory were significantly associated with declines in total hip BMD in men. Interventions that reduce systemic inflammation should be explored to reduce bone resorption and prevent a decline in BMD after hip fracture. © 2018 American Society for Bone and Mineral Research.