Mari Hoff

Cortical hand bone loss after 1 year in early rheumatoid arthritis predicts radiographic hand joint damage at 5-year and 10-year follow-up

Objective: To examine 1-year hand bone loss in early rheumatoid arthritis (RA) as a predictor of radiographic damage at 5-year and 10-year follow-up Methods: A total of 136 patients with RA (disease duration 0–4 years) were followed for 10 years with clinical data and hand radiographs. Joint damage was scored according to the van der Heijde modification of the Sharp method (vdH Sharp score) and hand bone mineral density (BMD) was measured by digital x ray radiogrammetry (DXR). Group comparisons, correlation analyses and multivariate analyses were performed to evaluate the relationship between hand bone loss and radiographic joint damage. Results: Patients with hand BMD loss at 1 year had a higher median increase in vdH Sharp score compared to patients without loss at 5 years (12 vs 2, p = 0.001) and 10 years (22 vs 4, p = 0.002). In a linear regression model adjusting for age, gender, baseline C-reactive protein (CRP), anti-cyclic citrullinated peptide (CCP), IgM rheumatoid factor (RF) and radiographic damage, absolute hand DXR-BMD loss at 1 year was an independent predictor of radiographic outcome at 5 years (p<0.01) and 10 years (p = 0.02). In a logistic regression model the odds ratio (95% CI) for radiographic progression among patients with hand BMD loss was 3.5 (1.4 to 8.8) and 3.5 (1.4 to 8.4) at 5 and 10 years, respectively. Conclusion: Early hand bone loss measured by DXR-BMD is an independent predictor of subsequent radiographic damage. Our findings support that quantitative hand bone loss in RA precedes radiographic joint damage and may be used as a tool for assessment of bone involvement in RA.

Adalimumab therapy reduces hand bone loss in early rheumatoid arthritis: Explorative analyses from the PREMIER study

Objective: The effect of adalimumab on hand osteoporosis was examined and related to radiographic joint damage in the three treatment arms of the PREMIER study: adalimumab plus methotrexate, adalimumab and methotrexate monotherapy. Predictors of hand bone loss were also searched for. Methods: 768 patients (537 fulfilled 2 years) with rheumatoid arthritis (RA) for less than 3 years, never treated with methotrexate, were included. Hand bone loss was assessed by digital x ray radiogrammetry (DXR) on the same hand radiographs scored with modified Sharp score at baseline, 26, 52 and 104 weeks. For DXR, metacarpal cortical index (MCI) was the primary bone measure. Results: At all time points the rate of percentage DXR–MCI loss was lowest in the combination group (−1.15; −2.16; −3.03) and greatest in the methotrexate monotherapy group (−1.42; −2.87; −4.62), with figures in between for the adalimumab monotherapy group (−1.33; −2.45; −4.03). Significant differences between the combination group and the methotrexate group were seen at 52 (p = 0.009) and 104 weeks (p<0.001). The order of hand bone loss across the three treatment arms was similar to the order of radiographic progression. Older age, elevated C-reactive protein and non-use of adalimumab were predictors of hand bone loss. Conclusion: This study supports a similar pathogenic mechanism for hand bone loss and erosions in RA. The combination of adalimumab and methotrexate seems to arrest hand bone loss less effectively than radiographic joint damage. Quantitative measures of osteoporosis may thus be a more sensitive tool for assessment of inflammatory bone involvement in RA.

Subclinical Thyroid Dysfunction and Fracture Risk: A Meta-analysis

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant data were obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid function were defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH ≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcome was hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70,298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762,401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age- and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidism was 1.36 for hip fracture (95% CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56,471); for any fracture, HR was 1.28 (95% CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25,901); for nonspine fracture, HR was 1.16 (95% CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21,722); and for spine fracture, HR was 1.51 (95% CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20,328). Lower TSH was associated with higher fracture rates: for TSH of less than 0.10 mIU/L, HR was 1.61 for hip fracture (95% CI, 1.21-2.15; 47 events in 510 participants); for any fracture, HR was 1.98 (95% CI, 1.41-2.78; 44 events in 212 participants); for nonspine fracture, HR was 1.61 (95% CI, 0.96-2.71; 32 events in 185 participants); and for spine fracture, HR was 3.57 (95% CI, 1.88-6.78; 8 events in 162 participants). Risks were similar after adjustment for other fracture risk factors. Endogenous subclinical hyperthyroidism (excluding thyroid medication users) was associated with HRs of 1.52 (95% CI, 1.19-1.93) for hip fracture, 1.42 (95% CI, 1.16-1.74) for any fracture, and 1.74 (95% CI, 1.01-2.99) for spine fracture. No association was found between subclinical hypothyroidism and fracture risk. CONCLUSIONS AND RELEVANCE Subclinical hyperthyroidism was associated with an increased risk of hip and other fractures, particularly among those with TSH levels of less than 0.10 mIU/L and those with endogenous subclinical hyperthyroidism. Further study is needed to determine whether treating subclinical hyperthyroidism can prevent fractures.

Adalimumab reduces hand bone loss in rheumatoid arthritis independent of clinical response: subanalysis of the PREMIER study.

BackgroundAnti-TNF therapy has been shown to reduce radiographic joint damage in rheumatoid arthritis (RA) independent of clinical response. This has previously not been examined for periarticular bone loss, the other characteristic feature of bone involvement in RA.The objective of this study was to examine if treatment with the TNF-α inhibitor adalimumab also could reduce periarticular bone loss in RA patients independent of disease activity.MethodsRA patients were recruited from the PREMIER study and included 214 patients treated with methotrexate (MTX) plus adalimumab and 188 patients treated with MTX monotherapy. Periarticular bone loss was assessed by digital X-ray radiogrammetry metacarpal cortical index (DXR-MCI). Change in DXR-MCI was evaluated in patients with different levels of clinical response, as assessed by changes in DAS28 score at 52 weeks and in mean C-reactive protein (CRP) levels during follow-up.ResultsIn the MTX group, there was a greater median DXR-MCI loss among patients with moderate and high disease activity compared to those in remission or with low disease activity (-3.3% vs. -2.2%, p = 0.01). In contrast, periarticular bone loss was independent of disease activity (-1.9% vs. -2.4%, p = 0.99) in the combination group. In the MTX group patients with a mean CRP of ≥ 10 mg/l lost significantly more DXR-MCI than patients with low CRP (-3.1% vs. -1.9%, p <0.01) whereas in the combination group no significant differences between the two CRP groups was seen (-2.4% vs. -2.0%, p = 0.48).ConclusionAdalimumab in combination with MTX reduces periarticular bone loss independently of clinical response. These results support the hypothesis that TNF-α stimulates the osteoclast not only by the inflammatory pathway but do also have a direct effect on the osteoclast.Trial RegistrationClinicalTrials (NCT): NCT001195663

Antibodies to cyclic citrullinated protein and erythrocyte sedimentation rate predict hand bone loss in patients with rheumatoid arthritis of short duration: a longitudinal study

IntroductionRadiographic progression in rheumatoid arthritis (RA) has in several studies been shown to be predicted by serological markers widely used in daily clinical practice. The objective of this longitudinal study was to examine if these serological markers also predict hand bone mineral density (BMD) loss in patients with RA of short disease duration.Methods163 patients with RA of short disease duration (2.4 years) were included and followed longitudinally. Antibodies to cyclic citrullinated protein (anti-CCP), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) were analysed from baseline blood-samples. Hand BMD was measured by digital X-ray radiogrammetry (DXR) based on hand and wrist radiographs obtained at baseline and 1, 2 and 5-year follow-up.ResultsDuring the study period, DXR-BMD decreased by median (inter quartile range) 1.7% (4.1 to 0.4), 2.8% (5.3 to 0.9) and 5.6% (11.7 to 2.3) after 1, 2 and 5 years, respectively. Elevated baseline anti-CCP, RF, ESR and CRP levels were in univariate linear regression analyses consistently associated with DXR-BMD change at all time-points. Anti-CCP and ESR were independently associated with hand DXR-BMD in multivariate linear regression analyses. Elevated anti-CCP levels were consistent and independent predictors of loss in cortical hand bone during the study period, with the odds ratios (95% confidence interval) 2.2 (1.0 to 4.5), 2.6 (1.1 to 6.2) and 4.9 (1.4 to 16.7) for the 1, 2, and 5-year follow-up periods, respectively.ConclusionsAnti-CCP and ESR were found to be independent predictors of early localised BMD loss. This finding adds to the understanding of anti-CCP and ESR as important predictors of bone involvement in RA.

Short-Time In Vitro and In Vivo Precision of Direct Digital X-ray Radiogrammetry

Digital X-ray radiogrammetry (DXR) calculates peripheral bone mineral density (BMD) from hand radiographs. The aim of this study was to examine in vitro and in vivo precision for the new direct digital version of DXR, a development of the conventional DXR. The in vitro precision for direct DXR was tested on 4 different X-ray equipment, based on 31 radiographs of the same phantom. The in vivo precision was based on duplicate hand radiographs from both hands in 39 individuals. For the 4 X-ray equipment, in vitro precision ranged from 0.14% to 0.30%, expressed as coefficient of variations (CV%) and from 0.0012 to 0.0028 g/cm2, expressed as smallest detectable difference (SDD). The precision was correlated to the resolution of the radiographic equipment (r=0.95, p=0.05). The corresponding values for the in vivo precision for mean values of both hands were: CV%=0.46%; SDD=0.0046 g/cm2, and least significant change (LSC%)=1.28%. The DXR-BMD for 1 of the X-ray equipment differed 1.1% from the overall mean. The precision for direct DXR was highly satisfactory both in vitro and in vivo. DXR-BMD values may differ between the radiographic equipment, and follow-up measurements should be performed with the same X-ray equipment.

Predictors of Short- and Long-Term Mortality in Males and Females with Hip Fracture - A Prospective Observational Cohort Study

Background Hip fracture is associated with increased mortality. Our aim was to study potential risk factors, including osteoporosis, associated with short- and long-term mortality in a prospectively recruited cohort of fragility hip fracture patients. Methodology/Principal Findings Fragility hip fracture patients aged >50 years admitted to a county hospital in Southern Norway in 2004 and 2005 were consecutively identified and invited for assessment. Patients with high energy or pathological fractures, patients with confusion, serious infections or who were non-residents in the catchment area were excluded. As part of a clinical routine, data were collected using questionnaires. Standardized bone density measurements of lumbar spine and hip were performed. Potential predictors of hip fracture mortality were tested using univariate and multivariate logistic regression analysis. A total of 432 hip fracture patients (129 males and 303 females) were prospectively identified. Among them 296 (85 males and 211 females) patients [mean age 80.7 (SD 9.1)] were assessed at the Osteoporosis center. Variables independently associated with short-term mortality (after 1 year) were in females older age [Odds Ratio (OR) 6.95] and in males older age (OR 5.74) and pulmonary disease (OR 3.20), whereas no associations were observed with mortality for 3 months after the fragility hip fracture. Variables independently associated with 5 years mortality in males was osteoporosis (OR 3.91) and older age (OR 6.95), and in females was dementia (OR 4.16) and older age (OR 2.80). Conclusion Apart from known predictors as age and comorbidity osteoporosis in our study was identified as a potential independent predictor of long-term hip fracture mortality in males. This is of particular importance as treatment with bisphosphonates after hip fracture has been shown to reduce hip fracture mortality and may be a clinical target to reduce the burden of the disease. Further studies however are needed to confirm the validity of this finding.

Short- and long-term mortality in males and females with fragility hip fracture in Norway. A population-based study

Background Hip fracture patients have, in several studies, been shown to have excessive mortality. There is, however, a lack of mortality data, in comparison to incidence data, from the last decade in particular. Objective To study short- and long-term mortality in a population-based cohort of hip fracture patients over the last decade and compare it to the background population. Patients and methods Fragility hip fracture patients in the two most southern counties in Norway who experienced fractures in 2004 and 2005 were studied. For each patient, three controls were randomly recruited from the background population matched for age, sex, and residency. Overall, age-, gender-, and group-specific mortality rates were calculated. Results A total of 942 (267 male and 675 female) patients with a fragility hip fracture were identified. In the hip fracture patients, overall mortality rate after 1 year was 21.3% (males 30.7% and females 19.1%, P < 0.005) and, after 5 years, 59.0% (males 70.0% and females 54.6%, P < 0.005). The corresponding figures for matched controls were 5.6% (males 5.9%, females 5.4%, P = 0.6) and 24.9% (males 25.9%, females 24.5%, P = 0.4), respectively. A statistically significant difference was seen in the log-rank statistical analysis between hip fracture patients and controls, both in males (P < 0.0005) and females (P < 0.0005), and for age groups 50–80 years (P < 0.0005) and 80 years and older (P < 0.0005). Conclusion Mortality in males and females with hip fractures is high not only in the first year after fracture, but remains higher than in the background population during 5 years of follow-up. The high mortality in hip fracture patients remains a challenge both in middle-aged and elderly individuals. Optimization of post-fracture treatment and care could reduce mortality of hip fracture in middle-aged and elderly individuals.

On the HUNT for cardiovascular risk factors and disease in patients with psoriatic arthritis: population-based data from the Nord-Trøndelag Health Study

Objective To compare the presence of cardiovascular (CV) risk factors and established CV disease in patients with psoriatic arthritis (PsA) and the general population and to compare the 10-year risk of a fatal CV event calculated by the Systematic Coronary Risk Evaluation (SCORE) algorithm. Methods Patients with PsA (n=338) and controls (n=50 468) were recruited from the Nord-Trøndelag Health Study 3. Age-adjusted and sex-adjusted prevalence rates of CV risk factors and comorbidity were calculated and the SCORE algorithm was applied. Results There was an increased prevalence of angina pectoris (5.0% vs 3.6%, p=0.01), history of percutaneous coronary intervention (2.4% vs 1.4%, p=0.04), hypertension (45.3% vs 39.3%, p=0.01), obesity (32.0% vs 22.4%) and tobacco smoking (21.3% vs 16.4%, p=0.02) in patients with PsA compared with controls. Patients with PsA had elevated levels of C reactive protein (CRP; p<0.001), body mass index (BMI; p<0.001) and triglycerides (p=0.01). The median calculated CV risk in patients with PsA was low and comparable with controls (0.87 vs 0.83, p=0.24). The distribution across CV risk classes was similar among patients with PsA and controls. Conclusions Patients with PsA have a higher risk of CV disease than the background population, although there was no difference between groups in 10-year risk of a fatal CV event estimated by SCORE. However, patients with PsA had elevated levels of CV risk factors not included in the SCORE algorithm, such as BMI, triglycerides and CRP.

Association between high plasma levels of hepatocyte growth factor and progression of radiographic damage in the joints of patients with rheumatoid arthritis

OBJECTIVE Hepatocyte growth factor (HGF) and dickkopf-1 (Dkk-1) inhibit osteoblast differentiation. The present study was thus undertaken to investigate whether plasma levels of HGF and Dkk-1 are related to bone damage in patients with rheumatoid arthritis (RA). METHODS RA patients with a disease duration of <4 years were followed up prospectively with collection of demographic, clinical, and radiographic data at study enrollment (1992) and after 1, 2, 5, and 10 years. Hand radiographs were scored according to the modified Sharp/van der Heijde score (SHS). Levels of HGF and Dkk-1 in stored plasma samples obtained from 136 patients at the time of enrollment were measured by enzyme-linked immunosorbent assay. Associations between cytokine levels and radiographic progression were examined by linear regression analysis. RESULTS Patients with above-median levels of HGF at enrollment had a significantly greater change in the SHS after 1, 2, 5, and 10 years than did patients with below-median levels of HGF (P < 0.001, P = 0.006, P = 0.01, and P = 0.01, respectively). In an unadjusted analysis, baseline HGF levels predicted the severity of joint damage at all time points studied. After adjustment for other known predictors of radiographic progression, baseline HGF levels remained significantly associated with radiographic progression. Plasma levels of Dkk-1 at enrollment were not significantly associated with radiographic progression at any time point studied. CONCLUSION Plasma levels of HGF predict joint damage in RA, and this finding suggests that HGF plays a role in RA joint destruction. The role of HGF as a potential prognostic biomarker or target for treatment warrants further exploration.