Trends in the occurrence of ischaemic heart disease over time in rheumatoid arthritis: 1821 patients from 1972 to 2017.

OBJECTIVE: To evaluate trends of acute myocardial infarction (AMI) and ischaemic heart disease (IHD) in rheumatoid arthritis (RA) patients compared with the general population over time. METHOD: We performed a retrospective cohort study of 1821 RA patients diagnosed from 1972 to 2013. Aggregated counts of the total population of the same county (Hordaland, Norway) and period were used for comparison. Information on AMI and IHD events was obtained from hospital patient administrative systems or cardiovascular registries. We estimated incidence rates and excess of events [standardized event ratio (SER) with 95% confidence interval (CI)] compared with the general population by Poisson regression. RESULTS: There was an average annual decline of 1.6% in age- and gender-adjusted AMI incidence rates from 1972 to 2017 (p < 0.035). The difference in events (excess events) in RA patients compared with the general population declined on average by 1.3% per year for AMI and by 2.3% for IHD from 1972 to 2014. There were no significant excess AMI (SER 1.05, 95% CI 0.82-1.35) or IHD events (SER 1.02, 95% CI 0.89-1.16) for RA patients diagnosed after 1998 compared with the general population. CONCLUSION: Incidence rates and excess events of AMI and IHD in RA patients declined from 1972 to 2017. There were no excess AMI or IHD events in RA patients diagnosed after 1998 compared with the general population.

Survival and death causes of patients with giant cell arteritis in Western Norway 1972-2012: a retrospective cohort study.

BACKGROUND: Our objective was to determine the survival and causes of death in a large and well-characterized cohort of patients with giant cell arteritis (GCA). METHODS: This is a hospital-based, retrospective, observational cohort study including patients diagnosed with GCA in Western Norway during 1972-2012. Patients were identified through computerized hospital records using the International Classification of Diseases (ICD)-coding system. Medical records were reviewed. Patients were randomly assigned population controls matched on age, sex, and geography from the Central Population Registry of Norway (CPRN). Date and cause of death were obtained from the Norwegian Cause of Death Registry (NCoDR). The survival was analyzed using Kaplan-Meier methods with the Gehan-Breslow test and the causes of death using cumulative incidence and Cox models for competing risks. RESULTS: We identified 881 cases with a clinical diagnosis of GCA of which 792 fulfilled the American College of Rheumatology (ACR) 1990 classification criteria. Among those fulfilling the ACR criteria, 528 were also biopsy-verified. Cases were matched with 2577 population controls. A total of 490 (56%) GCA patients and 1517 (59%) controls died during the study period. We found no difference in the overall survival of GCA patients compared to controls, p = 0.413. The most frequent underlying causes of death in both groups were diseases of the circulatory system followed by cancer. GCA patients had increased risk of dying of circulatory disease (HR 1.31, 95% CI 1.13-1.51, p < 0.001) but lower risk of dying of cancer (HR 0.56, 95% CI 0.42-0.73, p < 0.001) compared to population controls. CONCLUSIONS: We found no difference in the overall survival of GCA patients compared to matched controls, but there were differences in the distribution of underlying death causes.

Correction to: Incidence of giant cell arteritis in Western Norway 1972-2012: a retrospective cohort study.

Following publication of the original article [1], the authors reported an error.

Incidence of giant cell arteritis in Western Norway 1972-2012: a retrospective cohort study.

BACKGROUND: Giant cell arteritis (GCA) is the most common systemic vasculitis in persons older than 50 years. The highest incidence rates of the disease have been reported in Scandinavian countries. Our objective was to determine the epidemiology of GCA in an expected high-incidence region during a 41-year period. METHODS: This is a hospital-based, retrospective, cohort study. Patients diagnosed with GCA in Bergen health area during 1972-2012 were identified through computerized hospital records (n = 1341). Clinical information was extracted from patients' medical journals, which were reviewed by a standardized method. We excluded patients if data were unavailable (n = 253), if the reviewing rheumatologist found GCA to be an implausible diagnosis (n = 207) or if the American College of Rheumatology (ACR) 1990 classification criteria for GCA were not fulfilled (n = 89). Descriptive methods were used to characterize the sample. Incidence was analyzed by graphical methods and Poisson regression. RESULTS: A total of 792 patients were included. The average annual cumulative incidence of GCA was 16.7 (95% CI 15.5-18.0) per 100,000 of the population ≥ 50 years old. The corresponding incidence for biopsy-verified GCA was 11.2 (95% CI 10.2-12.3). The annual cumulative incidence increased with time in the period 1972-1992 (relative risk (RR) 1.1, p < 0.001) but not in 1993-2012 (RR 1.0, p = 0.543). The incidence was higher in women compared to men (average annual incidence 37.7 (95% CI 35.8-39.6) vs. 14.3 (95% CI 13.2-15.5), p < 0.001) with women having a twofold to threefold higher incidence rate throughout the study period. Average annual incidence increased with age until the 7th decade of life in both sexes throughout the study period (2.8 (95% CI 2.3-3.3) for age <60, 15.5 (95% CI 14.4-16.8) for age 60-69, 34.5 (95% CI 32.8-36.4) for age 70-79 and 26.8 (95% CI 25.3-28.4) for age ≥80 years, p < 0.001 for all age adjustments). CONCLUSIONS: Our study confirms an incidence of GCA comparable to previous reports on Scandinavian populations. Our results show increasing incidence from 1972 through 1992, after which the incidence has levelled out.

Assays for Infliximab Drug Levels and Antibodies: A Matter of Scales and Categories.

Immunogenicity is a frequent cause of secondary non-response to tumour necrosis factor (TNF) inhibitors. Drug level measurement and detection of antidrug antibodies have been shown to be cost effective and clinically relevant, and a large number of assays are available for these purposes. It is, however, difficult to compare assays and translate results into clinical meaningful information due to different methodological approaches and a lack of assay standardization. We have analysed infliximab drug levels and antidrug antibodies in 107 patient samples using enzyme-linked immunoassays (ELISA), immunofluorometric assays (IFMA) and reporter-gene assays (RGA). The RGA gave the lowest results for drug levels, whereas the IFMA detected the highest number of antidrug antibody positive sera. Applying individualized therapeutic ranges to each assay resulted in agreement among all three assays in 74% of samples for drug levels and 98% of samples for antidrug antibodies. We found that TNF inhibitor monitoring assays measure on different scales and that the agreement between quantitative results is limited. However, interassay differences can partially be overcome by assay-individualized translations of quantities into categories, which also is necessary for a meaningful clinical application. Our data demonstrate that assays should not be used interchangeably and that direct comparison of quantitative drug levels obtained with different assays should be avoided.

Identifying Low Muscle Mass in Patients with Hip Fracture: Validation of Biolectrical Impedance Analysis and Anthropometry Compared to Dual Energy X-ray Absorptiometry.

BACKGROUND: Older hip fracture patients often have reduced muscle mass, which is associated with adverse outcomes. Dual energy X-ray absorptiometry (DXA) can determine muscle mass, but is not practical in the acute phase. We investigated bioelectrical impedance analysis (BIA) and anthropometry compared against DXA for detecting low muscle mass in hip fracture patients. METHODS: This was a cross-sectional validation study at two Norwegian hospitals on 162 hip fracture patients aged ≥ 65 years. Appendicular lean mass (ALM) was determined by DXA, BIA and anthropometry 3 months after hip fracture. ALM by BIA was calculated by the Kyle, Janssen, Tengvall and Sergi equations, and ALM by anthropometry by the Heymsfield and Villani equations. The area under the receiver operating characteristic curve (AUC) was used to compare BIA and anthropometry for determining low ALM (≤5.67 kg/m2 for women and ≤7.25kg/m2 for men). RESULTS: Mean age was 79 years (SD 7.9), 74% were female. Mean ALM by DXA was 14.8 kg (SD 2.3) for women and 20.8 kg (SD 4.2) for men and 45% of women and 60% of men had low ALM. BIA (Kyle) in women (AUC 0.81, 95% confidence interval 0.72-0.89) and BIA (Sergi) in men (AUC 0.89, 95% CI 0.80-0.98) were best able to discriminate between low and normal ALM. Anthropometry (Heymsfield) was less accurate than BIA in women (AUC 0.64, 95% CI 0.54-0.75), and equal to BIA in men (AUC 0.72, 95% CI 0.72 0.56-0.87). CONCLUSION: BIA (Sergi, Kyle and Tengvall) and anthropometry (Heymsfield) can identify low muscle mass in hip fracture patients.

Continued decline in hip fracture incidence in Norway: a NOREPOS study.

UNLABELLED: The previously reported decline in age-adjusted hip fracture rates in Norway during 1999-2008 continued after 2008. The annual number of hip fractures decreased in women and increased in men. INTRODUCTION: Norway has among the highest hip fracture incidence rates ever reported despite previously observed declining rates from 1999 through 2008. The aim of the present study was to investigate whether this downward trend continued through 2013, and to compare gender-specific trends in 5 year age-groups during three time periods: 1999-2003, 2004-2008, and 2009-2013. METHODS: All hip fractures (cervical, trochanteric, and sub-trochanteric) admitted to Norwegian hospitals were retrieved. Annual age-standardized incidence rates of hip fracture per 10,000 person-years by gender were calculated for the period 1999-2013. Time trends were tested by age-adjusted Poisson regression. RESULTS: From 1999 through 2013 there were 140,136 hip fractures in persons aged 50 years and above. Age-adjusted hip fracture incidence rates declined by 20.4 % (95 % CI: 18.6-20.1) in women and 10.8 % (95 % CI: 7.8-13.8) in men, corresponding to an average annual age-adjusted decline of 1.5 % in women and 0.8 % in men. Except for the oldest men, hip fracture rates declined in all age-groups 70 years and older. The average annual number of fractures decreased in women (-0.3 %) and increased in men (+1.1 %). CONCLUSIONS: During the past 15 years, hip fracture rates have declined in Norway. The forecasted growing number of older individuals might, however, cause an increase in the absolute number of fractures, with a substantial societal economic and public health burden.

Plasma dimethylglycine, nicotine exposure and risk of low bone mineral density and hip fracture: the Hordaland Health Study.

UNLABELLED: In the large community-based Hordaland Health Study, low plasma dimethylglycine was associated with low bone mineral density in both middle-aged and elderly subjects and to an increased risk of subsequent hip fracture among the elderly. These associations seemed to be particularly strong among subjects exposed to nicotine. INTRODUCTION: Dimethylglycine (DMG) is a product of the choline oxidation pathway and formed from betaine during the folate-independent remethylation of homocysteine (Hcy) to methionine. Elevated plasma DMG levels are associated with atherosclerotic cardiovascular disease and inflammation, which in turn are related to osteoporosis. High plasma total Hcy and low plasma choline are associated with low bone mineral density (BMD) and hip fractures, but the role of plasma DMG in bone health is unknown. METHODS: We studied the associations of plasma DMG with BMD among 5315 participants (46-49 and 71-74 years old) and with hip fracture among 3310 participants (71-74 years old) enrolled in the Hordaland Health Study. RESULTS: In age and sex-adjusted logistic regression models, subjects in the lowest versus highest DMG tertile were more likely to have low BMD (odds ratio [OR] 1.68, 95% confidence interval [CI] 1.43-1.99). The association was stronger in participants exposed compared to those unexposed to nicotine (OR 2.31, 95% CI 1.73-3.07 and OR 1.43, 95% CI 1.16-1.75, respectively, p interaction = 0.008). In the older cohort, Cox regression analyses adjusted for sex showed that low plasma DMG was associated with an increased risk of hip fracture (hazard ratio [HR] 1.70, 95% CI 1.28-2.26). A trend toward an even higher risk was found among women exposed to nicotine (HR 3.41, 95% CI 1.40-8.28). CONCLUSION: Low plasma DMG was associated with low BMD and increased risk of hip fractures. A potential effect modification by nicotine exposure merits particular attention.

Low serum concentrations of alpha-tocopherol are associated with increased risk of hip fracture. A NOREPOS study.

UNLABELLED: We investigated the risk of hip fracture according to circulating alpha-tocopherol, a plant-derived substance with antioxidant properties, in community-dwelling older Norwegians. We found a linear increasing risk of hip fracture with lower serum alpha-tocopherol concentrations, with a 51% higher risk in the lowest compared to the highest quartile. INTRODUCTION: Oxidative stress is a suggested contributing cause of osteoporosis and fractures. Vitamin E (α-tocopherol) has potent antioxidant properties in humans. The relationship between circulating α-tocopherol and fracture risk is not established. The aim of this study was to investigate the association between serum α-tocopherol concentrations and risk of hip fracture during up to 11 years of follow-up. METHODS: We performed a case-cohort analysis among 21,774 men and women aged 65-79 years who participated in four community-based health studies in Norway 1994-2001. Serum α-tocopherol concentrations at baseline were determined in 1,168 men and women who subsequently suffered hip fractures (median follow-up 8.2 years) and in a random sample (n = 1,434) from the same cohort. Cox proportional hazard regression adapted for gender-stratified case-cohort data was performed. RESULTS: Median (25, 75 percentile) serum α-tocopherol was 30.0 (22.6, 38.3) µmol/L, and it showed a linear inverse association with hip fracture: hazard ratio (HR) 1.11 (95% confidence interval (CI) 1.04-1.20) per 10-µmol/L decrease in serum α-tocopherol, adjusted for gender and study center. The lowest compared to the highest quartile conferred an HR of 1.51 (95% CI 1.17-1.95), adjusted for gender and study center. Adjustment for smoking, month of blood sample, BMI, education, physical inactivity, self-rated health, and serum 25-hydroxyvitamin D (25(OH)D) yielded similar results. Taking serum total cholesterol concentration into account attenuated the association somewhat: HR of hip fracture was 1.37 (95% CI 1.05-1.77) in first versus fourth quartile of serum α-tocopherol/total cholesterol ratio. CONCLUSIONS: Low serum concentrations of α-tocopherol were associated with increased risk of hip fracture in older Norwegians.

Interferon gamma (IFN-γ)-mediated inflammation and the kynurenine pathway in relation to risk of hip fractures: the Hordaland Health Study.

UNLABELLED: The cytokine interferon gamma (IFN-γ) stimulates neopterin release and tryptophan degradation into kynurenines through the kynurenine pathway. High levels of neopterin were associated with increased hip fracture risk, as were some of the kynurenines, suggesting a role of IFN-γ-mediated inflammation in the processes leading to hip fracture. INTRODUCTION: Low-grade systemic inflammation has been associated with bone loss and risk of fractures. Interferon gamma (IFN-γ) initiates macrophage release of neopterin and also stimulates degradation of tryptophan along the kynurenine pathway as part of cell-mediated immune activation. Plasma neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Risk of hip fracture was investigated in relation to markers of inflammation and metabolites in the kynurenine pathway (kynurenines). METHODS: Participants (71 to 74 years, N = 3,311) in the community-based Hordaland Health Study (HUSK) were followed for hip fractures from enrolment (1998-2000) until 31 December 2009. Plasma C-reactive protein (CRP), neopterin, KTR, and six kynurenines were investigated as predictors of hip fracture, using Cox proportional hazards regression analyses. RESULTS: A hazard ratio (HR) of 1.9 (95% confidence interval (CI) 1.3-2.7) for hip fracture was found in the highest compared to the lowest quartile of neopterin (p trend across quartiles <0.001). CRP and KTR were not related to hip fracture risk. Among the kynurenines, a higher risk of fracture was found in the highest compared to the lowest quartiles of anthranilic acid and 3-hydroxykynurenine. For subjects in the highest quartiles of neopterin, CRP, and KTR compared to those in no top quartiles, HR was 2.5 (95% CI 1.6-4.0). CONCLUSIONS: This may indicate a role for low-grade immune activation in the pathogenic processes leading to hip fracture.

Interferon (IFN)-γ-mediated inflammation and the kynurenine pathway in relation to bone mineral density: the Hordaland Health Study.

The risk of osteoporosis increases in inflammatory disorders. In cell-mediated immune activation, interferon (IFN)-γ stimulates macrophage release of neopterin and increases the activity of indoleamine 2,3-dioxygenase (IDO), thereby stimulating tryptophan degradation along the kynurenine pathway. Plasma levels of neopterin and the kynurenine/tryptophan ratio (KTR) are thus markers of IFN-γ-mediated inflammation. Several kynurenine pathway metabolites (kynurenines) possess immunomodulatory properties. The aim of this study was to investigate associations between markers of IFN-γ-mediated inflammation and kynurenines with bone mineral density (BMD). The community-based Hordaland Health Study (HUSK), with middle-aged (46-49 years) and older (71-74 years) participants, was conducted from 1998 to 2000 (n = 5312). Hip BMD in relation to neopterin, KTR and kynurenines were investigated, using linear and logistic regression analyses. In the oldest group, neopterin (P ≤ 0·019) and KTR (P ≤ 0·001) were associated inversely with BMD after multiple adjustment. Comparing the highest to the lowest quartiles, the odds ratios of low BMD (being in the lowest quintile of BMD) in the oldest cohort were for neopterin 2·01 among men and 2·34 among women (P ≤ 0·007) and for KTR 1·80 for men and 2·04 for women (P ≤ 0·022). Xanthurenic acid was associated positively with BMD in all sex and age groups while 3-hydroxyanthranilic acid was associated positively with BMD among women only (P ≤ 0·010). In conclusion, we found an inverse association between BMD and markers of IFN-γ-mediated inflammation in the oldest participants. BMD was also associated with two kynurenines in both age groups. These results may support a role of cell-mediated inflammation in bone metabolism.

Vitamin K2 supplementation does not influence bone loss in early menopausal women: a randomised double-blind placebo-controlled trial.

UNLABELLED: Vitamin K2 may preserve bone strength and reduce fracture risk. In this randomised double-blind placebo-controlled trial among healthy postmenopausal Norwegian women, 1 year supplementation of vitamin K2 in the form of Natto capsules had no effect on bone loss rates. INTRODUCTION: Japanese studies indicate that vitamin K2 (menaquinone-7 (MK-7)) intake may preserve bone strength, but this has not been documented in Europeans. The aim of this study was to assess the effect of MK-7 on bone mineral density (BMD) changes in postmenopausal Norwegian women. METHODS: Three hundred thirty-four healthy women between 50 and 60 years, 1-5 years after menopause, were recruited to a randomised double-blind placebo-controlled trial. The participants were randomly assigned into two groups, one receiving 360 microg MK-7 in the form of Natto capsules and the other the same amount of identical-looking placebo capsules containing olive oil. BMD was measured at total hip, femoral neck, lumbar spine and total body at baseline and 12 months together with serum levels of bone-specific alkaline phosphatase, Crosslaps, total osteocalcin (N-mid OC), carboxylated (cOC) and under-carboxylated osteocalcin (ucOC). RESULTS: After 12 months, there were no statistical differences in bone loss rates between the groups at the total hip or any other measurement site. Serum levels of cOC increased and ucOC decreased in the treatment versus the placebo group (p < 0.001). CONCLUSION: MK-7 taken as Natto over 1 year reduced serum levels of ucOC but did not influence bone loss rates in early menopausal women.

Low-energy distal radius fractures in middle-aged and elderly men and women--the burden of osteoporosis and fracture risk : A study of 1794 consecutive patients.

UNLABELLED: One third of 218 men and half of 1,576 women with low-energy distal radius fractures met the bone mineral density (BMD) criteria for osteoporosis treatment. A large proportion of patients with increased fracture risk did not have osteoporosis. Thus, all distal radius fracture patients >or=50 years should be referred to bone densitometry. INTRODUCTION: Main objectives were to determine the prevalence of patients with a low-energy distal radius fracture in need of osteoporosis treatment according to existing guidelines using T-score or=50 years were included. BMD was assessed by dual energy X-ray absorptiometry (DXA) at femoral neck, total hip, and lumbar spine (L2-L4). The WHO fracture risk assessment tool (FRAX(R)) was applied to calculate the 10-year fracture risk. RESULTS: T-scores or=50 years should be referred to bone densitometry, and if indicated, offered medical treatment.

Weight loss and distal forearm fractures in postmenopausal women: the Nord-Trøndelag health study, Norway.

SUMMARY: Weight loss is a risk factor for hip fractures, but few studies have evaluated the effect of weight loss on distal forearm fracture risk. In this longitudinal study including 7,871 postmenopausal women, weight loss of 5% or more was associated with an increased risk of distal forearm fractures. INTRODUCTION: Weight loss is an established risk factor for hip fractures, but little is known about weight loss and distal forearm fractures risk. METHODS: The study included 7,871 women aged 65 years or more in the Nord-Trøndelag health study (HUNT) in 1994-1995 (HUNT II) who also had their height and weight measured in 1984-1986 (HUNT I). Forearm bone mineral density (BMD) by single energy x-ray absorptiometry was available for 5,688 women (HUNT II). Fractures sustained after HUNT II were registered during an average of 5.8 years. RESULTS: A total of 536 women sustained a distal forearm fracture. After adjustments for age and body mass index (BMI) at HUNT I, women who lost > or =5% of their weight between HUNT I and HUNT II had a relative risk of fractures of 1.33 (95% confidence interval: 1.09, 1.62) compared with the rest of the women. The higher risk of forearm fracture among women with weight loss was at least partially explained by their lower forearm BMD. CONCLUSION: Weight loss of 5% or more was associated with a 33% increased risk of distal forearm fractures.

Regional differences in hip bone mineral density levels in Norway: the NOREPOS study.

SUMMARY: Large regional differences in hip fracture rates within Norway have previously been shown. However, regional differences in hip bone mineral density (BMD) have not yet been assessed. In this study including 10,504 hip scans, there were significant regional differences in BMD. Further studies to address reasons for the regional differences in hip fracture risk are warranted. INTRODUCTION: Bone mineral density (BMD) at the hip is an important determinant of hip fracture. While regional differences in Norwegian hip fracture rates have previously been shown, no comparative studies of hip BMD have been conducted. METHODS: Total hip BMD was measured by DXA in two population-based studies across Norway during 1997-2002. Valid hip scans with in vivo calibration were obtained from 5127 subjects in Tromsø (age 30-89 years) and 5377 subjects in Bergen (age 47-50 and 71-75 years). RESULTS: Women >or=60 years in Tromsø had 0.052 g/cm(2) higher age-adjusted BMD than women in Bergen, whereas BMD among women <60 years was similar in Tromsø and Bergen. Age-adjusted total hip BMD was 0.035 g/cm(2) lower in men >or=60 years in Bergen compared with Tromsø, and the corresponding figure for men <60 years was 0.028 g/cm(2). While adjustment for body mass index explained some, but not all of the differences, smoking, physical activity, diabetes prevalence, self-perceived health, intake of alcohol and estrogen use did not. CONCLUSIONS: Regional differences in BMD at the hip were found in Norway. Reasons for this and potential impact on hip fracture rates should be explored in further studies.