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Publisher's version (útgefin grein)., Bone area is one measure of bone size that is easily derived from dual-energy X-ray absorptiometry (DXA) scans. In a GWA study of DXA bone area of the hip and lumbar spine (N ≥ 28,954), we find thirteen independent association signals at twelve loci that replicate in samples of European and East Asian descent (N = 13,608 – 21,277). Eight DXA area loci associate with osteoarthritis, including rs143384 in GDF5 and a missense variant in COL11A1 (rs3753841). The strongest DXA area association is with rs11614913[T] in the microRNA MIR196A2 gene that associates with lumbar spine area (P = 2.3 × 10−42, β = −0.090) and confers risk of hip fracture (P = 1.0 × 10−8, OR = 1.11). We demonstrate that the risk allele is less efficient in repressing miR-196a-5p target genes. We also show that the DXA area measure contributes to the risk of hip fracture independent of bone density., We thank all the study subjects for their valuable participation, the staff from all studies and the participating physicians. A part of this research has been conducted using the UK Biobank Resource under Application Number 23359. arcOGEN (http://www.arcogen.org.uk/) was funded by a special purpose grant from Arthritis Research UK (grant 18030).

Publisher's version (útgefin grein), Osteoarthritis is an increasingly important health problem for which the main treatment remains joint replacement. Therapy developments have been hampered by a lack of biomarkers that can reliably predict disease, while 2D radiographs interpreted by human observers are still the gold standard for clinical trial imaging assessment. We propose a 3D approach using computed tomography—a fast, readily available clinical technique—that can be applied in the assessment of osteoarthritis using a new quantitative 3D analysis technique called joint space mapping (JSM). We demonstrate the application of JSM at the hip in 263 healthy older adults from the AGES-Reykjavík cohort, examining relationships between 3D joint space width, 3D joint shape, and future joint replacement. Using JSM, statistical shape modelling, and statistical parametric mapping, we show an 18% improvement in prediction of joint replacement using 3D metrics combined with radiographic Kellgren & Lawrence grade (AUC 0.86) over the existing 2D FDA-approved gold standard of minimum 2D joint space width (AUC 0.73). We also show that assessment of joint asymmetry can reveal significant differences between individuals destined for joint replacement versus controls at regions of the joint that are not captured by radiographs. This technique is immediately implementable with standard imaging technologies., K.P. acknowledges the support of Cambridge NIHR Biomedical Research Centre. T.T. thanks the Wellcome Trust for funding support (100676/Z/12/Z) for part of this work. All authors acknowledge funding support grants from the National Institute on Aging (NO1-AG-1-2100), Bethesda, USA, and the Icelandic Government. All authors thank Dr Ilya Burkov, formerly PhD student at the University of Cambridge, for his work on segmentation of the proximal femur from CT data, Professor Lee Shepstone, University of East Anglia, for guidance with generalised estimating equation analysis, and Professor Karl Friston, University College London, for guidance with statistical parametric mapping analysis.

Objective: To explore differences in response to a low dosage regimen of infliximab with an escalating dosage in comparison to a standard dosage of etanercept and adalimumab in patients with psoriatic arthritis (PsA). Methods: Biologically naïve PsA patients who were beginning anti-TNF-α therapy were selected from the ICEBIO registry. Demographics and clinical differences were compared in four treatment groups: infliximab 4 mg/kg; etanercept or adalimumab at baseline and on follow-up (6 and 12 months, last visit). The Kruskal–Wallis rank sum test was used for comparison of the groups and the Wilcoxon test to compare the two infliximab dosage regimens. Results: One hundred and eighty-five patients (61% female) were identified; 84 patients received infliximab, 66 etanercept, and 35 adalimumab. A total of 19% of the patients treated with infliximab escalated their dosage ≥4 mg/kg. No significant differences were observed at baseline in respect to visual analog scale (VAS) pain, VAS fatigue, Health Assessment Questionnaire, C-reactive protein (CRP), numbers of swollen or tender joints, or Disease Activity Score (DAS) 28-CRP values. A similar treatment response was observed in all four treatment groups on follow-up. Conclusion: In respect to treatment effects, a low dosage of infliximab with possible escalating dosage is acceptable for the majority of PsA patients who are in need of biological treatment., The study was partly funded by a study grant from The Icelandic Society for Rheumatology.

Background: Hand photography has been used in a number of studies to determine the presence and severity of hand osteoarthritis (HOA). The aim of this study was to present age and gender specific prevalences of HOA diagnosed by this method. Methods: Six thousand three hundred forty three photographs (from 3676 females and 2667 males aged 40–96) were scored for hand osteoarthritis by a 0–3 grade (0 = no evidence of OA, 1 = possible OA, 2 = definite OA and 3 = severe OA) for each of the three main sites, distal interphalangeal joints (DIP), proximal interphalangeal joints (PIP) and thumb base (CMC1). An aggregate score of 0–9 was thus obtained (HOASCORE) to reflect the severity of HOA in each case. Results: DIP joints were most commonly affected, followed by the thumb base and the PIP joints. Having definite DIP joint OA starts at a younger age compared with the other two sites, and there is a marked female preponderance in the age groups from 55 to 69, but after 70 the gender differences are less marked and the prevalence is fairly stable. PIP joint prevalence also indicates a female preponderance from 60 to 79. Thumb base OA has a more marked female preponderance and a rising prevalence thoughout life. The prevalence of individuals with no evidence of photographic OA (HOASCORE = 0) drops from 88% to 57% between the age categories 40–49 and 50–54 and decreased to 33% in the 70–74 age group with a slower decline after that age. DIP and PIP prevalence were strongly associated with each other with an OR of 16.6(12.8–21.5),p < 0.001 of having definite OA at the other site. This was less marked for the thumb base with an OR of 2.2(1.8–2.7, p < 0.001), and 2.7(2.0–3.5, p < 0.001) of having definite DIP or PIP HOA respectively. Conclusions: The prevalence of hand OA in DIP, PIP and thumb base joints obtained by the photographic HOASCORE method is higher in women and increases after the age of fifty. These results are in line with those obtained by clinical examination and radiography. The advantage of the method lies in easy applicability and low cost.

Putblisher's version (útgefin grein)., Background: To determine the longitudinal construct validity of assessing hand OA progression on digital photographs over 7 years compared with progression determined from radiographs, clinical features and change in symptoms. Methods: Participants were community-dwelling older adults (≥50 years) in North Staffordshire, UK. Standardized digital hand photographs were taken at baseline and 7 years, and hand joints graded for OA severity using an established photographic atlas. Radiographic hand OA was assessed using the Kellgren and Lawrence grading system. Hand examination determined the presence of nodes, bony enlargement and deformity. Symptoms were reported in self-complete questionnaires. Radiographic and clinical progression and change in symptoms were compared to photographic progression. Differences were examined using analysis of covariance and Chi-Square tests. Results: Of 253 individuals (61% women, mean age 63 years) the proportion with photographic progression at the joint and joint group-level was higher in individuals with radiographic or clinical progression compared to those without, although differences were not statistically significant. At the person-level, those with moderate photographic progression over 7 years had significantly higher summed radiographic and clinical scores (adjusted for baseline scores) compared to those with no or mild photographic progression. Similar findings were observed for change in symptoms, although differences were small and not statistically significant. Conclusion: Assessing hand OA on photographs shows modest longitudinal construct validity over 7 years compared with change in radiographic and clinical hand OA at the person-level. Using photographs to assess overall long-term change in a person with hand OA may be a reasonable alternative when hand examinations and radiographs are not feasible., This work was supported by Programme Grants awarded by the Medical Research Council, UK (Grant Code: G9900220) and Arthritis Research UK (Grant Code: 18174) and NHS service support costs were provided by Support for Sciences funding secured from North Staffordshire Primary Care Consortium. The funders had no role in the study design, data collection, analysis, interpretation, in the writing of the paper or in the decision to submit the paper for publication.

The purpose of this study was to examine the infuence of trunk lean and contralateral hip abductor strength on the peak knee adduction moment (KAM) and rate of loading in persons with moderate medial knee osteoarthritis. Tirty-one males (17 with osteoarthritis, 14 controls) underwent 3-dimensional motion analysis, strength testing of hip abductors, and knee range of motion (ROM) measures, as well as completing the knee osteoarthritis outcome score (KOOS). No diferences were found between groups or limbs for gait cycle duration, but the osteoarthritis group had longer double-limb support during weight acceptance (p < 0.001) and delayed frontal plane trunk motion towards the stance limb (p < 0.01). Tis was refected by a lower rate of loading for the osteoarthritis group compared to controls (p < 0.001), whereas no diferences were found for peak KAM. Trunk angle, contralateral hip abductor strength, and BMI explained the rate of loading at the involved knee (p < 0.001), an association not found for the contralateral knee or control knees. Prolonged trunk lean over the stance limb may help lower peak KAM values. Rate of frontal plane knee joint loading may partly be mediated by the contralateral limb’s abductor strength, accentuating the importance of bilateral lower limb strength for persons with knee osteoarthritis., Financial support was received from the Icelandic Physiotherapy Association.

To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files. This article is open access. Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. We performed a two-stage meta-analysis on more than 78,000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. We accumulated 11,277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9×10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p=5.6×10(-8)) and follow-up studies (p=7.3×10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9×10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2×10(-6), OR=1.27 in male specific analysis). Novel genetic loci for hip OA were found in this meta-analysis of GWAS. info:eu-repo/grantAgreement/EC/FP7/200800 info:eu-repo/grantAgreement/EC/FP7/286213

Osteoarthritis has been intensively studied within the field of palaeopathology. For decades there was assumed to be a direct link between activity and the development of osteoarthritis, and this was reflected in the work which was carried out, with often very specific interpretations of occupation and activity on the basis of the diagnosis of osteoarthritis. By the 1990s it began to be more accepted within the field that the aetiology of osteoarthritis is far too multifactorial to allow for such simplistic conclusions to be drawn. This has resulted in a great reduction in the interest in the study of osteoarthritis within palaeopathology in the past few decades, as the condition appears to have somewhat lost its place within the archaeological discussion. Within the medical community, the focus has shifted in the past three decades to the genetic aetiopathogenesis of osteoarthritis. There has been a great deal of work in this field in Iceland, where the genetic link to hip, hand, and to a lesser extent knee osteoarthritis has been demonstrated, with the identification of several osteoarthritis families within the population. The main aim of this thesis is to reclaim the study of osteoarthritis within palaeopathology using the analysis of the condition within five Icelandic skeletal populations, kuml, Skeljastaðir, Hofstaðir, Haffjarðarey and Reykjavík, which span the occupation of Iceland, from the earliest settlement in the late 9th century to the 19th century. The approach to this is twofold. First of all, to avoid focusing on just one aetiological aspect of osteoarthritis, but rather to embrace its multifactorial nature, and consider multiple aetiological agents of the condition. These are in particular genetics, activity, anatomy, age and sex. The aim is then to place the results of the analysis within the social and physical environments of the populations under study, and so attempt to find osteoarthritis a place within the osteoarchaeological discussion again. Secondly, the aim is to consider a more theoretical approach to the study of palaeopathology in general, and osteoarthritis in particular. To this end the question is raised whether it is possible to consider disease in archaeology from factors external to the aetiology of the disease, but rather from the lived experience of those who suffer from it. Considering the degenerative effects of osteoarthritis, the focus is placed on how it is possible to discuss issues such as disability, ageing and quality of life within palaeopathological research. The conclusions drawn from this thesis demonstrates that by avoiding focusing on one feature of osteoarthritis but rather take into account its complex nature, it is possible to offer a varied discussion on osteoarthritis in archaeological material. The identification of a genetic osteoarthritis opens up a discussion on the family in archaeology and the use of the medieval cemetery in Iceland; the variation between sites in terms of activity related osteoarthritis demonstrates changes both geographically and through time in the intensity of the activities being carried out, while thinking about age in terms of osteoarthritis opens up new avenues for exploring age and ageing within archaeological populations., Háskólasjóður Eimskipafélags Íslands