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Introduction Scheduled routine visits in patients with rheumatoid arthritis (RA) may be in a stable period without active disease. Consequently, there is a demand for developing outpatient control procedures which cater to the needs of the individual patient. Objective This study aims to compare a patient-controlled outpatient follow-up system, Open Outpatient Clinic Programme (OOCP), with traditional scheduled routine follow-up (TSRF) regarding patient satisfaction and disease activity markers in RA patients. Method In a 2-year randomized controlled trial, RA patients were allocated to OOCP or TSRF. OOCP patients had no scheduled appointments but were allowed acute appointments with their rheumatologist and had access to nurse-led consultations and a telephone helpline. Appointments for the TSRF group were scheduled according to routine procedures (clinical parameters: DAS-28, C-reactive protein, VAS pain, tender and swollen joint count, HAQ-DI and radiographs; psychological parameters: VAS patient satisfaction and EQ-5D). Results Of 282 patients, 239 completed the study (OOCP/TSRF characteristics: age 61.4 ± 10.5/60.9 ± 12.2 years, females 77/74%, ACPA positive 66/65%). At years 1 and 2, OCCP had fewer visits (year 2: 2.6 ± 1.6 vs. 3.5 ± 2; p < 0.0005) but more phone calls (year 2: 0.7 ± 1.4 vs. 0.1 ± 0.3; p < 0.0005) compared to TSRF. OOCP was comparable to TSRF regarding clinical and psychological outcome measures, and no radiographic progression was observed. Conclusions OOCP was associated with significantly fewer visits but with more phone calls to the nurse and was comparable with TSGentofte University HospitalRF regarding clinical, psychological and radiographic outcomes. Thus, the organization of outpatient care according to OOCP may be applied to strengthen patient-centred care in patients with RA. ClinicalTrials.gov Identifier (July 20, 2020): NCT04476875Key points• In a patient-controlled outpatient follow-up system, RA patients had significantly fewer visits compared to traditional follow-up.• The patient-controlled follow-up system was comparable with traditional follow-up regarding clinical, psychological and radiographic outcomes.• Organization of outpatient care according to a patient-controlled follow-up system may be applied to strengthen patient-centred care in patients with RA. Supplementary Information The online version contains supplementary material available at 10.1007/s10067-021-05674-y.

OBJECTIVE To investigate whether magnetic resonance imaging (MRI) pathologies in the wrist/hand of rheumatoid arthritis (RA) patients are associated with patient-reported outcomes (PROs) at clinical remission and relapse. METHODS Wrist/hand MRIs and wrists/hands/feet radiographs were obtained in 114 established RA patients in clinical remission, before tapering their biologic disease-modifying antirheumatic drugs. MRIs were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI score (RAMRIS) for inflammation (synovitis/tenosynovitis/bone marrow edema) and damage (bone erosion/joint space narrowing) at baseline (ie remission) and in case of a relapse (n = 70). Radiographs were assessed according to the Sharp/van der Heijde (SvH) method at baseline. These scores were assessed for associations with health assessment questionnaires (HAQ), visual analog scales (VAS global/pain), EuroQol-5 dimensions and Short-Form 36 physical and mental component summary (SF-36 PCS/MCS) using Spearman correlations, univariate/multivariable linear regression analyses and generalized estimating equations. Furthermore, MRI pathologies were assessed for association with specific hand-related HAQ items using Jonckheere trend tests. RESULTS Magnetic resonance imaging-assessed damage was associated with impaired HAQ and SF-36 PCS at remission and relapse (P

ObjectiveTo identify predictors of flare in a 2-year follow-up study of patients with rheumatoid arthritis (RA) in sustained clinical remission tapering towards withdrawal of biological disease-modifying anti-rheumatic drugs (bDMARDs).MethodsSustained clinical remission was defined as Disease Activity Score for 28 joints (DAS28)-C reactive protein (CRP) ≤2.6 without radiographic progression for >1 year. bDMARDs were tapered according to a mandatory clinical guideline to two-thirds of standard dose at baseline, half of dose at week 16 and discontinuation at week 32. Prospective assessments for 2 years included clinical evaluation, conventional radiography, ultrasound and MRI for signs of inflammation and bone changes. Flare was defined as DAS28-CRP ≥2.6 with ∆DAS28-CRP ≥1.2 from baseline. Baseline predictors of flare were assessed by logistic regression analyses.ResultsOf 142 included patients, 121 (85%) flared during follow-up of which 86% regained remission within 24 weeks after flare. Patients that flared were more often rheumatoid factor positive, had tried more bDMARDs and had higher baseline ultrasound synovitis sum scores than those not flaring. For patients on standard dose, predictors of flare within 16 weeks after reduction to two-thirds of standard dose were baseline MRI-osteitis (OR 1.16; 95% CI 1.03 to 1.33; p=0.014), gender (female) (OR 6.71; 95% CI 1.68 to 46.12; p=0.005) and disease duration (OR 1.06; 95% CI 1.01 to 1.11; p=0.020). Baseline predictors for flare within 2 years were ultrasound grey scale synovitis sum score (OR 1.19; 95% CI 1.02 to 1.44; p=0.020) and number of previous bDMARDs (OR 4.07; 95% CI 1.35 to 24.72; p=0.007).ConclusionThe majority of real-world patients with RA tapering bDMARDs flared during tapering, with the majority regaining remission after stepwise dose increase. Demographic and imaging parameters (MR-osteitis/ultrasound greyscale synovitis) were independent predictors of immediate flare and flare overall and may be of importance for clinical decision-making in patients eligible for tapering.

Objectives In a 2-year follow-up study of patients with axial spondyloarthritis (axSpA) in clinical remission who tapered TNF inhibitor (TNFi) treatment according to a clinical guideline, we aimed to investigate the proportion who successfully tapered/discontinued therapy and baseline predictors thereof. The proportion regaining clinical remission after flare and the progression on MRI/radiography were also assessed. Methods One-hundred-and-nine patients (78 [72%]/31 [28%] receiving standard and reduced dose, respectively) in clinical remission (BASDAI < 40, physician global score < 40) and no signs of disease activity the previous year tapered TNFi as follows: to two-thirds of standard dose at baseline, half at week 16, one-third at week 32 and discontinuation at week 48. Patients experiencing clinical, BASDAI or MRI flare (predefined criteria) stopped tapering and escalated to previous dose. Prediction analyses were performed by multivariable regression. Results One hundred and six patients (97%) completed 2 years’ follow-up; 55 patients (52%) had successfully tapered: 23 (22%) receiving two-thirds, 15 (14%) half, 16 (15%) one-third dose and 1 (1%) discontinued. In patients at standard dose at baseline (n = 78), lower physician global score was the only independent predictor of successful tapering (odds ratio [OR] = 0.79 [95% CI: 0.64, 0.93]; P = 0.003). In the entire patient group lower physician global score (OR = 0.86 [0.75, 0.98]; P = 0.017), lower Spondyloarthritis Research Consortium of Canada (SPARCC) Sacroiliac Joint Erosion score (OR = 0.78 [0.57, 0.98]; P = 0.029) and current smoker (OR = 3.28 [1.15, 10.57]; P = 0.026) were independent predictors of successful tapering. At 2 years, 97% of patients were in clinical remission. Minimal changes in imaging findings were observed. Conclusion After 2 years following a clinical guideline, 52% of patients with axSpA in clinical remission had successfully tapered TNFi, only 1% discontinued. Baseline physician global score was an independent predictor of successful tapering.

Over the past decades, the disciplinary boundaries between Roman history and archaeology have begun to fade, as archaeological proxy data started playing an important role in studying socioeconomic processes and phenomena. This is especially true for several key debates such as those on Roman economic performance, diet and nutrition, and migration and mobility. More recently, archaeological sciences, such as stable isotope studies, have increasingly started contributing to these debates too. This paper is aimed at reviewing the valuable contributions stable isotope studies can make to these debates from the economic historian’s perspective and focuses on the interpretative side of such studies: what sort of economic meaning is attributed to certain results? It will be ascertained that there sometimes seems to be a divergence between the interpretations made by isotope experts and what many economic historians would conclude. The main cause for this lies in differences in the underlying assumptions as to the working and performance of ancient economies. We will provide examples where the same isotope results can be interpreted completely differently by switching between sets of underlying assumptions. We will argue that greater interaction between economic historians and stable isotope experts is desirable so as to avoid the emergence of parallel debates and to facilitate the construction of stronger, well-integrated narratives.

Over the past years, climate change has increasingly found its way into grand historical narratives, sometimes explaining the rise and fall of civilizations. In most narratives, regardless of their disposition towards the magnitude and extent of the societal impact of climate change, plants have received relatively little in-depth attention. This is problematic as there is often a strong oversimplification of the relationship between reconstructed climate changes and their extrapolated effects on agricultural output. In this chapter we therefore aim to provide an introduction into the complexities of climate change from the crop perspective for the historian and archaeologist. Our aim is to present a nuanced overview based on insights from current research in crop biology and agricultural science on crop responses to climate change, whilst taking into account the role of the farmer and the artificial biotope of the field, providing a framework upon which historical climate studies may draw.

Background Haemophilic arthropathy is a chronic and debilitating joint disease caused by recurrent spontaneous joint bleeds in patients with haemophilia. Understanding how characteristics of individual joint bleeds relate to the subsequent development of arthropathy could improve management and prevention of this joint disease. Here, we aimed to explore relations between joint bleed characteristics and development of bone pathology in a mouse model of haemophilic arthropathy by using novel in vivo imaging methodology. Methods We characterised induced knee bleeds in a murine model of haemophilic arthropathy by quantitative in vivo fluorescence molecular tomography (FMT) and by measurements of changes in the diameter of the injured knee. Wild-type mice and non-injured haemophilic mice acted as controls. Development of arthropathy was characterised by post mortem evaluation of bone pathology by micro-CT 14 days after bleed-induction. In an in vitro study, we assessed the effect of blood on the quantification of fluorescent signal with FMT. Results In most injured haemophilic mice, we observed significant loss of trabecular bone, and half of the mice developed pathological bone remodelling. Development of pathological bone remodelling was associated with significantly increased fluorescent signal and diameter of the injured knee just 1 day after induction of the bleed. Further, a correlation between the fluorescent signal 1 day after induction of the bleed and loss of trabecular bone reached borderline significance. In the in vitro study, we found that high concentrations of blood significantly decreased the fluorescent signal. Conclusion Our results add novel insights on the pathogenesis of haemophilic arthropathy and underline the importance of the acute phase of joint bleeds for the subsequent development of arthropathy.

OBJECTIVE: Several biomarkers for glucocorticoid (GC) sensitivity have been proposed relevant for the inter-individual variation seen in treatment response and side effects to GC treatment. Four single nucleotide polymorphisms (SNPs) of the GC receptor (GR) gene have been associated with increased (Bcl1 and N363S) or decreased (9β and ER23/23EK) GC sensitivity. We investigated the influence of these proposed biomarkers for GC sensitivity on GC-induced adrenal insufficiency. SUBJECTS AND METHODS: We included 239 patients receiving long-term prednisolone treatment for rheumatoid arthritis (RA), polymyalgia rheumatica (PMR) / giant cell arteritis (GCA), or after renal transplantation (RTx). Four GR gene SNPs (Bcl1 rs41423247; 9β rs6198; N363S rs56149945; ER22/23EK rs6189 + rs6190) were sequenced by Sanger sequencing. Adrenal function was evaluated by a 250 µg corticotropin stimulation test. To compare allele frequencies with background population, two control groups were generated from two regional whole-genome databases. We downscaled each genome dataset to 239 individuals/group to balance statistical analysis. RESULTS: In total 239 patients were genotyped and 178 of these (RA n=103, PMR/GCA n=47, RTx n=28) treated with a median current dose of 5 mg prednisolone/day (interquartile range 5-7 mg) and a median treatment duration of 48 months (interquartile range 22-111 months) completed the corticotropin test. Seventy-three (41%, CI95%: 34-48%) patients had an insufficient response to the corticotropin test. Neither the risk of adrenal insufficiency, unstimulated nor stimulated P-cortisol levels were directly associated with any of the GR SNPs. However, for both insensitive SNPs 9β and ER23/23EK the effect of current prednisolone dose on stimulated P-cortisol was smaller (higher dose did not suppress the cortisol level as much) in carriers vs. non-carriers (p=0.035 and p=0.0075). The same sensitivity-associated tendency was seen for the N363S, but not the Bcl1 SNP. The Bcl1 SNP occurred more frequently in our cohort compared with control groups (63% vs. 40%, p CONCLUSION: The GR SNPs did not directly associate to the risk of adrenal insufficiency, unstimulated nor stimulated cortisol levels, respectively. However, the effect of prednisolone dose on stimulated cortisol depended on the GR SNPs: Cortisol was less suppressed with higher current prednisolone dose in patients carrying the insensitive SNPs. The substantially higher frequency of the Bcl1 SNP is remarkable even with modest n=239. It questions whether there is an association between carrying the sensitive GR SNPs and inability to taper GC treatment ending up in this cohort of long-term treated patients.

IntroductionThe provision of healthcare for patients with inflammatory arthritis occurs in the context of somewhat conflicting targets, values and drivers. Therefore, there is a need for introducing ‘value-based healthcare’ defined as the value of patient relevant health outcomes in relation to costs. This term is a central part of tomorrow’s healthcare sector, especially for rheumatic diseases, yet the transition is a huge challenge, as it will impact the development, delivery and assessment of healthcare.AimsThe aim of this study is to compare medical and patient evaluated impact of the traditional settlement and financing production (DAGS) controlled healthcare setting with a value-based and patient-centred adjunctive to standard care.Methods and analysisPatients with inflammatory arthritis receiving treatment in routine care at the outpatient clinics in the Capital Region of Denmark will prospectively and consecutively be enrolled in a Non-Intervention-Study framework providing a pragmatic value-based management model. A Danish reference cohort, used for comparison will be collected as part of routine clinical care. The enrolment period will be from 1 June 2018 until 31December 2023. Baseline and follow-up visits will be according to routine clinical care. Registry data will be obtained directly from patients and include personal, clinical and outcomes information. The study results will be reported in accordance with the STROBE statement.Ethics and disseminationThe study has been notified to the Danish Data Protection Agency and granted authorisation for the period June 2018 to January 2025 (pending). Informed consent will be obtained from all patients before enrolment in the study. The study is approved by the ethics committee, Capital Region of Denmark (H-18013158). Results of the study will be disseminated through publication in international peer-reviewed journals.

Formålet med oppgaven vår er å se på områder i organisasjonen som ikke tilrettelegger for læring og endring. Basert på våre konklusjoner skal vi presentere et sett med anbefalinger for hvordan dette kan bedres. Vårt subjekt og samarbeidspartner i denne oppgaven er Seksjon Arkiv. Seksjonen er del av avdelingen for Økonomi og Digitalisering og er ansvarlig for alle arkiv i Trøndelag fylkeskommune. Arkivtjenesten er som mange andre fagfelt i stadig utvikling med tanke på digitalisering og robotisering. Derfor må seksjonen kunne videreutvikle kompetanse i takt med utviklingene som skjer i samfunnet. Regionreformen med sammenslåing av Nord- og Sør-Trøndelag trådte i kraft 01. januar 2018. Det resulterte i sammenslåing av arkivtjenesten i de to fylkene som hadde kontorer i Trondheim og på Steinkjer. Strukturen ble sist reorganisert 1.januar 2019, seksjonen har fortsatt kontorer på to lokasjoner og er inndelt i to team på tvers av lokasjonene. Med dette som utgangspunkt valgte vi følgende problemstilling: «Hvordan sikre fremtidig kompetanseutvikling i Seksjon Arkiv?» For å svare problemstillingen har vi gjennomført en kvalitativ case-studie av seksjonen. Vi har gjennomført åpne, individuelle intervju med til sammen 11 respondenter fra de to lokasjonene. Respondentene ble valgt ut med en stratifisert, tilfeldig metode. Undersøkelsen konkluderer med følgende: • Det brukes kommunikasjonsverktøy på en måte som gjør at kunnskapsdeling i seksjonen blir skadelidende. • Ledelsen legger stort sett opp til autonomi blant medarbeiderne. Imidlertid er det påvist mangel på involvering og informasjon ved beslutningstaking. • Det er også lite konstruktiv bruk av medarbeidersamtalene, og det er mangelfull kartlegging av medarbeidernes kompetanse. • Det er lite antydning til felles kultur i seksjonen i dag. Lokasjonene har i stor grad hver sin kultur. Etter å ha drøftet resultatene våre, har vi kommet med ulike tiltak Seksjon Arkiv kan gjennomføre. The purpose of this thesis is to shed light on elements that are not adapted for organizational learning and capacity to change. Based on our conclusions, we will present a set of recommendations to rectify this. Our subject and partner in this thesis is Seksjon Arkiv – the county’s archival section. Administered by the Department of Economy and Digitalization, this institution is responsible for managing all archives in Trøndelag county. Like with many other disciplines, archival services are continuously in development in terms of digitalization and automation. As such, Trøndelag’s archival section must have competency development in accordance with changes in society. The regional reform and unification of the northern and southern counties in Trøndelag came into effect on January 1, 2018, as did the merger of the archive sections in Trondheim and Steinkjer. Furthermore, the organizational structure was reorganized on January 1, 2019. As of today, the section has offices on both locations, each with members from both respective teams. Based on this, we have chosen the following problem for our thesis: “How do we secure future competency development in Seksjon Arkiv?” To answer this, we have conducted a qualitative case study of the section. We have conducted open, in-depth interviews with 11 respondents from the two respective locations. These were selected by means of stratified random sampling. Our research came to the following conclusions: • The use of social tools is in some respect inadequate and has a negative impact on knowledge exchange in the section. • The management emphasizes autonomy for the employees. However, there is a shortage of information and involvement of employees in terms of organizational changes. • There is little constructive use of performance appraisals, and there is inadequate mapping of the employees’ competence. • There is little indication of a shared corporate culture in the section as of today. Each location largely has its own culture. After discussing our results, we conclude our thesis with a set of recommendations for the section to implement.

Background:Medical treatment and care are often life-long in patients with rheumatoid arthritis (RA). During periods of stable disease, patients typically attend routine visits every 3–8 months at the rheumatology outpatient clinic. Between scheduled medical visits, it may be difficult to get acute appointments with the rheumatologist. Scheduled routine visits may be in a stable period without any symptoms and with no need for control and adjustment of treatment. Consequently, there is a demand for developing outpatient control procedures that cater to the needs of the individual patient and which support the patient‘s experience of active participation in the control and treatment of their own disease.Objectives:To compare a patient self-controlled outpatient follow up system (Open Outpatient Clinic System (OOCS)) with traditional scheduled routine visits at a rheumatology outpatient clinic.Methods:A two-year randomised controlled trial with RA patients aged 18 to 80 years with a disease duration of at least one year. Patients were recruited consecutively from the rheumatology outpatient clinic of a major university hospital in the Copenhagen region of Denmark from February 2015 to January 2017. Patients were randomised electronically. Joints were examined by a blinded rheumatologist. Patients in the OOCS group had no scheduled appointments but were allowed to book acute appointments with their contact rheumatologist within 5 days and had access to nurse-led consultations without pre-booking, and a nurse-led telephone helpline. Appointments for the control group were scheduled according to routine procedures. Outcome measures were collected at baseline, year 1 and year 2. Clinical parameters: DAS28, CRP, VAS pain, 28-tender and swollen joint count (28-TJC and 28-SJC), HAQ score and radiographs of hands and feet. Psychological parameters: VAS patient satisfaction (Pt satisfact) and quality of life (EQ-5D).Results:Of 282 patients, 266 completed the first year, 239 the second year. Patient characteristics (OOCS/controls): age 61.4±10.5/60.9±12.2 years, females 77/74%, ACPA positive 66/65%, treatment with synthetic DMARDs 67/65% and/or biologics 33/35%. Clinical and psychological parameters are shown in Table 1. OOCS at year one and two was comparable to traditional scheduled routine procedures regarding clinical and psychological outcome measures. Radiographic progression was detected in 2.9% (4/138) and 2.1% (3/140) of the OOCS and control group, respectively (p=0.69; Chi-squared test).Table 1.Outcome measures in patients with RA randomised to on demand Open Outpatient Clinic System (OOCS) or traditional follow-up (control group) in a rheumatology out-patient clinic. Results are shown as mean±SD.OOCSControlsOOCSControlsOOCSControlsTimeBaselineBaselineYear 1Year 1Year 2Year 2Visits3.2±1.93.8±1.6*2.6±1.63.5±2.2**Phone calls1.8±3.30.4±0.8**0.7±1.40.1±0.3**DAS283.0±1.22.9±1.02.6±1.12.6±1.02.7±1.22.5±1.0CRP10.2±7.210.1±8.08.2±9.95.7±5.1*9.6±8.85.5±8.9*28-SJC0.6±1.50.6±1.20.2±0.50.3±1.00.3±0.90.4±1.228-TJC3.3±5.72.4±4.22.4±4.72.1±3.72.4±4.92.3±4.7VAS pain27±2526±2128±2628±2432±2729±25HAQ-score0.6±0.60.6±0.60.7±0.60.6±0.60.8±0.70.6±0.7EQ-5D0.8±0.20.8±0.10.8±0.20.8±0.20.8±0.20.8±0.1Pt satisfact88±2187±1984±2582±2382±2483±23*pConclusion:The patient self-controlled outpatient follow up system OOCS was associated with fewer visits, but more phone calls to the nurse, and was comparable with traditional scheduled routine procedures regarding clinical, psychological and radiographic outcomes after two years. Thus, organisation of outpatient care according to OOCS may be applied to strengthen patient-centred care in patients with RA.Disclosure of Interests:René Panduro Poggenborg Speakers bureau: Novartis, Ole Rintek Madsen: None declared, Lene Dreyer: None declared, Annette Hansen Consultant of: AbbVie, Speakers bureau: Eli Lily

Background:Patients with rheumatic diseases, routinely consult the outpatient clinic 1-2 times a year to see their rheumatologist. Many of the patients also attend nurse-led consultations to receive instructions, regarding treatment in association to their intravenous treatment, or DMARD dispensing in the clinic. As clinicians we have an assumption of what the ”good practice” is in relation to the patients, but we have little insight, into the patients’ own experience and satisfaction.Objectives:To investigate the patients views on the level of information, and their experience and satisfaction with the doctor and nurse-led consultations in the outpatient clinic.Methods:The approach of the survey was both quantitative and qualitative. A questionnaire was designed with four questions on a matrix scale concerningtheir information level on their disease/symptoms;their treatment;if they had received written material and if so, it’s value; andtheir possibility to talk about subjects that matters for them during consultations. To gain a qualitative approach with focus on the patients’ experiences and comments, every question was constructed with space for comments. Comments were transcribed, indexed, analysed, and thematically divided. The inclusion of patients were all patients visiting the clinic within a specific week in January 2019.Results:The results from the four questions, are shown in the figures below, measured in percentage. In total, 283 participated (response rate 60%).Four themes covered from the analysis of patients’ comments.“Seeking own answers”, “Own coping – effort”, “Conversation with doctor/nurse”and“Treatment/medication”.Comments revealed many descriptions and stories of patients, showered with all types of suggestions of taking control or managing the disease by them self, from their family or media. It also revealed their interest in discussing, these subjects and matters with the doctor/nurse, without being rejected. The feeling of rejection resulted in some patients trying other treatments or introducing changes in their lifestyle, without involving the doctor. The patients also called for more knowledge about physical training, and not only medical treatment.Conclusion:In general, the patients had a very positive perception towards the consultations, and the information from the outpatient clinic. Despite that, the themes indicated a pattern, that needs to be considered, so clinicians acknowledge the patients wish for guidance, besides the medical treatment. To support the patient, without leaving them with a feeling of being rejected, we need to consider how to articulate the subjects the patients are exposed to outside our clinic, so the patients feel free to inform or involve the clinic instead of being silent, in risk of counteracting the medical treatment.Acknowledgments:We are grateful to the participants who shared their experiences. We also thank an internal research group taking part of the investigation.Disclosure of Interests:Ida Lund: None declared, Annette Hansen Consultant of: AbbVie, Speakers bureau: Eli Lily, Betina Stampe: None declared, René Cordtz: None declared, Lene Dreyer: None declared

Objectives A cohort of routine care RA patients in sustained remission had biological DMARD (bDMARDs) tapered according to a treatment guideline. We studied: the proportion of patients whose bDMARD could be successfully tapered or discontinued; unwanted consequences of tapering/discontinuation; and potential baseline predictors of successful tapering and discontinuation. Methods One-hundred-and-forty-three patients (91% receiving TNF inhibitor and 9% a non-TNF inhibitor) with sustained disease activity score (DAS28-CRP)⩽2.6 and no radiographic progression the previous year were included. bDMARD was reduced to two-thirds of standard dose at baseline, half after 16 weeks, and discontinued after 32 weeks. Patients who flared (defined as either DAS28-CRP ⩾ 2.6 and ΔDAS28-CRP ⩾ 1.2 from baseline, or erosive progression on X-ray and/or MRI) stopped tapering and were escalated to the previous dose level. Results One-hundred-and-forty-one patients completed 2-year follow-up. At 2 years, 87 patients (62%) had successfully tapered bDMARDs, with 26 (18%) receiving two-thirds of standard dose, 39 (28%) half dose and 22 (16%) having discontinued; and 54 patients (38%) were receiving full dose. ΔDAS28-CRP0-2yrs was 0.1((-0.2)-0.4) (median (interquartile range)) and mean ΔTotal-Sharp-Score0-2yrs was 0.01(1.15)(mean(s.d.)). Radiographic progression was observed in nine patients (7%). Successful tapering was independently predicted by: ⩽1 previous bDMARD, male gender, low baseline MRI combined inflammation score or combined damage score. Negative IgM-RF predicted successful discontinuation. Conclusion By implementing a clinical guideline, 62% of RA patients in sustained remission in routine care were successfully tapered, including 16% successfully discontinued at 2 years. Radiographic progression was rare. Maximum one bDMARDs, male gender, and low baseline MRI combined inflammation and combined damage scores were independent predictors for successful tapering.

Objective Patients receiving long-term glucocorticoid treatment are at risk of developing adrenal insufficiency during treatment. We investigated the prevalence of prednisolone-induced adrenal insufficiency in the particular clinical situation where patients receive ongoing low-dose (5 mg/day) prednisolone treatment, a dose by itself too low to cover glucocorticoid needs during stress. Design and methods Cross-sectional study in 42 patients with rheumatoid arthritis (29 women, aged 36–86 years) treated with 5 mg prednisolone/day, who had received prednisolone for ≥6 months (median: 66, range: 6–444 months). Adrenal function was evaluated by a 250 μg Synacthen test performed after mean 48.7 h prednisolone pause. Local assay-specific cut-off for normal adrenal function was P-cortisol ≥420 nmol/L 30 min after Synacthen injection. Results Overall, 20 of the 42 patients (48%, 95% CI: 33–62%) had an insufficient adrenal response to the Synacthen test. Including only patients who had not received concomitant treatment with any other glucocorticoid formulas within the last 3 months, 13 of 33 patients (39%, 95% CI: 25–56%) had an insufficient response. Adrenocorticotrophic hormone (ACTH) concentrations were generally low and anti-adrenal antibodies were negative indicating secondary adrenal insufficiency as the most likely diagnosis. There was no correlation between duration of treatment and 30 min P-cortisol (P = 0.62). Adrenal function did not depend on sex or seropositivity of rheumatoid arthritis. Conclusion We demonstrate a high prevalence of adrenal insufficiency during ongoing low-dose prednisolone treatment. The results urge to increase focus on the condition to ensure identification and correct management of insufficient patients during stress and withdrawal. Strategies for adrenal function evaluation during ongoing low-dose glucocorticoid treatment need to be established.

Aims: To compare nationwide time trends and mortality in hip and proximal humeral fractures; to explore associations between incidences of falls risk related comorbidities (FRICs) and incidence of fractures. Methods: The study is a retrospective cohort study using nationwide Danish administrative registries from 2000 through 2009. Individuals aged 65 years or older who experienced a hip or a proximal humeral fracture were included. Incidence of hip and of proximal humeral fractures, incidence of FRICs (ischemic heart disease, COPD, dementia, depression, diabetes, heart failure, osteoporosis, Parkinson’s disease and stroke) and incidence rate ratios (IRR) for fractures in patients with FRICs, and all-cause mortality up to 10 years after a hip or a proximal humeral fracture were analysed. Results: A total of 89,150 patients experienced hip fractures and 48,581 proximal humeral fractures. From 2000 through 2009, the incidence of hip fractures per 100,000 individuals declined by 198 (787 to 589, OR = 0.75, CI: 0.72–0.80) among males and by 483 (1758 to 1275, OR = 0.74, CI: 0.72–0.77) among females. Incidences of FRICs decreased. The absolute reduction in fractures was most pronounced for the age group above 75 years (2393 to 1884, OR = 0.81, CI: 0.78–0.83), but the relative reduction was more pronounced in the age group of 65–75 years old (496 to 342, OR = 0.70, CI: 0.66–0.74). IRRs for hip fractures and for proximal humeral fractures were significantly elevated in patients with FRICs. Conclusions: The results suggest that the overall reduction in fractures can be explained by reduction in falls related comorbidity.

OBJECTIVE: To examine the association between classes of antidepressants and hyponatremia, and between specific antidepressants and hyponatremia.DESIGN: Retrospective register-based cohort study using nationwide registers from 1998 to 2012.SETTING: The North Denmark Region.PARTICIPANTS: In total, 638 352 individuals were included.PRIMARY AND SECONDARY OUTCOME MEASURES: Plasma sodium was obtained from the LABKA database. The primary outcome was hyponatremia defined as plasma sodium (p-sodium) below 135 mmol/L and secondary outcome was severe hyponatremia defined as p-sodium below 130 mmol/L. The association between use of specific antidepressants and hyponatremia was analysed using multivariable Poisson regression models.RESULTS: An event of hyponatremia occurred in 72 509 individuals and 11.36% (n=6476) of these events happened during treatment with antidepressants. Incidence rate ratios and CIs for the association with hyponatremia in the first p-sodium measured after initiation of treatment were for citalopram 7.8 (CI 7.42 to 8.20); clomipramine 4.93 (CI 2.72 to 8.94); duloxetine 2.05 (CI 1.44 to 292); venlafaxine 2.90 (CI 2.43 to 3.46); mirtazapine 2.95 (CI 2.71 to 3.21); and mianserin 0.90 (CI 0.71 to 1.14).CONCLUSIONS: All antidepressants except mianserin are associated with hyponatremia. The association is strongest with citalopram and lowest with duloxetine, venlafaxine and mirtazapine.

Outside In Acquisition and analysis of large data sets promises to move us toward a greater understanding of the mechanisms by which biological systems are dynamically regulated to respond to external cues. Now, two papers explore the responses of a bacterium to changing nutritional conditions (see the Perspective by Chalancon et al. ). Nicolas et al. (p. 1103 ) measured transcriptional regulation for more than 100 different conditions. Greater amounts of antisense RNA were generated than expected and appeared to be produced by alternative RNA polymerase targeting subunits called sigma factors. One transition, from malate to glucose as the primary nutrient, was studied in more detail by Buescher et al. (p. 1099 ) who monitored RNA abundance, promoter activity in live cells, protein abundance, and absolute concentrations of intracellular and extracellular metabolites. In this case, the bacteria responded rapidly and largely without transcriptional changes to life on malate, but only slowly adapted to use glucose, a shift that required changes in nearly half the transcription network. These data offer an initial understanding of why certain regulatory strategies may be favored during evolution of dynamic control systems.

OBJECTIVE: To determine whether drugs used in treatment of cardiovascular diseases (CVD-drugs), including hypertension, increase the risk of fragility fractures in individuals above the age of 65 years.DESIGN: Retrospective nationwide cohort study.SETTING: Danish nationwide national registers.PARTICIPANTS: All individuals in Denmark ≥65 years who used specified CVD-drugs in the study period between 1999 and 2012.MAIN OUTCOMES MEASURES: Time-dependent exposure to CVD-drugs (nitrates, digoxin, thiazides, furosemide, ACE inhibitors, angiotensin receptor antagonists, β-blockers, calcium antagonists and statins) was determined by prescription claims from pharmacies. The association between use of specific CVD-drugs and fragility fractures was assessed using multivariable Poisson regression models, and adjusted incidence rate ratios (IRRs) were calculated.RESULTS: Overall, 1 586 554 persons were included, of these 16.1% experienced a fall-related fracture. The multivariable Poisson regression analysis showed positive associations between fracture and treatment with furosemide, thiazide and digoxin. IRRs during the first 14 days of treatment were for furosemide IRR 1.74 (95% CI 1.61 to 1.89) and for thiazides IRR 1.41 (1.28 to 1.55); IRR during the first 30 days of treatment with digoxin was 1.18 (1.02 to 1.37).CONCLUSIONS: Use of furosemide, thiazides and digoxin was associated with elevated rates of fragility fractures among elderly individuals. This may warrant consideration when considering diuretic treatment of hypertension in elderly individuals.

Objectives To describe drug survival, disease activity and clinical response in patients with rheumatoid arthritis (RA) treated with abatacept or tocilizumab in routine care, based on prospectively registered observational data from the nationwide Danish DANBIO registry. Methods 150 Patients with RA treated with abatacept and 178 treated with tocilizumab were identified. Drug survival was investigated. Response data were available in 104 and 97 patients, respectively. Changes in 28-joint Disease Activity Score (DAS28) based on C-reactive protein (CRP) and European League Against Rheumatism (EULAR) response after 24 and 48 weeks were investigated. No direct comparison of drugs was made. Results Median (IQR) disease duration was 8.5 (3–14)/9 (3–12) years (abatacept/tocilizumab). 95%/93% of patients had previously received one or more tumour necrosis factor inhibitor (TNFi). After 48 weeks, 54%/64% of patients (abatacept/tocilizumab) maintained treatment. Among patients with available response data, DAS28 was 5.3 (4.7–6.1), 3.4 (2.7–4.9) and 3.3 (2.5–4.3) at baseline, weeks 24 and 48, respectively, in the abatacept group and 5.4 (4.7–6.2), 2.9 (2.3–4.0) and 2.5 (1.9–4.5) in the tocilizumab group. At weeks 24 and 48, the remission rates for abatacept/tocilizumab were 19%/39% and 26%/58%, respectively. EULAR good-or-moderate response rates were 70%/88% and 77%/84%, respectively. The decline in DAS28 variables over time appeared similar between drugs, except for CRP, which seemed to decline more rapidly among tocilizumab-treated patients. Conclusions In patients with RA (≥90% TNFi failures), a good-or-moderate EULAR response was achieved in ≥70% of patients treated with abatacept or tocilizumab for 24 weeks in routine care. Apparent declines in DAS28 variables over time were similar between drugs, except for the more rapid CRP decline among tocilizumab-treated patients, directly caused by interleukin 6 inhibition.

ObjectivesTo investigate construct validity and responsiveness of the novel ankylosing spondylitis (AS) disease activity score (ASDAS) in patients with spondyloarthritis (SpA).MethodsIn a 46-week prospective longitudinal multicentre study of 60 patients with SpA (80% men, median age 40 years (range 21–62)) treated with tumour necrosis factor α (TNFα) inhibitors (infliximab, n=41; etanercept, n=13; adalimumab, n=6), the responsiveness of ASDAS, conventional clinical measures of disease activity and treatment response and the Berlin MRI sacroiliac joint (SIJ) and lumbar spine inflammation scores were compared.ResultsAfter 22 weeks, 58.3% of the patients were clinical responders (50% or 20 mm reduction in the Bath AS Disease Activity Index (BASDAI)). At baseline, clinical responders had significantly higher median (range) ASDAS than non-responders (4.15 (1.98–6.04) vs 2.99 (2.05–6.19), p=0.008). Changes in ASDAS correlated with changes in clinical measures of disease activity (including BASDAI (ρ=0.76) and C-reactive protein (CRP) (0.79)), MRI SIJ inflammation (0.46) and MRI total inflammation scores (0.34). Patients with higher BASDAI or Assessment of SpondyloArthritis International Society (ASAS) responses obtained more profound reductions in ASDAS. ASDAS had the highest responsiveness with an effect size of 2.04 and a standardised response mean of 1.45, whereas BASDAI (effect size 1.86; standardised response mean 1.36) and CRP (effect size 0.63; standardised response mean 0.70) were less responsive. Linear regression showed that a change in BASDAI of 20 mm or 50% corresponded to a change in ASDAS of 1.38 and 1.95, respectively.ConclusionASDAS demonstrates construct validity and high responsiveness during treatment with TNFα inhibitors in patients with SpA. The proposed thresholds for disease activity and treatment response need further validation.Trial registration number NCT00133315.

Data from a refraction seismic profile parallel to the coast of Labrador (Canada) were used to determine the crustal structure across the boundary of the Nain and Makkovik provinces, and to look for evidence for an offshore continuation of the Mesoproterozoic Nain Plutonic Suite (NPS). Seven seismometers recorded airgun shots along the 283 km long line. P- and S-wave velocity models were developed from forward and inverse modeling of travel times. The velocity model distinguishes three distinct zones. In the Saglek block of the Nain Province, the crust is divided into three layers with P-wave velocities between 5.8 and 6.9 km/s. Farther to the south, upper crustal velocities increase to 6.3–6.5 km/s and the Poisson’s ratio increases from 0.24 to 0.27. This zone correlates with a gravity low that is interpreted to outline the offshore continuation of the NPS. The upper crustal velocities are intermediate between anorthositic and granitoid rock samples collected from the NPS. A lower crustal reflector is limited to the area underneath the NPS and may be related to dioritic magmas. Mid-crustal and lower crustal velocities do not vary along the line and no underplating was detected. Within the Makkovik Province, upper crustal velocities of 5.9–6.2 km/s may indicate a dioritic composition similar to the Island Harbour Bay plutonic suite. Moho depth varies between 28 and 36 km with the maximum beneath the NPS. The variations could not be linked to effects of the Makkovikian orogeny but are thought to relate to Mesozoic rifting in Labrador Sea.

Objective: To investigate the efficacy of switching to a second biological drug in rheumatoid arthritis (RA) patients. Methods: Since 2000, Danish RA patients (n = 1021) receiving biological therapy have been registered in the nationwide DANBIO database. The first and second treatment series of patients, who switched therapy before 2005 (n = 235), were analysed for their reasons for switching, Disease Activity Score 28 (DAS28), DAS28 improvement, European League against Rheumatology (EULAR) response and drug survival. Most patients switched from infliximab to etanercept or adalimumab. Results: Median survivals for switchers’ first/second treatment were 37/92 weeks (all patients’ first treatment 119 weeks). Reasons for switching were lack of efficacy (LOE; 109 patients), adverse events (AE; 72), other reasons (54). If patients experienced AE to the first drug, 15% had AE to the second. Median DAS28 improvements in first/second treatment at 3 months were: LOE switchers 1.1/1.6; AE switchers 1.5/0.8. In LOE switchers, a good/moderate EULAR response was more prevalent during the second treatment course than during the first (63% versus 54%, p = 0.02). AE switchers achieved similar EULAR responses to both treatments (59% versus 50%, p = 0.38). Conclusion: LOE switchers had a better clinical response to the second treatment. AE switchers responded equally well to both treatments, with a low risk of discontinuing the second drug as a result of AE. Drug survival of the switchers’ second biological therapy was higher than of the first, but lower than that of non-switchers. No difference between various sequences of drugs were found. Danish post-marketing data thus support that RA patients may benefit from switching biological therapy.

Summary Background Accidental falls during hospitalisation have a range of complications and more information is needed to improve prevention. We investigated patterns of in-hospital fall-related major injuries in the period 2000–2012 and the association between chronic conditions and in-hospital fall-related major injuries. Methods Using administrative databases, patients aged 65+ years with in-hospital falls causing fractures or head injuries with need for surgery or intensive observation were identified as cases and were individually matched with five controls. Joinpoint regression was used to examine time trends and conditional logistic regression was used to analyse odds ratio (OR) for in-hospital falls-related major injuries according to a range of comorbidities. Results Four thousand seven hundred and fifty-four cases were identified from 2000 to 2012 and the most common injury was femur fracture (61.55%). For individuals aged 65–74 and 75+ years, the incidence of in-hospital falls-related major injuries per 100,000 hospital days increased significantly in 2000–2012 (average annual change: 3.2%, CI: 0.6–5.8) and 2007–2012 (average annual change: 11.4%, CI: 5.7–17.5), respectively. Significantly increased OR for in-hospital fall-related major injuries were found for individuals with dementia (OR = 2.34, CI: 1.87–2.92), osteoporosis (OR = 1.68, CI: 1.43–1.99), stroke (OR = 1.63, CI: 1.41–1.88), depression (OR = 1.24, CI: 1.09–1.41), chronic obstructive pulmonary disease (OR = 1.18, CI: 1.01–1.39) and Parkinson disease (OR = 1.17, CI: 1.01–1.34). Conclusions In-hospital falls-related major injuries increased significantly during the study period. Elderly with dementia, osteoporosis, stroke, depression, chronic obstructive pulmonary disease and Parkinson disease were associated with increased OR for in-hospital fall-related major injuries. Increased focus on patients with these comorbidities is warranted to decrease the increasing incidence in in-hospital major injuries.

Background. The etiology of pelvic joint syndrome (PJS) is not fully clarified. As a consequence, there is a lack of diagnostic methods to confirm the diagnosis, which today is mainly based on medical history. Objective. The aim of this study was to examine women with PJS using various diagnostic methods. The hypothesis is that there are characteristics in this group of women that separate them from women who only suffer from pelvic pain during pregnancy and shortly after delivery, or healthy women. Methods. Fifty-eight women participated in this follow-up study - twenty-one with PJS, 17 women who suffered from pelvic pain during pregnancy and shortly after delivery, and 20 controls with no history of pregnancy-induced pelvic pain. Clinical examination, gynecologic examination, psychological tests, spine X-ray, magnetic resonance imaging (MRI), blood samples, and urine dipsticks were performed. Results. Clinical examination showed significant differences with regard to provocative tests and tenderness in ...

Objective.To investigate baseline characteristics associated with radiographic progression and the effect of disease activity, drug, switching, and withdrawal on radiographic progression in tumor necrosis factor (TNF) inhibitor-naive patients with rheumatoid arthritis (RA) followed for about 2 years after anti-TNF initiation in clinical practice.Methods.DANBIO-registered patients with RA who had available radiographs (anti-TNF initiation and ∼2 yrs followup) were included. Radiographs were scored, blinded to chronology with the Sharp/van der Heijde method and linked with DANBIO data. Baseline characteristics were investigated with univariate regression and significant variables included in a multivariable logistic regression analysis with ± radiographic progression [Δ total Sharp score (TSS) > 0] as dependent variable. Effect of time-averaged C-reactive protein (CRP), 28-joint Disease Activity Score with CRP (DAS28-CRP), and treatment status at followup were investigated with univariate regression analysis.Results.The study included 930 patients. They were 75% women, 79% positive for IgM-rheumatoid factor (IgM-RF), median age was 57 yrs (range 19–88), disease duration 9 yrs (1–59), DAS28-CRP 5.0 (1.4–7.8), TSS median 15 [3–45 interquartile range (IQR)] and mean 31 (SD 40). Patients started treatment with infliximab (59%), etanercept (18%), or adalimumab (23%). At followup (median 526 days, IQR 392–735), 61% were treated with the initial anti-TNF, 29% had switched TNF inhibitor, and 10% had withdrawn. Twenty-seven percent of patients had progressed radiographically. ΔTSS was median 0.0 [0.0–0.5 IQR/mean 0.6 (SD 2.4)] units/year. Higher TSS, older age, positive IgM-RF, and concomitant prednisolone at baseline were associated with radiographic progression. Time-averaged DAS28-CRP and time-averaged CRP, but not type of TNF inhibitor, were associated with radiographic progression. Patients who stopped/switched during followup progressed more than patients who continued treatment.Conclusion.High TSS, older age, IgM-RF positivity, and concomitant prednisolone were associated with radiographic progression during 2 years of followup of 930 anti-TNF–treated patients with RA in clinical practice. High disease activity and switching/stopping anti-TNF treatment were associated with radiographic progression.

As part of a larger study 48 patients with rheumatoid arthritis (33 women, aged 34-85 years) treated with a mean prednisolone dose of 7.0 mg (range 5-20 mg) per day, and a mean duration of treatment of 95 months (range: 6-360 months) had a 250 μg Synacthen® test performed in the morning, fasting, after a mean prednisolone pause of 47 hours (range: 36-60 hours). P-cortisol was measured before, 30 and 60 min after Synacthen® injection.

Background Pelvic pain in pregnancy appears to be a problem that is increasing. This study was undertaken to describe and analyze the relationship between subjective symptoms, daily disability, and clinical findings in women with symptom-giving pelvic girdle relaxation in pregnancy Materials and methods Out of 1600 pregnant women 238 had pelvic pain. After a clinical examination 11 women were excluded due to low back pain. The rest, 227 women, was considered having symptom-giving pelvic girdle relaxation during pregnancy. Results Symptom-giving pelvic girdle relaxation in pregnancy seriously interferes with many activities of daily living such as housekeeping, walking, working, and sexual life. The women's statements of pelvic pain are well correlated to the number of positive clinical tests. Conclusion Symptom-giving pelvic girdle relaxation in pregnancy causes considerable disabilities concerning daily activities.

Background Previous studies concerning symptom-giving pelvic girdle relaxation in pregnancy have to our knowledge been retrospective. We wanted to 1) determine the incidence during pregnancy and the prevalence two, six, and twelve months post partum, 2) identify possible predisposing factors, and 3) determine the frequency and duration of sicklisting, prospectively. Material and methods. A cohort of 1600 consecutive pregnant women filled in a questionnaire. At the routine prenatal examinations they were asked about pelvic pain. Those who fulfilled the inclusion criteria were examined by a rheumatologist to confirm the diagnosis. The affected women were seen again two, six, and twelve months post partum. All participants were asked about sicklisting in pregnancy. Results. The incidence during pregnancy was 14%, the prevalence two, six, and twelve months post partum were 5%, 4%, and 2% respectively. Multivariate analysis indicates that the most important predisposing factor is pelvic pain in a previous pregnancy. Other factors were uncomfortable working conditions, lack of exercise, and previous low back pain and low abdominal pain. At least 37% of the women with symptom-giving pelvic girdle relaxation had been sicklisted in pregnancy due to pelvic pain, on average for twelve weeks. Conclusion, Symptom-giving pelvic girdle relaxation is a considerable problem both in pregnancy and post partum. The occupational risk can possibly be prevented. The syndrome has a great social impact because of the frequent sicklisting.

ObjectiveTo investigate frequencies and reasons for switching, treatment responses and drug survival in patients with ankylosing spondylitis (AS) switching tumour-necrosis-factor-α inhibitor (TNFi) treatment in routine clinical care.MethodsAS patients were identified in the Danish nationwide DANBIO registry. Disease activity, treatment responses (50% or 20 mm reduction in Bath AS Disease Activity Index (BASDAI)), duration and rates of drug survival and predictors thereof were studied in patients receiving ≥2 different biological drugs.ResultsOf 1436 AS patients starting TNFi treatment, 432 patients (30%) switched to a second and 137 (10%) to a third biological drug. Compared with non-switchers, switchers were more frequently women (33%/22%), had shorter disease duration (3 years/5 years) and higher BASDAI (62(52–76) mm/56(43–69) mm (median(interquartile-range))), Bath AS Functional Index (BASFI) (54(39–71) mm/47(31–65) mm) and visual-analogue-scale (VAS) global, pain and fatigue scores when they started the first TNFi (all pConclusionsNearly one-third of AS patients in clinical practice switched biological treatment. Response rates and drug survivals were lower among switchers, however, half of switchers achieved treatment response.

To compare radiographic progression during treatment with disease-modifying antirheumatic drugs (DMARD) and subsequent treatment with tumour necrosis factor α inhibitors (TNF-I) in rheumatoid arthritis (RA) patients in clinical practice.Conventional radiographs (x-rays) of hands and wrists were obtained ∼2 years before start (prebaseline), at baseline and ∼2 years after start (follow-up) of TNF-I. Clinical data were obtained from the DANBIO registry and the patient files. x-Rays were scored blinded to chronology according to the Sharp/van der Heijde method. Annual radiographic progression rates during the DMARD (prebaseline to baseline x-ray) and TNF-I (baseline to follow-up x-ray) periods were calculated.517 RA patients (76% women, 80% IgM rheumatoid factor positive, 65% anticyclic citrullinated peptide positive, 40% current smokers, age 54 years (range 21-86), median disease duration 5 years (range 0-57)) were included. Patients were treated with infliximab (61%), etanercept (15%) or adalimumab (24%). During the DMARD period 85% of patients received methotrexate, 51% sulphasalazine and 78% prednisolone. The median DMARD period was 733 days (IQR 484-1002) and the median TNF-I period was 562 days (IQR 405-766). The median radiographic progression rate decreased from 0.7 (IQR 0-2.9) total Sharp score units/year (dTSS) in the DMARD period to 0 (0-0.9) units/year in the TNF-I period (p0.0001, Wilcoxon). Corresponding mean dTSS values were 2.1 (SD 3.7) versus 0.7 (SD 2.3) units/year (p0.0001, paired t test). 305 patients progressed (dTSS0) in the DMARD period compared with 158 patients in the TNF-I period (p0.0001, χ(2)).This nationwide observational study of RA patients documented significantly reduced radiographic progression during TNF-I treatment compared with the previous period of DMARD treatment.

Background Different remission criteria are available for patients with rheumatoid arthritis (RA). None of the criteria includes imaging remission, even though studies have shown that many RA patients in sustained clinical remission have synovitis detectable by ultrasound (US), i.e. grey scale synovial hypertrophy and/or Doppler signal in the synovium. Objectives We aimed to investigate the agreement between different clinical remission criteria and remission defined by US in patients with RA receiving biological therapy in routine care. Methods A total of 117 RA patients in sustained remission (i.e. DAS28 ≤2.6 for ≥1 year and no radiographic progression the last year) on biological therapy were recruited. All patients underwent US of 24 joints for grading of grey scale (GS) synovial hypertrophy (0–3) and synovial Colour Doppler activity (CD) (0–3). Imaging remission was defined in two ways: either GS=0 and CD=0 in all 24 joints, or GS≤1 and CD=0 in all 24 joints. Results Baseline characteristics are shown in table 1. At baseline patients received the following disease-modifying antirheumatic drugs (DMARDs): methotrexate (MTX; 72%), sulphasalazine (3%), azathioprine (2%), leflunomide (2%), no DMARDs (21%) and the following treatment with biological therapy: abatacept (2%), adalimumab (28%), certolizumab (3%), etanercept (28%), golimumab(3%), infliximab (27%), tocilizumab (9%). For patients fulfilling DAS28 remission criteria, US defined remission was present in 9% (GS=0 and CD=0 in all 24 joints, termed “very strict” US remission) or 29% (GS ≤1 per joint and CD=0 in all 24 joints, termed “strict” US remission) and 24% had CD>1 in at least 1 joint (table 1). For patients fulfilling other criteria for clinical remission (CDAI, SDAI and ACR/EULAR remission), patients were in very strict US remission in 12%, 12% and 10%, respectively and in strict US remission in 28%, 29% and 20%, respectively. CD activity >1 in at least 1 joint was present in 22%, 25% and 22% of patients, respectively. The anatomical distribution of the GS synovial hypertrophy was 31% in metacarpophalangeal joints, 27% in metatarsophalangeal joints, 19% in wrists, 10% in knees, 7% in elbows and 6% in ankles. Thus, 33% of the total GS synovial hypertrophy was observed in the feet, which are not included in the DAS28 remission criteria. There were no significant differences in US findings (GS or CD) between patients in remission vs patients not in remission, no matter which clinical remission criteria were used. Conclusions Subclinical synovitis was frequently detected by US in RA patients treated with biological drugs in routine care showing poor agreement between the clinical remission criteria and US remission. Further studies are needed to evaluate the benefit of US remission as a goal for treat to target strategies on patient-reported outcomes and radiographic progression. Disclosure of Interest C. H. Brahe: None declared, L. Terslev: None declared, S. Krabbe: None declared, M. Ostergaard Grant/research support from: Abbvie, BMS, Boehringer-Ingelheim, Eli Lilly, Janssen, Merck, Pfizer, Roche, UCB, Celgene, Sanofi, Regeneron, Novartis, T.Jensen, H. Rogind: None declared, H. Jensen: None declared, A. Hansen: None declared, J. Norregaard: None declared, S. Jacobsen: None declared, K. Ellegaard: None declared, V. Fana: None declared, L. Juul: None declared, T. Huynh: None declared, D. Jensen: None declared, N. Manilo: None declared, K. Asmussen Speakers bureau: Novartis, Abbvie, Pfizer, Berlin Chemie, MSD, UCB, P. Frandsen: None declared, S. Pedersen: None declared, N. Krogh: None declared, M. Hetland: None declared

Objectives To determine the accuracy of ultrasonography (US) for bone erosion detection in different areas of rheumatoid arthritis (RA) metacarpophalangeal (MCP) joints with multislice CT as the reference method. Second, to establish the necessary bone volume loss on CT for US to reliably detect it as an erosion, and finally to compare two semiquantitative US-erosion scoring methods. Methods The 2nd–5th MCP joints of 49 patients with RA were examined by CT and US, and evaluated for the presence of bone erosion in each MCP joint quadrant. On CT, erosion volume was scored according to the OMERACT-RAMRIS score (bone volume loss in 10% increments of original bone volume). US erosions were scored 0–3 according to the Szkudlarek and Scoring by UltraSound Structural erosion (ScUSSe) systems, respectively. Results Seven hundred and eighty-four MCP joint quadrants were examined. Erosions were detected by CT in 259 quadrants and by US in 142 quadrants. Sensitivity/specificity/accuracy of US was overall 44%/95%/78% compared with 71%/95%/90% in areas with good US accessibility (radial 2nd MCP, ulnar 5th MCP and all dorsal/palmar aspects). US detected 95% of erosions with bone volume loss >20%. In US accessible areas, 63% of erosions with 1–10% bone volume loss and 94% of erosions with >10% bone loss were detected. The two US scoring systems agreed well on large erosions, whereas the smallest erosions (Szkudlarek grade 1, of which 86% were confirmed by CT) were not scored by ScUSSe. Conclusion In accessible areas, US was highly accurate for detection and semiquantitative assessment of RA bone erosion. Even the smallest erosions, only detected in one plane, were generally confirmed by CT.

The CssRS two-component system responds to heat and secretion stresses in Bacillus subtilis by controlling expression of HtrA and HtrB chaperone-type proteases and positively autoregulating its own expression. Here we report on the features of the CssS extracellular loop domain that are involved in signal perception and on CssS subcellular localization. Individual regions of the CssS extracellular loop domain contribute differently to signal perception and activation. The conserved hydrophilic 26-amino-acid segment juxtaposed to transmembrane helix 1 is involved in the switch between the deactivated and activated states, while the conserved 19-amino-acid hydrophobic segment juxtaposed to transmembrane 2 is required for signal perception and/or transduction. Perturbing the size of the extracellular loop domain increases CssS kinase activity and makes it unresponsive to secretion stress. CssS is localized primarily at the septum but is also found in a punctate pattern with lower intensity throughout the cell cylinder. Moreover, the CssRS-controlled HtrA and HtrB proteases are randomly distributed in foci throughout the cell surface, with more HtrB than HtrA foci in unstressed cells.

Human dopamine D1a and D1b receptors were stably expressed in Baby Hamster Kidney (BHK) or Chinese Hamster Ovary (CHO) cells. [3H]SCH23390 saturation experiments indicated the presence of only a single binding site in the D1a expressing cell line with a Kd of 0.5 nM. In D1b expressing cell lines, two binding sites were observed with Kd values of 0.5 and 5 nM in CHO cells and 0.05 and 1.6 nM in BHK cells, respectively. Neither of the receptors affected Ca2+ metabolism whereas they both were coupled in a stimulatory fashion to adenylyl cyclase. The pharmacological profile of both the D1a and D1b receptors as assessed from inhibition of specific [3H]SCH 23390 binding was classical D1-like. Thus, benzazepine derivatives as well as the atypical neuroleptics, clozapine and fluperlapine, exhibited high affinity whereas D2 selective compounds like sulpiride and spiperone had low affinity for these receptors. Besides SCH 23390, only NNC 112, fluphenazine and bulbocapnine were able to discriminate between the two states of the D1b receptor. In case of the D1a receptor, the Ki values obtained in binding experiments were very similar to Ki values obtained from inhibition of dopamine stimulated adenylyl cyclase. In the D1b expressing cell line, the Ki values obtained from inhibition of the dopamine stimulated adenylyl cyclase indicated a significantly better correlation with the state of the D1b receptor showing high affinity for antagonists. In agreement with observations from binding experiments, dopamine was around 20 fold more potent in stimulating adenylyl cyclase via the D1b receptor as compared to the D1a receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

The high phosphate content of Bacillus subtilis cell walls dictates that cell wall metabolism is an important feature of the PhoPR-mediated phosphate limitation response. Here we report the expression profiles of cell-envelope-associated and PhoPR regulon genes, determined by live cell array and transcriptome analysis, in exponentially growing and phosphate-limited B. subtilis cells. Control by the WalRK two-component system confers a unique expression profile and high level of promoter activity on the genes of its regulon with yocH and cwlO expression differing both qualitatively and quantitatively from all other autolysin-encoding genes examined. The activity of the PhoPR two-component system is restricted to the phosphate-limited state, being rapidly induced in response to the cognate stimulus, and can be sustained for an extended phosphate limitation period. Constituent promoters of the PhoPR regulon show heterogeneous induction profiles and very high promoter activities. Phosphate-limited cells also show elevated expression of the actin-like protein MreBH and reduced expression of the WapA cell wall protein and WprA cell wall protease indicating that cell wall metabolism in this state is distinct from that of exponentially growing and stationary-phase cells. The PhoPR response is very rapidly deactivated upon removal of the phosphate limitation stimulus with concomitant increased expression of cell wall metabolic genes. Moreover expression of genes encoding enzymes involved in sulphur metabolism is significantly altered in the phosphate-limited state with distinct perturbations being observed in wild-type 168 and AH024 (ΔphoPR) cells.

Objectives To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial growth factor (VEGF)), cartilage (C-terminal crosslinking telopeptide of type II collagen (CTX-II), matrix metalloproteinase-3 (MMP-3), total aggrecan, cartilage oligomeric matrix protein) and bone (C-terminal crosslinking telopeptide of type I collagen, osteocalcin) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha (TNFα) inhibitor therapy. Methods ASDAS (CRP-based), BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy. Results Very high ASDAS were associated with high levels of inflammatory biomarkers, while high BASDAI were not related to any biomarkers. Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6, VEGF, MMP-3 and osteocalcin and between BASDAI and CRP, IL-6 and VEGF. Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation, angiogenesis, MMP-3 and increases in aggrecan and osteocalcin. BASDAI response was associated with larger decreases in CRP and IL-6. Biomarkers with moderate/high differences in responsiveness for major versus no/clinically important improvement in ASDAS were CRP, IL-6, VEGF, aggrecan and osteocalcin, and VEGF and CTX-II for BASDAI response versus non-response. Conclusion Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented. Construct validity and responsiveness of IL-6, VEGF, MMP-3, total aggrecan and osteocalcin were demonstrated. ASDAS was more associated with these biomarkers than BASDAI, and may better reflect the inflammatory disease processes. ClinicalTrials.gov identifier NCT00133315.

Objective To investigate the relationship of circulating biomarkers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6], and YKL-40), angiogenesis (vascular endothelial growth factor), cartilage turnover (C-terminal crosslinking telopeptide of type II collagen [CTX-II], total aggrecan, matrix metalloproteinase 3 [MMP-3], and cartilage oligomeric matrix protein [COMP]), and bone turnover (CTX-I and osteocalcin) to inflammation on magnetic resonance imaging (MRI) and radiographic progression in patients with axial spondylarthritis (SpA) beginning tumor necrosis factor α (TNFα) inhibitor therapy. Methods MRIs were evaluated according to the Berlin sacroiliac (SI) joint and spine inflammation scoring method at baseline, week 22, and week 46. Radiographs were evaluated using the modified Stoke Ankylosing Spondylitis Spine Score at baseline and week 46. Patients with new syndesmophytes were identified. Biomarker levels in patients were compared to levels in healthy subjects. Results Higher pretreatment MRI inflammation scores for SI joints and/or lumbar spine were associated with higher baseline CTX-II levels, but not with higher levels of biomarkers of inflammation and bone turnover. During treatment with TNFα inhibitors, a decrease in MRI inflammation scores from baseline to week 22 was associated with larger percentage decreases in and a normalization of CRP and IL-6 levels as compared to an increase or no change in MRI scores. Development of new syndesmophytes was associated with larger percentage decreases in CRP and IL-6 levels and an increase in osteocalcin level, and with normalization of CRP and IL-6 levels from baseline to week 22. Persistent systemic inflammation was associated with radiographic nonprogression. Conclusion Our findings indicate that inflammation on baseline MRI is associated with higher CTX-II levels. Radiographic progression is associated with decreased systemic inflammation, as assessed by IL-6 and CRP levels and MRI, supporting the notion of a link between the resolution of inflammation and new bone formation in SpA patients during anti-TNFα therapy.

Aim To monitor joint inflammation and destruction in rheumatoid arthritis (RA) patients receiving adalimumab/methotrexate combination therapy using MRI and ultrasonography. To assess the predictive value of MRI and ultrasonography for erosive progression on CT and compare MRI/ultrasonography/radiography for erosion detection/monitoring. Methods Fifty-two erosive biological-naive RA patients were followed with repeated MRI/ultrasonography/ radiography (0/6/12 months) and clinical/biochemical assessments during adalimumab/methotrexate combination therapy. Results No overall erosion progression or repair was observed at 6 or 12 months (Wilcoxon; p > 0.05), but erosion progressors and regressors were observed using the smallest detectable change cut-off. Scores of MRI synovitis, grey-scale synovitis (GSS) and power Doppler ultrasonography decreased after 6 and 12 months (p

INTRODUCTION: The aim of this study was to develop 3E (Evidence, Expertise, Exchange) recommendations (RCs) on the use of methotrexate in rheumatic disorders and to assess the agreement among Danish rheumatologists.MATERIAL AND METHODS: Based on a systematic literature review and Delphi votes, national and multinational (MN) RCs were developed by 751 rheumatologists from 17 countries including Denmark, and the degree of agreement among the participants was assessed. Subsequently, a survey regarding the agreement on the MN RCs was sent to all Danish rheumatologists.RESULTS: A total of 24 Danish RCs were elaborated by 43 rheumatologists at a national meeting. 71-100% (median 94%) of the participants agreed with each of the RCs. A total of 73 rheumatologists answered the survey on the ten MN RCs. On numerical rating scales with values ranging from zero to ten, the median agreement score for each of these RCs ranged from eight to ten. The RCs were already applied in daily practice by 70-100% (median 91%) of the specialists. Any direct conflict between the national and MN RCs was not evident.CONCLUSION: Based on evidence and expert opinion in a MN approach, national and MN RCs on methotrexate therapy were developed and a high level of agreement among Danish rheumatologists was evidenced.

Plasmid pBaSysBioII was constructed for high-throughput analysis of gene expression in Bacillus subtilis. It is an integrative plasmid with a ligation-independent cloning (LIC) site, allowing the generation of transcriptional gfpmut3 fusions with desired promoters. Integration is by a Campbell-type event and is non-mutagenic, placing the fusion at the homologous chromosomal locus. Using phoA, murAA, gapB, ptsG and cggR promoters that are responsive to phosphate availability, growth rate and carbon source, we show that detailed profiles of promoter activity can be established, with responses to changing conditions being measurable within 1 min of the stimulus. This makes pBaSysBioII a highly versatile tool for real-time gene expression analysis in growing cells of B. subtilis.

Udgivelsesdato: 2010-Jan OBJECTIVE: To compare tumor necrosis factor alpha inhibitors directly regarding the rates of treatment response, remission, and the drug survival rate in patients with rheumatoid arthritis (RA), and to identify clinical prognostic factors for response. METHODS: The nationwide DANBIO registry collects data on rheumatology patients receiving routine care. For the present study, we included patients from DANBIO who had RA (n = 2,326) in whom the first biologic treatment was initiated (29% received adalimumab, 22% received etanercept, and 49% received infliximab). Baseline predictors of treatment response were identified. The odds ratios (ORs) for clinical responses and remission and hazard ratios (HRs) for drug withdrawal were calculated, corrected for age, disease duration, the Disease Activity Score in 28 joints (DAS28), seropositivity, concomitant methotrexate and prednisolone, number of previous disease-modifying drugs, center, and functional status (Health Assessment Questionnaire score). RESULTS: Seventy percent improvement according to the American College of Rheumatology criteria (an ACR70 response) was achieved in 19% of patients after 6 months. Older age, concomitant prednisolone treatment, and low functional status at baseline were negative predictors. The ORs (95% confidence intervals [95% CIs]) for an ACR70 response were 2.05 (95% CI 1.52-2.76) for adalimumab versus infliximab, 1.78 (95% CI 1.28-2.50) for etanercept versus infliximab, and 1.15 (95% CI 0.82-1.60) for adalimumab versus etanercept. Similar predictors and ORs were observed for a good response according to the European League Against Rheumatism criteria, DAS28 remission, and Clinical Disease Activity Index remission. At 48 months, the HRs for drug withdrawal were 1.98 for infliximab versus etanercept (95% 1.63-2.40), 1.35 for infliximab versus adalimumab (95% CI 1.15-1.58), and 1.47 for adalimumab versus etanercept (95% CI 1.20-1.80). CONCLUSION: Older age, low functional status, and concomitant prednisolone treatment were negative predictors of a clinical response and remission. Infliximab had the lowest rates of treatment response, disease remission, and drug adherence, adalimumab had the highest rates of treatment response and disease remission, and etanercept had the longest drug survival rates. These findings were consistent after correction for confounders and sensitivity analyses and across outcome measures and followup times.