Effects of tapering conventional synthetic disease-modifying antirheumatic drugs to drug-free remission versus stable treatment in rheumatoid arthritis (ARCTIC REWIND): 3-year results from an open-label, randomised controlled, non-inferiority trial.

BACKGROUND: Tapering of disease-modifying antirheumatic drugs (DMARDs) to drug-free remission is an attractive treatment goal for patients with rheumatoid arthritis, although long-term effects of tapering and withdrawal remain unclear. We compared 3-year risks of flare between three conventional synthetic DMARD treatment strategies in patients with rheumatoid arthritis in sustained remission. METHODS: In this open-label, randomised controlled, non-inferiority trial, we enrolled patients aged 18-80 years with rheumatoid arthritis who had been in sustained remission for at least 1 year on stable conventional synthetic DMARD therapy. Patients from ten hospitals in Norway were randomly assigned (2:1:1) with centre stratification to receive stable conventional synthetic DMARDs, half-dose conventional synthetic DMARDs, or half-dose conventional synthetic DMARDs for 1 year followed by withdrawal of all conventional synthetic DMARDs. The primary endpoint of this part of the study was disease flare over 3 years, analysed as flare-free survival and risk difference in the per-protocol population with a non-inferiority margin of 20%. This trial is registered with ClinicalTrials.gov (NCT01881308) and is completed. FINDINGS: Between June 17, 2013, and June 18, 2018, 160 patients were enrolled and randomly assigned to receive stable-dose conventional synthetic DMARDs (n=80), half-dose conventional synthetic DMARDs (n=42), or half-dose conventional synthetic DMARDs tapering to withdrawal (n=38). Four patients did not receive the intervention and 156 patients received the allocated treatment strategy. One patient was excluded due to major protocol violation and 155 patients were included in the per-protocol analysis. 104 (67%) of 156 patients were women and 52 (33%) were men. 139 patients completed 3-years follow-up without major protocol violation; 68 (87%) of 78 patients in the stable-dose group, 36 (88%) of 41 patients in the half-dose group and 35 (95%) of 37 patients in the half-dose tapering to withdrawal group. During the 3-year study period, 80% (95% CI 69-88%) were flare-free in the stable-dose group, compared with 57% (41-71%) in the half-dose group and 38% (22-53%) in the half-dose tapering to withdrawal group. Compared with stable-dose conventional synthetic DMARDs, the risk difference of flare was 23% (95% CI 6-41%, p=0·010) in the half-dose group and 40% (22-58%, p<0·0001) in the half-dose tapering to withdrawal group, non-inferiority was therefore not shown. Adverse events were reported in 65 (83%) of 78 patients in the stable-dose group, 36 (90%) of 40 patients in the half-dose group, and 36 (97%) of 37 patients in the half-dose tapering to withdrawal group. One death occurred in the stable-dose conventional synthetic DMARD group (sudden death considered unlikely related to the study medication). INTERPRETATION: Two conventional synthetic DMARD tapering strategies were associated with significantly lower rates of flare-free survival compared with stable conventional synthetic DMARD treatment, and the data do not support non-inferiority. However, drug-free remission was achiveable for a significant subgroup of patients. This trial provides information on risk and benefits of different treatment strategies important for shared decision making. FUNDING: Research Council of Norway and South-Eastern Norway Regional Health Authority.

Effect of tapered versus stable treatment with tumour necrosis factor inhibitors on disease flares in patients with rheumatoid arthritis in remission: a randomised, open label, non-inferiority trial.

OBJECTIVES: Many patients with rheumatoid arthritis (RA) require treatment with tumour necrosis factor inhibitor (TNFi) to reach remission. It is debated whether tapering of TNFi to discontinuation should be considered in sustained remission. The aim of ARCTIC REWIND TNFi was to assess the effect of tapering TNFi to withdrawal compared with stable treatment on the risk of disease activity flares in patients with RA in remission ≥1 year. METHODS: This randomised, open-label, non-inferiority trial was undertaken at nine Norwegian rheumatology departments. Patients with RA in remission ≥12 months on stable TNFi therapy were allocated by computer-based block-randomisation to tapering to discontinuation of TNFi or stable TNFi. Conventional synthetic disease-modifying antirheumatic co-medication was unchanged. The primary endpoint was disease flare during the 12-month study period (non-inferiority margin 20%), assessed in the per-protocol population. RESULTS: Between June 2013 and January 2019, 99 patients were enrolled and 92 received the allocated treatment strategy. Eighty-four patients were included in the per-protocol population. In the tapering TNFi group, 27/43 (63%) experienced a flare during 12 months, compared with 2/41 (5%) in the stable TNFi group; risk difference (95% CI) 58% (42% to 74%). The tapering strategy was not non-inferior to continued stable treatment. The number of total/serious adverse events was 49/3 in the tapering group, 57/2 in the stable group. CONCLUSION: In patients with RA in remission for more than 1 year while using TNFi, an increase in flare rate was reported in those who tapered TNFi to discontinuation. However, most regained remission after reinstatement of full-dose treatment. TRIAL REGISTRATION NUMBERS: EudraCT: 2012-005275-14 and clinicaltrials.gov: NCT01881308.

Effectiveness and Persistence in SB4- and Reference Etanercept-Treated Rheumatoid Arthritis Patients in Ordinary Clinical Practice in Norway.

OBJECTIVE: Biosimilars represent cost-effective alternatives to reference biologic disease-modifying antirheumatic drugs. Our objective was to compare drug effectiveness and drug persistence in the treatment of rheumatoid arthritis (RA), assessing the etanercept biosimilar SB4 in efficacy and safety compared with reference etanercept in a Phase III, randomized controlled trial. We applied EULAR Points to Consider for Comparative Effectiveness Research in a retrospective database study of etanercept and SB4 in patients treated in clinical practice in Norway. METHODS: Patients with RA (n = 1,455) treated with etanercept or SB4 between 2010 and 2018 at 5 centers in Norway with ≥1 year of follow-up were included. Disease outcomes (Disease Activity Score in 28 joints [DAS28] at week 52) and drug persistence were compared between unmatched etanercept (n = 575) and SB4 (n = 299) cohorts and matched analyses (n = 172, both cohorts) using propensity score (PS) matching to adjust for confounders. RESULTS: In unmatched analyses, the difference in change from baseline between etanercept (n = 221) and SB4 (n = 106) for DAS28 at week 52 was mean -0.02 (95% confidence interval [95% CI] -0.32, 0.27), demonstrating equivalence by the predetermined equivalence margin (±0.6). In PS-matched analyses, the difference between etanercept (n = 49) and SB4 (n = 49) was 0.03 (95% CI -0.46, 0.52), within the predefined equivalence margin. Persistence using the drug at week 52 was similar between etanercept (0.62 [95% CI 0.57, 0.65]) and SB4 (0.66 [95% CI 0.60, 0.71]) cohorts in the unmatched analysis; in PS-matched cohorts, persistence at week 52 was 0.52 (95% CI 0.44, 0.59) for etanercept and 0.68 (95% CI 0.61, 0.75) for SB4. CONCLUSION: Outcomes for disease status/drug persistence at week 52 were similar between patients with RA treated with etanercept or SB4.

Comparative Evaluation of Carboxyhemoglobin Quantification in Postmortem Whole Blood by CO-Oximetry and Headspace Gas Chromatography with Flame Ionization Detection and Atom Absorption Spectrophotometry.

A comparative evaluation of two methods used for carboxyhemoglobin (COHb) determination in postmortem whole blood was performed: carbon monoxide (CO)-oximetry measuring at 128 wavelengths and headspace gas chromatography with flame ionization detection (HS-GC--FID) where CO was determined after catalytic reduction of CO to CH4 and Fe was determined by atom absorption spectrophotometry (AAS, 248.3 nm). An aliquot of 100 µL whole blood was loaded into the CO-oximetry module. In the HS-GC--FID analysis, to 1.0 mL of whole blood, 3.0 mL of saponin solution was added, mixed and centrifuged. To 20 mL HS vials, 400 µL of the supernatant was added and the vials were immediately sealed. One milliliter of potassium hexacyanoferrat (III) solution was added through the HS septum and mixed. The samples were incubated at 70°C for 5 min. CO was separated using He as carrier gas and a CP-Molsieve 5 Å PLOT capillary column. Fe was determined using 400 µL of the saponin supernatant diluted to 10 mL by water. During a period of ∼3 years, 124 postmortem whole blood samples were analyzed. Bland-Altman method comparison showed satisfactory agreement and no significant bias between the methods for the whole saturation range (5 to 85% COHb). Five samples, all with %COHb >40, showed deviations of more than 10% COHb in absolute terms. One sample, in the lower COHb range <10%, was false negative on the CO-oximetry method. The between-assay accuracy, reported as bias, at 60% COHb was -0.8% and -9.0%, and precision, reported as relative standard deviation, was 1.6% and 7.7%, for the CO-oximetry and HS-GC--FID-AAS methods, respectively. Both methods obtained satisfactory results in proficiency testing rounds, with z-scores <±2 (n = 11). This study showed that the CO-oximetry method based on the 128-wavelength principle and the HS-GC--FID-AAS method are comparable and satisfactory for %COHb determination in postmortem whole blood.

Clinical presentation and treatment response in patients with polymyalgia rheumatica and giant cell arteritis during a 40-week follow-up.

OBJECTIVES: The aim was to study the clinical features of PMR/GCA and clinical predictors of treatment response during a 40-week follow-up period. METHODS: Clinical data on 77 patients with newly diagnosed PMR/GCA who were treated with oral glucocorticoids were gathered at baseline and during a 40-week follow-up period. A unilateral temporal artery biopsy (TAB) and 18F-fluorodeoxyglucose (18F-FDG) PET/CT were undertaken at diagnosis. In total, each patient was seen on five occasions (i.e. baseline and weeks 4, 16, 28 and 40). Treatment response was assessed by considering clinical evaluations and results of inflammatory markers. RESULTS: Of 77 patients [49 (63.6%) female; mean age 71.8 (8.0) years], 64 (83.1%) patients had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. The patients reported that clinical symptoms, apart from scalp pain and duration of morning stiffness, improved significantly at week 4 and remained lower at week 40 compared with the relative frequencies at baseline. Besides, all components of physical examination showed significant improvement and remained lower at week 40 compared with the baseline. A complete response was seen in 68.7, 62.9, 44.1 and 33.3% of patients at weeks 4, 16, 28 and 40, respectively. Several clinical features, including female biological sex, younger age, fewer relapses and a lower level of baseline ESR, were significantly associated with a better treatment response. Treatment response during the follow-up period was independent of TAB results and fluorodeoxyglucose uptakes on 18F-FDG PET/CT at diagnosis. CONCLUSION: Obtaining valid disease-specific outcome measures for evaluating treatment efficacy in PMR and GCA that can be applied universally is clearly an unmet clinical need. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT02985424.

Rheumatoid arthritis patients with predominantly tender joints rarely achieve clinical remission despite being in ultrasound remission.

OBJECTIVES: Given that subjective variables might reduce remission by composite DAS (CDAS), the main objectives were to explore whether RA patients with mainly tender vs mainly swollen joints had differences in patient-reported outcome measures (PROMs), clinical or US assessments or in achieving remission defined by CDAS or US. METHODS: In a Nordic multicentre study, RA patients initiating tocilizumab were assessed by PROMs, clinical, laboratory and US assessments (36 joints and 4 tendons) at baseline, 4, 12 and 24 weeks. Remission was defined according to clinical disease activity index (CDAI)/Boolean or no Doppler activity present. Tender-swollen joint differences (TSJDs) were calculated. Statistics exploring changes over time/differences between groups included Wilcoxon, Mann-Whitney, Kruskal-Wallis and Spearman tests. RESULTS: One hundred and ten patients were included [mean (s.d.) age 55.6 (12.1) years, RA duration 8.7 (9.5) years]. All PROMs, clinical, laboratory and US scores decreased during follow-up (P < 0.001). During follow-up, tender joint counts were correlated primarily with PROMs [r = 0.24-0.56 (P < 0.05-0.001)] and swollen joint counts with US synovitis scores [r = 0.33-0.72 (P < 0.05-0.001)]. At 24 weeks, patients with TSJD > 0 had higher PROMs and CDAI (P < 0.05-0.001) but lower US synovitis scores (P < 0.05). Remission by CDAI/Boolean was seen in 26-34% and by Doppler 53%, but only 2-3% of patients with TSJD > 0 achieved CDAI/Boolean remission. CONCLUSION: Patients with more tender than swollen joints scored higher on subjective assessments but had less US synovitis. They seldom achieved CDAS remission despite many being in Doppler remission. If patients with predominantly tender joints do not reach CDAS remission, objective assessments of inflammation should be performed. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov/, NCT02046616.

Effect of Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Disease Flares in Patients With Rheumatoid Arthritis in Remission: The ARCTIC REWIND Randomized Clinical Trial.

Importance: Sustained remission has become an achievable goal for patients with rheumatoid arthritis (RA) receiving conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), but how to best treat patients in clinical remission remains unclear. Objective: To assess the effect of tapering of csDMARDs, compared with continuing csDMARDs without tapering, on the risk of flares in patients with RA in sustained remission. Design, Setting, and Participants: ARCTIC REWIND was a multicenter, randomized, parallel, open-label noninferiority study conducted in 10 Norwegian hospital-based rheumatology practices. A total of 160 patients with RA in remission for 12 months who were receiving stable csDMARD therapy were enrolled between June 2013 and June 2018, and the final visit occurred in June 2019. Interventions: Patients were randomly assigned to half-dose csDMARDs (n = 80) or stable-dose csDMARDs (n = 80). Main Outcomes and Measures: The primary end point was the proportion of patients with a disease flare between baseline and the 12-month follow-up, defined as a combination of Disease Activity Score (DAS) greater than 1.6 (threshold for RA remission), an increase in DAS score of 0.6 units or more, and at least 2 swollen joints. A disease flare could also be recorded if both the patient and investigator agreed that a clinically significant flare had occurred. A risk difference of 20% was defined as the noninferiority margin. Results: Of 160 enrolled patients (mean [SD] age, 55.1 [11.9] years; 66% female), 156 received the allocated therapy, of which 155 without any major protocol violations were included in the primary analysis population (77 receiving half-dose and 78 receiving stable-dose csDMARDs). Flare occurred in 19 patients (25%) in the half-dose csDMARD group compared with 5 (6%) in the stable-dose csDMARD group (risk difference, 18% [95% CI, 7%-29%]). Adverse events occurred in 34 patients (44%) in the half-dose group and 42 (54%) in the stable-dose group, none leading to study discontinuation. No deaths occurred. Conclusions and Relevance: Among patients with RA in remission taking csDMARD therapy, treatment with half-dose vs stable-dose csDMARDs did not demonstrate noninferiority for the percentage of patients with disease flares over 12 months, and there were significantly fewer flares in the stable-dose group. These findings do not support treatment with half-dose therapy. Trial Registration: ClinicalTrials.gov Identifier: NCT01881308.

The Prognostic Value of Pain Phenotyping in Relation to Treatment Outcomes in Patients with Axial Spondyloarthritis Treated in Clinical Practice: A Prospective Cohort Study.

Despite the control of inflammation, many patients with axial spondyloarthritis (axSpA) still report pain as a significant concern. Our objective was to explore the prognostic value of the painDETECT questionnaire (PDQ) in relation to treatment outcomes in axSpA patients treated in clinical practice. AxSpA patients with high disease activity initiating or switching a biological Disease-Modifying Antirheumatic Drug (bDMARD) were eligible. The PDQ score (range: -1 to 38) was used to distinguish participants with nociceptive pain (NcP) mechanisms from participants with a mixed pain mechanism (MP). The primary outcome was the proportion of individuals achieving a 50% improvement of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50) at 12 weeks; logistic regression analysis models were used to determine the prognostic value of the nociceptive pain phenotype. Changes in continuous outcomes such as the Assessment of SpondyloArthritis International Society (ASAS) core outcome domains were analyzed using analysis of covariance (ANCOVA). Health-related quality of life (HR-QoL) was addressed using the Medical Outcomes Study SF-36. During a period of 22 months, 49 axSpA patients were included. Twenty (41%) had an NcP phenotype according to the PDQ score. BASDAI50 responses were reported by 40% (8/20) and 28% (8/29) NcP and MP groups, respectively. However, a prognostic value was not found in relation to the primary outcome (crude odds ratio [95% confidence interval]: 1.75 [0.52 to 5.87]). Across most of the secondary outcomes, axSpA NcP phenotype patients were reported having the most improvements in the HR-QoL measures. These data indicate the influence of personalized management strategies according to patients' pain phenotypes for stratification of axSpA patients in randomized controlled trials.

Prognostic impacts of glucocorticoid treatment in patients with polymyalgia rheumatica and giant cell arteritis.

Identifying comorbidities in polymyalgia rheumatica/giant cell arteritis (PMR/GCA) is crucial for patients' outcomes. The present study aimed to evaluate the impact of the inflammatory process and glucocorticoid treatment on aortic arterial stiffness and body composition in PMR/GCA. 77 patients with newly diagnosed PMR/GCA were treated with oral glucocorticoids and followed for 40 weeks. Aortic pulse wave velocity (PWV) was measured at baseline and during the follow-up period and compared to the results of temporal artery biopsy (TAB) and 18F-FDG PET/CT. Body composition was assessed by total body DXA at baseline and the end of the study. Of 77 patients (49 (63.6%) female, mean of age: (71.8 ± 8.0)), 64 (83.1%) had pure PMR, 10 (13.0%) concomitant PMR and GCA, and 3 (3.9%) pure GCA. Compared to baseline values, aortic PWV was initially decreased at week 16 (p = 0.010) and remained lower than baseline at week 28 (p = 0.002) and week 40 (p < 0.001), with no association with results of TAB and 18F-FDG PET/CT. Aortic PWV was significantly associated with age, male gender, left systolic and diastolic blood pressure, right diastolic blood pressure, and CRP. Total bone mineral content (BMC) was decreased in both genders (p < 0.001), while fat mass (FM) was significantly increased (p < 0.001). However, lean body mass did not significantly change during the study. Changes in FM were correlated with cumulative prednisolone dose (rho: 0.26, p = 0.031). Glucocorticoid treatment of patients with PMR/GCA had several prognostic impacts. Arterial stiffness was decreased due either to the treatment or a reduction in the inflammatory load. Additionally, treatment led to changes in body composition, including a decrease in BMC and FM excess.

Tick-borne Pathogens Detected in the Blood of Immunosuppressed Norwegian Patients Living in a Tick-endemic Area.

BACKGROUND: The knowledge regarding the occurrence and the clinical implications of tick-borne infections in immunosuppressed patients living in tick-endemic areas is limited. METHODS: Adult patients with autoimmune conditions requiring immunosuppressive treatment such as infliximab and rituximab were invited to participate in the study when they attended the hospital for treatment and/or control of the disease. Whole-blood samples were analyzed by real-time polymerase chain reaction for Borrelia burgdorferi sensu lato, Borrelia miyamotoi, Anaplasma phagocytophilum, Rickettsia spp., Candidatus Neoehrlichia mikurensis, and Babesia spp. RESULTS: The occurrence of tick-borne pathogens in the blood of patients (n = 163) with autoimmune conditions requiring immunosuppressive treatment was evaluated. Pathogen DNA was detected in 8.6% (14/163) of the patients. The predominant pathogen was Ca. Neoehrlichia mikurensis (12/14), which was carried in the blood of infected patients for 10-59 days until treatment with doxycycline. B. burgdorferi s.l. and Rickettsia spp. were detected in 1 patient each. The B. burgdorferi-infected patient presented with fever, whereas the remaining patients were judged to have subclinical infections. B. miyamotoi, A. phagocytophilum, and Babesia spp. were not detected in any patient. CONCLUSIONS: Patients treated with biologicals and living in a tick-endemic area seem to have a high risk of contracting Ca. Neoehrlichia mikurensis infection, which, if left untreated, could result in thromboembolic complications.

Prevalence of Newly Diagnosed Malignancies in Patients with Polymyalgia Rheumatica and Giant Cell Arteritis, Comparison of 18F-FDG PET/CT Scan with Chest X-ray and Abdominal Ultrasound: Data from a 40 Week Prospective, Exploratory, Single Centre Study.

The aim of the study was to identify the prevalence of newly diagnosed malignancies in patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), with the aid of 18F-FDG PET/CT scan compared to conventional imaging techniques: Chest X-ray (CXR) and abdominal ultrasound (US). Secondarily, to examine the relative diagnostic accuracy of these two imaging modalities for the detection of cancer. Eighty consecutive patients with newly diagnosed PMR, GCA, or concomitant PMR and GCA, were included and followed up for 40 weeks. All patients underwent an 18F-FDG PET/CT scan, CXR, and abdominal US at diagnosis. Imaging findings were dichotomously categorized into malignant or benign. Among 80 patients, three patients were diagnosed with seronegative rheumatoid arthritis and were excluded from the analysis. Of the remaining 77, 64 (83.1%) patients were diagnosed with pure PMR, 3 (3.9%) with pure GCA, and 10 (13.0%) with concomitant PMR and GCA. Five types of cancer that were more prevalent than the one-year prevalence of 1.2% among the background population were found in four (5.2%; 95%CI: 1.4-12.8%) patients. CXR/abdominal US could detect the solid cancer in one patient, whereas 18F-FDG PET/CT could identify all four solid cancers. Furthermore, four (5.2%; 95%CI: 1.4-12.8%) cases of monoclonal gammopathy of undetermined significance (MGUS) were found. An increase in C reactive protein (CRP) implicated an increased risk for cancer of 2.4% (OR: 1.024, 95%CI: 1.001-1.047; p = 0.041). 18F-FDG PET/CT can reveal occult cancers at an early stage with a high negative predictive value, and it is specifically beneficial in PMR/GCA patients with nonspecific symptoms.

Assessing the effect of interventions for axial spondyloarthritis according to the endorsed ASAS/OMERACT core outcome set: a meta-research study of trials included in Cochrane reviews.

The Assessment of SpondyloArthritis international Society (ASAS) has defined core sets for (i) symptom-modifying anti-rheumatic drugs (SM-ARD), (ii) clinical record keeping, and (iii) disease-controlling anti-rheumatic therapy (DC-ART). These include the following domains for all three core sets: "physical function," "pain," "spinal mobility," "spinal stiffness," and "patient's global assessment" (PGA). The core set for clinical record keeping further includes the domains "peripheral joints/entheses" and "acute phase reactants," and the core set for DC-ART further includes the domains "fatigue" and "spine radiographs/hip radiographs." The Outcome Measures in Rheumatology (OMERACT) endorsed the core sets in 1998.Using empirical evidence from axSpA trials, we investigated the efficacy (i.e., net benefit) according to the ASAS/OMERACT core outcome set for axSpA across all interventions tested in trials included in subsequent Cochrane reviews. For all continuous scales, we combined data using the standardized mean difference (SMD) to meta-analyze outcomes involving the same domains. Also, through meta-regression analysis, we examined the effect of the separate SMD measures (independent variables) on the primary endpoint (log [OR], dependent variable) across all trials.Based on 11 eligible Cochrane reviews, from these, 85 articles were screened; we included 43 trials with 63 randomized comparisons. Mean (SD) number of ASAS/OMERACT core outcome domains measured for SM-ARD/physical therapy trials was 4.2 (1.7). Six trials assessed all proposed domains. Mean (SD) for number of core outcome domains for DC-ART trials was 5.8 (1.7). No trials assessed all nine domains. Eight trials (16%) were judged to have inadequate (i.e., high risk of) selective outcome reporting bias. The most responsible core domains for achieving success in meeting the primary objective per trial were pain, OR (95% CI) 5.19 (2.28, 11.77), and PGA, OR (95% CI) 1.87 (1.14, 3.07). In conclusion, selective outcome reporting (and "missing data") should be reduced by encouraging the use of the endorsed ASAS/OMERACT outcome domains in clinical trials. Overall outcome reporting was good for SM-ARD/physical therapy trials and poor for DC-ART trials. Our findings suggest that both PGA and pain provide a valuable holistic construct for the assessment of improvement beyond more objective measures of spinal inflammation.

The Utility of 18F-FDG PET/CT in Patients With Clinical Suspicion of Polymyalgia Rheumatica and Giant Cell Arteritis: A Prospective, Observational, and Cross-sectional Study.

OBJECTIVE: To define the proportions of agreement between fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT), clinical diagnosis, and temporal artery biopsy (TAB) in patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). Furthermore, the association of 18F-FDG PET/CT uptake patterns and clinical presentation of newly diagnosed PMR and GCA was investigated. METHODS: Eighty patients newly suspected of having PMR, GCA, or concomitant PMR and GCA were included and followed for 40 weeks. Every patient underwent an 18F-FDG PET/CT scan before or within 3 days of initiation of steroids in case of GCA. FDG uptakes in 8 paired articular/periarticular sites and 14 arterial segments were evaluated based on a 4-point visual grading scale. RESULTS: Of the 80 patients (female: 50 [62.5%]; mean age ± SD: 72.0 ± 7.9), 64 (80.0%) patients were diagnosed with pure PMR, 3 (3.7%) with pure GCA, and 10 (12.5%) with concomitant PMR and GCA. Additionally, three (3.7%) patients were diagnosed with seronegative rheumatoid arthritis during the follow-up period. For the diagnosis of PMR, 18F-FDG PET/CT had a proportion of agreement of 75.3 (64.2-84.4), compared with clinical diagnosis. When comparing findings of 18F-FDG PET/CT with TAB, 18F-FDG PET/CT had a proportion of agreement of 93.0 (84.3-97.7) in all included patients and 69.2 (38.6-90.9) in the subgroup of patients with vasculitis. C-reactive protein was significantly higher in patients with PMR activity on 18F-FDG PET/CT compared with those without 18F-FDG PET/CT activity (P value = 0.006). CONCLUSIONS: 18F-FDG PET/CT is a powerful imaging technique in PMR and GCA that was in good agreement with clinical diagnosis and TAB.

Measuring Faecal Glucocorticoid Metabolites to Assess Adrenocortical Activity in Reindeer.

Several non-invasive methods for assessing stress responses have been developed and validated for many animal species. Due to species-specific differences in metabolism and excretion of stress hormones, methods should be validated for each species. The aim of this study was to conduct a physiological validation of an 11-oxoaetiocholanolone enzyme immunoassay (EIA) for measuring faecal cortisol metabolites (FCMs) in male reindeer by administration of adrenocorticotrophic hormone (ACTH; intramuscular, 0.25 mg per animal). A total of 317 samples were collected from eight male reindeer over a 44 h period at Tverrvatnet in Norway in mid-winter. In addition, 114 samples were collected from a group of reindeer during normal handling and calf marking at Stjernevatn in Norway. Following ACTH injection, FCM levels (median and range) were 568 (268-2415) ng/g after two hours, 2718 (414-8550) ng/g after seven hours and 918 (500-6931) ng/g after 24 h. Levels were significantly higher from seven hours onwards compared to earlier hours (p < 0.001). The FCM levels at Stjernevatn were significantly (p < 0.001) different before (samples collected zero to two hours; median: 479 ng/g) and after calf marking (eight to ten hours; median: 1469 ng/g). Identification of the faecal samples belonging to individual animals was conducted using DNA analysis across time. This study reports a successful validation of a non-invasive technique for measuring stress in reindeer, which can be applied in future studies in the fields of biology, ethology, ecology, animal conservation and welfare.

The impact of sex and disease classification on patient-reported outcome measures in axial spondyloarthritis: a descriptive prospective cross-sectional study.

BACKGROUND: The aim of this study was to explore the impact of sex and disease classification on outcomes in axial spondyloarthritis (axSpA) patients, including both radiographic (r-) axSpA and non-radiographic (nr-) axSpA, in males and females, respectively. METHODS: AxSpA patients were consecutively recruited from two rheumatology outpatient university clinics. We explored how sex and axSpA disease classification affected patient-reported outcome measures (PROMs). General linear models were used to investigate if there was an association between the continuous variables and each of the main effects of interest (sex and axSpA classification), as well as the possible interaction between them. Categorical outcome measures were analyzed with the use of logistic regression with the same fixed effects. We analyzed the relationship between tender point count (TPC) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). The prevalence of extra-articular manifestations (EAMs) and the Charlson Comorbidity Index (CCI) were determined. RESULTS: According to the protocol, a total of 100 outpatients with axSpA were enrolled (r-axSpA males 30, r-axSpA females 10, nr-axSpA males 25, nr-axSpA females 35). The BASDAI scores appeared higher among nr-axSpA females (median [Q1; Q3], 47 [21; 60]) compared with the combined median for the 3 other subgroups 25 [12; 25]. Female sex was associated with a higher number of tender point count (TPC, P < 0.001). TPC and BASDAI were correlated for female nr-axSpA patients (r = 0.44, P = 0.008) and male nr-axSpA patients (r = 0.56, P = 0.003). Being classified as nr-axSpA was associated with a lower SF-36 Mental Component Summary (median for the 4 subgroups: nr-axSpa females 46.7, nr-axSpA males 52.3 vs. r-axSpA males 56.9 and r-axSpA females 50.4). EAMs were frequent (up to 50%). The CCI was low in all 4 subgroups, and no difference in the CCI between the subgroups was observed (P = 0.14). However, male sex had a significant impact on the CCI (P = 0.03). CONCLUSIONS: In summary, patients with r-axSpA, regardless of sex, appeared less affected on most PROMs compared with nr-axSpA patients. However, female sex was associated with a higher number of TPC. TPC could possibly confound disease activity outcomes such as BASDAI, and one can consider different thresholds for defining high disease activity depending on the patient's sex. TRIAL REGISTRATION: The trial is registered and approved by the Region of Southern Denmark's Ethics Committee ( S-20150219 ). Registered 19 February 2015.

Carnivore Management Zones and their Impact on Sheep Farming in Norway.

We investigated the impact of Norway's current zonal carnivore management system for four large carnivore species on sheep farming. Sheep losses increased when the large carnivores were reintroduced, but has declined again after the introduction of the zoning management system. The total number of sheep increased outside, but declined slightly inside the management zones. The total sheep production increased, but sheep farming was still lost as a source of income for many farmers. The use of the grazing resources became more extensive. Losses decreased because sheep were removed from the open outfield pastures and many farmers gave up sheep farming. While wolves expel sheep farming from the outfield grazing areas, small herds can still be kept in fenced enclosures. Bears are in every respect incompatible with sheep farming. Farmers adjust to the seasonal and more predictable behavior of lynx and wolverine, although these species also may cause serious losses when present. The mitigating efforts are costly and lead to reduced animal welfare and lower income for the farmers, although farmers in peri-urban areas increasingly are keeping sheep as an avocation. There is a spillover effect of the zoning strategy in the sense that there is substantial loss of livestock to carnivores outside, but geographically near the management zones. The carnivore management policy used in Norway is a reasonably successful management strategy when the goal is to separate livestock from carnivores and decrease the losses, but the burdens are unequally distributed and farmers inside the management zones are at an economic disadvantage.

Treat to target strategy in early rheumatoid arthritis versus routine care - A comparative clinical practice study.

OBJECTIVE: To assess the 2-year effect on disease activity and health-related quality of life (HRQoL) of implementing a clinical practice treat-to-target (T2T) strategy in patients with rheumatoid arthritis (RA). METHODS: Patients in the Norwegian Very Early Arthritis Cohort 2.0 (NOR-VEAC 2.0), included 2010-2015, were treated according to T2T principles with visits at baseline, 3, 6, 9, 12 months, then every 6 months plus monthly visits until DAS28 <2.6. These patients were compared to a pre-T2T cohort of patients included in the Norwegian Disease Modifying Anti-Rheumatic Drug (NOR-DMARD) register 2006-2009. Both groups had a clinical diagnosis of RA (≤1 year) and were DMARD naïve. Disease activity and HRQoL outcomes were analysed, and the primary outcome was SDAI remission (≤3.3) at 2years. RESULTS: The T2T cohort included 293 patients (mean (SD) age 54 (13) years, 66% females, disease duration median (25,75 perc) 98 (57,164) days) and the routine care cohort 392 patients (age 54 (13) years, 68% females, 4 (0,30) days since diagnosis). At 2years, the proportion of patients achieving SDAI remission was 46% in the T2T cohort compared to 31% in the routine care cohort. EQ-5D was similar at baseline, but differed significantly between groups at 2years (median (25,75 perc) 0.77 (0.69, 0.85) vs 0.73 (0.59, 0.80), p < 0.001). Methotrexate monotherapy was the dominant DMARD regimen used to achieve SDAI remission in both cohorts. CONCLUSION: Higher remission rates and better HRQoL were achieved in patients following a T2T strategy in clinical practice compared to routine care.

To switch or not to switch: results of a nationwide guideline of mandatory switching from originator to biosimilar etanercept. One-year treatment outcomes in 2061 patients with inflammatory arthritis from the DANBIO registry.

OBJECTIVES: Real-world evidence on effectiveness of switching to biosimila r etanercept is scarce. In Denmark, a nationwide guideline of mandatory switch from 50 mg originator (ETA) to biosimilar (SB4) etanercept was issued for patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) in 2016. Clinical characteristics and treatment outcomes were studied in ETA-treated patients, who switched to SB4 (switchers) or maintained ETA (non-switchers). Retention rates were compared with that of a historic cohort of ETA-treated patients. Switchers who resumed ETA treatment (back-switchers) were characterised. METHODS: Observational cohort study based on the DANBIO registry. Treatment retention was explored by Kaplan-Meier plots and Cox regression (crude, adjusted). RESULTS: 1621 (79%) of 2061 ETA-treated patients switched to SB4. Disease activity was unchanged 3 months' preswitch/postswitch. Non-switchers often received 25 mg ETA (ETA 25 mg pens/syringes and powder solution were still available). One-year adjusted retention rates were: non-switchers: 77% (95% CI: 72% to 82%)/switchers: 83% (79% to 87%)/historic cohort: 90% (88% to 92%). Patients not in remission had lower retention rates than patients in remission, both in switchers (crude HR 1.7 (1.3 to 2.2)) and non-switchers (2.4 (1.7 to 3.6)). During follow-up, 120 patients (7% of switchers) back-switched to ETA. Back-switchers' clinical characteristics were similar to switchers, and reasons for SB4 withdrawal were mainly subjective. CONCLUSION: Seventy-nine per cent of patients switched from ETA to SB4. After 1 year, adjusted treatment retention rates were lower in switchers versus the historic ETA cohort, but higher than in non-switchers. Withdrawal was more common in patients not in remission. The results suggest that switch outcomes in routine care are affected by patient-related factors and non-specific drug effects.