Use of direct-acting anticoagulants (DOACs) delays surgery and is associated with increased mortality in hip fracture patients.

PURPOSE: Treatment with direct-acting oral anticoagulants (DOACs) is increasing among hip-fracture patients, with accompanying safety concerns regarding spinal anesthesia (SA). The aim of this study was to investigate if DOAC use is associated with increased waiting time before surgery, increased mortality, or other adverse events. METHODS: Registry data on surgically treated hip-fracture cases at a single hospital between 2015 and 2021 were analyzed. Multivariable regression analyses were performed with DOAC-status and choice of anesthesia as exposures, and waiting time, length of stay, transfusion, and mortality as outcomes. RESULTS: 2885 cases were included, 467 patients (16%) were using DOACs. DOAC users were older (86.3 vs. 82.2 years, p < 0.001), had a higher Charlson Comorbidity Index (2.1 vs. 1.5, p < 0.001) and had longer median time to surgery than non-DOAC cases (36 h vs 17 h, p < 0.001). General anesthesia (GA) was used in 19.3% of DOAC patients and in 3.0% of non-DOAC patients. DOAC-patients had an increased risk of one-month mortality (Adjusted Odds Ratio (AOR) 1.6 (1.1-2.3)) and one-year mortality (AOR 1.4 (1.1-1.8)). There were no differences in risk of blood transfusion. Patients on DOAC operated under GA had a lower risk of one-year mortality (AOR 0.5 (0.3-0.9)), but a similar one-month mortality to DOAC-patients operated under SA. CONCLUSION: DOAC users had a longer waiting time to surgery, indicating postponement of surgery due to concerns of the safety of SA. The clinical practice should be changed to allow earlier surgery for DOAC patients.

Follow-Up of Patients With Axial Spondyloarthritis in Specialist Health Care With Remote Monitoring and Self-Monitoring Compared With Regular Face-to-Face Follow-Up Visits (the ReMonit Study): Protocol for a Randomized, Controlled Open-Label Noninferiority Trial.

BACKGROUND: Patients with chronic inflammatory joint diseases such as axial spondyloarthritis have traditionally received regular follow-up in specialist health care to maintain low disease activity. The follow-up has been organized as prescheduled face-to-face visits, which are time-consuming for both patients and health care professionals. Technology has enabled the remote monitoring of disease activity, allowing patients to self-monitor their disease and contact health care professionals when needed. Remote monitoring or self-monitoring may provide a more personalized follow-up, but there is limited research on how these follow-up strategies perform in maintaining low disease activity, patient satisfaction, safety, and cost-effectiveness. OBJECTIVE: The Remote Monitoring in Axial Spondyloarthritis (ReMonit) study aimed to assess the effectiveness of digital remote monitoring and self-monitoring in maintaining low disease activity in patients with axial spondyloarthritis. METHODS: The ReMonit study is a 3-armed, single-site, randomized, controlled, open-label noninferiority trial including patients with axial spondyloarthritis with low disease activity (Ankylosing Spondylitis Disease Activity Score <2.1) and on stable treatment with a tumor necrosis factor inhibitor. Participants were randomized 1:1:1 to arm A (usual care, face-to-face visits every sixth month), arm B (remote monitoring, monthly digital registration of patient-reported outcomes), or arm C (patient-initiated care, self-monitoring, no planned visits during the study period). The primary end point was disease activity measured with the Ankylosing Spondylitis Disease Activity Score, evaluated at 6, 12, and 18 months. We aimed to include 240 patients, 80 in each arm. Secondary end points included other measures of disease activity, patient satisfaction, safety, and cost-effectiveness. RESULTS: The project is funded by the South-Eastern Norway Regional Health Authority and Centre for the treatment of Rheumatic and Musculoskeletal Diseases (REMEDY), Diakonhjemmet Hospital, Norway. Enrollment started in September 2021 and was completed with 242 patients by June 2022. The data collection will be completed in December 2023. CONCLUSIONS: To our knowledge, this trial will be among the first to evaluate the effectiveness, safety, and cost-effectiveness of remote digital monitoring and self-monitoring of patients with axial spondyloarthritis compared with usual care. Hence, the ReMonit study will contribute important knowledge to personalized follow-up strategies for patients with axial spondyloarthritis. These results may also be relevant for other patient groups with inflammatory joint diseases. TRIAL REGISTRATION: ClinicalTrials.gov NCT05031767; hpps://www.clinicaltrials.gov/study/NCT05031767. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/52872.

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.

All-cause and cause-specific mortality in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis: a nationwide registry study.

OBJECTIVES: To explore mortality and causes of death among Norwegian patients with RA, PsA and axial spondyloarthritis (axSpA) compared with the general population by conducting a nationwide registry-based cohort study. METHODS: Patients with RA, PsA and axSpA were identified from the Norwegian Patient Registry based on ICD-10 codes between 2008 and 2017. Using age as the time variable, all-cause and cause-specific mortality were estimated between 2010 and 2017 with the Kaplan-Meier estimator and the cumulative incidence competing risk method, respectively. Sex-, education level-, health region- and age group-adjusted hazard ratios (HRs) for mortality were estimated using Cox regression models. RESULTS: We identified 36 095 RA, 18 700 PsA and 16 524 axSpA patients (70%, 53% and 45% women, respectively). RA and axSpA were associated with increased all-cause mortality (HR 1.45 [95% CI: 1.41, 1.48] and HR 1.38 [95% CI: 1.28, 1.38], respectively). Women but not men with PsA had a slightly increased mortality rate (HR 1.10 [95% CI: 1.00, 1.21] among women and 1.02 [95% CI: 0.93, 1.11] among men). For all patient groups as well as for the general population, the three leading causes of death were cardiovascular diseases, neoplasms and respiratory diseases. RA patients had increased mortality from all of these causes, while axSpA patients had increased mortality from cardiovascular and respiratory diseases. CONCLUSION: Even in the era of modern treatments for IJDs, patients with RA and axSpA still have shortened life expectancy. Our findings warrant further attention to the prevention and management of comorbidities.

Serious infections in patients with rheumatoid arthritis and psoriatic arthritis treated with tumour necrosis factor inhibitors: data from register linkage of the NOR-DMARD study.

OBJECTIVES: To estimate the incidence of serious infections (SIs) in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) treated with tumour necrosis factor inhibitor (TNFi), and compare risk of SIs between patients with RA and PsA. METHODS: We included patients with RA and PsA from the NORwegian-Disease Modifying Anti-Rheumatic Drug registry starting TNFi treatment. Crude incidence rates (IRs) and IR ratio for SIs were calculated. The risk of SIs in patients with RA and PsA was compared using adjusted Cox-regression models. RESULTS: A total of 3169 TNFi treatment courses (RA/PsA: 1778/1391) were identified in 2359 patients. Patients with RA were significantly older with more extensive use of co-medication. The crude IRs for SIs were 4.17 (95% CI 3.52 to 4.95) in patients with RA and 2.16 (95% CI 1.66 to 2.81) in patients with PsA. Compared with the patients with RA, patients with PsA had a lower risk of SIs (HR 0.59, 95% CI 0.41 to 0.85, p=0.004) in complete set analysis. The reduced risk in PsA versus RA remained significant after multiple adjustments and consistent across strata based on age, gender and disease status. CONCLUSIONS: Compared with patients with RA, the risk of SIs was significantly lower in patients with PsA during TNFi exposure.

Rheumatoid Arthritis Patients, Both Newly Diagnosed and Methotrexate Treated, Show More DNA Methylation Differences in CD4+ Memory Than in CD4+ Naïve T Cells.

Background: Differences in DNA methylation have been reported in B and T lymphocyte populations, including CD4+ T cells, isolated from rheumatoid arthritis (RA) patients when compared to healthy controls. CD4+ T cells are a heterogeneous cell type with subpopulations displaying distinct DNA methylation patterns. In this study, we investigated DNA methylation using reduced representation bisulfite sequencing in two CD4+ T cell populations (CD4+ memory and naïve cells) in three groups: newly diagnosed, disease modifying antirheumatic drugs (DMARD) naïve RA patients (N = 11), methotrexate (MTX) treated RA patients (N = 18), and healthy controls (N = 9) matched for age, gender and smoking status. Results: Analyses of these data revealed significantly more differentially methylated positions (DMPs) in CD4+ memory than in CD4+ naïve T cells (904 vs. 19 DMPs) in RA patients compared to controls. The majority of DMPs (72%) identified in newly diagnosed and DMARD naïve RA patients with active disease showed increased DNA methylation (39 DMPs), whereas most DMPs (80%) identified in the MTX treated RA patients in remission displayed decreased DNA methylation (694 DMPs). Interestingly, we also found that about one third of the 101 known RA risk loci overlapped (±500 kb) with the DMPs. Notably, introns of the UBASH3A gene harbor both the lead RA risk SNP and two DMPs in CD4+ memory T cells. Conclusion: Our results suggest that RA associated DNA methylation differences vary between the two T cell subsets, but are also influenced by RA characteristics such as disease activity, disease duration and/or MTX treatment.

The role of anti-citrullinated protein antibody reactivities in an inception cohort of patients with rheumatoid arthritis receiving treat-to-target therapy.

BACKGROUND: Anti-citrullinated protein antibody (ACPA) reactivities precede clinical onset of rheumatoid arthritis (RA), and it has been suggested that ACPA reactivities towards distinct target proteins may be associated with differences in RA phenotypes. We aimed to assess the prevalence of baseline ACPA reactivities in an inception cohort of patients with early RA, and to investigate their associations with disease activity, treatment response, ultrasound findings and radiographic damage. METHODS: Disease-modifying antirheumatic drug (DMARD)-naïve patients with early RA, classified according to the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria, were included in the ARCTIC trial and assessed in the present analysis. During follow up, patients were monitored frequently and treatment was adjusted according to a predetermined protocol, starting with methotrexate monotherapy with prednisolone bridging. Analysis of 16 different ACPA reactivities targeting citrullinated peptides from fibrinogen, alpha-1 enolase, vimentin, filaggrin and histone was performed using a multiplex chip-based assay. Samples from 0, 3, 12 and 24 months were analysed. Controls were blood donors with similar characteristics to the patients (age, gender, smoking status). RESULTS: A total of 217 patients and 94 controls were included. Median [25, 75 percentile] number of ACPA reactivities in all patients was 9 [4, 12], and were most prevalent in anti-cyclic citrullinated peptide /rheumatoid factor-positive patients 10 [7, 12]. Disease activity measures and ultrasound scores at baseline were lower in ACPA reactivity-positive compared to ACPA reactivity-negative patients. ACPA reactivity levels decreased after 3 months of DMARD treatment, most pronounced for fibrinogenß 60-74 to 62% of baseline antibody level, with least change in filaggrin 307-324 to 81% of baseline antibody level, both p < 0.001. However, outcomes in disease activity measures, ultrasound and radiographic scores after 12 and 24 months were not associated with baseline levels or changes in ACPA reactivity levels and/or seroreversion after 3 months. CONCLUSIONS: The clinical relevance of analysing ACPA reactivities in intensively treated and closely monitored early RA was limited, with no apparent associations with disease activity, prediction of treatment response or radiographic progression. Further studies in larger patient materials are needed to understand the role of ACPA reactivities in patients with RA classified according to the 2010 ACR/EULAR criteria and treated according to modern treatment strategies. TRIAL REGISTRATION: www.ClinicalTrials.gov, NCT01205854 . Registered on 21 September 2010.

The OMERACT MRI in Arthritis Working Group - Update on Status and Future Research Priorities.

OBJECTIVE: To provide an update on the status and future research priorities of the Outcome Measures in Rheumatology (OMERACT) magnetic resonance imaging (MRI) in arthritis working group. METHODS: A summary is provided of the activities of the group within rheumatoid arthritis (RA), psoriatic arthritis (PsA), and osteoarthritis (OA), and its research priorities. RESULTS: The OMERACT RA MRI score (RAMRIS) evaluating bone erosion, bone edema (osteitis), and synovitis is now the standard method of quantifying articular pathology in RA trials. Cartilage loss is another important part of joint damage, and at the OMERACT 12 conference, we provided longitudinal data demonstrating reliability and sensitivity to change of the RAMRIS JSN component score, supporting its use in future clinical trials. The MRI group has previously developed a PsA MRI score (PsAMRIS). At OMERACT 12, PsAMRIS was evaluated in a randomized placebo-controlled trial of patients with PsA, demonstrating the responsiveness and discriminatory ability of applying the PsAMRIS to hands and feet. A hand OA MRI score (HOAMRIS) was introduced at OMERACT 11, and has subsequently been further validated. At OMERACT 12, good cross-sectional interreader reliability, but variable reliability of change scores, were reported. Potential future research areas were identified at the MRI session at OMERACT 12 including assessment of tenosynovitis in RA and enthesitis in PsA and focusing on alternative MRI techniques. CONCLUSION: MRI has been further developed and validated as an outcome measure in RA, PsA, and OA. The group will continue its efforts to optimize the value of MRI as a robust biomarker in rheumatology clinical trials.

Iterative development and reliability of the OMERACT hand osteoarthritis MRI scoring system.

OBJECTIVE: To develop and test the interreader reliability of the OMERACT Hand Osteoarthritis Magnetic Resonance Scoring System (HOAMRIS) for assessment of structural and inflammatory hand OA features in the interphalangeal joints. METHODS: The HOAMRIS was developed through an iterative process. Selection of features and their scaling was agreed upon through consensus by members of the OMERACT Magnetic Resonance Imaging (MRI) Task Force, using the Oslo Hand Osteoarthritis (OA) MRI Score system as a template. Two reliability exercises were performed, in which 6 and 4 readers participated, respectively. After the first exercise, an atlas was developed and used in the second exercise to facilitate reading. In each exercise, readers independently scored 8 MRI scans from the Oslo Hand OA cohort (coronal/axial short-tau inversion recovery and coronal/axial/sagittal T1-weighted fat-suppressed pre-/post-Gadolinium images). Interreader reliability was assessed by intraclass correlation coefficients (ICC), percentage exact and close agreement (PEA/PCA). RESULTS: The preliminary OMERACT HOAMRIS included assessment of synovitis, erosive damage, cysts, osteophytes, cartilage space loss, malalignment, and bone marrow lesions (BML), of which all were scored on a 0-3 scale for normal, mild, moderate, and severe (increments of 0.5 for synovitis, erosive damage, and BML). In the first exercise, most features showed good to very good ICC values (0.64-0.94), except synovitis (0.34). In the second exercise using the atlas, the ICC values were > 0.74 for all MRI features, and the PEA/PCA values were higher than in the first exercise. CONCLUSION: A preliminary HOAMRIS with good to very good interreader reliability was developed. Longitudinal studies are needed to assess its sensitivity to change.

The OMERACT Psoriatic Arthritis Magnetic Resonance Imaging Score (PsAMRIS) is reliable and sensitive to change: results from an OMERACT workshop.

OBJECTIVE: The aim of this multireader exercise was to assess the reliability and sensitivity to change of the psoriatic arthritis magnetic resonance imaging score (PsAMRIS) in PsA patients followed for 1 year. METHODS: MRI was acquired from 12 patients with PsA before initiation of treatment and after 12 months. MR images were scored according to PsAMRIS (for synovitis, tenosynovitis, periarticular inflammation, bone marrow edema, bone erosion, and bone proliferation) under standardized conditions, in unknown chronological order. Intraobserver/interobserver reliability was examined by intraclass correlation coefficients (ICC) and sensitivity to change by standardized response means (SRM). RESULTS: The interobserver reliability of PsAMRIS was high for synovitis, tenosynovitis, periarticular inflammation, and bone edema status and change scores (interobserver ICC 0.87-0.97). The intraobserver reliability was moderate to high (ICC 0.60-0.98) for status and change scores, except for change in periarticular inflammation (ICC 0.33). PsAMRIS sensitivity to change was moderate for synovitis, tenosynovitis, and periarticular inflammation (SRM 0.5-0.8), while poor (SRM 0.1-0.3) for bone marrow edema, erosion, and bone proliferation. Rare occurrence and minimal change contributed to poor SRM and change-score ICC for bone parameters. CONCLUSION: This multireader exercise, performed under standardized conditions, confirmed PsAMRIS to have high interobserver and intraobserver reliability for hand PsA. Measures of inflammation were sensitive to change, implying that PsAMRIS may be a valuable tool for monitoring change in inflammation during PsA clinical trials.

Update on research and future directions of the OMERACT MRI inflammatory arthritis group.

The OMERACT Magnetic Resonance Imaging (MRI) Task Force has developed and evolved the psoriatic arthritis MRI score (PsAMRIS) over the last few years, and at OMERACT 10, presented longitudinal evaluation by multiple readers, using PsA datasets obtained from extremity MRI magnets. Further evaluation of this score will require more PsA imaging datasets. As well, due to improved image resolution since the development of the original rheumatoid arthritis MRI scoring system (RAMRIS), the Task Force has worked on semiquantitative assessment of joint space narrowing, and developed a reliable method as a potential RAMRIS addendum, although responsiveness will need to be evaluated. One of the strengths of MRI is the ability to detect subclinical synovitis, so the group worked on obtaining low disease activity/clinical remission datasets from a number of international centers and presented cross-sectional findings. Subsequent longitudinal evaluation of this unique resource will be a major continuing focus for the group.

Hand osteoarthritis and MRI: development and first validation step of the proposed Oslo Hand Osteoarthritis MRI score.

OBJECTIVES: MRI scoring systems for hand osteoarthritis (HOA) are currently not available. The present work proposes the Oslo HOA MRI (OHOA-MRI) score and examines the intrareader and inter-reader reliability. METHODS: Relevant HOA features were included in the initial version of the OHOA-MRI score after literature review and informal group discussions. After a training session and two calibration exercises (with three readers), features with low reliability and/or low prevalence were excluded, and feature definitions/gradings were improved. In the reliability exercise 3 readers independently evaluated MRI scans of distal interphalangeal (DIP) and proximal interphalangeal (PIP) joints in 10 patients with HOA according to the final proposed score. The reading was repeated after 1 week. Intraclass correlation coefficients (ICCs), percentage exact agreement/percentage close agreement (PEA/PCA) and smallest detectable difference were calculated. RESULTS: The final proposed OHOA-MRI score includes assessment of synovitis, flexor tenosynovitis, erosions, osteophytes (OPs), joint space narrowing (JSN) and bone marrow lesions (BMLs) on a 0-3 scale, and absence/presence of cysts, malalignment (frontal/sagittal plane), collateral ligaments (CLs) and BMLs at CL insertion sites. Inter-reader reliability was very good for synovitis, erosions, OPs, JSN, malalignment (frontal) and BMLs (ICCs ≥ 0.83, PCA ≥ 89%), and good for flexor tenosynovitis (ICC 0.64, PCA 80%) and CL presence (ICC 0.79, PEA 63%). Cysts, malalignment (sagittal) and BMLs at CL insertion sites showed high PEA (≥ 85%), but poor to moderate ICCs (0.00-0.59). Intrareader reliability was similar. The reliability was generally highest in PIP joints. CONCLUSIONS: The proposed OHOA-MRI score could reliably assess HOA features. However, further validation is needed.