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SARS-CoV-2 vaccination in rheumatoid arthritis (RA) patients treated with B cell-depleting drugs induced limited seroconversion but robust cellular response. We aimed to document specific T and B cell immunity in response to vaccine booster doses and breakthrough infection (BTI). We included 76 RA patients treated with rituximab who received up to four SARS-CoV-2 vaccine doses or three doses plus BTI, in addition to vaccinated healthy donors (HD) and control patients treated with tumor necrosis factor inhibitor (TNFi). We quantified anti-SARS-CoV-2 receptor-binding domain (RBD) Spike IgG, anti-nucleocapsid (NC) IgG, 92 circulating inflammatory proteins, Spike-binding B cells, and Spike-specific T cells along with comprehensive high-dimensional phenotyping and functional assays. The time since the last rituximab infusion, persistent inflammation, and age were associated with the anti-SARS-CoV-2 RBD IgG seroconversion. The vaccine-elicited serological response was accompanied by an incomplete induction of peripheral Spike-specific memory B cells but occurred independently of T cell responses. Vaccine- and BTI-elicited cellular immunity was similar between RA and HD in terms of frequency or phenotype of Spike-specific cytotoxic T cells and in terms of the functionality and differentiation profile of Spike-specific T cells. SARS-CoV-2 vaccination in RA can induce persistent effector T-cell responses that are reactivated by BTI. Paused rituximab medication allowed serological responses after a booster dose (D4), especially in RA with lower inflammation, enabling efficient humoral and cellular immunity after BTI, and contributed overall to the development of potential durable immunity.

ObjectiveProactive therapeutic drug monitoring (pTDM) intends to optimise tumour necrosis factor (TNF) inhibitor treatment through regular assessment of drug and antidrug antibody levels, enabling individualised dosing. However, health economic evidence for this strategy is limited. This study aims to evaluate the health benefits and costs of pTDM with infliximab compared with standard therapy.MethodsBased on the 52-week randomised, controlled, open-label, multicentre Norwegian Drug Monitoring trial (NOR-DRUM) B trial, we estimated the cost-effectiveness of pTDM compared with standard infliximab maintenance therapy in patients with six different immune-mediated inflammatory diseases. For each patient (n=454), we estimated the 12-month healthcare costs, including pharmaceuticals, biochemical tests and other types of resource use. Reported in 2024 Euros, unit costs were based on market prices, diagnosis-related group cost weights and reimbursement schedules. We evaluated health outcomes with quality-adjusted life-years (QALYs), using the EuroQol five-dimension, three-level questionnaire (EQ-5D-3L) and Short Form six-dimension health utility measure (SF-6D). Indicator of cost-effectiveness was the incremental cost-effectiveness ratio, expressed as Euros/QALY, compared with an assumed cost-effectiveness threshold value of €23 755. We assessed sampling uncertainty using the non-parametric bootstrap.ResultsThe mean 1-year cost per patient in the pTDM group was lower than in the standard therapy group, with a difference of €592 (95% CI −1304 to 107), while the QALYs based on EQ-5D-3L were 0.0018 higher (95% CI −0.0126 to 0.0165). Based on the bootstrap results, pTDM has a probability of 95% of being cost-effective. In explorative subgroup analyses, pTDM appeared cost-effective for some, but not all diagnoses.ConclusionpTDM is very likely a cost-effective treatment strategy for patients with immune-mediated inflammatory diseases on infliximab maintenance therapy.Trial registration number NCT03074656.

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. 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. 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. 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. 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. ClinicalTrials.gov NCT05031767; hpps://www.clinicaltrials.gov/study/NCT05031767. DERR1-10.2196/52872.

Although flexibility traditionally has been the main focus for physical therapy in patients with ankylosing spondylitis (AS), there is now evidence for an increased risk of cardiovascular diseases (CVDs) in this group. The purposes of this study were: (1) to compare physical fitness (cardiorespiratory fitness, muscular capacity, flexibility, and balance) in patients with AS and controls and (2) to explore associations between physical fitness and disease activity in the patient group. This was a cross-sectional study. The physical fitness variables were cardiorespiratory fitness (treadmill test for estimation of peak oxygen uptake [V(O(2))peak]), muscular capacity (push-ups test), balance (30-second single-leg stand and walking in a figure-of-eight pattern), and flexibility (Bath Ankylosing Spondylitis Metrology Index [BASMI]). The Ankylosing Spondylitis Disease Activity Score (ASDAS) was used to assess disease activity. Group differences and associations were tested with the chi-square test for categorical variables, the Mann-Whitney U test for ordinal variables, and analysis of covariance for continuous variables. One hundred forty-nine of 250 of the invited patients with AS and 133 of 329 of the invited controls were included in the study. The mean ASDAS score of the patient group was 2.3 (range=0.5-4.7), and the median disease duration was 23 years (range=7-55). The patient group had significantly lower V(O(2)) peak values, with a mean difference of -2.7 mL·kg(-1)·min(-1) (95% confidence interval=-4.3, -1.1), and higher BASMI scores, with a mean difference of 1.6 (95% confidence interval=1.5, 1.8), compared with the control group. No group differences were found in balance or muscular capacity. In the patient group, significant inverse associations were found between ASDAS scores and V(O(2))peak and muscular capacity. The response rate was lower in the control group (40.4%) than in the patient group (59.6%). The lower cardiorespiratory fitness and reduced flexibility in the AS group indicate that physical therapy programs should include cardiorespiratory fitness exercises as a basic component to reduce the risk of cardiovascular disease.

ObjectivesTo assess incidence, severity and predictors of COVID-19, including protective post-vaccination levels of antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD), informing further vaccine strategies for patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive medication.MethodsIMIDs on immunosuppressives and healthy controls (HC) receiving SARS-CoV-2 vaccines were included in this prospective observational study. COVID-19 and outcome were registered and anti-RBD antibodies measured 2–5 weeks post-immunisation.ResultsBetween 15 February 2021 and 15 February 2023, 1729 IMIDs and 350 HC provided blood samples and self-reported COVID-19. The incidence of COVID-19 was 66% in patients and 67% in HC, with re-infection occurring in 12% of patients. Severe COVID-19 was recorded in 22 (2%) patients and no HC. No COVID-19-related deaths occurred. Vaccine-induced immunity gave higher risk of COVID-19 (HR 5.89 (95% CI 4.45 to 7.80)) than hybrid immunity. Post-immunisation anti-RBD levels <6000 binding antibody units/mL were associated with an increased risk of COVID-19 following three (HR 1.37 (95% CI 1.08 to 1.74)) and four doses (HR 1.28 (95% CI 1.02 to 1.62)), and of COVID-19 re-infection (HR 4.47 (95% CI 1.87 to 10.67)).ConclusionVaccinated patients with IMID have a low risk of severe COVID-19. Hybrid immunity lowers the risk of infection. High post-immunisation anti-RBD levels protect against COVID-19. These results suggest that knowledge on COVID-19 history, and assessment of antibody levels post-immunisation can help individualise vaccination programme series in high-risk individuals.Trial registration number NCT04798625.

ObjectiveTo develop and validate definitions for disease flares in rheumatoid arthritis (RA) based on the quantitative Simplified and Clinical Disease Activity Indices (SDAI, CDAI).MethodsWe analysed RA treatment courses from the Norwegian disease-modifying antirheumatic drug registry (NOR-DMARD) and the Vienna RA cohort. In a receiver operating curve analysis, we determined flare definitions for absolute changes in SDAI and CDAI based on a semiquantitative patient anchor. NOR-DMARD was sampled into an 80%-training cohort for cut point derivation and a 20%-test cohort for internal validation. The definitions were then externally validated in the independent Vienna RA cohort and tested regarding their performance on longitudinal, content, face, and construct validity.ResultsWe analysed 4256 treatment courses from NOR-DMARD and 2557 from the Vienna RA cohort. The preliminary definitions for absolute changes in SDAI and CDAI for flare are an increase of 4.7 and 4.5, respectively. The definitions performed well in the test and external validation cohorts, and showed clinical face and construct validity, as flares significantly impact both functional (∆Health Assessment Questionnaire flare vs no-flare +0.43; p<0.001) and structural (∆modified Sharp Score 43% higher after flare; p<0.001) disease outcomes, and reflect consistent worsening across all disease core sets, both patient reported and objective.ConclusionWe here provide novel definitions for flare in RA based on SDAI and CDAI, validated in two large independent real-world cohorts. In times of highly effective medications for RA, and consideration of their tapering, these definitions will be useful for guiding decision making in clinical practice and designing clinical trials.

ObjectivesJoint swelling and tenderness are considered a proxy for inflammation in patients with rheumatoid arthritis (RA). With ultrasound-detected inflammation as reference, our objectives were to explore on patient and joint level the associations between ultrasound synovitis and joint swelling, tenderness and patient-reported joint pain (PRJP).Methods209 patients with established RA were examined six times during 12 months with assessment of 32 joints in upper/lower extremities for joint swelling/tenderness and Grey scale (GS)/power Doppler (PD) synovitis. PRJP was assessed on a manikin. Correlations between different sum scores were at each examination calculated using Spearman’s rho (r), agreement at joint level was examined by Cohen’s kappa and logistic regression models were used to explore the associations between joint assessment and GS/PD scores.ResultsAt patient level, swollen joints were strongly correlated with GS/PD sum scores (r=0.64–0.88), while tender joints were primarily associated with PRJP (r=0.54–0.68). At joint level, GS/PD pathology had higher agreement with swelling (kappa 0.54–0.57) than tenderness (kappa 0.20–0.21) or PRJP (0.23–0.25). Higher percentages of joints were swollen according to increasing GS/PD scores, independently of joint tenderness. However, joints being tender, but not swollen, were not associated with GS/PD scores. Receiver operating curves showed swollen but not tender joints to be associated with GS/PD scores.ConclusionsSwollen joints were strongly associated with ultrasound detected synovitis at both patient and joint level, while this association was not found for tender joints. These results may question if tender joints reflect ongoing inflammation in established RA.

Apolipoprotein E (APOE) genotypes are associated with cardiovascular disease (CVD) and lipid levels. In rheumatoid arthritis (RA), an association has been found with disease activity. We examined the associations between APOE genotypes and disease susceptibility and markers of disease severity in RA, including radiographic joint damage, inflammatory markers, lipid levels and cardiovascular markers. A Norwegian cohort of 945 RA patients and 988 controls were genotyped for two APOE polymorphisms. We examined longitudinal associations between APOE genotypes and C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) as well as hand radiographs (van der Heijde Sharp Score(SHS)) in 207 patients with 10 year longitudinal data. Lipid levels, cardiovascular markers and history of CVD were compared across genotypes in a cross sectional study of 136 patients. Longitudinal radiological data of cohorts from Lund and Leiden were available for replication. (N = 935, with 4799 radiographs). In the Norwegian cohort, associations between APOE genotypes and total cholesterol (TC) and low-density lipoproteins (LDL) were observed (ε2 < ε3/ε3 < ε4, p = 0.03 and p = 0.02, respectively). No association was present for acute phase reactant or CVD markers, but a longitudinal linear association between APOE genotypes and radiographic joint damage was observed (p = 0.007). No association between APOE genotypes and the severity of joint destruction was observed in the Lund and Leiden cohorts, and a meta- analysis combining all data was negative. APOE genotypes are associated with lipid levels in patients with RA, and may contribute to dyslipidemia in some patients. APOE genotypes are not consistently associated with markers of inflammation or joint destruction in RA.

ObjectivesTo 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.MethodsWe 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.ResultsA 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.ConclusionsCompared with patients with RA, the risk of SIs was significantly lower in patients with PsA during TNFi exposure.

Clinically relevant fatigue is common in patients with rheumatoid arthritis (RA) and might be expected to be related to patient age and disease severity. This review provides a brief introduction to fatigue as a patient-reported outcome that contributes significantly to burden of disease, with a focus on the evidence in elderly patients, and gives an overview of our current understanding of the factors that contribute to fatigue. We summarize the evidence for the effects of pharmacological (disease-modifying anti-rheumatic drugs, DMARDs) and non-pharmacological interventions for fatigue. The underlying pathophysiology of fatigue is complex and often multifactorial. The experience of fatigue varies between individuals, and subtypes of fatigue are increasingly being recognized. Fatigue can therefore be challenging to recognize and quantify. Recent systematic reviews have shown that fatigue can be improved as a result of treatment with traditional and biological anti-rheumatic drugs, and also with non-pharmacological approaches (physical activity, psychosocial interventions). Age does not appear to be of major importance for fatigue in RA, and similar strategies for treating fatigue apply to all age groups, including the elderly.