Tore Kristian Kvien

Objective: Plasma calprotectin is a marker of neutrophil activity. Its relation to the clinical phenotype and autoantibodies in rheumatoid arthritis (RA) is only partly understood. We therefore aimed to investigate the association between calprotectin and the clinical parameters C‐reactive protein (CRP), erythrocyte sedimentation rate (ESR), anti–cyclic citrullinated peptide 2 (anti‐CCP2), and other anti–modified protein antibodies (AMPAs) in patients with RA. Methods: Rheumatoid factor (RF), anti‐CCP2 isotypes, and plasma calprotectin were centrally measured in a cross‐sectional cohort of 4,521 Scandinavian patients with RA using fluoro‐enzyme immunoassays. IgG to 15 citrullinated (Cit) and 4 carbamylated or acetylated (Carb/Acet) peptides were measured by multiplex solid‐phase array. CRP and ESR values were obtained from clinical measurements at the time of blood sampling. Results: Calprotectin levels correlated with ESR (ρ = 0.53), CRP (ρ = 0.47), visual analog scale (VAS) pain (ρ = 0.24), Swollen Joint Count in 28 joints (SJC28; ρ = 0.39), and Tender Joint Count in 28 joints (TJC28; ρ = 0.26; P < 0.0001 for all). Patients with both elevated CRP (>10 mg/L) and calprotectin (>15 arbitrary units/mL) (14%, n = 613) had significantly higher VAS pain, SJC28, and TJC28 scores than patients with only elevated CRP ( P < 0.0001), in early and established disease. Patients with elevated calprotectin, independent of CRP levels, had significantly higher proportions of AMPA positivity, including anti‐CCP2. When patients were divided into six groups based on increasing number of Cit/Carb/Acet reactivities and anti‐CCP2 IgG levels, elevated calprotectin was associated with increasing AMPA load, particularly in the presence of RF IgM. The differences between AMPA load groups remained after adjusting for sex, age, RF IgM, and disease duration. Conclusion: Plasma calprotectin is positively associated with seropositivity and AMPA load by autoantibody levels and the breadth of the autoantibody response.

Objectives: This population-based study assesses comorbidities, autoimmune conditions and all-cause mortality in [1] adults with juvenile idiopathic arthritis (JIA) against general population comparators and [2] adults with JIA with vs without recent disease-modifying anti-rheumatic drug (DMARD) exposure. Methods: We included adults who, between 2009 and 2024, had ≥2 specialist health contacts with a JIA-specific ICD-10 code in the mandatory Norwegian Patient Registry (NPR). Each case was matched randomly, by age, gender and county of residence, to 10 general population comparators at the time of receiving the second JIA diagnosis in adulthood. We compared 5-year retrospective comorbidity prevalences in descriptive analyses and prospective all-cause mortality in [1] adults with JIA vs comparators and [2] adult JIA with vs without recent DMARD exposure. Results: Adults with JIA (N = 2932) had higher prevalence than comparators (N = 29 097) of ischemic heart disease excluding myocardial infarction [JIA vs comparators (%): 1.0 vs 0.6], hypertension (3.6 vs 1.4), chronic kidney disease (0.5 vs 0.2), type 1 diabetes (1.7 vs 0.7), coeliac disease (1.4 vs 0.7), autoimmune thyroiditis (0.3 vs 0.1) and autoimmune alopecia (0.4 vs 0.1). Prospective all-cause mortality was higher in JIA than comparators (mortality rate 2.4 vs 1.8 per 1000 person-years). In adult JIA, prevalences of comorbidities and autoimmune conditions as well as all-cause mortality was similar in those with and without recent DMARD exposure. Conclusion: In this study we found an increased 5-year retrospective prevalence of several comorbidities and increased all-cause mortality in adults with JIA compared with population controls.

Objective: To develop, externally validate, and simplify a machine learning model to predict remission between 6 and 24 months in patients with rheumatoid arthritis (RA) initiating tumor necrosis factor inhibitors, JAK inhibitors, interleukin‐6 inhibitors, abatacept, or rituximab using data from 11 international registries in the JAK‐pot collaboration. Methods: We analyzed 21,675 treatment courses for model training, 5,418 courses for internal validation, and 1,807 courses from Switzerland for external validation. Remission was defined as a Clinical Disease Activity Index score ≤2.8 within 6 to 24 months after treatment initiation or switching. An XGBoost model was trained on 63 baseline demographic and clinical variables. Model performance was evaluated using the area under the curve (AUC), sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Predictor contributions were quantified using Shapley Additive Explanations values. A simplified model using the top 10 predictors and a logistic regression benchmark were also evaluated. Results: In external validation, the full model achieved an AUC of 0.797 (95% confidence interval 0.774–0.821), sensitivity of 0.804, specificity of 0.650, PPV of 0.454, and NPV of 0.902. The simplified model performed comparably (AUC 0.802). Logistic regression using the same 10 predictors achieved an AUC of 0.809. Key predictors included patient global assessment, 28‐tender joint count, previous biologic/targeted synthetic disease‐modifying antirheumatic drug exposure, and Health Assessment Questionnaire Disability Index score. Conclusion: Using routinely collected baseline data across 11 registries, prediction of remission showed limited discrimination and was best suited to ruling out remission. Performance was similar for a 10‐variable model and logistic regression, indicating limited incremental value of model complexity without richer predictors. image

Objective: Proactive 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. Methods: Based 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. Results: The 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. Conclusion: pTDM is very likely a cost-effective treatment strategy for patients with immune-mediated inflammatory diseases on infliximab maintenance therapy. Trial registration number: NCT03074656 .

Objective: The Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is widely used for assessing disease activity in patients with axial spondyloarthritis (axSpA), particularly in settings where markers of inflammation are unavailable. As no consensus on BASDAI cut‐off values exists for disease activity states in axSpA, we aimed to develop and validate such cut‐offs against external criteria. Methods: Routine care patients with axSpA initiating a biologic disease‐modifying antirheumatic drug in eight European registries were included. Receiver operating characteristic analyses against external criteria were performed to determine optimal BASDAI values for separating remission, low disease activity (LDA), high disease activity (HDA), and very high disease activity (VHDA). Follow‐up data at 6 months were used to select BASDAI cut‐off values between remission and LDA and between LDA and HDA, whereas baseline data were used to select the cut‐off for VHDA. The level of agreement between disease activity states based on BASDAI and Axial Spondyloarthritis Disease Activity Score (ASDAS) cut‐off values was assessed using the proportion of discordance and weighted kappa. Results: In this cohort of 4,633 patients, the optimal BASDAI cut‐off values between remission, LDA, HDA and VHDA were estimated to be 4,600 patients. These cut‐off values can be used for assessing disease activity and monitoring patients with axSpA, particularly when laboratory markers are unavailable.

Introduction Osteoarthritis (OA) is associated with joint pain and disability, with increasing prevalence and economic burden. This study explored non-steroidal anti-inflammatory drugs (NSAID) treatment patterns, gastrointestinal (GI) complications and burden of disease in patients with OA based on Nordic registry data, with emphasis on individuals aged 60 or younger. Methods This non-interventional observational study analysed registry data from Norway, Finland, and Sweden. Adults with primary OA diagnosis in specialty care were matched 1:1 by age and sex with individuals of the general population. The primary outcome was NSAID treatment patterns, assessed by dispensations and daily defined doses (DDD) 1 year before and after diagnosis. Secondary outcomes included prevalence of comorbidities, the incidence of GI complications, sick leave, and joint replacements. Results The study included 189,553 patients with OA from Norway, 341,548 from Sweden, and 218,253 from Finland, 34.1% to 40.4% aged ≤ 60. About half of patients had NSAIDs dispensed before and after diagnosis, (Norway 56.6% and 48.6%; Sweden 50.1% and 44.0%; Finland 58.8% and 58.2%), compared to about one-fifth of the matches (Norway 19.1% and 18.5%; Sweden 12.7% and 12.2%; Finland 22.5% and 21.7%). NSAID use increased with age until approximately 55 years, then declined. After diagnosis, fewer patients had NSAID dispensations, but mean DDDs per prescription were generally higher. Secondary analyses showed a higher comorbidity burden, higher rates of GI complications, more sick leave days, and more joint replacements in patients with OA than in matched individuals. Conclusion Across Nordic countries, patients with OA had more NSAID dispensations, and GI complications were more prevalent compared to matched individuals. Notably, this was already evident in younger patients under the age of 60, underscoring the need for comprehensive GI risk assessment for every patient with OA. The substantial burden of OA was also evidenced by considerable numbers of sick leave days and joint replacements.

Objective: To explore health-related quality of life (HRQOL) measured by the 36-item Short Form Health Survey (SF-36), SF-36 physical component summary (PCS), SF-36 mental component summary (MCS), and Short Form 6D (SF-6D) in adults with juvenile idiopathic arthritis (JIA) compared to patients with rheumatoid arthritis (RA) and the general population. Methods: We used 6-month follow-up data from the Norwegian Disease-Modifying Antirheumatic Drug Register (NOR-DMARD), including adult patients with JIA and RA starting or switching disease-modifying antirheumatic drug (DMARD) treatment. Age- and gender-adjusted regression analyses were used to compare outcomes among JIA, RA, and the general Norwegian population. Results: Register data were available for 232 patients with JIA and 2764 with RA at 6 months follow-up. Patients with JIA had poorer physical health compared to those with RA (adjusted difference [95% CI]: PCS −3.58 [−6.09 to −1.08]). Compared to the general population, PCS scores were lower in both JIA and RA (adjusted differences [95% CI]: JIA–general population −15.70 [−18.21 to −13.19], RA–general population −12.12 [−12.76 to −11.47]). Mental health measured by MCS was similar across the 3 groups. Average SF-6D utility levels were comparable in JIA and RA, but lower than in the general population. Similar proportions of patients with JIA and RA experienced improvements exceeding minimum clinically important difference (MCID) in SF-36 scale scores, PCS, MCS, and SF-6D after 6 months. Conclusion: Compared to patients with RA and the general population, patients with JIA had lower physical HRQOL 6 months after DMARD initiation. Mental health composite scores were similar among patients with JIA, those with RA, and the general population. Both disease groups showed similar levels of improvement with treatment.

Objective: Tapering of tumor necrosis factor inhibitor (TNFi) treatment in rheumatoid arthritis (RA) remission is debated. We assessed the effect of tapering TNFi to withdrawal versus continued stable TNFi on flare‐free survival and joint damage progression over three years.Methods: ARCTIC REWIND was a multicenter open‐label, noninferiority trial that included patients with RA in remission for ≥12 months taking stable TNFi therapy. Patients were randomized 1:1 to taper TNFi to withdrawal or continue stable treatment. The primary end points of the current study were flare‐free survival and radiographic progression over three years. Flare‐free survival was analyzed by Kaplan‐Meier methods, flare rates were analyzed by Cox regression, and radiographic progression was analyzed by logistic mixed‐effects models.Results: Of 99 randomized patients, 92 received the allocated therapy, and 80 completed the three‐year follow‐up. The mean baseline Disease Activity Score based on the 44 joint count was 0.8, and conventional synthetic disease‐modifying antirheumatic drug comedication was used by 90% of patients. After three years, 25% (95% confidence interval [CI] 13%–38%) remained flare free in the tapering TNFi group, compared to 85% (95% CI 70%–93%) in the stable group, and the corresponding hazard ratio for flare was 9.4 (95% CI 3.9–22.8, P < 0.0001). In the tapering group, 6 of 41 (15%) experienced radiographic progression, compared with 3 of 38 (8%) in the stable group (risk difference 6.7%, 95% CI −7.1% to 20.5%, P = 0.3). Adverse events occurred in 81% of the patients in the tapering group and 89% of the patients in the stable group.Conclusion: In contrast to those receiving stable TNFi treatment, a minority of patients with RA in remission tapering TNFi to withdrawal remained flare free over three years. There was no statistically significant difference in radiographic progression between the groups.

The introduction of biosimilars into healthcare systems globally is recognized by many as a healthcare success. Despite this, questions have been raised about whether biosimilars can deliver sufficient value to patients and healthcare professionals, as well as sufficient cost saving, for their use in treatment to be worthwhile. In this review, we discuss how the increasing financial burden of complex therapeutic medicines, such as biologics, can be ameliorated by off-patent biosimilar medicines, particularly with increasing worldwide incidences of cancer and other chronic diseases. We then describe real-world cases that demonstrate the significant direct and indirect benefits of biosimilars to patients and healthcare systems beyond costs. Healthcare sustainability is crucial to ensuring that healthcare systems can continue to deliver high-quality care to patients. The savings realized from the introduction of biosimilars have expanded treatment options and improved access to therapies across a spectrum of diseases. Cost savings from biosimilar use have also led to changes in treatment guidelines, increasing the availability of biologic medicines for earlier lines of therapy. This expansion of access can have a positive impact on the overall patient experience and can reduce the overall disease burden. However, the adoption of biosimilars has not been universally successful, and faces challenges in the current healthcare landscape and in the pharmaceutical development pipeline.

Objective: Our objective was to assess the incidence of major adverse cardiovascular events (MACEs) in patients with rheumatoid arthritis (RA) treated with JAK inhibitors (JAKi), tumor necrosis factor inhibitors (TNFi), or biologic disease‐modifying antirheumatic drugs with other modes of action (bDMARD‐OMA) in a multicountry, real‐world population.Methods: Patients with RA from 15 registries in the JAK‐pot collaboration were included. MACE incidence was analyzed using two approaches: a within‐registry analysis aggregating country‐specific estimates from registers with >25 incident MACEs through meta‐analysis and an individual‐level data combined analysis. We used adjusted linear mixed Poisson regression to obtain incidence rate ratios (IRRs) of MACEs between treatment groups, accounting for multiple treatment courses.Results: The study included 73,008 treatment courses (16,417 JAKi, 35,373 TNFi, and 21,218 bDMARD‐OMA) and 828 incident MACEs among 51,233 patients. Median follow‐up time was 1.3 years, with most of the follow‐up concentrated in the first two years of treatment. Incidence rates were 7.0, 7.6, and 11.8 per 1,000 person‐years for JAKi, TNFi, and bDMARD‐OMA, respectively. Compared to TNFi, JAKi (within‐registry adjusted IRR 0.89, 95% confidence interval [CI] 0.63–1.25) had similar incidence rates of MACEs and bDMARD‐OMA had higher rates (within‐registry adjusted IRR 1.35, 95% CI 1.10–1.66). Combined analysis showed similar results.Conclusion: Observational data from the JAK‐pot collaboration show no evidence of an increase in cardiovascular events during the first two years of use with JAKi compared to TNFi in the general RA population.