Espen Andre Haavardsholm

• Østergaard, Mikkel; Haavardsholm, Espen Andre; Nowak, Miroslawa; Luo, Yi; Landis, Jessica & Fura, Aberra [Vis alle 14 forfattere av denne artikkelen] (2026). Efficacy and safety of branebrutinib (BMS-986195), an irreversible Bruton's tyrosine kinase inhibitor, for the treatment of rheumatoid arthritis: a phase 2a, randomised, double-blind, placebo-controlled study. The Lancet Rheumatology. 8(7), s. e539–e549. doi: 10.1016/S2665-9913(25)00374-1. Fulltekst i vitenarkiv
• Smolen, Josef S.; Edwards, Christopher J.; Konzett, Victoria; Laskou, Faidra; Aletaha, Daniel & Caporali, Roberto [Vis alle 50 forfattere av denne artikkelen] (2026). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biologic disease-modifying antirheumatic drugs: 2025 update. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1016/j.ard.2026.01.023. Fulltekst i vitenarkiv
• Lampa, Jon; Nordström, Dan; Vollenhoven, Ronald van; Hetland, Merete Lund; Haavardsholm, Espen A. & Østergaard, Mikkel [Vis alle 71 forfattere av denne artikkelen] (2026). Certolizumab pegol, abatacept, tocilizumab or active conventional therapy in early rheumatoid arthritis: 48-week patient-reported outcomes from the NORD-STAR trial. The Lancet Rheumatology. 8(4), s. e285–e294. doi: 10.1016/s2665-9913(26)00007-x. Fulltekst i vitenarkiv Vis sammendrag

  Background Pain, fatigue, and impaired health-related quality of life are common manifestations of rheumatoid arthritis. The aim of this study was to compare the effects of active conventional treatment with three different biological disease-modifying antirheumatic drugs (DMARDs) on patient-reported outcomes after 48 weeks, in patients with early rheumatoid arthritis using data from the NORD-STAR trial. Methods NORD-STAR was an investigator-initiated open-label randomised controlled trial done at 29 rheumatology centres across Denmark, Finland, Iceland, Norway, Sweden, and the Netherlands. Newly diagnosed patients aged 18 years or older, with rheumatoid arthritis (according to the 2010 American College of Rheumatology–European Allience of Associations for Rheumatology classification criteria for rheumatoid arthritis), symptom duration less than 24 months and who were naïve to DMARDs were randomly assigned (1:1:1:1) to receive active conventional treatment, certolizumab pegol, abatacept, or tocilizumab. The patient-reported outcomes assessed at baseline and weeks 4, 8, 12, 16, 24, 32, 40, and 48 included pain, patient's global assessment of disease activity, Health Assessment Questionnaire Disability Index, Fatigue, Short Form-36 (reflecting health-related quality of life, morning stiffness, and patient's acceptable symptom state). Linear mixed regression and logistic regression analyses were adjusted for sex, country, baseline patient-reported outcomes values, anti-citrullinated protein antibody status, and treatment group. Proportions of patients reporting improvements greater than or equal to the minimal clinically important difference (MCID) were assessed. There was lived experience involvement in the design and implementation of the study. This trial was registered with ClinicalTrials.gov, NCT01491815, and EudraCT, 2011-004720-35. Findings Between Dec 14, 2012, and Dec 11, 2018, 812 patients were enrolled and randomly assigned; after exclusion of 17 patients not receiving tocilizumab due to administrative issues, the intention-to-treat population consisted of 795 patients (200 [25%] received active conventional treatment, 203 [26%] received certolizumab pegol plus methotrexate, 204 [26%] received abatacept plus methotrexate, and 188 [24%] received tocilizumab plus methotrexate). 547 (69%) of 795 patients were female, 248 (31%) were male, the mean age was 54 years (SD 15). Between baseline and week 48 large and clinically relevant improvements in patient-reported outcomes were observed in all treatment groups. At 48 weeks the biological DMARD groups had larger improvements in pain, fatigue, physical component score, and bodily pain of SF-36 compared with the active conventional treatment group. For pain, improvement exceeding MCID was reported by 155 (76%) of 203 patients with certolizumab pegol plus methotrexate and 162 (79%) of 204 patients with abatacept plus methotrexate compared with 136 (68%) of 200 patients in the active conventional treatment group. In the group of patients with tocilizumab and methotrexate 132 (70%) of 188 patients reported pain improvement exceeding MCID. The absolute differences between the biological DMARD groups and the active conventional treatment group were otherwise generally marginal. Interpretation All treatment groups showed substantial improvements in patient-reported outcomes over time. Biological DMARDs produced somewhat greater gains in pain, fatigue, and physical quality of life measures than conventional treatments, though overall differences between groups were small. The results highlight that early treatment and effective disease control in rheumatoid arthritis lead to strong patient-reported benefits regardless of therapy type. Funding Stockholm County Council, Swedish Medical Research Council, Swedish Rheumatism Association, Academy of Finland, Finska Läkaresällskapet, South-Eastern Health Region Norway, HUS Institutional grant, Icelandic Society for Rheumatology, Interregional grant from all health regions in Norway, NordForsk, Regionernes Medicinpulje, The Research Fund of University Hospital Reykjavik, UCB, Bristol Myers Squibb.

• Anderle, Karolina; Sieghart, Daniela; Durechova, Martina; Bonnay, François; Kerschbaumer, Andreas & Chatzidionysiou, Katerina [Vis alle 19 forfattere av denne artikkelen] (2026). An international, multicentre, interventional, randomised, assessor-blinded trial to MAXimise the METHotrexate therapy potential in patients with active rheumatoid arthritis (MethMax trial): study protocol for a randomised controlled trial. Trials. 27. doi: 10.1186/s13063-026-09519-4. Fulltekst i vitenarkiv Vis sammendrag

  Background Methotrexate (MTX) is recommended as first-line therapy in patients with rheumatoid arthritis (RA), proven to be effective, safe and inexpensive. However, a significant proportion of patients does not achieve disease remission with MTX monotherapy. Main reasons include insufficient dose up-titration to the maximal recommended oral dose or the delayed switch to a subcutaneous administration route. We hypothesise, that by dose and route optimisation, a higher proportion of patients can achieve remission. Further, exploratory biomarkers will give new insights on individual MTX metabolism and drug adherence. Methods The MethMax trial is a prospective, randomised, assessor-blinded, parallel-group, superiority, low-intervention trial, including 182 patients across 7 European countries. Patients with active RA, naïve to biologic (except tumour necrosis factor alpha inhibitors; TNFi) or targeted synthetic antirheumatic drugs, who have been on a stable oral MTX therapy for the past 3 months are randomised in a 1:1 ratio to 25 mg MTX weekly, either administered orally or subcutaneously. Additionally, both arms receive a short-term glucocorticoid regimen with a four-week tapering and withdrawal protocol. The primary endpoint is the difference in proportion of patients achieving remission defined as the Clinical Disease Activity Index (CDAI) ≤ 2.8 at week 24, comparing the dose/route optimisation and oral dose optimisation. The active study duration for each patient is 24 weeks. Study visits take place at baseline, weeks 4, 12, 16 and 24. Clinical efficacy and safety parameters are obtained at each visit. Patient-reported outcomes, exploratory biomarkers as well as medication adherence are assessed. Written consent is obtained for all participants. The study has received regulatory approval via the Clinical Trials Information System and Medicines and Healthcare products Regulatory Agency and has included the first patient in August 2024. Discussion The anticipated results will provide insights whether the subcutaneous administration of 25 mg MTX is advantageous in achieving CDAI remission when compared to the oral intake after 24 weeks and inform the community regarding the utility of established and newly developed biomarkers, as well as the potential impact of inadequate drug adherence. The MethMax study is aimed to optimise individual therapy in RA and provide more precise pharmacological MTX management recommendations.

• Uhlig, Tillmann; Karoliussen, Lars Fridtjof; Sexton, Joseph; Haavardsholm, Espen Andre; Provan, Sella Aarrestad & Solomon, D. H. [Vis alle 7 forfattere av denne artikkelen] (2026). Duration and dose of allopurinol needed to attain the serum urate target in gout. Scandinavian Journal of Rheumatology. ISSN 0300-9742. doi: 10.1080/03009742.2026.2648357. Fulltekst i vitenarkiv Vis sammendrag

  Objective: To examine, in patients with gout using escalating urate-lowering therapy (ULT), the treatment durationand allopurinol dose required to attain the serum urate (SU) target (< 360 μmol/L; < 6 mg/dL). Method: We studied patients in the NOR-Gout prospective cohort with a recent gout flare and increased SU(> 360 μmol/L). Patients escalated allopurinol dosage until reaching the SU treatment target of <360 µmol/L,switching, if needed, to febuxostat. Results: Of 211 patients, 95.2% were male; mean ± sd age was 56.7 ± 13.7 years, disease duration 8.1 years, 16.6%had clinical tophi, and 12.8% used allopurinol at cohort entry. Mean SU (μmol/L) was reduced from 500 at baseline to312 at 1 year and 325 at 2 years. Target SU was attained at least once during year 1 by 197 patients (93.4%). Mediantime to attaining the treatment target was 2 months (mean 2.9 months), and median allopurinol dose was 200 mg(mean 243 mg). Eighty per cent of patients reached the treatment target by 3 months. Patients with SU >480 μmol/L atbaseline needed a median of 3 months to attain target SU versus 2 months for patients with SU <480 μmol/L (log-rankp < 0.001). A switch to febuxostat was seen in 12.4% at year 1 and 15.1% at year 2. Conclusion: Treat-to-target ULT using allopurinol leads to attainment of the SU target within 2–3 months at lowdoses for most patients. Very few patients did not achieve the treatment target at least once during year 1. Trial registration: ACTRN12618001372279

• Nagafuchi, Yasuo; Maarseveen, Tjardo D.; Lend, Kristina; Rudin, Anna; Gudbjornsson, Bjorn & Nordström, Dan [Vis alle 21 forfattere av denne artikkelen] (2026). Hand-dominant joint involvement pattern associates with favourable, and polyarthritis with unfavourable, treatment response to both csDMARDs and bDMARDs in early rheumatoid arthritis: a combined analysis of NORD-STAR and BeSt trials. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1016/j.ard.2026.02.005. Fulltekst i vitenarkiv
• Lend, Kristina; Twisk, Jos W.R.; Koopman, Frieda A.; Rudin, Anna; Hetland, Merete Lund & Uhlig, Tillmann [Vis alle 17 forfattere av denne artikkelen] (2026). Flare risk after oral glucocorticoid bridging with methotrexate or intra-articular bridging with triple therapy in early rheumatoid arthritis. Journal of Internal Medicine. ISSN 0954-6820. doi: 10.1111/joim.70094. Fulltekst i vitenarkiv
• Gehin, Johanna; Klaasen, Rolf; Kristianslund, Eirik; Jyssum, Ingrid; Sexton, Joseph & Warren, David John [Vis alle 11 forfattere av denne artikkelen] (2026). The Effect of Certolizumab Pegol Dose and Dose Changes on Plasma Trough Levels: Data From a Randomized Phase III Trial. Therapeutic Drug Monitoring. ISSN 0163-4356. doi: 10.1097/FTD.0000000000001440. Fulltekst i vitenarkiv
• Brinkmann, Gina Charlotte Hetland; Sundlisæter, Nina Paulshus; Nordberg, Lena Kristine Bugge; Sexton, Joseph; Ikdahl, Eirik & Aga, Anna-Birgitte [Vis alle 10 forfattere av denne artikkelen] (2026). Successful discontinuation of oral glucocorticoids after short-term bridging therapy in patients with newly diagnosed rheumatoid arthritis. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1016/j.ard.2026.01.003. Fulltekst i vitenarkiv
• Holly, Teresa; Brun, Marthe Kirkesæther; Jørgensen, Kristin Kaasen; Goll, Guro Løvik; Sexton, Joseph & Gehin, Johanna [Vis alle 15 forfattere av denne artikkelen] (2026). Cost-effectiveness of proactive therapeutic drug monitoring of maintenance infliximab treatment in patients with immune-mediated inflammatory diseases: results from a randomised controlled trial. RMD Open. 12(1), s. 11–11. doi: 10.1136/rmdopen-2025-006329. Fulltekst i vitenarkiv
• Yoshida, Yusuke; Hammer, Hilde Berner; Sexton, Joseph; Nordberg, Lena Kristine Bugge; Aga, Anna-Birgitte & Terslev, Lene [Vis alle 8 forfattere av denne artikkelen] (2025). How to score the wrist joint by ultrasound: exploration of the most sensitive joint assessment during follow-up of early or established rheumatoid arthritis. Arthritis Research & Therapy. ISSN 1478-6354. 27(1). doi: 10.1186/s13075-025-03668-8. Fulltekst i vitenarkiv
• Hammer, Hilde Berner; Karoliussen, Lars Fridtjof; Terslev, Lene; Haavardsholm, Espen A. & Uhlig, Till (2025). Ultrasound-detected crystal depositions and clinical flares dissolve during successful urate-lowering therapy: 5-year follow-up results from the treat-to-target NOR-Gout study. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1016/j.ard.2025.10.029. Fulltekst i vitenarkiv
• Riskedal, Espen; Jugessur, Astanand; Syversen, Silje Watterdal; Hadley, Cathrine Lund; Harris, Jennifer Ruth & Mjaavatten, Maria Dahl [Vis alle 16 forfattere av denne artikkelen] (2025). A DNA methylation-based algorithm for diagnosing rheumatoid arthritis. Arthritis Research & Therapy. ISSN 1478-6354. 27. doi: 10.1186/s13075-025-03649-x. Fulltekst i vitenarkiv Vis sammendrag

  Background Rheumatoid arthritis (RA), particularly seronegative disease, is difficult to diagnose early, which can delay treatment initiation. This study aims to develop a binary DNA methylation (DNAm)-based algorithm to diagnose RA. Methods Three datasets (discovery, training, holdout) were constructed from DNAm profiles from 1366 persons (treatment-naïve RA, other inflammatory/autoimmune diseases, healthy individuals). DNAm features that differentiate RA from other inflammatory/autoimmune diseases and healthy individuals were identified using the discovery set. Our classification algorithm was developed using machine learning techniques in the training set. Its diagnostic performance, with and without serological status, was evaluated in the holdout set containing RA cases (15 seropositive, 6 seronegative) and controls (14 other arthritides, 11 healthy individuals). Results Our algorithm included 391 DNAm features. Combined with serological status, it classified RA from controls in the holdout set with the following performance: sensitivity 0.90 [95% CI: 0.70–0.99], specificity 0.88 [95% CI: 0.69–0.97], and AUC 0.96 [95% CI: 0.91–1.00]. Its performance in classifying patients with seronegative RA versus those with other arthritides was: sensitivity 0.83 [95% CI: 0.36–1.00], specificity 0.79 [95% CI: 0.49–0.95], and AUC 0.81 [95% CI: 0.61–1.00]. Conclusions The present DNAm-based classification algorithm may be clinically useful for the early diagnosis of RA, especially in seronegative patients, which currently often poses a diagnostic challenge.

• Vasileiadis, Georgios K.; Zhang, Yuan; Laudette, Marion; Fatima, Tahzeeb; Ekwall, Anna-Karin Hultgård & Sureshkumar, Reshmi [Vis alle 23 forfattere av denne artikkelen] (2025). Acylcarnitine enrichment as a characteristic of rheumatoid arthritis fibroblast-like synoviocyte metabolic fingerprint. Journal of Translational Autoimmunity. 11, s. 100310–100310. doi: 10.1016/j.jtauto.2025.100310. Fulltekst i vitenarkiv
• Fatima, Tahzeeb; Zhang, Yuan; Vasileiadis, Georgios K.; Rawshani, Araz; Vollenhoven, Ronald van & Lampa, Jon [Vis alle 20 forfattere av denne artikkelen] (2025). Disease activity and treatment response in early rheumatoid arthritis: an exploratory metabolomic profiling in the NORD-STAR cohort. Arthritis Research & Therapy. ISSN 1478-6354. 27(1). doi: 10.1186/s13075-025-03616-6. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background The variability in treatment response in people with rheumatoid arthritis (RA) warrants the prediction of patients at high risk of treatment failure. Identification of biomarkers linked to clinical remission in RA is currently a challenge. Metabolomics may help to identify such biomarkers as it allows for a comprehensive exploration of disease-related variations that extends beyond the genome and proteome. This hypothesis-free exploratory metabolomics study aimed to profile serum metabolic alterations in early RA to understand the metabolic changes associated with disease activity and therapeutic response. Methods The study included 220 early RA participants from the NORD-STAR study, randomized at baseline into four arms, ranging from conventional anti-rheumatic treatment to biological drugs: methotrexate combined with prednisolone (1), certolizumab (2), abatacept (3), or tocilizumab (4). Untargeted metabolomics was performed in serum samples at baseline and 24-week follow-up. Participants achieving clinical disease activity index remission at 24 weeks were defined as responders. Machine learning models for treatment response were constructed using random forest, logistic regression, support vector machine and extreme gradient boosting algorithms based on selected features. Results We identified 278 metabolites, of which 39 were associated with baseline disease activity, including several acylcarnitines and amino acids. We also found 17 baseline metabolites associated with remission at 24 weeks in the overall cohort, including malic acid (β=-0.4), cytidine (β = 0.4), arginine (β = 0.3), and citrulline (β = 0.2), as well as specific metabolites and metabolic pathways associated with remission in the four treatment arms. Fifteen features were identified using machine learning-based multivariable selection. The best predictive model using logistic regression achieved AUC of 0.75 in training and 0.73 in the test set. Conclusions Our study has identified several baseline metabolites and metabolic pathways associated with disease activity and response to different treatments in early RA. By integrating metabolomics and clinical data, we developed predictive models for response to treatment in early RA, though their predictive performance remains limited.

• Alm, Linda Mathsson; Westerlind, Helga; Gehring, Isabel; Hansson, Monika; Ghasemzadeh, Nasim & Rojas-Restrepo, Jessica [Vis alle 17 forfattere av denne artikkelen] (2025). Recognition of Glycine Versus Nonglycine Citrulline Motifs Dictating the HLA Class II Association of Anticitrullinated Protein Antibodies: Insights From Autoantibody Profiling of 6,900 Scandinavian Patients With Rheumatoid Arthritis. Arthritis & Rheumatology. ISSN 2326-5191. doi: 10.1002/art.43161. Fulltekst i vitenarkiv Vis sammendrag

  Objective. Rheumatoid arthritis (RA)–associated anticitrullinated protein antibodies (ACPAs) target various anti-gens by binding short citrulline amino acid motifs, resulting in heterogeneous ACPA profiles among patients. Herewe analyzed ACPA patterns by recognized citrulline motifs in relation to the RA risk factors HLA-DRB1 shared epitope(SE) alleles and history of smoking.Methods. Rheumatoid factor (RF) and anticyclic citrullinated peptide (CCP2) isotypes, 15 anti-Cit- and four anti-Carb/Acet-peptide-IgG, were centrally measured in 6,907 patients from five Scandinavian RA cohorts using fluoroen-zyme immunoassay and a custom-made multiplex solid-phase microarray. HLA-DRB1 SE alleles were imputed fromsingle-nucleotide polymorphism genotyping data.Results. Single-citrulline peptides derived from four multicitrulline peptides (Cit Fibα36-50 , Cit Fibβ60-74, Cit TNC5,and Cit Vim60-75) showed differential binding patterns, supporting recognition of citrulline motifs rather than long peptides.Four citrulline peptides (Cit Fibβ36-52, Cit Fibβ60-74-Cit3, Cit Fil307-324, and Cit Vim60-75-Cit1) captured 97% of IgG anti-CCP2+ patients. Patient subsets based on ACPA, anti-Carb/Acet, and RF displayed differences in ACPA compositionand disease activity but not comorbidities. Different ACPAs overlapped, but when dichotomizing patients based on highreactivity to peptide citrulline motifs, only ACPA to nonglycine citrulline motif associated with HLA SE alleles. In IgG anti-CCP2+ patients, 90% of those with only high nonglycine ACPA were HLA SE allele carriers compared with 67% in thegroup with glycine motif–only ACPA (odds ratio 4.5). Smoking status associated with IgA and glycine motif ACPA.Conclusion. Although citrulline-glycine motifs are prevalent ACPA targets, our data reveal that HLA SE alleles areprimarily associated with ACPA to nonglycine citrulline motifs, providing insight in ACPA T cell dependance. Yet, theetiologic significance of ACPA targeting different protein structures remains unknown.

• Berg, Inger Jorid; Kristianslund, Eirik; Tveter, Anne Therese; Sexton, Joseph; Bakland, Gunnstein & Gossec, Laure [Vis alle 15 forfattere av denne artikkelen] (2025). Remote monitoring or patient-initiated care in axial spondyloarthritis: a 3-armed randomised controlled noninferiority trial. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1016/j.ard.2025.04.019. Fulltekst i vitenarkiv
• Hetland, Merete Lund; Heiberg, Marte Schrumpf; Sokka-Isler, Tuulikki; Rudin, Anna; Østergaard, Mikkel & Haavardsholm, Espen A. [Vis alle 21 forfattere av denne artikkelen] (2025). Treatment with methotrexate plus oral prednisolone versus triple therapy (methotrexate/sulfasalazine/hydroxychloroquine) plus intra-articular glucocorticoids in early rheumatoid arthritis: a prespecified nonrandomised subgroup analysis of clinical and radiographic data at 48 weeks from the NORD-STAR trial's conventional treatment arm. Annals of the Rheumatic Diseases. ISSN 0003-4967. 84, s. 937–948. doi: 10.1016/j.ard.2025.03.002. Fulltekst i vitenarkiv Vis sammendrag

  Objectives In the NOrdic Rheumatic Diseases Strategy Trials And Registries (NORD-STAR) trial, the active conventional arm had 2 nonrandomised regimens: arm 1A (oral group; Sweden, Norway, Netherlands, and Iceland) and arm 1B (injection group; Denmark and Finland). We report clinical, patient-reported, safety, and radiographic outcomes after 48 weeks. Methods Oral group received methotrexate plus oral prednisolone (20.0 mg/d, tapered rapidly, discontinued week 36); Injection group received triple therapy (methotrexate, sulphasalazine, hydroxychloroquine) and mandatory intra-articular glucocorticoid injections. The primary end point was analysed by logistic regression with several approaches for handling missing outcomes. Results In total, 137 and 80 patients were included in the oral group and injection group; 78% vs. 89% completed, respectively. At 48 weeks, adjusted clinical disease activity index remission ≤2.8 rates (95% CI) were 36% (28-44) and 55% (42-68), respectively; the risk difference (primary outcome) was 19% (2-35). Similarly, key secondary clinical, patient-reported and safety outcomes showed numerically better results in the injection group vs oral group, for example, infections occurred in 53% vs 30%, respectively. Radiographic progression (Δtotal van der Heijde-modified Sharp Score) was low: oral group: adjusted mean, 0.26 (95% CI, 0.08-0.43); injection group: adjustedd mean, 0.80 (95% CI, 0.55-1.05). Cumulative dose of oral/intra-articular glucocorticoids (median) was 1905 mg prednisolone for the oral group and 165 mg for the injection group. Conclusions In treatment-naïve patients with early rheumatoid arthritis, triple therapy and mandatory glucocorticoid joint injections had numerically better clinical outcomes, fewer withdrawals, fewer adverse events, and lower cumulative dose of glucocorticoids, but slightly worse radiographic outcomes than treatment with methotrexate and oral prednisolone. These findings, although nonrandomised, suggest a potential for optimising treatment strategy with conventional therapies in early rheumatoid arthritis.

• Lorentsen, Jing Lisa Li; Brunborg, Cathrine; Aasebø, Anders Theodor Michaelsen; Valeur, Jørgen; Haavardsholm, Espen A. & Molberg, Øyvind [Vis alle 8 forfattere av denne artikkelen] (2025). Incidence and prevalence of Behçet's disease in Oslo, Norway: a two-decade population-based analysis. Rheumatology. ISSN 1462-0324. 64(8), s. 4703–4712. doi: 10.1093/rheumatology/keaf224. Fulltekst i vitenarkiv
• Uhlig, Till; Stjärne, Johan Folke Håkan; Karoliussen, Lars Fridtjof; Sexton, Joseph; Eskild, Tron Hovind & Provan, Sella Aarrestad [Vis alle 8 forfattere av denne artikkelen] (2025). Remission in gout is possible: 5-year follow-up in the NOR-Gout study. Seminars in Arthritis & Rheumatism. ISSN 0049-0172. 72. doi: 10.1016/j.semarthrit.2025.152698. Fulltekst i vitenarkiv
• Kjørholt, Kaja Eriksrud; Sundlisæter, Nina Paulshus; Aga, Anna-Birgitte; Sexton, Joseph; Olsen, Inge Christoffer & Lexberg, Åse S. [Vis alle 21 forfattere av denne artikkelen] (2025). Three-Year Results of Tapering Tumor Necrosis Factor Inhibitor to Withdrawal Compared to Stable Tumor Necrosis Factor Inhibitor Among Patients With Rheumatoid Arthritis in Sustained Remission: A Multicenter Randomized Trial. Arthritis & Rheumatology. ISSN 2326-5191. 77(10), s. 1327–1336. doi: 10.1002/art.43199. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Li, Gaoyang; Kolan, Shrikant; Grimolizzi, Franco; Sexton, Joseph; Malachin, Giulia & Goll, Guro Løvik [Vis alle 12 forfattere av denne artikkelen] (2025). Development of machine learning models for predicting non-remission in early RA highlights the robust predictive importance of the RAID score-evidence from the ARCTIC study. Frontiers of Medicine. ISSN 2095-0217. 12. doi: 10.3389/fmed.2025.1526708. Fulltekst i vitenarkiv Vis sammendrag

  Introduction: Achieving remission is a critical therapeutic goal in the management of rheumatoid arthritis (RA). Despite methotrexate being the cornerstone of early RA treatment, a significant proportion of patients fail to achieve remission. This study aims to predict 6-month non-remission in 222 disease-modifying antirheumatic drug (DMARD)-naïve RA patients initiating methotrexate monotherapy, using baseline patient characteristics from the ARCTIC trial. Methods: Machine learning models were developed utilizing twenty-one baseline demographic, clinical and laboratory features to predict non-remission according to ACR/EULAR Boolean, SDAI and CDAI criteria. The model employed a super learner algorithm that combine three base algorithms of elastic net, random forest and support vector machine. The model performance was evaluated through five independent unseen tests with nested 5-fold cross-validation. The predictive power of each feature was assessed using a composite measure derived from individual algorithm estimates. Results: The model demonstrated a mean AUC-ROC of 0.75-0.76, with mean sensitivity of 0.77-0.81, precision (also referred to as Positive Predictive Value) of 0.77-0.79 and specificity of 0.63-0.66 across the criteria. Predictive power analysis of each feature identified the baseline Rheumatoid Arthritis Impact of Disease (RAID) score as the strongest predictor of non-remission. A simplified model using RAID score alone demonstrated comparable performance to the full-feature model. Conclusion: These findings highlight the potential utility of baseline RAID scorebased model as an effective tool for early identification of patients at risk of nonremission in clinical practise.

• Brun, Marthe Kirkesæther; Gehin, Johanna; Hammersbøen, Kristin Reine; Warren, David; Klaasen, Rolf & Sexton, Joseph [Vis alle 15 forfattere av denne artikkelen] (2024). Clinical consequences of infliximab immunogenicity and the effect of proactive therapeutic drug monitoring: exploratory analyses of the randomised, controlled NOR-DRUM trials. The Lancet Rheumatology. 6(4), s. e226–e236. doi: 10.1016/S2665-9913(23)00341-7. Fulltekst i vitenarkiv
• Wolf, Asia-Sophia Fumika Michaela; Hammersbøen, Kristin Reine; Ørbo, Hilde Sofie Sager; Bhandari, Sabin; Solum, Guri & Kjønstad, Ingrid Fadum [Vis alle 30 forfattere av denne artikkelen] (2024). T cell responses to repeated SARS-CoV-2 vaccination and breakthrough infections in patients on TNF inhibitor treatment: a prospective cohort study. EBioMedicine. 108. doi: 10.1016/j.ebiom.2024.105317. Fulltekst i vitenarkiv Vis sammendrag

  Background Understanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection. Methods This prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2–4 weeks after vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor-binding domain (anti-RBD) antibodies. Findings Between March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 73 healthy controls were included. In patients with either IBD or arthritis, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p = 0.008) after three SARS-CoV-2 vaccine doses. Patients with IBD had comparable quantities (median CD4 0.11% vs. 0.11%, p = 0.26, CD8 0.031% vs. 0.047%, p = 0.33) and quality (polyfunctionality score: 0.403 vs. 0.371, p = 0.39; 0.105 vs. 0.101, p = 0.87) of spike-specific T cells to healthy controls. Patients with arthritis had lower frequencies but comparable quality of responding T cells to controls. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides. Interpretation Patients with IBD on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality of T cell responses. Our study adds evidence that, in the absence of other risk factors, this group may in future be able to follow the general recommendations for COVID-19 vaccines.

• Kared, Hassen; Jyssum, Ingrid; Alirezaylavasani, Amin; Egner, Ingrid Marie; Tran, Trung & Tietze, Lisa [Vis alle 17 forfattere av denne artikkelen] (2024). Dynamics of SARS-CoV-2 immunity after vaccination and breakthrough infection in rituximab-treated rheumatoid arthritis patients: a prospective cohort study. Frontiers in Immunology. 15:1296273, s. 1–12. doi: 10.3389/fimmu.2024.1296273. Fulltekst i vitenarkiv Vis sammendrag

  Background: 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). Methods: 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. Findings: 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 ex vivo in terms of frequency or phenotype of Spike-specific cytotoxic T cells and in vitro in terms of the functionality and differentiation profile of Spike-specific T cells. Interpretation: 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.

• Ferreira, Ricardo J O; Henriques, Adriana; Moe, Rikke Helene; Matos, Cristiano; Tveter, Anne Therese & Østerås, Nina [Vis alle 11 forfattere av denne artikkelen] (2024). Presentation of the first international research network to foster high-quality clinical trials testing non-pharmacological interventions (TRACTION network). BMJ Open. 14(7). doi: 10.1136/bmjopen-2023-081864. Fulltekst i vitenarkiv Vis sammendrag

  Clinical trials are essential for evaluating the efficacy and safety of new treatments and health interventions. However, while pharmacological trials are well-established, non-pharmacological trials face unique challenges related to their complexity and difficulties such as recruitment, retention, intervention standardisation, selection of outcome measures and blinding of clinicians, participants and data collectors. This communication paper describes the objectives, implementation steps and bylaws of the ‘Trials foR heAlth Care inTerventIONs’ Network (TRACTION), established by an international multiprofessional task force of experts to foster high-quality non-pharmacological research, ultimately improving patient care and healthcare outcomes. The TRACTION research network will provide information and resources through a collaborative hub for researchers, health professionals, patient research partners and stakeholders in diverse biomedical and healthcare areas, connecting people with different levels of expertise but with the same interests (eg, to evaluate the effect of non-pharmacological interventions, recruiting participants). This open network will support researchers in optimising trial design, participant recruitment, data management and analysis, and disseminating and implementing trial results. The network will also facilitate specialisation training and provide educational materials and mentoring.

• Holten, Karen; Sundlisæter, Nina Paulshus; Sexton, Joseph; Kjørholt, Kaja Eriksrud; Nordberg, Lena Bugge & Uhlig, Tillmann [Vis alle 11 forfattere av denne artikkelen] (2024). Agreement between patient-reported flares and clinically significant flare status in patients with rheumatoid arthritis in sustained remission: data from the ARCTIC REWIND trials. RMD Open. 10(3). doi: 10.1136/rmdopen-2024-004444. Fulltekst i vitenarkiv Vis sammendrag

  Objectives To explore the agreement between patient-reported flare status and clinically significant flare status in patients with rheumatoid arthritis (RA) in sustained remission. Method Patients with RA in remission for ≥12 months on stable treatment were included in the ARCTIC REWIND tapering trials and pooled 12-month data used in current analyses. Patient-reported flare status was assessed according to the Outcome Measures in Rheumatology flare questionnaire; ‘Are you having a flare of your RA at this time?’ (yes/no). A clinically significant flare was defined as a combination of Disease Activity Score (DAS) >1.6, increase in DAS of ≥0.6 and 2 swollen joints, or the rheumatologist and patient agreed that a clinically significant flare had occurred. Agreement coefficient, sensitivity, specificity and predictive values of patient-reported flare status with regard to clinically significant flare status were determined. Results Of 248 patients, 64% were women, age 56.1 (11.8) years, disease duration 4.1 (2.8–7.4) years, DAS 0.8 (0.3). 35% of patients reported a flare at least once, clinically significant flares were recorded in 21%. 48/53 clinically significant flares (91%) led to an intensification of disease-modifying antirheumatic drugss. In 621/682 (91%) visits, patient-reported and clinically significant flare status were in agreement, agreement coefficient 0.89. Sensitivity and specificity were both 91%, positive predictive value of patient-reported flare status 46% and negative predictive value 99%. Conclusion Among patients in sustained remission, patient-reported flare status was accurate in ruling out a clinically significant flare. About half of the patient-reported flares were assessed to be clinically significant. These findings support a potential for using patient-reported flare status in remote monitoring of patients with RA in sustained remission.

• Holten, Karen; Sundlisæter, Nina Paulshus; Sexton, Joseph; Nordberg, Lena Bugge; Uhlig, Till & Kvien, Tore Kristian Aaserud [Vis alle 10 forfattere av denne artikkelen] (2024). Performance of the Rheumatoid Arthritis Impact of Disease (RAID) score in relation to flares in disease activity. RMD Open. 10(1). doi: 10.1136/rmdopen-2023-003486. Fulltekst i vitenarkiv Vis sammendrag

  Objectives To explore the performance of the EULAR-initiated patient-reported Rheumatoid Arthritis Impact of Disease (RAID) questionnaire in relation to flares in disease activity, including comparison with other disease activity outcomes. Methods Patients with rheumatoid arthritis in sustained remission were randomised to continued stable treatment or tapering in the ARCTIC REWIND project. In patients with flares within 12 months, we compared RAID (total score and components) at the flare visit with the visit prior to and the visit following flare, using Wilcoxon signed-rank test. Similar analyses were performed for patient global assessment, Disease Activity Score (DAS) and C reactive protein (CRP). The discriminative accuracies of RAID, patient global assessment, DAS and CRP with respect to disease activity flares were assessed by receiver operating characteristic (ROC) analyses based on logistic regression models. Flare was defined as a combination of DAS >1.6, a DAS increase ≥0.6 and ≥two swollen joints (of 44 examined) or could be recorded if patient and rheumatologist agreed that a clinically significant flare had occurred. Results In total, 248 patients were included in the analyses, with 56 flares. RAID, patient global assessment, DAS and CRP all changed significantly at the visits related to flare (p<0.001). Area under the curve (95% CI) values indicated that RAID (0.88 (0.83 to 0.93)) was significantly more accurate than CRP (0.76 (0.69 to 0.84)) in discriminating flare, and less accurate than patient global assessment (0.92 (0.87 to 0.97)) and DAS (0.94 (0.90 to 0.98)). The RAID components with highest and lowest discriminative accuracies were pain (0.91 (0.86 to 0.95)) and sleep (0.69 (0.59 to 0.79)). Conclusion Disease activity flares were associated with a significant increase in median RAID, supporting its ability to respond to flare.

• Ørbo, Hilde Sofie Sager; Kasahara, Taissa de Matos; Wolf, Asia-Sophia Fumika Michaela; Bjørlykke, Kristin Hammersbøen; Sexton, Joseph & Jyssum, Ingrid [Vis alle 24 forfattere av denne artikkelen] (2024). Humoral and cellular responses to a fifth bivalent SARS-CoV-2 vaccine dose in patients with immune-mediated inflammatory diseases on tumour necrosis factor inhibitors: a prospective cohort study. The Lancet Regional Health - Europe. 48. doi: 10.1016/j.lanepe.2024.101121. Fulltekst i vitenarkiv Vis sammendrag

  Background As most people now have established hybrid immunity, the need for regular, updated SARS-CoV-2 vaccine boosters in patients with immune-mediated inflammatory diseases (IMIDs) is unclear. The study aim was to assess humoral and cellular immunogenicity of a fifth bivalent vaccine dose in patients with IMID on tumour necrosis factor inhibitors (TNFi). Methods In the longitudinal, observational Nor-vaC study, we assessed anti-spike and neutralising antibodies against Wuhan, Omicron BA.1 and BA.4, as well as frequency and polyfunctionality of responding T cells, following a fourth monovalent and a fifth bivalent (BA.1 or BA.4/5) vaccine dose in patients with or without hybrid immunity using TNFi. Findings Between December 17, 2021, and June 20, 2023, 456 infection-naïve patients with IMIDs using TNFi received a fourth vaccine dose and were otherwise eligible for inclusion. A total of 373/456 (82%) received a fifth vaccine dose, of these 190/373 (51%) had hybrid immunity defined as having had COVID-19 between the fourth and fifth dose. In patients with hybrid immunity, the fifth dose did not induce improved humoral responses compared to infection, neither with BA.1 (median anti-spike antibody concentrations 23,244 IU/ml (IQR 15,138–45,233) vs 36,341 IU/ml (11,887–53,710), p = 0.52) nor BA.4/5 (31,693 IU/ml (15,176–54,186), p = 0.30). Comparison of neutralising antibodies yielded similar results. In infection-naïve patients, a fifth BA.4/5 vaccine, but not the BA.1, induced slightly higher humoral responses (18,890 IU/ml (6494–50,211)) compared to the fourth dose (7304 IU/ml (3245–17,260), p < 0.0001). CD8 T cell responses remained stable following a fourth dose (median frequency of spike-specific cells 0.039% (IQR 0.010–0.14)), infection (0.058% (0.026–0.17)) and a fifth dose (0.058% (0.013–0.20). Interpretation In patients on TNFi with hybrid immunity, there was no immunological benefit of an updated fifth SARS-CoV-2 booster dose. Stable CD8 cellular responses following four doses indicate established protective immunity. Patients whose only risk factor is TNFi may in future follow vaccine recommendations for the general population.

• Gehin, Johanna; Klaasen, Rolf; Kristianslund, Eirik; Jyssum, Ingrid; Sexton, Joseph & Warren, David [Vis alle 11 forfattere av denne artikkelen] (2024). Therapeutic serum level for adalimumab in rheumatoid arthritis: explorative analyses of data from a randomised phase III trial. RMD Open. 10(4). doi: 10.1136/rmdopen-2024-004888. Fulltekst i vitenarkiv Vis sammendrag

  Objectives The objectives of this study are to identify a therapeutic serum level for adalimumab associated with remission and low disease activity in patients with rheumatoid arthritis. Methods Associations between serum adalimumab trough levels and disease activity were examined using longitudinal data from a 48-week randomised phase III trial including patients with tumour necrosis factor inhibitor-naïve rheumatoid arthritis with active disease starting adalimumab treatment. Disease activity was classified according to 28-joint Disease Activity Score (DAS28)-erythrocyte sedimentation rate and C reactive protein (CRP) levels. Results Adalimumab trough levels were recorded longitudinally for 336, 330 and 302 patients at weeks 12, 24 and 48, respectively. All patients received concomitant methotrexate. Median adalimumab trough levels were 6.4 mg/L (IQR 3.4–9.5) at week 12, 7.5 mg/L (IQR 3.5–10.9) at week 24 and 7.6 mg/L (IQR 3.6–12.0) at week 48. In serial serum samples from weeks 12, 24 and 48, trough levels ≥3.9 mg/L were associated with DAS28 remission (OR 3.88 (95% CI 1.80, 8.38), p<0.001) and lower CRP levels (p<0.001). Week 12 trough levels ≥3.5 mg/L were associated with DAS28 low disease activity at week 24 (OR 2.62 (1.50, 4.56), p<0.001) and remission at week 48 (OR 1.99 (1.02, 3.88), p=0.04), as well as lower CRP levels at both time points (p<0.001). Conclusion Adalimumab trough levels above 4.0 mg/L were associated with remission/low disease activity throughout the first year of adalimumab therapy and can be considered a lower target level for therapeutic drug monitoring of adalimumab therapy.

• Vasileiadis, Georgios K.; Zhang, Yuan; Fatima, Tahzeeb; Vollenhoven, Ronald van; Lampa, Jon & Gudbjornsson, Bjorn [Vis alle 18 forfattere av denne artikkelen] (2024). Circulating Adipokines and Response to Treatment in Patients With Early Rheumatoid Arthritis. ACR Open Rheumatology. doi: 10.1002/acr2.11756. Fulltekst i vitenarkiv Vis sammendrag

  Objective The objective of this study was to determine if baseline adiponectin, leptin, and resistin levels are associated with response to antirheumatic treatment in early rheumatoid arthritis (RA). Methods This study included 341 participants of the Nordic Rheumatic Diseases Strategy Trials and Registries trial with untreated early RA, randomized at baseline into four treatment arms: methotrexate combined with (1) prednisolone, (2) certolizumab, (3) abatacept, or (4) tocilizumab. Follow-up was up to 48 weeks. Adipokines were measured in plasma at baseline with enzyme-linked immunosorbent assay. The primary outcome for this report was the difference in remission (Clinical Disease Activity Index [CDAI] ≤2.8) over 48 weeks stratified by median adipokine levels. Results At baseline, levels of adiponectin and leptin were not associated with markers of RA activity, whereas participants with higher resistin levels had higher C-reactive protein (CRP) levels, swollen joint count, and Disease Activity Score in 28 joints based on CRP compared to participants with lower resistin. Overall, participants with baseline adipokine levels above the median and those with adipokine levels below the median had similar mean CDAI and changes in CDAI throughout follow-up for up to 48 weeks. Adjusted Cox proportional hazards models did not show any effect of baseline adiponectin, leptin, and resistin levels on the likelihood of achieving CDAI remission (adiponectin: hazard ratio [HR] 1.08, 95% confidence interval [CI] 0.80–1.45, P = 0.62; leptin: HR 0.89, 95% CI 0.64–1.26, P = 0.52; resistin: HR 0.86, 95% CI 0.65–1.13, P = 0.26). Conclusion Baseline adiponectin, leptin, and resistin levels are not associated with the likelihood of achieving CDAI remission over 48 weeks of treatment in a large cohort of people with untreated early RA.

• Dubovyk, Violetta; Vasileiadis, Georgios K.; Fatima, Tahzeeb; Zhang, Yuan; Kapetanovic, Meliha Crnkic & Kastbom, Alf [Vis alle 25 forfattere av denne artikkelen] (2024). Obesity is a risk factor for poor response to treatment in early rheumatoid arthritis: a NORD-STAR study. RMD Open. 10(2). doi: 10.1136/rmdopen-2024-004227. Fulltekst i vitenarkiv Vis sammendrag

  Objective This report from the NORD-STAR (Nordic Rheumatic Diseases Strategy Trials and Registries) trial aimed to determine if obesity is associated with response to conventional and biological antirheumatic treatment in early rheumatoid arthritis (RA). Methods This report included 793 participants with untreated early RA from the randomised, longitudinal NORD-STAR trial, all of whom had their body mass index (BMI) assessed at baseline. Obesity was defined as BMI ≥30 kg/m2. All participants were randomised 1:1:1:1 to one of four treatment arms: active conventional treatment, certolizumab-pegol, abatacept and tocilizumab. Clinical and laboratory measurements were performed at baseline and at 8, 12, 24 and 48-week follow-up. The primary endpoint for this report was response to treatment based on Clinical Disease Activity Index (CDAI) and Simple Disease Activity Index (SDAI) remission and Disease Activity Score with 28 joints using C-reactive protein (DAS28-CRP) <2.6 stratified by BMI. Results Out of 793 people included in the present report, 161 (20%) had obesity at baseline. During follow-up, participants with baseline obesity had higher disease activity compared with those with lower BMI, despite having similar disease activity at baseline. In survival analyses, obesity was associated with a lower likelihood of achieving response to treatment during follow-up for up to 48 weeks (CDAI remission, HR 0.84, 95% CI 0.67 to 1.05; SDAI, HR 0.77, 95% CI 0.62 to 0.97; DAS28-CRP <2.6, HR 0.78, 95% CI 0.64 to 0.95). The effect of obesity on response to treatment was not influenced by the treatment arms. Conclusion In people with untreated early RA followed up for up to 48 weeks, obesity was associated with a lower likelihood of good treatment response, irrespective of the type of randomised treatment received.

• Kjørholt, Kaja Eriksrud; Sundlisæter, Nina Paulshus; Aga, Anna-Birgitte; Sexton, Joseph; Olsen, Inge Christoffer & Fremstad, Hallvard [Vis alle 22 forfattere av denne artikkelen] (2024). 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. The Lancet Rheumatology. 6(5), s. e268–e278. doi: 10.1016/S2665-9913(24)00021-3. Fulltekst i vitenarkiv Vis sammendrag

  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, analyse

• Ørbo, Hilde Sofie Sager; Hammersbøen, Kristin Reine; Sexton, Joseph; Jyssum, Ingrid; Tveter, Anne Therese & Christensen, Ingrid Egeland [Vis alle 18 forfattere av denne artikkelen] (2024). Incidence and outcome of COVID-19 following vaccine and hybrid immunity in patients on immunosuppressive therapy: identification of protective post-immunisation anti-RBD antibody levels in a prospective cohort study. RMD Open. 10(2). doi: 10.1136/rmdopen-2023-003545. Fulltekst i vitenarkiv Vis sammendrag

  Objectives To 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. Methods IMIDs 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. Results Between 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)). Conclusion Vaccinated 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.

• Scheffler, Julia M.; Drevinge, Christina; Lindholm, Catharina; Gjertsson, Inger; Lend, Kristina & Hetland, Merete Lund [Vis alle 23 forfattere av denne artikkelen] (2024). Circulating Baseline CXCR3⁺Th2 and Th17 Cell Proportions Correlate With Trabecular Bone Loss After 48 Weeks of Biological Treatment in Early Rheumatoid Arthritis. ACR Open Rheumatology. doi: 10.1002/acr2.11742. Fulltekst i vitenarkiv Vis sammendrag

  Objective The high prevalence of osteoporosis in rheumatoid arthritis (RA) is due to inflammation that stimulates differentiation of osteoclasts, a process involving circulating monocytes and T cell–derived factors. The aim of this study was to evaluate relations between circulating monocytes, T cell subsets, and changes in bone characteristics before and after treatment with biological disease-modifying antirheumatic drugs (bDMARDs) in RA. Methods Thirty patients with untreated early RA who met the American College of Rheumatology/EULAR 2010 criteria were included. Data were collected before and 48 weeks after treatment with methotrexate (MTX) together with one of three bDMARDs (abatacept, tocilizumab, or certolizumab pegol). Disease activity was measured using the Clinical Disease Activity Index, swollen or tender joint counts, C-reactive protein levels, and erythrocyte sedimentation rates. Proportions of monocyte and CD4+ T cell subsets in blood samples were analyzed by flow cytometry. Bone densitometry was performed using high-resolution peripheral quantitative computed tomography (HR-pQCT). Results HR-pQCT revealed an overall decrease in cortical (P = 0.009) and trabecular (P = 0.034) bone mineral density, although a subset of patients showed no bone loss after 48 weeks of treatment. The overall bone loss was not associated with age, body mass index, sex, intraarticular glucocorticoid injections, or baseline disease activity. Loss of trabecular bone volume fraction correlated with high proportions of circulating CXCR3+Th2 cells (r = −0.38, P = 0.04) and CXCR3+Th17 cells (r = −0.36, P = 0.05) at baseline. Similarly, no loss of trabecular bone volume fraction correlated with high proportions of regulatory T cells (r = 0.4, P = 0.03) at baseline. However, the associations were not significant when corrected for confounders and multiple testing. Conclusion MTX together with bDMARDs efficiently reduce disease activity but only prevent bone loss in a subset of patients with RA after 48 weeks of treatment. The correlations of circulating baseline T helper cell and regulatory T cell populations with trabecular bone changes suggest a potential novel role for these cells in systemic bone homeostasis during early RA.

• Uhlig, Tillmann; Karoliussen, Lars Fridtjof; Sexton, Joseph; Provan, Sella Aarrestad; Haavardsholm, Espen Andre & Hammer, Hilde Berner (2024). Non-adherence to urate lowering therapy in gout after 5 years is related to poor outcomes: results from the NOR-Gout study. Rheumatology. ISSN 1462-0324. 64(4), s. 1799–1806. doi: 10.1093/rheumatology/keae514. Fulltekst i vitenarkiv Vis sammendrag

  Objectives Patients with gout need to adhere to medication over time to achieve good outcomes. We assessed self-reported adherence to medication with urate lowering therapy (ULT) 5 years after a treat-to-target intervention and studied how non-adherence was related to baseline demographic and disease variables. Methods Patients in the NOR-Gout observational study were included after a recent gout flare and serum urate >360 µmol/l. Patients [mean age 56.2 (S.D. 13.6), 94.5% males, 17.2% with tophi] attended tight-control visits over one year with escalating urate lowering therapy using a treat-to-target strategy. Five-year follow-up included the Medication Adherence Report Scale (MARS-5) questionnaire (range 5–25) for adherence. Flares and SUA target achievement were compared for 5-year adherence to medication. Results At 5 years most of the 163 patients used ULT (95.1%). MARS-5 adherence scores after 5 years were high (median 24, interquartile range 22–25). Patients in the lowest MARS-5 quartile had, compared with the highest quartile, more often a flare during the last year of follow-up (33.3% vs 9.5%, P = 0.004) and reached the 5-yr serum urate treatment target less frequently (45.2% vs 87.5%, P < 0.001). Baseline lower age (OR 0.56, 95%CI 0.39–0.79), non-European origin (OR 0.22, 95%CI 0.06–0.80), lower SF-36 mental health scores (OR 0.94, 95%CI 0.91–0.98) and less joint pain during last flare (OR 0.73, 95%CI 0.58–0.92) were independent risk factors for non-adherence to medication. Conclusions Patients reported high adherence to medication after 5 years. Non-adherence was related to more flares and less urate target achievement. Younger age and non-European origin were associated with non-adherence.

• Lend, Kristina; Lampa, Jon; Padyukov, Leonid; Hetland, Merete Lund; Schrumpf, Marte & Nordström, Dan C [Vis alle 21 forfattere av denne artikkelen] (2024). Association of rheumatoid factor, anti-citrullinated protein antibodies and shared epitope with clinical response to initial treatment in patients with early rheumatoid arthritis: data from a randomised controlled trial. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1136/ard-2024-226024. Fulltekst i vitenarkiv Vis sammendrag

  Objectives To investigate whether rheumatoid factor (RF), anti-citrullinated protein antibodies (ACPAs) and shared epitope (SE) allele-related genetic markers associate with treatment response to abatacept, certolizumab pegol or tocilizumab versus active conventional treatment (ACT). Methods Patients with treatment-naïve early rheumatoid arthritis were randomised in the NORD-STAR trial to ACT, certolizumab pegol, abatacept or tocilizumab, all with methotrexate. Centralised laboratory analyses for ACPA, RF and SE were performed. Clinical Disease Activity Index remission was analysed longitudinally with logistic generalised estimating equations. Differences in treatment effect across RF, ACPA and SE subgroups were assessed with interaction terms at 24 and 48 weeks, adjusted for sex, country, age, body mass index, Disease Activity Score of 28 joints based on C-reactive protein and smoking. Results In total, 778 patients were included. At 24 weeks, abatacept treatment showed a better response than ACT in the RF and/or ACPA-positive subgroups, but this effect was not significantly different from the negative subgroups. By 48 weeks, abatacept treatment showed better response regardless of RF/ACPA status. No differences were found across RF, ACPA, SE allele, valine at amino acid position 11 or valine-arginine-alanine haplotype subgroups for any biological treatment at 48 weeks. Conclusions Based on this randomised controlled trial, abatacept treatment was associated with a better response than ACT in the RF and/or ACPA-positive subgroup at 24 weeks, but this was no longer seen at 48 weeks; adding SE allele-related genetic markers did not strengthen the association. Moreover, ACPA, RF and SE allele-related genotypes were not, alone or in combination, associated with clinical responses of importance sufficiently strongly to warrant implementation in clinical practice.

• Dijkshoorn, Bas; Hansildaar, Romy; Vedder, Daisy; Soutari, Nida; Rudin, Anna & Nordström, Dan [Vis alle 19 forfattere av denne artikkelen] (2024). Impaired coagulation parameters in early RA are restored by effective antirheumatic therapy: a prospective pilot study. RMD Open. 10(4). doi: 10.1136/rmdopen-2024-004838. Fulltekst i vitenarkiv Vis sammendrag

  Objectives To assess the effect of treatment on haemostatic parameters in patients with early rheumatoid arthritis (RA). Methods Patients with newly diagnosed RA started methotrexate and were randomised to additional conventional treatment, certolizumab pegol, abatacept or tocilizumab. Several biomarkers for haemostasis were analysed including parameters of the two global haemostatic assays—overall haemostatic potential (OHP) and endogenous thrombin potential (ETP), as well as single haemostatic factors—fibrinogen, prothrombin fragment 1+2 (F1+2), D-dimer, thrombin activatable fibrinolysis inhibitor (TAFI) and clot lysis time (CLT) in 24 patients at baseline, 12 and 24 weeks after the start of the treatment. Results At baseline, patients had elevated levels of the following biomarkers compared with reference values: fibrinogen, F1+2, D-dimer and parameters of the two global haemostatic assays, that is, ETP and OHP. After 24 weeks we observed a significant reduction in F1+2 (p<0.01), fibrinogen (p<0.01), D-dimer (p<0.01), OHP (p<0.01), ETP (p<0.01), CLT (p<0.01), TAFI (p<0.01) and an increase of OFP (p<0.01). Tocilizumab treatment resulted in the most significant reduction of global haemostatic assays after 24 weeks, that is, a reduction of OHP 73% (p<0.01) compared with certolizumab pegol arm 32% (p<0.01), abatacept arm 24% (p=0.25) or conventional treatment arm 7% (p=0.66). Conclusion Newly diagnosed RA patients have enhanced coagulation activation and impaired fibrinolysis as demonstrated by our results. Effective antirheumatic treatments during the first 24 weeks after diagnosis improved this haemostatic imbalance, with prominent effects of biological drugs and especially tocilizumab, compared with conventional treatment.

• Brun, Marthe Kirkesæther; Hammersbøen, Kristin Reine; Viken, Marte Kathrine; Stenvik, Grethe-Elisabeth; Klaasen, Rolf & Gehin, Johanna [Vis alle 18 forfattere av denne artikkelen] (2023). HLA-DQ2 is associated with anti-drug antibody formation to infliximab in patients with immune-mediated inflammatory diseases. Journal of Internal Medicine. ISSN 0954-6820. 293(5), s. 648–655. doi: 10.1111/joim.13616. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background Immunogenicity to tumour necrosis factor inhibitors is a significant clinical problem leading to treatment failure and adverse events. The study aimed to assess human leukocyte antigen (HLA) associations with anti‐drug antibody (ADAb) formation to infliximab. Methods Immune‐mediated inflammatory disease patients on infliximab therapy ( n  = 612) were included. Neutralising ADAb were assessed with a drug‐sensitive assay. Next generation sequencing‐based HLA typing was performed. Results Overall, 147 (24%) patients developed ADAb. Conditional analyses indicated HLA‐DQB1 ( p  = 1.4 × 10 −6 ) as a primary risk locus. Highest risk of ADAb was seen when carrying at least one of the HLA‐DQ2 haplotypes; DQB1*02:01–DQA1*05:01 or DQB1*02:02–DQA1*02:01 (OR 3.18, 95% CI 2.15–4.69 and p  = 5.9 × 10 −9 ). Results were consistent across diseases and when adjusting for concomitant immunomodulator. Computational predictions indicated that these HLA‐DQ2 haplotypes bind to peptide motifs from infliximab light chain. Conclusion A genome‐wide significant association between two HLA‐DQ2 haplotypes and the risk of ADAb formation to infliximab was identified, suggesting that HLA‐DQ2 testing may facilitate personalised treatment decisions.

• Brkic, Alen; Diamantopoulos, Andreas P; Hoff, Mari; Haavardsholm, Espen A.; Fevang, Bjørg Tilde Svanes & Brekke, Lene Kristin [Vis alle 11 forfattere av denne artikkelen] (2023). Exploring the impact of the national tender system on the use of costly drugs treating rheumatoid arthritis patients in ten rheumatology centers in Norway (2010–2019). BMC Health Services Research. 23(1). doi: 10.1186/s12913-023-09975-7. Fulltekst i vitenarkiv Vis sammendrag

  Background Biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) are highly effective in treating rheumatoid arthritis (RA), albeit high drug cost has restricted their use in many countries. As a countermeasure, Norway implemented pharmaceutical tendering as a cost-reducing strategy. The aim of this study was to assess the annual proportion of different b/tsDMARDs registered to treat RA patients under the influence of a Norwegian pharmaceutical tendering between 2010 and 2019. Method The data is collected from ten Norwegian outpatient centers. The included patients are categorized as naïve, non-naïve, and current b/tsDMARD users. 13 individual b/tsDMARDs are assessed and compared with the tender rankings from each year. Overview of subcutaneous (sc) with per oral vs. intravenous (iv) and biosimilars vs. non-biosimilar are also described. Result The tender-winning b/tsDMARD was the most or second most used drug in nine out of ten years for naïve users, seven for non-naïve users, and twice for current users. The average sum of the highest and second highest proportion among naïve, non-naïve, and current b/tsDMARD users were 75%, 53%, and 50% during the ten years, respectively. The tender-winning drug was iv in eight out of ten years. However, the average total proportion of sc and per oral b/tsDMARDs was about 70% for naïve b/tsDMARD users, 50% for non-naïve b/tsDMARD users, and 60% for current b/tsDMARD users. The main contributors to sc and per oral b/tsDMARD were etanercept (reference and biosimilar) and certolizumab pegol. The main contributors to iv b/tsDMARD were rituximab reference and infliximab biosimilar. Despite low-ranking offers, rituximab reference (offered as a second-line drug) often achieved a high proportion among non-naïve and current b/tsDMARD users. After the introduction of biosimilars, their average proportion was about 40%, 40%, and 20% for naïve, non-naïve, and current b/tsDMARD users, respectively. Conclusion Based on observed data, a higher tender rank was associated with a higher proportion among naïve and non-naïve b/tsDMARD users. However, in most cases, sc b/tsDMARDs achieved a higher proportion with lower tender ranks than iv b/tsDMARDs with higher tender ranks.

• Jyssum, Ingrid; Gehin, Johanna; Sexton, Joseph; Kristianslund, Eirik; Hu, Yi & Warren, David [Vis alle 11 forfattere av denne artikkelen] (2023). Adalimumab serum levels and anti-drug antibodies: associations to treatment response and drug survival in inflammatory joint diseases. Rheumatology. ISSN 1462-0324. 63(6), s. 1746–1755. doi: 10.1093/rheumatology/kead525. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Objectives To explore associations between serum adalimumab level, treatment response and drug survival in order to identify optimal drug levels for therapeutic drug monitoring of adalimumab. Also, to assess the occurrence and risk factors of anti-drug antibody (ADAb) formation. Methods Non-trough adalimumab and ADAb levels were measured by automated fluorescence assays in serum collected after 3 months of adalimumab treatment in patients with RA, PsA or axial SpA (axSpA) included in the observational NOR-DMARD study. Treatment response was evaluated after 3 months and drug survival was evaluated during long-term follow-up. Results In 340 patients (97 RA, 69 PsA, 174 axSpA), the median adalimumab level was 7.3 mg/l (interquartile range 4.0–10.3). A total of 33 (10%) patients developed ADAbs. Findings were comparable across diagnoses. In RA and PsA, adalimumab levels ≥6.0 mg/l were associated with treatment response [odds ratio (OR) 2.2 (95% CI 1.0, 4.4)] and improved drug survival [hazard ratio 0.49 (95% CI 0.27, 0.80)]. In axSpA, a therapeutic level could not be identified, but higher adalimumab levels were associated with response. Factors associated with ADAb formation were previous bDMARD use, no methotrexate comedication and the use of adalimumab originator compared with GP2017. Conclusion Higher adalimumab levels were associated with a better response and improved drug survival for all diagnoses, with a suggested lower threshold of 6.0 mg/l for RA/PsA. This finding, the large variability in drug levels among patients receiving standard adalimumab dose and the high proportion of patients developing ADAbs encourages further investigations into the potential role of therapeutic drug monitoring of adalimumab.

• Lillegraven, Siri; Sundlisæter, Nina Paulshus; Aga, Anna-Birgitte; Sexton, Joseph; Solomon, Daniel H. & Heijde, Désirée Van Der [Vis alle 7 forfattere av denne artikkelen] (2023). Discontinuation of Conventional Synthetic Disease-Modifying Antirheumatic Drugs in Patients with Rheumatoid Arthritis and Excellent Disease Control. Journal of the American Medical Association (JAMA). ISSN 0098-7484. 329(12), s. 1024–1026. doi: 10.1001/jama.2023.0492. Fulltekst i vitenarkiv
• Østergaard, Mikkel; Vollenhoven, Ronald F Van; Rudin, Anna; Hetland, Merete Lund; Schrumpf, Marte & Nordström, Dan C [Vis alle 45 forfattere av denne artikkelen] (2023). Certolizumab pegol, abatacept, tocilizumab or active conventional treatment in early rheumatoid arthritis: 48-week clinical and radiographic results of the investigator-initiated randomised controlled NORD-STAR trial. Annals of the Rheumatic Diseases. ISSN 0003-4967. 82(10), s. 1286–1295. doi: 10.1136/ard-2023-224116. Fulltekst i vitenarkiv Vis sammendrag

  Background - The optimal first-line treatment in early rheumatoid arthritis (RA) is debated. We compared clinical and radiographic outcomes of active conventional therapy with each of three biological treatments with different modes of action. Methods - Investigator-initiated, randomised, blinded-assessor study. Patients with treatment-naïve early RA with moderate–severe disease activity were randomised 1:1:1:1 to methotrexate combined with (1) active conventional therapy: oral prednisolone (tapered quickly, discontinued at week 36) or sulfasalazine, hydroxychloroquine and intra-articular glucocorticoid injections in swollen joints; (2) certolizumab pegol; (3) abatacept or (4) tocilizumab. Coprimary endpoints were week 48 Clinical Disease Activity Index (CDAI) remission (CDAI ≤2.8) and change in radiographic van der Heijde-modified Sharp Score, estimated using logistic regression and analysis of covariance, adjusted for sex, anticitrullinated protein antibody status and country. Bonferroni’s and Dunnet’s procedures adjusted for multiple testing (significance level: 0.025). Results - Eight hundred and twelve patients were randomised. Adjusted CDAI remission rates at week 48 were: 59.3% (abatacept), 52.3% (certolizumab), 51.9% (tocilizumab) and 39.2% (active conventional therapy). Compared with active conventional therapy, CDAI remission rates were significantly higher for abatacept (adjusted difference +20.1%, p<0.001) and certolizumab (+13.1%, p=0.021), but not for tocilizumab (+12.7%, p=0.030). Key secondary clinical outcomes were consistently better in biological groups. Radiographic progression was low, without group differences. The proportions of patients with serious adverse events were abatacept, 8.3%; certolizumab, 12.4%; tocilizumab, 9.2%; and active conventional therapy, 10.7%. Conclusions - Compared with active conventional therapy, clinical remission rates were superior for abatacept and certolizumab pegol, but not for tocilizumab. Radiographic progression was low and similar between treatments.

• Berg, Inger Jorid; Tveter, Anne Therese; Bakland, Gunnstein; Hakim, Sarah; Kristianslund, Eirik & Lillegraven, Siri [Vis alle 15 forfattere av denne artikkelen] (2023). 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. JMIR Research Protocols. 12(1), s. e52872–e52872. doi: 10.2196/52872. Fulltekst i vitenarkiv Vis sammendrag

  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.<p> <p>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.<p> <p>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.<p> <p>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.<p> <p>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.

• Lend, Kristina; Koopman, Frieda A.; Lampa, Jon; Jansen, Gerrit; Hetland, Merete L. & Uhlig, Till [Vis alle 18 forfattere av denne artikkelen] (2023). Methotrexate Safety and Efficacy in Combination Therapies in Patients With Early Rheumatoid Arthritis: A Post Hoc Analysis of a Randomized Controlled Trial. Arthritis & Rheumatology. ISSN 2326-5191. s. 1–14. doi: 10.1002/art.42730. Fulltekst i vitenarkiv Vis sammendrag

  Objective We investigated methotrexate safety and the influence of dose on efficacy outcomes in combination with three different biologic treatments and with active conventional treatment (ACT) in early rheumatoid arthritis (RA). Methods This post hoc analysis included 812 treatment-naïve patients with early RA who were randomized (1:1:1:1) in the NORD-STAR trial to receive methotrexate in combination with ACT, certolizumab-pegol, abatacept, or tocilizumab. Methotrexate safety, doses, and dose effects on Clinical Disease Activity Index (CDAI) remission were assessed after 24 weeks of treatment. Results Compared with ACT, the prevalence of methotrexate-associated side effects was higher when methotrexate was combined with tocilizumab (hazard ratio [HR] 1.48, 95% confidence interval [CI] 1.20–1.84) but not with certolizumab-pegol (HR 0.99, 95% CI 0.79–1.23) or with abatacept (HR 0.93, 95% CI 0.75–1.16). With ACT as the reference, the methotrexate dose was significantly lower when used in combination with tocilizumab (β −4.65, 95% CI −5.83 to −3.46; P < 0.001) or abatacept (β −1.15, 95% CI −2.27 to −0.03; P = 0.04), and it was numerically lower in combination with certolizumab-pegol (β −1.07, 95% CI −2.21 to 0.07; P = 0.07). Methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the treatment combinations. Conclusion Methotrexate was generally well tolerated in combination therapies, but adverse events were a limiting factor in receiving the target dose of 25 mg/wk, and these were more frequent in combination with tocilizumab versus ACT. On the other hand, methotrexate dose reductions were not associated with decreased CDAI remission rates within any of the four treatment combinations at 24 weeks.

• Lillegraven, Siri; Sundlisæter, Nina Paulshus; Aga, Anna-Birgitte; Sexton, Joseph; Olsen, Inge Christoffer & Lexberg, Åse [Vis alle 19 forfattere av denne artikkelen] (2023). 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. Annals of the Rheumatic Diseases. ISSN 0003-4967. 82(11), s. 1394–1403. doi: 10.1136/ard-2023-224476. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Uhlig, Till; Karoliussen, Lars Fridtjof; Sexton, Joseph; Provan, Sella Aarrestad; Kvien, Tore Kristian Aaserud & Haavardsholm, Espen A. [Vis alle 7 forfattere av denne artikkelen] (2023). Course and predictors of work productivity in gout - results from the NOR-Gout longitudinal 2-year treat-to-target study. Rheumatology. ISSN 1462-0324. 62(12), s. 3886–3892. doi: 10.1093/rheumatology/kead124. Fulltekst i vitenarkiv Vis sammendrag

  Objectives In patients with gout there is a lack of longitudinal studies on the course of work productivity. We explored longitudinal changes in and predictors of work productivity over 2 years. Methods Patients in the NOR-Gout observational study with a recent gout flare and serum urate (sUA) >360 µmol/l attended tight-control visits during escalating urate lowering therapy according to a treat-to-target strategy. From the Work Productivity and Activity Impairment (WPAI) questionnaire, scores for work productivity and activity impairment were assessed over 2 years together with the Beliefs about Medicines Questionnaire and a variety of demographic and clinical variables. Results At baseline patients had a mean age of 56.4 years and 95% were males. WPAI scores at baseline were 5.0% work missed (absenteeism), 19.1% work impairment (presenteeism), 21.4% overall work impairment and 32.1% activity impairment. Work productivity and activity impairment improved during the first months, and remained stable at 1 and 2 years. Comorbidities were not cross-sectionally associated with WPAI scores at baseline, but predicted worse work impairment and activity impairment at year 1. The Beliefs about Medicines Questionnaire subscale with concerns about medicines at baseline independently predicted worse overall work impairment and worse activity impairment at year 1. Conclusions In patients with gout who were intensively treated to the sUA target, work productivity and activity impairment were largely unchanged and at 1 year predicted by comorbidities and patient concerns about medication.

• Uhlig, Till; Karoliussen, Lars Fridtjof; Sexton, Joseph; Kvien, Tore Kristian Aaserud; Haavardsholm, Espen A. & Taylor, W.J. [Vis alle 7 forfattere av denne artikkelen] (2023). Beliefs about medicines in gout patients: results from the NOR-Gout 2-year study. Scandinavian Journal of Rheumatology. ISSN 0300-9742. doi: 10.1080/03009742.2023.2213507. Fulltekst i vitenarkiv Vis sammendrag

  Objective Adherence to urate-lowering therapy (ULT) in gout is challenging. This longitudinal study aimed to determine 2 year changes in beliefs about medicines during intervention with ULT. Method Patients with a recent gout flare and increased serum urate received a nurse-led ULT intervention with tight control visits and a treatment target. Frequent visits at baseline and 1, 2, 3, 6, 9, 12, and 24 months included the Beliefs about Medicines Questionnaire (BMQ), and demographic and clinical variables. The BMQ subscales on necessity, concerns, overuse, harm, and the necessity–concerns differential were calculated as a measure of whether the patient perceived that necessity outweighed concerns. Results The mean serum urate reduced from 500 mmol/L at baseline to 324 mmol/L at year 2. At years 1 and 2, 85.5% and 78.6% of patients, respectively, were at treatment target. The 2 year mean ± sd BMQ scores increased for the necessity subscale from 17.0 ± 4.4 to 18.9 ± 3.6 (p < 0.001) and decreased for the concerns subscale from 13.4 ± 4.9 to 12.5 ± 2.7 (p = 0.001). The necessity–concerns differential increased from 3.52 to 6.58 (p < 0.001), with a positive change independent of patients achieving treatment targets at 1 or 2 years. BMQ scores were not significantly related to treatment outcomes 1 or 2 years later, and achieving treatment targets did not lead to higher BMQ scores. Conclusion Patient beliefs about medicines improved gradually over 2 years, with increased beliefs in the necessity of medication and reduced concerns, but this improvement was unrelated to better outcomes.

• Uhlig, Till; Karoliussen, Lars Fridtjof; Sexton, Joseph; Kvien, Tore Kristian Aaserud; Haavardsholm, Espen A. & Hammer, Hilde Berner (2023). Lifestyle factors predict gout outcomes: Results from the NOR-Gout longitudinal 2-year treat-to-target study. RMD Open. 9(4). doi: 10.1136/rmdopen-2023-003600. Fulltekst i vitenarkiv Vis sammendrag

  Objective Gout is associated with lifestyle, body mass index (BMI) and comorbidities, including dyslipidaemia. We studied how in actively treated patients, anthropometric measures and lipid levels changed over 2 years and whether they predicted gout outcomes. Methods Patients with a recent gout flare and elevated serum urate (sUA) received gout education and treat-to-target urate-lowering therapy over 1 year. Anthropometric measures with BMI, waist circumference (WC) and waist–height ratio (WHR) as well as lipid levels were measured yearly over 2 years. We examined whether baseline anthropometric measures and lipid levels were related to flares and to achieving the sUA target. Results At baseline, patients (n=211) were with mean age of 56.4 years and 95% were male. Over 2 years, anthropometric measures were largely unchanged while cholesterol and low-density lipoprotein cholesterol (LDL-C) were reduced at year 1. Anthropometric measures were associated with presence of tophi. Higher baseline WC (OR: 0.96 per cm, 95% CI: 0.93 to 0.99) decreased and high level of high-density lipoprotein cholesterol (OR: 5.1 per mmol/L, 95% CI: 1.2 to 22.1) increased the chance of sUA target achievement at year 2. High LDL-C (OR: 1.8 per mmol/L, 95% CI: 1.2 to 2.6) predicted the chance of having a gout flare during year 2. Conclusion In actively treated patients with gout, anthropometric measures were largely unchanged over 2 years and lipid levels were reduced. High WC and lipid levels predicted unfavourable gout outcomes after 2 years.

• Hammer, Hilde Berner; Pedersen, Sigve Lars; Jonsson, Maria Karolina; Mathsson-Alm, Linda; Gehring, Isabel & Sexton, Joseph [Vis alle 8 forfattere av denne artikkelen] (2023). Calprotectin, a sensitive marker of inflammation, is robustly assessed in plasma from patients with early or established rheumatoid arthritis by use of different laboratory methods. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 83(5), s. 330–335. doi: 10.1080/00365513.2023.2225223. Fulltekst i vitenarkiv Vis sammendrag

  Calprotectin (S100A8/S100A9, MRP8/MRP14) is a major leukocyte protein found to be more sensitive than C-Reactive Protein (CRP) and Erythrocyte Sedimentation Rate (ESR) as a marker of inflammation in patients with rheumatoid arthritis (RA). The present objective was to explore the robustness of calprotectin assessments by comparing two different laboratory methods assessing calprotectin in plasma samples from patients with early or established RA. A total of 212 patients with early RA (mean (SD) age 52(13.3) years, disease duration 0.6(0.5) years) and 177 patients with established RA (mean (SD) age 52.9(13.0) years, disease duration 10.0(8.8) years) were assessed by clinical, laboratory, and ultrasound examinations. Frozen plasma samples (−80 °C) were analysed for calprotectin levels at baseline, 1, 2, 3, 6 and 12 months by use of either enzyme-linked immunosorbent assay (ELISA) or fluoroenzyme immunoassay (FEIA). The ELISA technique used kits from Calpro AS and the FEIA technology was assessed on an automated Thermo Fisher Scientific instrument. The results showed high correlations between the two methods at baseline and during follow-up, with Spearman correlation at baseline 0.93 (p < 0.001) in the early and 0.96 (p < 0.001) in the established RA cohorts. The correlations between each of the two calprotectin assessments and clinical examinations had similar range. Calprotectin correlated well with clinical examinations, with at least as high correlations as CRP and ESR. The present study showed similar results for the two analytical methods, supporting the robustness of calprotectin analyses, and suggest calprotectin in plasma to be included in the assessments offered by clinical routine laboratories.

• Bjørlykke, Kristin H.; Ørbo, Hilde Sofie Sager; Tveter, Anne Therese; Jyssum, Ingrid; Sexton, Joseph & Tran, Trung [Vis alle 21 forfattere av denne artikkelen] (2022). Four SARS-CoV-2 vaccine doses or hybrid immunity in patients on immunosuppressive therapies: a Norwegian cohort study. The Lancet Rheumatology. 5(1), s. e36–e46. doi: 10.1016/S2665-9913(22)00330-7. Fulltekst i vitenarkiv Vis sammendrag

  Background Data on response and safety of repeated vaccinations and hybrid immunity in patients with immune-mediated inflammatory diseases on immunosuppressive therapy is needed to further develop vaccination strategies in this vulnerable population. This study aimed to evaluate hybrid immunity and humoral immune response and safety of four SARS-CoV-2 vaccine doses in patients with immune-mediated inflammatory diseases on immunosuppressive therapy. Methods This prospective observational Norwegian study of vaccine response to COVID-19 (Nor-vaC) included adult patients aged 18 years and older with immune-mediated inflammatory diseases (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis) on immunosuppressive therapy, who had received four SARS-CoV-2 vaccine doses (vaccine group) or three vaccine doses followed by COVID-19 (hybrid group), and healthy controls receiving three vaccine doses (control group). Patients were recruited from the Division of Rheumatology at Diakonhjemmet Hospital, Oslo, and the Department of Gastroenterology at Akershus University Hospital, Lørenskog. Patients who had COVID-19 before the third vaccine dose, and patients with allergies or intolerances to elements of the vaccine were excluded. Antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD antibodies) were assessed 2–4 weeks following vaccination or COVID-19. This study is registered at Clinialtrials.gov, NCT04798625. Findings Between Nov 12, 2021, and April 19, 2022, 1458 participants with immune-mediated inflammatory diseases provided post-vaccination samples at 2–4 weeks following a third vaccine dose. After 544 participants were excluded, 715 (78%) of the remaining 914 participants received the fourth dose of the vaccine, and of these, 536 (75%) provided post-vaccination samples 2–4 weeks after their fourth vaccination (vaccine group). 199 (22%) of the 914 had COVID-19 after their third dose of the vaccine and of these, 167 (84%) provided samples (hybrid group). 256 of the eligible 703 patients had rheumatoid arthritis, 107 had spondyloarthritis, 115 had psoriatic arthritis, 130 had Crohn's disease, and 95 had ulcerative colitis). Median age was 56 years [IQR 45–65], 398 (57%) were women, and 305 (43%) were men. Patients in the vaccine group had higher anti-RBD antibody concentrations following the fourth vaccine dose (median 6192 BAU/ml [IQR 2878–11 243]) than after the third dose (median 5087 BAU/ml [1250–9081]; p< 0·0001), but lower antibody concentrations than the control group following the third dose (median 7595 BAU/ml [5916–12 001]; p< 0·0001). Antibody concentrations were higher in the patients in the hybrid group (23 548 BAU/ml [IQR 11 440–35 935]) than in the vaccine group (p<0·0001). No difference was found in antibody concentrations between the fourth dose of BNT162b2 (full-dose) and mRNA-1273 (half-dose). Patients and controls had a comparable safety profile after both three and four vaccine doses. Interpretation Vaccine boosters improve humoral immune responses and are safe in patients with immune-mediated inflammatory diseases on immunosuppressive therapy, and administration should be considered regularly in this patient group. Hybrid immunity with omicron induces a strong humoral response suggesting longer intervals between booster doses in this patient group.

• Tønnessen, Theis Christian; Melleby, Arne Olav; Hauge-Iversen, Ida Marie; Espe, Emil Knut Stenersen; Ahmed, Muhammad Shakil & Ueland, Thor [Vis alle 12 forfattere av denne artikkelen] (2022). Impact of delayed type hypersensitivity arthritis on development of heart failure by aortic constriction in mice. PLOS ONE. 17(1). doi: 10.1371/journal.pone.0262821. Fulltekst i vitenarkiv Vis sammendrag

  Aims Patients with rheumatoid arthritis (RA) have increased risk of heart failure (HF). The mechanisms and cardiac prerequisites explaining this association remain unresolved. In this study, we sought to determine the potential cardiac impact of an experimental model of RA in mice subjected to HF by constriction of the ascending aorta. Methods Aorta was constricted via thoracotomy and placement of o-rings with inner diameter 0.55 mm or 0.66 mm, or sham operated. RA-like phenotype was instigated by delayed-type hypersensitivity arthritis (DTHA) two weeks after surgery and re-iterated after additional 18 days. Cardiac magnetic resonance imaging (MRI) was performed before surgery and at successive time points throughout the study. Six weeks after surgery the mice were euthanized, blood and tissue were collected, organ weights were documented, and expression levels of cardiac foetal genes were analysed. In a supplemental study, DTHA-mice were euthanized throughout 14 days after induction of arthritis, and blood was analysed for important markers and mediators of RA (SAP, TNF-α and IL-6). In order to put the latter findings into clinical context, the same molecules were analysed in serum from untreated RA patients and compared to healthy controls. Results Significant elevations of inflammatory markers were found in both patient- and murine blood. Furthermore, the DTHA model appeared clinically relevant when compared to the inflammatory responses observed in three prespecified RA severity disease states. Two distinct trajectories of cardiac dysfunction and HF development were found using the two o-ring sizes. These differences were consistent by both MRI, organ weights and cardiac foetal gene expression levels. Still, no difference within the HF groups, nor within the sham groups, could be found when DTHA was induced. Conclusion DTHA mediated systemic inflammation did not cause, nor modify HF caused by aortic constriction. This indicates other prerequisites for RA-induced cardiac dysfunction.

• Norvang, Vibeke; Haavardsholm, Espen A.; Tedeschi, Sara K.; Lyu, Houchen; Sexton, Joseph & Mjaavatten, Maria Dahl [Vis alle 9 forfattere av denne artikkelen] (2022). Using observational study data as an external control group for a clinical trial: an empirical comparison of methods to account for longitudinal missing data. BMC Medical Research Methodology. 22(152), s. 1–10. doi: 10.1186/s12874-022-01639-0. Fulltekst i vitenarkiv Vis sammendrag

  Background Observational data are increasingly being used to conduct external comparisons to clinical trials. In this study, we empirically examined whether different methodological approaches to longitudinal missing data affected study conclusions in this setting. Methods We used data from one clinical trial and one prospective observational study, both Norwegian multicenter studies including patients with recently diagnosed rheumatoid arthritis and implementing similar treatment strategies, but with different stringency. A binary disease remission status was defined at 6, 12, and 24 months in both studies. After identifying patterns of longitudinal missing outcome data, we evaluated the following five approaches to handle missingness: analyses of patients with complete follow-up data, multiple imputation (MI), inverse probability of censoring weighting (IPCW), and two combinations of MI and IPCW. Results We found a complex non-monotone missing data pattern in the observational study (N = 328), while missing data in the trial (N = 188) was monotone due to drop-out. In the observational study, only 39.0% of patients had complete outcome data, compared to 89.9% in the trial. All approaches to missing data indicated favorable outcomes of the treatment strategy in the trial and resulted in similar study conclusions. Variations in results across approaches were mainly due to variations in estimated outcomes for the observational data. Conclusions Five different approaches to handle longitudinal missing data resulted in similar conclusions in our example. However, the extent and complexity of missing observational data affected estimated comparative outcomes across approaches, highlighting the need for careful consideration of methods to account for missingness in this setting. Based on this empirical examination, we recommend using a prespecified advanced missing data approach to account for longitudinal missing data, and to conduct alternative approaches in sensitivity analyses.

• Brun, Marthe Kirkesæther; Goll, Guro Løvik; Jørgensen, Kristin Kaasen; Sexton, Joseph; Gehin, Johanna Elin & Sandanger, Øystein [Vis alle 15 forfattere av denne artikkelen] (2022). Risk factors for anti-drug antibody formation to infliximab: Secondary analyses of a randomised controlled trial. Journal of Internal Medicine. ISSN 0954-6820. 292(3), s. 477–491. doi: 10.1111/joim.13495. Fulltekst i vitenarkiv Vis sammendrag

  Background Anti-drug antibodies (ADAb) frequently form early in the treatment course of infliximab and other tumour necrosis factor (TNF) inhibitors, leading to treatment failure and adverse events. Objective To identify risk factors for ADAb in the early phase of infliximab treatment. Methods Patients (n = 410) with immune-mediated inflammatory diseases who initiated infliximab treatment were included in the 38-week Norwegian Drug Monitoring Trial (NOR-DRUM) A and randomised 1:1 to therapeutic drug monitoring (TDM) or standard therapy. Serum levels of infliximab and ADAb were measured at each infusion. Possible risk factors for ADAb formation were assessed using logistic regression, adjusting for potential confounders. Results ADAb were detected in 78 (19%) patients. A diagnosis of rheumatoid arthritis (RA) (odds ratio [OR], 1.9 [95% confidence interval [CI] 1.0–3.6]) and lifetime smoking (OR, 2.0 [CI 1.1–3.6]) were baseline risk factors, while baseline use of concomitant immunosuppressors (OR, 0.4 [CI 0.2–0.8]) and a diagnosis of spondyloarthritis (SpA) (OR, 0.4 [CI 0.2–0.8]) reduced the risk of ADAb. Higher disease activity during follow-up (OR, 1.1 [CI 1.0–1.1]) and “drug holidays” of more than 11 weeks (OR, 4.1 [CI 1.2–13.8]) increased the risk of ADAb, whereas higher infliximab doses (OR, 0.1 [CI 0.0–0.3) and higher serum infliximab concentrations (OR, 0.7 [CI 0.6–0.8]) reduced the risk of immunogenicity. Conclusion Several risk factors for ADAb formation during early-phase infliximab treatment were identified. This knowledge provides a basis for treatment strategies to mitigate the formation of ADAb and identify patients in whom these measures are of particular importance.

• Podewski, A.F.; Glimm, A.M.; Fischer, I.; Bruyn, G.A.W.; Hanova, P. & Hammer, Hilde Berner [Vis alle 12 forfattere av denne artikkelen] (2022). The MCP2 and the wrist plus two extensor compartments are the most affected and responsive joints/tendons out of the US7 score in patients with rheumatoid arthritis-an observational study. Arthritis Research & Therapy. ISSN 1478-6354. 24(1), s. 1–13. doi: 10.1186/s13075-022-02874-y. Fulltekst i vitenarkiv Vis sammendrag

  Background There is no international consensus on an optimal ultrasound score for monitoring of rheumatoid arthritis (RA) on patient-level yet. Our aim was to reassess the US7 score for the identification of the most frequently pathologic and responsive joint/tendon regions, to optimize it and contribute to an international consensus. Furthermore, we aimed to evaluate the impact of disease duration on the performance of the score. Methods RA patients were assessed at baseline and after 3 and 6 months of starting/changing DMARD therapy by the US7 score in greyscale (GS) and power Doppler (PD). The frequency of pathologic joint/tendon regions and their responsiveness to therapy were analyzed by Friedman test and Cochrane-Q test respectively, including the comparison of palmar vs. dorsal regions (chi-square test). The responsiveness of different reduced scores and the amount of information retained from the original US7 score were assessed by standardized response means (SRM)/linear regression. Analyses were also performed separately for early and established RA. Results A total of 435 patients (N = 138 early RA) were included (56.5 (SD 13.1) years old, 8.2 (9.1) years disease duration, 80% female). The dorsal wrist, palmar MCP2, extensor digitorum communis (EDC) and carpi ulnaris (ECU) tendons were most frequently affected by GS/PD synovitis/tenosynovitis (wrist: 45%/43%; MCP2: 35%/28%; EDC: 30%/11% and ECU: 25%/11%) and significantly changed within 6 months of therapy (all p ≤0.003 by GS/PD). The dorsal vs. palmar side of the wrist by GS/PD (p < 0.001) and the palmar side of the finger joints by PD (p < 0.001) were more frequently pathologic. The reduced US7 score (GS/PD: palmar MCP2, dorsal wrist, EDC and ECU, only PD: dorsal MCP2) showed therapy response (SRM 0.433) after 6 months and retained 76% of the full US7 score’s information. No major differences between the groups of early and established RA could be detected. Conclusions The wrist, MCP2, EDC, and ECU tendons were most frequently pathologic and responsive to therapy in both early and established RA and should therefore be included in a comprehensive score for monitoring RA patients on patient-level.

• Hammer, Hilde Berner; Rollefstad, Silvia Christin Hellerud; Semb, Anne Grete; Jensen, Gro Elisabeth; Karoliussen, Lars Fridtjof & Terslev, L [Vis alle 9 forfattere av denne artikkelen] (2022). Urate crystal deposition is associated with inflammatory markers and carotid artery pathology in patients with intercritical gout: results from the NOR-Gout study. RMD Open. 8(2), s. 1–5. doi: 10.1136/rmdopen-2022-002348. Fulltekst i vitenarkiv Vis sammendrag

  Background Gout is of unknown reason associated with cardiovascular disease. Ultrasound is sensitive for detecting crystal deposition and plasma calprotectin is a sensitive inflammatory marker. This study explores the associations between crystal deposition, inflammation and carotid artery pathology. Method A cross-sectional analysis of baseline assessments from the NOR-Gout study was undertaken. Crystal deposition was assessed by ultrasound (double contour, tophi, aggregates) and dual-energy CT (DECT) and laboratory assessments included plasma calprotectin. The carotid arteries were bilaterally examined for carotid intima–media thickness (cIMT) and presence of plaques. Spearman correlations, Mann-Whitney tests and linear regression analyses were used to explore associations between crystal deposition, inflammatory markers,and carotid pathology. Results 202 patients with intercritical gout (95.5% men, mean (SD) age 56.5 (13.8) years, disease duration 7.9 (7.7) years) were included. Calprotectin was correlated with all scores of crystal deposition by ultrasound (r=0.26–0.32, p&lt;0.001) and DECT (r=0.15, p&lt;0.05). cIMT was correlated with sum score aggregates (r=0.18–0.22, p&lt;0.05). Patients with large tophi had higher levels of calprotectin as well as more frequent carotid plaque (p&lt;0.05). Conclusions Study findings point towards crystal deposition contributing to subclinical inflammation with subsequent vascular implications. However, future longitudinal studies are needed to confirm such causal relationships.

• Kerola, A.M.; Rollefstad, Silvia Christin Hellerud; Kazemi, Amirhossein; Wibetoe, Grunde; Sexton, Joseph & Mars, N. [Vis alle 10 forfattere av denne artikkelen] (2022). Psoriatic arthritis, axial spondyloarthritis and rheumatoid arthritis in Norway: nationwide prevalence and use of biologic agents. Scandinavian Journal of Rheumatology. ISSN 0300-9742. s. 1–9. doi: 10.1080/03009742.2021.1997436. Fulltekst i vitenarkiv Vis sammendrag

  Objective To estimate the prevalence of psoriatic arthritis (PsA), axial spondyloarthritis (axSpA) and rheumatoid arthritis (RA) and the use of biologic agents in these diseases in Norway. Methods From the Norwegian Patient Registry (NPR), we identified as PsA, axSpA and RA patients ≥18 years those with ≥2 recorded episodes with diagnostic coding for index disease (L40.5, M07.0-M07.3 for PsA; M45, M46.0, M46.1, M46.8 and M46.9 for axSpA; M05-M06 for RA). We calculated the point prevalence of PsA, axSpA and RA as per the 1st of January 2017 in the Norwegian adult population (age ≥18). Dispensed disease-modifying antirheumatic drug (DMARD) prescriptions were obtained from the Norwegian Prescription Database and biologic DMARDs given in hospitals from the NPR. Results The point prevalence of PsA, axSpA, RA, and any of these diseases in total was 0.46%, 0.41%, 0.78%, and 1.56%, respectively. Among women, the prevalence of PsA, axSpA, and RA was 0.50%, 0.37%, and 1.10%, and among men 0.43%, 0.45%, and 0.46%, respectively. In 2017, 27.3% of RA patients, 25.7% of PsA patients and 35.1% of axSpA patients used biologic DMARDs. Treatment with biologics was more frequent in younger age groups in all three diseases, and became more infrequent especially after age ≥55 years. Conclusion In Norway, the combined prevalence of PsA, axSpA, and RA was over 1.5%. Reflecting the good overall access to highly effective but costly biologic treatments, more than a fourth of these patients used biologic agents, which corresponds to over 0.4% of Norwegian adult population.

• Syversen, Silje Watterdal; Jyssum, Ingrid; Tveter, Anne Therese; Tran, Trung; Sexton, Joseph & Provan, Sella Aarrestad [Vis alle 22 forfattere av denne artikkelen] (2022). Immunogenicity and Safety of Standard and Third-Dose SARS-CoV-2 Vaccination in Patients Receiving Immunosuppressive Therapy. Arthritis & Rheumatology. ISSN 2326-5191. 74(8), s. 1321–1332. doi: 10.1002/art.42153. Fulltekst i vitenarkiv Vis sammendrag

  Objective Immunogenicity and safety following receipt of the standard SARS–CoV-2 vaccination regimen in patients with immune-mediated inflammatory diseases (IMIDs) are poorly characterized, and data after receipt of the third vaccine dose are lacking. The aim of the study was to evaluate serologic responses and adverse events following the standard 2-dose regimen and a third dose of SARS–CoV-2 vaccine in IMID patients receiving immunosuppressive therapy. Methods Adult patients receiving immunosuppressive therapy for rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis, as well as healthy adult controls, who received the standard 2-dose SARS–CoV-2 vaccination regimen were included in this prospective observational study. Analyses of antibodies to the receptor-binding domain (RBD) of the SARS–CoV-2 spike protein were performed prior to and 2–4 weeks after vaccination. Patients with a weak serologic response, defined as an IgG antibody titer of ≤100 arbitrary units per milliliter (AU/ml) against the receptor-binding domain of the full-length SARS–Cov-2 spike protein, were allotted a third vaccine dose. Results A total of 1,505 patients (91%) and 1,096 healthy controls (98%) had a serologic response to the standard regimen (P < 0.001). Anti-RBD antibody levels were lower in patients (median 619 AU/ml interquartile range [IQR] 192–4,191) than in controls (median 3,355 AU/ml [IQR 896–7,849]) (P < 0.001). The proportion of responders was lowest among patients receiving tumor necrosis factor inhibitor combination therapy, JAK inhibitors, or abatacept. Younger age and receipt of messenger RNA–1273 vaccine were predictors of serologic response. Of 153 patients who had a weak response to the standard regimen and received a third dose, 129 (84%) became responders. The vaccine safety profile among patients and controls was comparable. Conclusion IMID patients had an attenuated response to the standard vaccination regimen as compared to healthy controls. A third vaccine dose was safe and resulted in serologic response in most patients. These data facilitate identification of patient groups at risk of an attenuated vaccine response, and they support administering a third vaccine dose to IMID patients with a weak serologic response to the standard regimen.

• Uhlig, Till; Karoliussen, Lars Fridtjof; Sexton, Joseph; Kvien, Tore Kristian; Haavardsholm, Espen A. & Perez-Ruiz, Fernando [Vis alle 7 forfattere av denne artikkelen] (2022). One- and 2-year flare rates after treat-to-target and tight-control therapy of gout: results from the NOR-Gout study. Arthritis Research & Therapy. ISSN 1478-6354. 24:88, s. 1–11. doi: 10.1186/s13075-022-02772-3. Fulltekst i vitenarkiv Vis sammendrag

  Objectives To explore the frequency and predictors of flares over 2 years during a treat-to-target strategy with urate-lowering therapy (ULT) in patients with gout. Methods In the treat-to-target, tight control NOR-Gout study patients started ULT with escalating doses of allopurinol. Flares were recorded over 2 years. Baseline predictors of flares during months 9–12 in year 1 and during year 2 were analyzed by multivariable logistic regression. Results Of 211 patients included (mean age 56.4 years, disease duration 7.8 years, 95% males), 81% (150/186) of patients experienced at least one gout flare during the first year and 26% (45/173) during the second year. The highest frequency of flares in the first year was seen during months 3–6 (46.8% of patients). Baseline crystal depositions detected by ultrasound and by dual-energy computed tomography (DECT) were the only variables which predicted flares both during the first period of interest at months 9–12 (OR 1.033; 95% CI 1.010–1.057, and OR 1.056; 95% CI 1.007–1.108) and also in year 2. Baseline subcutaneous tophi (OR 2.42, 95% CI 1.50–5.59) and prior use of colchicine at baseline (OR 2.48, 95% CI 1.28-4.79) were independent predictors of flares during months 9–12, whereas self-efficacy for pain was a protective predictor (OR 0.98 per unit, 95% CI 0.964–0.996). Conclusions In patients with gout, flares remain frequent during the first year of a treat-to-target ULT strategy, especially during months 3–6, but are much less frequent during year 2. Baseline crystal depositions predict flares over 2 years, supporting ULT early during disease course. Trial registration ACTRN12618001372279

• Lend, Kristina; Vollenhoven, Ronald F van; Lampa, Jon; Hetland, Merete Lund; Haavardsholm, Espen A. & Nordström, Dan [Vis alle 18 forfattere av denne artikkelen] (2022). Sex differences in remission rates over 24 weeks among three different biological treatments compared to conventional therapy in patients with early rheumatoid arthritis (NORD-STAR): a post-hoc analysis of a randomised controlled trial. The Lancet Rheumatology. 4(10), s. e688–e698. doi: 10.1016/S2665-9913(22)00186-2. Fulltekst i vitenarkiv Vis sammendrag

  Background Rheumatoid arthritis is a chronic inflammatory disease with a well-recognised female preponderance. In this post-hoc analysis of the NORD-STAR trial, we aimed to examine sex differences in remission rates with three different biological treatments combined with methotrexate versus active conventional treatment over 24 weeks, in patients with early rheumatoid arthritis. Methods NORD-STAR was a multicentre, investigator-initiated, assessor-blinded, phase 4, randomised, controlled trial of early rheumatoid arthritis, done in Denmark, Finland, Iceland, Norway, Sweden, and the Netherlands. Newly diagnosed patients, naive to disease-modifying antirheumatic drugs, aged 18 years or older with early rheumatoid arthritis and with a symptom duration less than 24 months were randomly assigned (1:1:1:1) to receive active conventional treatment, certolizumab-pegol, abatacept, or tocilizumab. Sex was reported in case report forms by study physicians or by study nurses. Data on gender were not collected. Remission outcomes were analysed with logistic generalised estimating equations (GEE), using a logit link and exchangeable correlation matrix. The model included treatment, time, sex, and the relevant interactions. For this post-hoc analysis, the co-primary outcomes were differences in Clinical Disease Activity Index (CDAI) remission (CDAI score ≤2·8) between sexes over time and at week 24, assessed with interaction terms (men vs women within each treatment comparison) and using active conventional treatment as the reference. We present adjusted average marginal differences in remission rates (risk differences) with 95% CIs. Findings Between Dec 14, 2012, and Dec 11, 2018, 812 patients were enrolled and randomly assigned; 217 received active conventional treatment, 203 received certolizumab-pegol, 204 received abatacept, and 188 received tocilizumab. All 812 patients were included in this analysis; 561 (69%) were women and 251 (31%) were men. Observed CDAI remission rates at 24 weeks were numerically higher among men than among women despite comparable disease activity at baseline (55% vs 50% with active conventional treatment, 57% vs 52% with certolizumab-pegol, 65% vs 51% with abatacept, and 61% vs 40% with tocilizumab). In the adjusted analysis, with active conventional treatment as the reference, the only significant difference between men and women was in the tocilizumab group (pinteraction=0·015); men in the tocilizumab group had a higher probability of CDAI remission, on average over time, than did men in the active conventional treatment group (0·12; 95% CI 0·00 to 0·23), whereas women in the tocilizumab group had a lower probability of remission than did women in the active conventional treatment group (–0·05, 95% CI –0·13 to 0·02). Interpretation Numerically higher remission rates were observed in men than in women in all four treatment groups at week 24, suggesting that this generalised sex difference is not related to the treatment. The difference between men and women was significantly greater with tocilizumab, an interleukin (IL)-6 inhibitor, than with active conventional treatment, suggesting a possible additional sex-based effect specific for IL-6 blockade.

• Kerola, Anne Mirjam; Kazemi, Amirhossein; Rollefstad, Silvia Christin Hellerud; Lillegraven, Siri; Sexton, Joseph & Wibetoe, Grunde [Vis alle 9 forfattere av denne artikkelen] (2022). All-cause and cause-specific mortality in rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis: a nationwide registry study. Rheumatology. ISSN 1462-0324. 61(12), s. 4656–4666. doi: 10.1093/rheumatology/keac210. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Smolen, Josef S; Landewé, Robert B M; Bergstra, Sytske Anne; Kerschbaumer, Andreas; Sepriano, Alexandre & Aletaha, Daniel [Vis alle 48 forfattere av denne artikkelen] (2022). EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2022 update. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1136/ard-2022-223356. Fulltekst i vitenarkiv
• Brkic, Alen; Diamantopoulos, Andreas P; Haavardsholm, Espen A.; Fevang, Bjørg Tilde Svanes; Brekke, Lene Kristin & Loli, Liz Paucar [Vis alle 11 forfattere av denne artikkelen] (2022). Exploring drug cost and disease outcome in rheumatoid arthritis patients treated with biologic and targeted synthetic DMARDs in Norway in 2010–2019 – a country with a national tender system for prescription of costly drugs. BMC Health Services Research. 22(1), s. 1–15. doi: 10.1186/s12913-021-07425-w. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Background In Norway, an annual tender system for the prescription of biologic and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) has been used since 2007. This study aimed to explore annual b/tsDMARDs costs and disease outcomes in Norwegian rheumatoid arthritis (RA) patients between 2010 and 2019 under the influence of the tender system. Methods RA patients monitored in ordinary clinical practice were recruited from 10 Norwegian centers. Data files from each center for each year were collected to explore demographics, disease outcomes, and the prescribed treatment. The cost of b/tsDMARDs was calculated based on the drug price given in the annual tender process. Results The number of registered RA patients increased from 4909 in 2010 to 9335 in 2019. The percentage of patients receiving a b/tsDMARD was 39% in 2010 and 45% in 2019. The proportion of b/tsDMARDs treated patients achieving DAS28 remission increased from 42 to 67%. The estimated mean annual cost to treat a patient on b/tsDMARDs fell by 47%, from 13.1 thousand euros (EUR) in 2010 to 6.9 thousand EUR in 2019. The mean annual cost to treat b/tsDMARDs naïve patients was reduced by 75% (13.0 thousand EUR in 2010 and 3.2 thousand EUR in 2019). Conclusions In the period 2010–2019, b/tsDMARD treatment costs for Norwegian RA patients were significantly reduced, whereas DAS28 remission rates increased. Our data may indicate that the health authorities’ intention to reduce treatment costs by implementing a tender system has been successful.

• Syversen, Silje Watterdal; Jyssum, Ingrid; Tveter, Anne Therese; Sexton, Joseph; Christensen, Ingrid Egeland & Tran, Trung [Vis alle 20 forfattere av denne artikkelen] (2022). Immunogenicity and safety of a three-dose SARS-CoV-2 vaccination strategy in patients with immune-mediated inflammatory diseases on immunosuppressive therapy. RMD Open. 8(2). doi: 10.1136/rmdopen-2022-002417. Fulltekst i vitenarkiv Vis sammendrag

  Objectives Humoral vaccine responses to SARS-CoV-2 vaccines are impaired and short lasting in patients with immune-mediated inflammatory diseases (IMID) following two vaccine doses. To protect these vulnerable patients against severe COVID-19 disease, a three-dose primary vaccination strategy has been implemented in many countries. The aim of this study was to evaluate humoral response and safety of primary vaccination with three doses in patients with IMID. Methods Patients with IMID on immunosuppressive therapy and healthy controls receiving three-dose and two-dose primary SARS-CoV-2 vaccination, respectively, were included in this prospective observational cohort study. Anti-Spike antibodies were assessed 2–4 weeks, and 12 weeks following each dose. The main outcome was anti-Spike antibody levels 2–4 weeks following three doses in patients with IMID and two doses in controls. Additional outcomes were the antibody decline rate and adverse events. Results 1100 patients and 303 controls were included. Following three-dose vaccination, patients achieved median (IQR) antibody levels of 5720 BAU/mL (2138–8732) compared with 4495 (1591–6639) in controls receiving two doses, p=0.27. Anti-Spike antibody levels increased with median 1932 BAU/mL (IQR 150–4978) after the third dose. The interval between the vaccine doses and vaccination with mRNA-1273 or a combination of vaccines were associated with antibody levels following the third dose. Antibody levels had a slower decline-rate following the third than the second vaccine dose, p<0.001. Adverse events were reported by 464 (47%) patients and by 196 (78%) controls. Disease flares were reported by 70 (7%) patients. Conclusions This study shows that additional vaccine doses to patients with IMID contribute to strong and sustained immune-responses comparable to healthy persons vaccinated twice, and supports repeated vaccination of patients with IMID. Trial registration number NCT04798625.

• Sundlisæter, Nina Beate Paulshus; Sundin, Ulf Gunnar; Aga, Anna-Birgitte; Sexton, Joseph; Hammer, Hilde Berner & Uhlig, Till [Vis alle 9 forfattere av denne artikkelen] (2022). Inflammation and biologic therapy in patients with rheumatoid arthritis achieving versus not achieving ACR/EULAR Boolean remission in a treat-to-target study. RMD Open. 8(1), s. 1–6. doi: 10.1136/rmdopen-2021-002013. Fulltekst i vitenarkiv Vis sammendrag

  Objective To investigate limiting factors of American College of Rheumatology (ACR)/EULAR Boolean remission in rheumatoid arthritis (RA), and compare patients who fulfil the criteria to patients who only partly fulfil the criteria, with respect to imaging inflammation and biologic disease modifying anti-rheumatic drug (DMARD) usage. Methods Patients with DMARD-naïve RA were treated according to current recommendations in the the ARCTIC trial (Aiming for Remission in rheumatoid arthritis: a randomised trial examining the benefit of ultrasound in a Clinical TIght Control regimen). Limiting factors of reaching ACR/EULAR Boolean remission at 2 years were assessed. Imaging inflammation (ultrasound and MRI) in patients in remission was compared with patients failing to fulfil different components of the criteria. The OR of biologic therapy was calculated using logistic regression. Results Of 203 patients, 112 (55%) reached ACR/EULAR Boolean remission; 49 (24%) fulfilled three of four criteria. The main limiting factors were patient global assessment (PGA) (59%) and tender joints (22%). Imaging inflammation was not significantly different for patients in remission and patients not fulfilling the criteria due to elevated PGA and/or tender joints, but higher odds of using biologics (OR 3.63, 95% CI 1.73 to 7.61) were observed. Conclusions PGA and tender joints were the factors most often limiting achievement of ACR/EULAR Boolean remission. The level of imaging inflammation was not elevated in these patients compared with patients in remission, but the odds of using biologic DMARDs were higher. http://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

• Uhlig, Till; Karoliussen, Lars Fridtjof; Sexton, Joseph; Kvien, Tore Kristian; Haavardsholm, Espen A. & Perez-Ruiz, F. [Vis alle 7 forfattere av denne artikkelen] (2022). Fluctuation and change of serum urate levels and flares in gout: results from the NOR-Gout study. Clinical Rheumatology. ISSN 0770-3198. 41, s. 3817–3823. doi: 10.1007/s10067-022-06416-4. Fulltekst i vitenarkiv Vis sammendrag

  A gout attack may evolve after a purine-rich diet or alcohol and after starting urate-lowering therapy (ULT). The relationships between fluctuation and change in serum urate (SU) with the occurrence of flares were investigated in this study. In the prospective NOR-Gout study, gout patients with increased SU and a recent flare were treated to target with ULT over 1 year, with follow-up at year 2 with SU and flare as outcomes. SU and flares were assessed at both monthly and 3-monthly intervals until target SU was reached. Fluctuation over periods and changes in SU between two time points were assessed and compared in patients with and without flares. At year 1, 186 patients completed follow-up (88.2%) and 173 (82.0%) at year 2. Mean age (SD) at baseline was 56.4 (13.7) years, disease duration was 7.8 (7.6) years, and 95.3% were men. The first-year SU fluctuation and change were related to flare occurrence during year 1 (both p < 0.05). High fluctuation with an absolute sum of all SU changes during the first 9 months was related to flares over 3-month periods (all p < 0.05), and high fluctuation during the first 3 months was related to flares in months 3–6 (p = 0.04). Monthly and high SU changes or again reaching higher SU levels > 360 µmol/l were not related to flares. Fluctuation and change in SU were related to flare occurrence during the first year of ULT, while changes between visits and reaching SU levels > 360 µmol/L were not related to flares.

• Christensen, Ingrid Egeland; Jyssum, Ingrid; Tveter, Anne Therese; Sexton, Joseph; Tran, Trung & Mjaaland, Siri [Vis alle 19 forfattere av denne artikkelen] (2022). The persistence of anti-Spike antibodies following two SARS-CoV-2 vaccine doses in patients on immunosuppressive therapy compared to healthy controls—a prospective cohort study. BMC Medicine. 20(1), s. 1–13. doi: 10.1186/s12916-022-02587-8. Fulltekst i vitenarkiv Vis sammendrag

  Background The durability of vaccine-induced humoral immunity against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy is not known. The aim of this study was to compare the persistence of anti-Spike antibodies following two-dose SARS-CoV-2 vaccination between IMID patients and healthy controls and to identify factors associated with antibody decline. Methods IMID patients on immunosuppressive medication enrolled in the prospective observational Nor-vaC study were included. Participants received two-dose SARS-CoV-2 vaccination. Serum collected at two time points following vaccination (first assessment within 6–48 days, second within 49–123 days) were analyzed for antibodies binding the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. Multivariable regression models estimated percent reduction in anti-RBD over 30 days and factors associated with reduction. Results A total of 1108 patients (403 rheumatoid arthritis, 195 psoriatic arthritis, 195 spondyloarthritis, 124 ulcerative colitis, 191 Crohn’s disease) and 134 controls provided blood samples within the defined intervals (median 19 days [IQR 15–24] and 97 days [87–105] after second vaccine dose). Antibody levels were lower in patients compared to controls at both time points, with median anti-RBD 2806 BAU/ml [IQR 1018–6068] in patients and 6187 BAU/ml [4105–7496] in controls (p<0.001) at first assessment, and 608 BAU/ml [IQR 58–1053] in patients and 1520 BAU/ml [979–3766] in controls (p<0.001) at second assessment. At second assessment, low anti-RBD antibody levels (defined as <200 BAU/ml) were found in 449 (41%) patients, and 6 (5%) controls (p<0.001). The change was − 83% in patients and − 66% in controls (p<0.001). Patients had a greater estimated 30 days percent reduction in anti-RBD levels compared to controls − 4.9 (95% CI − 7.4 to − 2.4), (p<0.05). Among therapies, mono- or combination treatment with tumor necrosis factor inhibitors was associated with the greatest decline. Conclusions Within 4 months after vaccination, antibody levels declined considerably in both IMID patients and controls. Patients had lower initial antibody levels and a more pronounced decline compared to healthy controls and were therefore more likely to decline to low antibody levels. These results support that IMID patients need additional vaccine doses at an earlier stage than healthy individuals.

• Sundin, Ulf Gunnar; Sundlisæter, Nina Beate Paulshus; Aga, Anna-Birgitte; Sexton, Joseph; Nordberg, Lena Kristine Bugge & Hammer, Hilde Berner [Vis alle 10 forfattere av denne artikkelen] (2021). Value of MRI and ultrasound for prediction of therapeutic response and erosive progression in patients with early rheumatoid arthritis managed by an aggressive treat-To-Target strategy. RMD Open. 7:e001525(1), s. 1–11. doi: 10.1136/rmdopen-2020-001525. Fulltekst i vitenarkiv Vis sammendrag

  Objectives To investigate if inflammation detected by MRI or ultrasound at rheumatoid arthritis (RA) onset is predictive of erosive progression or poor response to methotrexate monotherapy, and to investigate if subclinical inflammation in remission is predictive of future treatment escalation or erosive progression. Methods In a 2-year study, 218 patients with disease-modifying antirheumatic drug-naïve early RA were treated by a tight-control treat-to-target strategy corresponding to current recommendations. MRI and ultrasound were performed at regular intervals. Baseline imaging-based inflammation measures were analysed as predictors for early methotrexate failure and erosive progression using univariate and multivariate regression adjusted for clinical, laboratory and radiographic measures. In patients in remission after 1 year, imaging measures were analysed as predictors of treatment escalation and erosive progression during the second year. The added value of imaging in prediction models was assessed using receiver operating characteristic analyses. Results Baseline MRI inflammation was associated with MRI erosive progression and ultrasound with radiographic erosive progression. No imaging inflammation measure was associated with early methotrexate failure. Imaging inflammation was present in a majority of patients in clinical remission. Tenosynovitis was associated with treatment escalation, and synovitis and tenosynovitis with MRI/radiographic erosive progression during the second year. Imaging information did not improve prediction models for any of the outcomes. Conclusions Imaging-detected inflammation, both at diagnosis and in remission, is associated with elements of future disease development. However, the lack of a significant effect on prediction models indicates limited value of systematic MRI and ultrasound in management of early RA.

• Jyssum, Ingrid; Kared, Hassen; Tran, Trung; Tveter, Anne Therese; Provan, Sella Aarrestad & Sexton, Joseph [Vis alle 22 forfattere av denne artikkelen] (2021). Humoral and cellular immune responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis: a prospective, cohort study. The Lancet Rheumatology. 00. doi: 10.1016/S2665-9913(21)00394-5. Fulltekst i vitenarkiv Vis sammendrag

  Background In rituximab-treated patients with rheumatoid arthritis, humoral and cellular immune responses after two or three doses of SARS-CoV-2 vaccines are not well characterised. We aimed to address this knowledge gap. Methods This prospective, cohort study (Nor-vaC) was done at two hospitals in Norway. For this sub-study, we enrolled patients with rheumatoid arthritis on rituximab treatment and healthy controls who received SARS-CoV-2 vaccines according to the Norwegian national vaccination programme. Patients with insufficient serological responses to two doses (antibody to the receptor-binding domain [RBD] of the SARS-CoV-2 spike protein concentration <100 arbitrary units [AU]/mL) were allotted a third vaccine dose. Antibodies to the RBD of the SARS-CoV-2 spike protein were measured in serum 2–4 weeks after the second and third doses. Vaccine-elicited T-cell responses were assessed in vitro using blood samples taken before and 7–10 days after the second dose and 3 weeks after the third dose from a subset of patients by stimulating cryopreserved peripheral blood mononuclear cells with spike protein peptides. The main outcomes were the proportions of participants with serological responses (anti-RBD antibody concentrations of ≥70 AU/mL) and T-cell responses to spike peptides following two and three doses of SARS-CoV-2 vaccines. The study is registered at ClinicalTrials.gov, NCT04798625, and is ongoing. Findings Between Feb 9, 2021, and May 27, 2021, 90 patients were enrolled, 87 of whom donated serum and were included in our analyses (69 [79·3%] women and 18 [20·7%] men). 1114 healthy controls were included (854 [76·7%] women and 260 [23·3%] men). 49 patients were allotted a third vaccine dose. 19 (21·8%) of 87 patients, compared with 1096 (98·4%) of 1114 healthy controls, had a serological response after two doses (p<0·0001). Time since last rituximab infusion (median 267 days [IQR 222–324] in responders vs 107 days [80–152] in non-responders) and vaccine type (mRNA-1273 vs BNT162b2) were significantly associated with serological response (adjusting for age and sex). After two doses, 10 (53%) of 19 patients had CD4+ T-cell responses and 14 (74%) had CD8+ T-cell responses. A third vaccine dose induced serological responses in eight (16·3%) of 49 patients, but induced CD4+ and CD8+ T-cell responses in all patients assessed (n=12), including responses to the SARS-CoV-2 delta variant (B.1.617.2). Adverse events were reported in 32 (48%) of 67 patients and in 191 (78%) of 244 healthy controls after two doses, with the frequency not increasing after the third dose. There were no serious adverse events or deaths. Interpretation This study provides important insight into the divergent humoral and cellular responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis. A third vaccine dose given 6–9 months after a rituximab infusion might not induce a serological response, but could be considered to boost the cellular immune response.

• Syversen, Silje Watterdal; Jørgensen, Kristin Kaasen; Goll, Guro Løvik; Brun, Marthe Kirkesæther; Sandanger, Øystein & Hammersbøen, Kristin Reine [Vis alle 33 forfattere av denne artikkelen] (2021). Effect of Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy on Disease Control in Patients With Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. Journal of the American Medical Association (JAMA). ISSN 0098-7484. 326(23), s. 2375–2384. doi: 10.1001/jama.2021.21316. Fulltekst i vitenarkiv Vis sammendrag

  IMPORTANCE Proactive therapeutic drug monitoring (TDM), consisting of individualized treatment based on scheduled assessments of serum drug levels, has been proposed as an alternative to standard therapy to optimize efficacy and safety of infliximab and other biologic drugs. However, it remains unclear whether proactive TDM improves clinical outcomes during maintenance therapy. OBJECTIVE To assess whether proactive TDM during maintenance therapy with infliximab improves treatment efficacy by preventing disease worsening compared with standard infliximab therapy without TDM. DESIGN, SETTING, AND PARTICIPANTS Randomized, parallel-group, open-label clinical trial including 458 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis undergoing maintenance therapy with infliximab in 20 Norwegian hospitals. Patients were recruited from June 7, 2017, to December 12, 2019. Final follow-up took place on December 14, 2020. INTERVENTIONS Patients were randomized 1:1 to proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 228) or to standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 230). MAIN OUTCOME AND MEASURES The primary outcomewas sustained disease control without disease worsening, defined by disease-specific composite scores or consensus about disease worsening between patient and physician leading to a major change in treatment (switching to another biologic drug, adding an immunosuppressive drug including glucocorticoids, or increasing the infliximab dose), during the 52-week study period. RESULTS Among 458 randomized patients (mean age, 44.8 [SD, 14.3] years; 216 women [49.8%]), 454 received their randomly allocated intervention and were included in the full analysis set. The primary outcome of sustained disease control without disease worsening was observed in 167 patients (73.6%) in the TDM group and 127 patients (55.9%) in the standard therapy group. The estimated adjusted difference was 17.6%(95%CI, 9.0%-26.2%; P < .001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. CONCLUSIONS AND RELEVANCE Among patients with immune-mediated inflammatory diseases undergoing maintenance therapy with infliximab, proactive TDMwas more effective than treatment without TDM in sustaining disease control without diseaseworsening. Further research is needed to compare proactive TDM with reactive TDM, to assess the effects on long-term disease complications, and to evaluate the cost-effectiveness of this approach. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03074656

• Syversen, Silje Watterdal; Goll, Guro Løvik; Jørgensen, Kristin Kaasen; Sandanger, Øystein; Sexton, Joseph & Olsen, Inge Christoffer [Vis alle 33 forfattere av denne artikkelen] (2021). Effect of Therapeutic Drug Monitoring vs Standard Therapy During Infliximab Induction on Disease Remission in Patients With Chronic Immune-Mediated Inflammatory Diseases: A Randomized Clinical Trial. Journal of the American Medical Association (JAMA). ISSN 0098-7484. 325(17), s. 1744–1754. doi: 10.1001/jama.2021.4172. Fulltekst i vitenarkiv Vis sammendrag

  Importance: Proactive therapeutic drug monitoring (TDM), defined as individualized drug dosing based on scheduled monitoring of serum drug levels, has been proposed as an alternative to standard therapy to maximize efficacy and safety of infliximab and other biological drugs. However, whether proactive TDM improves clinical outcomes when implemented at the time of drug initiation, compared with standard therapy, remains unclear. Objective: To assess whether TDM during initiation of infliximab therapy improves treatment efficacy compared with standard infliximab therapy without TDM. Design, setting, and participants: Randomized, parallel-group, open-label clinical trial of 411 adults with rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, ulcerative colitis, Crohn disease, or psoriasis initiating infliximab therapy in 21 hospitals in Norway. Patients were recruited from March 1, 2017, to January 10, 2019. Final follow-up occurred on November 5, 2019. Interventions: Patients were randomized 1:1 to receive proactive TDM with dose and interval adjustments based on scheduled monitoring of serum drug levels and antidrug antibodies (TDM group; n = 207) or standard infliximab therapy without drug and antibody level monitoring (standard therapy group; n = 204). Main outcomes and measures: The primary end point was clinical remission at week 30. Results: Among 411 randomized patients (mean age, 44.7 [SD, 14.9] years; 209 women [51%]), 398 (198 in the TDM group and 200 in the standard therapy group) received their randomized intervention and were included in the full analysis set. Clinical remission at week 30 was achieved in 100 (50.5%) of 198 and 106 (53.0%) of 200 patients in the TDM and standard therapy groups, respectively (adjusted difference, 1.5%; 95% CI, -8.2% to 11.1%; P = .78). Adverse events were reported in 135 patients (68%) and 139 patients (70%) in the TDM and standard therapy groups, respectively. Conclusions and relevance: Among patients with immune-mediated inflammatory diseases initiating treatment with infliximab, proactive therapeutic drug monitoring, compared with standard therapy, did not significantly improve clinical remission rates over 30 weeks. These findings do not support routine use of therapeutic drug monitoring during infliximab induction for improving disease remission rates.

• Stockfelt, Marit; Lundell, Anna-Carin; Hetland, Merete Lund; Østergaard, Mikkel; Uhlig, Till & Schrumpf, Marte [Vis alle 19 forfattere av denne artikkelen] (2021). Plasma interferon-alpha is associated with double-positivity for autoantibodies but is not a predictor of remission in early rheumatoid arthritis-a spin-off study of the NORD-STAR randomized clinical trial. Arthritis Research & Therapy. ISSN 1478-6354. 23(1). doi: 10.1186/s13075-021-02556-1. Fulltekst i vitenarkiv Vis sammendrag

  Background: The type I interferon (IFN) gene signature is present in a subgroup of patients with early rheumatoid arthritis (RA). Protein levels of IFNα have not been measured in RA and it is unknown whether they associate with clinical characteristics or treatment effect. Methods: Patients with early untreated RA (n = 347) were randomized to methotrexate combined with prednisone, certolizumab-pegol, abatacept, or tocilizumab. Plasma IFNα protein levels were determined by single molecular array (Simoa) before and 24 weeks after treatment initiation and were related to demographic and clinical factors including clinical disease activity index, disease activity score in 28 joints, swollen and tender joint counts, and patient global assessment. Results: IFNα protein positivity was found in 26% of the patients, and of these, 92% were double-positive for rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). IFNα protein levels were reduced 24 weeks after treatment initiation, and the absolute change was similar irrespective of treatment. IFNα protein positivity was associated neither with disease activity nor with achievement of CDAI remission 24 weeks after randomization. Conclusion: IFNα protein positivity is present in a subgroup of patients with early RA and associates with double-positivity for autoantibodies but not with disease activity. Pre-treatment IFNα positivity did not predict remission in any of the treatment arms, suggesting that the IFNα system is distinct from the pathways of TNF, IL-6, and T-cell activation in early RA. A spin-off study of the NORD-STAR randomized clinical trial, NCT01491815 (ClinicalTrials), registered 12/08/2011, https://clinicaltrials.gov/ct2/show/NCT01491815 .

• Uhlig, Till; Karoliussen, Lars Fridtjof; Sexton, Joseph; Borgen, Tove; Haavardsholm, Espen A. & Kvien, Tore Kristian [Vis alle 7 forfattere av denne artikkelen] (2021). 12-month results from the real-life observational treat-to-target and tight-control therapy NOR-Gout study: Achievements of the urate target levels and predictors of obtaining this target. RMD Open. 7(1). doi: 10.1136/rmdopen-2021-001628. Fulltekst i vitenarkiv Vis sammendrag

  Objectives Gout is often not adequately treated, and we aimed to apply urate lowering treatment (ULT) combined with individual information to achieve target serum urate (sUA) in clinical practice, and to identify predictors of achievement of this sUA target. Methods Patients with a recent gout flare and sUA &gt;360 µmol/L (&gt;6 mg/dL) were consecutively included in a single-centre study and managed with a treat-to-target approach combining nurse-led information about gout with ULT. All patients were assessed with tight controls at baseline, 1, 2, 3, 6, 9 and 12 months including clinical examination, information on demographics, lifestyle, self-efficacy and beliefs about medicines. The treatment target was sUA &lt;360 µmol/L and multivariable logistic regression was used to identify predictors of target attainment with ORs and 95% CIs. Results Of 211 patients (mean age 56.4 years, disease duration 7.8 years, 95% males), 186 completed the 12-month study. Mean sUA levels decreased from baseline mean 500 to 311 µmol/L at 12 months with 85.5% achieving the treatment target. Alcohol consumption at least weekly versus less frequently (OR 0.14; 95% CI 0.04 to 0.55) as well as beliefs in overuse of medicines (OR per unit 0.77; 95 CI 0.62 to 0.94) decreased the chance of reaching the treatment target, while higher self-efficacy for arthritis symptoms (OR 1.49 per 10 units; 95% CI 1.09 to 2.05) increased the likelihood. Conclusions This study shows that target sUA can be achieved with ULT in most patients. Less self-reported alcohol consumption, low beliefs in overuse of medicines and higher self-efficacy are associated with treatment success.

• Aldridge, Jonathan; Lundell, Anna-Carin; Andersson, Kerstin; Mark, Linda; Hetland, Merete Lund & Østergaard, Mikkel [Vis alle 17 forfattere av denne artikkelen] (2021). Blood chemokine levels are markers of disease activity but not predictors of remission in early rheumatoid arthritis. Clinical and Experimental Rheumatology. ISSN 0392-856X. 40(7), s. 1393–1402. doi: 10.55563/clinexprheumatol/idogmj. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: In early rheumatoid arthritis (eRA) plasma levels of specific chemokines have been shown to correlate with disease activity. However, it is unclear whether pre-treatment chemokine levels can predict disease remission at week 24, and it is not known how biological treatments with different modes of action affect plasma chemokine levels in patients with untreated eRA. Methods: This study included 347 Swedish patients with untreated eRA from the larger NORD-STAR randomised treatment trial. Here, eRA patients were treated with methotrexate combined with either prednisolone, anti-TNF (certolizumab-pegol), CTLA-4Ig (abatacept) or anti-IL6 receptor (tocilizumab). The primary clinical outcome was remission by clinical disease activity index (CDAI) defined as CDAI ≤ 2.8. Disease activity was assessed by CDAI, DAS28-ESR, DAS28-CRP, swollen joint counts, tender joint counts, ESR and CRP. The plasma concentrations of 14 chemokines were measured at baseline and after 24 weeks of treatment by bead-based immunoassay or ELISA. Results: Baseline plasma concentrations of CXCL10, CXCL8, CXCL9, CXCL11, CXCL5 and CCL2 correlated with baseline disease activity measures. After 24 weeks of treatment, plasma levels of CXCL10, CXCL8, CXCL9, CXCL11 and CXCL13 decreased in all treatment groups except in patients treated with anti-IL6 receptor. In multivariate factor analysis, plasma chemokine levels at baseline could not differentiate patients who attained remission by week 24 from those who did not in any of the treatment groups. Conclusions: In patients with untreated eRA, plasma levels of several chemokines correlate with disease activity at baseline but cannot predict remission after 24 weeks of treatment with methotrexate combined with prednisolone, anti‑TNF, CTLA‑4Ig or anti‑IL6R.

• Heinicke, Fatima; Zhong, Xiangfu; Flåm, Siri Tennebø; Breidenbach, Johannes; Leithaug, Magnus & Mæhlen, Marthe Thoresen [Vis alle 14 forfattere av denne artikkelen] (2021). MicroRNA Expression Differences in Blood-Derived CD19+ B Cells of Methotrexate Treated Rheumatoid Arthritis Patients. Frontiers in Immunology. 12. doi: 10.3389/fimmu.2021.663736. Fulltekst i vitenarkiv Vis sammendrag

  Rheumatoid arthritis (RA) is a complex disease with a wide range of underlying susceptibility factors. Recently, dysregulation of microRNAs (miRNAs) in RA have been reported in several immune cell types from blood. However, B cells have not been studied in detail yet. Given the autoimmune nature of RA with the presence of autoantibodies, CD19+ B cells are a key cell type in RA pathogenesis and alterations in CD19+ B cell subpopulations have been observed in patient blood. Therefore, we aimed to reveal the global miRNA repertoire and to analyze miRNA expression profile differences in homogenous RA patient phenotypes in blood-derived CD19+ B cells. Small RNA sequencing was performed on CD19+ B cells of newly diagnosed untreated RA patients (n=10), successfully methotrexate (MTX) treated RA patients in remission (MTX treated RA patients, n=18) and healthy controls (n=9). The majority of miRNAs was detected across all phenotypes. However, significant expression differences between MTX treated RA patients and controls were observed for 27 miRNAs, while no significant differences were seen between the newly diagnosed patients and controls. Several of the differentially expressed miRNAs were previously found to be dysregulated in RA including miR-223-3p, miR-486-3p and miR-23a-3p. MiRNA target enrichment analysis, using the differentially expressed miRNAs and miRNA-target interactions from miRTarBase as input, revealed enriched target genes known to play important roles in B cell activation, differentiation and B cell receptor signaling, such as STAT3, PRDM1 and PTEN. Interestingly, many of those genes showed a high degree of correlated expression in CD19+ B cells in contrast to other immune cell types. Our results suggest important regulatory functions of miRNAs in blood-derived CD19+ B cells of MTX treated RA patients and motivate for future studies investigating the interactive mechanisms between miRNA and gene targets, as well as the possible predictive power of miRNAs for RA treatment response.

• Holten, Karen; Sundlisæter, Nina Beate Paulshus; Lillegraven, Siri; Sexton, Joseph; Nordberg, Lena Kristine Bugge & Moholt, Ellen [Vis alle 11 forfattere av denne artikkelen] (2021). Fatigue in patients with early rheumatoid arthritis undergoing treat-to-target therapy: predictors and response to treatment. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1136/annrheumdis-2021-220750. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: Fatigue is a frequent symptom in rheumatoid arthritis (RA) and has high impact on quality of life. We explored associations between disease activity and fatigue in patients with early RA during the initial 24 months of modern treat-to-target therapy and predictors of fatigue after 24 months of follow-up. Methods: Data were obtained from the treat-to-target, tight control Aiming for Remission in Rheumatoid Arthritis: a Randomised Trial Examining the Benefit of Ultrasound in a Clinical Tight Control Regime (ARCTIC) trial. Fatigue was measured on a visual analogue scale (VAS) from 0 to 100 mm and defined as clinically relevant if VAS was ≥20 mm. Baseline predictors of fatigue at 24 months were analysed by multivariable logistic regression. Results: 205 patients with fatigue data at baseline and 24 months were included. Median (25th, 75th percentiles) symptom duration was 5.4 months (2.8, 10.4), fatigue VAS 37.0 mm (13.0, 62.0) and mean Disease Activity Score (DAS) 3.4 (SD 1.1) at baseline. Prevalence of fatigue declined from 69% at baseline to 38% at 24 months. Fewer swollen joints (OR 0.92, 95% CI 0.87 to 0.98, p=0.006), lower power Doppler ultrasound score (OR 0.95, 95% CI 0.90 to 0.99, p=0.027) and higher patient global assessment (PGA) (OR 1.03, 95% CI 1.01 to 1.04, p<0.001) increased the risk of clinically relevant fatigue at 24 months. Not achieving remission at 6 months was associated with a higher risk of reporting fatigue at 24 months. Conclusions: Fatigue in patients with early RA was prevalent at disease onset, with a rapid and sustained reduction during treatment. Low objective disease activity and high PGA at baseline were predictors of clinically relevant fatigue at 24 months.

• Lillegraven, Siri; Sundlisæter, Nina Beate Paulshus; Aga, Anna-Birgitte; Sexton, Joseph; Olsen, Inge Christoffer & Fremstad, Hallvard [Vis alle 21 forfattere av denne artikkelen] (2021). 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. Journal of the American Medical Association (JAMA). ISSN 0098-7484. 325(17), s. 1755–1764. doi: 10.1001/jama.2021.4542. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Uhlig, Till; Eskild, Tron Hovind; Karoliussen, Lars Fridtjof; Sexton, Joseph; Kvien, Tore Kristian & Haavardsholm, Espen A. [Vis alle 8 forfattere av denne artikkelen] (2021). Two-year reduction of dual-energy CT urate depositions during a treat-to-target strategy in gout in the NOR-Gout longitudinal study. Rheumatology. ISSN 1462-0324. 61, s. S181–S185. doi: 10.1093/rheumatology/keab533. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: There is a lack of large longitudinal studies of urate deposition measured by dual-energy computed tomography (DECT) during urate lowering therapy (ULT) in people with gout. We explored longitudinal changes in DECT urate depositions during a treat-to-target strategy with ULT in gout. Methods: Patients with a recent gout flare and serum-urate (sUA) >360 µmol/l attended tight-control visits during escalating ULT. The treatment target was sUA <360 µmol/l, and <300 µmol/l if presence of tophi.A DECT scanner (General Electric Discovery CT750 HD) acquired data from bilateral forefeet and ankles at baseline and after one and two years. Images were scored in known order, using the semi-quantitative Bayat method, by one experienced radiologist who was blinded to serum urate and clinical data. Four regions were scored: the first metatarsophalangeal (MTP1) joint, the other joints of the toes, the ankles and midfeet, and all tendons in the feet and ankles. Results: DECT was measured at baseline in 187 of 211 patients. The mean (S.D.) serum urate level (μmol/l) decreased from 501 (80) at baseline to 311 (48) at 12 months, and 322 (67) at 24 months.DECT scores at all locations decreased during both the first and the second year (p< 0.001 for all comparisons vs baseline), both for patients achieving and not achieving the sUA treatment target. Conclusions: In patients with gout, urate depositions in ankles and feet as measured by DECT decreased both in the first and the second year, when patients were treated using a treat-to-target ULT strategy.

• Kerola, Anne Mirjam; Sexton, Joseph; Wibetoe, Grunde; Rollefstad, Silvia Christin Hellerud; Crowson, Cynthia Sue & Mars, Nina [Vis alle 10 forfattere av denne artikkelen] (2021). Incidence, sociodemographic factors and treatment penetration of rheumatoid arthritis and psoriatic arthritis in Norway. Seminars in Arthritis & Rheumatism. ISSN 0049-0172. 51(5), s. 1081–1088. doi: 10.1016/j.semarthrit.2021.08.006. Fulltekst i vitenarkiv Vis sammendrag

  Objectives: To evaluate nationwide incidence, sociodemographic associations and treatment penetration of rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in Norway. Methods: The study combined data from nationwide registries on the total Norwegian adult population (age ≥ 18). From the Norwegian Patient Registry, incident RA and PsA cases during 2011-2015 were identified with records of first and second healthcare episodes listing RA/PsA diagnostic codes, and ≥ 1 episode in an internal medicine or rheumatology unit with RA/PsA code during the two-year period after the first episode. Dispensed DMARD prescriptions were obtained from the Norwegian Prescription Database. Persons with dispensed DMARD prescriptions or biologic DMARDs given in hospitals > 12 months before the index date were excluded. Results: Incidence of RA/PsA in Norway was 42/26 per 100,000 person-years (55/28 among women and 28/23 among men). RA peak incidence was observed at ages 70-79 in both sexes, whereas the peak incidence of PsA occurred at ages 50-59. Age- and sex-standardized incidences of RA and PsA were lower among persons with higher education levels. Within a year from the index date, 82.4/57.4% of RA/PsA patients used synthetic DMARDs while 9.4/9.5% used biologic DMARDs. Conclusions: Register-based incidence estimates for RA and PsA in Norway are similar to other Nordic countries, but slightly higher than in previous Norwegian studies. Furthermore, we found that higher socioeconomic status was associated with lower incidence of both RA and PsA. Although conventional synthetic DMARDs were less often used in early PsA than RA, frequency of biologic DMARD prescriptions was comparable.

• Guderud, Kari; Sunde, Line Hagen; Flåm, Siri Tennebø; Mæhlen, Marthe Thoresen; Mjaavatten, Maria Dahl & Lillegraven, Siri [Vis alle 16 forfattere av denne artikkelen] (2020). Rheumatoid Arthritis Patients, Both Newly Diagnosed and Methotrexate Treated, Show More DNA Methylation Differences in CD4+ Memory Than in CD4+ Naïve T Cells. Frontiers in Immunology. 11:194, s. 1–14. doi: 10.3389/fimmu.2020.00194. Fulltekst i vitenarkiv Vis sammendrag

  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.

• Hammer, Hilde Berner; Karoliussen, Lars Fridtjof; Terslev, Lene; Haavardsholm, Espen A; Kvien, Tore Kristian & Uhlig, Till (2020). Ultrasound shows rapid reduction of crystal depositions during a treat-to-target approach in gout patients: 12-month results from the NOR-Gout study. Annals of the Rheumatic Diseases. ISSN 0003-4967. 79(11), s. 1500–1505. doi: 10.1136/annrheumdis-2020-217392. Fulltekst i vitenarkiv
• Syversen, Silje Watterdal; Goll, Guro Løvik; Jørgensen, Kristin Kaasen; Olsen, Inge Christoffer; Sandanger, Øystein & Gehin, Johanna Elin [Vis alle 13 forfattere av denne artikkelen] (2020). Therapeutic drug monitoring of infliximab compared to standard clinical treatment with infliximab: study protocol for a randomised, controlled, open, parallel-group, phase IV study (The NOR-DRUM study). Trials. 21(13). doi: 10.1186/s13063-019-3734-4. Fulltekst i vitenarkiv Vis sammendrag

  Background Infliximab (INX) and other tumour necrosis factor inhibitors (TNFi) have revolutionised the treatment of several immune mediated inflammatory diseases. Still, many patients do not respond sufficiently to therapy or lose efficacy over time. The large interindividual variation in serum drug concentrations on standard doses and the development of anti-drug antibodies are thought to be major reasons for treatment failures. Therapeutic drug monitoring (TDM), an individualised treatment strategy based on systematic assessments of serum drug concentrations, has been proposed as a clinical tool to optimise efficacy of INX treatment. TDM seems reasonable both from a clinical and an economical point of view, but the effectiveness of this treatment strategy has not yet been demonstrated in randomised clinical trials. The NORwegian DRUg Monitoring study (NOR-DRUM) aims to assess the effectiveness of TDM, both with regard to the achievement of remission in patients starting INX treatment (part A) as well as to maintain disease control in patients on INX treatment (part B). Methods The NOR-DRUM study is a randomised, open, controlled, parallel-group, comparative, multi-centre, national, superiority, phase IV study with two separate parts, NOR-DRUM A and NOR-DRUM B. Patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, ulcerative colitis, Crohn’s disease and psoriasis are included. In both study parts participants are randomised 1:1 to either TDM of infliximab (intervention group) or to standard treatment with infliximab without knowledge of drug levels or ADAb status (control group). NOR-DRUM A will include 400 patients starting INX therapy. The primary outcome is remission at 30 weeks. In NOR-DRUM B, 450 patients on maintenance treatment with INX will be included. The primary endpoint is occurrence of disease worsening during the 52-week study period. Discussion As the first trial to assess the effectiveness, safety and cost-effectiveness of TDM in patients receiving TNFi for a range of immune mediated inflammatory diseases, we hope that the NOR-DRUM study will contribute to the advancement of evidence based personalised treatment with biological medicines. Trial registration Clinicaltrials.gov, NCT03074656. Registered on 090317.

• Gjefsen, Elisabeth; Bråten, Lars Christian Haugli; Goll, Guro Løvik; Wigemyr, Monica; Bolstad, Nils & Valberg, Morten [Vis alle 27 forfattere av denne artikkelen] (2020). The effect of infliximab in patients with chronic low back pain and Modic changes (the BackToBasic study): study protocol of a randomized, double blind, placebo-controlled, multicenter trial. BMC Musculoskeletal Disorders. 21:698, s. 1–14. doi: 10.1186/s12891-020-03720-5. Fulltekst i vitenarkiv Vis sammendrag

  Low back pain is common and a significant number of patients experience chronic low back pain. Current treatment options offer small to moderate effects. Patients with vertebral bone marrow lesions visualized as Modic changes on magnetic resonance imaging may represent a subgroup within the low back pain population. There is evidence for inflammatory mediators being involved in development of Modic changes; hence, suppression of inflammation could be a treatment strategy for these patients. This study examines the effect of anti-inflammatory treatment with the TNF-α inhibitor infliximab in patients with chronic low back pain and Modic changes.Methods/design: The BackToBasic trial is a multicenter, double blind, randomized controlled trial conducted at six hospitals in Norway, comparing intravenous infusions with infliximab with placebo. One hundred twenty-six patients aged 18–65 with chronic low back pain and type 1 Modic changes will be recruited from secondary care outpatients’ clinics. The primary outcome is back pain-specific disability at day 154 (5 months). The study is designed to detect a difference in change of 10 (SD 18) in the Oswestry Disability Index at day 154/ 5 months. The study also aims to refine MRI-assessment, investigate safety and cost-effectiveness and explore the underlying biological mechanisms of Modic changes..Discussion: Finding treatments that target underlying mechanisms could pose new treatment options for patients with low back pain. Suppression of inflammation could be a treatment strategy for patients with low back pain and Modic changes. This paper presents the design of the BackToBasic study, where we will assess the effect of an anti-inflammatory treatment versus placebo in patients with chronic low back pain and type 1 Modic changes.

• Sundin, Ulf Gunnar; Aga, Anna-Birgitte; Skare, Øivind; Nordberg, Lena Kristine Bugge; Uhlig, Till & Hammer, Hilde Berner [Vis alle 10 forfattere av denne artikkelen] (2020). Conventional versus ultrasound treat to target: No difference in magnetic resonance imaging inflammation or joint damage over 2 years in early rheumatoid arthritis. Rheumatology. ISSN 1462-0324. 59(9), s. 2550–2555. doi: 10.1093/rheumatology/kez674. Fulltekst i vitenarkiv Vis sammendrag

  Abstract Objective To investigate whether an ultrasound-guided treat-to-target strategy for early RA would lead to reduced MRI inflammation or less structural damage progression compared with a conventional treat-to-target strategy. Methods A total of 230 DMARD-naïve early RA patients were randomized to an ultrasound tight control strategy targeting DAS &amp;lt;1.6, no swollen joints and no power Doppler signal in any joint or a conventional strategy targeting DAS &amp;lt;1.6 and no swollen joints. Patients in both arms were treated according to the same DMARD escalation strategy. MRI of the dominant hand was performed at six time points over 2 years and scored according to the OMERACT RA MRI scoring system. A total of 218 patients had baseline and one or more follow-up MRIs and were included in the analysis. The mean MRI score change from baseline to each follow-up and the 2 year risk for erosive progression were compared between arms. Results MRI bone marrow oedema, synovitis and tenosynovitis improved over the first year and was sustained during the second year of follow-up, with no statistically significant differences between the ultrasound and the conventional arms at any time point. The 2 year risk for progression of MRI erosions was similar in both treatment arms: ultrasound arm 39%, conventional arm 33% [relative risk 1.16 (95% CI 0.81, 1.66), P = 0.40]. Conclusion Incorporating ultrasound information in treatment decisions did not lead to reduced MRI inflammation or less structural damage compared with a conventional treatment strategy. The findings support that systematic use of ultrasound does not provide a benefit in the follow-up of patients with early RA. Trial registration number Clinicaltrials.gov, http://clinicaltrials.gov, NCT01205854.

• Norvang, Vibeke; Brinkmann, Gina Charlotte Hetland; Yoshida, Kazuki; Lillegraven, Siri; Aga, Anna-Birgitte & Sexton, Joseph Andrew [Vis alle 14 forfattere av denne artikkelen] (2020). Achievement of Remission in Two Early Rheumatoid Arthritis Cohorts Implementing Different Treat-to-Target Strategies. Arthritis & Rheumatology. ISSN 2326-5191. 72(7), s. 1072–1081. doi: 10.1002/art.41232. Fulltekst i vitenarkiv Vis sammendrag

  Objective The objective of this study was to compare achievement of remission in 2 early rheumatoid arthritis (RA) treat‐to‐target (TTT) cohorts, a tight control cohort with a target of stringent remission in a randomized controlled trial and an observational cohort targeting a looser definition of remission in clinical practice. Methods We analyzed data from the Aiming for Remission in Rheumatoid Arthritis: a randomised trial examining the benefit of ultrasound in a Clinical Tight Control regimen (ARCTIC) trial and the Norwegian Very Early Arthritis Clinic (NOR‐VEAC) observational study. Both were Norwegian multicenter studies that included disease‐modifying antirheumatic drug (DMARD)–naive RA patients and implemented TTT. The target in the ARCTIC trial was remission defined as a Disease Activity Score (DAS) of <1.6 plus 0 swollen joints on a 44‐joint count, while the target in the NOR‐VEAC study was the less stringent remission target of a DAS28 of <2.6. We assessed achievement of the study‐specific targets and compared the odds of achieving the American College of Rheumatology(ACR)/European League Against Rheumatism (EULAR) Boolean remission during 2 years of follow‐up. Results We included 189 patients from the ARCTIC trial and 330 patients from the NOR‐VEAC study. The study‐specific target had been achieved in more than half of the patients in each cohort at 6 months, increasing to >60% at 12 and 24 months. The odds of achieving ACR/EULAR Boolean remission during follow‐up were higher in the ARCTIC trial than in the NOR‐VEAC study, with significant differences at 3 months (odds ratio 1.73 [95% confidence interval 1.03–2.89]), 12 months (odds ratio 1.97 [95% confidence interval 1.21–3.20]), and 24 months (odds ratio 1.82 [95% confidence interval 1.05–3.16]). Conclusion A majority of patients in both cohorts reached the study‐specific treatment targets. More patients in the ARCTIC trial than in the NOR‐VEAC study achieved ACR/EULAR Boolean remission during follow‐up, suggesting that targeting a more stringent definition of remission provides further potential for favorable outcomes of a TTT strategy.

• Jørgensen, Kristin Kaasen; Goll, Guro Løvik; Sexton, Joseph; Bolstad, Nils; Olsen, Inge Christoffer & Asak, Øivind Wessel [Vis alle 29 forfattere av denne artikkelen] (2020). Efficacy and safety of CT-P13 in inflammatory bowel disease after switching from originator infliximab: Exploratory analyses from the NOR-SWITCH main and extension trials. BioDrugs. ISSN 1173-8804. 34(5), s. 681–694. doi: 10.1007/s40259-020-00438-7. Fulltekst i vitenarkiv Vis sammendrag

  Background: The NOR-SWITCH main and extension trials demonstrated that switching from originator to biosimilar infliximab (CT-P13) is efficacious and safe across six diseases. However, a subgroup analysis of Crohn's disease (CD) in the main trial displayed a close to significant difference favouring originator infliximab, and more scientific data have therefore been requested. Objective: The aim was to assess treatment efficacy, safety, and immunogenicity in an explorative subgroup analysis in CD and ulcerative colitis (UC) in the NOR-SWITCH trials. Patients and methods: The 52-week, randomised, non-inferiority, double-blind, multicentre, phase 4 NOR-SWITCH study was followed by a 26-week open extension trial where all patients received treatment with CT-P13. Treatment efficacy, safety, and immunogenicity in CD and UC were assessed throughout the 78-week study period. Results: The main and extension trials included 155 and 93 patients with CD and 93 and 80 patients with UC, respectively. Demographic and baseline characteristics were comparable in both treatment arms within patient groups. There were no differences in the main and extension trials regarding changes in activity indices, C-reactive protein, faecal calprotectin, patient's and physician's global assessment of disease activity and patient-reported outcome measures in CD and UC. Moreover, comparable results were also demonstrated for trough serum levels, presence of anti-drug antibodies, and reported adverse events. Conclusion: Efficacy, safety, and immunogenicity of both the originator and biosimilar infliximab were comparable in CD and UC in the NOR-SWITCH main and extension trials. These explorative subgroup analyses confirm that there are no significant concerns related to switching from originator infliximab to CT-P13 in CD and UC.

• Hetland, Merete Lund; Haavardsholm, Espen A.; Rudin, Anna; Nordström, Dan C.; Nurmohamed, Michael & Gudbjornsson, Bjorn [Vis alle 43 forfattere av denne artikkelen] (2020). Active conventional treatment and three different biological treatments in early rheumatoid arthritis: Phase IV investigator initiated, randomised, observer blinded clinical trial. The BMJ. 371, s. 1–10. doi: 10.1136/bmj.m4328. Fulltekst i vitenarkiv Vis sammendrag

  Objective To evaluate and compare benefits and harms of three biological treatments with different modes of action versus active conventional treatment in patients with early rheumatoid arthritis. Design Investigator initiated, randomised, open label, blinded assessor, multiarm, phase IV study. Setting Twenty nine rheumatology departments in Sweden, Denmark, Norway, Finland, the Netherlands, and Iceland between 2012 and 2018. Participants Patients aged 18 years and older with treatment naive rheumatoid arthritis, symptom duration less than 24 months, moderate to severe disease activity, and rheumatoid factor or anti-citrullinated protein antibody positivity, or increased C reactive protein. Interventions Randomised 1:1:1:1, stratified by country, sex, and anti-citrullinated protein antibody status. All participants started methotrexate combined with (a) active conventional treatment (either prednisolone tapered to 5 mg/day, or sulfasalazine combined with hydroxychloroquine and intra-articular corticosteroids), (b) certolizumab pegol, (c) abatacept, or (d) tocilizumab. Main outcome measures The primary outcome was adjusted clinical disease activity index remission (CDAI≤2.8) at 24 weeks with active conventional treatment as the reference. Key secondary outcomes and analyses included CDAI remission at 12 weeks and over time, other remission criteria, a non-inferiority analysis, and harms. Results 812 patients underwent randomisation. The mean age was 54.3 years (standard deviation 14.7) and 68.8% were women. Baseline disease activity score of 28 joints was 5.0 (standard deviation 1.1). Adjusted 24 week CDAI remission rates were 42.7% (95% confidence interval 36.1% to 49.3%) for active conventional treatment, 46.5% (39.9% to 53.1%) for certolizumab pegol, 52.0% (45.5% to 58.6%) for abatacept, and 42.1% (35.3% to 48.8%) for tocilizumab. Corresponding absolute differences were 3.9% (95% confidence interval −5.5% to 13.2%) for certolizumab pegol, 9.4% (0.1% to 18.7%) for abatacept, and −0.6% (−10.1% to 8.9%) for tocilizumab. Key secondary outcomes showed no major differences among the four treatments. Differences in CDAI remission rates for active conventional treatment versus certolizumab pegol and tocilizumab, but not abatacept, remained within the prespecified non-inferiority margin of 15% (per protocol population). The total number of serious adverse events was 13 (percentage of patients who experienced at least one event 5.6%) for active conventional treatment, 20 (8.4%) for certolizumab pegol, 10 (4.9%) for abatacept, and 10 (4.9%) for tocilizumab. Eleven patients treated with abatacept stopped treatment early compared with 20-23 patients in the other arms. Conclusions All four treatments achieved high remission rates. Higher CDAI remission rate was observed for abatacept versus active conventional treatment, but not for certolizumab pegol or tocilizumab versus active conventional treatment. Other remission rates were similar across treatments. Non-inferiority analysis indicated that active conventional treatment was non-inferior to certolizumab pegol and tocilizumab, but not to abatacept. The results highlight the efficacy and safety of active conventional treatment based on methotrexate combined with corticosteroids, with nominally better results for abatacept, in treatment naive early rheumatoid arthritis.

• Hammer, Hilde Berner; Michelsen, Brigitte; Sexton, Joseph; Haugen, Ida Kristin; Provan, Sella Aarrestad & Haavardsholm, Espen A. [Vis alle 8 forfattere av denne artikkelen] (2019). Swollen, but not tender joints, are independently associated with ultrasound synovitis: Results from a longitudinal observational study of patients with established rheumatoid arthritis. Annals of the Rheumatic Diseases. ISSN 0003-4967. 78, s. 1179–1185. doi: 10.1136/annrheumdis-2019-215321. Fulltekst i vitenarkiv
• Sundin, Ulf Gunnar; Østergaard, Mikkel; Glinatsi, Daniel; Aga, Anna-Birgitte; Hørslev-Petersen, Kim & Hetland, Merete L. [Vis alle 13 forfattere av denne artikkelen] (2019). Validity and responsiveness of combined inflammation and combined joint damage scores based on the OMERACT rheumatoid arthritis MRI scoring system (RAMRIS). Journal of Rheumatology. ISSN 0315-162X. 46(9), s. 1222–1227. doi: 10.3899/jrheum.181064. Fulltekst i vitenarkiv
• Goll, Guro Løvik; Jørgensen, Kristin Kaasen; Sexton, Joseph; Olsen, Inge Christoffer; Bolstad, Nils & Haavardsholm, Espen A. [Vis alle 48 forfattere av denne artikkelen] (2019). Long‐term efficacy and safety of biosimilar infliximab (CT‐P13) after switching from originator infliximab: Open‐label extension of the NOR‐SWITCH trial. Journal of Internal Medicine. ISSN 0954-6820. 285(6), s. 653–669. doi: 10.1111/joim.12880. Fulltekst i vitenarkiv Vis sammendrag

  Background and objectives The 52‐week, randomized, double‐blind, noninferiority, government‐funded NOR‐SWITCH trial demonstrated that switching from infliximab originator to less expensive biosimilar CT‐P13 was not inferior to continued treatment with infliximab originator. The NOR‐SWITCH extension trial aimed to assess efficacy, safety and immunogenicity in patients on CT‐P13 throughout the 78‐week study period (maintenance group) versus patients switched to CT‐P13 at week 52 (switch group). The primary outcome was disease worsening during follow‐up based on disease‐specific composite measures. Methods Patients were recruited from 24 Norwegian hospitals, 380 of 438 patients who completed the main study: 197 in the maintenance group and 183 in the switch group. In the full analysis set, 127 (33%) had Crohn's disease, 80 (21%) ulcerative colitis, 67 (18%) spondyloarthritis, 55 (15%) rheumatoid arthritis, 20 (5%) psoriatic arthritis and 31 (8%) chronic plaque psoriasis. Results Baseline characteristics were similar in the two groups at the time of switching (week 52). Disease worsening occurred in 32 (16.8%) patients in the maintenance group vs. 20 (11.6%) in the switch group (per‐protocol set). Adjusted risk difference was 5.9% (95% CI −1.1 to 12.9). Frequency of adverse events, anti‐drug antibodies, changes in generic disease variables and disease‐specific composite measures were comparable between arms. The study was inadequately powered to detect noninferiority within individual diseases. Conclusion The NOR‐SWITCH extension showed no difference in safety and efficacy between patients who maintained CT‐P13 and patients who switched from originator infliximab to CT‐P13, supporting that switching from originator infliximab to CT‐P13 is safe and efficacious.

• Provan, Sella Aarrestad; Lillegraven, Siri; Sexton, Joseph; Angel, Kristin; Austad, Cathrine & Haavardsholm, Espen A. [Vis alle 8 forfattere av denne artikkelen] (2019). Trends in All-Cause and Cardiovascular Mortality in Patients With Incident Rheumatoid Arthritis: A 20-year Follow-Up Matched Case-Cohort Study. Rheumatology. ISSN 1462-0324. doi: 10.1093/rheumatology/kez371. Fulltekst i vitenarkiv Vis sammendrag

  To examine all-cause and cardiovascular disease (CVD) mortality in consecutive cohorts of patients with incident RA, compared with population comparators. The Oslo RA register inclusion criteria were diagnosis of RA (1987 ACR criteria) and residency in Oslo. Patients with disease onset 1994–2008 and 10 matched comparators for each case were linked to the Norwegian Cause of Death Registry. Hazard ratios for all-cause and CVD mortality were calculated for 5, 10, 15 and 20 years of observation using stratified cox-regression models. Mortality trends were estimated by multivariate cox-regression. 443, 479 and 469 cases with disease incidence in the periods 94–98, 99–03 and 04–08 were matched to 4430, 4790 and 4690 comparators, respectively. For cases diagnosed between 1994 and 2003, the all-cause mortality of cases diverged significantly from comparators after 10 years of disease duration [hazard ratio (95% CI) 94–98 cohort 1.42 (1.15–1.75): 99–03 cohort 1.37 (1.08–1.73)]. CVD related mortality was significantly increased after 5 years for the 94–98 cohort [hazard ratio (95% CI) 1.86 (1.16–2.98) and after 10 years for the 99–03 cohort 1.80 (1.20–2.70)]. Increased mortality was not observed in the 04–08 cohort where cases had significantly lower 10-year all-cause and CVD mortality compared with earlier cohorts. All-cause and CVD mortality were significantly increased in RA patients diagnosed from 1994 to 2003, compared with matched comparators, but not in patients diagnosed after 2004. This may indicate that modern treatment strategies have a positive impact on mortality in patients with RA.

• Jonsson, Maria Karolina; Kantyka, Tomasz Tadeusz; Falkowski, Katherine; Aliko, Ardita; Aga, Anna-Birgitte & Lillegraven, Siri [Vis alle 10 forfattere av denne artikkelen] (2019). Peptidylarginine deiminase 4 (PAD4) activity in early rheumatoid arthritis. Scandinavian Journal of Rheumatology. ISSN 0300-9742. 49, s. 87–95. doi: 10.1080/03009742.2019.1641216. Fulltekst i vitenarkiv
• Terslev, Lene; Christensen, Robin; Aga, Anna-Birgitte; Sexton, Joseph; Haavardsholm, Espen A. & Hammer, Hilde Berner (2019). Assessing synovitis in the hands in patients with rheumatoid arthritis by ultrasound: an agreement study exploring the most inflammatory active side from two Norwegian trials. Arthritis Research & Therapy. ISSN 1478-6354. 21. doi: 10.1186/s13075-019-1930-y. Fulltekst i vitenarkiv Vis sammendrag

  Objective To assess if the right hand, the dominant hand, or the hand with more clinically swollen joints (SwJ) is per se the most inflamed and exhibits the greatest change during treatment and hence preferred for unilateral scoring of synovitis by ultrasound in rheumatoid arthritis (RA) patients. Methods Using data from two previously published Norwegian RA patient cohorts initiating treatment, bilateral metacarpophalangeal joint 1–5, proximal phalangeal joint 2+3, and wrists were evaluated by ultrasound. Using a 0–3 scoring system a grey-scale (GS), power Doppler (PD) and global synovitis score (GLOESS) was calculated for each hand (0–30). For precision, a difference of < ± 3 in sum score was pre-specified as indicating clinically insignificant difference in inflammatory activity for all three scores. Results Four hundred thirty-seven RA patients were included. Baseline ultrasound inflammation was statistically significantly higher in hands with more vs fewer SwJ ([mean difference, 95%CI] GS sum score 2.21[1.30 to 3.12], PD sum score 1.70 [0.94 to 2.47] and GLOESS 2.31[1.36 to 3.26]) and also exhibited significantly more change for all sum scores at 3 months follow-up (GS sum score 1.34 [0.60 to 2.08], PD sum score 1.17 [0.44 to 1.91], and GLOESS 1.43 [0.63 to 2.22]). No such differences were found between the dominant and the non-dominant or the right and the left hands at any time points. Conclusion The hand with clinically more SwJ is statistically more inflammatory active according to GS, Doppler, and GLOESS sum scores, exhibits a change during treatment, and is potentially the best choice for unilateral scoring systems.

• Lillegraven, Siri & Haavardsholm, Espen A. (2019). Subclinical treatment targets in rheumatology: Lessons from randomized clinical trials in rheumatoid arthritis. Rheumatic Disease Clinics of North America. ISSN 0889-857X. 45(4), s. 593–604. doi: 10.1016/j.rdc.2019.07.007. Fulltekst i vitenarkiv
• Nordberg, Lena Kristine Bugge; Lillegraven, Siri; Aga, Anna-Birgitte; Sexton, Joseph; Olsen, Inge Christoffer & Lie, Elisabeth [Vis alle 11 forfattere av denne artikkelen] (2018). Comparing the disease course of patients with seronegative and seropositive rheumatoid arthritis fulfilling the 2010 ACR/EULAR classification criteria in a treat-to-target setting: 2-year data from the ARCTIC trial. RMD Open. 4(2), s. 11–17. doi: 10.1136/rmdopen-2018-000752. Fulltekst i vitenarkiv Vis sammendrag

  Objectives Recent studies suggest that implementation of the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA) leads to higher inflammatory activity in seronegative compared with seropositive patients at time of diagnosis. Our aim was to compare the disease course in seronegative and seropositive patients classified according to the 2010 criteria. Methods DMARD-naïve patients with RA fulfilling the 2010 criteria were included in the treat-to-target ARCTIC trial and followed for 24 months. We stratified patients as seropositive (rheumatoid factor (RF)+, anticitrullinated protein antibodies (ACPA)+ or both) or seronegative (RF– and ACPA–) and compared disease activity, radiographic progression, treatment response and remission rates across groups. Results 230 patients were included with mean (SD) age 51.4 (13.7) years, and 61% were female. 34 patients (15%) were seronegative. At 24  months, disease activity measures, radiographic progression and remission rates were similar between groups, despite more inflammatory activity in seronegative patients at baseline. Treatment response was slower in seronegative compared with seropositive patients. The groups received similar treatment. Conclusion Our findings suggest that among patients with RA classified according to the 2010 ACR/EULAR criteria, seronegative patients respond well to modern treatment strategies. However, treatment response was somewhat slower in seronegative patients and radiographic progression was similar in seronegative and seropositive patients. Our results indicate that seronegative RA is not a mild form of the disease and requires intensive treat-to-target therapy similar to treatment of seropositive RA.

• Sundlisæter, Nina Beate Paulshus; Olsen, Inge Christoffer; Aga, Anna-Birgitte; Hammer, Hilde Berner; Uhlig, Till & Heijde, Desirée van der [Vis alle 9 forfattere av denne artikkelen] (2018). Predictors of sustained remission in patients with early rheumatoid arthritis treated according to an aggressive treat-to-target protocol. Rheumatology. ISSN 1462-0324. 57(11), s. 2022–2031. doi: 10.1093/rheumatology/key202. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (2024). Revmatologi. Universitetsforlaget. ISBN 9788215068589. 400 s. Fulltekst i vitenarkiv

Se alle arbeider i NVA

• Østerås, Nina; Haavardsholm, Espen A.; Mæhlen, Marthe Thoresen; Andersson, Helena & Goll, Guro Løvik (2026). Panelsamtale - Hva inspirerte deg på årets EULAR? doi: https:/www.diakonhjemmetsykehus.no/49d70f/contentassets/dd1c5c9a796d4c4ca72e0ebe655d8545/program-gronn-kongress-2026.pdf. Fulltekst i vitenarkiv
• Haavardsholm, Espen A. (2026). Får Gleditschprisen 2026. [Journal]. Dagens Medisin. Fulltekst i vitenarkiv Vis sammendrag

  Professor og forskningssjef Espen A. Haavardsholm tildeles Gleditschprisen 2026.

• Haavardsholm, Espen A. & Bergsmark, Kjetil (2026). Diakonhjemmet sykehus ønsker flere industristudier - NorTrials. Fulltekst i vitenarkiv Vis sammendrag

  - Vi rigger oss til å bli et studieklart sykehus, og ønsker oss flere industristudier, sier administrerende direktør Kari-Jussie Lønning.

• Hagen, Gunhild; Syversen, Silje & Haavardsholm, Espen A. (2026). Skreddersydd infliksimab-behandling kan spare 5772 kroner per pasient – Legemiddelindustrien. [Internet]. LMI - Legemiddelindustrien. Fulltekst i vitenarkiv Vis sammendrag

  Pasienter med revmatiske sykdommer, tarmsykdommer og hudsykdommer som får infliksimab-dosen tilpasset etter blodprøver, opplever færre sykdomsoppbluss – og helsetjenesten sparer penger. Det viser nye analyser fra NOR-DRUM-studien ved Diakonhjemmet sykehus, skriver HealthTalk.

• Hagen, Gunhild; Syversen, Silje & Haavardsholm, Espen A. (2026). Skreddersydd infliksimab-behandling gir færre oppbluss og sparer 5772 kroner per pasient. [Journal]. Health Talk. Fulltekst i vitenarkiv Vis sammendrag

  Tilpasset infliksimab-behandling med terapeutisk legemiddelmonitorering gir færre sykdomsoppbluss og lavere ressursbruk, viser NOR-DRUM-studien ved Diakonhjemmet sykehus. Helseøkonomiske analyser anslår en besparelse på 5772 kroner per pasient i året.

• Berg, Inger Jorid; Asphaug, Lars; Kristianslund, Eirik; Tveter, Anne Therese; Gossec, Laure & Macfarlane, Gary J [Vis alle 12 forfattere av denne artikkelen] (2026). Patient-initiated follow-up is more cost-effective than remote monitoring or usual care in axial spondyloarthritis, results from the ReMonit randomized controlled trial. Fulltekst i vitenarkiv
• Hetlevik, Siri Opsahl; Lilleby, Vibke; Pesonen, Maiju; Nordal, Ellen Berit; Rygg, Marite & Austad, Cathrine [Vis alle 17 forfattere av denne artikkelen] (2026). Moving towards optimized treatment for children and adolescents with juvenile idiopathic arthritis in sustained remission randomized to continue stable treatment, methotrexate withdrawal or tumor necrosis factor inhibitor withdrawal: study protocol for the Norwegian multi-center MOVE-JIA trial. doi: 10.1186/s13063-026-09539-0. Fulltekst i vitenarkiv
• Fatima, Tahzeeb; Zhang, Yuan; Vasileiadis, Georgios K.; Rawshani, Araz; Vollenhoven, Ronald van & Lampa, Jon [Vis alle 20 forfattere av denne artikkelen] (2025). Correction: Disease activity and treatment response in early rheumatoid arthritis: an exploratory metabolomic profiling in the NORD-STAR cohort. Arthritis Research & Therapy. ISSN 1478-6354. 27(1). doi: 10.1186/s13075-025-03657-x. Fulltekst i vitenarkiv
• Herder, Ingrid; Hetlevik, Siri Opsahl; Gehin, J. E.; Pesonen, Maiju; Lilleby, Vibke & Rygg, Marite [Vis alle 17 forfattere av denne artikkelen] (2025). PT006 Adalimumab serum levels and associations with disease activity in juvenile idiopathic arthritis. Pediatric Rheumatology. 23(2). Fulltekst i vitenarkiv
• Bøyesen, Pernille; Aga, Anna-Birgitte; Lilleby, Vibke; Pesonen, Maiju; Rygg, Marite & Nordal, Ellen Berit [Vis alle 17 forfattere av denne artikkelen] (2025). O09 Long-term treatment efficacy of intra-articular triamcinolone hexacetonide injections in juvenile idiopathic arthritis patients starting tumor necrosis factor inhibitor therapy: 48-week results from a randomized, phase 4 trial - the myjia trial. Pediatric Rheumatology. 23(2). Fulltekst i vitenarkiv
• Haavardsholm, Espen A. (2025). Professor og forskningssjef Espen A. Haavardsholm fyller 50 år. [Journal]. Budstikka og Aftenposten NTB. Fulltekst i vitenarkiv
• Vigeland, Maria Dehli; Heinicke, Fatima; Flåm, Siri Tennebø; Lillegraven, Siri; Mjaavatten, Maria Dahl & Syversen, Silje Watterdal [Vis alle 8 forfattere av denne artikkelen] (2025). ABS0248 METHOTREXATE TREATMENT CHANGES GENE EXPRESSION IN CD19+ B-CELLS FROM RHEUMATOID ARTHRITIS PATIENTS. Annals of the Rheumatic Diseases. ISSN 0003-4967. 84, s. 1950–1950. doi: 10.1016/j.ard.2025.06.1500. Fulltekst i vitenarkiv
• Holly, T.; Brun, Marthe Kirkesæther; Jørgensen, K.K.; Goll, Guro Løvik; Sexton, Joseph & Gehin, Johanna [Vis alle 15 forfattere av denne artikkelen] (2025). POS1077 Cost-effectiveness of proactive terapeutic drug monitoring (TDM) in patients with inflmmatory disease-results from the Nor-Drum trial. doi: 10.1016/j.ard.2025.06.431. Fulltekst i vitenarkiv
• Lillejordet, Even; Sundlisæter, Nina Paulshus; Sexton, Joseph; Fongen, Birgit Camilla; Moholt, Ellen & Ljoså, Maud-Kristine Aga [Vis alle 19 forfattere av denne artikkelen] (2025). POS1047 CLINICAL AND ULTRASOUND FEATURES IN AN INCEPTION COHORT OF TREATMENT NAÏVE PATIENTS WITH PSORIATIC ARTHRITIS. Annals of the Rheumatic Diseases. ISSN 0003-4967. 84(Supplement 1), s. 1149–1149. doi: https:/www.sciencedirect.com/science/article/pii/S0003496725024537. Fulltekst i vitenarkiv Vis sammendrag

  Background: Assessing a newly diagnosed patient with psoriatic arthritis (PsA) can be challenging, and the correct evaluation of clinical features may influence treatment decisions and prognosis. Current treatment recommendations underline this, as patients are stratified based on features such as enthesitis, predominant axial disease, or predominant skin and nail disease [1]. Ultrasound can be an important clinical tool to ensure correct treatment decisions from the onset of the disease. Objectives: To describe the clinical and ultrasound characteristics of treatment naïve PsA patients starting their first disease-modifying anti-rheumatic drug, including structured assessment of disease activity in joints, entheses, skin, and nails. Methods: Patients diagnosed with PsA who fulfilled the ClASsification for Psoriatic Arthritis (CASPAR) criteria starting their first disease-modifying antirheumatic drug were included in an ongoing Norwegian multi-center study (NCT05291819). Patients underwent extensive clinical and ultrasound assessments. The clinical examination of joints included assessments of 66/68 swollen (SJC) and tender (TJC) joints and identification of dactylitis. The presence of enthesitis was evaluated clinically according to the Leeds Enthesitis Index (LEI) and the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis scoring system. Skin- and nail involvement was assessed by psoriasis body surface area (BSA), static Physician Global Assessment of Psoriasis (sPGA), and modified Nail Psoriasis Severity Index (mNAPSI). The Disease Activity Index for Psoriatic Arthritis (DAPSA) was used to assess the disease activity, and patient-reported outcomes were collected, such as patient global assessment of disease, pain, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). All patients underwent a comprehensive ultrasound protocol with evaluation of 74 joints, 20 tendons of the hands, and 14 entheses, all scored according to OMERACT definitions. Ultrasound inflammation was defined by power Doppler (PD) >0 in any joint, enthesis, flexor tendon sheath of the fingers, or within a peritenonitis proximal to the MCP joints. The grayscale (GS) sum score is comprised of joints, the flexor tendons of the hands, peritenonitis, and the inflammatory enthesis findings of hypoechogenicity and increased thickness. Results: A total of 111 consecutive patients were included in this analysis; 64% were male, and the mean (SD) age was 44.2 (14.0) years. 93% of the patients had a history of psoriasis, while in the remaining 7% it was present in a first-degree family member (Table 1). Physician-reported history of arthritis was the most prevalent disease feature, identified in 86% of patients. A history of axial involvement was documented in 29%, enthesitis in 30%, and nail psoriasis in 47% of patients. At the time of assessment, the median (IQR) SJC was 2 (1-4) and TJC 4 (2-8). Patient global assessment of disease activity visual analog scale (VAS) was 59 (41-70), VAS pain was 60 (40-70), and CRP 5 mg/L (2-11 mg/L), whereas the VAS physician global assessment of disease was 25 (15-40). 80% had a SJC>0. The baseline DAPSA had a median (IQR) value of 18.4 (12.5-28.3), corresponding to moderate disease activity. The skin disease among the patients was mild. Although 87% had any psoriasis plaque, the median (IQR) BSA was 2% (1-4%), sPGA score 3 (2-4), and mNAPSI score 1 (0-8). The median ultrasound GS sum score was 11 (5-22) (Table 2). When focusing solely on the GS score for joints, a GS >1 was observed in 75% of patients. The median PD sum score was 3 (0-7), with 69% having a value >0 in any of the ultrasound-examined structures. 52% had any joint with PD>0. A PD-signal >0 was observed in an enthesis in 35% of the patients, with the lateral epicondyle being the most commonly affected enthesis (12%), followed by the proximal patellar tendon insertion (11%). Additionally, peritenonitis was identified in 19%, and flexor tenosynovitis in 21%. Conclusion: In this treatment naïve early PsA inception cohort with an aim to include all PsA patients starting DMARD treatment, extensive examinations illustrated the heterogeneous nature of the disease. After skin psoriasis, arthritis was the feature affecting most patients, with clinically swollen joints in 80% and ultrasound PD joint synovitis in 52%. Other aspects of PsA, such as a clinical finding of dactylitis and ultrasound findings of enthesitis, tenosynovitis, and peritenonitis, each had an overall prevalence of at least 20%, reflecting the diversity of this patient population. Ultrasound might add useful information about inflammation in a number of structures. In conclusion, extensive examination of affected structures is necessary to guide treatment decisions in early PsA.

• Holly, Teresa; Brun, Marthe Kirkesæther; Jørgensen, Kristin Kaasen; Goll, Guro Løvik; Sexton, Joseph & Gehin, Johanna [Vis alle 16 forfattere av denne artikkelen] (2025). Cost-effectiveness of proactive therapeutic drug monitoring (TDM) in patients with inflmmatory disease-results from the Nor-Drum trial. Fulltekst i vitenarkiv
• Hagen, Gunhild; Arif, Sonia; Karoliussen, Lars Fridtjof; Sexton, Joseph; Haavardsholm, Espen Andre & Provan, Sella Aarrestad [Vis alle 8 forfattere av denne artikkelen] (2025). Treating gout to target serum urate improves health-related quality of life and utility over five years. Fulltekst i vitenarkiv
• Kjørholt, Kaja Eriksrud; Sundlisæter, Nina Paulshus; Haavardsholm, Espen A. & Lillegraven, Siri (2024). Norsk leddgikt-studie: Overraskende funn om medisiner. [Journal]. VG papirutgave. Fulltekst i vitenarkiv
• Helsingen, Lise Mørkved; Langeland, Eline Aurvoll; Pisani, Synne Eline Rotihaug; Vandvik, Per Olav; Haavardsholm, Espen A. & Malt, Ulrik Fredrik [Vis alle 10 forfattere av denne artikkelen] (2024). Glansbilder av nasjonale faglige retningslinjer fra Helsedirektoratet. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 144(5). doi: 10.4045/tidsskr.24.0141. Fulltekst i vitenarkiv
• Vikse, Jens; Mjaavatten, Maria Dahl & Haavardsholm, Espen A. (2024). Reaktiv artritt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 211–212. Fulltekst i vitenarkiv
• Vikse, Jens; Lillejordet, Even; Fagerli, Karen Minde; Bakland, Gunnstein & Haavardsholm, Espen A. (2024). Spondyloartritt: en oversikt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 190–201. Fulltekst i vitenarkiv
• Vikse, Jens; Hammer, Hilde Berner; Nystad, Tone Wikene; Uhlig, Till & Haavardsholm, Espen A. (2024). Urinsyregikt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 216–228. Fulltekst i vitenarkiv
• Vikse, Jens; Hammer, Hilde Berner; Bader, Lucius & Haavardsholm, Espen A. (2024). Leddsmerter. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. Fulltekst i vitenarkiv
• Vikse, Jens; Bakland, Gunnstein; Berg, Inger Jorid & Haavardsholm, Espen A. (2024). Aksial spondyloartritt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 202–206. Fulltekst i vitenarkiv
• Vikse, Jens; Fevang, Bjørg Tilde Svanes & Haavardsholm, Espen A. (2024). Artrittsykdommer: en oversikt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. Fulltekst i vitenarkiv
• Vikse, Jens; Bader, Lucius; Goll, Guro Løvik; Molberg, Øyvind & Haavardsholm, Espen A. (2024). Immunsupprimerende behandling. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. Fulltekst i vitenarkiv
• Vikse, Jens; Hammer, Hilde Berner; Nystad, Tone Wikene; Uhlig, Till & Haavardsholm, Espen A. (2024). Krystallartritt: en oversikt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 213–215. Fulltekst i vitenarkiv
• Vikse, Jens; Haavardsholm, Erik; Lillejordet, Even; Aaløkken, Trond Mogens; Hammer, Hilde Berner & Diamantopoulos, Andreas P [Vis alle 8 forfattere av denne artikkelen] (2024). Bildeundersøkelser. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. Fulltekst i vitenarkiv
• Vikse, Jens; Aga, Anna-Birgitte; Fevang, Bjørg Tilde Svanes & Haavardsholm, Espen A. (2024). Revmatoid artritt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 180–189. Fulltekst i vitenarkiv
• Vikse, Jens; Fagerli, Karen Minde; Lillejordet, Even; Madland, Tor Magne & Haavardsholm, Espen A. (2024). Psoriasisartritt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 207–210. Fulltekst i vitenarkiv
• Kjørholt, Kaja Eriksrud; Sundlisæter, Nina Beate Paulshus; Aga, Anna-Birgitte; Sexton, Joseph; Olsen, Inge Christoffer & Madland, Tor Magne [Vis alle 21 forfattere av denne artikkelen] (2024). OP0021 3-YEAR RESULTS OF TAPERING TNFi TO WITHDRAWAL COMPARED TO STABLE TNFi AMONG RHEUMATOID ARTHRITIS PATIENTS IN SUSTAINED REMISSION: A MULTICENTER RANDOMIZED TRIAL. Annals of the Rheumatic Diseases. ISSN 0003-4967. 83, s. 188–189. doi: 10.1136/annrheumdis-2024-eular.299. Fulltekst i vitenarkiv
• Heiberg, Marte Schrumpf; Kisten, Yogan; Kazemi, Amirhossein; Rezaei, Hamed; Klint, Erik af & Ljoså, Maud-Kristine Aga [Vis alle 26 forfattere av denne artikkelen] (2024). POS0474 ULTRASOUND REMISSION RATES AFTER 1 YEAR ARE HIGH IN EARLY RA PATIENTS ON INDUCTION TREATMENT: RESULTS FROM THE RANDOMIZED NORD-STAR TRIAL. Annals of the Rheumatic Diseases. ISSN 0003-4967. 83, s. 839–840. doi: 10.1136/annrheumdis-2024-eular.5080. Fulltekst i vitenarkiv
• Vikse, Jens; Hammer, Hilde Berner; Nystad, Tone Wikene; Uhlig, Till & Haavardsholm, Espen A. (2024). Kalsiumpyrofosfatartritt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 229–230. Fulltekst i vitenarkiv
• Vikse, Jens; Fevang, Bjørg Tilde Svanes; Haugeberg, Glenn; Bitter, Helle; Haavardsholm, Espen A. & Molberg, Øyvind (2024). Revmatologi: en oversikt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. Fulltekst i vitenarkiv
• Vikse, Jens; Schrumpf, Marte & Haavardsholm, Espen A. (2024). Revmatologi og malignitet. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 367–370. Fulltekst i vitenarkiv
• Vikse, Jens; Wallenius, Marianne; Skorpen, Carina Götestam & Haavardsholm, Espen A. (2024). Svangerskap og revmatisk sykdom. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 373–377. Fulltekst i vitenarkiv
• Vikse, Jens; bos-haugen, ida & Haavardsholm, Espen A. (2024). Artrose. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. s. 236–240. Fulltekst i vitenarkiv
• Vikse, Jens; Salte, Tore; Dale, Håvard; Nystad, Tone Wikene; Syversen, Silje Watterdal & Karoliussen, Lars Fridtjof [Vis alle 9 forfattere av denne artikkelen] (2024). Infeksiøs artritt. I Vikse, Jens; Haavardsholm, Espen A. & Molberg, Øyvind (Red.), Revmatologi. Universitetsforlaget. ISSN 9788215068589. Fulltekst i vitenarkiv
• Moe, Rikke Helene; Haavardsholm, Espen A.; Lillegraven, Siri & semb, anne grete (2023). To av tre kan bli symptomfrie. [Journal]. VG online og papirutgave. Fulltekst i vitenarkiv
• Melokhina, Valeriia; Sundlisæter, Nina Paulshus; Sexton, Joseph; Sundin, Ulf Gunnar; Aga, Anna-Birgitte & Kjørholt, Kaja Eriksrud [Vis alle 10 forfattere av denne artikkelen] (2023). Subclinical inflammation and joint damage progression in patients with early RA fulfilling 2011 vs 2022 ACR/EULAR Boolean remission criteria: Data from the ARCTIC study. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1136/ard-2023-224950. Fulltekst i vitenarkiv
• Syversen, Silje Watterdal; Gehin, Johanna; Goll, Guro Løvik; Bolstad, Nils; Haavardsholm, Espen A. & Bakke, Emilie Andrea [Vis alle 7 forfattere av denne artikkelen] (2023). Therapeutic Drug Monitoring: A Tool to Optimize Treatment of Inflammatory Joint Diseases. Arthritis & Rheumatology. ISSN 2326-5191. doi: 10.1002/art.42764. Fulltekst i vitenarkiv
• Haavardsholm, Espen A. & Lillegraven, Siri (2023). Brukermedvirkning kan gi bedre forskning. Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(9). doi: 10.4045/tidsskr.23.0245. Fulltekst i vitenarkiv
• Haavardsholm, Espen A. (2023). Er retningslinjene fra Helsedirektoratet til å stole på? Tidsskrift for Den norske legeforening (Tidsskriftet). ISSN 0029-2001. 143(14). doi: 10.4045/tidsskr.23.0622. Fulltekst i vitenarkiv
• Haavardsholm, Espen A. (2023). Norsk ekspert: Dette er de viktigste nyhetene innen behandling av leddgikt. [Internet]. HealthTalk. Fulltekst i vitenarkiv
• Østergaard, Mikkel; Vollenhoven, Ronald van; Rudin, Anna; Hetland, Merete L.; Schrumpf, Marte & Nordström, Dan [Vis alle 44 forfattere av denne artikkelen] (2022). CERTOLIZUMAB-PEGOL, ABATACEPT, TOCILIZUMAB OR ACTIVE CONVENTIONAL THERAPY IN EARLY RHEUMATOID ARTHRITIS: CLINICAL AND RADIOGRAPHIC 48-WEEKS RESULTS OF THE INVESTIGATOR-INITIATED RANDOMIZED NORD-STAR TRIAL. Annals of the Rheumatic Diseases. ISSN 0003-4967. 81, s. 38–40. Fulltekst i vitenarkiv
• Syversen, Silje Watterdal; Jahnsen, Jørgen & Haavardsholm, Espen A. (2022). Therapeutic Drug Monitoring vs Standard Therapy During Maintenance Infliximab Therapy and Control of Immune-Mediated Inflammatory Diseases-Reply. Journal of the American Medical Association (JAMA). ISSN 0098-7484. 327(15), s. 1506–1507. doi: 10.1001/jama.2022.2938. Fulltekst i vitenarkiv
• Lillegraven, Siri; Sundlisæter, Nina Paulshus; Aga, Anna-Birgitte; Sexton, Joe; Olsen, Inge Christoffer & Fremstad, Hallvard [Vis alle 21 forfattere av denne artikkelen] (2022). Drug Free Remission in Rheumatoid Arthritis: Data from the Randomized Controlled ARCTIC REWIND Trial. Arthritis & Rheumatology. ISSN 2326-5191. 74, s. 3970–3972. doi: 10.1002/art.42355. Fulltekst i vitenarkiv
• Sundlisæter, Nina Beate Paulshus; Aga, Anna-Birgitte; Olsen, Inge Christoffer; Hammer, Hilde Berner; Uhlig, Till & Heijde, Désirée van der [Vis alle 9 forfattere av denne artikkelen] (2021). Joint tenderness and ultrasound inflammation in DMARD-naïve patients with early rheumatoid arthritis. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1136/annrheumdis-2021-220265. Fulltekst i vitenarkiv
• Lillegraven, Siri; Sundlisæter, Nina Paulshus & Haavardsholm, Espen A. (2021). Half-Dose vs Stable-Dose Conventional Synthetic Disease-Modifying Antirheumatic Drugs and Disease Flare in Patients with Rheumatoid Arthritis-Reply. Journal of the American Medical Association (JAMA). ISSN 0098-7484. 326(9), s. 873–873. doi: 10.1001/jama.2021.10651. Fulltekst i vitenarkiv
• Lillegraven, Siri; Sundlisæter, Nina Beate Paulshus; Aga, Anna-Birgitte; Sexton, Joseph; Olsen, Inge Christoffer & Lexberg, Åse [Vis alle 19 forfattere av denne artikkelen] (2020). STABLE VERSUS TAPERED AND WITHDRAWN TREATMENT WITH TUMOR NECROSIS FACTOR INHIBITOR IN RHEUMATOID ARTHRITIS REMISSION (ARCTIC REWIND): A RANDOMISED, OPEN-LABEL, PHASE 4, NON-INFERIORITY TRIAL. Annals of the Rheumatic Diseases. ISSN 0003-4967. 79, s. 14–15. doi: 10.1136/annrheumdis-2020-eular.1955. Fulltekst i vitenarkiv
• Lillegraven, Siri; Sundlisæter, Nina Beate Paulshus; Aga, Anna-Birgitte; Sexton, Joseph; Olsen, Inge Christoffer & Fremstad, Hallvard [Vis alle 21 forfattere av denne artikkelen] (2020). TAPERING OF CONVENTIONAL SYNTHETIC DISEASE MODIFYING ANTI-RHEUMATIC DRUGS IN SUSTAINED RHEUMATOID ARTHRITIS REMISSION: RESULTS FROM A RANDOMIZED CONTROLLED TRIAL. Annals of the Rheumatic Diseases. ISSN 0003-4967. 79, s. 1012–1013. doi: 10.1136/annrheumdis-2020-eular.3090. Fulltekst i vitenarkiv
• Norvang, Vibeke; Kvien, Tore Kristian; Uhlig, Till; Lillegraven, Siri; Mjaavatten, Maria Dahl & Yoshida, Kazuki [Vis alle 8 forfattere av denne artikkelen] (2020). Reply. Arthritis & Rheumatology. ISSN 2326-5191. 72(8), s. 1407–1408. doi: 10.1002/art.41268. Fulltekst i vitenarkiv
• Hammer, Hilde Berner; Karoliussen, Lars Fridtjof; Terslev, Lene; Haavardsholm, Espen A.; Kvien, Tore Kristian & Uhlig, Till (2020). Response to: € Correspondence on € Ultrasound shows rapid reduction of crystal depositions during a treat-to-target approach in gout patients: 12-month results from the NOR-Gout study'' by Hung et al. Annals of the Rheumatic Diseases. ISSN 0003-4967. doi: 10.1136/annrheumdis-2020-218908. Fulltekst i vitenarkiv
• Brinchmann, Bendik Christian; Dietrichs, Erik Sveberg; Haavardsholm, Espen A. & Kalager, Mette (2020). Leger som forsker er navet i kunnskapsbasert medisin. Fulltekst i vitenarkiv

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