Nils Bolstad

• Gehin, Johanna; Klaasen, Rolf; Kristianslund, Eirik; Jyssum, Ingrid; Sexton, Joseph & Warren, David John [Show all 11 contributors for this article] (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. Full text in Research Archive
• Høgestøl, Einar August; Brustad, Åge Winje; Celius, Elisabeth Gulowsen; Meling, Martine; Berg-Hansen, Pål & Kro, Grete Anette Birkeland [Show all 13 contributors for this article] (2026). Serum drug levels and JCV assay discrepancies after switching from originator to biosimilar natalizumab. BMJ Neurology Open. 8(1). doi: 10.1136/bmjno-2025-001477. Full text in Research Archive
• Holly, Teresa; Brun, Marthe Kirkesæther; Jørgensen, Kristin Kaasen; Goll, Guro Løvik; Sexton, Joseph & Gehin, Johanna [Show all 15 contributors for this article] (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), p. 11–11. doi: 10.1136/rmdopen-2025-006329. Full text in Research Archive
• Carlsen, Arne; Steinsbø, Øyvind; Kvaløy, Jan Terje; Aabakken, Lars; Bolstad, Nils & Warren, David John [Show all 10 contributors for this article] (2025). Optimizing serum adalimumab levels in maintenance therapy via proactive therapeutic drug monitoring improves markers of disease activity in Crohn’s disease. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 60(12), p. 1214–1225. doi: 10.1080/00365521.2025.2573725. Full text in Research Archive Show summary

  Objects The benefit of a proactive therapeutic drug monitoring (TDM) strategy in patients with inflammatory bowel disease receiving biological therapy remains disputed. We aimed to evaluate whether optimizing serum adalimumab levels (s-ADL), guided by proactive TDM, is associated with improved markers of disease activity in patients with Crohn’s disease. Materials and methods In this longitudinal cross-sectional study, 72 patients receiving adalimumab maintenance therapy from our outpatient clinic, were included. Patients underwent five study visits at 3-month intervals over one year. Disease activity was assesed using the Harvey-Bradshaw Index, plasma C-reactive protein (CRP), and fecal calprotectin. s-ADL levels were measured at each visit, and dosing was adjusted to maintain a therapeutic target range of 5.0–12.0 mg/L. Results At baseline, subtherapeutic s-ADL levels were associated with higher CRP levels (p = 0.03), and in these patients’ drug levels increased significantly over the study (p = 0.001), whereas CRP levels decreased (p = 0.03). Longitudinal analysis demonstrated that higher s-ADL levels (≥5.0 mg/L) were associated with lower CRP levels (p = 0.008) and lower HBI scores (p = 0.03). Additionally, lower CRP- and fecal calprotectin levels at any visit were associated with higher s-ADL levels at the preceding visit (p = 0.04 for both). Lower CRP levels were also associated with higher s-ADL levels using 7.0 mg/L as the therapeutic threshold in longitudinal analyses (p = 0.003). Conclusion Proactive TDM-guided optimization of s-ADL levels in Crohn’s disease patients on adalimumab maintenance therapy was associated with the modest but significant improvements in markers of disease activity over one year of follow-up.

• Gjefsen, Elisabeth; Bråten, Lars Christian Haugli; Ponzi, Erica; Dagestad, Magnhild Hammersland; Marchand, Gunn Hege & Kadar, Thomas Istvan Edelsvärd [Show all 22 contributors for this article] (2025). Efficacy of a Tumor Necrosis Factor Inhibitor in Chronic Low-Back Pain With Modic Type 1 Changes: A Randomized Controlled Trial. Arthritis & Rheumatology. ISSN 2326-5191. 77(5), p. 615–623. doi: 10.1002/art.43073. Full text in Research Archive Show summary

  Objective: The efficacy of tumor necrosis factor inhibitors for treating chronic low-back pain with Modic changes is uncertain. This study investigated the superiority of infliximab over placebo in patients with Modic type 1 changes. Methods: In this multicenter, randomized, triple-blind, placebo-controlled trial, patients aged 18 to 65 years with moderate to severe chronic low-back pain and Modic type 1 changes were enrolled from five Norwegian public hospitals between January 2019 and October 2022. Participants were randomly assigned to four intravenous infusions of 5 mg/kg infliximab or placebo. The primary outcome was difference in change in the Oswestry Disability Index (ODI) score from baseline to five months. Secondary outcomes included changes in low-back pain intensity, disability, and health-related quality of life. A linear mixed model was used for efficacy analyses. Results: A total of 128 patients (mean age 43 years, 65.6% women) participated (64 in each group). All patients who received at least one dose of the allocated infusion were included in the primary analyses. The average ODI score (±SD) change was −7.0 (±9.7) in the group who received infliximab and −6.4 (±10.4) in the group who received placebo. The difference in the ODI score change between the two groups was 1.3 ODI points (95% confidence interval −2.1 to 4.6, P = 0.45). Analyses showed no effect of infliximab compared to placebo on secondary outcomes. Adverse event rates were similar between groups. Conclusion: Infliximab did not demonstrate superiority over placebo in reducing pain-related disability in patients with moderate to severe chronic low-back pain with Modic type 1 changes at five months.

• Grimstad, Tore Bjørn; Carlsen, Arne; Kvaløy, Jan Terje; Bolstad, Nils; Warren, David & Aabakken, Lars [Show all 10 contributors for this article] (2025). Fatigue in Inflammatory Bowel Disease: No Effect of Serum Concentrations of Infliximab, Adalimumab or Anti-Drug Antibodies During Maintenance Therapy. Scandinavian Journal of Immunology. ISSN 0300-9475. 101(5). doi: 10.1111/sji.70029. Full text in Research Archive Show summary

  Several studies have shown that infliximab and adalimumab ameliorate fatigue in inflammatory bowel disease. We investigated whether serum levels of these agents above or below a selected threshold influence fatigue severity. In this cross-sectional study, we measured serum concentrations (s-) of infliximab and adalimumab and corresponding anti-drug antibody levels. Therapeutic thresholds were defined as s-infliximab ≥ 5.0 mg/L and s-adalimumab ≥ 7.0 mg/L. Disease activity was assessed using the Harvey–Bradshaw Index for Crohn's disease, Partial Mayo Score for ulcerative colitis, and C-reactive protein (CRP) and faecal calprotectin levels for both conditions. Fatigue was assessed with the Fatigue Visual Analog Scale and Fatigue Severity Scale, and depression was evaluated with the Hospital Anxiety and Depression Scale, Depression subscale. Of 171 included patients (112 with Crohn's disease, 59 with ulcerative colitis), 66 (38.6%) were on infliximab and 105 (61.4%) were on adalimumab. Scores on the two fatigue scales were similar for serum values above versus below therapeutic thresholds for both drugs and did not differ with versus without anti-drug antibodies against either drug. CRP was numerically higher with infliximab levels below versus above the threshold (p = 0.06), whereas both CRP and faecal calprotectin were increased with adalimumab below versus above the threshold (p = 0.022, p = 0.0242). In patients with inflammatory bowel disease on maintenance therapy, s-infliximab and s-adalimumab levels below or above therapeutic thresholds or the presence of anti-drug antibodies did not affect fatigue severity.

• Lukina, Polina; Andersen, Ina Lervåg; Klaasen, Rolf; Warren, David John; Bolstad, Nils & Mjønes, Patricia Gjertrud [Show all 11 contributors for this article] (2025). The Prevalence and Rate of Undiagnosed Celiac Disease in an Adult General Population, the Trøndelag Health Study, Norway. Clinical Gastroenterology and Hepatology. ISSN 1542-3565. 23(7), p. 1143–1151. doi: 10.1016/j.cgh.2024.06.027. Full text in Research Archive Show summary

  Background & Aims This study aimed to determine the total prevalence of celiac disease (CeD), including undiagnosed cases, in a population-based study of adults screened for CeD. Methods The study used the fourth Trøndelag Health Study (HUNT4), conducted in 2017–2019, where 56,042 adult (aged >20 years) residents of Nord-Trøndelag County, Norway, participated. Serum samples from 54,505 participants were analyzed for anti-transglutaminase 2 IgA and IgG. Seropositive individuals were invited for a clinical assessment, including upper endoscopy with duodenal biopsies. Previously diagnosed and seronegative CeD cases were identified through linkage to hospital records and the Norwegian Patient Registry. Results The rate of CeD seropositivity was 2.0% (1107/54,505). Out of these, 724 individuals attended the clinical assessment. Additionally, the hospital records and registry identified individuals with a known CeD diagnosis, that were seronegative or without serology in HUNT4 or seropositive in HUNT4 but did not participate in the clinical assessment. In total, the study confirmed a new CeD diagnosis after participation in HUNT4 in 470 individuals and a known CeD diagnosis before participation in HUNT4 in 383 individuals. The total biopsy-confirmed prevalence of CeD was 1.5% (853/56,042), and the ratio of new, previously undiagnosed CeD cases (after HUNT4) to known, previously diagnosed CeD cases (before HUNT4) was 1.2:1 (470/383). Conclusions The total prevalence of CeD in this population-based study of adults in Norway was high and many individuals were previously undiagnosed. Detection of CeD should be improved, because early diagnosis is crucial for effective management and prevention of complications.

• Andersen, Ina Lervåg; Lukina, Polina; Dyrli, Ole Thomas; Klaasen, Rolf; Warren, David & Bolstad, Nils [Show all 12 contributors for this article] (2025). Serological screening for coeliac disease in an adult general population: the HUNT study. Gut. ISSN 0017-5749. 74(6), p. 918–925. doi: 10.1136/gutjnl-2024-333886. Full text in Research Archive Show summary

  Background A large proportion of individuals with coeliac disease (CeD) remain undiagnosed. Objective The aim of this study was to assess serological screening for CeD in the adult general population. Design The study was based on the fourth Trøndelag Health Study, a population-based study performed 2017–2019 in Nord-Trøndelag County, Norway, including 56 042 participants >20 years of age (54% participation rate). Serum samples were analysed with a dual antitransglutaminase 2 (TG2) IgA and IgG assay and seropositive participants were invited to endoscopy with duodenal biopsies. A CeD diagnosis was given if mucosal damage (Marsh grade 3) was found. Results Histological evaluation of 657 seropositive participants confirmed CeD in 423. The positive predictive value (PPV) of a positive TG2 IgA was 73.3% (95% CI 69.7% to 77.0%) for biopsy-confirmed CeD. TG2 IgA ≥10 times the upper limit of normal (ULN), as used in the no-biopsy approach in children, increased the PPV to 88.1% (95% CI 84.8% to 91.4%). Primary TG2 IgG response was found in 87 participants, five of whom had biopsy-confirmed CeD. One of the participants with CeD primarily responding with TG2 IgG was IgA deficient. The PPV of a positive TG2 IgG was 5.8% (95% CI 1.9% to 12.9%) and of TG2 IgG ≥10× ULN was 9.5% (95% CI 1.2% to 30.4%) for biopsy-confirmed CeD in TG2 IgA-negative individuals. Conclusion The TG2 IgA assay showed excellent abilities as a screening tool for CeD in the adult general population. However, the diagnostic accuracy of TG2 IgG was too poor for selectively identifying individuals with CeD.

• Lundekvam, Jonas Andre; Høivik, Marte Lie; Anisdahl, Karoline; Hagen, Milada; Warren, David & Bolstad, Nils [Show all 7 contributors for this article] (2025). Tumour necrosis factor inhibitors in Ulcerative colitis: real-world data on Therapeutic drug monitoring and evaluation of current treatment targets (STRIDE II). Annals of Medicine. ISSN 0785-3890. 57(1). doi: 10.1080/07853890.2024.2424447. Full text in Research Archive Show summary

  Background The benefit of therapeutic drug monitoring (TDM) and implementation of recommendations from the Selection of Therapeutic Targets in Inflammatory Bowel Disease (IBD, STRIDE) are discussed in the IBD community. We report real-world data in ulcerative colitis patients receiving first-line tumour necrosis factor inhibitor (TNFi) treatment followed by TDM, and assess how implementation of the STRIDE II recommendations might affect clinical practice. Methods Adult, biologically naïve UC patients starting TNFi between 2014 and 2021 at Oslo University Hospital were included in a medical chart review study, and data were collected at three and twelve months after the start of treatment. Target serum drug levels were defined as ≥7.5 mg/L for adalimumab and ≥5 mg/L for infliximab. Results Of 141 included patients, 36% were in clinical and biochemical (combined) remission after twelve months. Among 102 treatment persistent patients, 54% were in combined remission after twelve months. Target drug level at three months was associated with clinical remission at twelve months (OR = 2.97, 95% CI [1.24–7.12]) and biochemical remission at twelve months (OR = 2.64, 95% CI [1.03–6.77]). In total, 56% of recorded dosage adjustments were related only to serum drug levels. Conclusions Combined remission rates at twelve months for treatment persistent patients suggest that 46% should have been considered for a change of treatment according to the STRIDE II recommendations. A majority of dosage adjustments were made proactively. Target drug level at three months was associated with remission at twelve months and supports the use of proactive TDM.

• Helm, Thea Elisabeth; Høivik, Marte Lie; Anisdahl, Karoline; Buer, Lydia Celine Tansem; Warren, David & Bolstad, Nils [Show all 9 contributors for this article] (2024). Subcutaneous Vedolizumab Treatment in a Real-World Inflammatory Bowel Disease Cohort Switched From Intravenous Vedolizumab: Eighteen-Month Prospective Follow-up Study. Crohn's & Colitis 360. 6(1). doi: 10.1093/crocol/otae013. Full text in Research Archive Show summary

  Background: Vedolizumab has since 2021 been available as a subcutaneous formulation. We aimed to assess 18-month drug persistence and possible predictive factors associated with discontinuation, safety, serum drug profile, drug dosing, and disease activity in a real-world cohort of patients with inflammatory bowel disease switched from intravenous to subcutaneous vedolizumab maintenance treatment. Methods: Eligible patients were switched to subcutaneous vedolizumab and followed for 18 months or until discontinuation of subcutaneous treatment. Data on preferred route of administration, adverse events, drug dosing, serum-vedolizumab, disease activity, fecal calprotectin, and C-reactive protein were collected. Persistence was described using Kaplan–Meier analysis. The impact of clinical and biochemical variables on persistence was analyzed with Cox proportional hazard models. Results: We included 108 patients, and the estimated 18-month drug persistence was 73.6% (95% CI [64.2–80.1]). Patients in clinical remission at switch were less likely to discontinue SC treatment (HR = 0.34, 95% CI [0.16–0.73], P = .006), and patients favoring intravenous treatment at switch were almost 3 times more likely to discontinue (HR = 2.78, 95% CI [1.31–5.90], P = .008). Four patients discontinued subcutaneous vedolizumab due to injection site reactions. At 18 months, 88% of patients administered subcutaneous vedolizumab with an interval of ≥ 14 days, and serum-vedolizumab was 39.1 mg/L. Disease activity was stable during follow-up. Conclusions: Three of the four patients remained on subcutaneous vedolizumab after 18 months, a large proportion received treatment at standard dosing intervals, and disease activity remained stable. This indicates that switching from intravenous to subcutaneous vedolizumab treatment is convenient and safe.

• Brun, Marthe Kirkesæther; Gehin, Johanna; Hammersbøen, Kristin Reine; Warren, David; Klaasen, Rolf & Sexton, Joseph [Show all 15 contributors for this article] (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), p. e226–e236. doi: 10.1016/S2665-9913(23)00341-7. Full text in Research Archive
• Lukina, Polina; Andersen, Ina Lervåg; Eggen, Petter Tinbod; Mjønes, Patricia Gjertrud; Rønne, Elin & Bolstad, Nils [Show all 18 contributors for this article] (2024). Coeliac disease in the Trøndelag Health Study (HUNT), Norway, a population-based cohort of coeliac disease patients. BMJ Open. 14:e077131(1), p. 1–7. doi: 10.1136/bmjopen-2023-077131. Full text in Research Archive Show summary

  Purpose - Coeliac disease (CD) is a common disorder and affects about 1% of the population worldwide. CD in the Trøndelag Health Study (HUNT) is a population-based cohort study which was established to provide new knowledge about CD that can improve the diagnostics and management, prevent the onset or progression and expand the knowledge about the role of genetics of the disease. Participants - The cohort is based on the fourth wave of the population-based HUNT study (HUNT4), Norway, performed during 2017–2019, also including linkage to hospital records and the Norwegian Patient Registry (NPR). A total of 54 541 HUNT4 participants with available sera were screened for CD by serology. All seropositive participants were invited to a clinical assessment, including endoscopy with duodenal biopsies, during 2019–2023. Findings to date - A total of 1107 HUNT4 participants (2%) were seropositive for CD and 1048 were eligible for clinical assessment, including biopsy. Of these, 724 participants attended the clinical assessment and 482 were identified with CD. In addition, 371 participants with CD were identified through the hospital records and NPR. In total, 853 participants in HUNT4 with biopsy-verified CD diagnosis were identified. Future plans - All participants in the study will be invited to a follow-up assessment after at least 1 year, including repeated standard serological testing, endoscopy and tissue sampling. The collected data and material will be used to establish the true population-based prevalence of CD. The consequences of CD, including symptoms, deficiencies and comorbidity, will be investigated and possible triggers and predictors, will be studied. With access to serum samples from the previous HUNT surveys in HUNT Biobank, serological signs of CD in prediagnostic samples of seropositive individuals will be used. Genetic studies will identify new CD markers, assess genotype–phenotype links and explore gene–environment correlations.

• Nome, Ragnhild Veline; Paus, Elisabeth; Gehin, Johanna; Bolstad, Nils & Bjøro, Trine (2024). Managing hemolysis in serum neuron-specific enolase measurements–an automated algorithm for routine practice. Scandinavian Journal of Clinical and Laboratory Investigation. ISSN 0036-5513. 84(4), p. 225–229. doi: 10.1080/00365513.2024.2359091. Full text in Research Archive Show summary

  Neuron-specific enolase (NSE) derived from neurons and peripheral neuroendocrine cells is a biomarker for neuroendocrine tumors and for prognostication in comatose cardiac arrest survivors. However, as platelets and erythrocytes contain NSE, hemolysis causes falsely elevated NSE. We used native serum and hemolysate derived from the same patients to make serial dilutions, and subsequently measured NSE (mNSE) and hemolytic index (HI) in each dilution. An algorithm suitable for the laboratory information system was developed based on the mNSE, HI and the estimated gradient of hemolytic interference from 30 patients. We estimated the associated uncertainty of the corrected NSE (cNSE) results based on the observed range of the gradient and derived an equation for cNSE for samples with limited hemolysis (i.e. 5 < HI ≤ 30): cNSE = mNSE − HI × (0.34 ± 0.23) µg/L. By semi-quantitatively grading the contribution from limited hemolysis, a texted result noting the hemolysis-associated degree of uncertainty can accompany the cNSE result. The major challenge of hemolysis when using serum NSE as a biomarker can be managed using an automated algorithm for correction of NSE results based on degree of hemolysis. However, laboratorians and clinicians should be aware of the limitations associated with in vivo hemolysis.

• Nome, Ragnhild Veline; Flatebø, Øystein; Bøe, Sigurd; Klaasen, Rolf; Aamdal, Elin & Normann, Marius [Show all 8 contributors for this article] (2024). A simple automated assay format for measuring multiple immune checkpoint inhibitors. Journal of Pharmaceutical and Biomedical Analysis. ISSN 0731-7085. 255. doi: 10.1016/j.jpba.2024.116657. Full text in Research Archive Show summary

  Immune checkpoint inhibitors (ICIs) have improved survival rates in oncology, but there is a rising concern for immune-related adverse health outcomes. Monitoring drug serum concentration would enable tailored dosing, however this strategy has not yet been evaluated for ICIs. Fully automated analyte capture assays with time-resolved fluorometry using protein A as tracer, were developed for three different ICIs; the cytotoxic T lymphocyte Antigen-4 (CTLA4) inhibitor ipilimumab (Yervoy; Bristol-Myers Squibb) and the Programmed Death-1 (PD-1) inhibitors nivolumab (Opdivo; Bristol-Myers Squibb) and pembrolizumab (Keytruda; Merck). Drug trough levels were measured in serum samples from ICI-treated patients. Measuring ranges were 1–100 mg/L for all three drugs. Automation allowed for 110 samples to be analyzed in

• Gehin, Johanna; Klaasen, Rolf; Kristianslund, Eirik; Jyssum, Ingrid; Sexton, Joseph & Warren, David [Show all 11 contributors for this article] (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. Full text in Research Archive Show summary

  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.

• Ovesen, Pernille Dige; Attauabi, Mohamed; Ilvemark, Johan F.K.F.; Wewer, Mads Damsgaard; Warren, David & Burisch, Johan [Show all 10 contributors for this article] (2024). Effects of prednisolone tapering on effectiveness of infliximab in patients with ulcerative colitis: Data from a retrospective cohort. BMJ open gastroenterology. 11(1). doi: 10.1136/bmjgast-2024-001343. Full text in Research Archive
• Randel, Kristin Ranheim; Botteri, Edoardo; Lange, Thomas de; Schult, Anna Lisa; Eskeland, Sigrun Losada & El-Safadi, Badboni [Show all 11 contributors for this article] (2024). Performance of Faecal Immunochemical Testing for Colorectal Cancer Screening at Varying Positivity Thresholds. Alimentary Pharmacology and Therapeutics. ISSN 0269-2813. 61(1), p. 122–131. doi: 10.1111/apt.18314. Full text in Research Archive Show summary

  Background: The positivity thresholds of faecal immunochemical testing (FIT) in colorectal cancer (CRC) screening vary between countries. Aims: To explore the trade-off between colonoscopies performed, adverse events and lesions detected at different FIT thresholds in a Norwegian CRC screening trial. Methods: We included first participation in biennial FIT screening for 47,265 individuals aged 50-74 years. Individuals with FIT > 15 μg Hb/g faeces were referred for colonoscopy. We estimated the number of colonoscopies, adverse events, screen-detected CRCs, advanced adenomas and serrated lesions expected at FIT thresholds currently or recently used in other European countries ranging between 20 and 150 μg/g. Results: At the 15 μg/g threshold (Norway), 3705 participants underwent colonoscopy, of whom 203 had CRC, 1119 advanced adenomas and 256 advanced serrated lesions. Using a 47 μg/g threshold, 1826 (49.3%) individuals would have undergone colonoscopy, and 154 (75.9%) would have been diagnosed with CRC, 702

• Brun, Marthe Kirkesæther; Hammersbøen, Kristin Reine; Viken, Marte Kathrine; Stenvik, Grethe-Elisabeth; Klaasen, Rolf & Gehin, Johanna [Show all 18 contributors for this article] (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), p. 648–655. doi: 10.1111/joim.13616. Full text in Research Archive Show summary

  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.

• Jyssum, Ingrid; Gehin, Johanna; Sexton, Joseph; Kristianslund, Eirik; Hu, Yi & Warren, David [Show all 11 contributors for this article] (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), p. 1746–1755. doi: 10.1093/rheumatology/kead525. Full text in Research Archive Show summary

  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.

• Helm, Thea Elisabeth; Høivik, Marte Lie; Buer, Lydia Celine Tansem; Warren, David; Bolstad, Nils & Moum, Bjørn Allan [Show all 9 contributors for this article] (2023). Switching from intravenous to subcutaneous vedolizumab maintenance treatment in patients with inflammatory bowel disease followed by therapeutic drug monitoring. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 58(8), p. 863–873. doi: 10.1080/00365521.2023.2176252. Full text in Research Archive Show summary

  Objective: Vedolizumab (VDZ) for subcutaneous (SC) administration has recently become available. We aimed to assess feasibility, safety and clinical outcome when switching from intravenous (IV) to SC VDZ maintenance treatment in a real world cohort of patients with inflammatory bowel disease (IBD) followed by therapeutic drug monitoring (TDM). Methods: Eligible IBD patients were switched from IV to SC treatment and assessed six months prior to switch, at baseline and six, twelve and twenty-six weeks after switch. Primary outcome was propor- tion of patients on SC treatment after 26 weeks. Secondary outcomes included adverse events (AEs), clinical disease activity, biochemical markers, treatment interval, serum-VDZ (s-VDZ), preferred route of administration and health-related quality of life. Results: In total, 108 patients were switched. After 26 weeks, 100 patients (92.6%) were still on SC treatment and median s-VDZ was 47.6 mg/L (IQR 41.3 54.6). The most frequent AE was injection site reaction (ISR), reported by 20 patients (18.5%). There were no clinically significant changes in disease activity, biochemical markers and quality of life. The proportion of patients preferring SC administra- tion increased from 28.0% before switch to 59.4% after 26 weeks (p < 0.001). Conclusions: Nine out of ten patients still received SC treatment after 26 weeks. No change in disease activity occurred, and levels of serum VDZ increased. Although almost one fifth of patients experi- enced ISRs, a higher proportion favored SC administration at 26 weeks. This study demonstrates that SC maintenance treatment is a safe and feasible alternative to IV treatment.

• Jørgensen, Kristin Kaasen; Høivik, Marte Lie; Chopra, Adity; Benth, Jurate Saltyte; Ricanek, Petr & Moum, Bjørn Allan [Show all 18 contributors for this article] (2023). Humoral immune response to SARS-CoV-2 vaccination in patients with inflammatory bowel disease on immunosuppressive medication: association to serum drug levels and disease type. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 58(8), p. 874–882. doi: 10.1080/00365521.2023.2177884. Full text in Research Archive Show summary

  Objectives Immune responses following SARS-CoV-2 vaccination in patients with inflammatory bowel disease (IBD) are not well characterized. The aims of this study were to explore the serological response associated with IBD, and immunosuppressive medications including serum concentrations of biologics and thiopurine metabolites. Materials and methods This prospective, observational study included adult patients with ulcerative colitis (UC) and Crohn’s disease (CD), and healthy controls. Antibodies to the receptor-binding domain of SARS-CoV-2 spike proteins, and serum concentrations of ongoing biologic and immunomodulatory medications were assessed prior to, and 2-5 weeks after the second vaccine dose. Serologic response was defined as anti-Spike antibodies ≥70 AU/ml. Results In 958 IBD patients (380 UC, 578 CD) and 323 healthy controls, the median (Q1; Q3) anti-Spike antibody level (AU/ml) was lower in patients (618 (192; 4370)) compared to controls (3355 (896; 7849)) (p < 0.001). The antibody levels were lower in CD (439 (174; 3304)) compared to UC (1088 (251; 5975)) (p < 0.001). No associations were demonstrated between antibody levels and serum drug concentrations for TNF inhibitor (TNFi), vedolizumab and ustekinumab. Patients receiving TNFi + thiopurines with a subtherapeutic 6-thioguanine nucleotide (6-TGN) level had higher response rate (93%) compared to patients with 6-TGN within the therapeutic range (53%) (p = 0.003). A diagnosis of UC, mRNA-1273 vaccine, and other treatments than TNFi + thiopurines were associated with humoral response. Conclusions Patients with CD had an attenuated humoral response to SARS-COV-2 vaccination as compared to patients with UC. The lack of association between serum levels of biologics and serologic response indicates vaccination regardless of proximity to drug administration.

• Dorn-Rasmussen, Maria; Buhl, Sine; Brynskov, Jørn; Bay, Jakob T.; Bolstad, Nils & Klausen, Tobias W. [Show all 9 contributors for this article] (2022). Drug Levels Associated With Optimal Discrimination Between Remission and Nonremission and Comparison of Antibody Assays During First Year of Stable Infliximab Maintenance Therapy in Inflammatory Bowel Disease. Therapeutic Drug Monitoring. ISSN 0163-4356. 44(2), p. 290–300. doi: 10.1097/FTD.0000000000000913. Full text in Research Archive Show summary

  Background: To implement therapeutic drug monitoring–based strategies for infliximab (IFX) in inflammatory bowel disease, the authors assessed IFX levels for optimal discrimination between remission and nonremission and compared assays for anti-IFX antibodies (Abs). Methods: The retrospective cohort comprised 163 bionaive patients with inflammatory bowel disease who received stable IFX maintenance therapy (5 mg/kg every 8 weeks [q8w]) for 1 year. The clinical and biochemical remission status was assessed at all infusions (weeks 14-22-30-38-46-54), and IFX and anti-IFX Abs were estimated using a time-resolved fluorometric assay (n = 690; 88% of infusions). Samples positive for anti-IFX Abs or IFX levels < limit of detection (n = 102) were analyzed by 2 binding assays [enzyme-linked immunosorbent assay (ELISA)] and functional reporter gene assay/drug-tolerant enzyme immunoassay. Results: At all assessed time points, IFX levels were more than double in patients presenting clinical or biochemical remission. An IFX concentration of 4.5 mcg/mL was associated with clinical remission during the entire first year of therapy [sensitivity 54% (49–59), specificity 73% (67–78), AUCROC 0.65 (0.60–0.69), P < 0.0001]; these values were comparable with biochemical remission. Exploratory assessments for endoscopic remission (n = 131) were performed at the discretion of the treating physician. Anti-IFX Abs were associated with undetectable IFX and treatment failure [OR 2.9 (1.4–6.0), P < 0.01], irrespective of persistency or transiency. All performed assays detected anti-IFX Abs were picked up by all assays in ∼2/3 of samples. Binding assays demonstrated a higher sensitivity to anti-IFX Abs. Conclusions: IFX at ∼5 mcg/mL was associated with clinical and biochemical remission during the first year of maintenance therapy. During this phase of therapy, standard binding assays are appropriate for therapeutic drug monitoring.

• Brun, Marthe Kirkesæther; Goll, Guro Løvik; Jørgensen, Kristin Kaasen; Sexton, Joseph; Gehin, Johanna Elin & Sandanger, Øystein [Show all 15 contributors for this article] (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), p. 477–491. doi: 10.1111/joim.13495. Full text in Research Archive Show summary

  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.

• Klaasen, Rolf; Warren, David; Iversen, Rasmus; Bolstad, Nils; Andersen, Ina Lervåg & Mjønes, Patricia [Show all 10 contributors for this article] (2022). The development and validation of a high-capacity serological assay for celiac disease. Clinical Biochemistry. ISSN 0009-9120. 107, p. 13–18. doi: 10.1016/j.clinbiochem.2022.05.010. Full text in Research Archive Show summary

  Background The aim of the present study was to develop and clinically validate a high-throughput assay for serum IgA and IgG antibodies against transglutaminase-2 (TG2) and to determine appropriate assay cut-offs for large-scale population screening for celiac disease. Method An automated method was developed using dual label time-resolved fluorometry on the AutoDELFIA platform. Individuals (n = 1920) from the general population were screened. Subjects with serum anti-TG2 concentrations above a preliminary cut-off (>0.3 mg*/L anti-TG2 IgA or >0.5 mg*/L anti-TG2 IgG) were offered endoscopic examination and biopsy. A diagnosis of celiac disease was given if villous atrophy (Marsh grade 3) was found. Results The assay had a limit of quantification of 0.25 mg*/L (anti-TG2 IgA) and 0.60 mg*/L (anti-TG2 IgG) with imprecision (CV) < 16% and <18% respectively. A total of 66 individuals were above the preliminary cut-off, and 56 underwent endoscopy. Of these, 26 were diagnosed with celiac disease. Sixty-eight percent of subjects with anti-TG2 IgA ≥ 0.7 mg*/L or anti-TG2 IgG ≥ 1.0 mg*/L had biopsy-proven celiac disease, and utilization of these higher cut-offs identified 96% of biopsy-positive patients. At the time of endoscopy, all individuals with anti-TG2 IgA > 2.0 mg*/L had celiac disease, and this cut-off identified 88% of newly diagnosed celiac patients. Eight percent (2/26) of the newly diagnosed patients had primarily anti-TG2 IgG. Conclusions In this study we developed and clinically validated a robust and automated assay suitable for celiac disease screening in the general population.

• Gehin, Johanna Elin; Goll, Guro Løvik; Brun, Marthe Kirkesæther; Jani, Meghna; Bolstad, Nils & Syversen, Silje Watterdal (2022). Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine. BioDrugs. ISSN 1173-8804. 36, p. 731–748. doi: 10.1007/s40259-022-00559-1. Full text in Research Archive Show summary

  Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.

• Syversen, Silje Watterdal; Jørgensen, Kristin Kaasen; Goll, Guro Løvik; Brun, Marthe Kirkesæther; Sandanger, Øystein & Hammersbøen, Kristin Reine [Show all 33 contributors for this article] (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), p. 2375–2384. doi: 10.1001/jama.2021.21316. Full text in Research Archive Show summary

  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 [Show all 33 contributors for this article] (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), p. 1744–1754. doi: 10.1001/jama.2021.4172. Full text in Research Archive Show summary

  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.

• Gehin, Johanna Elin; Warren, David; Syversen, Silje Watterdal; Lie, Elisabeth; Sexton, Joseph & Loli, Liz Paucar [Show all 11 contributors for this article] (2021). Serum golimumab concentration and anti-drug antibodies are associated with treatment response and drug survival in patients with inflammatory joint diseases: data from the NOR-DMARD study. Scandinavian Journal of Rheumatology. ISSN 0300-9742. 50(6), p. 445–454. doi: 10.1080/03009742.2021.1875040. Full text in Research Archive Show summary

  Objectives: This study aimed to identify the therapeutic target concentration and frequency of anti-drug antibodies (ADAbs) in golimumab-treated patients with inflammatory joint disease (IJD). Method: Associations between golimumab concentration, ADAbs, and treatment response were examined in 91 patients with IJD [41 axial spondyloarthritis (axSpA), 20 rheumatoid arthritis (RA), and 30 psoriatic arthritis (PsA)] included in the NOR-DMARD study. Treatment response was defined by Ankylosing Spondylitis Disease Activity Score (ASDAS) clinically important improvement in axSpA, European League Against Rheumatism (EULAR) good/moderate response in RA, and improvement of ≥ 50% in modified Disease Activity index for PSoriatic Arthritis (DAPSA) (28 swollen/tender joint counts) in PsA. Serum drug concentrations and ADAbs were analysed using automated in-house assays. Results: At inclusion, 42% were biological disease-modifying anti-rheumatic drug naïve and 42% used concomitant synthetic disease-modifying anti-rheumatic drug. The median golimumab concentration was 2.2 (interquartile range 1.0–3.5) mg/L. The proportions of responders after 3 months among patients with golimumab concentration < 1.0, 1.0–3.9, and ≥ 4.0 mg/L were 19%, 49%, and 74%, respectively. A higher rate of treatment discontinuation was seen in patients with serum golimumab concentration < 1.0 compared to ≥ 1.0 mg/L (hazard ratio 3.3, 95% confidence interval 1.8–6.0, p < 0.05). ADAbs were detected in 6%, and were associated with lower drug concentrations and both reduced treatment response and drug survival. Conclusions: Golimumab concentrations ≥ 1.0 mg/L were associated with improved treatment response and better drug survival, although some patients may benefit from higher concentrations. This study suggests a rationale for dosing guided by therapeutic drug monitoring in golimumab-treated patients with IJD. The results should be confirmed in larger studies including trough samples, and the efficacy of such a strategy must be examined in randomized controlled trials.

• Gehin, Johanna Elin; Klaasen, Rolf; NORLI, ELLEN SAUAR; Warren, David; Syversen, Silje Watterdal & Goll, Guro Løvik [Show all 10 contributors for this article] (2021). Rheumatoid factor and falsely elevated results in commercial immunoassays: data from an early arthritis cohort. Rheumatology International. ISSN 0172-8172. 41, p. 1657–1665. doi: 10.1007/s00296-021-04865-9. Full text in Research Archive Show summary

  The aim of the study was to assess RF cross-reactivity to animal antibodies used in immunoassays, and to test if selected commercial immunoassays are vulnerable to interference from RF, causing false test results. Our study included samples from patients with RF-positive rheumatoid arthritis (RA) and controls (patients with RF-negative RA and psoriatic arthritis), included in an early arthritis-cohort. Reactivity to mouse IgG1, mouse IgG2a, rabbit IgG, bovine IgG, sheep/goat IgG and human IgG was analysed using in-house interference assays. RF-positive sera with strong reactivity to mouse IgG1 were analysed in three commercial immunoassays. To reveal interference, results before and after addition of blocking aggregated murine IgG1 were compared. Samples from 124 RF-positive RA patients and 66 controls were tested. We found considerably stronger reactivity toward animal antibodies, particularly mouse IgG1 (73% vs. 12%) and rabbit IgG (81% vs. 6%), in sera from RF-positive RA-patients compared to controls (p < 0.001). After selecting samples for testing in commercial assays, interference was revealed in 6/30 sera in the Architect β-hCG assay, 7/10 sera in the 27-plex cytokine assays, and in 2/33 samples in the Elecsys Soluble Transferrin Receptor assay. Our study revealed considerable RF reactivity to animal antibodies used in immunoassays and RF was associated with falsely elevated results in immunoassays used in clinical care and research. Clinicians, laboratorians, researchers and assay manufacturers must be alert to the risk of falsely elevated test results in RF-positive RA patients.

• Gehin, Johanna Elin; Syversen, Silje Watterdal; Warren, David; Goll, Guro Løvik; Sexton, Joseph & Bolstad, Nils [Show all 7 contributors for this article] (2021). Serum etanercept concentrations in relation to disease activity and treatment response assessed by ultrasound, biomarkers and clinical disease activity scores: results from a prospective observational study of patients with rheumatoid arthritis. RMD Open. 7(3), p. 1–9. doi: 10.1136/rmdopen-2021-001985. Full text in Research Archive Show summary

  Objectives: To identify the therapeutic range for etanercept and to assess the incidence of anti-etanercept antibody formation. Methods: Associations between etanercept serum concentration and disease activity as well as treatment response were examined in a longitudinal observational study of rheumatoid arthritis patients starting etanercept. Disease activity was assessed by ultrasound (grey scale and power Doppler), 28-joint Disease Activity Score (DAS28), Simplified Disease Activity Index, plasma calprotectin and C reactive protein. Etanercept concentration and anti-etanercept antibodies were analysed using automated in-house fluorescence assays. Results: A total of 89 patients were included, whereof 66% were biological disease-modifying antirheumatic drug (DMARD) naïve and 91% used concomitant synthetic DMARD. At 3 months, the median etanercept concentration was 1.8 (IQR 1.1-2.5) mg/L. Longitudinal associations were found between etanercept concentration and disease activity assessed by plasma calprotectin, C reactive protein and DAS28, but not between etanercept concentration and improvement in disease activity by any of the parameters at 3, 6 or 12 months of treatment. Etanercept concentrations were not significantly different among patients who achieved response or remission, compared with non-response or non-remission. Hence, no therapeutic range could be identified. None of the patients developed anti-etanercept antibodies. Conclusion: Despite the use of sensitive and objective markers of inflammation, a therapeutic range could not be identified for etanercept. Hence, this study suggests that proactive therapeutic drug monitoring is unlikely to benefit rheumatoid arthritis patients treated with etanercept, but a potential benefit in certain clinical situations cannot be excluded.

• Yang, Mingyi; Lin, Xiaolin; Segers, Filip; Suganthan, Rajikala; Hildrestrand, Gunn Annette & Rinholm, Johanne Egge [Show all 21 contributors for this article] (2020). OXR1A, a Coactivator of PRMT5 Regulating Histone Arginine Methylation. Cell reports. 30(12), p. 4165–4178. doi: 10.1016/j.celrep.2020.02.063. Full text in Research Archive Show summary

  Oxidation resistance gene 1 (OXR1) protects cells against oxidative stress. We find that male mice with brain-specific isoform A knockout (Oxr1A−/−) develop fatty liver. RNA sequencing of male Oxr1A−/− liver indicates decreased growth hormone (GH) signaling, which is known to affect liver metabolism. Indeed, Gh expression is reduced in male mice Oxr1A−/− pituitary gland and in rat Oxr1A−/− pituitary adenoma cell-line GH3. Oxr1A−/− male mice show reduced fasting-blood GH levels. Pull-down and proximity ligation assays reveal that OXR1A is associated with arginine methyl transferase PRMT5. OXR1A-depleted GH3 cells show reduced symmetrical dimethylation of histone H3 arginine 2 (H3R2me2s), a product of PRMT5 catalyzed methylation, and chromatin immunoprecipitation (ChIP) of H3R2me2s shows reduced Gh promoter enrichment. Finally, we demonstrate with purified proteins that OXR1A stimulates PRMT5/MEP50-catalyzed H3R2me2s. Our data suggest that OXR1A is a coactivator of PRMT5, regulating histone arginine methylation and thereby GH production within the pituitary gland.

• Hager, Helle Borgstrøm; Bolstad, Nils; Warren, David; Ness, Marianne Vindal; Seierstad, Birgitte & Lindberg, Morten (2020). Falsely markedly elevated 25-hydroxyvitamin D in patients with monoclonal gammopathies. Clinical Chemistry and Laboratory Medicine. ISSN 1434-6621. 59(4), p. 663–669. doi: 10.1515/cclm-2020-1411. Full text in Research Archive Show summary

  Objectives Monoclonal immunoglobulins can cause interference in many laboratory analyses. During a 4 month period we observed seven patients with monoclonal disease and falsely extremely elevated 25-hydroxyvitamin D (25(OH)D) results above 160 ng/mL (>400 nmol/L) measured using an immunoassay from Abbott Diagnostics. Based on these findings, we studied the occurrence of falsely elevated 25(OH)D in samples with paraproteins and investigated possible mechanisms of the observed interference. Methods 25(OH)D was analyzed using the Architect i2000 platform from Abbott Diagnostics and a higher order method, liquid chromatography-mass spectrometry (LC-MS/MS), in serum samples from 50 patients with known monoclonal disease. Patients with falsely elevated 25(OH)D were included in further studies to elucidate the cause of interference. Spuriously elevated results were in addition analyzed on two alternative platforms (Siemens and Roche). Results Falsely elevated 25(OH)D levels were present in eight patients on the Abbott analyzer and one on the Siemens platform. Results from Roche were comparable with LC-MS/MS. Additional investigations excluded elevated concentrations of rheumatoid factor and heterophilic antibodies as the cause of interference in the Abbott assay. Conclusions Laboratories should be aware of the risk of falsely elevated 25(OH)D in samples run on the Architect analyzer from patients with monoclonal disease. Highly elevated vitamin D results should be diluted and if the dilution is non-linear, rerun by a different method, preferably LC-MS/MS. In patients with spuriously elevated 25(OH)D without known monoclonal disease, the laboratory should consider requesting protein electrophoresis to exclude paraprotein interference.

• Kolstad, Arne; Illidge, Tim; Bolstad, Nils; Spetalen, Signe; Madsbu, Ulf Erik & Stokke, Caroline [Show all 19 contributors for this article] (2020). Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma. Blood Advances. ISSN 2473-9529. 4(17), p. 4091–4101. doi: 10.1182/bloodadvances.2020002583. Full text in Research Archive Show summary

  For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20-based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the "cold" anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

• Syversen, Silje Watterdal; Goll, Guro Løvik; Jørgensen, Kristin Kaasen; Olsen, Inge Christoffer; Sandanger, Øystein & Gehin, Johanna Elin [Show all 13 contributors for this article] (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. Full text in Research Archive Show summary

  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 [Show all 27 contributors for this article] (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, p. 1–14. doi: 10.1186/s12891-020-03720-5. Full text in Research Archive Show summary

  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.

• Randel, Kristin Ranheim; Schult, Anna Lisa; Botteri, Edoardo; Hoff, Geir; Bretthauer, Michael & Ursin, Giske [Show all 20 contributors for this article] (2020). Colorectal cancer screening with repeated fecal immunochemical test versus sigmoidoscopy: baseline results from a randomized trial. Gastroenterology. ISSN 0016-5085. 160(4), p. 1085–1096. doi: 10.1053/j.gastro.2020.11.037. Full text in Research Archive Show summary

  Background and aims: The comparative effectiveness of sigmoidoscopy and fecal immunochemical testing (FIT) for colorectal cancer (CRC) screening is unknown. Methods: Individuals aged 50-74 years living in South-East Norway were randomly invited between 2012 and 2019 to either once-only flexible sigmoidoscopy or FIT screening every second year. Colonoscopy was recommended after sigmoidoscopy if any polyp ≥10 mm, ≥ three adenomas, any advanced adenomas, or CRC was found or subsequent to FIT > 15 μg hemoglobin/g feces. Data for this report were obtained after complete recruitment in both groups and included two full FIT rounds and part of the third round. Outcome measures were participation, neoplasia detection, and adverse events. Age-standardized detection rates and age-adjusted odds ratios (OR) were calculated. Results: We included 139,291 individuals; 69,195 randomized to sigmoidoscopy and 70,096 to FIT. Participation rate was 52% for sigmoidoscopy, 58% in the first FIT round and 68% for three cumulative FIT rounds. Compared to sigmoidoscopy, detection rate for CRC was similar in the first FIT round (0.25% vs 0.27%, OR 0.92, 95% CI 0.75-1.13), but higher after three FIT rounds (0.49% vs 0.27%, OR 1.87, 95% CI 1.54-2.27). Advanced adenoma detection rate was lower in the first FIT round compared to sigmoidoscopy, 1.4% vs 2.4% (OR 0.57, 95% CI 0.53-0.62), but higher after three cumulative FIT rounds, 2.7% vs 2.4% (OR 1.14, 95% CI 1.05-1.23). There were 33 (0.05%) serious adverse events in the sigmoidoscopy group compared to 47 (0.07%) in the FIT group (p =.13). Conclusion: Participation was higher and more CRC and advanced adenomas were detected with repeated FIT compared to sigmoidoscopy. The risk of perforation and bleeding was comparable. Clinicaltrials.gov (NCT01538550).

• Buhl, Sine; Dorn-Rasmussen, Maria; Brynskov, Jørn; Ainsworth, Mark A.; Bendtzen, Klaus & Klausen, Pia Helene [Show all 9 contributors for this article] (2020). Therapeutic thresholds and mechanisms for primary non-response to infliximab in inflammatory bowel disease. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 55(8), p. 884–890. doi: 10.1080/00365521.2020.1786852. Full text in Research Archive Show summary

  Background Primary non-response to infliximab (IFX) inherits a poor prognosis in inflammatory bowel disease (IBD). We explored underlying mechanisms and therapeutic thresholds in an effort to provide basis for optimizing therapy. Methods A prospectively followed cohort of 166 IBD patients having received standard IFX induction therapy (5 mg/kg at weeks 2, 6, and 14) had trough IFX and anti-IFX antibodies (Abs) retrospectively assessed at weeks 2 (n = 148) and 6 (n = 108). Circulating TNFα was measured in matched primary non-responders (n = 29) and responders (n = 21) at baseline and weeks 6 and 14. Clinical outcome at week 14 was supported by disease activity scores in half of patients. Results In all, 18 patients (11%) had primary non-response. Infliximab was consistently lower throughout the induction phase in non-responders as compared to responders (Week 2: IFX median 18.9 μg/mL vs. 23.3, p < .05. Week 6: 8.4 vs. 17.0, p < .05). Optimal IFX thresholds associated with response was 22.9 μg/mL at week 2 (sensitivity 51%, specificity 80%, AUCROC 0.67, p < .05) and 11.8 at week 6 (72%, 77%, 0.71, p < .05). Anti-IFX Abs occurred in 28% of primary non-responders and associated with low IFX and treatment failure (OR 13.7 [2.8–67.5], p < .01). Markers of disease activity (disease activity scores, albumin, CRP) also associated with low IFX. Circulating TNFα was higher throughout induction in non-responders with ulcerative colitis but not Crohn’s disease. Conclusion IBD patients with primary IFX failure generally have lower IFX trough than responders during early induction phase. Pharmacokinetic failure seems common in ulcerative colits, whereas pharmacodynamic failure appears common in Crohn’s disease.

• Grišić, Ana-Marija; Dorn-Rasmussen, Maria; Ungar, Bella; Brynskov, Jørn; Ilvemark, Johan F K F & Bolstad, Nils [Show all 12 contributors for this article] (2020). Infliximab clearance decreases in the second and third trimesters of pregnancy in inflammatory bowel disease. United European Gastroenterology Journal (UEG Journal). ISSN 2050-6406. doi: 10.1177/2050640620964619. Full text in Research Archive Show summary

  Background Infliximab therapy during pregnancy in inflammatory bowel disease is challenged by a dilemma between maintaining adequate maternal disease control while minimizing fetal infliximab exposure. We investigated the effects of pregnancy on infliximab pharmacokinetics. Methods The study population comprised 23 retrospectively identified pregnancies. Patients with inflammatory bowel disease were generally in clinical remission at pregnancy conception (74%) and received steady infliximab maintenance therapy (5 mg/kg q8w n = 17; q6w n = 4; q10w n = 1; 10 mg/kg q8w n = 1). Trough blood samples had been obtained in the same patients prior to pregnancy (n = 119), the first trimester (n = 16), second trimester (n = 18), third trimester (n = 7), and postpregnancy (n = 12). Data were analyzed using nonlinear mixed‐effects population pharmacokinetic modeling. Results Dose‐normalized infliximab concentrations were significantly higher during the second trimester (median 15 mg/ml/kg, interquartile range 10–21) compared to prepregnancy (7, 2–12; p = 0.003), the first trimester (9, 1–12; p = 0.04), or postpregnancy (6, interquartile range 3–11; p > 0.05) in patients with inflammatory bowel disease. Similar trends were observed in the third trimester (13, 7–36; p > 0.05). A one‐compartment model with linear elimination described the pharmacokinetics of infliximab (volume of distribution n = 18.2 L; clearance 0.61 L/day). Maternal infliximab exposure was influenced by the second and third trimester of pregnancy and anti‐infliximab antibodies, and not by pregnancy‐imposed physiological changes in, for example, body weight or albumin. Infliximab clearance decreased significantly during the second and third trimesters by up to 15% as compared to pre‐ and postpregnancy and the first trimester. The increased maternal infliximab exposure was weakly associated with lowered clinical disease activity. Pharmacokinetic model simulations of virtual patients indicated the increased maternal infliximab trough concentrations imposed by pregnancy will not completely counteract the decrease in infliximab concentration if therapy is paused in the third trimester. Conclusion Infliximab clearance decreases significantly in the second and third trimesters, leading to increasing maternal infliximab concentrations in any given regimen. Maternal infliximab levels may thus be maintained as constant in a de‐intensified regimen by therapeutic drug monitoring guidance in inflammatory bowel disease.

• Mitlid-Mork, Birgitte; Bowe, Sophie; Gran, Jon Michael; Bolstad, Nils; Berg, Jens Petter & Redman, Christopher W.G. [Show all 8 contributors for this article] (2020). Maternal placental growth factor and soluble fms-like tyrosine kinase-1 reference ranges in post-term pregnancies: A prospective observational study. PLOS ONE. 15:e0240473(10), p. 1–14. doi: 10.1371/journal.pone.0240473. Full text in Research Archive Show summary

  Background Post-term pregnancies have increased risks for adverse fetal and maternal outcomes. Maternal concentrations of the placenta-associated proteins placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) have been identified as predictors for preeclampsia and fetal growth restriction, both syndromes of placental dysfunction. We have proposed that low maternal circulating PlGF and increased sFlt-1 are general markers for syncytiotrophoblast stress, which increases at and beyond term, even in apparently uncomplicated pregnancies. Our aim was to establish circulating PlGF, sFlt-1, and sFlt-1/PlGF reference ranges in healthy post-term pregnancies (gestational week ≥40+2), comparing with healthy term pregnancies and evaluating associations between time to delivery and biomarker percentiles. Methods Of 501 healthy, singleton post-term pregnancies prospectively recruited between September 2016 and December 2017 at our tertiary obstetric department, 426 with an uncomplicated delivery outcome contributed PlGF and sFlt-1 serum concentrations for reference range construction. A retrospective, cross-sectional, term group with an uncomplicated delivery outcome (n = 146) served as comparison. Differences in percentile values between groups and confidence intervals were calculated by quantile regression. Results In post-term pregnancies the 5th, 50th, and 95th percentiles for PlGF were: 70, 172, and 496 pg/mL; for sFlt-1: 2074, 4268, and 9141 pg/mL; and for sFlt-1/PlGF 5.3, 25.5, and 85.2. Quantile regression analyses comparing the post-term to the term group showed for PlGF a trend towards higher 10th through 30th percentiles, for sFlt-1 significantly higher 10th through 80th percentiles, and for sFlt-1/PlGF ratio significantly higher 30th percentile and significantly lower 95th percentile. PlGF below the 5th percentile and sFlt-1/PlGF ratio above the 95th percentile was associated with shorter time to delivery (p = 0.031 and p = 0.025, respectively). Conclusions Our findings support the concept of increasing syncytiotrophoblast stress post-term in clinically healthy pregnancies. Whether post-term dysregulated angiogenic markers reflect a biological placental clock merits further investigation.

• Jørgensen, Kristin Kaasen; Goll, Guro Løvik; Sexton, Joseph; Bolstad, Nils; Olsen, Inge Christoffer & Asak, Øivind Wessel [Show all 29 contributors for this article] (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), p. 681–694. doi: 10.1007/s40259-020-00438-7. Full text in Research Archive Show summary

  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.

• Salminen, Liina; Nadeem, Nimrah; Rolfsen, Anne Lone Denny; Dørum, Anne; Laajala, Teemu D & Grénman, Seija [Show all 17 contributors for this article] (2020). Exploratory Analysis of CA125-MGL and -STn Glycoforms in the Differential Diagnostics of Pelvic Masses. The Journal of Applied Laboratory Medicine (JALM). ISSN 2576-9456. 5(2), p. 263–272. doi: 10.1093/jalm/jfz012. Full text in Research Archive
• Klaasen, Rolf; Egeland, Erlend Johannessen; Chan, Wai Joe; Midtvedt, Karsten; Svensson, My Hanna Sofia & Bolstad, Nils [Show all 12 contributors for this article] (2019). A Fully Automated Method for the Determination of Serum Belatacept and Its Application in a Pharmacokinetic Investigation in Renal Transplant Recipients. Therapeutic Drug Monitoring. ISSN 0163-4356. 41(1), p. 11–18. doi: 10.1097/FTD.0000000000000580. Full text in Research Archive
• Gehin, Johanna Elin; Goll, Guro Løvik; Warren, David John; Syversen, Silje Watterdal; Sexton, Joseph & Strand, Eldri Kveine [Show all 9 contributors for this article] (2019). Associations between certolizumab pegol serum levels, anti-drug antibodies and treatment response in patients with inflammatory joint diseases: data from the NOR-DMARD study. Arthritis Research & Therapy. ISSN 1478-6354. 21, p. 1–10. doi: 10.1186/s13075-019-2009-5. Full text in Research Archive Show summary

  Objectives To identify a therapeutic target interval for certolizumab pegol drug levels and examine the influence of anti-drug antibodies in patients with inflammatory joint diseases. Methods Certolizumab pegol and anti-drug antibody levels were measured in serum samples collected after 3 months of certolizumab pegol treatment in 268 patients with inflammatory joint diseases (116 axial spondyloarthritis, 91 rheumatoid arthritis and 61 psoriatic arthritis) in the NOR-DMARD study. Treatment response was defined by Ankylosing Spondylitis Disease Activity Score Clinically important improvement in axial spondyloarthritis, European League Against Rheumatism good/moderate response in rheumatoid arthritis, and improvement in 28-joint Disease Activity Score of ≥ 0.6 in PsA. Serum drug levels and anti-drug antibodies were analysed using automated in-house assays. Results Certolizumab pegol serum levels varied considerably between individuals (median (IQR) 32.9 (17.3–43.9) mg/L). Certolizumab pegol level ≥ 20 mg/L was associated with treatment response for the total inflammatory joint disease population, with odds ratio (OR) 2.3 (95% CI 1.2–4.5, P = 0.01) and OR 1.9 (95% CI 1.0–3.5, P = 0.05) after 3 and 6 months of treatment, respectively. For individual diagnoses, this association was most consistent for axial spondyloarthritis, with OR 3.4 (95% CI 1.0–11.1, P < 0.05) and OR 3.3 (95% CI 1.0–10.8, P < 0.05), respectively. Certolizumab pegol level > 40 mg/L was not associated with any additional benefit for any of the diagnoses. Anti-drug antibodies were detected in 6.1% (19/310) of samples and were associated with low certolizumab pegol levels (P < 0.01). Conclusions Serum certolizumab pegol levels 20–40 mg/L were associated with treatment response in inflammatory joint diseases. Our study is the first to show this association in axial spondyloarthritis and psoriatic arthritis patients. The results suggest a possible benefit of therapeutic drug monitoring in patients with inflammatory joint disease on certolizumab pegol treatment.

• Carlsen, Arne; Omdal, Roald; Karlsen, Lars Normann; Kvaløy, Jan Terje; Aabakken, Lars & Steinsbø, Øyvind [Show all 10 contributors for this article] (2019). Determination of lower cut-off levels of adalimumab associated with biochemical remission in Crohn's disease. Journal of Gastroenterology and Hepatology Open (JGH Open). p. 1–7. doi: 10.1002/jgh3.12266. Full text in Research Archive Show summary

  Background and Aim: Adalimumab is administered and dosed using a standardized treatment regimen. Although therapeutic drug monitoring (TDM) may help optimize treatment efficacy, the lower cut‐off concentration of adalimumab needed to retain disease remission has not been established. This cross‐sectional study of patients with Crohn's disease on stable medication aimed to determine a lower therapeutic drug concentration threshold of adalimumab associated with biochemical disease remission. Methods: C‐reactive protein (CRP) and fecal calprotectin were used as established markers and albumin as an explorative marker of disease activity. Time since introduction, treatment interval, drug dosage, serum drug concentration and antidrug antibodies, disease duration, age, and sex were recorded. Results: The study included 101 patients who were divided into “active disease” and “remission” groups for inflammatory markers based on cut‐off levels of 5 mg/L for CRP and 50 mg/kg for fecal calprotectin. Cut‐off levels for albumin of 36.5 and 41.5 g/L were also added as further indicatives of remission. Receiver operating characteristic analysis found optimal thresholds for adalimumab associated with remission at 6.8–7.0 mg/L for the combination of CRP and fecal calprotectin and when combining CRP, fecal calprotectin, and albumin. Conclusions: In patients with Crohn's disease, serum adalimumab of at least 6.8 mg/L was associated with biochemical disease remission based on CRP and fecal calprotectin, supporting the use of TDM to ensure disease control. Albumin should be further tested in this setting.

• Goll, Guro Løvik; Jørgensen, Kristin Kaasen; Sexton, Joseph; Olsen, Inge Christoffer; Bolstad, Nils & Haavardsholm, Espen A. [Show all 48 contributors for this article] (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), p. 653–669. doi: 10.1111/joim.12880. Full text in Research Archive Show summary

  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.

• Buer, Lydia Celine Tansem; Moum, Bjørn; Småstuen, Milada Cvancarova; Warren, David; Bolstad, Nils & Medhus, Asle Wilhelm [Show all 7 contributors for this article] (2018). Real world data on effectiveness, safety and therapeutic drug monitoring of vedolizumab in patients with inflammatory bowel disease. A single center cohort. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. p. 1–9. doi: 10.1080/00365521.2018.1548646. Full text in Research Archive
• Bergan, Stein & Bolstad, Nils (2018). Persontilpasset behandling med biologiske legemidler. Norsk Farmaceutisk Tidsskrift (NFT). ISSN 0029-1935. 126(1), p. 40–43. Full text in Research Archive
• Carlsen, Arne; Omdal, Roald; Leitao, Kristian Øgreid; Isaksen, Kjetil; Hetta, Anne Kristine & Karlsen, Lars Normann [Show all 11 contributors for this article] (2018). Subtherapeutic concentrations of infliximab and adalimumab are associated with increased disease activity in Crohn's disease. Therapeutic Advances in Gastroenterology. ISSN 1756-283X. 11, p. 1–11. doi: 10.1177/1756284818759930. Full text in Research Archive
• Ueland, Thor; Gullestad, Lars; Kou, Lei; Aukrust, Pål; Anand, Inder S. & Nordlund, Marianne Sparby [Show all 10 contributors for this article] (2018). Pro-gastrin-releasing peptide and outcome in patients with heart failure and anaemia: results from the RED-HF study. ESC Heart Failure. p. 1–8. doi: 10.1002/ehf2.12312. Full text in Research Archive Show summary

  <p><i>Aims</i>: Neuroendocrine activation is associated with poor outcome in heart failure (HF). The neuropeptide gastrin‐releasing peptide (GRP), derived from the precursor proGRP1‐125 (proGRP), has recently been implicated in inflammation and wound repair. We investigated the predictive value of proGRP on clinical outcomes in HF patients with reduced ejection fraction.</p> <p><i>Methods and results</i>: The association between plasma proGRP (time‐resolved immunofluorometric assay) and the primary endpoint of death from any cause or first hospitalization for worsening of HF was evaluated using multivariable Cox proportional hazard models in 1541 patients with systolic HF and mild to moderate anaemia, enrolled in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED‐HF) trial. Median proGRP levels in the RED‐HF cohort were markedly increased [95 ng/L (25th, 75th percentile, 69–129 ng/L)] with 64% patients above the 80 ng/L reference limit. Baseline proGRP correlated with estimated glomerular filtration rate (r = 0.52), N terminal pro brain natriuretic peptide (r = 0.33), troponin T (r = 0.34), and haemoglobin (r = 0.16) (all P < 0.001). The incidence outcome increased with increasing tertiles of baseline proGRP (primary endpoint third tertile vs. the lowest tertile; hazard ratio 1.91; 95% confidence interval 1.60–2.28, P < 0.001). However, these associations were markedly attenuated and non‐significant in adjusted models. No interaction between baseline proGRP and the effect of darbepoetin alfa treatment was detected. Moreover, no significant association between changes in proGRP during 6 month follow‐up and outcome was observed.</p> <p><i>Conclusions</i>: Pro‐gastrin‐releasing peptide is increased in patients with HF with reduced ejection fraction and anaemia, in particular in patients with poor renal function. However, proGRP adds little as a prognostic marker on top of conventional HF risk factors.</p>

• Rieber-Mohn, Amalie; Sugulle, Meryam; Wallukat, Gerd; Alnæs-Katjavivi, Patji; Størvold, Gro Leite & Bolstad, Nils [Show all 9 contributors for this article] (2018). Auto-antibodies against the angiotensin II type I receptor in women with uteroplacental acute atherosis and preeclampsia at delivery and several years postpartum. Journal of Reproductive Immunology. ISSN 0165-0378. 128, p. 23–29. doi: 10.1016/j.jri.2018.05.008. Full text in Research Archive Show summary

  Background Uteroplacental acute atherosis is a pregnancy-specific lesion resembling early stages of atherosclerosis found frequently in preeclampsia. Preeclampsia is associated with an increased risk for future maternal atherosclerotic cardiovascular disease. The renin-angiotensin-system plays a role both in atherosclerosis and in preeclampsia. Circulating agonistic autoantibodies at the angiotensin-II type 1 receptor (AT1-AA) are increased in preeclampsia. We hypothesized an association between AT1-AA at delivery and postpartum with acute atherosis in pregnancy. Material and Methods Maternal serum and decidua basalis tissue was collected at elective cesarean section (n = 41; 24 preeclampsia, 17 normotensive controls). Circulating AT1-AA were detected by a bioassay using spontaneously beating rat cardiomyocytes at delivery (n = 41) and 5–8 years postpartum in a subgroup (n = 10). Decidual acute atherosis was assessed by immunohistochemistry. Results Significantly less normotensive controls (18%; 3/17) than women with preeclampsia (58%; 14/24) were AT1-AA positive at delivery, p<0.01. Uteroplacental acute atherosis and circulating AT1-AA at delivery were not significantly correlated. Postpartum, 2 prior preeclamptic women had circulating AT1-AA, both without acute atherosis in pregnancy. Conclusions Our results confirm that circulating AT1-AA are present significantly more often in preeclampsia than in normotensive pregnancy, however without association to acute atherosis. Whether circulating maternal AT1-AA or acute atherosis target young women at increased long-term cardiovascular risk warrants further investigations.

• Høivik, Marte Lie; Buer, Lydia Celine Tansem; Småstuen, Milada Cvancarova; Warren, David; Bolstad, Nils & Moum, Bjørn [Show all 7 contributors for this article] (2018). Switching from originator to biosimilar infliximab?real world data of a prospective 18 months follow-up of a single-centre IBD population. Scandinavian Journal of Gastroenterology. ISSN 0036-5521. 53(6), p. 692–699. doi: 10.1080/00365521.2018.1463391. Full text in Research Archive
• Thomsen, Maria; Skovlund, Eva; Sorbye, Halfdan; Bolstad, Nils; Nustad, Kjell Johannes & Glimelius, Bengt [Show all 12 contributors for this article] (2018). Prognostic role of carcinoembryonic antigen and carbohydrate antigen 19-9 in metastatic colorectal cancer: a BRAF-mutant subset with high CA 19-9 level and poor outcome. British Journal of Cancer. ISSN 0007-0920. 118(12), p. 1609–1616. doi: 10.1038/s41416-018-0115-9. Full text in Research Archive Show summary

  Background Mutation status of RAS and BRAF, as well as serum levels of carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA 19-9), are biomarkers used in clinical management of patients with gastrointestinal cancers. This study aimed to examine the prognostic role of these biomarkers in a patient population that started first-line chemotherapy for unresectable metastatic colorectal cancer (mCRC) in the NORDIC-VII study. Methods CEA and CA 19-9 were measured in serum samples from 545 patients obtained before the start of chemotherapy. Four hundred and ninety-four patients had detectable levels of carbohydrate antigen 19-9 (CA 19-9). RAS (exons 2–4) and BRAF (V600E) mutation status were available from 440 patients. Overall survival (OS) was estimated in patient groups defined by serum CEA or CA 19-9 levels using cut-off values of 5 µg/L and 35 kU/L, respectively, in the total population and in subgroups according to RAS and BRAF mutation status. Results For both CEA and CA 19-9, elevated serum levels were associated with reduced OS in adjusted analyses which included RAS and BRAF mutation status, baseline World Health Organization performance status, and levels of alkaline phosphatase and C-reactive protein. The negative prognostic information provided by an elevated CA 19-9 level was particularly marked in patients with BRAF mutation (hazard ratio = 4.35, interaction P = 0.003, in an adjusted model for OS). Conclusions High baseline serum concentrations of CEA and CA 19-9 provide independent information of impaired prognosis in mCRC. In patients with BRAF-mutant tumours, elevated serum CA 19-9 may identify a subgroup with highly aggressive disease and could contribute to improving therapeutic decisions.

• Smeland, Knut Bjøro; Loge, Jon Håvard; Aass, Hans Christian Dalsbotten; Aspelin, Trude; Bersvendsen, Hanne Skjerven & Bolstad, Nils [Show all 16 contributors for this article] (2018). Chronic fatigue is highly prevalent in survivors of autologous stem cell transplantation and associated with IL-6, neuroticism, cardiorespiratory fitness, and obesity. Bone Marrow Transplantation. ISSN 0268-3369. p. 1–4. doi: 10.1038/s41409-018-0342-y. Full text in Research Archive
• Nome, Ragnhild Veline; Bjøro, Trine; Paus, Elisabeth; Bjerner, Johan; Fosså, Sophie Dorothea & Steen, Rita [Show all 8 contributors for this article] (2017). Lowered reference limits for hCG improve follow-up of patients with hCG-producing tumors. Clinical Biochemistry. ISSN 0009-9120. 52, p. 73–79. doi: 10.1016/j.clinbiochem.2017.11.016. Full text in Research Archive
• Hov, Karen Roksund; Bolstad, Nils; Idland, Ane-Victoria; Zetterberg, Henrik; Blennow, Kaj & Chaudhry, Farrukh Abbas [Show all 10 contributors for this article] (2017). Cerebrospinal Fluid S100B and Alzheimer's Disease Biomarkers in Hip Fracture Patients with Delirium. Dementia and Geriatric Cognitive Disorders Extra. 7(3), p. 374–385. doi: 10.1159/000481853. Full text in Research Archive Show summary

  Objectives: This study aimed to investigate the relationship between cerebrospinal fluid (CSF) S100B astrocyte-derived protein and delirium and to perform stratified analyses according to clinical and CSF markers of dementia. Methods: We performed a prospective cohort study in a university hospital setting. The participants were patients admitted for hip fracture (n = 98) or for elective surgery (n = 50). Delirium was assessed daily perioperatively in hip fracture patients using the Confusion Assessment Method. A consensus-based diagnosis of prefracture dementia was made using all available information. CSF was drawn at the onset of spinal anesthesia. S100B and phosphorylated tau (P-tau) concentrations were measured using electrochemiluminescence immunoassay and enzyme-linked immunosorbent assays, respectively. Results: In the hip fracture population (n = 98) there was no significant difference in CSF S100B concentrations between patients with ongoing preoperative (i.e., prevalent) delirium (n = 36, median [interquartile range] 1.11 μg/L [0.91–1.29]) and patients who never developed delirium (n = 46, 1.08 μg/L [0.92–1.28], p = 0.92). In patients without preoperative delirium, those who developed delirium postoperatively (i.e., incident delirium) (n = 16, 1.38 μg/L [1.08–1.62]) had higher concentrations of S100B than the 46 who never did (p = 0.013). This difference was confined to patients with pathological concentrations of P-tau (≥60 ng/L, n = 38). We also found that P-tau and S100B were correlated in CSF in the elective surgery patients. Conclusions: CSF S100B was elevated in patients with incident delirium who also had pathological levels of the Alzheimer disease biomarker P-tau, suggesting vulnerability caused by a preexisting process of astrocytic activation and tau pathology.

• Salvador, Cathrin Lytomt; Tøndel, Camilla; Rowe, Alexander D.; Bjerre, Anna Kristina; Brun, Atle & Brackman, Damien [Show all 8 contributors for this article] (2017). Renal Function Influences Diagnostic Markers in Serum and Urine: A Study of Guanidinoacetate, Creatine, Human Epididymis Protein 4, and Neutrophil Gelatinase–Associated Lipocalin in Children. The Journal of Applied Laboratory Medicine. ISSN 2374-9679. 2(3), p. 297–308. doi: 10.1373/jalm.2016.022145. Full text in Research Archive
• Bader, Lucius; Solberg, Silje Michelsen; Kaada, Silje Katrine Helland; Bolstad, Nils; Warren, David & Gavasso, Sonia [Show all 8 contributors for this article] (2017). Assays for Infliximab Drug Levels and Antibodies: A Matter of Scales and Categories. Scandinavian Journal of Immunology. ISSN 0300-9475. 86(3), p. 165–170. doi: 10.1111/sji.12572. Full text in Research Archive
• Jørgensen, Kristin Kaasen; Olsen, Inge Christoffer; Goll, Guro Løvik; Lorentzen, Merete; Bolstad, Nils & Haavardsholm, Espen A. [Show all 10 contributors for this article] (2017). Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. The Lancet. ISSN 0140-6736. 389(10086), p. 2304–2316. doi: 10.1016/S0140-6736(17)30068-5. Full text in Research Archive Show summary

  Background TNF inhibitors have improved treatment of Crohn's disease, ulcerative colitis, spondyloarthritis, rheumatoid arthritis, psoriatic arthritis, and chronic plaque psoriasis, but are expensive therapies. The aim of NOR-SWITCH was to examine switching from originator infliximab to the less expensive biosimilar CT-P13 regarding efficacy, safety, and immunogenicity. Methods The study is a randomised, non-inferiority, double-blind, phase 4 trial with 52 weeks of follow-up. Adult patients on stable treatment with infliximab originator treated in a hospital setting for at least 6 months were eligible for participation. Patients with informed consent were randomised in a 1:1 ratio to either continued infliximab originator or to switch to CT-P13 treatment, with unchanged dosing regimen. Data were collected at infusion visits in 40 Norwegian study centres. Patients, assessors, and patient care providers were masked to treatment allocation. The primary endpoint was disease worsening during 52-week follow-up. 394 patients in the primary per-protocol set were needed to show a non-inferiority margin of 15%, assuming 30% disease worsening in each group. This trial is registered with ClinicalTrials.gov, number NCT02148640. Findings Between Oct 24, 2014, and July 8, 2015, 482 patients were enrolled and randomised (241 to infliximab originator, 241 to CT-P13 group; one patient was excluded from the full analysis and safety set for CT-P13) and 408 were included in the per-protocol set (202 in the infliximab originator group and 206 in the CT-P13 group). 155 (32%) patients in the full analysis set had Crohn's disease, 93 (19%) had ulcerative colitis, 91 (19%) had spondyloarthritis, 77 (16%) had rheumatoid arthritis, 30 (6%) had psoriatic arthritis, and 35 (7%) had chronic plaque psoriasis. Disease worsening occurred in 53 (26%) patients in the infliximab originator group and 61 (30%) patients in the CT-P13 group (per-protocol set; adjusted treatment difference −4·4%, 95% CI −12·7 to 3·9). The frequency of adverse events was similar between groups (for serious adverse events, 24 [10%] for infliximab originator vs 21 [9%] for CT-P13; for overall adverse events, 168 [70%] vs 164 [68%]; and for adverse events leading to discontinuation, nine [4%] vs eight [3%], respectively). Interpretation The NOR-SWITCH trial showed that switching from infliximab originator to CT-P13 was not inferior to continued treatment with infliximab originator according to a prespecified non-inferiority margin of 15%. The study was not powered to show non-inferiority in individual diseases.

• Paur, Ingvild; Lilleby, Wolfgang; Bøhn, Siv Kjølsrud; Hulander, Erik; Klein, Willibrord & Vlatkovic, Ljiljana [Show all 19 contributors for this article] (2016). Tomato-based randomized controlled trial in prostate cancer patients: Effect on PSA. Clinical Nutrition. ISSN 0261-5614. 36(3), p. 672–679. doi: 10.1016/j.clnu.2016.06.014. Full text in Research Archive Show summary

  Background & aims: The effect of lycopene-containing foods in prostate cancer development remains undetermined. We tested whether a lycopene-rich tomato intervention could reduce the levels of prostate specific antigen (PSA) in prostate cancer patients. Methods: Prior to their curative treatment, 79 patients with prostate cancer were randomized to a nutritional intervention with either 1) tomato products containing 30 mg lycopene per day; 2) tomato products plus selenium, omega-3 fatty acids, soy isoflavones, grape/pomegranate juice, and green/black tea (tomato-plus); or 3) control diet for 3 weeks. Results: The main analysis, which included patients in all risk categories, did not reveal differences in changes of PSA-values between the intervention and control groups. Post-hoc, exploratory analyses within intermediate risk (n = 41) patients based on tumor classification and Gleason score post-surgery, revealed that median PSA decreased significantly in the tomato group as compared to controls (−2.9% and +6.5% respectively, p = 0.016). In separate post-hoc analyses, we observed that median PSA-values decreased by 1% in patients with the highest increases in plasma lycopene, selenium and C20:5 n-3 fatty acid, compared to an 8.5% increase in the patients with the lowest increase in lycopene, selenium and C20:5 n-3 fatty acid (p = 0.003). Also, PSA decreased in patients with the highest increase in lycopene alone (p = 0.009). Conclusions: Three week nutritional interventions with tomato-products alone or in combination with selenium and n-3 fatty acids lower PSA in patients with non-metastatic prostate cancer. Our observation suggests that the effect may depend on both aggressiveness of the disease and the blood levels of lycopene, selenium and omega-3 fatty acids.

• Halvorsen, Ann Rita; Bjaanæs, Maria Moksnes; LeBlanc, Marissa; Holm, Are Martin; Bolstad, Nils & Rubio, Luis [Show all 12 contributors for this article] (2016). A unique set of 6 circulating microRNAs for early detection of non-small cell lung cancer. OncoTarget. 7(24), p. 37250–37259. doi: 10.18632/oncotarget.9363. Full text in Research Archive
• Benterud, Torkil; Pankratov, Leonid; Solberg, Rønnaug; Bolstad, Nils; Skinningsrud, Anders & Baumbusch, Lars Oliver [Show all 8 contributors for this article] (2015). Perinatal asphyxia may influence the level of beta-amyloid (1-42) in cerebrospinal fluid: An experimental study on newborn pigs. PLOS ONE. 10(10). doi: 10.1371/journal.pone.0140966. Full text in Research Archive
• Gislefoss, Randi Elin; Langseth, Hilde; Bolstad, Nils; Nustad, Kjell Johannes & Mørkrid, Lars (2015). HE4 as an Early Detection Biomarker of Epithelial Ovarian Cancer: Investigations in Prediagnostic Specimens from the Janus Serumbank. International Journal of Gynecological Cancer. ISSN 1048-891X. 25(9), p. 1608–1615. doi: 10.1097/IGC.0000000000000532. Full text in Research Archive
• Bolstad, Nils; Warren, David & Nustad, Kjell Johannes (2013). Heterophilic antibody interference in immunometric assays. Baillière's Best Practice & Research. Clinical Endocrinology & Metabolism. ISSN 1521-690X. 27(5), p. 647–661. doi: 10.1016/j.beem.2013.05.011. Full text in Research Archive
• Bolstad, Nils; Øijordsbakken, Miriam; Nustad, Kjell Johannes & Bjerner, Johan (2012). Human epididymis protein 4 reference limits and natural variation in a Nordic reference population. Tumour Biology. ISSN 1010-4283. 33(1), p. 141–148. doi: 10.1007/s13277-011-0256-4. Full text in Research Archive

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• Risnes, Louise Fremgaard; Dahal-Koirala, Shiva; Hjort, Rebecka; Bolstad, Nils; Lundin, Knut & Ness-Jensen, Eivind [Show all 7 contributors for this article] (2025). Detection of gluten-specific CD4+ T cells with tetramer test among anti-transglutaminase seropositive participants in the HUNT4 study. Full text in Research Archive
• Herder, Ingrid; Hetlevik, Siri Opsahl; Gehin, J. E.; Pesonen, Maiju; Lilleby, Vibke & Rygg, Marite [Show all 17 contributors for this article] (2025). PT006 Adalimumab serum levels and associations with disease activity in juvenile idiopathic arthritis. Pediatric Rheumatology. 23(2). Full text in Research Archive
• Holly, T.; Brun, Marthe Kirkesæther; Jørgensen, K.K.; Goll, Guro Løvik; Sexton, Joseph & Gehin, Johanna [Show all 15 contributors for this article] (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. Full text in Research Archive
• Holly, Teresa; Brun, Marthe Kirkesæther; Jørgensen, Kristin Kaasen; Goll, Guro Løvik; Sexton, Joseph & Gehin, Johanna [Show all 16 contributors for this article] (2025). Cost-effectiveness of proactive therapeutic drug monitoring (TDM) in patients with inflmmatory disease-results from the Nor-Drum trial. Full text in Research Archive
• Askeland, Frida Bugge; Frøen, Hege; Bolstad, Nils; Thorsby, Per Medbøe; Schjesvold, Fredrik & Marmion, Anne Cathrine W. [Show all 8 contributors for this article] (2024). Monoclonal Insulin Autoimmune Syndrome Successfully Treated With Plasma Cell Directed Therapy. Clinical Lymphoma, Myeloma & Leukemia. ISSN 2152-2650. doi: 10.1016/j.clml.2024.10.005. Full text in Research Archive
• Dyrli, Ole Thomas; Bolstad, Nils & Ness-Jensen, Eivind (2024). TG2-IgG i screening for cøliaki. Full text in Research Archive
• Lukina, Polina; Andersen, Ina Lervåg; Klaasen, Rolf; Warren, David John; Bolstad, Nils & Sollid, Ludvig Magne [Show all 8 contributors for this article] (2024). Serological signs of coeliac disease in pre-diagnostic samples from a population-based cohort of coeliacs, the Trøndelag Health Study (HUNT), Norway. Full text in Research Archive
• Risnes, Louise Fremgaard; Dahal-Koirala, Shiva; Hjort, Rebecka Louise; Bolstad, Nils; Christophersen, Asbjørn Otto & Sarna, Vikas Kumar [Show all 9 contributors for this article] (2024). Påvisning av glutenspesifikke CD4+ T-celler med tetramertest blant anti-transglutaminase seropositive deltakere i HUNT4-studien. Full text in Research Archive
• Lukina, Polina; Andersen, Ina Lervåg; Klaasen, Rolf; Warren, David John; Bolstad, Nils & Iversen, Rasmus [Show all 9 contributors for this article] (2024). Serologiske tegn på cøliaki i pre-diagnostiske prøver fra en populasjonsbasert kohort av voksne cøliakere, Helseundersøkelsen i Trøndelag (HUNT). Full text in Research Archive
• Dyrli, Ole Thomas; Andersen, Ina Lervåg; Lukina, Polina; Klaasen, Rolf; Bolstad, Nils & Warren, David John [Show all 9 contributors for this article] (2024). Anti-transglutaminase 2 immunoglobulin G in population-based screening for coeliac disease, the Trøndelag Health Study, Norway. United European Gastroenterology Journal (UEG Journal). ISSN 2050-6406. 12, p. 11–12. Full text in Research Archive
• Dyrli, Ole Thomas; Andersen, Ina Lervåg; Lukina, Polina; Klaasen, Rolf; Bolstad, Nils & Warren, David John [Show all 9 contributors for this article] (2024). Anti-transglutaminase 2 immunoglobulin G in population-based screening for coeliac disease, the Trøndelag Health Study, Norway. Full text in Research Archive
• Wammer, Anne Cathrine Parelius; Nermoen, Ingrid; Thorsby, Per Medbøe; Bolstad, Nils; Lima, Kari & Tran, Hoa Thi Tuyet [Show all 7 contributors for this article] (2023). Insulin autoimmune syndrome: not just one but two different diseases with therapeutic implications. Endocrinology, Diabetes and Metabolism Case Reports. 2023(4). doi: 10.1530/EDM-23-0032. Full text in Research Archive Show summary

  We present a young woman with treatment resistant insulin autoimmune syndrome (IAS) with a protracted course. Her serum insulin level was 6945 pmol/l (<160), C-peptide 4042 pmol/L (<1480), anti-insulin antibodies 5305 U/mL (<0.4) were monoclonal IgG kappa. After 12 h of fasting, her blood glucose fell to 1.2 mmol/L. Post-meal blood glucose peaked at 12.2 mmol/L with reactive hypoglycaemia below 2 mmol/L. Frequent meals and continuous blood glucose monitoring were helpful, but further treatments advocated in the literature with prednisolone, rituximab, plasmapheresis, cyclophosphamide and ciclosporin were without beneficial effect. Based on this case and a review of the literature, we propose that IAS is not one but two different diseases with different therapeutic strategies. The first disease, polyclonal IAS, predominates in Asia and is characterized by polyclonal anti-insulin antibodies, association with certain HLA genotypes and other autoimmune conditions, medications and viral infections possibly triggering the disease, a possible female predominance among young patients and a tendency towards spontaneous remission. The other disease, monoclonal IAS, predominates in Caucasians. Typical features are monoclonal anti-insulin antibodies, only weak HLA association, no drug predisposition, no sex difference, rare remission and conventional therapy often being without any clinical effect. We suggest that monoclonal IAS with IgG or IgA anti-insulin antibodies should receive therapy targeting plasma cells rather than lymphocytes.

• Lukina, Polina; Andersen, Ina Lervåg; Klaasen, Rolf Anton; Warren, David; Bolstad, Nils & Sollid, Ludvig Magne [Show all 8 contributors for this article] (2023). SEROLOGICAL SIGNS OF COELIAC DISEASE IN PRE-DIAGNOSTIC SAMPLES FROM A POPULATION-BASED COHORT OF COELIACS, THE TRØNDELAG HEALTH STUDY (HUNT), NORWAY. United European Gastroenterology Journal (UEG Journal). ISSN 2050-6406. 11. Full text in Research Archive
• Lukina, Polina; Andersen, Ina Lervåg; Klaasen, Rolf Anton; Warren, David; Iversen, Rasmus & Mjønes, Patricia Gjertrud [Show all 11 contributors for this article] (2023). THE TOTAL PREVALENCE AND RATE OF UNDIAGNOSED CELIAC DISEASE IN AN ADULT GENERAL POPULATION – THE HUNT STUDY, NORWAY. Gastroenterology. ISSN 0016-5085. 164(6), p. S-218–S-218. Full text in Research Archive
• Bitter, Helle; Warren, David; Bolstad, Nils; Noraas, Anne Lindtner & Østensen, Monika Elisabeth (2023). Transplacental passage of belimumab during pregnancy and follow-up of a child exposed in utero. Annals of the Rheumatic Diseases. ISSN 0003-4967. 82(4), p. 577–579. doi: 10.1136/ard-2022-223684. Full text in Research Archive
• Syversen, Silje Watterdal; Gehin, Johanna; Goll, Guro Løvik; Bolstad, Nils; Haavardsholm, Espen A. & Bakke, Emilie Andrea [Show all 7 contributors for this article] (2023). Therapeutic Drug Monitoring: A Tool to Optimize Treatment of Inflammatory Joint Diseases. Arthritis & Rheumatology. ISSN 2326-5191. doi: 10.1002/art.42764. Full text in Research Archive
• Lukina, Polina; Andersen, Ina Lervåg; Klaasen, Rolf Anton; Warren, David J; Bolstad, Nils & Mjønes, Patricia Gjertrud [Show all 11 contributors for this article] (2023). Prevalensen av cøliaki i den generelle befolkningen (HUNT4). Full text in Research Archive
• Lukina, Polina; Andersen, Ina Lervåg; Klaasen, Rolf Anton; Warren, David; Iversen, Rasmus & Mjønes, Patricia Gjertrud [Show all 11 contributors for this article] (2023). THE TOTAL PREVALENCE AND RATE OF UNDIAGNOSED CELIAC DISEASE IN AN ADULT GENERAL POPULATION – THE HUNT STUDY, NORWAY. Full text in Research Archive
• Lukina, Polina; Andersen, Ina Lervåg; Klaasen, Rolf Anton; Warren, David; Bolstad, Nils & Sollid, Ludvig Magne [Show all 8 contributors for this article] (2023). SEROLOGICAL SIGNS OF COELIAC DISEASE IN PRE-DIAGNOSTIC SAMPLES FROM A POPULATION-BASED COHORT OF COELIACS, THE TRØNDELAG HEALTH STUDY (HUNT), NORWAY. Full text in Research Archive
• Andersen, Ina Lervåg; Klaasen, Rolf Anton; Warren, David; Lukina, Polina; Mjønes, Patricia & Rønne, Elin [Show all 11 contributors for this article] (2022). Screening for adult celiac disease in the general population. Gastroenterology. ISSN 0016-5085. 162(7), p. S-353–S-353. Full text in Research Archive
• Klaasen, Rolf; Warren, David; Iversen, Rasmus; Bolstad, Nils; Andersen, Ina Lervåg & Mjønes, Patricia [Show all 10 contributors for this article] (2022). THE DEVELOPMENT AND VALIDATION OF A HIGH CAPACITY SEROLOGICAL ASSAY FOR CELIAC DISEASE. Full text in Research Archive
• Klaasen, Rolf; Warren, David; Iversen, Rasmus; Bolstad, Nils; Andersen, Ina Lervåg & Mjønes, Patricia [Show all 10 contributors for this article] (2022). THE DEVELOPMENT AND VALIDATION OF A HIGH CAPACITY SEROLOGICAL ASSAY FOR CELIAC DISEASE. Gastroenterology. ISSN 0016-5085. 162(7), p. S-359–S-359. Full text in Research Archive
• Lukina, Polina; Andersen, Ina Lervåg; Klaasen, Rolf; Warren, David; Iversen, Rasmus & Mjønes, Patricia [Show all 11 contributors for this article] (2022). THE PREVALENCE OF COELIAC DISEASE IN THE UNSELECTED GENERAL POPULATION. Full text in Research Archive
• Lukina, Polina; Andersen, Ina Lervåg; Hjort, Rebecka; Eggen, Petter Tinbod; Næss, Marit & Mjønes, Patricia [Show all 20 contributors for this article] (2022). Cøliaki i HUNT. Forekomst, konsekvenser og årsaker. Full text in Research Archive
• Andersen, Ina Lervåg; Klaasen, Rolf; Warren, David; Lukina, Polina; Mjønes, Patricia & Rønne, Elin [Show all 11 contributors for this article] (2022). Screening for cøliaki i den voksne befolkningen. Full text in Research Archive
• Klaasen, Rolf; Warren, David; Iversen, Rasmus; Bolstad, Nils; Andersen, Ina Lervåg & Mjønes, Patricia [Show all 10 contributors for this article] (2022). The development and validation of a high-capacity serological assay for coeliac disease. Full text in Research Archive
• Andersen, Ina Lervåg; Klaasen, Rolf Anton; Warren, David; Lukina, Polina; Mjønes, Patricia & Rønne, Elin [Show all 11 contributors for this article] (2022). SCREENING FOR ADULT COELIAC DISEASE IN THE GENERAL POPULATION. Full text in Research Archive
• Andersen, Ina Lervåg; Klaasen, Rolf Anton; Warren, David; Lukina, Polina; Mjønes, Patricia & Rønne, Elin [Show all 11 contributors for this article] (2021). Screening for adult coeliac disease in the general population. Full text in Research Archive
• Klaasen, Rolf; Warren, David; Iversen, Rasmus; Bolstad, Nils; Andersen, Ina Lervåg & Mjønes, Patricia [Show all 10 contributors for this article] (2021). THE DEVELOPMENT AND VALIDATION OF A HIGH-CAPACITY SEROLOGICAL ASSAY FOR COELIAC DISEASE. Full text in Research Archive
• Klaasen, Rolf; Warren, David; Iversen, Rasmus; Bolstad, Nils; Andersen, Ina Lervåg & Mjønes, Patricia [Show all 10 contributors for this article] (2021). THE DEVELOPMENT AND VALIDATION OF A HIGH-CAPACITY SEROLOGICAL ASSAY FOR COELIAC DISEASE. United European Gastroenterology Journal (UEG Journal). ISSN 2050-6406. 9, p. 348–348. Full text in Research Archive
• Andersen, Ina Lervåg; Klaasen, Rolf; Warren, David; Lukina, Polina; Mjønes, Patricia & Rønne, Elin [Show all 11 contributors for this article] (2021). SCREENING FOR ADULT COELIAC DISEASE IN THE GENERAL POPULATION. United European Gastroenterology Journal (UEG Journal). ISSN 2050-6406. 9, p. 354–355. Full text in Research Archive
• Klaasen, Rolf; Warren, David; Iversen, Rasmus; Bolstad, Nils; Andersen, Ina Lervåg & Mjønes, Patricia [Show all 10 contributors for this article] (2021). THE DEVELOPMENT AND VALIDATION OF A HIGH-CAPACITY SEROLOGICAL ASSAY FOR COELIAC DISEASE. Full text in Research Archive
• Andersen, Ina Lervåg; Klaasen, Rolf; Warren, David; Lukina, Polina; Mjønes, Patricia & Rønne, Elin [Show all 11 contributors for this article] (2021). SCREENING FOR ADULT COELIAC DISEASE IN THE GENERAL POPULATION. Full text in Research Archive
• Glintborg, Bente; Kringelbach, Tina Marie; Bolstad, Nils; Warren, David; Eng, Grith Petersen & Sørensen, Inge Juul [Show all 22 contributors for this article] (2018). Drug concentrations and anti-drug antibodies during treatment with biosimilar infliximab (CT-P13) in routine care. Scandinavian Journal of Rheumatology. ISSN 0300-9742. 47(5), p. 418–421. doi: 10.1080/03009742.2017.1376110. Full text in Research Archive
• Jørgensen, Kristin Kaasen; Christoffer, Olsen Inge; Goll, Guro Løvik; Lorentzen, Merete; Bolstad, Nils & Berset, Ingrid Prytz [Show all 11 contributors for this article] (2017). Biosimilar Infliximab (CT-P13) is not Inferior to Originator Infliximab: Explorative IBD Subgroup-Analyses in Crohn's Disease and Ulcerative Colitis from the Nor-Switch Trial. Gastroenterology. ISSN 0016-5085. 152(5), p. 65–66. doi: 10.1016/S0016-5085(17)30572-3. Full text in Research Archive
• Jørgensen, Kristin Kaasen; Christoffer, Olsen Inge; Goll, Guro Løvik; Lorentzen, Merete; Bolstad, Nils & Berset, Ingrid Prytz [Show all 11 contributors for this article] (2017). Biosimilar infliximab (CT-P13) is not inferior to originator infliximab: explorative IBD subgroup-analyses in Crohn’s disease and ulcerative colitis from the NOR-SWITCH trial. Journal of Crohn's and Colitis. ISSN 1873-9946. 11, p. 62–63. doi: 10.1093/ecco-jcc/jjx002.099. Full text in Research Archive

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