Therapeutic drug monitoring in inflammatory bowel disease : implementation, utilization, and barriers in clinical practice in Scandinavia

Background and aims Therapeutic drug monitoring (TDM) may optimize biologic and thiopurine therapies in inflammatory bowel disease (IBD). The study aimed to investigate implementation and utilization of TDM in Scandinavia. Methods A web-based questionnaire on the use of TDM was distributed to Scandinavian gastroenterologists via the national societies. Results In total, 297 IBD physicians prescribing biologic therapies, equally distributed between community and university hospitals, were included (response rate 42%) (Norway 118 (40%), Denmark 86 (29%), Sweden 50 (17%), Finland 33 (11%), Iceland 10 (3%)). Overall, TDM was applied during biologic therapies by 87%, and for TNF-inhibitors >90%. Among the users, reactive and proactive TDM were utilized by 90% and 63%, respectively. Danish physicians were significantly less inclined to use TDM compared to other Scandinavian countries; (58% vs 98%); OR 0.03 [0.01-0.09], p 10 IBD patients/week (p = 0.005). TDM scenarios were interpreted in accord with available evidence but with discrepancies for proactive TDM. The main barriers to TDM were lack of guidelines (51%) and time lag between sampling and results (49%). TDM of thiopurines was routinely used by 87%. Conclusion TDM of biologic and thiopurine therapies has been broadly implemented into clinical practice in Scandinavia. However, physicians call for TDM guidelines detailing indications and interpretations of test results along with improved test response times.Peer reviewe

The persistence of anti-Spike antibodies following two SARS-CoV-2 vaccine doses in patients on immunosuppressive therapy compared to healthy controls—a prospective cohort study

The durability of vaccine-induced humoral immunity against SARS-CoV-2 in patients with immune mediated inflammatory diseases (IMIDs) on immunosuppressive therapy is not known. The aim of this study was to compare the persistence of anti-Spike antibodies following two-dose SARS-CoV-2 vaccination between IMID patients and healthy controls and to identify factors associated with antibody decline.publishedVersio

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.

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

Dickkopf-1 is associated with periarticular bone loss in patients with rheumatoid arthritis

Objective: To examine whether cytokines shown to suppress osteoblasts, Dickkopf-1 (DKK1) and hepatocyte growth factor (HGF), are associated with periarticular bone loss in rheumatoid arthritis (RA). Methods: RA patients with short disease duration were prospectively followed and hand bone mineral density was assessed by digital X-ray radiogram- metry (DXR) at baseline and after 1, 2 and 5 years. Plasma samples collected at baseline from 136 of the included pa- tients were analyzed for HGF and DKK1. Group comparisons, correlation analyses and multivariate analyses were per- formed to evaluate the relationship between baseline cytokine levels and DXR-BMD. Results: Patients with hand bone loss after 1 year had significantly higher baseline plasma levels of DKK1 than patients without bone loss. Patients with periarticular bone loss after 2 and 5 years had significantly higher baseline plasma levels of HGF. Baseline DKK1 but not HGF levels were independently associated with periarticular bone loss after 1 year. Conclusion: High serum levels of DKK1 are weakly but independently associated with periarticular bone loss in RA. The importance of DKK1 and HGF for loss of periarticular bone needs to be defined in future studies.Copyright © 2013 Berit Grandaunet et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

Rheumatoid factor and falsely elevated results in commercial immunoassays: data from an early arthritis cohort

Abstract 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

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

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

Immunogenicity and safety of a three-dose SARS-CoV-2 vaccination strategy in patients with immune-mediated inflammatory diseases on immunosuppressive therapy

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