Search

Intravenous loading with 500 ml of 2.7% saline increased the clearance of PAH and inulin and urine sodium excretion in 14 healthy subjects. Intravenous propranolol (0.075 and 0.15 mg/kg) did not alter PAH or inulin clearance at rest but abolished the increase expected during saline infusion. There was no consistent effect on urinary sodium excretion. Intravenous nadolol (0.05 and 0.75 mg/kg) reduced resting PAH and inulin clearances by up to 25%. Both clearances fell significantly during saline infusion but natriuresis was not significantly reduced in spite of the changes in renal function. There was no evidence from these studies in normal volunteers that nadolol confers any advantages over propranolol in its effects on renal function. [ABSTRACT FROM AUTHOR]

Acebutolol was administered orally in a single dose of 200 mg to 17 individuals whose renal function varied markedly. The plasma half-life and elimination rate constant for acebutolol showed a four-fold variation but these did not correlate with the degree of renal impairment. However, there was a good correlation between the renal clearance of creatinine and that of acebutolol (P less than 0.001). The half-life and elimination rate of the acetyl metabolite, diacetolol, were subject to 10-fold inter-individual variability which correlated significantly with the creatinine clearance and serum creatinine concentration. The AUC for the acetyl metabolite showed a 40-fold individual variation which also correlated with renal function. It is concluded that renal elimination is the principal route of excretion for diacetolol but not the parent compound, acebutolol. [ABSTRACT FROM AUTHOR]

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 < 4 h. Median drug trough-levels after 5-7 weeks of treatment were 20 (range <1.0-45) mg/L for ipilimumab (n = 113), 60 (range 14-75) mg/L) for nivolumab (n = 21) and 19 (range 7.4-39) mg/L for pembrolizumab (n = 20). Routine drug concentration monitoring for ipilimumab, nivolumab and pembrolizumab is feasible using fully automated analyte capture assays constructed with commercially available reagents. The large drug serum concentration ranges in samples from real-world patients, should be further investigated to assess the clinical relevance of ICI concentration monitoring., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Objective: Fatigue-resistant and graded muscle forces can be evoked through asynchronous intrafascicular multi-electrode stimulation (aIFMS). Prior studies on controlled force generation using aIFMS employed either a feedback controller featuring a multiple-input single-output delayed-integral (MISO-I) control law, or a feedforward controller with a non-predictive model-based policy. However, these controllers resulted in lagged responses as stimulation was coordinated via intentional time delays and lacked immediate control corrections. To address these limitations, this paper presents an adaptive feedforward model predictive controller (aF-MPC) for isometric torque control., Methods: The aF-MPC was evaluated in experiments in anesthetized felines implanted with Utah Slanted Electrode Arrays in their sciatic nerves. This controller redesigned the existing aIFMS feedforward controller by enhancing it with a predictive policy and an online model learning algorithm to compensate for unaccounted aIFMS effects. Statistical comparisons of the aF-MPC and the (non-adaptive) F-MPC trials and observational comparisons of the aF-MPC and the MISO-I controller were performed for different desired trajectories., Results: The aF-MPC exhibited significant performance improvements over the F-MPC across multiple metrics. Observationally, the aF-MPC showed improvements in all performance metrics over the MISO-I controller., Conclusion: Despite unknown dynamics in the aIFMS system, this paper's aF-MPC outperformed alternate approaches as it accurately tracked desired torque profiles even under high-frequency commands., Significance: The application of the aF-MPC in conjunction with aIFMS could provide a better avenue for developing naturalistic motor neuroprosthesis than F-MPCs or MISO-I controllers.

As the clinical applicability of peripheral nerve stimulation (PNS) expands, the need for PNS-specific safety criteria becomes pressing. This study addresses this need, utilizing a novel machine learning and computational bio-electromagnetics modeling platform to establish a safety criterion that captures the effects of fields and currents induced on axons. Our approach is comprised of three steps: experimentation, model creation, and predictive simulation. We collected high-resolution images of control and stimulated rat sciatic nerve samples at varying stimulation intensities and performed high-resolution image segmentation. These segmented images were used to train machine learning tools for the automatic classification of morphological properties of control and stimulated PNS nerves. Concurrently, we utilized our quasi-static Admittance Method-NEURON (AM-NEURON) computational platform to create realistic nerve models and calculate induced currents and charges, both critical elements of nerve safety criteria. These steps culminate in a cellular-level correlation between morphological changes and electrical stimulation parameters. This correlation informs the determination of thresholds of electrical parameters that are found to be associated with damage, such as maximum cell charge density. The proposed methodology and resulting criteria combine experimental findings with computational modeling to generate a safety threshold curve that captures the relationship between stimulation current and the potential for axonal damage. Although focused on a specific exposure condition, the approach presented here marks a step towards developing context-specific safety criteria in PNS neurostimulation, encouraging similar analyses across varied neurostimulation scenarios. Bioelectromagnetics., (© 2025 Bioelectromagnetics Society.)

Objective. Neuroprostheses typically operate under supervised learning, in which a machine-learning algorithm is trained to correlate neural or myoelectric activity with an individual's motor intent. Due to the stochastic nature of neuromyoelectric signals, algorithm performance decays over time. This decay is accelerated when attempting to regress proportional control of multiple joints in parallel, compared with the more typical classification-based pattern recognition control. To overcome this degradation, neuroprostheses and commercial myoelectric prostheses are often recalibrated and retrained frequently so that only the most recent, up-to-date data influences the algorithm performance. Here, we introduce and validate an alternative training paradigm in which training data from past calibrations is aggregated and reused in future calibrations for regression control. Approach. Using a cohort of four transradial amputees implanted with intramuscular electromyographic recording leads, we demonstrate that aggregating prior datasets improves prosthetic regression-based control in offline analyses and an online human-in-the-loop task. In offline analyses, we compared the performance of a convolutional neural network (CNN) and a modified Kalman filter (MKF) to simultaneously regress the kinematics of an eight-degree-of-freedom prosthesis. Both algorithms were trained under the traditional paradigm using a single dataset, as well as under the new paradigm using aggregated datasets from the past five or ten trainings. Main results. Dataset aggregation reduced the root-mean-squared error (RMSE) of algorithm estimates for both the CNN and MKF, although the CNN saw a greater reduction in error. Further offline analyses revealed that dataset aggregation improved CNN robustness when reusing the same algorithm on subsequent test days, as indicated by a smaller increase in RMSE per day. Finally, data from an online virtual-target-touching task with one amputee showed significantly better real-time prosthetic control when using aggregated training data from just two prior datasets. Significance. Altogether, these results demonstrate that training data from past calibrations should not be discarded but, rather, should be reused in an aggregated training dataset such that the increased amount and diversity of data improve algorithm performance. More broadly, this work supports a paradigm shift for the field of neuroprostheses away from daily data recalibration for linear classification models and towards daily data aggregation for non-linear regression models., (Creative Commons Attribution license.)

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., Competing Interests: Competing interests: JG and RAK reports funding from the European Union’s Horizon Europe research and innovation program under grant agreement No 101095052. DA reports research grants from Lilly and Galapagos and consulting fees from Abbvie, Gilead, J&J, Lilly, MSD, Novartis and Sandoz. EAH reports funding from The Norwegian Regional Health Authorities (inter-regional KLINBEFORSK grants) and The Norwegian Research Council (grant number 328657), speakers' bureaus from Pfizer and UCB; and advisory board participation for Pfizer and AbbVie. SWS reports advisory board participation for AstraZeneca. GG reports personal fees from AbbVie, UCB, Janssen and Novartis. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Objective: The influence of concomitant prednisolone on clinical outcomes and safety in infliximab-treated ulcerative colitis (UC) patients is unknown., Design, Setting, Participants and Outcome Measures: A retrospective cohort study was performed, including 147 UC patients treated with infliximab at a tertiary inflammatory bowel disease (IBD) centre. Primary outcome was corticosteroid-free clinical remission (CFCR) at week 14 and week 52. Patients were grouped according to prednisolone tapering regimens: standard (≤5 mg/week), fast (>5 mg/week), direct discontinuation or no prednisolone. Patients intolerant to corticosteroids and patients stopping corticosteroids in preparation for surgery including colectomy during their initial admission were excluded., Results: There was no overall association between prednisolone exposure or no exposure and CFCR at weeks 14 or 52 of infliximab. The proportion of patients with C reactive protein ≤5 mg/L was higher in the standard tapering at week 14 as compared with faster regimens or no prednisolone. In subgroup analyses, the standard tapering was associated with a higher rate of CFCR at week 14 compared with the fast-tapering regimen in patients receiving ≥40 mg prednisolone at initiation of infliximab (64.3% vs 26.3%, p=0.04) and among patients admitted with acute severe UC (66.6% vs 23.5%, p<0.05). Similar data were seen at week 52. Prednisolone did not affect infliximab trough levels but increased infection rates (10/77 vs 2/70, p=0.03), in particular C. difficile infection., Conclusion: In UC patients with limited disease burden, prednisolone did not affect effectiveness of infliximab. However, patients with increased disease burden seem to benefit from corticosteroid combination therapy., Competing Interests: Competing interests: JFKF Ilvemark has received research grants from Takeda, Janssen, Abbvie, ParaTech, the Danish Research Council, and the Capital Region of Denmark. MDW has received grants from Bristol Myers Squibb, Novo Nordisk Foundation, Aage og Johanne Louis-Hansens Fond, Boehringer Ingelheim. JB: reports grants and personal fees from AbbVie, grants and personal fees from Janssen-Cilag, personal fees from Celgene, grants and personal fees from MSD, personal fees from Pfizer, grants and personal fees from Takeda, grants and personal fees from Tillots Pharma, personal fees from Samsung Bioepis, grants, and personal fees from Bristol Myers Squibb, grants from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Ferring, personal fees from Galapagos CS: Speaker and advisory board for MSD and Janssen-Cilag. Jakob Benedict Seidelin: Research grants from Takeda and the Capital Region Denmark, national coordinator of studies from AbbVie, Arena Pharmaceuticals, Ely Lilly, and Boehringer Ingelheim. PDO, MA, DJW, RAK, NB: no disclosures., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Background: Ovarian cancer (OC) is the leading cause of death from gynecologic malignancies in the Western world. Contributing factors include a high frequency of late-stage diagnosis, the development of chemoresistance, and the evasion of host immune responses. Currently, debulking surgery and platinum-based chemotherapy are the treatment cornerstones, although recurrence is common. As the clinical efficacy of immune checkpoint blockade is low, new immunotherapeutic strategies are needed. Chimeric antigen receptor (CAR) T cell therapy empowers patients' own T cells to fight and eradicate cancer, and has been tested against various targets in OC. A promising candidate is the MUC16 ectodomain. This ectodomain remains on the cell surface after cleavage of cancer antigen 125 (CA125), the domain distal from the membrane, which is currently used as a serum biomarker for OC. CA125 itself has not been tested as a possible CAR target. In this study, we examined the suitability of the CA125 as a target for CAR T cell therapy., Methods: We tested a series of antibodies raised against the CA125 extracellular repeat domain of MUC16 and adapted them to the CAR format. Comparisons between these candidates, and against an existing CAR targeting the MUC16 ectodomain, identified K101 as having high potency and specificity. The K101CAR was subjected to further biochemical and functional tests, including examination of the effect of soluble CA125 on its activity. Finally, we used cell lines and advanced orthotopic patient-derived xenograft (PDX) models to validate, in vivo, the efficiency of our K101CAR construct., Results: We observed a high efficacy of K101CAR T cells against cell lines and patient-derived tumors, in vitro and in vivo. We also demonstrated that K101CAR functionality was not impaired by the soluble antigen. Finally, in direct comparisons, K101CAR, which targets the CA125 extracellular repeat domains, was shown to have similar efficacy to the previously validated 4H11CAR, which targets the MUC16 ectodomain., Conclusions: Our in vitro and in vivo results, including PDX studies, demonstrate that the CA125 domain of MUC16 represents an excellent target for treating MUC16-positive malignancies., Competing Interests: Competing interests: SW, EMI, DJW, NPC and EB have filled a patent application on chimeric antigen receptor for ovarian cancer. The other authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Antidrug antibodies to TNF inhibitors might affect clinical outcomes. Proactive therapeutic drug monitoring allows for early detection of antidrug antibodies and might reduce negative clinical consequences. We aimed to explore how antidrug antibodies to the TNF inhibitor infliximab influence treatment outcomes, and to assess the effect of proactive therapeutic drug monitoring., Methods: This was a predefined exploratory analysis of data from the randomised, controlled NOR-DRUM trials. The trials were conducted in rheumatology, gastroenterology, and dermatology departments at 21 Norwegian hospitals. Adult patients (aged 18-75 years) with immune-mediated inflammatory diseases were randomly assigned to proactive therapeutic drug monitoring or standard infliximab dosing in the NOR-DRUM A trial (30-week follow-up) and the NOR-DRUM B trial (52-week follow-up). Antidrug antibodies were assessed with a drug-sensitive assay before each infusion. The outcomes of remission (at week 30), disease worsening (during 52 weeks), infusion reactions, and infliximab discontinuation were assessed according to the presence of antidrug antibodies and use of therapeutic drug monitoring., Findings: Between March 1, 2017, and Dec 12, 2019, 616 patients were included in the NOR-DRUM trials, of whom 615 had at least one serum infliximab and antidrug antibody assessment and were included in the present analyses. Mean age was 45 years (IQR 32-56), 305 (50%) patients were women, and 310 (50%) patients were men. Antidrug antibodies were detected in 147 (24%) patients. Remission at week 30 occurred in 25 (35%) of 72 patients with antidrug antibodies and 180 (54%) of 335 without antidrug antibodies (risk ratio 0·62 [95% CI 0·45-0·86]; p=0·0037). In patients with antidrug antibodies compared with patients without antidrug antibodies, higher rates were found for: disease worsening over 52 weeks (0·76 per person-year vs 0· 35 per person-year, hazard ratio [HR] 2·02 [95% CI 1·33-3·07]; p=0·0009), infusion reactions (0·16 per person-year vs 0·03 per person-year, HR 17·02 [6·98-41·47]; p<0·0001), and infliximab discontinuation (1·00 per person-year vs 0·20 per person-year, HR 6·64 [4·84-9·11]; p<0·0001). These associations were more pronounced in patients with high concentrations of antidrug antibodies than in those with low concentrations of antidrug antibodies. Independent of antibody status, therapeutic drug monitoring was associated with a lower risk of disease worsening (HR 0·41 [0·29-0·59]; p=0·0001) or an infusion reaction (HR 0·30 [0·12-0·73]; p=0·0076), and was associated with an increase in the rate of infliximab discontinuation (HR 1·37 [1·02-1·83]; p=0·037)., Interpretation: In patients where antidrug antibodies were detected, remission was less likely to be reached and sustained, and infusion reaction or discontinuation of infliximab was more likely. Timely detection of antidrug antibodies by proactive therapeutic drug monitoring facilitated treatment decisions that reduced the negative consequences, both regarding infliximab effectiveness and safety. This highlights the role of proactive therapeutic drug monitoring in optimising infliximab therapy., Funding: Inter-regional KLINBEFORSK grants and South-Eastern Norway Regional Health Authority grants., Competing Interests: Declaration of interests KHB reports speakers' bureaus for Janssen-Cilag. ØS reports speakers' bureau from Boehringer Ingelheim. TKK reports grants from AbbVie, Bristol Myers Squibb, Amgen, Novartis, Pfizer, Galapagos, and UCB; consulting fees from AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, and UCB; speakers' bureau from Grünenthal, Janssen, and Sandoz; and advisory board participation for AbbVie. CM reports consulting fees from AbbVie, ACO, Almiral, Bristol Myers Squibb, Celgene, Eli Lilly, Galderma, LEO Pharma, Novartis, Perrigo, Pfizer, and Sanofi. JJ reported consulting fees from AbbVie, Pfizer, and Takeda; speakers' bureaus from AbbVie, Boerhinger Ingelheim, Bristol Myers Squibb, Celltrion, Galapagos, Hikma, Janssen Cilag, Novartis, Orion Pharma, Pfizer, Roche, Takeda, and Sandoz; and advisory board participation for AbbVie, Galapagos, Gilead, Janssen Cilag, Lilly, Pfizer, and Takeda. NB reports speakers' bureau from Roche, Janssen, and Novartis. KKJ reports speakers' bureau from Bristol Myers Squibb and Roche. EAH reports funding from The Norweigian Regional Health Authorities (inter-regional KLINBEFORSK grants) and The Norwegian Research Council (grant number 328657); speakers' bureaus from Pfizer and UCB; and advisory board participation for Pfizer and AbbVie. GLG reports consulting fees from AbbVie and Pfizer; and speakers' bureau from AbbVie, Pfizer, Sandoz, Celltrion, Lilly, UCB, and Boehringer Ingelheim. SWS reports funding from The South-Eastern Norway Regional Health Authority; and advisory board participation for AstraZeneca. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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., Competing Interests: T.H.W. and K.A. report consultant fees from Takeda outside the submitted work. A.W.M. reports research grant from Takeda. B.M. reports consultant fees from Takeda, Janssen, AbbVie, Pfizer; advisory board Takeda, Janssen, AbbVie, Pfizer, Sandoz, Pharma Cosmos; speaker fees from Takeda, Janssen, AbbVie, Sandoz, Orion Pharma. M.L.H. reports speaker fees from AbbVie, Meda, Tillotts, and Takeda; advisory board Takeda. M.H., L.B., N.B., and D.J.W. report no conflicts of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Crohn's & Colitis Foundation.)

Cochlear implants are among the most successful neural prosthetic devices to date but exhibit poor frequency selectivity and the inability to consistently activate apical (low frequency) spiral ganglion neurons. These issues can limit hearing performance in many cochlear implant patients, especially for understanding speech in noisy environments and in perceiving or appreciating more complex inputs such as music and multiple talkers. For cochlear implants, electrical current must pass through the bony wall of the cochlea, leading to widespread activation of auditory nerve fibers. Cochlear implants also cannot be implanted in some individuals with an obstruction or severe malformations of the cochlea. Alternatively, intraneural stimulation delivered via an auditory nerve implant could provide direct contact with neural fibers and thus reduce unwanted current spread. More confined current during stimulation can increase selectivity of frequency fiber activation. Furthermore, devices such as the Utah Slanted Electrode Array can provide access to the full cross section of the auditory nerve, including low frequency fibers that are difficult to reach using a cochlear implant. However, further scientific and preclinical research of these Utah Slanted Electrode Array devices is limited by the lack of a chronic large animal model for the auditory nerve implant, especially one that leverages an appropriate surgical approach relevant for human translation. This paper presents a newly developed transbullar translabyrinthine surgical approach for implanting the auditory nerve implant into the cat auditory nerve. In our first of a series of studies, we demonstrate a surgical approach in non-recovery experiments that enables implantation of the auditory nerve implant into the auditory nerve, without damaging the device and enabling effective activation of the auditory nerve fibers, as measured by electrode impedances and electrically evoked auditory brainstem responses. These positive results motivate performing future chronic cat studies to assess the long-term stability and function of these auditory nerve implant devices, as well as development of novel stimulation strategies that can be translated to human patients., Competing Interests: ML was employed by Blackrock Neurotech. DW has licensed intellectual property to Blackrock Neurotech that was utilized in the research described herein and he may receive financial gain from the use of that intellectual property. He has in place an approved plan for managing any potential conflicts arising from this intellectual property. MA has served on a Medical Advisory Council for Advanced Bionics, a manufacturer of cochlear implants, unrelated to the current work. FS declares financial interest in Blackrock Neurotech, Blackrock Microsystems Europe, and Sentiomed. Conflict of interest is managed through The University of Utah conflict of interest management. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Thomas, Zuniga, Sondh, Leber, Solzbacher, Lenarz, Lim, Warren, Rieth and Adams.)

Electrical stimulation of the peripheral nervous system (PNS) is becoming increasingly important for the therapeutic treatment of numerous disorders. Thus, as peripheral nerves are increasingly the target of electrical stimulation, it is critical to determine how, and when, electrical stimulation results in anatomical changes in neural tissue. We introduce here a convolutional neural network and support vector machines for cell segmentation and analysis of histological samples of the sciatic nerve of rats stimulated with varying current intensities. We describe the methodologies and present results that highlight the validity of the approach: machine learning enabled highly efficient nerve measurement collection, while multivariate analysis revealed notable changes to nerves' anatomy, even when subjected to levels of stimulation thought to be safe according to the Shannon current limits., (© 2024. The Author(s).)

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., Registration: clinicaltrials.gov identifier: NCT04041622., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Following tetraplegia, independence for completing essential daily tasks, such as opening doors and eating, significantly declines. Assistive robotic manipulators (ARMs) could restore independence, but typically input devices for these manipulators require functional use of the hands. We created and validated a hands-free multimodal input system for controlling an ARM in virtual reality using combinations of a gyroscope, eye-tracking, and heterologous surface electromyography (sEMG). These input modalities are mapped to ARM functions based on the user's preferences and to maximize the utility of their residual volitional capabilities following tetraplegia. The two participants in this study with tetraplegia preferred to use the control mapping with sEMG button functions and disliked winking commands. Non-disabled participants were more varied in their preferences and performance, further suggesting that customizability is an advantageous component of the control system. Replacing buttons from a traditional handheld controller with sEMG did not substantively reduce performance. The system provided adequate control to all participants to complete functional tasks in virtual reality such as opening door handles, turning stove dials, eating, and drinking, all of which enable independence and improved quality of life for these individuals.

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 proportion 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 administration 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 experienced 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.

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 (Q 1; Q 3 ) 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.

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., (© 2023 The Association for the Publication of the Journal of Internal Medicine.)

Electrical stimulation of the peripheral nervous system is a promising therapeutic option for several conditions; however, its effects on tissue and the safety of the stimulation remain poorly understood. In order to devise stimulation protocols that enhance therapeutic efficacy without the risk of causing tissue damage, we constructed computational models of peripheral nerve and stimulation cuffs based on extremely high-resolution cross-sectional images of the nerves using the most recent advances in computing power and machine learning techniques. We developed nerve models using nonstimulated (healthy) and over-stimulated (damaged) rat sciatic nerves to explore how nerve damage affects the induced current density distribution. Using our in-house computational, quasi-static, platform, and the Admittance Method (AM), we estimated the induced current distribution within the nerves and compared it for healthy and damaged nerves. We also estimated the extent of localized cell damage in both healthy and damaged nerve samples. When the nerve is damaged, as demonstrated principally by the decreased nerve fiber packing, the current penetrates deeper into the over-stimulated nerve than in the healthy sample. As safety limits for electrical stimulation of peripheral nerves still refer to the Shannon criterion to distinguish between safe and unsafe stimulation, the capability this work demonstrated is an important step toward the development of safety criteria that are specific to peripheral nerve and make use of the latest advances in computational bioelectromagnetics and machine learning, such as Python-based AM and CNN-based nerve image segmentation.

Background: Data on response and safety of repeated vaccinations and hybrid immunity in patients with immune-mediated inflammatory diseases on immunosuppressive therapy is needed to further develop vaccination strategies in this vulnerable population. This study aimed to evaluate hybrid immunity and humoral immune response and safety of four SARS-CoV-2 vaccine doses in patients with immune-mediated inflammatory diseases on immunosuppressive therapy., Methods: This prospective observational Norwegian study of vaccine response to COVID-19 (Nor-vaC) included adult patients aged 18 years and older with immune-mediated inflammatory diseases (rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis) on immunosuppressive therapy, who had received four SARS-CoV-2 vaccine doses (vaccine group) or three vaccine doses followed by COVID-19 (hybrid group), and healthy controls receiving three vaccine doses (control group). Patients were recruited from the Division of Rheumatology at Diakonhjemmet Hospital, Oslo, and the Department of Gastroenterology at Akershus University Hospital, Lørenskog. Patients who had COVID-19 before the third vaccine dose, and patients with allergies or intolerances to elements of the vaccine were excluded. Antibodies to the receptor-binding domain of SARS-CoV-2 spike protein (anti-RBD antibodies) were assessed 2-4 weeks following vaccination or COVID-19. This study is registered at Clinialtrials.gov, NCT04798625., Findings: Between Nov 12, 2021, and April 19, 2022, 1458 participants with immune-mediated inflammatory diseases provided post-vaccination samples at 2-4 weeks following a third vaccine dose. After 544 participants were excluded, 715 (78%) of the remaining 914 participants received the fourth dose of the vaccine, and of these, 536 (75%) provided post-vaccination samples 2-4 weeks after their fourth vaccination (vaccine group). 199 (22%) of the 914 had COVID-19 after their third dose of the vaccine and of these, 167 (84%) provided samples (hybrid group). 256 of the eligible 703 patients had rheumatoid arthritis, 107 had spondyloarthritis, 115 had psoriatic arthritis, 130 had Crohn's disease, and 95 had ulcerative colitis). Median age was 56 years [IQR 45-65], 398 (57%) were women, and 305 (43%) were men. Patients in the vaccine group had higher anti-RBD antibody concentrations following the fourth vaccine dose (median 6192 BAU/ml [IQR 2878-11 243]) than after the third dose (median 5087 BAU/ml [1250-9081]; p< 0·0001), but lower antibody concentrations than the control group following the third dose (median 7595 BAU/ml [5916-12 001]; p< 0·0001). Antibody concentrations were higher in the patients in the hybrid group (23 548 BAU/ml [IQR 11 440-35 935]) than in the vaccine group (p<0·0001). No difference was found in antibody concentrations between the fourth dose of BNT162b2 (full-dose) and mRNA-1273 (half-dose). Patients and controls had a comparable safety profile after both three and four vaccine doses., Interpretation: Vaccine boosters improve humoral immune responses and are safe in patients with immune-mediated inflammatory diseases on immunosuppressive therapy, and administration should be considered regularly in this patient group. Hybrid immunity with omicron induces a strong humoral response suggesting longer intervals between booster doses in this patient group., Funding: The South-Eastern Norway Regional Health Authority, The Coalition for Epidemic Preparedness Innovations, Akershus University Hospital., Competing Interests: KHB reports funding from Akershus University Hospital and speaker bureaus for Janssen-Cilag. TKK reports grants from AbbVie, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Union Chimique Belge; consulting fees from AbbVie, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz, Sanofi; and speakers bureaus from Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, and Sanofi. JJ reports grants from Boehringer-Ingelheim; speakers bureaus from AbbVie, Bristol-Myers Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, and Takeda; and participation on advisory board for AbbVie, Bristol-Myers Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, and Takeda. LAM reports funding from KG Jebsen foundation, support for infrastructure and biobanking from the university of Oslo and Oslo University Hospital, grants from the Coalition of Epidemic Preparedness Innovations, and speakers bureaus from Novartis, and Cellgene. EAH reports consultant fees from AbbVie, Boehringer-Ingelheim, Eli Lilly, and Gilead; and speakers bureaus from Pfizer and UCB. GG reports speaker bureaus from Bayer, Sanofi, ThermoFisher, and participation on advisory board for AstraZeneca. JTV reports grants from the Coalition of Epidemic Preparedness Innovations. GLG reports funding from the South-Eastern Norway Regional Health Authority, The Coalition for Epidemic Preparedness Innovations, RCN Covid (312693), a KG Jebsen Foundation (grant 19), Dr Trygve Gythfeldt og frues forskningsfond, Karin Fossum Foundation, the Research Foundation at Diakonhjemmet Hospital, and Oslo University Hospital; speakers bureaus from AbbVie, Galapagos, Pfizer, and Union Chimique Belge; and participation on advisory board of AbbVie, Galapagos, Pfizer, and Union Chimique Belge. KKJ reports speakers bureaus from Bristol-Myers Squibb and Roche. All other authors declare no competing interests., (© 2022 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Competing interests: TKK reports grants from AbbVie, Amgen, BMS MSD, Novartis, Pfizer, UCB, consulting fees from AbbVie, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz, Sanofi, speakers bureaus Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, Sanofi, LM reports funding from KG Jebsen foundation, support for infrastructure and biobanking from the university of Oslo and Oslo University Hospital, grants from the Coalition of Epidemic Preparedness Innovations CEPI, speakers bureaus Novartis, Cellgene, JTV reports grant from the Coalition of Epidemic Preparedness Innovations (CEPI), KKJ reports speakers bureaus from Roche and BMS, advisory board Celltrion and Norgine, GLG reports funding from The Karin Fossum foundation, Diakonhjemmet Hospital, Oslo University Hospital, Akershus University Hospital, Trygve Gydtfeldt og frues Foundation, South-East region Health authority, consulting fees AbbVie and Pfizer, speakers fees AbbVie, Pfizer, Sandoz, Orion Pharma, Novartis and UCB, advisory board Pfizer, AbbVie., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The durability of vaccine-induced humoral immunity against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs) on immunosuppressive therapy is not known. The aim of this study was to compare the persistence of anti-Spike antibodies following two-dose SARS-CoV-2 vaccination between IMID patients and healthy controls and to identify factors associated with antibody decline., Methods: IMID patients on immunosuppressive medication enrolled in the prospective observational Nor-vaC study were included. Participants received two-dose SARS-CoV-2 vaccination. Serum collected at two time points following vaccination (first assessment within 6-48 days, second within 49-123 days) were analyzed for antibodies binding the receptor-binding domain (RBD) of the SARS-CoV-2 Spike protein. Multivariable regression models estimated percent reduction in anti-RBD over 30 days and factors associated with reduction., Results: A total of 1108 patients (403 rheumatoid arthritis, 195 psoriatic arthritis, 195 spondyloarthritis, 124 ulcerative colitis, 191 Crohn's disease) and 134 controls provided blood samples within the defined intervals (median 19 days [IQR 15-24] and 97 days [87-105] after second vaccine dose). Antibody levels were lower in patients compared to controls at both time points, with median anti-RBD 2806 BAU/ml [IQR 1018-6068] in patients and 6187 BAU/ml [4105-7496] in controls (p<0.001) at first assessment, and 608 BAU/ml [IQR 58-1053] in patients and 1520 BAU/ml [979-3766] in controls (p<0.001) at second assessment. At second assessment, low anti-RBD antibody levels (defined as <200 BAU/ml) were found in 449 (41%) patients, and 6 (5%) controls (p<0.001). The change was - 83% in patients and - 66% in controls (p<0.001). Patients had a greater estimated 30 days percent reduction in anti-RBD levels compared to controls - 4.9 (95% CI - 7.4 to - 2.4), (p<0.05). Among therapies, mono- or combination treatment with tumor necrosis factor inhibitors was associated with the greatest decline., Conclusions: Within 4 months after vaccination, antibody levels declined considerably in both IMID patients and controls. Patients had lower initial antibody levels and a more pronounced decline compared to healthy controls and were therefore more likely to decline to low antibody levels. These results support that IMID patients need additional vaccine doses at an earlier stage than healthy individuals., (© 2022. The Author(s).)

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., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

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., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Immunogenicity and safety following receipt of the standard SARS-CoV-2 vaccination regimen in patients with immune-mediated inflammatory diseases (IMIDs) are poorly characterized, and data after receipt of the third vaccine dose are lacking. The aim of the study was to evaluate serologic responses and adverse events following the standard 2-dose regimen and a third dose of SARS-CoV-2 vaccine in IMID patients receiving immunosuppressive therapy., Methods: Adult patients receiving immunosuppressive therapy for rheumatoid arthritis, spondyloarthritis, psoriatic arthritis, Crohn's disease, or ulcerative colitis, as well as healthy adult controls, who received the standard 2-dose SARS-CoV-2 vaccination regimen were included in this prospective observational study. Analyses of antibodies to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein were performed prior to and 2-4 weeks after vaccination. Patients with a weak serologic response, defined as an IgG antibody titer of ≤100 arbitrary units per milliliter (AU/ml) against the receptor-binding domain of the full-length SARS-Cov-2 spike protein, were allotted a third vaccine dose., Results: A total of 1,505 patients (91%) and 1,096 healthy controls (98%) had a serologic response to the standard regimen (P < 0.001). Anti-RBD antibody levels were lower in patients (median 619 AU/ml interquartile range [IQR] 192-4,191) than in controls (median 3,355 AU/ml [IQR 896-7,849]) (P < 0.001). The proportion of responders was lowest among patients receiving tumor necrosis factor inhibitor combination therapy, JAK inhibitors, or abatacept. Younger age and receipt of messenger RNA-1273 vaccine were predictors of serologic response. Of 153 patients who had a weak response to the standard regimen and received a third dose, 129 (84%) became responders. The vaccine safety profile among patients and controls was comparable., Conclusion: IMID patients had an attenuated response to the standard vaccination regimen as compared to healthy controls. A third vaccine dose was safe and resulted in serologic response in most patients. These data facilitate identification of patient groups at risk of an attenuated vaccine response, and they support administering a third vaccine dose to IMID patients with a weak serologic response to the standard regimen., (© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

The Utah Electrode Array (UEA) and its variants (e.g., the Utah Slanted Electrode Array, or USEA) have been prominent contributors to advances in the field of neural engineering over the past decade. The most common means of inserting UEA and USEA devices into neural tissue is pneumatic insertion performed by an insertion wand and a pneumatic controller. As design changes from the well-established standards occur to better suit specialized surgical applications, it becomes essential to verify that the alterations do not compromise the structural integrity of the device during insertion. This paper characterizes and demonstrates the reliability of specialized USEAs and insertion wands designed for auditory nerve implants following pneumatic insertion into a rat sciatic nerve. The results show that proposed changes in the USEA form factor and pneumatic insertion ergonomics do not compromise implant stability and device structural viability.

Alpha-methylacyl-CoA racemase (AMACR) deficiency is a rare peroxisomal disorder causing pristanic acid accumulation. Only 16 cases have been described so far. A female in her seventh decade presented with episodes of dysphasia, headache and sensory disturbance inconsistent with migraine, epilepsy or transient ischaemic attack. An MRI demonstrated unusual changes in the pons, red nuclei, thalami and white matter. Mitochondrial disease was suspected but detailed testing was negative. After eight years of symptoms, she developed a febrile encephalopathy with hemispheric dysfunction, focal convulsive seizures and coma. Her condition stabilised after one month. Lacosamide was continued for seizure prevention. The diagnosis remained elusive until whole genome sequencing revealed AMACR deficiency. Pristanic acid levels were highly elevated and dietary modification was recommended. Genetic peroxisomal disorders can present in older age; our patient is the oldest in the AMACR deficiency literature. Novel features in our case include central apnoea, dystonia and rapid eye movement behaviour disorder., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Within the last 2 years, S. Buhl has served as a speaker for Janssen and Takeda Pharmaceutical Company and as a consultant for Takeda Pharmaceutical Company. J. Brynskov has served as an advisory board member for AbbVie, Janssen, MSD, Takeda, and as a primary investigator for AbbVie and Janssen. J. T. Bay received speaker honoraria from Alexion and CSL Behring. N. Bolstad received speaker/consulting honoraria from Takeda, Roche, Janssen, and Novartis. C. Steenholdt has served as a speaker and advisory board member for MSD. The remaining authors have no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In rituximab-treated patients with rheumatoid arthritis, humoral and cellular immune responses after two or three doses of SARS-CoV-2 vaccines are not well characterised. We aimed to address this knowledge gap., Methods: This prospective, cohort study (Nor-vaC) was done at two hospitals in Norway. For this sub-study, we enrolled patients with rheumatoid arthritis on rituximab treatment and healthy controls who received SARS-CoV-2 vaccines according to the Norwegian national vaccination programme. Patients with insufficient serological responses to two doses (antibody to the receptor-binding domain [RBD] of the SARS-CoV-2 spike protein concentration <100 arbitrary units [AU]/mL) were allotted a third vaccine dose. Antibodies to the RBD of the SARS-CoV-2 spike protein were measured in serum 2-4 weeks after the second and third doses. Vaccine-elicited T-cell responses were assessed in vitro using blood samples taken before and 7-10 days after the second dose and 3 weeks after the third dose from a subset of patients by stimulating cryopreserved peripheral blood mononuclear cells with spike protein peptides. The main outcomes were the proportions of participants with serological responses (anti-RBD antibody concentrations of ≥70 AU/mL) and T-cell responses to spike peptides following two and three doses of SARS-CoV-2 vaccines. The study is registered at ClinicalTrials.gov, NCT04798625, and is ongoing., Findings: Between Feb 9, 2021, and May 27, 2021, 90 patients were enrolled, 87 of whom donated serum and were included in our analyses (69 [79·3%] women and 18 [20·7%] men). 1114 healthy controls were included (854 [76·7%] women and 260 [23·3%] men). 49 patients were allotted a third vaccine dose. 19 (21·8%) of 87 patients, compared with 1096 (98·4%) of 1114 healthy controls, had a serological response after two doses (p<0·0001). Time since last rituximab infusion (median 267 days [IQR 222-324] in responders vs 107 days [80-152] in non-responders) and vaccine type (mRNA-1273 vs BNT162b2) were significantly associated with serological response (adjusting for age and sex). After two doses, 10 (53%) of 19 patients had CD4 + T-cell responses and 14 (74%) had CD8 + T-cell responses. A third vaccine dose induced serological responses in eight (16·3%) of 49 patients, but induced CD4 + and CD8 + T-cell responses in all patients assessed (n=12), including responses to the SARS-CoV-2 delta variant (B.1.617.2). Adverse events were reported in 32 (48%) of 67 patients and in 191 (78%) of 244 healthy controls after two doses, with the frequency not increasing after the third dose. There were no serious adverse events or deaths., Interpretation: This study provides important insight into the divergent humoral and cellular responses to two and three doses of SARS-CoV-2 vaccines in rituximab-treated patients with rheumatoid arthritis. A third vaccine dose given 6-9 months after a rituximab infusion might not induce a serological response, but could be considered to boost the cellular immune response., Funding: The Coalition for Epidemic Preparedness Innovations, Research Council of Norway Covid, the KG Jebsen Foundation, Oslo University Hospital, the University of Oslo, the South-Eastern Norway Regional Health Authority, Dr Trygve Gythfeldt og frues forskningsfond, the Karin Fossum Foundation, and the Research Foundation at Diakonhjemmet Hospital., Competing Interests: KKJ reports speakers bureaus from Roche and BMS and advisory board participation for Celltrion and Norgine. JJ reports grants from Abbvie, Pharmacosmos, and Ferring; consulting fees from Abbvie, Boerhinger Ingelheim, BMS, Celltrion, Ferring, Glihead, Janssen Cilag, MSD, Napp Pharma, Novartis, Orion Pharma, Pfeizer, Pharmacosmos, Takeda, Sandoz, and Unimedic Pharma; and speakers bureaus from Abbvie, Astro Pharma, Boerhinger Ingelheim, BMS, Celltrion, Ferring, Glihead, Hikma, Janssen Cilag, Meda, MSD, Napp Pharma, Novartis, Oriuon Pharma, Pfeizer, Pharmacosmos, Roche, Takeda, and Sandoz. TKK reports grants from AbbVie, Amgen, BMS, MSD, Novartis, Pfizer, and UCB; consulting fees from AbbVie, Amgen, Biogen, Celltrion, Eli Lilly, Gilead, Mylan, Novartis, Pfizer, Sandoz, and Sanofi; speakers bureaus from Amgen, Celltrion, Egis, Evapharma, Ewopharma, Hikma, Oktal, Sandoz, and Sanofi; and participation on a data safety monitoring board for AbbVie. LAM reports funding from the KG Jebsen foundation; support for infrastructure and biobanking from the University of Oslo and Oslo University Hospital; grants from the Coalition of Epidemic Preparedness Innovations (CEPI); and speakers bureaus from Novartis and Cellgene. GG reports consulting fees from the Norwegian System of Compensation to Patients and AstraZeneca, and speakers bureaus from Bayer, Sanofi Pasteur, and Thermo Fisher. JTV reports grant from the CEPI. FL-J reports grants from the CEPI and the South-Eastern Norway Regional Health Authority. GLG reports funding from the Karin Fossum foundation, Diakonhjemmet Hospital, Oslo University Hospital, Akershus University Hospital, the Dr Trygve Gydtfeldt og frues Foundation, and the South-Eastern Norway Regional Health Authority; consulting fees from AbbVie and Pfizer; speakers fees from AbbVie, Pfizer, Sandoz, Orion Pharma, Novartis, and UCB; and advisory board participation for Pfizer and AbbVie. All other authors declare no competing interests., (© 2021 Elsevier Ltd. All rights reserved.)

Tolosa-Hunt syndrome is understood as a steroid-responsive, relapsing-remitting, unilateral headache disorder associated with ipsilateral cranial neuropathies, of a probable granulomatous aetiology. The diagnosis is made clinically from the history and examination, supported by appropriate imaging. Here the authors report a case of Tolosa-Hunt syndrome with a headache phenotype mimicking a trigeminal autonomic cephalalgias (hemicrania continua), and serial MRI studies showing a stable enlarged pituitary. Due to her initial lack of clinical signs, she was diagnosed with chronic migraine, revised to hemicrania continua based on indomethacin response, then revised back to chronic migraine. Her final diagnosis was achieved after she developed a left cavernous sinus syndrome 4 years into her disease course. This case shows that Tolosa-Hunt syndrome may present with a non-side-locked headache and delayed development of clinical signs. Clinicians should also maintain a high degree of suspicion when faced with incidental MRI findings., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

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 outcome was 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 TDM was more effective than treatment without TDM in sustaining disease control without disease worsening. 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.

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., Competing Interests: Competing interests: HBH has received fees for speaking and/or consulting from AbbVie, Pfizer, Roche, Novartis and Lilly. SWS has received speaking fee from Thermo Fisher. NB has received fees for speaking and/or consulting from Takeda, Roche, Janssen and Novartis. GLG has received fees for speaking and/or consulting Abbvie, Biogen, Boehringer Ingelheim, Orion Pharma, Eli Lilly, Novartis, Pfizer, MSD, Roche and UCB. The remaining authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Multiarticulate bionic hands are now capable of recreating the endogenous movements and grip patterns of the human hand, yet amputees continue to be dissatisfied with existing control strategies. One approach towards more dexterous and intuitive control is to create a semi-autonomous bionic hand that can synergistically aid a human with complex tasks. To that end, we have developed a bionic hand that can automatically detect and grasp nearby objects with minimal force using multi-modal fingertip sensors. We evaluated performance using a fragile-object task in which participants must move an object over a barrier without applying pressure above specified thresholds. Participants completed the task under three conditions: 1) with their native hand, 2) with the bionic hand using surface electromyography control, and 3) using the semi-autonomous bionic hand. We show that the semi-autonomous hand is extremely capable of completing this dexterous task and significantly outperforms a more traditional surface-electromyography controller. Furthermore, we show that the semi-autonomous bionic hand significantly increased users' grip precision and reduced users' perceived task workload. This work constitutes an important step towards more dexterous and intuitive bionic hands and serves as a foundation for future work on shared human-machine control for intelligent bionic systems.

Competing Interests: Competing interests: None declared.

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., (© 2021. The Author(s).)

Immunogenicity related to treatment with TNF inhibitors (TNFi) is one of the causes for the decreased attainment of clinical response in patients with rheumatoid arthritis (RA). The B-cell activating factor (BAFF) may be playing a role in the development of immunogenicity. The objective of this study was to analyse the association of baseline concentration of serum B-cell activating factor (BAFF) with immunogenicity after 6 months of TNFi treatment. A total of 127 patients with RA starting a TNFi (infliximab, adalimumab, certolizumab pegol or golimumab) were followed-up for 6 months. Serum samples were obtained at baseline and at 6 months and anti-drug antibody (ADA) and BAFF concentrations were measured. Logistic regression models were employed in order to analyse the association between BAFF concentrations and immunogenicity. Receiver operating characteristic analysis was performed to determine the BAFF concentrations with a greater likelihood of showing immunogenicity association. At 6 months, 31 patients (24%) developed ADA. A significant interaction between the age and baseline BAFF concentration was found for the development of ADA (Wald chi-square value = 5.30; p = 0.02); therefore, subsequent results were stratified according to mean age (≤ / > 55 years). Baseline serum BAFF concentration was independently associated with ADA development only in patients over 55 years (OR = 1.51; 95% CI 1.03-2.21). Baseline serum BAFF ≥ 1034 pg/mL predicted the presence of ADA at 6 months (AUC = 0.81; 95% confidence interval (CI) 0.69-0.93; p = 0.001; positive likelihood ratio = 3.7). In conclusion, our results suggest that the association of BAFF concentration and immunogenicity depends on the patient's age. Baseline serum BAFF concentration predicts the presence of ADA within 6 months of TNFi therapy in older patients with RA.