BackgroundAfter adalimumab treatment failure, tumour necrosis factor inhibition (TNFi) and non-TNFi biological disease-modifying anti-rheumatic drugs (bDMARDs) are equally viable options on a group level as subsequent treatment in rheumatoid arthritis (RA) based on the current best evidence synthesis. However, preliminary data suggest that anti-adalimumab antibodies (anti-drug antibodies, ADA) and adalimumab serum levels (ADL) during treatment predict response to a TNFi as subsequent treatment.ObjectiveTo validate the association of presence of ADA and/or low ADL with response to a subsequent TNFi bDMARD or non-TNFi bDMARD. Sub-analyses were performed for primary and secondary non-responders.MethodsA diagnostic test accuracy retrospective cohort study was done in consenting RA patients who discontinued adalimumab after >3 months of treatment due to inefficacy and started another bDMARD. Inclusion criteria included the availability of (random timed) serum samples between ≥8 weeks after start and ≤2 weeks after discontinuation of adalimumab, and clinical outcome measurements Disease Activity Score in 28 joints - C-reactive protein (DAS28-CRP) between 3 to 6 months after treatment switch. Test characteristics for EULAR (European League Against Rheumatism) good response (DAS28-CRP based) after treatment with the next (non-)TNFi bDMARD were assessed using area under the receiver operating characteristic and sensitivity/specificity.Results137 patients were included. ADA presence was not predictive for response in switchers to a TNFi (sensitivity/specificity 18%/75%) or a non-TNFi (sensitivity/specificity 33%/70%). The same was true for ADL levels in patients that switched to a TNFi (sensitivity/specificity 50%/52%) and patients that switched to a non-TNFi (sensitivity/specificity 32%/69%). Predictive value of ADA and ADL were similar for both primary and secondary non-responders to adalimumab.ConclusionsIn contrast to earlier research, we could not find predictive value for response to a second TNFi or non-TNFi for either ADA or random timed ADL.

Objective Whole-body Positron Emission Tomography with CT-scanning using fluorine-18 fluorodeoxyglucose (18F-FDG) is occasionally used in rheumatoid arthritis (RA) patients to detect arthritis. FDG-PET/CT might also detect malignancies, but the amount of incidental findings and the number of relevant malignant disease that could be missed are currently unknown. We aimed to study the malignancy screening performance of whole-body FDG-PET/CT in longstanding RA patients with low disease activity. Methods FDG-PET/CT-scanning was done in the intervention arm of the Dose REduction Strategy of Subcutaneous TNF-inhibitors (DRESS) study, a randomized controlled trial on dose-tapering of biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs). The reference standard was clinical diagnosis of malignancy during the 3 year follow-up of the study. Prevalence of extra-articular abnormalities, follow-up, and treatments were summarized post-hoc. Results 121 scans were made in 79 patients. Extra-articular abnormalities were found in 59/121 (49%) scans, resulting in additional diagnostic procedures in 21/79 (26.6%) patients. Nine patients (7.4%) were suspected of malignancy, none turned out to be malignant. Six clinical malignancies that developed during follow-up were all negative on baseline FDG-PET/CT. Conclusion Whole-body FDG-PET/CT-scanning used in RA patients for imaging of arthritis results in frequent incidental extra-articular findings, while some who apparently had normal scans also developed malignancies. Trial registration Netherlands Trial Register, www.trialregister.nl, NL6771

Objectives To quantify the additional value of a hypothetical biomarker predicting response to treatment for rheumatoid arthritis (RA) regarding efficacy and costs by using a modelling design. Methods A Markov model was built comparing a usual care T2T strategy with a biomarker-steered strategy for RA patients starting biologic therapy. Outcome measures include time spent in remission or low disease activity (LDA) and costs. Four additional scenario analyses were performed by varying biomarker or clinical care characteristics, being 1) costs of the biomarker, 2) sensitivity and specificity of the biomarker, 3) proportion of eligible patients tapering and 4) medication costs. Results In the base model, patients spent 2.9 months extra in LDA or remission in the biomarker strategy compared with usual care T2T over 48 months. Total costs were €43 301 and €42 568 for respectively the usual care and biomarker strategy, and treatment costs accounted for 91% of total costs in both scenarios. Cost savings were driven due to patients in the biomarker strategy experiencing remission or LDA earlier, and starting tapering sooner. Cost-effectiveness was not so much driven by costs or test characteristics of the biomarker (scenario 1/2), but rather by the level of early and proactive tapering and drug costs (scenarios 3/4). Conclusions The use of a biomarker for prediction of response to b/tsDMARD treatment in RA can be of added value to current treat-to-target clinical care. However, gains in efficacy are modest and cost gains are depending on a combination of early proactive tapering and high medication costs.

BackgroundWhole-body Positron Emission Tomography with CT-scanning using fluorine-18 fluorodeoxyglucose (18F-FDG) is occasionally used in Rheumatoid Arthritis (RA) patients. Reasons to use FDG-PET/CT-scans are to diagnose arthritis or guide decisions on systemic therapy, as FDG uptake in affected joints may reflect disease activity [1]. FDG-PET/CT might also detect malignancies, but the frequency of incidental findings and the proportion of relevant malignant disease that could be missed are currently unknown.ObjectivesTo study the malignancy screening performance of whole-body FDG-PET/CT in longstanding RA patients with low disease activity.MethodsFDG-PET/CT-scanning was done in the intervention arm of the Dose REduction Strategy of Subcutaneous TNF-inhibitors (DRESS) study, a randomized controlled trial on dose-tapering of biological Disease Modifying Anti-Rheumatic Drugs (bDMARDs) [3]. Baseline and if applicable follow up whole-body FDG-PET/CT-scans were performed in consenting patients in the tapering arm to assess predictive value of subclinical PET-arthritis for risk of flaring [4]. The scans were also read by experienced nuclear medicine specialists immediately after they were performed for any unexpected extra-articular finding, conform routine clinical care.The reference standard was clinical diagnosis of malignancy during the 3 year follow-up. Prevalence of extra-articular abnormalities, follow-up, and received treatments were summarized post-hoc.Results121 scans were made in 79 patients. Extra-articular abnormalities were found in 59/121 (48.8%) scans (Table 1) in 45/79 (57%) patients.Table 1.Abnormalities found on FDG-PET/CT scans# abnormal results found on scans (%)No PET/CT result obtained3 (2.5)No abnormalities found on any scan59 (48.8)One or more abnormalities found per scan*59 (48.8)Total number of scans121 Inflammatory7 (5.7) Suspected malignancies9 (7.4) Cardiovascular2 (1.6) Pulmonary7 (5.8) Gastrointestinal10 (8.3) Muscles/tendons3 (2.5) Bone-related3 (2.5) Hypermetabolic lymph nodes (non-specific)16 (13.2) Thyroid4 (3.3)* Fifteen of these abnormalities were found on the second PET/CT, the rest was found on the first scan. 11 abnormalities on the second PET/CT were the same as the one seen on the first scan, and 7 abnormalities resolved after the first scan. One scan can show multiple abnormalities, from different categories.Follow-up action occurred in 21 (26.6%) patients, consisting of referral to a specialist or reassessing and/or scheduling diagnostics directly by the treating rheumatologist. In 5 (6.3%) patients, the rheumatologist followed-up. In 17 (21.5%) patients a consultation with a different specialist was scheduled. In five patients surgical/invasive intervention took place. In one patient a hemi-thyroidectomy was performed revealing a follicular adenoma. This resection was complicated by persistent recurrent laryngeal nerve paresis and hoarseness. In a second, an intra-uterine myomectomy took place. In a third, a colonoscopy was performe revealing two low-grade adenomas. In a fourth a benign cyst in the neck was extracted. A fifth patient underwent spinal marginal myotomy which turned out to be a benign schwannoma.Nine patients (7.4%) were suspected of malignancy, none turned out to be malignant. Six clinical malignancies (bladder, penile, lymphoma, 2x melanoma and prostate) that developed during follow-up were all negative on baseline FDG-PET/CT. The malignancies were diagnosed after an interval of between 5 and 34 months (mean 13 months).ConclusionWhole-body FDG-PET/CT-scanning for arthritis imaging in RA patients results in frequent incidental extra-articular findings, while some who apparently had normal scans developed malignancies.References[1]Mandl P. et al. RMD open 2019;5:e000950.[2]Van Herwaarden N. et al. BMJ 2015;350:1–8. doi:10.1136/bmj.h1389[3]Bouman C.A.M et al. Rheumatology 2021.Disclosure of InterestsNone declared

Background:After adalimumab treatment failure, TNFi and non-TNFi bDMARDs are equally viable as subsequent treatment in RA. However, preliminary data suggest that anti-drug antibodies (ADA) and adalimumab serum levels (ADL) predict response to a subsequent TNFi [1].Objectives:To assess the association of presence of ADA and/or low ADL with response to a subsequent TNFi bDMARD or non-TNFi bDMARD.Methods:A retrospective cohort study to assess the predictive value of ADA and ADL for response to a subsequent TNFi or non-TNFi bDMARD in RA patients.All RA patients who received adalimumab (standard dose, ≥ 3 months) and subsequently switched to another TNFi or a non-TNFi (rituximab, tocilizumab, abatacept) in the Sint Maartenskliniek or Radboud University Medical Centre between January 2012 and January 2018 were considered for inclusion in the current study. Further inclusion criteria were the availability of (random timed) serum samples between ≥8 weeks after start, and ≤2 weeks (for ADL) or ≤12 weeks (for ADA) after discontinuation of adalimumab, and clinical outcome measurements (DAS28-CRP/BSE) between 3-6 months after treatment switch. Serum samples were derived from a period of biobanking at every visit of RA patients and an observational cohort study including consecutive bDMARD starters.The primary outcome of this study was the association between ADL or ADA and EULAR good response (DAS28-CRP/ESR based) to the subsequent bDMARD. When DAS28-based response was unreliable due to glucocorticoid use, or low baseline DAS28 (if switching due to adverse effects), judgement of the rheumatologist was used.A drug-tolerant competitive enzyme-linked immunosorbent assay (Sanquin, the Netherlands) was used to quantify ADA, and thereafter, ADL was determined via an ELISA. Reference values were ≥5 µg/ml for ADL and <12 AU/ml for ADA [2,3]. Treatment was blinded for ADL and ADA levels.Prediction of response were assessed using the area under the receiver-operator characteristic (AUROC) and sensitivity/specificity. Sub-analyses were performed for primary and secondary non-responders. Correlations between ADL and ADA presence and clinical variables were also cross-sectionally explored.Results:137 patients were included, 47 of whom switched to a second TNFi and 90 to a non-TNFi. Sensitivity and specificity of the proposed ADA and ADL reference values were low (table 1). The AUROC did not differ appreciably or significantly from 0.5. Results were similar for both primary and secondary non-responders to adalimumab.Table 1.predictive values of ADA and ADL for response to a subsequent bDMARD in TNFi and non-TNFi switchers.sensitivity (%)specificity (%)AUCCITNFi switchersADA presence (>12AU/mL)18750.460.32-0.59low ADL (<5mg/L)32690.500.29-0.71non-TNFi switchersADA presence (>12AU/mL)33700.520.42-0.63low ADL (<5mg/L)50520.500.34-0.65Higher ADL (Spearman’s ρ = -0.68, p = 0.00) but not ADA (ρ = 0.23, p = 0.28) presence was associated with a lower DAS28 at the time of switching to a subsequent bDMARD, but not with follow-up DAS28 after starting the subsequent bDMARD (ρ = -0.29, p = 0.17, and ρ = 0.10, p = 0.65, respectively). In addition, higher ADL were associated with lower baseline CRP (ρ = – 0.67, p = 0.00) and ESR (ρ = – 0.546, p = 0.006) and higher ADA correlated with higher baseline ESR (ρ = 0.49, p = 0.01).Conclusion:No predictive value for response to a second TNFi or non-TNFi was found for either ADA or random timed ADL. Limitations of this study are the retrospective design and random timed serum sampling. An ongoing randomized blinded test-treatment trial will provide more definitive answers [4].References:[1]Van Herwaarden et al.Expert Opin Drug Metab Toxicol.2017;13:843–57.[2]Pouw et al.Ann Rheum Dis.2015 Mar;74(3):513-8.[3]Bartelds et al.Ann Rheum Dis.2007 Jul;66(7):921-6.[4]ADDORA-SWITCH study,www.trialregister.nl,no NL 8210Disclosure of Interests:Nathan den Broeder: None declared, Evy Ulijn: None declared, Maike Wientjes: None declared, Noortje van Herwaarden: None declared, Inger Meek: None declared, Lieke Tweehuysen: None declared, Aatke van der Maas: None declared, Bart van den Bemt Grant/research support from: UCB, Pfizer and Abbvie, Consultant of: Delivered consultancy work for UCB, Novartis and Pfizer, Speakers bureau: Pfizer, AbbVie, UCB, Biogen and Sandoz., Alfons den Broeder: None declared