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- Kharlamova, N., et al.
(författare)
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Drug Tolerant Anti-drug Antibody Assay for Infliximab Treatment in Clinical Practice Identifies Positive Cases Earlier
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- A subgroup of patients treated with infliximab lose response to the treatment and one reason for this is the development of anti-drug antibodies (ADA). If used optimally, measuring drug and ADA level could lead to a more personalized and efficient treatment regime, and enable identification of ADA-positive patients before the underlying disease flares or allergic reactions occur. With the use of a drug-tolerant ADA assay which can detect ADA irrespective of drug levels in the sample, we determined the impact of ADA on treatment failure to infliximab. The aims of this study were to estimate the real-life optimal serum infliximab (sIFX) level and set a clinical threshold value for a drug-tolerant ADA assay. Trough levels of sIFX were measured with ELISA. Free ADA was measured with two drug-sensitive methods (ELISA and a bioassay) and one drug-tolerant method (PandA). Two real-life cohorts treated with infliximab were included; a cross-sectional cohort including patients with inflammatory rheumatic diseases (n= 270) and a prospective cohort of rheumatoid arthritis (RA) patients (n= 73) followed for 1 year. Normal range of sIFX was estimated from the prospective cohort and an arbitrary optimal drug level was set to be between 1 and 6 mu g/mL. Using this range, optimal sIFX was found in only 60% (163/270) of the patients in the cross-sectional cohort. These patients had significantly better treatment response than those with a drug level under 1 mu g/mL, who had an ADA frequency of 34% (19/56) using the drug-tolerant method. In the prospective cohort, the drug-tolerant assay could identify 34% (53/155 samples) as ADA positive in samples with sIFX level >0.2 mu g/mL. ADA were seldom detected in patients with >1 mu g/mL sIFX, with three interesting exceptions. A clinically relevant ADA threshold was determined to be >3 RECL as measured with the drug-tolerant assay. In a real-life setting, there was a substantial number of patients with suboptimal drug levels and a proportion of these had ADA. Both too low and too high drug levels correlated with worse disease, but for different reasons. Adding a drug-tolerant assay enabled detection of ADA earlier and regardless of drug level at time of sampling.
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| 2. |
- Lourido, L., et al.
(författare)
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Circulating centromere protein F autoantibodies for predicting clinical response to infliximab in rheumatoid arthritis
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group. - 0003-4967 .- 1468-2060. ; 79, s. 1399-1399
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- One third of patients with rheumatoid arthritis (RA) respond poorly to TNF inhibitors and related studies are inconsistent in predictive biomarkers. The identification of biomarkers that predict the treatment response prior to drug exposure is a current priority on the RA field. ACPA and RF are ubiquitously tested in RA patients, but other autoantibodies exist and may provide additional information on RA treatment response.Objectives:This study aimed to identify circulating autoantibodies for predicting response to infliximab (IFX) in RA.Methods:We profiled the autoantibody repertoire of baseline sera from 155 biologic naïve RA patients treated with IFX. The sera were provided by three independent clinical sources and distributed in one exploratory cohort (N=20) collected from Hospital Clínico Universitario of Santiago de Compostela (Spain), one replication cohort (N=61) collected from Hospital Universitario de A Coruña (Spain) and samples from the Swedish Farmacotherapy (SWEFOT) trial (Sweden) (N=74) for clinical validation. The presence of autoantibodies and their levels in serum were analysed in association with EULAR clinical response at 6 months follow-up: good response (GR, N=56), moderate (MR, N=55) and non-response (NR, N=44). A suspension bead array platform built on protein fragments within Human Protein Atlas and selected from an initial untargeted screening using an array containing 42000 antigens was employed to identify the IgG and IgA autoantibodies on the exploratory cohort. A replication and validation phases were carried out on the other two serum sample cohorts. Meta-analysis and Receiver Operating Curves were performed in order to assess the clinical relevance of the findings observed.Results:Meta-analysis revealed that the levels in serum of IgG autoantibodies against Centromere protein F (CENPF) are significantly increased in responders (good responders and moderate responders; N=111) to IFX compared to non-responders (N=44) (P=0.018). CENP-F is a proliferation-associated and cell cycle-dependent centromere autoantigen that might be involved in the increased or abnormal cell proliferation that occurs during RA process. The combination of the anti-CENPF antibodies with clinical variables (age, sex, DAS28-ESR) resulted in the best model to discriminate the patients that will respond to IFX, showing an AUC of 0.756 (95% CI [0.639-0.874], P=0.001).Conclusion:High serum levels of IgG anti-CENPF antibodies might be potentially useful to identify RA patients more likely to benefit from IFXDisclosure of Interests:Lucía Lourido: None declared, Cristina Ruiz-Romero: None declared, flor picchi: None declared, Naomi Diz-Rosales: None declared, Sergio Vilaboa-Galán: None declared, Carlos Fernández-López: None declared, Jose Antonio Pinto Tasende: None declared, Eva Perez-Pampin: None declared, Cristina Regueiro Expósito: None declared, ANTONIO MERA VARELA: None declared, Antonio Gonzalez: None declared, Karen Hambardzumyan: None declared, Saedis Saevarsdottir Employee of: Part-time at deCODE Genetics/Amgen Inc, working on genetic research unrelated to this project, Peter Nilsson: None declared, Francisco J. Blanco Grant/research support from: Sanofi-Aventis, Lilly, Bristol MS, Amgen, Pfizer, Abbvie, TRB Chemedica International, Glaxo SmithKline, Archigen Biotech Limited, Novartis, Nichi-iko pharmaceutical Co, Genentech, Jannsen Research & Development, UCB Biopharma, Centrexion Theurapeutics, Celgene, Roche, Regeneron Pharmaceuticals Inc, Biohope, Corbus Pharmaceutical, Tedec Meiji Pharma, Kiniksa Pharmaceuticals, Ltd, Gilead Sciences Inc, Consultant of: Lilly, Bristol MS, Pfizer
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