Evaluation von Immunoassays zum Nachweis von Anti-Drug Antikörpern gegen Infliximab und korrespondierenden Infliximab Serumspiegeln bei Spondyloarthritis im klinischen Alltag

Zusammenfassung

Hintergrund TNF-α-Inhibitoren sind wirksame Medikamente bei vielen chronisch-inflammatorischen Erkrankungen. Trotz eines akzeptablen Wirkansprechens gibt es einen beachtlichen Anteil an Patienten, bei denen ein primärer oder sekundärer Wirkverlust beobachtet wird. Eine mögliche Erklärung für das fehlende Therapieansprechen wird in der Immunogenität von Biologika gesehen. Die resultierenden Anti-Drug-Antikörper (ADA) können die Wirkung der Biologika abschwächen und/oder unerwünschte Arzneimittelwirkungen hervorrufen.

Ziel Durch diese Arbeit sollten 2 neue Testverfahren zum Nachweis von ADA gegen Infliximab und die korrespondierenden Serumspiegel evaluiert werden. Dazu gehört ebenfalls die Klärung der Praktikabilität eines therapeutischen Drugmonitorings (TDM) sowie das Erfassen von ADA assoziierten Nebenwirkungen und Therapieversagen für den klinischen Alltag. Es sollte eine Einschätzung darüber gegeben werden, welche Effekte das Auftreten von ADA auf den Medikamentenspiegel und den Verlauf von entzündlich-rheumatischen Erkrankungen im Rahmen der Verlaufsuntersuchungen hat.

Patienten und Methodik Die vorliegende Studie umfasst 30 mit Infliximab behandelte Patienten (30% weiblich, mittleres Alter 55,5 Jahre, min. 33 Jahre, max. 73 Jahre) mit zuvor gesicherter PsA (20%) oder axialer SpA (80%). Bei 36,7% bestand eine Begleitmedikation mit einem konventionellen Basistherapeutikum (cDMARD). Bei den vorhandenen Proben wurden zu 2 Zeitpunkten (ZP) der Serumspiegel des Therapieantikörpers, sowie die totalen ADA (tADA) und freien ADA (fADA) mittels Enzyme-Linked-Immuno-Sorbent-Assay (ELISA) bestimmt und in Zusammenhang mit der Krankheitsaktivität gesetzt. Weiter wurde die Inter-Assay-Variabilität untersucht.

Ergebnisse Bei 19 Patienten (63,3%) wurden positive tADA nachgewiesen, bei 13 Patienten (43,3%) auch fADA. Bei Nachweis von positiven tADA fanden sich zu 94,7% zeitweise subtherapeutische Infliximabkonzentrationen. Hohe tADA Titer gingen mit einer höheren Krankheitsaktivität einher. fADA traten nur bei mittleren bis hohen tADA-Titern auf. Bei 30% der Patienten fanden sich tADA trotz klinischer Remission der Erkrankung. Zwischen den beiden Assays zur Erfassung des Infliximab Serumspiegels gab es zu beiden Messzeitpunkten eine hohe Interassay-Übereinstimmung (1. ZP r=0,78, p=0,01; 2. ZP r=0,96, p=0,01).

Schlussfolgerungen Eine Erfassung von ADA sollte im Kontext mit den korrespondierenden Medikamenten-Serumspiegeln im Rahmen der Verlaufsuntersuchungen erfolgen, um relevante Informationen für das Monitoring einer Infliximabtherapie im klinischen Alltag zu erhalten. Bei der Untersuchung auf ADA sollte zwischen niedrigen und hohen tADA unterschieden werden, da hohe Spiegel mit dem Auftreten von fADA und erhöhter Krankheitsaktivität assoziiert sind. Die Ergebnisse müssen jedoch immer auf den individuellen Fall im Zusammenhang mit der klinischen Situation bezogen werden, da ADA sogar bei klinischer Remission auftreten können.

Abstract

Background Tumour necrosis factor-α (TNF-α) inhibitors are an effective treatment option for various chronic inflammatory diseases. Despite acceptable responder rates, a considerable number of patients suffer from primary or secondary treatment failure. This phenomenon can be partially explained by the immunogenicity of biologicals with the formation of anti-drug antibodies (ADA), which may reduce treatment response and/or lead to side-effects.

Objectives The aim of this investigation was to evaluate two new commercial assays for the detection of ADA against infliximab and the corresponding drug levels in routine clinical practice. Furthermore, the clinical applicability of a therapeutic drug monitoring (TDM) as well as potential ADA-associated adverse events and loss of response were evaluated.

Methods The cohort consisted of 30 patients treated with infliximab (30% female, medium age 55.5 years, min. 33 years, max. 73 years), with an established diagnosis of axial spondylitis (80%) or psoriatic arthritis (20%). 36.7% received co-medication with a cDMARD. The patients were screened for total ADA (tADA) and free ADA (fADA) using enzyme-linked-immuno-sorbent-assays (ELISA) at least at two different sampling dates (SD) in correlation to clinical disease activity. The results of the assays were compared for inter-assay variability.

Results 19 patients (63.3%) were positive for tADA; 13 patients (43.3%) were also positive for fADA. Of note, 94.7% of cases with positive tADA had sub-therapeutic drug levels at least at one visit. In 36.7% of patients, tADA were detected at each measurement time point. In 10% of patients, fADA were detected permanently. High tADA titres correlated with a high disease activity. Of note, in 30% of patients, tADA were found despite clinical remission. Positive samples for fADA were only found in the presence of medium to high tADA levels. The inter-assay agreement for drug levels was high (1st SD r=0.78, p=0.01; 2nd SD r=0.96, p=0.01).

Conclusions Screening for ADA and the corresponding drug levels can provide useful information for the monitoring of infliximab therapy in daily clinical practice. It is advisable to differentiate between low and high tADA levels since high levels are associated with fADA and increased disease activity. However, the results must be interpreted on a case-by-case basis since ADA can even be detected in remission of disease.

Schlüsselwörter

Drug-Monitoring - Anti-Drug-Antikörper - Biologika - Infliximab

Key words

biologics - infliximab - drug monitoring - anti-drug antibodies

Publikationsverlauf

Artikel online veröffentlicht:
17. Dezember 2019

• Literatur

• 1 Vincent FB, Morand EF, Murphy K. et al. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Annals of the rheumatic diseases 2013; 72: 165-178
• 2 Kalden JR, Schulze-Koops H. Immunogenicity and loss of response to TNF inhibitors: implications for rheumatoid arthritis treatment. Nature reviews Rheumatology 2017; 13: 707-718
• 3 Bendtzen K. Immunogenicity of Anti-TNF-α Biotherapies: I. Individualized Medicine Based on Immunopharmacological Evidence. Frontiers in Immunology 2015; 6: 152
• 4 Ordas I, Mould DR, Feagan BG. et al. Anti-TNF monoclonal antibodies in inflammatory bowel disease: pharmacokinetics-based dosing paradigms. Clinical pharmacology and therapeutics 2012; 91: 635-646
• 5 Bartelds GM, Wijbrandts CA, Nurmohamed MT. et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Annals of the rheumatic diseases 2007; 66: 921-926
• 6 Chen DY, Chen YM, Tsai WC. et al. Significant associations of antidrug antibody levels with serum drug trough levels and therapeutic response of adalimumab and etanercept treatment in rheumatoid arthritis. Annals of the rheumatic diseases 2014; 74: e16
• 7 Bendtzen K. Immunogenicity of Anti-TNF-alpha Biotherapies: II. Clinical Relevance of Methods Used for Anti-Drug Antibody Detection. Front Immunol 2015; 6: 109
• 8 Kosmac M, Avcin T, Toplak N. et al. Exploring the binding sites of anti-infliximab antibodies in pediatric patients with rheumatic diseases treated with infliximab. Pediatric research 2011; 69: 243-248
• 9 van Schouwenburg PA, van de Stadt LA, de Jong RN. et al. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Annals of the rheumatic diseases 2013; 72: 104-109
• 10 van der Laken CJ, Voskuyl AE, Roos JC. et al. Imaging and serum analysis of immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to therapy for rheumatoid arthritis. Annals of the rheumatic diseases 2007; 66: 253-256
• 11 Gorovits B, Baltrukonis DJ, Bhattacharya I. et al. Immunoassay methods used in clinical studies for the detection of anti-drug antibodies to adalimumab and infliximab. Clinical and experimental immunology 2018; 192: 348-365
• 12 Hart MH, de Vrieze H, Wouters D. et al. Differential effect of drug interference in immunogenicity assays. Journal of immunological methods 2011; 372: 196-203
• 13 Afonso J, Lopes S, Goncalves R. et al. Detection of anti-infliximab antibodies is impacted by antibody titer, infliximab level and IgG4 antibodies: a systematic comparison of three different assays. Therapeutic advances in gastroenterology 2016; 9: 781-794
• 14 van Schouwenburg PA, Bartelds GM, Hart MH. et al. A novel method for the detection of antibodies to adalimumab in the presence of drug reveals “hidden” immunogenicity in rheumatoid arthritis patients. Journal of immunological methods 2010; 362: 82-88
• 15 Mitchell RA, Shuster C, Shahidi N. et al. The Utility of Infliximab Therapeutic Drug Monitoring among Patients with Inflammatory Bowel Disease and Concerns for Loss of Response: A Retrospective Analysis of a Real-World Experience. Canadian journal of gastroenterology &. hepatology 2016; 2016: 5203898
• 16 [Anonym]. P545. The effect of total and free anti-drug antibodies on infliximab pharmacokinetics between 2 drug administrations. Journal of Crohn̓s and Colitis 2016; 10: S377.371-S377
• 17 Bartelds GM, Wijbrandts CA, Nurmohamed MT. et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Annals of the rheumatic diseases 2007; 66: 921-926
• 18 Mok CC, van der Kleij D, Wolbink GJ. Drug levels, anti-drug antibodies, and clinical efficacy of the anti-TNFalpha biologics in rheumatic diseases. Clinical rheumatology 2013; 32: 1429-1435
• 19 Wolbink GJ, Vis M, Lems W. et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis and rheumatism 2006; 54: 711-715
• 20 van Schouwenburg PA, Krieckaert CL, Rispens T. et al. Long-term measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding test shows predictive value and transient antibody formation. Annals of the rheumatic diseases 2013; 72: 1680-1686
• 21 Ben-Horin S, Mazor Y, Yanai H. et al. The decline of anti-drug antibody titres after discontinuation of anti-TNFs: implications for predicting re-induction outcome in IBD. Alimentary pharmacology & therapeutics 2012; 35: 714-722
• 22 Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Annals of the rheumatic diseases 2013; 72: 1947-1955
• 23 Jamnitski A, Bartelds GM, Nurmohamed MT. et al. The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Annals of the rheumatic diseases 2011; 70: 284-288
• 24 Radstake TR, Svenson M, Eijsbouts AM. et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Annals of the rheumatic diseases 2009; 68: 1739-1745
• 25 Jani M, Dixon WG, Lunt M et al. OP0229 The association of biologic drug-levels with infection risk: results from the british society for rheumatology biologics register for rheumatoid arthritis. 2018
• 26 Ben-Horin S, Yavzori M, Katz L. et al. The immunogenic part of infliximab is the F(ab')2, but measuring antibodies to the intact infliximab molecule is more clinically useful. Gut 2011; 60: 41-48
• 27 Vultaggio A, Matucci A, Nencini F. et al. Anti-infliximab IgE and non-IgE antibodies and induction of infusion-related severe anaphylactic reactions. Allergy 2010; 65: 657-661
• 28 Afif W, Loftus Jr. EV, Faubion WA. et al. Clinical utility of measuring infliximab and human anti-chimeric antibody concentrations in patients with inflammatory bowel disease. The American journal of gastroenterology 2010; 105: 1133-1139
• 29 Liefferinckx C, Minsart C, Toubeau JF. et al. Infliximab Trough Levels at Induction to Predict Treatment Failure During Maintenance. Inflammatory bowel diseases 2017; 23: 1371-1381
• 30 Chen DY, Chen YM, Hsieh TY. et al. Drug trough levels predict therapeutic responses to dose reduction of adalimumab for rheumatoid arthritis patients during 24 weeks of follow-up. Rheumatology (Oxford, England) 2016; 55: 143-148