Abstract
Biologic drugs have greatly improved treatment outcomes of inflammatory joint diseases, but a substantial proportion of patients either do not respond to treatment or lose response over time. Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), constitute a significant clinical problem. Anti-drug antibodies influence the pharmacokinetics of the drug, are associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. The prevalence of ADAb differs among drugs and diseases, and the detection of ADAb also depends on the assay format. Most data exist for the tumor necrosis factor-alpha inhibitors infliximab and adalimumab, with a frequency of ADAb that ranges from 10 to 60% across studies. Measurement of ADAb and serum drug concentrations, therapeutic drug monitoring, has been suggested as a strategy to optimize therapy with biologic drugs. Although the recent randomized clinical Norwegian Drug Monitoring (NOR-DRUM) trials show promise towards a personalized medicine prescribing approach by therapeutic drug monitoring, several challenges remain. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb. Comparing results between different assays and laboratories is difficult, which complicates the development of cut-offs necessary for guidelines and the implementation of ADAb measurements in clinical practice. With the possible exception of infliximab, limited data on clinical relevance and cost effectiveness exist to support therapeutic drug monitoring as a routine clinical strategy to monitor biologic drugs in inflammatory joint diseases. The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of inflammatory joint diseases.
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In treatment with biologic drugs, anti-drug antibody formation is associated with reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions. |
Therapeutic drug monitoring of biologic drugs has shown promise as a strategy for treatment optimization, supported by emerging evidence including the recent randomized Norwegian Drug Monitoring (NOR-DRUM) clinical trials, but more data are needed. |
Widely differing characteristics of anti-drug antibody assays, a lack of reliable markers to identify patients at risk of anti-drug antibody development, and limited guidance on the interpretation of results are barriers that must be overcome to harness the potential of therapeutic drug monitoring in clinical practice. |
1 Introduction
Biologic drugs have become a cornerstone of treatment in inflammatory joint diseases (IJDs), including rheumatoid arthritis (RA), spondyloarthritis (SpA), and psoriatic arthritis (PsA), and have greatly improved treatment outcomes. Biologic drugs used in the treatment of IJDs include tumor necrosis factor inhibitor (TNFi) monoclonal antibodies (mAbs) and receptor fusion protein, a T-cell co-stimulation modulator fusion protein, an anti-CD20 mAb, and anti-interleukin (IL)-17A, anti-IL-6 receptor, and anti-IL-12/23 mAbs. Despite the advances in therapy, a substantial proportion of patients either do not respond to treatment or lose response over time [1,2,3].
Drug immunogenicity, manifested as the formation of anti-drug antibodies (ADAb), is a major cause of non-response [4, 5]. All biologic drugs, being large and complex allogenic proteins, are able to elicit patient immune responses against the drug, with the production of ADAb that influence the effectiveness and pharmacokinetics of the drug, namely by blocking binding to its target and by accelerating clearance of the drug [6]. Anti-drug antibody formation is a significant clinical problem leading to reduced clinical efficacy, and an increased risk of adverse events such as infusion reactions [4, 5].
Measurement of ADAb and serum drug concentrations, TDM, has been suggested as a strategy to optimize treatment with biologic drugs [7,8,9]. While TDM has shown promise and may be an effective strategy in personalizing treatment decisions in IJDs, there are also several challenges. While different methods used for drug measurements usually give comparable results, and published data on therapeutic drug concentrations may be relevant for laboratories and clinicians worldwide, this is not the case for ADAb [10, 11]. A plethora of assay formats, with widely differing properties, is currently used for measuring ADAb [12, 13]. Comparing results between different assays and laboratories is difficult, which complicates the implementation of ADAb measurements in clinical practice. The recent “points to consider (PtC)” from the European Alliance of Associations for Rheumatology (EULAR) Task Force on TDM of biologic drugs address the clinical relevance of ADAb assessments, and highlight several knowledge gaps within this field [10].
The aim of this review is to provide an overview of the characteristics and prevalence of ADAb, predisposing factors to ADAb formation, commonly used assessment methods, clinical consequences of ADAb, and the potential implications of ADAb assessments for everyday treatment of IJDs.
2 Structure and Evolution of Biologic Drugs
The first therapeutic mAb used in humans, the murine mAb muromonab (OKT3), was approved in 1986 for the treatment of transplant rejections. This and other early therapeutic mAbs were fully murine and rapidly induced anti-murine immune responses in the patients [14]. They were thus unsuitable for repeated use in diseases such as IJDs. To overcome these problems, chimeric mAbs were introduced in the 1990s. With recombinant antibodies, highly immunogenic murine sequences were replaced with human sequences, and only variable regions of light and heavy chains remained murine [15]. Following advancements in antibody engineering, humanized antibodies became available in the late 1990s. A humanized antibody is an immunoglobulin where only the complementarity-determining regions, the variable part of the antibody that determines the specific antigen recognition site, are non-human [15]. Adalimumab was the world’s first fully human therapeutic antibody and was approved for the treatment of RA in 2002 [15]. Although fully human antibodies are presumably less immunogenic than chimeric and humanized antibodies, they still contain allogenic sequences within the complementarity determining region [16].
3 Characteristics of ADAb and Mechanisms of Formation
The exact immunological mechanisms behind immune responses directed against therapeutic mAbs are not completely understood [17, 18], but the main mechanism for development of ADAb is thought to be T cell dependent with peptides from the therapeutic mAb presented by the human leukocyte antigen (HLA). Identifying and removing T-cell epitopes from a putative therapeutic molecule has been shown to be important to lower immunogenicity in the development of new biologic drugs [18]. Additionally, ADAb formation may be triggered by T-cell independent activation of B cells by cross-linking of B-cell receptors [17]. This mechanism depends on multiple closely spaced epitopes, which may be attributed to impurities and aggregates in the drug formulation [19].
A number of studies have shown that the risk of ADAb formation is greatest early in the treatment course [20,21,22,23,24], corresponding to the immune system’s reaction to an antigen. As in antibody formation generally, the response is first IgM, maturing into IgG. IgG1 and IgG4 are the dominating isotypes and IgG4 has been suggested to develop during long-term treatment [25, 26].
The ADAb formed may be neutralizing—they block the antigen-binding capacity of the therapeutic molecule—or non-neutralizing [6]. Neutralizing ADAb, i.e., anti-idiotype ADAb binding to the antigen-binding site will directly affect the ability of the therapeutic antibody to bind its target and diminish the efficacy of the drug. Non-neutralizing ADAb, i.e., anti-allotype ADAb binding to epitopes outside the antigen-binding region, may not directly interfere with antigen binding, but could form complexes with drugs and theoretically enhance Fcγ receptor-mediated drug clearance [27]. Both neutralizing and non-neutralizing ADAb could also be associated with immune complex-mediated alterations in Fc-mediated effector functions, including enhanced complement activation and Fcγ receptor-mediated effects of the drug [28]. Neutralizing ADAb are presumably of greatest clinical relevance, but both types of ADAb may decrease the availability of the drug, lessen its clinical effect, and affect the risk of adverse events.
4 Prevalence of ADAb in IJDs
An overview of the prevalence of ADAb formation to biologic drugs in IJDs is shown in Table 1. The most robust data exist for the TNFi infliximab and adalimumab with ADAb formation reported in 10–60% of patients across diseases [4, 5, 29]. For the fully human TNFi golimumab, the prevalence of ADAb is lower, which ranges from 2 to 15% across studies. Because of its structure, etanercept is presumably less immunogenic than other TNFi. Most studies report no formation of anti-etanercept antibodies [30,31,32,33], but anti-etanercept antibodies have been reported in up to 13% in RA [34,35,36,37]. Anti-drug antibodies measured in these studies were non-neutralizing, and not associated with lower drug concentrations or a lack of response. For certolizumab pegol, the reported frequency of ADAb in IJDs ranges from 5 to 65% [38,39,40,41,42,43,44]. The large variation is notable, but may be attributed to different time points, assay formats (including differences in detection of anti-PEG antibodies), and study populations.
Data regarding prevalence of ADAb are scarce for non-TNFi (Table 1). The discrepancy in available data for non-TNFi versus TNFi is likely related to differences in the duration of marketing and the more extensive use of TNFi.
The differences in the prevalence of ADAb development between drugs, both within and between classes, are striking. Inherent differences in the pharmacological compound as well as their mechanisms of action are important factors explaining the differences, as further discussed in the next section. Advances in antibody engineering and production likely explain lower immunogenicity of newer biologic drugs. However, comparisons of immunogenic potential across biologic drugs and diagnoses should be done with caution. The number of studies and study populations, the indications for use, as well as dosing regimens and use of concomitant immunomodulators differ among drugs and diagnoses. Importantly, the use of different assays for ADAb detection undoubtedly influences the results [10, 11] (as discussed in detail below).
5 Factors Affecting ADAb Development
The formation of ADAb to TNFi and other biologic drugs is a complex process, where both treatment-related and patient-related factors contribute. Identification of factors associated with ADAb development is important as they may aid in the selection of treatment and identify patients who could benefit from co-medication and close monitoring [45].
5.1 Treatment-Related Factors
5.1.1 Drug-Related Factors
As described above, all biologic drugs are allogenic molecules that may elicit immune responses, with molecules containing non-human regions more likely to trigger immune response [16]. Drug aggregates and impurities may also increase immunogenicity. The pharmacodynamic properties of individual drugs presumably also influence immunogenicity, i.e., drugs that inhibit B cells or IL-6 pathways likely have lower immunogenic potential [5].
5.1.2 Concomitant Immunosuppression
Several studies have found methotrexate comedication to reduce the risk of ADAb to adalimumab [46,47,48,49,50,51] and infliximab [50,51,52] therapy in patients with RA. The protective effect has been proposed to be dose dependent [48, 49]. Although concomitant use of methotrexate is less common in patients with SpA, methotrexate has also been suggested to reduce the risk of ADAb in patients with SpA receiving adalimumab and infliximab therapy [45, 53]. Data for sulfasalazine and leflunomide are limited [54]. In two studies comparing the effect of concomitant methotrexate to other concomitant synthetic disease-modifying antirheumatic drugs, patients takig methotrexate had a higher probability of detectable TNFi serum concentrations and clinical response [55, 56]. Unfortunately, results for ADAb were not reported.
5.1.3 Route and Mode of Administration
Subcutaneous (SC) drug administration is commonly perceived to be associated with enhanced immunogenic potential, as compared with intravenous (IV) administration. This has been proposed to be due to efficient antigen presentation in the immune response to subcutaneous proteins [57]. While enhanced immunogenic potential has been demonstrated for some SC biologic drugs, the prevalence of ADAb formation is similar for SC and IV formulations for other biologics [57, 58]. The latter has been suggested for tocilizumab and abatacept, which are used in both SC and IV formulations in IJDs [59,60,61,62]. Low drug doses, episodic therapy, and drug holidays are associated with an increased risk of ADAb to TNFi [5, 45]. This increased risk is likely attributed to low drug concentrations, which has been linked to ADAb formation [45, 63,64,65].
5.2 Patient-Related Factors
5.2.1 Genetic Factors
Because of the known involvement of antigen-presenting cells and HLA class II molecules in the mechanism underlying ADAb formation described above, variations in HLA class II genes have been suspected to be involved in ADAb formation [66]. This is supported by two genome-wide association studies that have linked the HLA-DQA*05 allele group to ADAb formation to biologic drugs in patients with IJDs other than immune-mediated inflammatory diseases [67, 68]. A study of patients with RA and hidradenitis suppurativa receiving adalimumab therapy examining the HLA-DQB1 and HLA-DRB1 loci found allele groups associated with both an increased and a reduced risk of ADAb [69]. The haplotype DRB1*03:01~DQB1*02:01~DQA1*05:01, which is strongly associated with several autoimmune diseases [70, 71], has also been associated with an increased risk of ADAb in patients with Crohn’s disease treated with infliximab [72]. A similar association was also found in a recent sub-analysis of the Norwegian Drug Monitoring (NOR-DRUM) trials assessing patients with immune-mediated inflammatory diseases receiving infliximab therapy [73]. This study, however, found the HLA-DQ2 haplotypes DQB1*02:01~DQA1*05:01 and DQB1*02:02~DQA1*02:01 to be the most important HLA variants associated with an increased risk of ADAb. HLA-DQB1 and HLA-DQA1 genes together form the HLA-DQ2 molecule, which was shown to bind strongly to peptide sequences derived from infliximab. The fact that similar findings have been presented by studies including different diseases suggests that the molecular mechanisms underlying ADAb formation are not disease specific. Other genetic polymorphisms, such as in the CXCL12, IL-10, and Fc gamma receptor (FCGR3A) genes, have also been proposed to be associated with a risk of ADAb formation to TNFi [67, 74,75,76]. Whilst an area of research interest, at present, there is no definitive evidence to support genetic testing to predict ADAb formation as most studies are limited by small patient numbers or a lack of replication.
5.2.2 Disease Type
In the NOR-DRUM trials, which included patients with RA, PsA, SpA, and inflammatory bowel disease, significant differences in immunogenicity were found between diagnoses, with patients with RA having the highest rate of ADAb formation and patients with SpA the lowest [45]. Despite concomitant use of immunosuppressant drugs being more common in patients with RA [77, 78], lower rates of ADAb formation in patients with SpA compared with RA have also been reported previously [5, 50]. Infliximab-treated patients with RA receive a lower starting dose than the other diagnoses, which might contribute to a higher proportion of patients with ADAb in this group. Another explanation may be related to higher levels of B-cell activating factor in patients with RA. This cytokine may be involved in the pathogenesis of RA, and has also been associated with ADAb to TNFi [79, 80].
5.2.3 Other Patient-Related and Disease-Related Factors
Smoking [45, 64, 67, 81], higher disease activity [20, 45, 81, 82], and longer disease duration [20] are other patient-related factors associated with ADAb to TNFi. Higher body mass index has been linked to the immunogenicity of TNFi in patients with Crohn’s disease [64]. Whether this relates to lower drug concentrations needs further clarification. Furthermore, anti-nuclear antibodies (ANA), rheumatoid factor positivity, and female sex have also been associated with ADAb to infliximab in patients with RA [83, 84].
5.2.4 Methods for Assessment of ADAb
Various assay formats exist for the measurement of ADAb [12, 13]. Assays may have widely differing capture and detection principles and some assays include elaborate sample pre-treatment steps. As a consequence, test results from different assays are rarely comparable, and clinicians should be familiar with the properties of the assay provided by their laboratory [10, 11]. Perhaps the most important factor to consider is whether the assay specifically measures neutralizing antibodies or also measures non-neutralizing antibodies (as discussed below). Most ADAb assays are drug sensitive, i.e., they have limited ability to detect ADAb in the presence of a circulating drug. Drug-tolerant assays usually incorporate sample pre-treatment steps and may allow the detection of ADAb in the presence of a drug [85]. There are three main categories of assay formats for the measurement of ADAb; immunoassay formats, liquid-phase methods, and functional assays.
5.3 Immunoassay Formats
Immunoassay formats are widely used in clinical practice and research, as they are (comparably) low-cost and high-throughput methods. The formats include antibody capture tests, bridging assays, antigen binding tests, and inhibition assays, as illustrated in Fig. 1a–d. The terminology may be confusing and (mis)classification of assay formats based on detection principles is common. In the subsequent section, we present an overview of the most common immunoassays used in routine practice. In most immunoassay formats, the tracer molecule can be conjugated to optional detection labels, commonly an enzyme, a radioisotope, or a fluorescent/electrochemiluminescent molecule. When an enzyme-substrate reaction is used as the detection method, the assay is commonly referred to as an enzyme-linked immunosorbent assay or enzyme immunoassay, irrespective of the assay format or assay property. This is common with other detection methods as well, i.e., radioimmunoassa or immunoradiometric assay with radioactive tracers, fluoroimmunassay or immunofluorometric assay with fluorescent labels, and electrochemiluminescence immunoassay with electrochemiluminescent labels. Although these names and acronyms are well established, they are not always used correctly and rarely reveal important information about an assay’s property. Below (and in Fig. 1a–d), we briefly describe common immunoassays used for ADAb detection based on format, not the detection label.
Immunoassay formats used for anti-drug antibody (ADAb) detection. a In antibody capture tests, ADAb is “captured” by binding to a solid-phase bound biologic drug, and quantified by labeled anti-human antibody tracers. b In the bridging test, ADAb are detected by cross-linking of the solid-phase and labeled biologic drug molecules. c In the antigen-binding test, human immunoglobulins are captured by protein A (or anti-human antibody) coated sepharose beads. After non-bound serum components are washed off, ADAb are detected by binding to labeled biologic drug/fragment. d In the inhibition test, samples are preincubated with a known amount of labeled biologic drug. Anti-drug antibodies inhibit binding of a labeled biologic drug to its target molecule (e.g., tumor necrosis factor alpha [TNFα]). The signal is thus inversely proportional to the amount of ADAb in the sample. Assay antibodies are illustrated as intact immunoglobulins, but immunoglobulin fragments are preferred in most formats. Created with BioRender
In antibody capture tests, ADAb is captured by binding to the solid-phase bound biologic drug, and quantified by labeled anti-human antibody tracers (Fig. 1a). These assays are inexpensive and easy to use, but limitations include high background signals and the potential for false-positive results due to unspecific binding. Bridging assays (Fig. 1b) are widely used to detect ADAb, partly because they can be established using the biologic drug both as a solid-phase and tracer protein. However, as they rely on both ADAb Fab’ fragments to be free to cross-link the biologic drug molecules [12], they are highly drug sensitive (i.e., have limited ability to detect ADAb in the presence of a detectable drug) and also have limited ability to detect ADAb of IgG4 subclass [86, 87]. Hence, bridging assays risk underestimating ADAb. In addition, if an unmodified (whole IgG) biologic drug is used as a solid-phase and tracer protein, interference from (Fc-binding) rheumatoid factor is a risk particularly relevant in patients with RA. In an antigen-binding test, beads coated with protein A or anti-human Fc antibodies capture immunoglobulins in the sample (Fig. 1c). Anti-drug antibodies immobilize to the beads then bind to labeled fragments of the biologic drug [12]. Inhibition assays are based on the ability of ADAb to inhibit binding of the labeled biologic drug to its target molecule (e.g., TNFα) [Fig. 1d], and thus selectively measure neutralizing antibodies [88, 89].
While inhibition assays and most antigen-binding tests (including Fab-fragments) measure neutralizing ADAb, antibody capture tests and bridging tests (Sect. 6.1 and Fig. 1) can measure both neutralizing and non-neutralizing ADAb, depending on whether whole Abs or Fab or F(ab′)2 fragments are used as capture and detection molecules [90]. Interpretation of results from different ADAb assays is complex, and distinction between neutralizing and non-neutralizing ADAb may be difficult unless assay characteristics are described in publications.
5.4 Liquid-Phase Methods
Liquid-phase methods include a high-performance liquid chromatography-based homogenous mobility shift assay [91]. The method is based on size exclusion high-performance liquid chromatography separating the free fluorescent-labeled drug from the ADAb-bound labeled drug. As antigen-antibody binding takes place in the liquid phase, these methods are suggested to circumvent potential interferences related to solid-phase assays [92].
5.5 Functional Assays
Neutralizing ADAb can be measured by reporter gene assays that employ cells carrying nuclear factor-κB regulated firefly luciferase reporter gene constructs activated by TNFα [93]. Presence of TNFi inhibits expression of the reporter gene, and the amount of TNFi is thus inversely proportional to the luminescence produced by the reporter cells. For the detection of neutralizing ADAb, the sample is spiked with a known amount of TNFi, before the inhibition of TNFi activity is quantified by the luminescence produced by the reporter cells [92]. Functional cell-based assays can be used in combination with immunoassay formats to quantify the amount of both binding and neutralizing ADAb [92]. However, the added value of cell-based assays is unclear, owing to lower sensitivity [94] and because some immunoassay formats are able to selectively detect neutralizing ADAb [95, 96]. The latter is particularly relevant for inhibition assays, but also apply to other immunoassay formats using antibody Fab′ or F(ab′)2 fragments (instead of intact IgG) as solid-phase and/or tracer molecule.
5.6 Drug Interference and Drug-Tolerant Assays
As ADAb detection usually relies on binding to the labeled drug, most assays are drug sensitive, i.e., they have limited ability to detect ADAb in the presence of a circulating drug, owing to the formation of ADAb-drug complexes. Drug-tolerant versions have been developed for most traditional ADAb assay formats [85, 97]. In most drug-tolerant assays, serum samples are preincubated in acidic buffer (typically pH < 2.5) to dissociate ADAb-drug complexes before the detection of free ADAb [98, 99]. As these assays can reduce underestimation of ADAb in the presence of a drug and detect ADAb earlier, they can provide insight into the process of ADAb formation [100]. However, their clinical relevance is unclear as the clinical consequences of ADAb primarily depend on whether they neutralize/reduce the amount of pharmacologically active drug to subtherapeutic concentrations. Thus, in the presence of therapeutic concentrations of the free drug, detection of ADAb is rarely clinically relevant [24, 101, 102], as supported by the recent EULAR PtC [10]. In addition, the low pH during the preincubation step may damage some ADAb, which is a concern should such assays be used in clinical practice.
5.7 Rheumatoid Factor Interference
Antibody interference in immunoassays is an important concern as it may confound research and lead to unnecessary and potentially harmful diagnostic and therapeutic interventions in patients [103, 104]. As for other frequently used immunoassays [105], ADAb assays vary in their susceptibility to interference from rheumatoid factor [106]. Rheumatoid factor interference is particularly important to consider when designing immunoassays for the detection of biologic drug concentrations and ADAb, as these assays are intended for use in a high-risk RA population and often rely on binding to human(-ized) immunoglobulins (i.e., biologic drugs). Rheumatoid factor has the potential to cross-link assay antibodies by unspecific binding to the Fc portion in the absence of ADAb. The antibody capture and bridging formats are particularly vulnerable to interference from rheumatoid factor if not properly protected. The use of antibody fragments (i.e., Fab′ or F(ab′)2 fragments) without Fc, instead of intact IgG, reduces the risk of rheumatoid factor interference and also favors detection of neutralizing ADAb. Other measures to avoid rheumatoid factor interference include the use of blocking reagents and sample dilutions [103]. It is also important to avoid reagent impurities and aggregation [107].
5.8 Assay Comparability
As mentioned earlier, results from different ADAb assays are rarely comparable [94, 108] because of different methodologies, ADAb thresholds, and calibration. In addition to differences in drug tolerance and abilities to detect ADAb with neutralizing potential, assays vary in their ability to detect some isotypes and subclasses of ADAb, and low-affinity ADAb [6, 86, 87, 90]. As immune responses may vary with regard to antibody isotypes, subclasses, and binding properties, ADAb results are often reported in arbitrary units or semiquantitative categories. Calibration against absolute antibody concentrations and reporting of results in mass units (e.g., µg/L) can facilitate an inter-assay comparison, but many assay developers are understandably hesitant given the heterogeneity of ADAb. Given the considerable inter-assay variability, the recent EULAR PtC recommend using the same assay when serial measurements are performed in the same patient for clinical purposes [10]. Antidrug antibodies should also be measured and interpreted alongside contemporaneous drug concentration assessments [10]. The latter is important in order to consider a possible underestimation of ADAb in the presence of the circulating drug, and to evaluate the influence of ADAb on biologic drug pharmacokinetics. Furthermore, we recommend that clinicians familiarize themselves with the assay used and maintain a close dialogue with their laboratory regarding the interpretation of results.
6 Clinical Consequences of ADAb
6.1 Influence on Treatment Outcomes
Neutralizing ADAb decrease biologic activity of the drug by interfering with epitope binding, and both neutralizing and non-neutralizing ADAb form immune complexes that could accelerate drug clearance [6]. As a consequence, ADAb are associated with lower serum drug concentrations and patients may lose response to therapy (Fig. 2) [4, 6, 20, 109]. A relationship between the presence of ADAb assessed by drug-sensitive assays, low serum biologic drug concentrations, and poorer treatment outcomes has been described in prospective observational studies and post-hoc analyses of RCTs for TNFi (adalimumab, infliximab, golimumab, and certolizumab) [20, 33, 42, 43, 46, 47, 65, 74, 89, 110,111,112,113,114,115,116,117,118]. For etanercept, however, an association between ADAb and treatment response likely does not exist [33, 119]. Most studies are performed in patients with RA or SpA. Data regarding other biologic drugs including rituximab, tocilizumab, abatacept, secukinumab, ustekinumab, and ixekizumab are limited or lacking.
Model of the relationship between anti-drug antibody (ADAb) development, decrease in tumor necrosis factor alpha inhibitor (TNFi) serum concentration, and subsequent loss of clinical response. a Free circulating TNFi in sample. b Incipient ADAb formation. TNFi and ADAb in complexes. c Free ADAb becomes detectable using drug-sensitive assays (when TNFi undetectable/very low). Anti-drug antibodies can presumably be detected earlier using drug-tolerant assays. The clinical effect of the drug diminishes when the concentration of TNFi becomes subtherapeutic (the relative amount of ADAb is higher than free TNFi). Created with BioRender
However, ADAb are not always associated with a loss of effectiveness and treatment discontinuation, i.e., ADAb assessed by drug-tolerant assays may not influence the drug concentration enough to affect the therapeutic response. Importantly, some ADAb-positive patients may have sufficient serum drug concentrations during the majority of the treatment interval. Additionally, some patients are in remission independent of the drug and are thus unlikely to have a disease flare in the presence of ADAb. Hence, ADAb results should always be interpreted in the context of drug concentrations and the clinical situation [10].
6.2 Influence on Drug Safety
Another important clinical consequence of ADAb development is the increased risk of infusion reactions seen in patients treated with intravenous biologic drugs. Several studies have demonstrated that ADAb to infliximab predispose to infusion reactions, and a meta-analysis has suggested a four-fold increase in infusion reactions to infliximab in patients with ADAb [4]. Data are less robust for other intravenous biologic drugs such as tocilizumab and rituximab [4, 59, 65, 109, 111, 120]. Infusion reactions can range from mild hypersensitivity reactions, including arthralgia and malaise, to more severe infusion reactions, serum sickness, and rare anaphylactic reactions. Such reactions are likely caused by complexes formed between ADAb and the biologic drug. The role of ADAb in low concentrations, sometimes only detectable by drug-tolerant assays, has not been established, but it has been suggested that high ADAb levels are mandatory for the formation of large complexes necessary for complement activation [28]. There is no evidence linking ADAb to injection-site reactions of subcutaneous biologic drugs [11, 119, 121].
Development of ADAb has also been linked to serious adverse events such as thrombotic events, autoimmune reactions such as lupus-like reactions, and paradoxical events such as drug-induced vasculitis, the evidence for which has been previously reviewed [122]. An early study [123] reported a higher incidence of serious arterial and venous thromboembolic events in adalimumab-treated patients with ADAb (4/76), compared with patients without ADAb (4/196). Whilst highlighting a potential signal for further explorations, the conclusions were limited because there were only eight thrombotic events in total and a number of methodological challenges [122]. Reports from clinical practice suggest associations between ADAb and biologic drugs, adalimumab in particular, and adverse events such as rash, arthralgia, and fever, but no data exist to support this association.
Immune manifestations associated with TNFi medications can vary from a spectrum of asymptomatic immunological variations to clinical autoimmune manifestations. Anti-nuclear antibody formation is commonly seen in patients initiating a TNFi [124, 125]. It has also been proposed that patients receiving TNFi therapy may develop ANA and anti-double-stranded DNA antibodies because of immunogenicity [84, 126, 127]. Seroconversion of ANA and double-stranded DNA has also been observed at higher rates in patients with RA [125, 128] and psoriasis [126] in association with secondary non-response to TNFi, with a direct association with ADAb seen in infliximab-treated patients [127]. Similarly, in patients with inflammatory bowel disease, perinuclear anti-neutrophil cytoplasmic antibodies positivity has been associated with a lower clinical response in monoclonal antibody-treated patients and with factors associated with the risk of ADAb formation such as monotherapy [129, 130]. Patients predisposed to ADAb formation may also therefore be prone to developing autoantibodies such as ANA, double-stranded DNA, and ANCA. However, in large biologic observational studies in RA, the development of lupus and vasculitis like-events is infrequent with an absolute risk of 1/1000 patient-years (95% confidence interval 8–13) and 15/10,000 patient-years (95% confidence interval 12–19), respectively [130]. More knowledge regarding the association between ADAb formation and adverse events is warranted [10].
7 Role of ADAb Measurement in Personalized Treatment Strategies: TDM
Therapeutic drug monitoring of biologic drugs refers to measurements of serum concentrations of drugs and ADAb to guide clinical decision making. Proactive TDM refers to scheduled measurements with subsequent dose optimization, irrespective of the clinical situation, whereas reactive TDM refers to measurements in response to particular clinical situations, such as a suspected treatment failure [10]. Suggested algorithms for the interpretation of TNFi serum concentrations and ADAb in proactive and reactive TDM are shown in Fig. 3. Data supporting the clinical value of TDM of biologic drugs are still limited and only derived from TNFi [11].
Suggested algorithm for the interpretation of tumor necrosis factor inhibitor (TNFi) levels and anti-drug antibodies (ADAb) in responders or non-responders to TNFi. a Proactive therapeutic drug monitoring; regular measurements with subsequent dose optimization and b reactive therapeutic drug monitoring; measurements in response to particular clinical situations, such as a suspected treatment failure
7.1 Proactive TDM
An individualized treatment strategy based on regular assessments of serum drug concentrations and ADAb, proactive TDM, has been proposed as a clinical tool to optimize efficacy, patient safety, and the cost effectiveness of biologic drugs. However, most data are available for TNFi in gastroenterology [88, 131, 132]. Proactive TDM may optimize biologic drug therapy by: (a) minimizing undertreatment, which might lead to a lack of response, a loss of response, and possibly also predispose to ADAb production; (b) reducing overtreatment, which predisposes patients to side effects and increases costs; and (c) allowing for early identification of ADAb development, with the possibility to detect treatment failures prior to a clinical flare, discontinue ineffective treatment, and prevent hypersensitivity reactions.
The NOR-DRUM trials were the first randomized clinical trials to compare the effectiveness of proactive TDM to standard infliximab therapy across patients with immune-mediated inflammatory diseases, including IJDs [88, 133]. The NOR-DRUM A trial including 411 adults with RA, SpA, PsA, ulcerative colitis, Crohn’s disease, or psoriasis initiating infliximab therapy showed that proactive TDM compared to standard therapy did not improve treatment outcomes during induction of infliximab therapy, with a comparable proportion of patients (51 vs 53%) achieving remission at week 30 in the TDM and standard therapy group [133]. The study, however, suggested a role of proactive TDM during induction in patients at a high risk of ADAb formation as the proportion of patients in remission was higher in the TDM group (56%) than the standard therapy group (35%), among the 70 (15%) patients who developed ADAb. Furthermore, the results suggested that regular ADAb measurements may prevent infusion reactions, as significantly fewer infusion reactions was seen in the TDM group (n = 5) than in the standard therapy group (n = 16). The NOR-DRUM B trial, addressing the effectiveness of proactive TDM in the maintenance phase of infliximab therapy included 458 patients with RA, SpA, PsA, ulcerative colitis, Crohn’s disease, or psoriasis receiving infliximab therapy, concluded that proactive TDM was more effective than treatment without TDM in maintaining disease control [88]. The primary endpoint of sustained disease control without disease worsening was observed in 167 (73.6%) patients in the TDM group, and 127 (55.9%) patients in the standard therapy group. The adjusted difference was 17.6% (95% confidence interval 9.0–26.2%; p < 0.001) favoring TDM. Adverse events were reported in 137 patients (60%) and 142 patients (63%) in the TDM and standard therapy groups, respectively. Twenty-one patients (9.2%) in the TDM group and 27 patients (15.0%) in the standard therapy group developed clinically significant levels of ADAb. In the TDM group, 17 (8%) patients discontinued infliximab because of ADAb. Importantly, drug consumption was similar in both groups. The different results of the two NOR-DRUM trials may be due to different mechanisms for lack of response/primary treatment failure during the induction period and loss of response/secondary treatment failure during maintenance therapy [134]. Low drug concentrations may induce therapeutic failure during the maintenance phase, whereas high drug exposure may diminish potential benefits of TDM during the induction phase [135].
The NOR-DRUM trials suggest that proactive TDM may be beneficial during maintenance infliximab therapy, but not during induction unless the patient is at a high risk of developing ADAb. Risk factors of ADAb formation are described in Sect. 5. The potential benefit of proactive TDM should be balanced against the costs of performing TDM [136], which may be both direct and indirect costs. Avoiding disease worsening has important implications for patients [137, 138], as well as inflicting a burden on healthcare systems and financial implications for society. Cost-effectiveness analyses are needed to further explore this issue. Because of the immunogenicity profile of infliximab, the results of the NOR-DRUM trials cannot be extrapolated to other TNFi or other biologics, and additional randomized clinical trials are needed to clarify a benefit of TDM for these biologics. Based on limited evidence, the EULAR PtC developed prior to the NOR-DRUM B study did not recommend routine proactive TDM in the management of IJDs [10]. Prospective studies comparing TDM with standard of care with regard to clinical utility and cost effectiveness of TDM, for a range of biologic drugs in different IJDs, are still needed.
7.2 Reactive TDM Strategies
7.2.1 Treatment Failure
Reactive TDM is suggested as a tool to understand the cause of treatment failure, and can guide treatment decisions [10, 139], as shown in Fig. 3. In choosing between increasing the dose of the current biologic drug or switching to another therapy in the case of low drug concentrations, a dose increase may be the most appropriate choice in the absence of ADAb (Fig. 3) [88, 140]. As ADAb may be transient [24], some clinicians advocate a dose increase also in the presence of ADAb. Low to moderate levels of ADAb can sometimes be overcome, at least temporarily, by increasing the dose of the biologic drug. However, this treatment strategy has not been supported by observational data in infliximab-treated patients with RA and SpA with ADAb [111, 141]. These studies showed that although ADAb levels decreased temporarily following dose escalation in some patients, in most patients ADAb levels continued to increase despite the intervention [111, 141]. A reduction in ADAb levels in response to dose increase was primarily observed in patients with low ADAb levels [141]. These data suggest that ADAb perceived as transient are truly transient only in a minority of cases, whereas in most cases ADAb are “hidden” by higher drug concentrations and remain undetected in drug-sensitive assays [24]. It remains unclear whether adding or increasing the dose of concomitant synthetic disease-modifying antirheumatic drugs can mitigate an ongoing ADAb response.
Antidrug antibodies against a TNFi do not cross-react with other TNFi (except the corresponding biosimilars). It is thus appropriate to switch within the class in the context of ADAb to first TNFi (Fig. 3). Observational data have suggested that ADAb formation to one TNFi predicted response to the subsequent TNFi in patients with RA and SpA [142,143,144], but results have been conflicting [145, 146]. It has, however, been suggested that patients who develop ADAb to first TNFi have an increased risk of developing de novo ADAb to the next TNFi [47, 147]. This probably reflects common risk factors/mechanisms behind ADAb development to different TNFi as described above. The effect of switching to less immunogenic etanercept in the case of ADAb remains unclear [10, 142, 145].
Reactive TDM has been applied in clinical practice by many rheumatologists, based on empirical and observational data. The recent EULAR PtC state that reactive TDM, including both ADAb and drug concentrations, should be considered to understand clinical non-response, but this statement is based on limited data [10, 11]. Clinical trials addressing the effectiveness of reactive TDM strategies in the case of a suspected treatment failure are warranted.
7.3 Other Clinical Situations
7.3.1 A Biomarker to Predict Response
Observational studies have indicated that early assessment of ADAb status (weeks 4–14), in combination with drug concentrations, can predict later non-response to TNFi [10, 23, 148,149,150]. However, the clinical value of ADAb as an early biomarker to predict non-response, must be further investigated.
7.3.2 Tapering
Tapering of biologic drugs is a topic of interest, and assessment of drug concentrations and ADAb may help identifying candidates for tapering and/or discontinuation. Patients in stable remission despite subtherapeutic TNFi concentrations (with or without ADAb) are likely to be in spontaneous remission, and may probably taper or discontinue treatment without risking a disease worsening. However, current data for the utility of such clinical strategies are conflicting, and further studies are needed [116, 151,152,153]. Also relevant in the context of tapering, low drug exposure has been linked to an increased risk of ADAb development [5, 45, 65], thus monitoring patients with drug concentrations and ADAb might be beneficial during tapering. Monitoring of ADAb is also relevant when restarting the same biologic drug, as drug holidays are associated with an increased risk of ADAb development [5, 45].
7.3.3 Infusion/Hypersensitivity Reactions
Because of the known relationship between ADAb and infusion/hypersensitivity reactions to infliximab [4], measurement of ADAb is often performed if a hypersensitivity reaction is suspected, in line with the EULAR PtC [10]. One could argue that in the case of a severe reaction, it seems appropriate to discontinue infliximab regardless of ADAb status. However, in the case of a milder or unspecific reaction, measuring ADAb might aid in further treatment decisions.
7.3.4 Non-medical Switching to Biosimilars
Despite reassuring evidence regarding the effectiveness and safety of switching among biosimilars and the reference product, including the NOR-SWITCH trial [154, 155], there are still concerns among some clinicians and patients that switching to a new biosimilar may result in disease flares [156]. Monitoring ADAb status may be helpful in this situation, for instance to assess whether an adverse event can be attributed to immunogenicity of the biosimilar. If ADAb to the reference product is present, switching to a corresponding biosimilar is not recommended because of the cross-reactivity of ADAb to biosimilar products [157, 158]. Based on current evidence, biosimilars can be expected to exhibit the same immunogenicity as the originator molecule [159]. Comparative immunogenicity studies are required by the European Medicines Agency and the US Food and Drug Administration as part of the approval process of biosimilars and data on immunogenicity are presented in the relevant European Public Assessment Reports [158].
8 Future Potential and Challenges of ADAb Assessments in Personalized Treatment
Biologic drugs are at the core of modern treatment strategies for rheumatic diseases, and their global use is increasing. Assessing serum drug concentrations and ADAb formation against these agents offers an opportunity to personalize treatment, which has long been a goal within modern medicine. To achieve this, however, several barriers must be overcome. High-quality clinical trials of TDM within rheumatology are lacking, except for the NOR-DRUM trials [11]. This knowledge gap is underlined by the EULAR PtC research agenda [10]. The conduct of such trials requires that the therapeutic range of the biologic drug investigated has been identified. With the exception of infliximab and adalimumab, therapeutic ranges remain largely undetermined [11]. Reliable markers identifying patients at high risk of ADAb formation will help clinicians make treatment decisions to minimize such risk. Though progress has been made, including research on HLA markers, reliable predictors for use in clinical practice are still lacking. Cost-effectiveness studies on TDM are much needed, but also difficult to carry out, among other reasons because the cost of biologic drugs and testing vary from region to region and over time [10, 11]. Anti-drug antibody assay heterogeneity will remain a challenge for the foreseeable future. Initiatives such as Abirisk [160] have sought to form regional consortia to harmonize ADAb assays. Further efforts to help clinicians navigate the landscape of widely different ADAb assays should be welcomed. Home-sampling techniques and point-of care rapid tests have been developed for drug concentration and ADAb testing and could facilitate implementation of TDM in clinical practice [161,162,163,164,165]. Further research into immunogenicity, potential benefits of ADAb monitoring, and clinically validated ADAb assays are required to support TDM as a management approach in the future. Finally, there remains a need to educate physicians in the use of serum drug concentrations and ADAb measurements and identify barriers to the implementation of TDM [10, 166].
9 Conclusions
Assessing ADAb in combination with drug concentrations has shown promise as a strategy to optimize treatment with biologic drugs widely used in the treatment of IJDs today. Several challenges must be overcome for these assessments to be widely implemented in clinical rheumatology. In particular, identifying therapeutic drug concentration ranges and guidance regarding the interpretation of drug concentrations and ADAb results in the context of the clinical situation are essential. Importantly, high-quality clinical trials assessing clinical utility and cost effectiveness of assessments of ADAb and drug concentrations, both reactive and proactive TDM, are needed to form the basis for future guidelines and recommendations in rheumatology.
References
Maini R, St Clair EW, Breedveld F, Furst D, Kalden J, Weisman M, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet. 1999;354(9194):1932–9.
Weinblatt ME, Kremer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340(4):253–9.
Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, et al. Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum. 2004;50(5):1400–11.
Thomas SS, Borazan N, Barroso N, Duan L, Taroumian S, Kretzmann B, et al. Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases: a systematic review and meta-analysis. BioDrugs. 2015;29(4):241–58.
Strand V, Balsa A, Al-Saleh J, Barile-Fabris L, Horiuchi T, Takeuchi T, et al. Immunogenicity of biologics in chronic inflammatory diseases: a systematic review. BioDrugs. 2017;31(4):299–316.
Strand V, Goncalves J, Isaacs JD. Immunogenicity of biologic agents in rheumatology. Nat Rev Rheumatol. 2021;17(2):81–97.
Papamichael K, Vogelzang EH, Lambert J, Wolbink G, Cheifetz AS. Therapeutic drug monitoring with biologic agents in immune mediated inflammatory diseases. Expert Rev Clin Immunol. 2019;15(8):837–48.
Medina F, Plasencia C, Goupille P, Ternant D, Balsa A, Mulleman D. Current practice for therapeutic drug monitoring of biopharmaceuticals in rheumatoid arthritis. Ther Drug Monit. 2017;39(4):364–9.
Medina F, Plasencia C, Goupille P, Paintaud G, Balsa A, Mulleman D. Current practice for therapeutic drug monitoring of biopharmaceuticals in spondyloarthritis. Ther Drug Monit. 2017;39(4):360–3.
Krieckaert CL, van Tubergen A, Gehin JE, Hernández-Breijo B, Le Mélédo G, Balsa A, et al. EULAR points to consider for therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal diseases. Ann Rheum Dis. 2022. https://doi.org/10.1136/annrheumdis-2022-222155.
Krieckaert C, Hernández-Breijo B, Gehin JE, le Mélédo G, Balsa A, Jani M, et al. Therapeutic drug monitoring of biopharmaceuticals in inflammatory rheumatic and musculoskeletal disease: a systematic literature review informing EULAR points to consider. RMD Open. 2022;8(2): e002216.
Vande CN. Assays for measurement of TNF antagonists in practice. Frontline Gastroenterol. 2017;8(4):236–42.
Atiqi S, Hooijberg F, Loeff FC, Rispens T, Wolbink GJ. Immunogenicity of TNF-inhibitors. Front Immunol. 2020;11:312.
Goldstein G, Fuccello AJ, Norman DJ, Shield CF 3rd, Colvin RB, Cosimi AB. OKT3 monoclonal antibody plasma levels during therapy and the subsequent development of host antibodies to OKT3. Transplantation. 1986;42(5):507–11.
Lu RM, Hwang YC, Liu IJ, Lee CC, Tsai HZ, Li HJ, et al. Development of therapeutic antibodies for the treatment of diseases. J Biomed Sci. 2020;27(1):1.
Harding FA, Stickler MM, Razo J, DuBridge RB. The immunogenicity of humanized and fully human antibodies: residual immunogenicity resides in the CDR regions. MAbs. 2010;2(3):256–65.
Vaisman-Mentesh A, Gutierrez-Gonzalez M, DeKosky BJ, Wine Y. The molecular mechanisms that underlie the immune biology of anti-drug antibody formation following treatment with monoclonal antibodies. Front Immunol. 2020;11:1951.
Jawa V, Terry F, Gokemeijer J, Mitra-Kaushik S, Roberts BJ, Tourdot S, et al. T-cell dependent immunogenicity of protein therapeutics pre-clinical assessment and mitigation-updated consensus and review 2020. Front Immunol. 2020;11:1301.
Kumar S, Singh SK, Wang X, Rup B, Gill D. Coupling of aggregation and immunogenicity in biotherapeutics: T- and B-cell immune epitopes may contain aggregation-prone regions. Pharm Res. 2011;28(5):949–61.
Bartelds GM, Krieckaert CL, Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. JAMA. 2011;305(14):1460–8.
Nencini F, Vultaggio A, Pratesi S, Cammelli D, Milla M, Fiori G, et al. The kinetics of antidrug antibodies, drug levels, and clinical outcomes in infliximab-exposed patients with immune-mediated disorders. J Allergy Clin Immunol Pract. 2018;6(6):2065-72.e2.
Siljehult F, Ärlestig L, Eriksson C, Rantapää-Dahlqvist S. Concentrations of infliximab and anti-drug antibodies in relation to clinical response in patients with rheumatoid arthritis. Scand J Rheumatol. 2018;47(5):345–50.
Ding X, Zhu R, Wu J, Xue L, Gu M, Miao L. Early Adalimumab and anti-adalimumab antibody levels for prediction of primary nonresponse in ankylosing spondylitis patients. Clin Transl Sci. 2020;13(3):547–54.
van Schouwenburg PA, Krieckaert CL, Rispens T, Aarden L, Wolbink GJ, Wouters D. Long-term measurement of anti-adalimumab using pH-shift-anti-idiotype antigen binding test shows predictive value and transient antibody formation. Ann Rheum Dis. 2013;72(10):1680–6.
van Schouwenburg PA, Kruithof S, Votsmeier C, van Schie K, Hart MH, de Jong RN, et al. Functional analysis of the anti-adalimumab response using patient-derived monoclonal antibodies. J Biol Chem. 2014;289(50):34482–8.
van Schouwenburg PA, Krieckaert CL, Nurmohamed M, Hart M, Rispens T, Aarden L, et al. IgG4 production against adalimumab during long term treatment of RA patients. J Clin Immunol. 2012;32(5):1000–6.
Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther. 2008;84(5):548–58.
van Schie KA, Kruithof S, Ooijevaar-de Heer P, Derksen NIL, van de Bovenkamp FS, Saris A, et al. Restricted immune activation and internalisation of anti-idiotype complexes between drug and antidrug antibodies. Ann Rheum Dis. 2018;77(10):1471–9.
Borrega R, Araújo C, Aguiam N, Magro F, Fonseca JE, Danese S, et al. Systematic review and principal components analysis of the immunogenicity of adalimumab. BioDrugs. 2021;35(1):35–45.
Balsa A, Sanmarti R, Rosas J, Martin V, Cabez A, Gómez S, et al. Drug immunogenicity in patients with inflammatory arthritis and secondary failure to tumour necrosis factor inhibitor therapies: the REASON study. Rheumatology (Oxford). 2018;57(4):688–93.
Jamnitski A, Krieckaert CL, Nurmohamed MT, Hart MH, Dijkmans BA, Aarden L, et al. Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. Ann Rheum Dis. 2012;71(1):88–91.
Hoshino M, Yoshio T, Onishi S, Minota S. Influence of antibodies against infliximab and etanercept on the treatment effectiveness of these agents in Japanese patients with rheumatoid arthritis. Mod Rheumatol. 2012;22(4):532–40.
Gehin JE, Syversen SW, Warren DJ, Goll GL, Sexton J, Bolstad N, et al. Serum etanercept concentrations in relation to disease activity and treatment response assessed by ultrasound, biomarkers and clinical disease activity scores: results from a prospective observational study of patients with rheumatoid arthritis. RMD Open. 2021;7(3):e001985.
Keystone EC, Schiff MH, Kremer JM, Kafka S, Lovy M, DeVries T, et al. Once-weekly administration of 50 mg etanercept in patients with active rheumatoid arthritis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2004;50(2):353–63.
Emery P, Vencovský J, Sylwestrzak A, Leszczynski P, Porawska W, Baranauskaite A, et al. 52-week results of the phase 3 randomized study comparing SB4 with reference etanercept in patients with active rheumatoid arthritis. Rheumatology (Oxford). 2017;56(12):2093–101.
Dore RK, Mathews S, Schechtman J, Surbeck W, Mandel D, Patel A, et al. The immunogenicity, safety, and efficacy of etanercept liquid administered once weekly in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2007;25(1):40–6.
Klareskog L, Gaubitz M, Rodríguez-Valverde V, Malaise M, Dougados M, Wajdula J. Assessment of long-term safety and efficacy of etanercept in a 5-year extension study in patients with rheumatoid arthritis. Clin Exp Rheumatol. 2011;29(2):238–47.
Keystone E, Heijde D, Mason D Jr, Landewe R, Vollenhoven RV, Combe B, et al. Certolizumab pegol plus methotrexate is significantly more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 2008;58(11):3319–29.
Smolen J, Landewe RB, Mease P, Brzezicki J, Mason D, Luijtens K, et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis. 2009;68(6):797–804.
Fleischmann R, Vencovsky J, van Vollenhoven RF, Borenstein D, Box J, Coteur G, et al. Efficacy and safety of certolizumab pegol monotherapy every 4 weeks in patients with rheumatoid arthritis failing previous disease-modifying antirheumatic therapy: the FAST4WARD study. Ann Rheum Dis. 2009;68(6):805–11.
Choy E, McKenna F, Vencovsky J, Valente R, Goel N, Vanlunen B, et al. Certolizumab pegol plus MTX administered every 4 weeks is effective in patients with RA who are partial responders to MTX. Rheumatology (Oxford). 2012;51(7):1226–34.
Gehin JE, Goll GL, Warren DJ, Syversen SW, Sexton J, Strand EK, et al. Associations between certolizumab pegol serum levels, anti-drug antibodies and treatment response in patients with inflammatory joint diseases: data from the NOR-DMARD study. Arthritis Res Ther. 2019;21(1):256.
Jani M, Isaacs JD, Morgan AW, Wilson AG, Plant D, Hyrich KL, et al. High frequency of antidrug antibodies and association of random drug levels with efficacy in certolizumab pegol-treated patients with rheumatoid arthritis: results from the BRAGGSS cohort. Ann Rheum Dis. 2017;76(1):208–13.
Berkhout LC, Vogelzang EH, Hart MM, Loeff FC, Dijk L, Derksen NIL, et al. The effect of certolizumab drug concentration and anti-drug antibodies on TNF neutralisation. Clin Exp Rheumatol. 2020;38(2):306–13.
Brun MK, Goll GL, Jørgensen KK, Sexton J, Gehin JE, Sandanger Ø, et al. Risk factors for anti-drug antibody formation to infliximab: secondary analyses of a randomised controlled trial. J Intern Med. 2022;292(3):477–91.
Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis. 2007;66(7):921–6.
Bartelds GM, Wijbrandts CA, Nurmohamed MT, Stapel S, Lems WF, Aarden L, et al. Anti-infliximab and anti-adalimumab antibodies in relation to response to adalimumab in infliximab switchers and anti-tumour necrosis factor naive patients: a cohort study. Ann Rheum Dis. 2010;69(5):817–21.
Burmester GR, Kivitz AJ, Kupper H, Arulmani U, Florentinus S, Goss SL, et al. Efficacy and safety of ascending methotrexate dose in combination with adalimumab: the randomised CONCERTO trial. Ann Rheum Dis. 2015;74(6):1037–44.
Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. Ann Rheum Dis. 2012;71(11):1914–5.
Thomas SS, Borazan N, Barroso N, Duan L, Taroumian S, Kretzmann B, et al. Comparative immunogenicity of TNF inhibitors: impact on clinical efficacy and tolerability in the management of autoimmune diseases. A systematic review and meta-analysis. BioDrugs. 2015;29(4):241–58.
Maneiro JR, Salgado E, Gomez-Reino JJ. Immunogenicity of monoclonal antibodies against tumor necrosis factor used in chronic immune-mediated Inflammatory conditions: systematic review and meta-analysis. JAMA Intern Med. 2013;173(15):1416–28.
Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41(9):1552–63.
Ducourau E, Rispens T, Samain M, Dernis E, Le Guilchard F, Andras L, et al. Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial. RMD Open. 2020;6(1): e001047.
Jani M, Barton A, Warren RB, Griffiths CE, Chinoy H. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology (Oxford). 2014;53(2):213–22.
Martínez-Feito A, Plasencia-Rodríguez C, Navarro-Compán V, Hernández-Breijo B, González M, Monjo I, et al. The effect of methotrexate versus other disease-modifying anti-rheumatic drugs on serum drug levels and clinical response in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors. Clin Rheumatol. 2019;38(3):949–54.
Vogelzang EH, Pouw MF, Nurmohamed M, Kneepkens EL, Rispens T, Wolbink GJ, et al. Adalimumab trough concentrations in patients with rheumatoid arthritis and psoriatic arthritis treated with concomitant disease-modifying antirheumatic drugs. Ann Rheum Dis. 2015;74(2):474–5.
Jarvi NL, Balu-Iyer SV. Immunogenicity challenges associated with subcutaneous delivery of therapeutic proteins. BioDrugs. 2021;35(2):125–46.
Hamuro L, Kijanka G, Kinderman F, Kropshofer H, Bu DX, Zepeda M, et al. Perspectives on subcutaneous route of administration as an immunogenicity risk factor for therapeutic proteins. J Pharm Sci. 2017;106(10):2946–54.
Burmester GR, Choy E, Kivitz A, Ogata A, Bao M, Nomura A, et al. Low immunogenicity of tocilizumab in patients with rheumatoid arthritis. Ann Rheum Dis. 2017;76(6):1078–85.
Iwahashi M, Inoue H, Matsubara T, Tanaka T, Amano K, Kanamono T, et al. Efficacy, safety, pharmacokinetics and immunogenicity of abatacept administered subcutaneously or intravenously in Japanese patients with rheumatoid arthritis and inadequate response to methotrexate: a phase II/III, randomized study. Mod Rheumatol. 2014;24(6):885–91.
Genovese MC, Covarrubias A, Leon G, Mysler E, Keiserman M, Valente R, et al. Subcutaneous abatacept versus intravenous abatacept: a phase IIIb noninferiority study in patients with an inadequate response to methotrexate. Arthritis Rheum. 2011;63(10):2854–64.
Keystone EC, Kremer JM, Russell A, Box J, Abud-Mendoza C, Elizondo MG, et al. Abatacept in subjects who switch from intravenous to subcutaneous therapy: results from the phase IIIb ATTUNE study. Ann Rheum Dis. 2012;71(6):857–61.
Brandse JF, Mould D, Smeekes O, Ashruf Y, Kuin S, Strik A, et al. A real-life population pharmacokinetic study reveals factors associated with clearance and immunogenicity of infliximab in inflammatory bowel disease. Inflamm Bowel Dis. 2017;23(4):650–60.
Kennedy NA, Heap GA, Green HD, Hamilton B, Bewshea C, Walker GJ, et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol. 2019;4(5):341–53.
Wolbink GJ, Vis M, Lems W, Voskuyl AE, de Groot E, Nurmohamed MT, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54(3):711–5.
Jawa V, Cousens LP, Awwad M, Wakshull E, Kropshofer H, De Groot AS. T-cell dependent immunogenicity of protein therapeutics: preclinical assessment and mitigation. Clin Immunol. 2013;149(3):534–55.
Hassler S, Bachelet D, Duhaze J, Szely N, Gleizes A, Hacein-Bey Abina S, et al. Clinicogenomic factors of biotherapy immunogenicity in autoimmune disease: a prospective multicohort study of the ABIRISK Consortium. PLoS Med. 2020;17(10): e1003348.
Sazonovs A, Kennedy NA, Moutsianas L, Heap GA, Rice DL, Reppell M, et al. HLA-DQA1*05 carriage associated with development of anti-drug antibodies to infliximab and adalimumab in patients with Crohn’s disease. Gastroenterology. 2020;158(1):189–99.
Liu M, Degner J, Davis JW, Idler KB, Nader A, Mostafa NM, et al. Identification of HLA-DRB1 association to adalimumab immunogenicity. PLoS ONE. 2018;13(4): e0195325.
Price P, Witt C, Allcock R, Sayer D, Garlepp M, Kok CC, et al. The genetic basis for the association of the 8.1 ancestral haplotype (A1, B8, DR3) with multiple immunopathological diseases. Immunol Rev. 1999;167:257–74.
Thorsby E, Lie BA. HLA associated genetic predisposition to autoimmune diseases: genes involved and possible mechanisms. Transpl Immunol. 2005;14(3–4):175–82.
Powell Doherty RD, Liao H, Satsangi JJ, Ternette N. Extended analysis identifies drug-specific association of 2 distinct HLA class II haplotypes for development of immunogenicity to adalimumab and infliximab. Gastroenterology. 2020;159(2):784–7.
Bjørlykke K, Brun MK, Viken MK, Stenvik GE, Klaasen RA, Gehin JE, et al. P696 Genetic predisposition to infliximab immunogenicity in patients with immune-mediated inflammatory diseases: secondary analyses from a randomised clinical trial. J Crohns Colitis. 2022;16(Suppl_1):594–5.
Bartelds GM, Wijbrandts CA, Nurmohamed MT, Wolbink GJ, de Vries N, Tak PP, et al. Anti-adalimumab antibodies in rheumatoid arthritis patients are associated with interleukin-10 gene polymorphisms. Arthritis Rheum. 2009;60(8):2541–2.
Curci D, Lucafò M, Cifù A, Fabris M, Bramuzzo M, Martelossi S, et al. Pharmacogenetic variants of infliximab response in young patients with inflammatory bowel disease. Clin Transl Sci. 2021;14(6):2184–92.
Romero-Cara P, Torres-Moreno D, Pedregosa J, Vílchez JA, García-Simón MS, Ruiz-Merino G, et al. A FCGR3A polymorphism predicts anti-drug antibodies in chronic inflammatory bowel disease patients treated with anti-TNF. Int J Med Sci. 2018;15(1):10–5.
Carmona L, Gómez-Reino JJ. Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER. Arthritis Res Ther. 2006;8(3):R72.
Fafa BP, Louzada-Junior P, Titton DC, Zandonade E, Ranza R, Laurindo I, et al. Drug survival and causes of discontinuation of the first anti-TNF in ankylosing spondylitis compared with rheumatoid arthritis: analysis from BIOBADABRASIL. Clin Rheumatol. 2015;34(5):921–7.
Bitoun S, Nocturne G, Ly B, Krzysiek R, Roques P, Pruvost A, et al. Methotrexate and BAFF interaction prevents immunization against TNF inhibitors. Ann Rheum Dis. 2018;77(10):1463–70.
Hernández-Breijo B, Navarro-Compán V, Plasencia-Rodríguez C, Parodis I, Gehin JE, Martínez-Feito A, et al. BAFF predicts immunogenicity in older patients with rheumatoid arthritis treated with TNF inhibitors. Sci Rep. 2021;11(1):11632.
Quistrebert J, Hassler S, Bachelet D, Mbogning C, Musters A, Tak PP, et al. Incidence and risk factors for adalimumab and infliximab anti-drug antibodies in rheumatoid arthritis: a European retrospective multicohort analysis. Semin Arthritis Rheum. 2019;48(6):967–75.
Gill KL, Machavaram KK, Rose RH, Chetty M. Potential sources of inter-subject variability in monoclonal antibody pharmacokinetics. Clin Pharmacokinet. 2016;55(7):789–805.
Hambardzumyan K, Hermanrud C, Marits P, Vivar N, Ernestam S, Wallman JK, et al. Association of female sex and positive rheumatoid factor with low serum infliximab and anti-drug antibodies, related to treatment failure in early rheumatoid arthritis: results from the SWEFOT trial population. Scand J Rheumatol. 2019;48(5):362–6.
Mori A, Saito T, Takahashi M, Shibata M, Tsuji G, Hatachi S, et al. Presence of anti-nuclear antibodies is a risk factor for the appearance of anti-drug antibodies during infliximab or adalimumab therapy in patients with rheumatoid arthritis. PLoS ONE. 2020;15(12): e0243729.
Bloem K, van Leeuwen A, Verbeek G, Nurmohamed MT, Wolbink GJ, van der Kleij D, et al. Systematic comparison of drug-tolerant assays for anti-drug antibodies in a cohort of adalimumab-treated rheumatoid arthritis patients. J Immunol Methods. 2015;418:29–38.
van der Neut KM, Schuurman J, Losen M, Bleeker WK, Martínez-Martínez P, Vermeulen E, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317(5844):1554–7.
Rispens T, Ooijevaar-de Heer P, Bende O, Aalberse RC. Mechanism of immunoglobulin G4 Fab-arm exchange. J Am Chem Soc. 2011;133(26):10302–11.
Syversen SW, Jørgensen KK, Goll GL, Brun MK, Sandanger Ø, Bjørlykke KH, et al. Effect of therapeutic drug monitoring vs standard therapy during maintenance infliximab therapy on disease control in patients with immune-mediated inflammatory diseases: a randomized clinical trial. JAMA. 2021;326(23):2375–84.
Gehin JE, Warren DJ, Syversen SW, Lie E, Sexton J, Loli L, et al. Serum golimumab concentration and anti-drug antibodies are associated with treatment response and drug survival in patients with inflammatory joint diseases: data from the NOR-DMARD study. Scand J Rheumatol. 2021;50(6):445–54.
Rispens T, de Vrieze H, de Groot E, Wouters D, Stapel S, Wolbink GJ, et al. Antibodies to constant domains of therapeutic monoclonal antibodies: anti-hinge antibodies in immunogenicity testing. J Immunol Methods. 2012;375(1–2):93–9.
Wang SL, Ohrmund L, Hauenstein S, Salbato J, Reddy R, Monk P, et al. Development and validation of a homogeneous mobility shift assay for the measurement of infliximab and antibodies-to-infliximab levels in patient serum. J Immunol Methods. 2012;382(1–2):177–88.
Lázár-Molnár E, Delgado JC. Immunogenicity assessment of tumor necrosis factor antagonists in the clinical laboratory. Clin Chem. 2016;62(9):1186–98.
Pavlov IY, Carper J, Lázár-Molnár E, Delgado JC. Clinical laboratory application of a reporter-gene assay for measurement of functional activity and neutralizing antibody response to infliximab. Clin Chim Acta. 2016;453:147–53.
Steenholdt C, Bendtzen K, Brynskov J, Thomsen O, Ainsworth MA. Clinical implications of measuring drug and anti-drug antibodies by different assays when optimizing infliximab treatment failure in Crohn’s disease: post hoc analysis of a randomized controlled trial. Am J Gastroenterol. 2014;109(7):1055–64.
van Schouwenburg PA, van de Stadt LA, de Jong RN, van Buren EE, Kruithof S, de Groot E, et al. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Ann Rheum Dis. 2013;72(1):104–9.
van Schie KA, Hart MH, de Groot ER, Kruithof S, Aarden LA, Wolbink GJ, et al. The antibody response against human and chimeric anti-TNF therapeutic antibodies primarily targets the TNF binding region. Ann Rheum Dis. 2015;74(1):311–4.
Bloem K, Hernandez-Breijo B, Martinez-Feito A, Rispens T. Immunogenicity of therapeutic antibodies: monitoring antidrug antibodies in a clinical context. Ther Drug Monit. 2017;39(4):327–32.
Lofgren JA, Wala I, Koren E, Swanson SJ, Jing S. Detection of neutralizing anti-therapeutic protein antibodies in serum or plasma samples containing high levels of the therapeutic protein. J Immunol Methods. 2006;308(1–2):101–8.
van Schouwenburg PA, Bartelds GM, Hart MH, Aarden L, Wolbink GJ, Wouters D. A novel method for the detection of antibodies to adalimumab in the presence of drug reveals “hidden” immunogenicity in rheumatoid arthritis patients. J Immunol Methods. 2010;362(1–2):82–8.
Kharlamova N, Hermanrud C, Dunn N, Ryner M, Hambardzumyan K, Vivar Pomiano N, et al. Drug tolerant anti-drug antibody assay for infliximab treatment in clinical practice identifies positive cases earlier. Front Immunol. 2020;11:1365.
Van Stappen T, Vande Casteele N, Van Assche G, Ferrante M, Vermeire S, Gils A. Clinical relevance of detecting anti-infliximab antibodies with a drug-tolerant assay: post hoc analysis of the TAXIT trial. Gut. 2018;67(5):818–26.
Leu JH, Adedokun OJ, Gargano C, Hsia EC, Xu Z, Shankar G. Immunogenicity of golimumab and its clinical relevance in patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Rheumatology (Oxford). 2019;58(3):441–6.
Bolstad N, Warren DJ, Nustad K. Heterophilic antibody interference in immunometric assays. Best Pract Res Clin Endocrinol Metab. 2013;27(5):647–61.
Rotmensch S, Cole LA. False diagnosis and needless therapy of presumed malignant disease in women with false-positive human chorionic gonadotropin concentrations. Lancet. 2000;355(9205):712–5.
Gehin JE, Klaasen RA, Norli ES, Warren DJ, Syversen SW, Goll GL, et al. Rheumatoid factor and falsely elevated results in commercial immunoassays: data from an early arthritis cohort. Rheumatol Int. 2021;41(9):1657–65.
van Schie KA, Wolbink GJ, Rispens T. Cross-reactive and pre-existing antibodies to therapeutic antibodies: effects on treatment and immunogenicity. MAbs. 2015;7(4):662–71.
Tatarewicz S, Miller JM, Swanson SJ, Moxness MS. Rheumatoid factor interference in immunogenicity assays for human monoclonal antibody therapeutics. J Immunol Methods. 2010;357(1–2):10–6.
Bertin D, Serrero M, Grimaud JC, Desjeux A, Desplat-Jégo S. Monitoring of infliximab trough levels and anti-infliximab antibodies in inflammatory bowel diseases: a comparison of three commercially available ELISA kits. Cytokine. 2020;126: 154859.
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. Ann Rheum Dis. 2013;72(12):1947–55.
Martinez-Feito A, Plasencia-Rodriguez C, Navarro-Compan V, Jurado T, Kneepkens EL, Wolbink GJ, et al. Optimal concentration range of golimumab in patients with axial spondyloarthritis. Clin Exp Rheumatol. 2018;36(1):110–4.
Pascual-Salcedo D, Plasencia C, Ramiro S, Nuno L, Bonilla G, Nagore D, et al. Influence of immunogenicity on the efficacy of long-term treatment with infliximab in rheumatoid arthritis. Rheumatology (Oxford). 2011;50(8):1445–52.
Mulleman D, Chu Miow Lin D, Ducourau E, Emond P, Ternant D, Magdelaine-Beuzelin C, et al. Trough infliximab concentrations predict efficacy and sustained control of disease activity in rheumatoid arthritis. Ther Drug Monit. 2010;32(2):232–6.
Takeuchi T, Miyasaka N, Inoue K, Abe T, Koike T. Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study. Mod Rheumatol. 2009;19(5):478–87.
Kneepkens EL, Plasencia C, Krieckaert CL, Pascual-Salcedo D, van der Kleij D, Nurmohamed MT, et al. Golimumab trough levels, antidrug antibodies and clinical response in patients with rheumatoid arthritis treated in daily clinical practice. Ann Rheum Dis. 2014;73(12):2217–9.
Vogelzang EH, Kneepkens EL, Nurmohamed MT, van Kuijk AW, Rispens T, Wolbink G, et al. Anti-adalimumab antibodies and adalimumab concentrations in psoriatic arthritis; an association with disease activity at 28 and 52 weeks of follow-up. Ann Rheum Dis. 2014;73(12):2178–82.
Chen DY, Chen YM, Hsieh TY, Hung WT, Hsieh CW, Chen HH, 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). 2016;55(1):143–8.
Chen DY, Chen YM, Hung WT, Chen HH, Hsieh CW, Chen YH, et al. Immunogenicity, drug trough levels and therapeutic response in patients with rheumatoid arthritis or ankylosing spondylitis after 24-week golimumab treatment. Ann Rheum Dis. 2015;74(12):2261–4.
Chimenti MS, Triggianese P, Narcisi A, Marinari B, Teoli M, Faleri S, et al. Long-term treatment with adalimumab in psoriatic arthritis: serum adalimumab concentration, immunogenicity and the link with clinical response. J Int Med Res. 2016;44(1 Suppl.):48–52.
de Vries MK, van der Horst-Bruinsma IE, Nurmohamed MT, Aarden LA, Stapel SO, Peters MJ, et al. Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis. Ann Rheum Dis. 2009;68(4):531–5.
Krintel SB, Grunert VP, Hetland ML, Johansen JS, Rothfuss M, Palermo G, et al. The frequency of anti-infliximab antibodies in patients with rheumatoid arthritis treated in routine care and the associations with adverse drug reactions and treatment failure. Rheumatology (Oxford). 2013;52(7):1245–53.
Bender NK, Heilig CE, Dröll B, Wohlgemuth J, Armbruster FP, Heilig B. Immunogenicity, efficacy and adverse events of adalimumab in RA patients. Rheumatol Int. 2007;27(3):269–74.
Jani M, Dixon WG, Chinoy H. Drug safety and immunogenicity of tumour necrosis factor inhibitors: the story so far. Rheumatology (Oxford). 2018;57(11):1896–907.
Korswagen L, Bartelds G, Krieckaert C, Turkstra F, Nurmohamed M, van Schaardenburg D, et al. Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: a case series and cohort study. Arthritis Rheum. 2011;63(4):877–83.
Benucci M, Saviola G, Baiardi P, Cammelli E, Manfredi M. Anti-nucleosome antibodies as prediction factor of development of autoantibodies during therapy with three different TNFalpha blocking agents in rheumatoid arthritis. Clin Rheumatol. 2008;27(1):91–5.
Takase K, Horton SC, Ganesha A, Das S, McHugh A, Emery P, et al. What is the utility of routine ANA testing in predicting development of biological DMARD-induced lupus and vasculitis in patients with rheumatoid arthritis? Data from a single-centre cohort. Ann Rheum Dis. 2014;73(9):1695–9.
Pink AE, Fonia A, Allen MH, Smith CH, Barker JN. Antinuclear antibodies associate with loss of response to antitumour necrosis factor-alpha therapy in psoriasis: a retrospective, observational study. Br J Dermatol. 2010;162(4):780–5.
Hoffmann JH, Hartmann M, Enk AH, Hadaschik EN. Autoantibodies in psoriasis as predictors for loss of response and anti-infliximab antibody induction. Br J Dermatol. 2011;165(6):1355–8.
Yukawa N, Fujii T, Kondo-Ishikawa S, Yoshifuji H, Kawabata D, Nojima T, et al. Correlation of antinuclear antibody and anti-double-stranded DNA antibody with clinical response to infliximab in patients with rheumatoid arthritis: a retrospective clinical study. Arthritis Res Ther. 2011;13(6):R213.
Nguyen DL, Nguyen ET, Bechtold ML. pANCA positivity predicts lower clinical response to infliximab therapy among patients with IBD. South Med J. 2015;108(3):139–43.
Jani M, Dixon WG, Kersley-Fleet L, Bruce IN, Chinoy H, Barton A, et al. Drug-specific risk and characteristics of lupus and vasculitis-like events in patients with rheumatoid arthritis treated with TNFi: results from BSRBR-RA. RMD Open. 2017;3(1): e000314.
Cheifetz AS, Abreu MT, Afif W, Cross RK, Dubinsky MC, Loftus EV Jr, et al. A comprehensive literature review and expert consensus statement on therapeutic drug monitoring of biologics in inflammatory bowel disease. Am J Gastroenterol. 2021;116:2014–25.
Papamichael K, Cheifetz AS, Melmed GY, Irving PM, Vande Casteele N, Kozuch PL, et al. Appropriate therapeutic drug monitoring of biologic agents for patients with inflammatory bowel diseases. Clin Gastroenterol Hepatol. 2019;17(9):1655-68.e3.
Syversen SW, Goll GL, Jørgensen KK, Sandanger Ø, Sexton J, Olsen IC, et al. Effect of therapeutic drug monitoring vs standard therapy during infliximab induction on disease remission in patients with chronic immune-mediated inflammatory diseases: a randomized clinical trial. JAMA. 2021;325(17):1744–54.
Roda G, Jharap B, Neeraj N, Colombel JF. Loss of response to anti-TNFs: definition, epidemiology, and management. Clin Transl Gastroenterol. 2016;7(1): e135.
Curtis JR, Ogdie A, George MD. Treatment strategies for patients with immune-mediated inflammatory diseases. JAMA. 2021;325(17):1726–8.
Jani M, Gavan S, Chinoy H, Dixon WG, Harrison B, Moran A, et al. A microcosting study of immunogenicity and tumour necrosis factor alpha inhibitor drug level tests for therapeutic drug monitoring in clinical practice. Rheumatology (Oxford). 2016;55(12):2131–7.
Flurey CA, Morris M, Richards P, Hughes R, Hewlett S. It’s like a juggling act: rheumatoid arthritis patient perspectives on daily life and flare while on current treatment regimes. Rheumatology (Oxford). 2014;53(4):696–703.
Markusse IM, Dirven L, Gerards AH, van Groenendael JH, Ronday HK, Kerstens PJ, et al. Disease flares in rheumatoid arthritis are associated with joint damage progression and disability: 10-year results from the BeSt study. Arthritis Res Ther. 2015;17(1):232.
Feuerstein JD, Nguyen GC, Kupfer SS, Falck-Ytter Y, Singh S. American Gastroenterological Association Institute guideline on therapeutic drug monitoring in inflammatory bowel disease. Gastroenterology. 2017;153(3):827–34.
Garcês S, Antunes M, Benito-Garcia E, da Silva JC, Aarden L, Demengeot J. A preliminary algorithm introducing immunogenicity assessment in the management of patients with RA receiving tumour necrosis factor inhibitor therapies. Ann Rheum Dis. 2014;73(6):1138–43.
Plasencia C, Pascual-Salcedo D, Nuño L, Bonilla G, Villalba A, Peiteado D, et al. Influence of immunogenicity on the efficacy of longterm treatment of spondyloarthritis with infliximab. Ann Rheum Dis. 2012;71(12):1955–60.
Jamnitski A, Bartelds GM, Nurmohamed MT, van Schouwenburg PA, van Schaardenburg D, Stapel SO, et al. The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis. 2011;70(2):284–8.
Plasencia C, Pascual-Salcedo D, García-Carazo S, Lojo L, Nuño L, Villalba A, et al. The immunogenicity to the first anti-TNF therapy determines the outcome of switching to a second anti-TNF therapy in spondyloarthritis patients. Arthritis Res Ther. 2013;15(4):R79.
Vincent FB, Pavy S, Krzysiek R, Lequerré T, Sellam J, Taoufik Y, et al. Effect of serum anti-tumour necrosis factor (TNF) drug trough concentrations and antidrug antibodies (ADAb) to further anti-TNF short-term effectiveness after switching in rheumatoid arthritis and axial spondyloarthritis. Jt Bone Spine. 2016;83(5):595–7.
Bingham CO 3rd, Ince A, Haraoui B, Keystone EC, Chon Y, Baumgartner S. Effectiveness and safety of etanercept in subjects with RA who have failed infliximab therapy: 16-week, open-label, observational study. Curr Med Res Opin. 2009;25(5):1131–42.
Ulijn E, den Broeder N, Wientjes M, van Herwaarden N, Meek I, Tweehuysen L, et al. Therapeutic drug monitoring of adalimumab in RA: no predictive value of adalimumab serum levels and anti-adalimumab antibodies for prediction of response to the next bDMARD. Ann Rheum Dis. 2020;79(7):867–73.
van der Bijl AE, Breedveld FC, Antoni CE, Kalden JR, Kary S, Burmester GR, et al. An open-label pilot study of the effectiveness of adalimumab in patients with rheumatoid arthritis and previous infliximab treatment: relationship to reasons for failure and anti-infliximab antibody status. Clin Rheumatol. 2008;27(8):1021–8.
Jani M, Chinoy H, Warren RB, Griffiths CE, Plant D, Fu B, et al. Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis. Arthritis Rheumatol. 2015;67(8):2011–9.
Martínez-Feito A, Plasencia C, Hernández-Breijo B, Navarro-Compán V, Peiteado D, Villalva A, et al. FRI0399 Infliximab trough levels and disease activity predict early clinical response in patients with axial spondyloarthritis. Ann Rheum Dis. 2019;78(Suppl 2):885.
van den Bemt BJ, den Broeder AA, Wolbink GJ, van den Maas A, Hekster YA, van Riel PL, et al. The combined use of disease activity and infliximab serum trough concentrations for early prediction of (non-)response to infliximab in rheumatoid arthritis. Br J Clin Pharmacol. 2013;76(6):939–45.
Lamers-Karnebeek FBG, Jacobs JWG, Radstake T, van Riel P, Jansen TL. Adalimumab drug and antidrug antibody levels do not predict flare risk after stopping adalimumab in RA patients with low disease activity. Rheumatology (Oxford). 2019;58(3):427–31.
l’Ami MJ, Krieckaert CL, Nurmohamed MT, van Vollenhoven RF, Rispens T, Boers M, et al. Successful reduction of overexposure in patients with rheumatoid arthritis with high serum adalimumab concentrations: an open-label, non-inferiority, randomised clinical trial. Ann Rheum Dis. 2018;77(4):484–7.
Bouman C, van Herwaarden N, van den Hoogen F, van der Maas A, van den Bemt B, den Broeder AA. Prediction of successful dose reduction or discontinuation of adalimumab, etanercept, or infliximab in rheumatoid arthritis patients using serum drug levels and antidrug antibody measurement. Expert Opin Drug Metab Toxicol. 2017;13(6):597–604.
Jorgensen KK, Olsen IC, Goll GL, Lorentzen M, Bolstad N, Haavardsholm EA, et al. Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator infliximab (NOR-SWITCH): a 52-week, randomised, double-blind, non-inferiority trial. Lancet. 2017;389(10086):2304–16.
Goll GL, Jorgensen KK, Sexton J, Olsen IC, Bolstad N, Haavardsholm EA, et al. Long-term efficacy and safety of biosimilar infliximab (CT-P13) after switching from originator infliximab: open-label extension of the NOR-SWITCH trial. J Intern Med. 2019;285(6):653–69.
Goll GL, Haavardsholm EA, Kvien TK. The confidence of rheumatologists about switching to biosimilars for their patients. Joint Bone Spine. 2018;85(5):507–9.
Ruiz-Argüello MB, Maguregui A, Ruiz Del Agua A, Pascual-Salcedo D, Martínez-Feito A, Jurado T, et al. Antibodies to infliximab in Remicade-treated rheumatic patients show identical reactivity towards biosimilars. Ann Rheum Dis. 2016;75(9):1693–6.
Strand V, Gonçalves J, Hickling TP, Jones HE, Marshall L, Isaacs JD. Immunogenicity of biosimilars for rheumatic diseases, plaque psoriasis, and inflammatory bowel disease: a review from clinical trials and regulatory documents. BioDrugs. 2020;34(1):27–37.
Kurki P, Barry S, Bourges I, Tsantili P, Wolff-Holz E. Safety, immunogenicity and interchangeability of biosimilar monoclonal antibodies and fusion proteins: a regulatory perspective. Drugs. 2021;81(16):1881–96.
Rup B, Pallardy M, Sikkema D, Albert T, Allez M, Broet P, et al. Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium. Clin Exp Immunol. 2015;181(3):385–400.
Nasser Y, Labetoulle R, Harzallah I, Berger AE, Roblin X, Paul S. Comparison of point-of-care and classical immunoassays for the monitoring infliximab and antibodies against infliximab in IBD. Dig Dis Sci. 2018;63(10):2714–21.
Rocha C, Lago P, Fernandes S, Correia L, Portela F, Vieira AI, et al. Rapid test detection of anti-infliximab antibodies: performance comparison with three different immunoassays. Therap Adv Gastroenterol. 2020;13:1756284820965790.
Facchin S, Buda A, Cardin R, Agbariah N, Zingone F, De Bona M, et al. Rapid point-of-care anti-infliximab antibodies detection in clinical practice: comparison with ELISA and potential for improving therapeutic drug monitoring in IBD patients. Therap Adv Gastroenterol. 2021;14:1756284821999902.
Bloem K, Schaap T, Boshuizen R, Kneepkens EL, Wolbink GJ, Vries A, et al. Capillary blood microsampling to determine serum biopharmaceutical concentration: Mitra(®) microsampler vs dried blood spot. Bioanalysis. 2018;10(11):815–23.
Mingas PD, Zdovc J, Grabnar I, Vovk T. The evolving role of microsampling in therapeutic drug monitoring of monoclonal antibodies in inflammatory diseases. Molecules. 2021; 22;26(6):1787.
Gavan SP, Daker-White G, Payne K, Barton A. AB1264 barriers against testing anti-TNF drug levels and anti-drug antibodies in routine clinical practice. Ann Rheum Dis. 2018;77(Suppl. 2):1726–7.
Vincent FB, Morand EF, Murphy K, Mackay F, Mariette X, Marcelli C. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis. 2013;72(2):165–78.
Dougados M, Kissel K, Conaghan PG, Mola EM, Schett G, Gerli R, et al. Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study. Ann Rheum Dis. 2014;73(5):803–9.
Sigaux J, Hamze M, Daien C, Morel J, Krzysiek R, Pallardy M, et al. Immunogenicity of tocilizumab in patients with rheumatoid arthritis. Jt Bone Spine. 2017;84(1):39–45.
Benucci M, Meacci F, Grossi V, Infantino M, Manfredi M, Bellio E, et al. Correlations between immunogenicity, drug levels, and disease activity in an Italian cohort of rheumatoid arthritis patients treated with tocilizumab. Biologics. 2016;10:53–8.
Kaine J, Gladstein G, Strusberg I, Robles M, Louw I, Gujrathi S, et al. Evaluation of abatacept administered subcutaneously in adults with active rheumatoid arthritis: impact of withdrawal and reintroduction on immunogenicity, efficacy and safety (phase Iiib ALLOW study). Ann Rheum Dis. 2012;71(1):38–44.
Amano K, Matsubara T, Tanaka T, Inoue H, Iwahashi M, Kanamono T, et al. Long-term safety and efficacy of treatment with subcutaneous abatacept in Japanese patients with rheumatoid arthritis who are methotrexate inadequate responders. Mod Rheumatol. 2015;25(5):665–71.
Thurlings RM, Teng O, Vos K, Gerlag DM, Aarden L, Stapel SO, et al. Clinical response, pharmacokinetics, development of human anti-chimaeric antibodies, and synovial tissue response to rituximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2010;69(2):409–12.
Einarsson JT, Evert M, Geborek P, Saxne T, Lundgren M, Kapetanovic MC. Rituximab in clinical practice: dosage, drug adherence, Ig levels, infections, and drug antibodies. Clin Rheumatol. 2017;36(12):2743–50.
Yoo DH, Suh CH, Shim SC, Jeka S, Molina FFC, Hrycaj P, et al. Efficacy, safety and pharmacokinetics of up to two courses of the rituximab biosimilar CT-P10 versus innovator rituximab in patients with rheumatoid arthritis: results up to week 72 of a phase I randomized controlled trial. BioDrugs. 2017;31(4):357–67.
Deodhar A, Gladman DD, McInnes IB, Spindeldreher S, Martin R, Pricop L, et al. Secukinumab immunogenicity over 52 weeks in patients with psoriatic arthritis and ankylosing spondylitis. J Rheumatol. 2020;47(4):539–47.
Coates LC, Mease P, Kronbergs A, Helt C, Sandoval D, Park SY, et al. Efficacy and safety of ixekizumab in patients with active psoriatic arthritis with and without concomitant conventional disease-modifying antirheumatic drugs: SPIRIT-P1 and SPIRIT-P2 3-year results. Clin Rheumatol. 2022;41(10):3035–47.
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Open access funding provided by University of Oslo (including Oslo University Hospital). MJ is funded by a National Institute for Health Research (NIHR) Advanced Fellowship [NIHR301413]. The views expressed in this publication are those of the authors and not necessarily those of the NIHR, National Health Service or the UK Department of Health and Social Care. SWS, MKB, and GLG are funded by grants from the Norwegian South-Eastern Regional Health Authorities.
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GLG has received honoraria, consulting fees, and payment for lectures from Pfizer, AbbVie, Boehringer Ingelheim, Roche, Orion Pharma, Sandoz, Novartis, and UCB, all unrelated to the present work. JEG, MKB, MJ, NB, and SWS report no relevant disclosures.
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Gehin, J.E., Goll, G.L., Brun, M.K. et al. Assessing Immunogenicity of Biologic Drugs in Inflammatory Joint Diseases: Progress Towards Personalized Medicine. BioDrugs 36, 731–748 (2022). https://doi.org/10.1007/s40259-022-00559-1
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DOI: https://doi.org/10.1007/s40259-022-00559-1