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Review
The effect of antidrug antibodies on the sustainable efficacy of biologic therapies in rheumatoid arthritis: practical consequences Expert Rev. Clin. Immunol. Early online, 1–9 (2014)
Mauro Keiserman*1, Catalin Codreanu2, Rohini Handa3, Daniel Xibille´-Friedmann4, Eduardo Mysler5, Francisco Bricen˜o6 and Servet Akar7 1 Rheumatology Section, Pontifical Catholic University RS, School of Medicine, Porto Alegre, Brazil 2 Center of Rheumatic Diseases, Bucharest, Romania 3 Apollo Indraprastha Hospitals, New Delhi, India 4 Universidad Autonoma del Estado de Morelos, Cuernavaca, Mexico 5 Organizacion Medica de Investigacion, Buenos Aires, Argentina 6 Instituto Venezolano de los Seguros Sociales, Maracaibo, Venezuela 7 Izmir Katip Celebi University, Izmir, Turkey *Author for correspondence: Tel.: +55 513 320 5057 Fax: +55 513 320 5152
[email protected]
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Biologic therapies, predominantly TNF-a inhibitors, have revolutionized the treatment of rheumatoid arthritis (RA). However, their clinical utility can be limited by the development of antidrug antibodies (ADAs). Immunogenicity is a complex phenomenon related to various drug, disease, and patient characteristics, and may be more common with the monoclonal antibodies than with etanercept, a soluble TNF receptor-Fc immunoglobulin fusion protein. Neutralizing antibodies – those that hinder bioactivity by preventing drug molecules from binding to TNF – are correlated with reduced serum drug concentrations, loss of therapeutic response, adverse events, and treatment discontinuation. Cost-effective use of these agents will depend on further research into drug and ADA assays, and how they should guide dose reduction or switching strategies. KEYWORDS: abatacept • adalimumab • antidrug antibodies • biologic therapies • etanercept • immunogenicity • infliximab • rheumatoid arthritis • rituximab • TNF antagonists
The introduction of biologic therapies, predominantly inhibitors of TNF-a, and improved use of nonbiologic disease-modifying antirheumatic drugs (DMARDs) have revolutionized the therapy of rheumatoid arthritis (RA) and made disease remission a realistic goal [1,2]. Biologic DMARDs target key pathogenic proteins, secondary signal interactions between antigenpresenting cells and T lymphocytes or cells such as B lymphocytes. The 2013 European League Against Rheumatism recommendations expressed no preference of one over another biological agent. However, the task force recognized that there was still more experience with anti-TNF agents than with other biologic therapies. Therefore, TNF inhibitors are preferentially recommended as the initial biologic therapy. However, if there are contraindications or special clinical circumstances, biologic therapy may be initiated with B cell-depleting drugs, modulators of costimulation of T cells and antibodies against the IL-6 receptors [3]. 10.1586/1744666X.2014.926219
Individual patients may respond differently to one biologic agent versus another. Immunogenicity might be a major contributor to these differences among patients [4]. The objective of this review is to summarize the current evidence on the immunogenicity of biologic agents used in the treatment of RA, in particular the development of antidrug antibodies (ADAs), their impact on treatment effectiveness and the practical implications for clinical use. Immunogenicity of biologic therapies for RA
Biologic DMARDs are engineered molecules designed to inhibit specific targets in the molecular or cellular pathways that drive active RA by mimicking human antibodies, antibody fragments or proteins. Although specifically designed and produced by recombinant DNA technology, these molecules may be recognized as foreign by the immune system, resulting in the production of antibodies that hinder their activity [4].
2014 Informa UK Ltd
ISSN 1744-666X
1
Review
Keiserman, Codreanu, Handa et al.
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Table 1. Summary of main immune-targeted biologic therapies for RA. Biologic type
Drug (and year of first approval for use in RA)
Structure
Mode of administration
TNF inhibitors
Etanercept (1998)
TNF receptor-Fc fusion protein human recombinant
SC
Infliximab (1999)
Chimeric human-mouse mAb
IV
Adalimumab (2002)
Human mAb
SC
Golimumab (2009)
Human mAb
SC †
Certolizumab pegol (2009)
PEGylated recombinant humanized Fab fragment of anti-TNF mAb
SC
IL-6 inhibitor
Tocilizumab (2009)
Humanized† mAb
IV
B-cell inhibitor
Rituximab (2006)
Chimeric mAb targeting CD20
IV
T-cell costimulation inhibitor
Abatacept (2005)
Immunoglobulin fused to the extracellular domain of CTLA4 Human mAb
IV/SC
Shaded rows indicate mAbs. † Humanized indicates that the molecule retains some nonhuman (usually murine) elements. Fab: Fragment antigen binding; Fc: Fragment crystallizable region; IV: Intravenous; mAb: Monoclonal antibody; RA: Rheumatoid arthritis; SC: Subcutaneous. Data taken from [11].
Factors influencing the development of immunogenicity
A number of drug-related and patient-related factors influence the immunogenicity of biologic therapies [5]. The drugrelated factors include the presence of nonhuman sequences or novel epitopes. The first therapeutic antibodies were murine in origin and produced ADAs in treated patients, limiting their clinical use [6,7]. Newer therapeutic antibodies, which are partly human-derived (chimeric: e.g., infliximab, rituximab) or predominantly human (e.g., adalimumab, golimumab, tocilizumab), generate lower immunogenicity than the original murine antibodies. However, both chimeric and human monoclonal antibodies (mAb) can induce anti-mAb antibodies [4,8,9]. Among 15 chimeric mAbs, nearly 40% (including infliximab) induced a marked anti-mAb response (defined as affecting more than 15% of exposed patients) compared with only 9% of humanized and human mAb [10]. Available immune-targeted biologic therapies for RA are summarized in TABLE 1 [11]. Clinical experience, current recommendations and reimbursement issues usually dictate that the TNF inhibitors are the first biologic DMARDs prescribed [11,12], and their immunogenicity has been the most widely studied. The three most commonly used TNF inhibitors are etanercept, infliximab and adalimumab. More recently, golimumab and certolizumab pegol have also become available in some countries. Three of these agents are mAb (infliximab, adalimumab and golimumab). Certolizumab pegol is a PEGylated Fab fragment of a humanized anti-TNF antibody [11]. Lacking an Fc region, it avoids potential Fc-mediated effects such as complement- or antibody-dependent cell-mediated cytotoxicity. Attachment of the PEG moiety to the Fab fragment further reduces its immunogenic potential and also extends the plasma half-life to approximately 2 weeks [13]. doi: 10.1586/1744666X.2014.926219
The major difference among the TNF inhibitors is between the mAb-based drugs and etanercept. Etanercept is a soluble TNF receptor–Fc immunoglobulin fusion protein. Immunogenicity of fusion proteins depends on their similarity to native proteins, and clinically relevant antibody formation against the fusion part of the molecule may occur. However, it appears to be rare in clinical practice. Anti-etanercept antibodies have been demonstrated in 0–6% of patients in short-term studies, 5% in one long-term study with RA [14,15] and in 0% of patients with ankylosing spondylitis [16]. By comparison, in other RA studies, ADAs occurred in 10–50% of patients treated with infliximab and 1–87% of patients treated with adalimumab [14,15]. For biologic DMARDs other than TNF inhibitors (TABLE 1 [11]), less information on immunogenicity is available. Like infliximab, rituximab is a chimeric mAb; it targets mature B cells by binding to CD20 receptors on their surface. Rituximab ADAs were reported in 4.3% of RA patients in the Randomized Evaluation of Long-term Efficacy of Rituximab trial, although no direct relationship with clinical response was observed [17]. Approximately 11% of RA patients developed ADAs to rituximab, but the clinical relevance is unknown [18]. The IL-6 inhibitor tocilizumab is a humanized mAb that binds to the soluble and membrane-bound IL-6 receptor and inhibits IL-6 activation. Response to tocilizumab has not been shown to be influenced by ADAs [19]. Abatacept is a soluble fusion protein that blocks the interaction between antigen-presenting cells and T cells (inhibition of costimulation) by inhibiting CD80/86 activation. Clinical trials in RA patients treated with abatacept, including long-term follow-up studies, have shown comparable low levels of immunogenicity for subcutaneous and intravenous administration [20,21]. The frequency of ADAs can vary considerably among studies of a given drug. This may be explained by differences in study Expert Rev. Clin. Immunol.
The effect of ADA on the sustainable efficacy of biologic therapies in RA
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populations and methodologies, but also reflects variability in individual patients’ immune responses as well as differences in concurrent medications, timing of sampling, duration of follow-up and drug administration (dose, frequency and route) [14,22,23]. For most TNF inhibitors, drug delivery mimics schedules used for vaccination, where the goal is to induce immune responses to exogenous proteins administered by repeated subcutaneous injection [24]. The extent of immunogenicity is also influenced by the choice of ADA assay [5], and tolerance may develop over time [25]. Techniques to measure immunogenicity
The complexity of measuring antibodies against antibodies is a major hurdle in the assessment of immunogenicity and its clinical relevance. Several assays are available for ADAs, but their specificities and sensitivities differ, making it difficult to compare results from different sources [4]. Standard ELISA techniques lack specificity and fail to distinguish between functionally active and inactive ADAs [4,24]. However, two improved types of assays have been developed [26]: two-sites (bridging) assays, which are highly specific and sensitive but may not detect certain ADA types more prominent after prolonged drug exposure (monovalent IgG4) [24]; and antigen-binding tests, which are based on a radioimmunoassay (RIA) system in which IgG from patient serum is immobilized to a solid phase and radiolabeled drug is captured by any drug-specific IgG present in the fluid phase [27]. Svenson et al. [28] analyzed different methods of assessing drug levels and ADAs in RA patients treated with infliximab for 1.5–18 months and concluded that fluid-phase RIA was superior to solid-phase, cross-binding tests, whether RIA or ELISA types.
Review
Mechanisms of immunogenicity against the TNF inhibitors & impact on drug pharmacokinetics
Not all ADAs interfere with the activity of the biologic agent. Distinctions have been made between binding ADAs that do not disrupt the clinical effect of a drug (i.e., non-neutralizing antibodies) and neutralizing ADAs, which have been shown to reduce a drug’s bioactivity. Neutralizing ADAs reduce the drug’s ability to bind TNF and thereby decrease its efficacy. The neutralizing effect of ADAs on some TNF inhibitors can be seen clearly by the inverse relationship between serum drug levels and ADAs. Bendtzen et al. were the first to demonstrate the dynamics of antibody development in infliximab-treated RA patients, and the consequences for drug removal, response failure and side effects [31]. Several other studies in patients treated with TNF inhibitors have shown that the development of ADAs over time correlates with reduced drug levels in the blood [14,24]. For etanercept, the observation that ADAs do not diminish clinical response suggests that they are non-neutralizing, although it is not yet known whether the ADAs affect plasma etanercept levels [14]. Non-neutralizing ADAs, while not directly inhibiting the bioactivity of the drug, are still of clinical relevance, particularly when the drug is administered subcutaneously (as for most TNF inhibitors). The injection of drug in the presence of ADAs results in the local formation of immune complexes at the injection site, reducing the release of the drug into circulation. These non-neutralizing antibodies reduce therapeutic efficacy indirectly by compromising bioavailability rather than by directly preventing the drug from binding to TNF [24]. Rapid clearance of these immune complexes can occur regardless of whether the ADAs neutralize the drug’s TNFbinding activity.
When to obtain samples to test immunogenicity
Regardless of whether ELISA or RIA methods are used, the presence of the drug in the serum will interfere with the detection of ADA. When the drug is administered in the presence of ADAs, free ADA binds to the drug to form immune complexes, resulting in lower levels of free ADA detectable by the antibody assay (as well as lower levels of unbound drug). Antibody assessments should therefore be interpreted in the light of the dosing schedule and relative timing of drug administration, and ideally serum drug levels [4]. Trough plasma levels are usually used in pharmacokinetic analyses of steady-state drug exposure, and this approach is also suitable for assessment of biologic drug levels and ADAs to ensure that drug levels are at their lowest and interference with ADA analysis is minimized [29]. However, some amount of drug may be present even in samples obtained immediately before the next dose and trough levels may differ considerably between patients and even within individuals over time [24]. This rationale is further confounded by different dosing schedules, drug holidays and intensified schedules. New methods (reporter gene assays) are being explored that directly measure TNF neutralization (the drug effect) and inhibition of this effect by ADAs to monitor actual net anti-TNF activity [30]. informahealthcare.com
Clinical implications of immunogenicity
As immunogenicity with biologic DMARDs has been studied most frequently with the TNF inhibitors, the following discussion of the clinical implications in patients with RA focuses on these agents. Although direct comparisons are not reliable because of variability in ADA assays, the differences among the TNF inhibitors with respect to ADAs and their relationship to clinical response are the topic of a number of recent reviews [9,14,32]. An overview of the findings reported for individual TNF inhibitors is presented in TABLE 2 [14]. Effects on efficacy, safety, dosing & drug survival
Studies of infliximab [32–35] and adalimumab [23,36,37] in patients with RA have shown that immunogenicity is strongly linked to subtherapeutic serum drug levels and a lack of clinical response. For the newer mAbs, there are fewer studies on the clinical relevance of ADAs. Although the frequency of ADAs may be lower, they may still diminish the clinical response (TABLE 2 [14]) or lead to adverse events. In a recent study of CT-P13, an infliximab biosimilar, the rate of ADAs in RA patients was identical with the biosimilar and the innovator compound (48%) after 30 weeks of treatment. For both compounds, doi: 10.1586/1744666X.2014.926219
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Table 2. Summary of evidence from randomized clinical trials of tumor necrosis factor inhibitors on the incidence of antidrug antibodies and their relationship with serum drug levels and clinical response in patients with rheumatoid arthritis. Drug
Studies (N)
Total patients (N)
Duration of treatment (weeks)
ADAs (percentage of patients)
Association between ADA levels and serum trough drug level
Association between ADA levels and clinical response
Etanercept
4
966
16–32
0–6
NR
No association in the two studies where ADAs were detected (ADA frequency 3–6%)
Etanercept (long term)
1
549
193
5
NR
None
Infliximab
8
452
2–54
10–50
Inversely associated (significant in six of seven studies reported)
Inversely associated (significant in three of five studies reported)
Infliximab (long term)
2
193
>360–400
33–41
Inversely associated (both studies)
Inversely associated in both studies (significant in one study; strength of correlation increased with duration of treatment)
Adalimumab
8
1559
12–56
1–87
Negatively associated (p < 0.001) but only reported in one study; ADA frequency 17%
Negatively associated (significant in two of four studies reported)
Adalimumab (long term)
1
148
156
28
Negatively associated (p < 0.001)
Negatively associated (p < 0.001)
Golimumab
8
2822
24–48
0–7
Negatively associated in the two studies reported (with ADA frequency 3–6%)
Negatively associated in one study (NS), with ADA frequency 5%. NR in other studies
Certolizumab pegol
4
1711
24–52
5–8
NR
Negatively associated (but only reported in one of four studies; n = 111)
ADA: Antidrug antibodies; NR: Not reported; NS: Not significant. Reproduced with permission from [14].
infusion-related reactions were more common in patients with ADAs than in those without (7 vs 4% for CT-P13 and 13 vs 3% for infliximab). Patients with ADAs also had lower serum concentrations of both compounds [38]. In studies of etanercept, even when ADAs were detectable, they demonstrated no relationship with clinical response [39,40], even during long-term treatment of over 3 years [41]. The association between ADAs and trough serum etanercept levels was not reported in these studies. Recent data show an association between lower trough serum drug concentrations and nonresponse to etanercept in RA patients, but without any etanercept ADAs detected [42]. In the meta-analysis of RA, spondyloarthritis, psoriasis and inflammatory bowel disease studies described above, the ADAs against infliximab and adalimumab decreased response to therapy by 68% [32]. Because it takes time to produce an antibody response to an exogenous protein, immunogenicity is not a likely explanation doi: 10.1586/1744666X.2014.926219
for primary response failures; however, it is a major contributor to secondary response failure, where up to 50% of patients with good primary responses to TNF inhibitors eventually experience a decline in efficacy [24]. Immunogenicity against biologics can be persistent or transient [4]. In some patients, antibodies to infliximab or adalimumab may become undetectable with continued treatment [33,36]. In patients with multiple sclerosis, ADA levels against natalizumab, a therapeutic antibody against a4 integrin, have also been observed to decline over time, suggesting the induction of immune tolerance [25]. Other emerging data also indicate that immune tolerance mechanisms and product-related factors may play a role in modulating host immune responses to biologic therapies [43]. Data on long-term outcomes of biologic therapy in RA are available from open-label extensions of randomized clinical trials and observational registries. Etanercept and adalimumab appear similar in inducing a good long-term Expert Rev. Clin. Immunol.
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The effect of ADA on the sustainable efficacy of biologic therapies in RA
clinical outcome, but for adalimumab, this is strongly dependent on the presence or absence of ADAs [44]. Observational data suggest that etanercept exhibits good drug survival. In the Italian Gruppo Italiano di Studio sulle Early Arthritides registry, the 4-year global drug survival of adalimumab, etanercept and infliximab was lower than 50%, but etanercept had the best retention rate [45]. Drug survival was also highest for etanercept in the Danish DANBIO registry [46]. In another study of 151 RA patients observed between 2000 and 2009, drug survival rates after 1 year were 83, 84 and 70% for infliximab, adalimumab and etanercept, respectively [47]. However, on long-term followup, drug survival rate remained 60% for etanercept (at 4 years), but had fallen substantially for infliximab (33% after 7 years) and adalimumab (45% after 5 years). Large interindividual differences in disease activity during maintenance therapy have also been observed (e.g., in the Dutch Rheumatoid Arthritis Monitoring registry [48] and the Norwegian DMARD database [49]). Several theories are being explored regarding drug detection and ADA levels and how these might be used to guide dose reduction or stopping strategies [50,51]. The presence of ADAs and/or higher ADA titers is significantly associated with a requirement for dose increases (to achieve or maintain treatment response) and with treatment discontinuation (due to treatment failure, infusion reactions or other causes) [31,52]. When anti-TNF therapy fails, one possible response is to intensify therapy by increasing the dosage or frequency of medication, but many patients do not derive a therapeutic benefit [24]. Furthermore, rather than increasing the drug available, increasing the dose may result in even higher ADA levels, as shown with infliximab [31,52]. Role of immunomodulators
Concomitant administration of immunomodulators such as methotrexate or azathioprine has been shown to reduce the immunogenicity of therapeutic antibodies in RA and other chronic inflammatory conditions, although the mechanism is unclear [9]. In a retrospective study of 108 infliximab-treated patients with RA or spondyloarthritis, those using methotrexate had a lower incidence of antibodies to infliximab [53]. Numerous other studies have also reported a lower frequency of anti-mAb antibodies in patients treated with concomitant immunosuppressive therapy [9]. In the meta-analysis of TNF inhibitor immunogenicity, subanalysis revealed that concomitant use of immunomodulator therapy with methotrexate or azathioprine/mercaptopurine reduced the frequency of ADAs to TNF inhibitors by 47% and attenuated the impact of ADAs on clinical response [32]. Potential risks associated with immunogenicity
Potentially serious adverse effects are mediated by ADA immune complexes and include infusion-related hypersensitivity reactions to infliximab [9,53,54] and, more rarely, serum sickness, bronchospasm and Arthus reactions [33,36,55,56]. informahealthcare.com
Review
Recent evidence also suggests an increased risk of thromboembolic events in patients with an immunogenic reaction [57]. Little information is available on the direct effects of ADAs on clinical safety [9]. Monitoring of drug levels & antibodies against anti-TNF therapies in clinical practice
In RA patients treated with TNF inhibitors, personalized care is not only essential for improving therapeutic outcomes and safety, but also for promoting cost–effective use [24]. However, clinical judgment may not be sufficient to predict the relationships between anti-TNF therapy, immunogenicity and treatment response in individual patients. Hence, there is a need for immunopharmacologic data to guide anti-TNF therapies, given the high variability in response to, and pharmacokinetics of, TNF inhibitors among patients [5]. However, the case for immunopharmacologic assays needs to be balanced against the potential costs, and epidemiologic evidence suggests that a gradual loss of efficacy occurs with all TNF inhibitors over the long term. Immunogenicity may change over time and patients may either become tolerant to treatment or continue to produce further antibodies [4]. As more data become available and more specific and reproducible tests are developed, immunopharmacologic assays may become a standard of care. However, further research is required to better establish the relationship between ADAs and clinical response. New treatment strategies for anti-TNF therapy in RA
Data from several national registries and open-label studies suggest that switching TNF inhibitors is a useful strategy in RA patients who respond initially but then fail treatment [14,37,58–60]. The efficacy of etanercept was assessed in a cohort study of 292 consecutive patients with RA [60]. In those who were switched after previous treatment with infliximab or adalimumab and who had ADAs to previous therapy, clinical response to etanercept was similar to that achieved in TNF inhibitor-naive patients, indicating that where immunogenicity was a reason for previous anti-TNF treatment failure, etanercept efficacy was not compromised. Conversely, patients who had failed previous TNF inhibitor therapy but had no ADAs showed a diminished response to etanercept. These observations suggest that there are different mechanisms underlying nonresponse, with secondary failure a result of ADA development, while primary failure is apparently unrelated to immunogenicity. Indeed, patients with primary nonresponse to anti-TNF therapy seldom respond to a second TNF inhibitor, although positive outcomes can be achieved with other biologic classes, as demonstrated with tocilizumab [61], abatacept [62] and rituximab [63] in patients with RA refractory to TNF inhibitors. Furthermore, while response rates after the first switch following secondary failure are similar to initial therapy, second-time switchers have lower response rates, suggesting that other treatment options should be considered in patients who have failed two TNF inhibitor doi: 10.1586/1744666X.2014.926219
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Keiserman, Codreanu, Handa et al.
therapies [64]. On the other hand, another study, in which immunogenicity was not evaluated, concluded that response to a second TNF inhibitor was not influenced by the reason for discontinuation of the first TNF inhibitor (primary failure vs secondary failure vs adverse effects) [65]. There is also the issue of secondary failures with etanercept that cannot be attributed to ADAs, which makes this result even more difficult to interpret. Recently proposed treatment algorithms for anti-TNF therapy utilize the results of therapeutic drug monitoring and immunogenicity testing to guide appropriate selection and tailoring of biologic therapy for patients with RA [14,24,66]. The potential clinical impact of one such preliminary algorithm was evaluated recently in a single-center study of 105 Portuguese RA patients treated with TNF inhibitors [66]. Patients who were treated according to the proposed immunogenicity-based algorithm had a significantly higher probability of clinical remission or low disease activity after 1 year than those who were treated according to existing evidence-based switching strategies. However, primary failures were not differentiated from secondary failures and much larger controlled studies would be needed to establish whether such an algorithm can significantly and cost–effectively improve clinical outcomes in RA. Much remains to be learned about how individual patients respond to biologic therapy and the potential influence of immunogenicity. Determining the immunogenic status of patients who fail to respond or stop responding to biologic therapy could become part of a personalized treatment approach in the future [60]. However, the clinical benefit needs to be established and immunogenicity testing needs to become more reliable and cost–effective before such an approach can be widely recommended. Summary
Biologic DMARDs are increasingly being incorporated into routine clinical practice for patients with RA, but treatment guidelines offer little information on immunogenicity as a possible cause of treatment failure. Better understanding and theoretical monitoring of the possible immunogenic effects of biologic therapies for RA and their clinical consequences may help to individualize therapy and may achieve the goals of low disease activity or full remission. Expert commentary
The advent of biologic DMARDs has revolutionized the treatment of RA and disease remission has become an achievable goal. The TNF inhibitors were the first biologics to be introduced and remain the first choice when conventional DMARDs are not sufficient. Treatment with another biologic is rarely initiated, even when guidelines allow the use of another drug. However, in a considerable percentage of patients, anti-TNF agents are not effective (or lose their initial effectiveness) or cause side effects. In this context,
doi: 10.1586/1744666X.2014.926219
the development of neutralizing ADAs is relevant as studies relate them to reduced circulating drug levels, lack of efficacy and frequent and severe adverse events. However, there are no validation techniques or kits and clinicians cannot yet use these findings in daily practice. Practical training combined with knowledge of these events should guide the management of patients who experience efficacy loss or adverse events. Five-year view
Over the coming 5 years, ADA research will be refined and optimized to improve the efficacy and consistency of treatment. These advances will fill a number of current gaps in knowledge regarding ADAs (those with no activity, those with neutralizing properties and those producing side effects), which will extend to all biologics in use. Furthermore, techniques will become more affordable and practical, allowing rational use of these drugs in daily practice. Considering that only some patients develop ADAs and marked variation from one individual to another, genetic studies will be implemented and treatment will be personalized to avoid the development of ADAs. Acknowledgements
Medical writing support was provided by Susanne Gilbert of ACUMED and was funded by Pfizer Inc. Financial & competing interest disclosure
M Keiserman has participated in Advisory Boards and/or lectures for Pfizer, Abbott, Actelion, AstraZeneca, Amgen, Roche, Bristol Myers Squibb, and Janssen and has received clinical trial honoraria from Pfizer, Amgen, AstraZeneca, Anthera Pharmaceuticals, Bristol-Myers Squibb, Biogen Idec Inc, Celltrion Inc., Eli Lilly, Human Genome Sciences, Novartis, Roche, Sanofi, UCB Inc. C Codreanu has received speaker fees from AbbVie, Amgen, Angellini, AstraZeneca, Bristol-Myers Squibb, Merck Sharpe & Dohme, Pfizer, Richter, Roche, Sanofi, Servier, Teva, UCB and Zentiva; and consulting fees from AbbVie, Amgen, Egis, Merck Sharpe & Dohme, Pfizer, Roche, Sanofi and UCB. R Handa has received honoraria as a speaker, consultant and advisory board member for Abbott India, Pfizer, Ranbaxy, IPCA, Glaxo SmithKline, Dr Reddy’ s Laboratories Ltd, Bristol-Myers Squibb India, Janssen, Piramal Life Sciences, Panasonic Health Care, Roche and Sanofi. D Xibille´-Friedmann has received speaker fees from Pfizer; and support for clinical trials from Pfizer and UCB. E Mysler has received honoraria as an investigator, speaker and advisor for AbbVie, BristolMyers Squibb, Pfizer and Roche. F Bricen˜o has received honoraria as a speaker and advisor for Bristol-Myers Squibb, Lilly and Pfizer. S Akar has received honoraria as a speaker and advisor for AbbVie, Pfizer and Merck Sharp & Dohme. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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The effect of ADA on the sustainable efficacy of biologic therapies in RA
Review
Key issues • Although the principles of targeted treatment in rheumatoid arthritis are accepted internationally, there are many barriers to implementation, particularly in developing regions such as Central and Eastern Europe, Russia, India, Turkey and Latin America. • Barriers include clinician inexperience and limited access to treatment, especially for relatively costly therapies such as biologic agents. • Even when biologic therapies are accessible to patients, their clinical utility can be limited by the development of neutralizing antidrug antibodies, which prevent drug molecules from binding to TNF-a. • Neutralizing antidrug antibodies are significantly correlated with reduced serum drug concentrations, diminished therapeutic response, adverse events and treatment discontinuation. • Among the TNF-a inhibitors, immunogenicity may be more common with mAbs than with etanercept, a soluble TNF receptor–Fc
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immunoglobulin fusion protein. However, direct comparisons are lacking. • Concomitant administration of immunomodulators such as methotrexate or azathioprine may reduce the immunogenicity of therapeutic antibodies, although the mechanism is unclear. • Cost–effective use of anti-TNF agents will depend on further research into drug and antidrug antibody assays and how they should be used to guide dose reduction or switching strategies. • Better understanding and monitoring of the immunogenic effects of biologic therapies and their clinical consequences will help to individualize therapy and achieve the goals of low disease activity or full remission.
Papers of special note have been highlighted as: • of interest •• of considerable interest 1.
••
2.
••
3.
4.
Saag KG, Teng GG, Patkar NM, et al. on behalf of the American College of Rheumatology. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008; 59(6):762-84
5.
Treatment algorithms developed by an international expert panel based on literature reviews and clinical experience including 15 specific recommendations for cost–effective treatment of RA. Smolen JS, Landewe´ R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014;73(3):492-509 Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of biologicals:
informahealthcare.com
Krieckaert CLM, Lems WF. Are we ready for therapeutic drug monitoring of biologic therapeutics? Arthritis Res Ther 2011;13(4): 120
13.
Smolen J, Landewe´ RB, Mease P, 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
6.
Schroff RW, Foon KA, Braty SM, et al. Human autoimmune immunoglobulin responses in patients receiving monoclonal antibody therapy. Cancer Res 1985;45: 879-85
14.
7.
Courtney Luck N, Epenetos AA, Moore R. Development of primary and secondary immune response to mouse monoclonal antibodies used in the diagnosis and therapy of malignant neoplasms. Cancer Res 1986;46:6489-91
Vincent FB, Morand EF, Murphy K, et al. Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective. Ann Rheum Dis 2013;72(2):165-78
••
8.
Clarck M. Antibody humanization: ‘a case of the Emperor’s new clothes’? Immunol Today 2000;8:397-402
9.
Krieckaert CLM, Bartelds GM, Lems WF, Wolbink GJ. The effect of immunomodulators on the immunogenicity of TNF-blocking therapeutic monoclonal antibodies: a review. Arthritis Res Ther 2010;12(5):217
A comprehensive update on the development of antidrug antibodies (ADAs) to biologic agents, with a proposed model for monitoring drug and antibody levels to guide treatment for chronic inflammatory diseases.
15.
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
16.
de Vries MK, van der Horst-Bruinsma IE, Nurmohamed MT, et al. Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis. Ann Rheum Dis 2009;68(4): 531-5
17.
Haraoui B, Pelletier J-P, Martel-Pelletier J. Immunogenicity of biologic agents: a new
Evidence-based consensus guidelines from a US task force on the optimal use of disease-modifying anti-rheumatic drugs for patients with rheumatoid arthritis (RA). Smolen JS, Landewe´ R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010; 69(6):964-75
Argentina, Brazil and Mexico. March 2010. Available from: www.comparatorreports.se/ LA%20RA%20barrier%20report_FINAL. pdf [Last accessed 25 April 2013]
assessment and clinical relevance. Curr Opin Rheumatol 2009;21(3):211-15
References
10.
Hwang WY, Foote J. Immunogenecity of engineered antibodies. Methods 2005;36(1): 3-10
11.
Jung YO, Kim HA. Recent paradigm shifts in the diagnosis and treatment of rheumatoid arthritis. Korean J Intern Med 2012;27(4):378-87
12.
Miltenburger C, Munkombwe M, Lekander I. A Survey of Barriers to Treatment Access in Rheumatoid Arthritis in Major Latin American Countries –
doi: 10.1586/1744666X.2014.926219
Review
Keiserman, Codreanu, Handa et al.
concern for the practicing rheumatologist? Curr Rheumatol Rep 2007;9(4):265-7 ••
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Pfizer Ltd on 06/25/14 For personal use only.
18.
19.
20.
21.
22.
23.
Summary of currently available data on immunogenic responses to biologic compounds and their impact on the safety and efficacy of treatment. Rituxan Prescribing Information. Biogen Idec Inc. and Genentech Inc. February 2010. Available from: www.accessdata.fda. gov/drugsatfda_docs/label/2010/ 103705s5311lbl.pdf [Last accessed 30 May 2013] Levi M, Grange S, Frey N. Exposure– response relationship of tocilizumab, an anti-IL-6 receptor monoclonal antibody, in a large population of patients with rheumatoid arthritis. J Clin Pharmacol 2013;53(2):151-9 Genovese MC, Schiff M, Luggen M, et al. Long term safety and efficacy of abatacept through 5 years of treatment in patients with rheumatoid arthritis and an inadequate response to tumor necrosis factor inhibitor therapy. J Rheumatol 2012;39(8):1546-154 Schiff M. Subcutaneous abatacept for the treatment of rheumatoid arthritis. Rheumatology (Oxford) 2013;52(6):986-97 Weinblatt ME, Keystone EC, Furst DE, et al. Adalimumab, a fully human anti-tumor necrosis factor a monoclonal antibody, for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial. Arthritis Rheum 2003;48(1):35-45 Bartelds GM, Krieckaert CL, Nurmohamed MT, 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
••
A 3-year prospective study showing that adalimumab ADAs are linked to lower serum drug levels and reduced rates of minimal disease activity and clinical remission in patients with RA.
24.
Bendtzen K. Anti-TNF-a biotherapies: perspectives for evidence-based personalized medicine. Immunotherapy 2012;4(11): 1167-79. Available from: www.medscape. com/viewarticle/778245 [Last accessed 20 Nov 2013]
25.
26.
•
doi: 10.1586/1744666X.2014.926219
A review of novel ADA assays that may offer greater sensitivity and fewer false-positive results than older methods.
27.
Bendtzen K. Immunogenicity of anti-TNF antibodies. In: van de Weert M, Mo¨ller EH, editors. Immunogenicity of Biopharmaceuticals. Berlin; Springer: 2008. p189-203
28.
Svenson M, Geborek P, Saxne T, Bendtzen K. Monitoring patients treated with anti-TNF-a biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies. Rheumatology 2007;46(12):1828-34
29.
Hart MH, de Vrieze H, Wouters D, et al. Differential effect of drug interference in immunogenicity assays. J Immunol Methods 2011;372(1-2):196-203
•
In patients with RA treated with adalimumab, the bridging enzyme-linked immunosorbent assay is susceptible to drug interference and detects ADAs only in the absence of detectable drug levels.
30.
Lallemand C, Kavrochorianou A, Steenholdt C, et al. Reporter gene assay for the quantification of the activity and neutralizing antibody response to TNFa antagonists. J Immunol Methods 2011; 373(1-2):229-39
31.
Bendtzen K, Geborek P, Svenson M, et al. Individualized monitoring of drug bioavailability and immunogenicity in rheumatoid arthritis patients treated with the tumor necrosis factor inhibitor Infliximab. Arthritis Rheum 2006;54(12): 3782-9
32.
Garceˆs 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
33.
Wolbink GJ, Vis M, Lems W, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. Arthritis Rheum 2006;54(3):711-15
34.
Radstake TR, Svenson M, Eijsbouts AM, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis 2009;68(11): 1739-45
Vennegoor A, Rispens T, Strijbis EM, et al. Clinical relevance of serum natalizumab concentration and anti-natalizumab antibodies in multiple sclerosis. Mult Scler 2013;19(5):593-600 Aarden L, Ruuls SR, Wolbink G. Immunogenicity of anti-tumor necrosis factor antibodies – toward improved
infliximab in rheumatoid arthritis. Rheumatology (Oxford) 2011;50(8): 1445-52
methods of anti-antibody measurement. Curr Opin Immunol 2008;20(4):431-5
35.
Pascual-Salcedo D, Plasencia C, Ramiro S, et al. Influence of immunogenicity on the efficacy of long-term treatment with
36.
Bartelds GM, Wijbrandts CA, Nurmohamed MT, et al. Clinical response to adalimumab: relationship to antiadalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. Ann Rheum Dis 2007;66(7): 921-6
37.
Bartelds GM, Wijbrandts CA, Nurmohamed MT, 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
38.
Yoo DH, Hrycaj P, Miranda P, et al. A randomised, double-blind, parallel-group study to demonstrate equivalence in efficacy and safety of CT-P13 compared with innovator infliximab when coadministered with methotrexate in patients with active rheumatoid arthritis: the PLANETRA study. Ann Rheum Dis 2013;72(10): 1613-20
39.
Keystone EC, Schiff MH, Kremer JM, 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
40.
Dore RK, Mathews S, Schechtman J, 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
41.
Klareskog L, Gaubitz M, Rodriguez-Valverde V, on behalf of the Etanercept Study 301 Investigators. 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
42.
Jamnitski A, Krieckaert CL, Nurmohamed MT, et al. Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. Ann Rheum Dis 2012; 71(1):88-91
43.
Singh SK, Cousens LP, Alvarez D, Mahajan PB. Determinants of immunogenic response to protein therapeutics. Biologicals 2012;40(5):364-8
44.
Krieckaert CL, Jamnitski A, Nurmohamed MT, et al. Comparison of long-term clinical outcome with etanercept treatment and adalimumab treatment of rheumatoid arthritis with respect to
Expert Rev. Clin. Immunol.
The effect of ADA on the sustainable efficacy of biologic therapies in RA
Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Pfizer Ltd on 06/25/14 For personal use only.
immunogenicity. Arthritis Rheum 2012; 64(12):3850-5 •
A long-term study demonstrating good outcomes with both etanercept and adalimumab, but the efficacy of adalimumab depended strongly on the absence of ADAs.
45.
Iannone F, Gremese E, Atzeni F, et al. on behalf of the Gruppo Italiano di Studio sulle Early Arthritides (GISEA). Longterm retention of tumor necrosis factor-a inhibitor therapy in a large Italian cohort of patients with rheumatoid arthritis from the GISEA registry: an appraisal of predictors. J Rheumatol 2012;39(6): 1179-84
46.
47.
48.
49.
50.
Hetland ML, Christensen IJ, Tarp U, et al. on behalf of all Departments of Rheumatology in Denmark. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum 2010; 62(1):22-32 Markatseli TE, Alamanos Y, Saougou I, et al. Survival of TNF-alpha antagonists in rheumatoid arthritis: a long-term study. Clin Exp Rheumatol 2012;30(1):31-8 de Punder YM, Fransen J, Kievit W, et al. The prevalence of clinical remission in RA patients treated with anti-TNF: results from the Dutch Rheumatoid Arthritis Monitoring (DREAM) registry. Rheumatology (Oxford) 2012;51(9): 1610-17 Kvien TK, Heiberg MS, Lie E, et al. A Norwegian DMARD register: prescriptions of DMARDs and biological agents to patients with inflammatory rheumatic diseases. Clin Exp Rheumatol 2005;23(Suppl 39):S188-94 van der Maas A, van den Bemt BJF, Wolbink G, et al. Low infliximab serum trough levels and anti-infliximab antibodies are prevalent in rheumatoid arthritis patients treated with infliximab in daily clinical practice: results of an observational cohort study. BMC Musculoskelet Disord 2012;13:184
informahealthcare.com
51.
van den Bemt BJF, den Broeder AA, Wolbink GJ, et al. Anti-infliximab antibodies are already detectable in most patients with rheumatoid arthritis halfway through an infusion cycle: an open-label pharmacokinetic cohort study. BMC Musculoskelet Disord 2011;12:12
52.
Haraoui B, Cameron L, Ouellet M, White B. Anti-infliximab antibodies in patients with rheumatoid arthritis who require higher doses of infliximab to achieve or maintain a clinical response. J Rheumatol 2006;33(1):31-6
53.
Ducourau E, Mulleman D, Paintaud G, et al. Antibodies toward infliximab are associated with low infliximab concentration at treatment initiation and poor infliximab maintenance in rheumatic diseases. Arthritis Res Ther 2011;13(3):R105. Available from: www.arthritis-research.com/content/13/3/ R105
54.
Toki H, Momohara S, Tsukahara S, Ikari K. Infusion reaction to infliximab in a patient with rheumatoid arthritis after discontinuation over 1 year and readministration. J Rheumatol 2008;35(9): 1896-7
55.
Descotes J, Gouraud A. Clinical immunotoxicity of therapeutic proteins. Expert Opin Drug Metab Toxicol 2008;4: 1537-49
Review
Rheumatology (Oxford) 2012;51(Suppl 5): v22-30 60.
Jamnitski A, Bartelds GM, Nurmohamed MT, et al. The presence or absence of antibodies to infliximab or adalimumab determines the outcome of switching to etanercept. Ann Rheum Dis 2011;70(2):284-8
61.
Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008;67(11):1516-23
62.
Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 2005;353(11):1114-23
63.
Emery P, Fleischmann R, Filipowicz-Sosnowska A, et al. on behalf of the DANCER Study Group. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum 2006;54(5):1390-400
64.
Solau-Gervais E, Laxenaire N, Cortet B, et al. Lack of efficacy of a third tumour necrosis factor alpha antagonist after failure of a soluble receptor and a monoclonal antibody. Rheumatology (Oxford) 2006; 45(9):1121-4
56.
Dubey S, Kerrigan N, Mills K, Scott DG. Bronchospasm associated with anti-TNF treatment. Clin Rheumatol 2009;28:989-92
57.
Korswagen LA, Bartelds GM, Krieckaert CL, 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
65.
Blom M, Kievit W, Fransen J, et al. The reason for discontinuation of the first tumor necrosis factor (TNF) blocking agent does not influence the effect of a second TNF blocking agent in patients with rheumatoid arthritis. J Rheumatol 2009;36(10):2171-7
58.
Greenberg JD, Reed G, Decktor D, et al. on behalf of the CORRONA Investigators. A comparative effectiveness study of adalimumab, etanercept and infliximab in biologically naive and switched rheumatoid arthritis patients: results from the US CORRONA registry. Ann Rheum Dis 2012;71(7):1134-42
66.
Garceˆs S, Antunes M, Benito-Garcia E, et al. 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
•
A treatment algorithm encompassing immunogenicity assessment significantly improved the chances of achieving response and low disease activity.
59.
Emery P. Optimizing outcomes in patients with rheumatoid arthritis and an inadequate response to anti-TNF treatment.
doi: 10.1586/1744666X.2014.926219