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Towards personalized treatment of rheumatic diseases with TNF inhibitors
l' Ami, M.J.
2020
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l' Ami, M. J. (2020). Towards personalized treatment of rheumatic diseases with TNF inhibitors.
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Chapter 1
Chapter 1 | General introduction
GENERAL INTRODUCTION
Treatment options for rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) have grown extensively with the introduction of biologic disease-modifying antirheumatic drugs (bDMARDs) and, more recently, targeted synthetic DMARDs (tsDMARD). The pro-inflammatory cytokine tumour necrosis factor (TNF) was one of the first successfully inhibited targets. Etanercept was the first out of five TNF inhibitors (TNFi) that was approved for RA (1998), followed by infliximab (1999), adalimumab (2002), golimumab (2008) and certolizumab pegol (2009). A few years later, they were also all approved for PsA, as well as for AS patients, except for certolizumab pegol. All TNFi are approved in a standard dose, similar for RA, PsA and AS.
TNFi are fully embedded nowadays in treatment of rheumatic diseases and improved disease activity, function and quality of life considerably. Treatment with TNFi has, however, also disadvantages. Studies showed an increased risk for serious infections and tuberculosis. Also, the risk for (non-)melanoma might be slightly increased.1 In
addition to these serious adverse events, TNFi have to deal with so called ‘financial toxicity’. The drug costs are still very high, which hampers the wide spread use of the drugs. Patients currently have to meet strict conditions to be treated with these expensive drugs. Because of these disadvantages and the fact that all TNFi are prescribed in a standard dose, it has become mandatory to personalize treatment.
Adalimumab and etanercept
Adalimumab and etanercept are two of the TNFi that are frequently prescribed in the Netherlands. This thesis focused on these two drugs. Adalimumab is a humanized monoclonal antibody with a half-life time of about 2-3 weeks. The approved standard dose is 40 mg every other week. Etanercept, in contrast, is a TNF receptor fusion protein with a short half-life time of about 3 days. The approved dose is 50 mg every week or 25 mg twice weekly. Apart from the differences in structure, half-life time and dose, the impact of immunogenicity is rather different. The vast majority of patients develop anti-drug antibodies (ADAs) against adalimumab, whereas negligible immunogenicity is reported towards etanercept.2,3 The amount of ADAs against adalimumab varies
widely between patients, affecting the drug concentration that is achieved.4,5
Adalimumab is, therefore, characterized by a wide variation in drug concentration. The ADAs detected against etanercept have not shown to be clinically relevant. Overall, the specific characteristics of adalimumab and etanercept are rarely addressed in studies, although they may affect treatment efficacy and dose-optimization.
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Long-term efficacy
It is important to control immunogenicity in order to improve efficacy in adalimumab treatment. Prior studies showed that ADAs are less frequently detected in patients treated with a combination of adalimumab and methotrexate (MTX) compared to adalimumab alone. Subsequently, higher adalimumab concentrations were detected in patients that used concomitant MTX, which is related to a better disease outcome.6,7 It is, however, unclear why MTX would have an additional
effect on etanercept efficacy, since it is suggested that immunogenicity plays a negligible role in etanercept. Nevertheless, a few clinical studies showed that a combination of etanercept with MTX resulted in a better clinical outcome compared to etanercept alone.8–11 The study populations used (mostly MTX naive patients),
however, do not necessarily reflect clinical practice. It is important to know whether MTX has a synergetic effect in etanercept treatment for patients intolerant to MTX at the start of their biologic treatment.
Moreover, this is a relevant question for AS patients. MTX is only prescribed occasionally in AS patients, because it does not affect disease activity itself. Immunogenicity might, therefore, be less controlled in adalimumab-treated AS patients. This could result in a reduced efficacy of adalimumab treatment in these patients. However, long-term studies that compared the efficacy and drug survival between adalimumab and etanercept in the AS population are scarce. Results from the RA population are, moreover, not directly applicable in AS, as studies have shown lower drug survival rates in RA patients compared to AS patients.12
Chapter 1 | General introduction
Personalize second treatment option
Around one-third of patients does not achieve a sufficient response to adalimumab or etanercept. These patients generally switch to a second TNFi, a bDMARD with another mode of action or to a tsDMARD. Switching to a non-TNFi has shown to be more effective than a second TNFi, but there is a subgroup of patients with a good response to a second TNFi.14 It is, however, not yet possible to identify those
patients.
Treatment failure can be a result of very low or undetectable drug concentrations, at which target blockade is inadequate.13,15 Increasing the dose or switching to a
second TNFi can enhance drug exposure and subsequent target blockade in this case. Contrary, there are also non-responders with adequate drug concentrations. The target is sufficiently blocked and there is no rationale to increase the dose or switch to a second TNFi. We expect that patients with low drug concentrations can successfully switch to a second TNFi.
Prior studies already showed that patients with detectable ADAs respond better to a second TNFi compared to patients without detectable ADAs.16 ADA detection is,
however, assay dependent.6 Serum drug concentrations are probably more useful than ADA detection in clinical practice, but are not investigated yet. We expect that concentrations can be useful to personalize treatment choice after failing a TNFi.
Reducing overexposure
Both adalimumab and etanercept are approved in a standard dose. This ‘one size fits all’ strategy is, however, under debate in the last years. Several studies showed that lowering the dose is feasible in the majority of patients and a substantial proportion of patients is able to stop the drug, at least temporarily.17–20
Pharmacokinetic aspects are rarely considered in these tapering studies, while they might explain why the dose can be reduced in the majority of the patients. For adalimumab, it is well described that serum drug concentrations vary widely between patients and that this variation is related to clinical response. It has been shown that higher adalimumab concentrations result in better clinical response, but that the curve plateaus around 5 µg/mL (Figure 1).13 Thus, patients with
steady-state trough concentrations above 5 µg/mL are most likely overexposed. This comprises about 70% of the patients, emphasizing the need to reduce the dose in the majority of patients.13 Moreover, it suggests that the dose can be reduced
General introduction | Chapter 1
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reduced. For example, patients with a concentration above 8 µg/mL might prolong the dosing-interval safely to once every three weeks. It is expected, given the linear clearance of adalimumab 21, that the concentration would remain above 5 µg/mL in
this case. The use of drug concentrations to optimize the dose in clinical practice is called therapeutic drug monitoring (TDM). Currently, dose-reduction is mainly based on trial-and-error principle. With the use of TDM the dose might be reduced more straightforward.
It is less clear what TDM can add in dose optimization of etanercept, as no clear relationship between drug concentration and clinical response could be demonstrated yet. Some studies suggest that lower concentrations were related to a worse disease outcome, but no validated cut-off point is determined. Nevertheless, a few studies showed that dose reduction is feasible in etanercept-treated RA patients too.22,23 Studies in AS and PsA populations are scarce and need to be investigated.
Dynamics of circulating TNF
A substantial proportion of patients is able to discontinue treatment, at least, temporarily.17,18 It would be beneficial to quantify TNF concentrations during TNFi
treatment in order to predict successful treatment discontinuation. We expect a decline in TNF concentrations in patients whom can discontinue TNFi successfully compared to patients that still need the drug. A prior study already showed that a decline in TNF was associated with a significant reduction in C-reactive protein (CRP).24,25 Numerous studies have investigated TNF concentrations during TNFi
treatment in patients before.24,26–29 However, the quantification of TNF is challenging
for a number of reasons. First, TNF is rapidly cleared from the circulation (TNF half-life is in the order of minutes).30 Consequently, TNF concentrations in circulation
are low, around the detection limit of most immunoassays, even during active disease.24,26,27 Second, TNF is unstable in biological samples31,32 due to continuous
monomeric subunit exchange.33 Last, the trimeric TNF structure is easily
compromised, e.g., during freezing and thawing of serum samples, with direct impact on TNF quantification.34 It is therefore unlikely that pretreatment TNF is a
reliable biomarker.
In contrast, TNF bound to a TNFi has a prolonged half-life, because the TNF-inhibiting antibodies themselves have a very long half-life of several weeks. This explains the observed increase in TNF concentrations shortly after initiation of TNFi treatment.24,26–29 However, measurement of TNF during TNFi treatment is also
challenging. TNFi interfere with the quantification of TNF, likely resulting in a severe underestimation of the TNF concentration.
Chapter 1 | General introduction
This limitation affects all of the abovementioned studies. We, therefore, developed a drug-tolerant assay to quantify TNF in complex with adalimumab and etanercept.
Outline of the thesis
This thesis focuses on 1) how the efficacy of adalimumab and etanercept in rheumatic diseases can be improved, 2) how overexposure of these biologics can be reduced and 3) how switching between these agents can be optimized. Finally, 4) the target TNF was measured in order to predict successful treatment discontinuation. The specific characteristics of adalimumab and etanercept are addressed in this thesis. In Chapter 2, we studied the clinical response and drug survival in RA patients starting adalimumab or etanercept with or without concomitant MTX. Patients were followed in a prospective cohort up to two years. Although both drugs have shown to be effective, long-term follow-up studies in the AS populations are scarce. We, therefore, studied in Chapter 3 the long-term drug survival of adalimumab and etanercept in AS patients. One of the concerns in biologic treatment is the amount of overexposure. It has become mandatory to tailor treatment in order to reduce adverse events and control high drug costs. Serum drug concentration can be useful in order to reduce the dose straightforward. In Chapter 4, we investigated in a randomized controlled trial whether the dosing-interval could be prolonged by 50% in patients with RA with adalimumab trough concentrations of at least 8 μg/mL without affecting disease control. In Chapter 5, we studied dose reduction of etanercept in a randomized controlled trial. We studied the proportion of patients with RA, PsA or AS that maintained minimal disease activity after dosing-interval prolongation compared to continuation of the standard dose. Secondly, we studied the success rate of discontinuation of etanercept and the serum drug concentration during tapering. In Chapter 6, we studied switching between adalimumab and etanercept. We investigated whether the adalimumab concentration is related to the efficacy of a second TNFi, etanercept, in RA patients. To optimize treatment and to predict successful treatment discontinuation, we aimed to quantify TNF concentrations during adalimumab and etanercept treatment. Therefore, a new drug-tolerant assay was developed to measure TNF. In Chapter 7, we quantified TNF concentrations in the presence of adalimumab and related these concentrations to clinical efficacy. In Chapter 8, we quantified TNF concentrations in the presence of etanercept and related these levels to the use of concomitant MTX.
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REFERENCES
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