Niels Vande Casteele

The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease

Objective Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohns disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab. Design In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission. Results Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An infliximab concentration of >2.79 μg/mL (area under the curve (AUC)=0.681; 95% CI 0.632 to 0.731) and ATI concentration of <3.15 U/mL (AUC=0.632; 95% CI 0.589 to 0.676) were associated with remission. Multivariable analysis showed that concentrations of both infliximab trough (OR 1.8; 95% CI 1.3 to 2.5; p<0.001) and ATI (OR 0.57; 95% CI 0.39 to 0.81; p=0.002) were independent predictors of remission. Conclusions The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective infliximab dose intensification, is needed.

Switch to adalimumab in patients with Crohn's disease controlled by maintenance infliximab: prospective randomised SWITCH trial

Background Elective switching between anti-tumour necrosis factor (TNF) agents not necessarily dictated by efficacy or tolerability occurs in clinical practice. A study was undertaken to evaluate prospectively the impact of elective switching of patients with Crohns disease well controlled with intravenous infliximab to subcutaneous adalimumab in a controlled trial. Methods An open-label randomised single-centre trial recruited 73 patients with ongoing response to at least 6 months of scheduled maintenance infliximab. Patients were randomised to continue intravenous 5 mg/kg infliximab or to switch to subcutaneous adalimumab 80 mg at baseline followed by 40 mg every other week for 1 year. Dose optimisation was allowed for intermittent flares, and patients with loss of response or intolerance could cross over to the alternative treatment group. Tolerability, patient preference and efficacy of both treatment options were the primary outcomes. Results Dose optimisation or interruption of treatment occurred in 17/36 patients (47%) in the adalimumab group and in 6/37 patients (16%) in the infliximab group (p=0.006). One patient interrupted infliximab treatment and 10 patients interrupted adalimumab treatment (p=0.003), mostly for loss of tolerance. Overall, patients preferred adalimumab treatment. All five serious adverse events were related to complicated Crohns disease and occurred in patients randomised to adalimumab. Injection site reactions were more frequent than infusion reactions (8 vs 1, p=0.01), but only the latter caused cessation of further dosing. Anti-TNF serum levels were stable throughout the 1-year period in both groups. Conclusion Elective switching from infliximab to adalimumab is associated with loss of tolerance and loss of efficacy within 1 year. Adherence to the first anti-TNF agent is recommended.

Therapeutic drug monitoring in inflammatory bowel disease: current state and future perspectives.

Current available anti-inflammatory drugs, in particular monoclonal antibodies directed against the cytokine tumor necrosis factor α (TNF), have greatly enhanced the treatment of inflammatory bowel diseases (IBD). Although many patients respond to ant-TNF therapy, a proportion of patients will not respond (primary non-response) or will lose response to the drug over time (secondary non-response). This loss of response can be caused by patient, TNF-inhibitor, or disease-related factors influencing the pharmacokinetics and pharmacodynamics of the drug. Therefore, monitoring pharmacological parameters (i.e. therapeutic drug monitoring) may help guide therapeutic decisions. This review emphasizes interesting and important new findings, and provides an updated overview, on the subject of therapeutic drug monitoring. While exploring the hypothesis that “one size does not fit all”, we focused on the first prospective studies investigating the novel approach in IBD of ‘target concentration adjusted dosing’ and personalized medicine.

Role for therapeutic drug monitoring during induction therapy with TNF antagonists in IBD: evolution in the definition and management of primary nonresponse.

Abstract:Primary nonresponse and primary nonremission are important limitations of tumor necrosis factor (TNF) antagonists, occurring in 10% to 40% and 50% to 80% of patients with inflammatory bowel disease, respectively. The magnitude of primary nonresponse differs between phase III clinical trials and cohort studies, indicating differences, e.g., in definition, patient population or blinding. The causes of nonresponse can be attributed to the drug (pharmacokinetics, immunogenicity), the patient (genetics, disease activity), the disease (type, location, severity), and/or the treatment strategy (dosing regimen, combination therapy). Primary nonresponse has been attributed to “non-TNF-driven disease” which is an overly simplified and potentially misleading approach to the problem. Many patients with primary nonresponse could successfully be treated with dose optimization during the induction phase or switching to another TNF antagonist. Therefore, primary nonresponse is frequently not a non-TNF-driven disease. Recent studies from rheumatoid arthritis and preliminary data from inflammatory bowel disease evaluating therapeutic drug monitoring have suggested that early measurement of drug and anti-drug antibody concentrations could help to define primary nonresponse and rationalize patient management of this problem. Moreover, a modeling approach including pharmacological parameters and patient-related covariants could potentially be predictive for response to the treatment. We describe an overview of this evolution in thinking, underpinned by previous findings, and assess the potential role of early measurement of drug and antidrug antibody concentrations in the definition and management of primary nonresponse.

Pharmacokinetics of anti‐TNF monoclonal antibodies in inflammatory bowel disease: Adding value to current practice

Since anti‐tumor necrosis factor (TNF) antibodies were introduced to treat patients with inflammatory bowel diseases, short‐ and long‐term clinical and endoscopic endpoints can be achieved that were unreachable with conventional anti‐inflammatory agents. Although a large proportion of patients (70–90%) initially respond to the treatment, remission rates after induction are still low (20–50%) and patients are at risk to lose response to the drug over time. This inter‐individual variability in response is likely to be influenced by the observed inter‐individual variability in pharmacokinetics. By extensively reviewing the literature, we evaluated the potential role of therapeutic drug monitoring to optimize dosing of anti‐TNF drugs. Thereby we emphasize some of the pharmacokinetic cornerstones that can help to understand the observed concentration–effect relationship. After discussing some of the most commonly used assays to measure anti‐TNF drug and anti‐drug antibody concentrations, we reviewed the application of those tests and their potential clinical value in retrospective and prospective studies.

Antibodies to adalimumab are associated with future inflammation in Crohn's patients receiving maintenance adalimumab therapy: a post hoc analysis of the Karmiris trial

Introduction Data on immunogenicity to adalimumab (ADL) therapy in patients with IBD is limited. We performed additional analyses on the Karmiris cohort using the homogeneous mobility shift assay (HMSA) focusing on the inter-relationship of serum ADL concentration, antibodies-to-adalimumab (ATA), inflammatory markers and sustained response. Methods 536 prospectively collected serum samples were available for analysis of ADL concentration and ATA using HMSA. We studied the role of week 4 serum ADL concentration and immunomodulator (IMM) use on ATA formation with a Cox proportional hazards model. Mixed model repeated measures analysis was performed to assess the independent effects of serum ADL concentration and ATA on C-reactive protein (CRP) and response. Results ATA was detected in 20% of patients after a median of 34 (12.4–60.5) weeks. ATA-positive samples correlated with lower serum ADL concentration (p<0.001). Cox regression modelling showed that week 4 ADL concentration of <5 µg/mL significantly increased the future risk of ATA formation (HR=25.1; 95% CI 5.6 to 111.9; p=0.0002) and that IMM co-treatment prevented ATA formation (HR=0.23; 95% CI 0.06 to 0.86; p=0.0293). Regression modelling showed a negative correlation between CRP and ADL concentration (p=0.0001) and a positive one with ATA (p=0.0186). The model revealed that both lower serum ADL concentration and ATA were independently associated with future CRP (p=0.0213 and p=0.0013 respectively). ATA positivity was associated with discontinuation of ADL because of loss or response (OR=3.04; 95% CI 1.039 to 9.093; p=0.034). Conclusions ATA were detected in 20% of patients. Risk of ATA formation increased with lower early serum ADL concentration and in patients not on IMM. ATA and ADL were strongly associated with higher future CRP level and discontinuation of ADL.

Characteristics of Skin Lesions Associated With Anti–Tumor Necrosis Factor Therapy in Patients With Inflammatory Bowel Disease: A Cohort Study

Context Tumor necrosis factor (TNF) antagonists are effective for the treatment of inflammatory bowel disease (IBD) that does not respond to conventional therapy. Some patients, however, have discontinued anti-TNF therapy because of the development of psoriasiform lesions. Contribution In this large study from a tertiary care center, nearly one third of patients with IBD who initiated anti-TNF therapy developed skin lesions. With dedicated dermatologic care, most were able to continue therapy without interruption. Caution Patients with IBD not receiving anti-TNF therapy were not studied. Implication Skin lesions seem to be commonly associated with anti-TNF therapy in patients with IBD but typically do not require treatment discontinuation for successful management. In the late 1990s, tumor necrosis factor (TNF) antagonists were introduced as treatment for several inflammatory disorders, including rheumatoid arthritis, ankylosing spondylitis, psoriasis, Crohn disease, and ulcerative colitis. Whereas conventional therapy primarily targets symptom control, anti-TNF therapy has been shown to reduce symptoms, heal mucosal ulcers, reduce hospitalizations and surgeries, and spare corticosteroids (110). Infliximab, the first biological agent targeted against TNF, was followed by other anti-TNF biologics, including adalimumab, golimumab, certolizumab pegol, and etanercept (which is not used for inflammatory bowel disease [IBD]). Anti-TNF therapy has also proved to have a favorable safety profile with respect to serious infections, cancer, and mortality as long as it is given for the right indication and comorbidities are taken into account (1120). However, psoriasiform skin manifestations have been reported (long after the completion of randomized, controlled trials) as adverse events associated with anti-TNF therapy (2130). The appearance of psoriasiform skin manifestations is intriguing and seems paradoxical because anti-TNF therapy is also successfully used in psoriasis treatment. Inflammatory bowel disease shares several pathophysiologic characteristics with psoriasis and atopic dermatitis. All of these conditions have a strong genetic component, with 163 loci identified for IBD, 36 identified for psoriasis, and 11 identified for atopic dermatitis thus far (3133). Of note, the reported regions of association overlap substantially (32, 34, 35). Because skin lesions may represent a significant burden to patients, it is important to advise patients on preventive measures or alternative therapeutic options, especially when they are at increased risk. This study aimed to accurately describe patients with IBD treated with anti-TNF therapy who did and did not develop skin lesions. We investigated the development of skin lesions in a retrospective cohort of such patients. We also looked at specific patient characteristics, autoimmune and genetic factors, and infliximab cumulative dose and trough levels (TLs) in patients with and without skin lesions. Methods Study Participants and Design We retrospectively analyzed a consecutive cohort of 917 patients with IBD for the occurrence of skin lesions during anti-TNF therapy. Diagnosis of IBD was well-established according to conventional endoscopic, radiologic, and histologic criteria (36, 37). A total of 955 patients initiated infliximab treatment at the University Hospitals Leuven between December 1994 and January 2009, of whom 917 agreed to participate in our research projects. At the time of initiation of infliximab treatment, they were naive to any other anti-TNF agent. A subset of patients were noted to have switched to another anti-TNF agent (adalimumab or certolizumab pegol) when they showed loss of response to infliximab. The Ethics Board of the University Hospitals Leuven approved the study before data collection (institutional review board approval number B322201213950/S53684). All participants provided written informed consent agreeing to take part in our current and future research projects when they were included in our ongoing patient registry. Diagnostic and Therapeutic Criteria for Patients With Skin Lesions At the Leuven IBD center, all patients were seen by the IBD gastroenterologists (S.V., G.V.A., P.R., and M.F.) every 8 weeks or more frequently if needed. Patients with skin symptoms (especially itching) or skin lesions that occurred during and were possibly linked to anti-TNF therapy were referred to a dermatologist (S.S.) experienced in anti-TNF therapies. Beginning in 2000, when the phenomenon of skin lesions associated with anti-TNF treatment became more clear, patients who came to consultation were systematically checked for lesions and referred to a dermatologist. We classified the patients in the following categories (listed in descending order of severity) according to the predominant or most distressing lesions (if 1 type of lesion was identified, the patient was placed in the most-severe category): palmoplantar pustulosis (pustules of the palms and soles with or without surrounding erythema or erythematosquamous lesions), psoriasis (sharply demarcated erythematosquamous lesion covered with silvery-white scales; histologic evaluation [when performed] showed psoriasis), psoriasiform eczema (dermatitis with some features of psoriasis, especially the orange-red color, but unsharply defined lesions, often superinfected; histologic evaluation [when performed] showed dermatitis), eczema (dermatitis without features of psoriasis), or xerosis (dryness of the skin without signs of inflammation). In cases of diagnostic uncertainty (especially psoriasis vs. psoriasiform eczema) (Appendix Figure 1), skin biopsy specimens were taken and histologic evaluation was done. Skin lesions that could not be classified into one of these categories, including infections, inflammatory skin disease, tumors, and alopecia areata, were classified as other. A full list of skin lesion types is provided in Appendix Table 1. Appendix Figure 1. Hematoxylin and eosin staining of psoriasis (top), psoriasiform eczema (middle), and eczema (bottom). All histologic pictures are original magnification50. Top. A skin lesion showing irregular acanthosis, focal parakeratosis, and crust/scale formation, resembling psoriasiform eczema. Middle. A skin lesion showing regular elongation and clubbing of rete ridges, thinning of suprapapillary epidermis, confluent parakeratosis, and superficial perivascular inflammation, resembling psoriasis. Bottom. A skin lesion showing irregular and plump acanthosis, multifocal parakeratosis and spongiosis, and superficial perivascular inflammation, resembling spongiotic eczema. Appendix Table 1. Types of Skin Lesions For dermatologic treatment of the most frequently occurring skin lesions, we used a standard protocol, which is provided in the Appendix. Patient Characteristics The medical records of the patients were systematically reviewed up to 1 July 2014. For each patient, sex, diagnosis, smoking (ever vs. never), age at diagnosis and at the start of infliximab treatment, start and stop dates of infliximab treatment, infliximab infusion dates, switch to other anti-TNF agent (adalimumab or certolizumab pegol) with respective start and stop dates, reason for discontinuing anti-TNF therapy, and cumulative infliximab dose (until development of skin lesion, discontinuation of therapy, or end of analysis) were retrieved. To correct for different durations of exposure to infliximab, the cumulative infliximab dose was divided by the duration of treatment. When the interval between infliximab infusions was more than 16 weeks (as happened in the first patients treated in the 1990s), the time between infusions was not included in the calculations of total duration of treatment. Loss of response to infliximab was assessed and was defined as the need to stop infliximab therapy or the need for surgery despite an attempt to optimize treatment. If a skin lesion was reported, date of onset, type, location, history of atopic dermatitis or psoriasis, and initiated treatment were obtained. Case patients who stopped anti-TNF treatment because of a lesion were also noted. For all patients with skin lesions, we noted at their last consultation whether they showed complete, partial, or no resolution of the lesions and whether they were still receiving treatment for them at that time. For patients in whom anti-TNF treatment was stopped because of lesions, we noted how the lesions subsequently evolved and, in cases of complete resolution, in what time frame. Measurement of Serum Trough Levels of Infliximab Infliximab TLs and anti-infliximab antibodies (ATIs) were measured at several time points during treatment by using enzyme-linked immunosorbent assays developed in-house (38, 39). We considered only samples from week 14 onward in patients receiving infliximab maintenance therapy (defined as receipt of 4 infliximab infusions and 6 months of therapy). A total of 8350 TL measurements in 433 patients were available (median, 18 [interquartile range {IQR}, 5 to 32] per patient). A patient was considered to have subtherapeutic TLs when at least 2 measurements were less than 3 g/mL and supratherapeutic TLs when at least 2 measurements were greater than 7 g/mL (40). A total of 2770 ATI measurements in 325 patients were available (median, 5 [IQR, 3 to 13] per patient). Anti-infliximab antibodies were evaluated only when TLs were not detectable. Patients were considered ATI-positive when they had at least 1 ATI concentration greater than 1 g/mL. Measurement of Antinuclear Antibodies and Double-Stranded DNA Antibodies Measurements at baseline (3 months before the first infliximab dose) and at several time points during follow-up were included. Antinuclear antibodies (ANAs) were determined on 1:40 diluted sera by an indirect immunofluorescent technique on Sjgren syndrome Atransfected HEp-2 cells. A total of 3820 ANA measurements in 847 patients were available (median, 3 [IQR, 1 to 5] per patien

Biosimilars in Inflammatory Bowel Disease: Facts and Fears of Extrapolation

Biologic drugs such as infliximab and other anti-tumor necrosis factor monoclonal antibodies have transformed the treatment of immune-mediated inflammatory conditions such as Crohns disease and ulcerative colitis (collectively known as inflammatory bowel disease [IBD]). However, the complex manufacturing processes involved in producing these drugs mean their use in clinical practice is expensive. Recent or impending expiration of patents for several biologics has led to development of biosimilar versions of these drugs, with the aim of providing substantial cost savings and increased accessibility to treatment. Biosimilars undergo an expedited regulatory process. This involves proving structural, functional, and biological biosimilarity to the reference product (RP). It is also expected that clinical equivalency/comparability will be demonstrated in a clinical trial in one (or more) sensitive population. Once these requirements are fulfilled, extrapolation of biosimilar approval to other indications for which the RP is approved is permitted without the need for further clinical trials, as long as this is scientifically justifiable. However, such justification requires that the mechanism(s) of action of the RP in question should be similar across indications and also comparable between the RP and the biosimilar in the clinically tested population(s). Likewise, the pharmacokinetics, immunogenicity, and safety of the RP should be similar across indications and comparable between the RP and biosimilar in the clinically tested population(s). To date, most anti-tumor necrosis factor biosimilars have been tested in trials recruiting patients with rheumatoid arthritis. Concerns have been raised regarding extrapolation of clinical data obtained in rheumatologic populations to IBD indications. In this review, we discuss the issues surrounding indication extrapolation, with a focus on extrapolation to IBD.

Development of a universal anti-adalimumab antibody standard for interlaboratory harmonization.

Background: Therapeutic drug monitoring of adalimumab (ADM) has been introduced recently. When no detectable ADM serum concentrations can be found, the formation of antidrug antibodies (ADA) should be investigated. A variety of assays to measure the occurrence of ADA have been developed. Results are expressed as arbitrary units or as a titration value. The aim was to develop a monoclonal antibody (MA) that could serve as a universal calibrator to quantify the amount of ADA in ADM-treated patients. Methods: Hybridoma technology was used to generate a MA toward ADM. The functionality of the MA was tested in a bridging enzyme linked immunosorbent assay (ELISA) setup and in a cell-based assay. Sera from 25 anti–tumor necrosis factor naive patients with inflammatory bowel disease were used to determine the cutoff values. Sera from 9 ADM-treated patients with inflammatory bowel disease, with undetectable serum concentrations of ADM were used to quantify the ADA response. Results: In this study, MA-ADM6A10, an IgG1 that can be used as a calibrator in both an ELISA to quantify the amount of binding antibodies and in a cell-based assay to quantify the amount of neutralizing antibodies, was generated. Combining the results of both assays showed that the sera with high concentrations of anti-ADM binding antibodies also had the highest neutralizing capacity. Conclusions: The availability of a universal calibrator could facilitate the interlaboratory harmonization of antibody titers in patients who develop anti-adalimumab antibodies.

American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases

Therapeutic drug monitoring (TDM), which involves measurement of drug or active metabolite levels and anti-drug antibodies, is a promising strategy that can be used to optimize inflammatory bowel disease therapeutics. It is based on the premise that there is a relationship between drug exposure and outcomes, and that considerable inter-individual variability exists in how patients metabolize the drug (pharmacokinetics) and the magnitude and duration of response to therapy (pharmacodynamics). Therefore, the American Gastroenterological Association has prioritized clinical guidelines on the role of TDM in the management of inflammatory bowel disease. To inform these clinical guidelines, this technical review was developed in accordance with the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework for interventional and prognostic studies, and focused on the application of TDM for biologic therapy, specifically anti-tumor necrosis factor-α agents, and for thiopurines. Focused questions address the benefits and risks of a strategy of reactive TDM (in patients with active inflammatory bowel disease) to guide treatment changes compared with empiric treatment changes, and the benefits and risks of a strategy of routine proactive TDM (during routine clinical care in patients with quiescent disease) compared with no routine TDM. Additionally, the review addresses the benefits and risks of routine measurement of thiopurine methyltransferase enzyme activity or genotype before starting thiopurine therapy compared with empiric weight-based dosing and explores the performance of different trough drug concentrations for anti-tumor necrosis factor agents and thiopurines to inform clinical decision making when applying TDM in a reactive setting. Due to a paucity of data, this review does not address the role of TDM for more recently approved biologic agents, such as vedolizumab or ustekinumab.