Vermeire S, Noman M, Van Assche G, et al.. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn's disease

Department of Internal Medicine, Division of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium.
Gut (Impact Factor: 14.66). 09/2007; 56(9):1226-31. DOI: 10.1136/gut.2006.099978
Source: PubMed

ABSTRACT Episodic infliximab (IFX) treatment is associated with the formation of antibodies to IFX (ATIs) in the majority of patients, which can lead to infusion reactions and a shorter duration of response. Concomitant use of immunosuppressives (IS) reduces the risk of ATI formation.
To investigate which of the IS-that is, methotrexate (MTX) or azathioprine (AZA)-is most effective at reducing the risk of ATI formation, a multicentre cohort of 174 patients with Crohn's disease, treated with IFX in an on-demand schedule, was prospectively studied. Three groups were studied: no IS (n = 59), concomitant MTX (n = 50) and concomitant AZA (n = 65). ATI and IFX concentrations were measured in a blinded manner at Prometheus Laboratories before and 4 weeks after each infusion.
ATIs were detected in 55% (96/174) of the patients. The concomitant use of IS therapy (AZA or MTX) was associated with a lower incidence of ATIs (53/115; 46%) compared with patients not taking concomitant IS therapy (43/59; 73%; p<0.001). The incidence of ATIs was not different for the MTX group (44%) compared with the AZA group (48%). Patients not taking IS therapy had lower IFX levels (median 2.42 microg/ml (interquartile range (IQR) 1-10.8), maximum 21 microg/ml) 4 weeks after any follow-up infusion than patients taking concomitant IS therapy (median 6.45 microg/ml (IQR 3-11.6), maximum 21 microg/ml; p = 0.065), but there was no difference between MTX or AZA. In patients who developed significant ATIs >8 microg/ml during follow-up, the IFX levels 4 weeks after the first infusion were retrospectively found to be significantly lower than in patients who did not develop ATIs on follow-up or had inconclusive ATIs.
Concomitant IS therapy reduces ATI formation associated with IFX treatment and improves the pharmacokinetics of IFX. There is no difference between MTX and AZA in reducing these risks. ATI profoundly influences the pharmacokinetics of IFX. The formation of ATIs >8 microg/ml is associated with lower serum levels of IFX already at 4 weeks after its first administration.

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Available from: Filip Baert, Sep 28, 2015
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    • "Antibodies to IFX (ATIs) were described in up to 60% when IFX was used on an ad hoc basis in practice and in 10 to 20% of patients in randomized controlled trials of maintenance therapy [43]. ATIs were associated with loss of clinical response, deterioration of endoscopic activity, infusion reactions, and low serum IFX concentrations [5, 41, 44, 46, 50–52]. However, some studies did not observe significant correlation between trough levels of IFX and CD activity or between positivity of ATIs and loss of clinical response or deterioration of endoscopic activity [3, 4, 53–55]. "
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    ABSTRACT: Since their appearance in the armamentarium for inflammatory bowel disease (IBD) more than a decade ago, antitumor necrosis factor (TNF) inhibitors have demonstrated beneficial activity in induction and maintenance of clinical remission, mucosal healing, improvement in quality of life, and reduction in surgeries and hospitalizations. However, more than one-third of patients present primary resistance, and another one-third become resistant over time. One of the main factors associated with loss of response is the immunogenicity of anti-TNF biologics leading to the production of antidrug antibodies (ADAbs) accelerating their clearance. In this review we present the current state of the literature on the place of TNF and its blockage in the treatment of patients with IBD and discuss the usefulness of serum trough levels and ADAb monitoring in the optimization of anti-TNF therapies.
    Mediators of Inflammation 03/2014; 2014:172821. DOI:10.1155/2014/172821 · 3.24 Impact Factor
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    • "Why do some patients develop an anti-drug antibody response while others do not? It is known that the use of concomitant immunosuppressants is associated with a lower frequency of anti-drug antibodies [10,11] and, in some studies, the presence of anti-drug antibodies has been associated with decreased serum drug levels and a diminished response [12,13]. Furthermore, in some cases, the combined presence of anti-drug antibodies and therapeutic monoclonal antibody (TmAb) concentrations leads to the formation of immune complexes, and their continuous presence in serum leads to adverse events. "
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    ABSTRACT: The use of tumour necrosis factor (TNF) antagonists (infliximab [IFN], etanercept [ETN], adalimumab [ADA]) has changed the course of many rheumatic diseases, including rheumatoid arthritis (RA). However, some questions concerning their safety have emerged since their approval because they can trigger immunisation, induce rare type I and III hypersensitivity, and cause acute and delayed reactions. The aim of this study was to evaluate the correlations between hypersensitivity reactions to biological agents, disease activity and the development of class-specific IgA and IgM antibodies against the three anti-TNF agents in patients with RA. This longitudinal observational study involved consecutive outpatients with active RA who started treatment with IFN (n=30), ETN (n=41) or ADA (n=28). Clinical data and systemic and local side effects were collected prospectively at baseline and after six months of anti-TNF treatment. Serum samples were taken at the same time points in order to measure antibodies against the TNF blockers, anti-nuclear (ANA) and anti-dsDNA antibodies. The IgA and IgM antibodies specific to all three anti-TNF-α agents were analysed using ImmunoCaP Phadia- Thermofisher especially developed in collaboration with the laboratory of Immunology and Allergy, San Giovanni di Dio, Florence. The mean age of the 99 patients (86% females) was 54.6±12.4 years, and the median disease duration was 11.2±.3.2 years (range 3-14.3). The three treatment groups were comparable in terms of age, gender, rheumatoid factor and anti-citrullinated peptide (CCP) antibody positivity, and baseline C-reactive protein levels, erythrocyte sedimentation rate, 28-joint disease activity scores, and concomitant medications. Twelve patients treated with INF (40%) had anti-IFN IgM, and two (6%) anti-IFN IgA; 19 patients treated with ADA (68%) had anti-ADA IgM, and four (6%) anti-ADA IgA; and 27 patients treated with ETN (66%) had anti-ETN IgM, and 24 (58%) anti-ETN IgA. There were five systemic reactions in the IFN group, and seven adverse local reactions in both the ADA and the ETN group. There was no correlation between drug-specific IgA and IgM antibodies (p=0.65). There was also no correlation between the antibodies and disease activity after six months of treatment (r=0.189;p=0.32). Our findings show that the development of antibodies against IFN, ADA or ETN of IgA and IgM class are not related to any decrease in efficacy or early discontinuation of anti-TNF treatment in RA patients, nor to systemic and local reactions. Further studies of larger series of RA patients are needed to confirm the relationships between the development of drug-specific antibodies, serum TNF blocker levels, and disease activity.
    The Open Rheumatology Journal 09/2013; 7(1):75-80. DOI:10.2174/1874312901307010075
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    • "Notably, when the commercially available assays are used, ATI can only be detected reliably (due to antigen binding) when the simultaneous s-IFX is low. Concomitant immunosuppression seems to lower the frequency of ATI in on-demand IFX therapy [19], but the effect is debatable in scheduled therapy [16]. "
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    ABSTRACT: Objective: To study serum infliximab (s-IFX) levels in pediatric patients with inflammatory bowel disease (IBD). Subjects and methods: s-IFX trough levels were measured in a total of 133 blood samples of 37 pediatric IBD patients (Crohn's disease, 23): 48 during the induction phase (weeks 2 and 6) and 85 during maintenance treatment. Antibodies to infliximab (ATI) were determined in 93 samples (30 patients). s-IFX values were related to fecal calprotectin (FC) and serum markers of inflammation. Results: During induction (5 mg/kg) and maintenance therapy, the median s-IFX levels were 17.6 μg/ml (range 0-48 μg/ml) and 3.55 μg/ml (range 0-40 μg/ml), respectively. The IFX levels were similar in ulcerative colitis and Crohn's disease (e.g. during maintenance median 3.2 vs. 2.8 μg/ml, p = 0.718), thus the data are pooled. During induction, the s-IFX level was associated with the total dose of IFX, that is, young children with lower body weight had lower levels (p < 0.001 at week 2 and p < 0.05 at week 6). Shorter administration interval resulted in higher trough levels (p < 0.005). All samples with undetectable s-IFX (6.8%) levels presented ATI. High inflammation (FC >1000 µg/g) during induction was associated with lower s-IFX levels (median 4.0 μg/ml, range 0.47-25 compared to median 20 μg/ml, range 0-48 when FC <1000 µg/g, p < 0.005). There was no significant association between the ESR or values of C-reactive protein and s-IFX levels during induction. Conclusions: In pediatric IBD, lower body weight and higher level of intestinal inflammation are associated to s-IFX levels during induction but relation to therapeutic response is unclear.
    Scandinavian Journal of Gastroenterology 11/2012; 48(1). DOI:10.3109/00365521.2012.741619 · 2.36 Impact Factor
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