Peripheral blood tregs (FOXP3+ CD4+) in patients with Inflammatory Bowel Disease (IBD) during treatment with anti TNFα agents
Luisa GuidiAnnabella ProcoliGiammarco MocciManuela MarzoGiambattista BonannoAlfredo PapaVitis I DeG FedeliSergio Rutella
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Peripheral blood CD4+ CD25high Tregs from patients with active rheumatoid arthritis (RA) have shown reduced FoxP3 expression and suppressive function which can be reversed by treatment with an anti TNFα monoclonal antibody (infliximab) both in vitro and in vivo. Anti TNFα agents are also used for the treatment of IBD, where a defective Treg activity has been detected within CD4+ T cells in the periphery but not lamina propria T cells. We evaluated FoxP3+CD4+ Tregs by flow cytometry and cytokine levels by ELISA (IL-17 and IL-23) or by flow cytometry (Th1/Th2 11plex, Bender MedSystem) in peripheral blood from 13 patients with active Crohn's disease (CD) and 2 patients with ulcerative colitis (UC) before and after (45-60 days) a first course of anti TNFα therapy. Ten CD and two UC patients were treated with infliximab, while three CD patients received certolizumab pegol (a human pegilated anti TNFα Fab'). In a group of 9 patients that we defined as “biological responders”, median pre-treatment frequencies of CD25highFoxP3+ cells among total CD4+ T cells were equal to 2.55% (range 0.2-8.0), while after treatment their frequency increased to 8.7% (range 5.7-21.5; p=0.019, Mann-Whitney test for paired determinations). All of these patients were also clinical responders. Six other patients did not show an increase or even had a decrease of peripheral blood Tregs (median pre-treatment values equal to 3.7% - range 2.9-8 - and median post-treatment values equal to range 2.7% - range 1.8-4.8. Of them, three were not clinical responders. Of the assayed cytokines, only IL-8 has shown a relevant modification, increasing in sera after anti TNFα treatment (from 33.9, range 1-217 pg/ml to 213.4, range 37-1169 pg/ml; p= 0.04 by Mann-Whitney test for paired determinations). Our preliminary data suggest the possibility that Tregs pharmacological modulation by anti TNFα treatment could be an additional mechanism to explain the beneficial effect of these drugs in IBD, at least in a subset of patients.This study in patients with rheumatoid arthritis (RA) treated with infliximab describes prospectively the course of (anti)infliximab levels within an infusion cycle to assess at what moment patients develop low/no infliximab trough levels and/or detectable anti-infliximab levels.Infliximab treated RA patients were included in this descriptive open-label cohort study. During one infusion cycle (anti-)infliximab levels were assessed just before and one hour after infusion, and subsequently at 50%, 75% and at the end of the infusion cycle (pre-infusion).27 patients were included. The median infliximab levels decreased from 77.0 mg/l (p25-p75: 65-89) one hour after the infusion to pre-infusion levels of 0.0 mg/l (p25-p75: 0.0-3.1). In 7 (26%) patients pre-infusion anti-infliximab antibodies were detected; these antibodies were already present halfway through the infusion cycle in 5 of the 7 individuals. Patients with detectable pre-infusion anti-infliximab antibodies have significantly more often low/no infliximab levels (< 1 mg/l) halfway trough the infusion cycle (in 5/7 patients) compared to patients without detectable pre-infusion anti-infliximab antibodies (0/20 patients, p < 0.001).Most anti-infliximab forming patients have detectable anti-infliximab antibodies halfway through an infusion cycle, which implies that these patients are exposed to nontherapeutical infliximab levels during more than half of their infusion cycle. As none of the patients without anti-infliximab antibodies had no/low-infliximab levels halfway through the infusion cycle, the presence of pre-infusion anti-infliximab antibodies seems a sensitive and specific predictor for no/low infliximab-levels.
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Introduction. The currently known prognostic criteria for biological therapy have limitations and have not been widely used in clinical practice. Aim. Find predictors of the effectiveness of biological therapy with infliximab in patients with ulcerative colitis. Materials and methods. The object of the study was patients (n = 52) diagnosed with Ulcerative Colitis in the active form of the disease, including 27 men and 25 women undergoing therapy with infliximab. Follow-up was carried out for three years from the start of therapy. The age of the examined persons ranged from 19 to 64 years (mean age 34.76 ± 2.13 years). The mean score on the Mayo scale was 6.1 ± 3.49. Results. In the course of our study, we obtained the following data on the effectiveness of infliximab therapy in patients with severe ulcerative colitis: a significant improvement in the dynamics of laboratory and instrumental parameters was recorded in 25 people (43.8%); the onset of stable clinical remission — in 15 people (26.3%); disease progression — in 5 cases (8.7%); lack of dynamics or a less pronounced effect — in 12 cases (21.2%). Conclusions. We have identified a system of clinical and laboratory factors that make it possible to predict the effectiveness of biological therapy with infliximab in patients with ulcerative colitis. The mathematical model in the form of a discriminant function makes it possible to divide patients into groups depending on the possible effect of the use of biological therapy with infliximab before its initiation (the sensitivity of the model is 83.3%, the specificity is 71.4%).
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Refractory (planetary science)
Rescue therapy
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OBJECTIVES: To review the frequency with which infliximab loses its effect and dose “intensification” is required for Crohn's disease treatment. METHODS: Bibliographical searches were performed in MEDLINE, and European (ECCO) and American (DDW) Congresses. Studies evaluating loss of efficacy and requirement of infliximab dose intensification—defined either as an increase of the infliximab dose (generally from 5 mg/kg to 10 mg/kg) or as a decrease in the frequency of infusion (to as often as every 4 weeks)—in Crohn's disease patients were included. RESULTS: Sixteen studies evaluating the incidence of loss of response to infliximab in Crohn's disease patients were found. A total of 2,236 patients were included (the majority of them receiving a three-dose induction regimen at weeks 0, 2, and 6, followed by maintenance therapy every 8 weeks), providing 6,284 patient-years of follow-up. The mean percentage of patients with loss of infliximab response was 37%. However, as the follow-up time varied markedly among studies, the risk of losing response to infliximab is better expressed as the incidence of this complication per patient-year of follow-up. Therefore, the annual risk for loss of infliximab response was calculated to be 13% per patient-year. CONCLUSIONS: A variable but relevant proportion of Crohn's disease patients on long-term infliximab treatment lose response. This may be interpreted in two different but compatible ways: a positive view, highlighting that infliximab therapy is relatively durable, with the majority of patients predicted to continue infliximab treatment at least during the first year; or a negative view, interpreting that a significant proportion of Crohn's disease patients—more than 10% per patient-year of infliximab treatment—on long term will lose response and will require an increase in dose and/or decrease in infusion interval.
Regimen
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Infliximab is a chimeric monoclonal anti TNFa whose effectiveness during IBD has been demonstrated especially in Crohn's disease and more recently in the course of ulcerative colitis. However, a significant number of patients estimated to be between 20 to 30% of patients with crohn's disease and 30 to 40% with ulcerative colitis, not responding to treatment with infliximab, thus the failure of infliximab is a real problem which the clinician should resolve quickly. This review aimed to describe predictif factors and mecanique of infliximab failure during MICI treatment and to precise differents therapeutique options.Literature reviewThe definition of failure of infliximab during inflammatory bowel disease is not consensual; it is very varied from one study to another. However, we define two types of non response to infliximab as either primary or secondary. Factors predisposing to failure of infliximab have been reported. Some alternative therapies may be recommended. The sequential treatment comparing to the episodic treatment by infliximab is better in obtaining an endoscopic and clinical response of patients with inflammatory bowel disease. The injection of infliximab should be preceded by the taking of immunosuppressive and concomitant use of these during treatment significantly improves the clinical response of patients. Also, the increased time of exposure to infliximab, either by increasing doses or shorter intervals of infusion therapy is a considerable therapy alternative. Moreover, thanks to the advent of new molecular anti TNFa, a relay by adalinumab or certolizumab may be proposed.The failure of infliximab is a common situation but not so easily solved by the clinician. The alternative therapies are aimed at strengthening; improve the action of infliximab or to change the therapeutic molecule. The efficacy of infliximab, being dependent on the rate of infliximab antibody, a therapeutic strategy based on the serum concentration of infliximab is proposed. If the serum concentration is low or undetectable suggesting a high rate of antibody, a change of molecule should be promoted. As if against the serum concentration is high or intermediate, increased time of exposure to infliximab or the addition of immunosuppressive can be proposed.
Concomitant
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Objective To observe the levels of plasma P-selection(P-sel) and in patients with ulcerative colitis and to study the clinical significance of them. Methods the concentrations of P-sel in 18 patients with active ulcerative colitis and 13 relief ulcerative colitis were determined with ELISA method. Results The results shown that the levels of P-sel in active ulcerative colitis patients were markedly elevated and were correlated with the severity of the disease. But the levels of P-sel in relief ulcerative colitis patients have no difference with normal controls. Conclusion It is suggested that the occurrence and development of ulcerative colitis may be related to the increase of plasma P-sel. Measurement of levels of plasma P-sel and might therefore provide a tool for monitoring the clinical course and for gaiding the treatment of ulcerative colitis.
Clinical Significance
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Objective:To investigate the action of TNF-a,IL-6 and sIL-2R in the mechanism of ulcerative colitis.Methods:Bi-antibody radioimmune methods and ELISA methods were used to analysis the samples in TNF-a,IL-6 and sIL-2R of 25 cases with active ulcerative colitis.30 normal persons were assigned as the contrast group.The data of cytokines(TNF-a,IL-6,sIL-2R)among contrast group,the active and catabolic phases of ulcerative colitis were compared.That in catabolic phases of ulcerative colitis was also compared with that in contrast group,the difference were compared among slight,moderate and severe groups,The relativity among the serum level in TNF-a,IL-6 of active ulcerative colitis had been observed.Results:The level of serum TNF-a,IL-6 and sIL-2R in active ulcerative colitis was much more higher than catabolic ulcerative colitis and contrast group(P0.05).The level had no significant difference between catabolic ulcerative colitis and contrast group(P0.005).The level in severe group is higher than that in moderate and slight group(P0.05).Serum cytokines,TNF-a and IL-6 are positively related to active ulcerative colitis.(r=0.8476,P0.05).Conclusion:There is a severe disorders of cellular immunity in the patients with active ulcerative colitis.TNF-a,IL-6,sIL-2R etc play the very important roles in the genesis and development of ulcerative colitis.The serum level of the above cytokines not only reflected the development of ulcerative colitis but also could be used as biological index of the effect and estimate the prognosis.
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To determine whether the need to use doses of infliximab greater than 3 mg/kg every 8 weeks to achieve or maintain clinical response in patients with rheumatoid arthritis (RA) is associated with differences in baseline clinical characteristics or anti-infliximab antibodies.Baseline clinical characteristics and anti-infliximab levels were evaluated retrospectively in a cohort of 51 consecutive patients with RA treated with infliximab at a single center. Patients were divided into 2 groups for comparison: Group 1 patients achieved and maintained clinical responses with infliximab 3 mg/kg every 8 weeks; Group 2 patients required higher doses.Thirty-two (63%) patients required infliximab dose escalation (Group 2). There were no statistically significant differences in baseline or clinical characteristics between Group 1 and Group 2 patients. Anti-infliximab antibodies occurred in 47% of Group 2 versus 27% of Group 1 patients, with higher anti-infliximab antibody concentrations in Group 2 patients (mean +/- SD: 18.3 +/- 8.9 g/ml vs 7.5 +/- 4.8 g/ml; p = 0.02). Patients who developed anti-infliximab antibodies were younger and receiving less prednisone at the time of infliximab initiation than patients who did not.Finding higher anti-infliximab antibody concentrations in patients who needed dose escalation of infliximab to achieve or maintain clinical responses with lower serum trough levels of infliximab suggests that development of anti-infliximab antibodies may reduce clinical efficacy of infliximab in some patients with RA.
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Infliximab is effective for the treatment of refractory inflammatory bowel disease (IBD). Nevertheless, up to 40% of patients lose response to infliximab over time. The aim was to assess the clinical value of measuring infliximab trough levels and antibodies to infliximab (ATI) concentrations in IBD patients who lost response to infliximab therapy.We retrospectively studied records of IBD patients who lost response to infliximab therapy. We first assessed clinical responses of different therapeutic strategies that were applied when patients lost response to infliximab and then we looked at the correlation between clinical response and infliximab trough levels and ATI concentrations.Seventy-six IBD patients were included. 31/76 patients (41%) continued infliximab therapy without any modification, 39 patients (51%) had an intensification of infliximab therapy, five patients (7%) had switched to adalimumab therapy, and one patient (1%) underwent surgery. Clinical response was observed in 27 patients (69%) with an intensification of infliximab therapy. There was no significant difference in mean infliximab trough level at inclusion in patients who responded to intensification of infliximab therapy (3.3 ± 4.1 μg/mL) as compared with patients who did not respond (2.3 ± 2.2 μg/mL, P = 0.85). In all, 16/76 patients (22.4%) presented detectable ATI in the serum. Ten ATI-positive patients had an intensification of infliximab therapy and six (60%) demonstrated a clinical response. After intensification of infliximab therapy the ATI concentration decreased in five patients.In patients with IBD who lose response to infliximab, clinical improvement may occur upon intensification of infliximab therapy, irrespective of infliximab serum concentration or presence of ATI.
Trough level
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