Summary The new subcutaneous (sc) formulation of the infliximab (IFX) biosimilar CT‐P13 results in homogeneous serum trough concentrations of IFX at steady state. The present study aimed to investigate in Crohn’s disease (CD) patients the intra‐individual variations of IFX drug levels at multiple time‐points during 2 consecutive cycles of maintenance therapy with CT‐P13 sc. Patients and Methods CD patients in clinico‐biological remission under maintenance therapy with intravenous (iv) IFX/CT‐P13 were switched to CT‐P13 sc 8 weeks (W) after the last infusion. They were treated with CT‐P13 sc, 120 mg every 2 W. Assessments were performed from 8 W after starting CT‐P13 sc and patients had to attend 6 visits on 2 consecutive cycles of treatment (cycles A and B). Visits were scheduled on days 4–6 (visit 1), days 7–9 (visit 2) and day 14 (visit 3) of each cycle, where days 1 and 14 were the days of sc injection of CT‐P13. At each visit, peripheral blood was collected to measure serum IFX levels and anti‐drug antibodies. Results Twenty patients underwent 120 evaluations. Large intra‐individual variations of serum drug levels of IFX were observed. When pooling the 120 evaluations, the mean drug level was 11.3 ± 4.9 μg/ml, and the median drug level was 10.9 μg/ml (IQR 7.5–15.5). During each cycle, the median drug levels were similar between visits 1 and 2 as well as between visits 1 and 3 and between visits 2 and 3. In cycle A, median drug levels were 11.1 μg/ml (7.8–14.5), 12.0 μg/ml (7.2–16.1) and 11.0 μg/ml (7.5–15.1) at V1, V2 and V3, respectively. Similar results were obtained in cycle B, where median drug levels were 11.6 μg/ml (7.9–14.9), 11.4 μg/ml (8.1–15.2) and 10.9 μg/ml (7.9–15.6) at V1, V2 and V3, respectively. In univariate analysis, we failed to identify factors predictive of low drug levels. Conclusions IFX drug levels are quite stable within 14‐day treatment cycle, without trough levels in CD patients in remission during the maintenance therapy with CT‐P13 sc. In patients with inactive CD under maintenance therapy with CT‐P13 sc, therapeutic drug monitoring of IFX can be performed at any time between two CT‐P13 sc injections.
Background Case reports of IBD flares after COVID-19 vaccination have been reported. These cases appear to be rare. In a recent study analyzing adverse event rates and impact on clinical activity of IBD after COVID-19 vaccination, the authors reported a rate of IBD reactivation in 2% of cases defined as reactivation of symptoms associated with a change in therapy (Prevent COVID Study) (Weaver et al. IBD 2022). Methods Any patient with IBD, followed as an outpatient in our department and having accepted to be vaccinated against COVID-19, was proposed this study. All the patients included in the study had to contact the department if, within one month of receiving the COVID-19 vaccine, they presented a clinical picture suggestive of an IBD relapse. The patients were reviewed in emergency and an assessment of IBD activity was made: clinical activity score, CRP and/or calprotectin dosage, short endoscopy in case of UC, colonoscopy or MRI in case of CD. The link between vaccine and relapse was defined by the absence of clinical activity for at least 3 months before vaccination and relapse of the disease at the latest within 30 days after vaccination without therapeutic modification in between. Results 231 patients (mean age: 44.6 years, sex ratio M/F=1.1, 43.3% MC) were eligible. 176 patients had at least three doses of vaccine, all with mRNA, and 55 with no more than two doses. 97 patients (42%) were infected at least once with COVID 19, confirmed by PCR after at least one dose of vaccine, all without resorting to hospitalization, resuscitation or death. 29 patients (12.5%) developed IBD after vaccination (43.6% MC, sex ratio=1, 80% of cases after 3 doses of vaccine) after a median time of 8.5 days (5-17 days). Patient characteristics, treatment received, number of vaccinations, or Covid infection were comparable between groups with and without reactivation after COVID-19 vaccine (P=NS). The risk of relapse after vaccination was 29 per 646 vaccine doses (4.4%). Table 1 reports pre-exacerbation treatments and proposed treatment changes as well as medium-term response. For IBD flares, no severe forms, hospitalization or surgery were observed. Fifteen patients were optimized on their treatment and 18 were switched to another treatment. All were put into clinical remission of their disease. In univariate analysis, no clinical parameter (type of IBD, age, sex, smoking), the number of previous vaccinations, a previous infection with covid 19 or the type of treatment was associated with a significant risk of relapse after vaccination. Conclusion The risk of IBD relapse in patients in durable clinical remission is possible after COVID-19 mRNA vaccination but remains low (4%). No risk factors were isolated in this work.
Background Monitoring of antibodies (ADA) under ustekinumab therapy in routine practice is not recommended in IBD patients. Aim of study to investigate the relationship between ADA detected by a drug-tolerant assay and loss of response to therapy in a cohort of IBD patients treated with ustekinumab. Methods This was a retrospective study enrolling consecutively all adult patients with moderate to severe active IBD and having a follow up period of at least 2 years after ustekinumab induction. Loss of clinical response was defined as CDAI > 220 or HBI > 4 for CD and partial Mayo subscore > 3 for UC associated with the decision to modify disease management or treatment. Results Ninety patients were included (78 CD and 12 UC, mean age 37 years). Median levels of anti-ustekinumab antibodies (AUA) were significantly higher in patients with LOR compared with those in responder patients (15.2 µg/mL-eq CI (7.9-21.5) and 4.7 µg/mL-eq CI (2.1-10.5), respectively; p=0.04). The area under the ROC curve (AUROC) for AUA in predicting LOR was 0.76. The optimal cut-off point capable to accurately identify patients with LOR was 9.5 µg/mL-eq with a sensitivity of 80 % and specificity of 85 %. In multivariate analysis, serum AUA ≥ 9.5 µg/mL-eq (HR=0.84), prior vedolizumab exposition (HR=0.78) and azathioprine (HR=3.78) exposures were the only independent factors associated with subsequent clinical response to ustekinumab therapy. Conclusion In our real-life cohort, AUA was identified as an independent predictor of LOR and subsequent drug failure to treatment
Background Serum calprotectin (SC), a novel biomarker of inflammatory bowel diseases (IBD), has been recently investigated with conflicting results. The purpose of this study was to assess the ability of SC for predicting disease relapse in patients with IBD treated by biologic therapies, and to evaluate the correlation between SC and clinical and endoscopic relapse and with other biomarkers including fecal calprotectin (FC) and C-reactive protein (CRP). Methods All consecutive IBD patients in deep remission (clinical and endoscopic or imaging remission) were recruited in this prospective study and followed 12 months. Blood and stool samples were collected for SC, serum CRP and FC measurement. SC was measured the day of inclusion (baseline, D0), 3 months (M3) and 6 months (M6) later and in case of relapse during the study period. Relapse was defined as clinical, biomarkers, or endoscopic/imaging activity. So, firstly, we looked at evolution of SC before relapse to analyze a predicting value of loss of response (LOR). We also compared SC for patients with active IBD and those with symptoms without inflammation. Results Among the 119 patients included, 54 (46.4%) patients experienced a disease relapse during follow-up. When we looked at the kinetic of SC during follow-up, median SC levels did not increase in patients who relapsed: 3.15 µg/l at baseline, 3.38 µg/l at M3, 3.33 µg/l at M6 and 3.99 µg/l in case of relapse (p=0.63). We compared SC during relapse with patients in endoscopic remission but clinical symptoms which defined secondary Irritable Bowel Syndrome, we found that SC levels were higher in active IBD and similar between the groups of patients with IBS or deep remission (3.05µg/l IBS vs 2.99µg/l remission vs 5.1µg/l for relapsers, p=0.04). In patients with clinical symptoms, SC presents a good predictive value for relapse. (AUROC 0.764, IC95: 0.68–0.88), giving a sensitivity of 72% with a specificity of 77%, using a cut-off value of 4.45mg/ml. A weak, but significant correlation was found between SC and FC levels (r=0.35, P= 0.001). A combined score with CRP, FC and SC didn’t improve its diagnostic accuracy. Conclusion SC was significantly higher in patients with relapse compared to those in endoscopic remission with or without clinical symptoms. It seemed that it permit to oppose patients with active IBD and those with symptoms of IBS. However, it failed to predict relapse.
Background Under IFX sc, we do not know if there is a residual level of IFX. The aim of this work was to investigate this point by analyzing the intra-individual variability of the serum level of IFX sc. Methods This was an observational, prospective study that included patients with CD undergoing maintenance treatment with IFX sc (120mg every, 14 days). Patients had IFX determinations (i Track, 10; Theradiag (France) at visit, 1 (day, 4 to, 6 after SC injection), visit, 2 (day, 7 to, 9 after sc injection) and visit, 3 (day, 13 to, 14 after sc injection) on two consecutive cycles. The first determinations were made only after, 8 weeks of switching from IV to SC. All patients at inclusion were in clinical remission (CDAI <, 150) with calprotectin levels <, 250 µg/g stool. Results 20 patients (mean age:, 36 years, sex ratio M/F:, 1, mean duration of IFX IV:, 16 months) were included, i.e. meaning, 120 determinations., 8 patients were treated in combination with thiopurines. Mean residual levels before switch to sc were, 3.9 +/-1.2 µg/mL. Mean intraindividual levels between the two cycles were comparable (Visit, 1: cycle, 1:, 11.1 +/-, 4.4 µg/mL, cycle, 2:, 11.6 +/-, 4.6 µg/mL; p=0.65; Visit, 2: cycle, 1:, 12.0 +/-, 5.1 µg/mL, cycle, 2:, 11.3 +/-4.9 µg/mL; p=0.25; Visit, 3 cycle, 1:, 11.0 +/-4., 7 µg/mL, cycle, 2:, 10.9 +/-, 4.2 µg/mL; p=0.21. Serum IFX sc levels remained stable over the, 14 days between the two SC injections (p=0.36). Mean IFX levels at any dosing time were comparable in patients with and without thiopurines (IFX sc monotherapy: mean:, 11.5 +/-, 5.5 µg/mL versus IFX sc with thiopurines: mean:, 11.8 +/-, 4.6 µg/mL, p=0.54). Finally, residual IFX IV levels before switch did not influence the results of IFX sc serum concentrations (p=NS). Conclusion Measure of IFX levels for IFX SC can be proposed at any time between two injections. No residual levels were found. These data are important for our clinical practice.
Background If the use of anti-TNF trough levels (TDM) are proposed in case of loss of response (reactive attitude), a proactive strategy has not shown in most randomized trials its interest. The aim of this study was to analyze the predictive value of a decrease of TLI in IBD patients in terms of loss of response over time. Methods This was a retrospective study that included all IBD patient followed in our university hospital. Eligible patients had to have IBD treated with IFX as maintenance therapy (5mg/kg/8weeks). Patients had to be in clinical remission of the disease at inclusion with calprotectin levels < 100 µg/g stool and therapeutic levels of IFX concentration (TLI > 5 µg/ml) on IFX mono- or combination therapy. IFX levels were analyzed by ELISA (Theradiag, France). Every two months, patients were reviewed in the day hospital with fecal calprotectin, TLI and a measure of the clinical activity score (CDAI for CD and Mayo clinical score for UC). Loss of response was defined for CD as a CDAI > 220 with fecal calprotectin > 250µg/g stool and for UC as a full Mayo score > 5 with an endoscopic Mayo score > 1. Low TLI during follow-up was defined as a level below 3 µg/mL. Patients who had dose optimization based on calprotectin or TLI alone were excluded from the study. Results 145 patients (65% CD, mean age 34 years, disease duration 4.5 years) were included. The mean follow-up was 66 months. 79 patients (55%) showed a loss of response. A decrease of TLI was found in 65% of patients who relapsed within 6 months versus 33% in patients in long-term clinical remission (p=0.14). The predictive value of loss of response within 6 months was moderate in the presence of low IFX levels (sensitivity: 71%, specificity: 73%; PPV: 73%, NPV: 68%). Conversely, fecal calprotectin (> 250 µg/g stools) increase was strongly predictive of loss of response within 6 months (sensitivity: 85%, specificity: 85%). The association of the two markers (decrease of TLI and/or increase of fecal calprotectin) improved the predictivity of relapse in the follow-up (sensitivity: 90%, Specificity: 89%). For the 79 patients who relapsed, for 35% (28 patients) of the cases, the rise of fecal calprotectin preceded the fall of TLI but for 25% of the cases (25 patients), apparition of low TLI preceded the rise of fecal calprotectin. Conclusion The decrease of TLI is n moderately predictive of a loss of clinical response in the short or medium term under IFX for IBD. These results may explain the negative results of a proactive attitude based on TDM alone. A proactive strategy based on TDM and fecal calprotectin could be very interesting but needs to be confirmed.
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