Background: Although cyclosporine is an accepted and effective therapeutic choice in patients with severe ulcerative colitis (UC), long term colectomy rate varies between 60 88% among patients in whom cyclosporine initially induced remission.The aim of our study was to evaluate the long-term outcome and the optimal duration of cyclosporine therapy in patients with acute, severe UC.Methods: 73 (40 females, 33 males; mean age at the diagnosis 31.7 years, mean disease duration 13.4 years) of 183 patients hospitalized for severe exacerbation of UC between January 1998 and June 2009 revealed steroid-refractory after intravenous methylprednisolone therapy.They underwent intravenous cyclosporine treatment for 5 days following oral treatment in the case of a good initial response.Results: The mean follow up after the initiation of cyclosporine therapy was 4.2 years.The median duration of cyclosporine therapy was 9.6 months.Side effects developed in 37 patients.20 patients underwent early colectomy.Cyclosporine therapy had to be discontinued due to intolerable or severe side effects in 22 patients.Cyclosporine failed and late colectomy was performed in 14 of the 53 responders during the longterm follow up.Duration of cyclosporine treatment was significantly longer in those who avoided colectomy (5.4 vs. 13.3 months, p = 0.009).The optimal cut-point of the duration of cyclosporine therapy to avoid colectomy was 4.5 months.No association was revealed between the duration of cyclosporine therapy and the development of side effects.Conclusions: Cyclosporine is effective in acute, severe UC.After a median follow up of more than 4 years, 53.4% of the patients remained colectomy free.The optimal time for cyclosporine treatment proved to be 4.5 months.
Abstract Background First generation of biologicals (infliximab (IFX) and adalimumab (ADA)) has revolutionised the treatment of patients with Crohn’s disease (CD) and ulcerative colitis (UC), however, primary resistance or loss of efficacy are serious clinical challenges. Although there is currently insufficient evidence to recommend for or against the use of therapeutic drug monitoring to improve clinical outcomes, the determination of IFX and ADA levels with point-of-care tests (POCT) is fast, simple and can be a helpful tool to guide the therapy. Our aim was to evaluate the impact and duration of IFX and ADA level measurement with POCT on the medium-term course of the disease. Methods In our retrospective study we enrolled patients with UC and CD who were treated at our department with IFX or ADA and underwent a reactive drug level (DL) measurement which was carried out with POCT method between October 2021 and May 2023. We examined the types of therapeutical decision (dose intensification, switch or swap) were performed knowing DL and how the changes have affected the half-yearly outcome. Laboratory findings such as C-reactive protein (CRP), iron, albumin, haemoglobin, platelet, stool calprotectin level and calculated disease activity indices, Crohn’s disease activity index (CDAI), Harvey-Bradshaw Index (HBI), partial Mayo score and Simple clinical colitis activity index (SCCAI) were analysed at baseline and after 6 months. Results 99 patients were enrolled; median age was 37 years (IQR 29-51 years). Baseline characteristics are shown in table 1. In 46 cases the drug level was subtherapeutical while in 53 cases was in normal range. At baseline patients with low drug level had significantly higher CRP (22.09 vs 10.7 mg/l, p=0.026), platelet count (344.6 vs 272.8 G/l, p=0.004) and significantly lower iron level (12.28 vs 15.6 umol/l, p=0.033) compared to patients with normal drug level while there was no difference between the activity indices (CDAI p=0.091; HBI p=0.187; SCCAI p=0.830; pMayo p=0.662) within the two groups. 70% of the patients in the low DL group had a therapeutic change: in 52% dose increase, in 13% switch, and swap in 15%. Changes in the therapy were significantly more frequent in the low DL group (p<0,0001). The difference in baseline CRP and iron level between the two groups was no longer detectable at month 6 (CRP 7.55 vs 8.7 mg/l, p=0.669, iron 14.1 vs 15.6 umol/l, p=0.325). All activity indices were significantly lower in low DL group at month 6 compared to baseline (CDAI p=0.022; HBI p=0.016; SCCAI p=0.047; pMayo p=0.046). Conclusion The drug level monitoring with POCT affected the decision-making process and presented beneficial effect for medium-term and helped to achieve stride therapy goals.
Anti-TNF therapy showed high efficacy in the maintenance of remission in ulcerative colitis (UC) based on study results. However, there is still high need for long-term assessment of biological treatments based on full population analysis. This is an observational/non-interventional, retrospective, epidemiological study using the National Health Insurance Fund social security databases and the special drug reimbursement database of patients. Study population contained all of the adult Hungarian patients suffering from UC who are observable in the database between 2010 and 2016. Patients were treated with anti-TNF therapy during the study period were eligible. Our aim was to analyse patient characteristics and therapeutic outcome of UC patients treated with anti-TNF agents in Hungary. In total, 0.24% of total Hungarian population suffered from UC in 2016. This is more than 23000 patients. The median age of the patients with UC is 51 (male 49, female 53) in the examined period. Annual prevalence of anti-TNF therapy was increasing continuously from 1.1% to 2.1%; 497 patients with UC were on anti-TNF therapy at the end of 2016. The prevalence of infliximab and adalimumab was similar in 2016 (1.2 and 1.1%, respectively). The onset of anti-TNF therapy in UC is between 20 and 39 years, the average age is 37 years. This is 16 years less compared with the average age of total UC population. Anti-TNF therapy was started within 3 years after the diagnosis in 35% of the patients, while disease duration was more than 10 years in every third cases. Top-down therapy was applied only in 0.1% of the patients. Primary non-response was observed in 9.7% of anti-TNF therapy. Ratio of dose escalation was 13.6%. Dose escalation was equally common among patients on infliximab and adalimumab therapy; however it occurred significantly later in case of infliximab. Frequency of switch was 15.7% and 83.1% of switch was performed after dose escalation. Ratio of infliximab to adalimumab switch was 6.7%, adalimumab to infliximab switch was 0.8% in 2016. Thirty-two point four% of the patients received azathioprine and anti-TNF combination therapy in the first 5 month of anti-TNF therapy. Steroid therapy was prescribed significantly less frequently in the subsequent 2 years after starting anti-TNF. Both the prevalence and incidence of UC are high in Hungary. Patients receiving anti-TNF therapy are significantly younger than the other part of the total UC population. Our results show the steroid-sparing effect of anti-TNF in a real-life, population-based setting.
The introduction of anti-TNF therapy has dramatically changed the treatment of refractory inflammatory bowel disease (IBD-Crohn’s disease [CD], ulcerative colitis [UC]). However, the clinical use of anti-TNF therapies is limited by loss of response posing significant challenge for clinicians. Therapeutic drug monitoring has gained increasing popularity in the management of IBD. However, relationship between clinical outcomes and serum anti-TNF levels is complex and controversial in many cases. The aim of this study is to simultaneously analyse the serum, mucosal and faecal infliximab and adalimumab levels, to determine the mucosal expression of TNF-α and to assess the relationship between the levels of anti TNF-α in the above-mentioned biological samples with endoscopic and clinical activities of IBD patients receiving anti-TNF maintenance therapy. Patients with luminal CD and UC receiving maintenance anti TNF-α therapy have been started to enrol in the study and the enrolment is still ongoing. Clinical disease activity is assessed, blood samples and faecal specimens are collected and colonoscopy with biopsy samples is performed in every patient. Biopsy samples are obtained from inflamed and uninflamed tissue from the colon. Mucosal TNF-α expression is detected by confocal microscopy after immunofluorescent staining. Serum, mucosal and faecal anti TNF-α and anti-drug antibody levels is determined by ELISA assay. Kendall-tau correlation coefficient was used to assess bivariate correlations. Data of 19 patients have been analysed. Our preliminary measurements confirmed the higher number of TNF-α positive cell in the mucosal samples of active vs. inactive part of the bowel. However, no association could be detected between TNF-α-positive cell and mucosal anti TNF-α concentration. We were unable to find evidence against the hypothesis of no association between serum drug levels and mucosal anti TNF-α concentration, between serum drug levels and clinical or endoscopic response to anti-TNF therapy. Our study would be the first that simultaneously examine serum, tissue and faecal concentrations of anti TNF-α comparing with clinical and endoscopic activities. Monitoring of serum drug levels is a widely accepted approach during biological therapy. However, the sample size is currently very low, and more data are needed to be collected in order to better investigate the association between serum and tissue drug levels or disease activity. Nevertheless, it is hoped that these measurements will allow a better overview of the drug distribution and clearance and may help to identify a useful surrogate marker of clinical and endoscopic activity.
Safety data of the 'real life' use of an infliximab biosimilar, CT-P13 in inflammatory bowel disease (IBD) are still lacking. Our aim was to assess the frequency and characteristics of infusion reactions during CT-P13 therapy in 13 Hungarian and 1 Czech IBD centres.Clinical and safety data was registered at fixed appointments. Trough levels and anti-drug antibody (ADA) concentration were measured by ELISA. Association between demographic, clinical, laboratory parameters and infusion reaction rates were evaluated statistically.Three hundred and eighty-four IBD patients were included. Twenty-eight Hungarian IBD patients (9.6%) developed infusion reaction during the treatment, 64.3% of them was previously exposed to anti TNF therapy. No infusion reaction occurred in the Czech population. CT-P13 therapy had to be stopped in 17 patients who developed infusion reaction and was switched to adalimumab in 12 patients. However in 39.3% of patients developing infusion reaction CT-P13 therapy was continued with the use of premedication. Cumulative ADA positivity rates were 8.7%, 19.3%, and 28.0% at weeks 0, 14, and 30. Previous anti-TNF-alpha exposure (30% vs. 3.1%, p < 0.001, OR 6.3 (2.7-14.6)) and ADA positivity (32.6% vs. 4.1%, p < 0.001, OR 19(5-73)) during the induction therapy were predictive factors for infusion reactions.Patients with previous exposure to anti-TNF-alpha and ADA positivity during the induction therapy were more likely to develop infusion reactions.
Az endoszkópiát és az ultrahangtechnikát ötvöző, a tápcsatorna falának és a környező szerveknek és szöveteknek a vizualizálására minimálisan invazív módon alkalmas endoszkópos ultrahangvizsgálat az 1980-as évekbeli kifejlesztése óta jelentős technikai fejlesztéseken esett át. Ezáltal a vizsgálat indikációs köre folyamatosan bővül, így a diagnosztikus indikációk mellett már terápiás beavatkozásokra is lehetőséget biztosíthat. A rectumtumorok stádiummeghatározásában a legfrissebb ajánlások alapján a rectalis ultrahangvizsgálat – néhány speciális esettől eltekintve – elsősorban másodvonalbeli, kiegészítő modalitásként jön szóba a mágneses rezonanciás képalkotás mellett. Előretekintő echoendoszkópok és a munkacsatornán bevezethető ultrahangos miniszondák alkalmazásával a proximálisabb vastagbél területére is kiterjeszthető az endoszkópos ultrahangvizsgálat alkalmazása. A rectalis vizsgálat emellett a subepithelialis laesiók differenciáldiagnosztikájában, a rectalis varixok azonosításában, valamint a gyulladásos bélbetegségek és a perianalis szövődmények diagnosztikájában is fontos szerepet játszhat. Az eljárás diagnosztikus pontossága bizonyos esetekben ultrahangvezérelt mintavétellel növelhető. A rectalis ultrahangvizsgálat terápiás alkalmazási területei egyelőre inkább ígéretes lehetőségek, mintsem a bevett klinikai gyakorlat részei, a jövőben azonban várhatóan egyre nagyobb teret nyerhetnek. A jelen összefoglaló célja az alsó tápcsatornai ultrahangvizsgálattal kapcsolatos általános ismeretek bemutatása mellett a vizsgálat indikációs körének áttekintése, beleértve a diagnosztikus és a terápiás indikációkat is. Orv Hetil. 2023; 164(30): 1176–1186.
The relationship between clinical outcomes and serum anti-TNF levels is controversial. The aim of this study was to perform simultaneous analyses of serum, mucosal, and fecal anti-TNF-α levels. Consecutive IBD patients who received maintenance anti-TNF-α therapy were enrolled. The number of TNF-α positive cells in the mucosa was detected using immunofluorescent labeling on biopsy samples. Serum, mucosal and fecal anti-TNF-α, serum anti-drug antibody, and fecal calprotectin levels were determined using ELISA. Each patient underwent body composition analysis as well. Data of 50 patients were analyzed. The number TNF-α positive cells was significantly higher in the inflamed part of the colon than in the un-inflamed part of the colon. Tissue and fecal drug levels did not show any association with serum drug levels; moreover, serum anti-TNF concentration did not correlate with endoscopic activity. Mucosal anti-TNF levels were higher only in IFX-treated patients in remission and IFX-treated patients with detectable fecal anti-TNF had lower tissue drug levels. Presence of the drug in the feces was significantly different according to disease activity. Fecal drug concentration is suggested to be a better predictor of endoscopic activity and loss of response, and fecal drug monitoring may improve the estimation accuracy of tissue drug levels.
Clinical data suggest a synergistic effect between thiopurine and anti-tumour necrosis factor (anti-TNF) therapy both in ulcerative colitis (UC) and Crohn’s disease (CD). In previous studies, azathioprine (AZA) metabolites and biological drug trough levels have not been investigated simultaneously to verify the mechanism behind the favourable outcomes. This prospective, cross-sectional study aimed to evaluate potential correlation between AZA metabolite (6-thioguanine nucleotide; 6-TGN) levels and anti-TNF drug (infliximab [IFX] and adalimumab [ADA]) serum trough levels. Consecutive IBD patients on maintenance AZA, IFX or ADA monotherapies, and on IFX/AZA or ADA/AZA combinations were prospectively enrolled. 6-TGN level was measured with high-performance liquid chromatography, and IFX and ADA levels were assessed by ELISA method. Anti-TNF drug (IFX or ADA) trough levels were compared in patients on IFX or ADA monotherapy with those on combined IFX/AZA or ADA/AZA therapy using one-way analysis of variance. Significance of correlation between 6-TGN level in patients on AZA monotherapy and those on combination therapy (IFX/AZA or ADA/AZA) was also assessed. A total of 41 consecutive IBD (30 CD, 11 UC) patients were involved. Male/female ratio was 19 of 22, mean patient age was 36 years, and average disease duration was 10.3 years. Average CDAI score for CD patients was 99, and average partial Mayo score for UC patients was 1. Eleven patients were on maintenance AZA, 9 on IFX, and 6 on ADA monotherapies, 9 received IFX/AZA, and 6 ADA/AZA combination. No significant difference was found between IFX trough levels in those on combined IFX/AZA therapy compared with those on IFX monotherapy (5.34 ± 2.95 μg/ml vs. 7.32 ± 9.68 μg/ml, p = 0.526). Similar results were found in case of ADA trough levels (6.71 ± 2.98 µg/ml for ADA monotherapy vs. 5.87 ± 5.40 µg/ml for combined ADA/AZA therapy, p = 0.798). 6-TGN levels were lower in patients on combined IFX/AZA and ADA/AZA therapy (316 ± 33 pmol/8 × 108 RBC and 326 ± 9.9 pmol/8 × 108 RBC, respectively) compared with those on AZA monotherapy (428 ± 49.5 pmol/8 × 108 RBC). A slight negative correlation could be observed between 6-TGN levels and both IFX and ADA levels in patients on combination therapy (correlation coefficient −0.227 and −0.425 for IFX and ADA, respectively), but none proved to be significant (p = 0.557 for IFX, and p = 0.401 for ADA). Preliminary results of our study suggest that favourable outcomes of thiopurine and anti-TNF combination therapy may not be related to a synergistic effect between AZA metabolites and IFX or ADA trough levels.
