Infliximab and Adalimumab Monitoring versus Clinical Control during Maintenance Therapy in Randomized Patients with Inflammatory Bowel Disease

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Merino, L. Gómez, R. Higuera, P. Arreba, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7537370/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Although the serum levels of infliximab (IFX) and adalimumab (ADA) are correlated with the clinical response in patients with inflammatory bowel disease (IBD), the optimal management strategy during maintenance therapy remains controversial. We performed a randomized trial to determine whether proactive monitoring drug in patients with inflammatory bowel disease is better than control clinical to keep clinical remission Methods We conducted a randomized, prospective, multicenter trial involving 209 patients with Crohn's disease (CD) or ulcerative colitis (UC) who had been in clinical remission for at least 12 weeks. Patients were randomized into two groups: 104 in the TDM group and 105 in the clinical practice (CP) group. In the TDM group, the dosing and intervals of IFX and ADA were adjusted at each visit to maintain optimal serum concentrations (3–7 μg/mL for IFX and 5–8 μg/mL for ADA). The primary endpoint was the proportion of patients who remained in clinical remission at 12 months of follow-up. The secondary endpoints included the number of disease flares, duration of clinical remission, rate of hospital admissions related to IBD, and quality of life. Results The primary endpoint of remission was achieved in 94 patients (90.3%) in the TDM group and 86 patients (81.9%) in the CP group, with a difference of 8.4% between the groups (p = 0.079; 95% CI: –17.70.91). The mean duration of remission over the 12-month follow-up was significantly longer in the TDM group [48.04 ± 10.76 weeks] than in the CP group [45.69 ± 14.21 weeks] (p = 0.03). The number of disease flares was lower in the TDM group (15 flares) than inthe CP group (24 flares). At baseline, optimal IFX levels were present in 51 patients (48.5%), and optimal ADA levels were present in 36 patients (35.3%). Conclusions In this prospective randomized trial of patients with CD or UC in clinical remission receiving IFX or ADA, compared withstandard clinical management, proactive TDM did not significantly increase the overall remission rate at one year. However, patients in the TDM group remained in clinical remission for a significantly longer duration. ClinicalTrials.gov Identifier: NCT06666569. (30 oct 2024). Retrospectively registered. Inflammatory Bowel Disease Adalimumab Infliximab Therapeutic Drug Monitoring Clinical Remission Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 BACKGROUND The high efficacy of the anti-TNF, infliximab(IFX) and later adalimumab(ADA) in the treatment of Inflammatory Bowel Disease (IBD): Crohn´s Disease (CD) and Ulcerative Colitis (CU) is well known [ 1 ]. However,10–30% of patients have a lack of primary response [ 2 ] and 20–40% of those who respond, lose this response after one year of treatment [ 3 ]. There is evidence that the presence of low plasma levels of anti-TNF agents and/or antidrug antibodies, is related to the loss of response[ 4 ]. Although different studies have shown that there is a relationship between the levels of IFX and/or ADA and clinical outcomes [ 1 ], most of the available data are from post hoc analyses or retrospective studies, data regarding ADA are even scarcer than are those for I than are those for IFX. Questions remain to be answered, such as what are the optimal ranges of plasma levels for these drugs or what is the most appropriate time for their determination. In the Classic I study, a higher percentage of remission at week 4 was described in patients with CD treated with a higher dose of ADA [ 5 ]. However, in week 56 of the Classic II study, no relationship was found between plasma ADA levels and clinical remission status [ 6 ]. In other studies, endoscopic and histological remission have been shown to be related to higher plasma levels of ADA [ 7 ]. Similarly, the ACT-1 and ACT-2 studies have shown that both the clinical response and mucosal healing are more favorable in patients with higher plasma levels of IFX[ 8 ]. Some factors that can modify the pharmacokinetics of drugs have also been identified [ 9 ]. The place of drug monitoring in the induction phase of the treatment is better established, whereas in the maintenance phase, the timing or the clinical usefulness of its determination is poorly understood. The TAXIT study included patients who were in the maintenance phase, and the usual management of the patients according to clinical parameters and usual biomarkers were compared with therapeutic monitoring of IFX levels. First, they performed an optimization phase with respect to the IFX levels of all patients, which reached a range of 3–7 ng/ml, which are considered optimal values. They did not find differences in terms of clinical remission after a year of follow-up between the two groups, but they did find a lower relapse rate in the control group [ 10 ]. Currently, various organizations, including the NICE Guide, have considered monitoring biological drugs in the management of IBD as a new tool, which can help optimize the treatment of these patients [ 11 ]. The available data seem to indicate that optimizing the dose of the drug on the basis of plasma levels could improve the response and avoid some losses. The aim of this study was to compare the effects of proactive management of plasma IFX and ADA with those of usual clinical management in patients with CD or UC who are in the clinical remission phase of the disease. MATERIAL AND METHODS Study Design and Population This is a multicenter, randomized open–label study of superiority with equal monitoring conducted at University Hospital of Basurto and two other hospitals in the Basque Country (Spain). The study was designed by investigators of the participating centers in conjunction with the sponsors (Progenika S.A.), and its adheres to CONSORT guidelines. The protocol was approved by the Clinical Research Ethics Committee (CEIC) of the Basque Country, and all patients signed informed consent (IC) forms. We recruited patients who were adults with a previously confirmed diagnosis of CD or UC [ 12 ][ 13 ], in the remission phase with respect to disease activity for at least the previous 12 weeks, and in maintenance treatment with IFX or ADA at a stable dose (for the previous 3 months). Patients with positive antibody levels (> 10 AU/ml) at baseline were excluded. To evaluate the clinical activity of patients, different assessments used in routine clinical practice have been used, such as: the partial Mayo score (PMS), with a total score ranging between 0 and 9 [ 14 ]. Clinical remission was considered a PMS < 2, and blood in feces was 0. In patients with CD, the CD Activity Index (CDAI) [ 15 ] was used at the baseline visit and after 12 months. For the remaining visits, the Harvey‒Bradshaw index (HBI) was used [ 16 ]. CDAI values < 150 or HBI < 4 were considered to indicate clinical remission. At screening, the IFX dosing regimen ranged from the standard dosing regimen of 5 mg/kg every 8 weeks to 5 mg/kg every 4 weeks or 10 mg/kg every 6 or 8 weeks. ADA was increased from 40 mg every two weeks to 40 mg per week. Treatment with immunosuppressants (azathioprine, mercaptopurine or methotrexate) and/or corticosteroids at low levels (< 10 mg of prednisone) was allowed at the beginning. Randomization and Masking The patients were randomly assigned to one of two cohorts: the therapeutic drug monitoring (TDM) cohort, in which the clinician had information on drug levels as support for decision-making, and the second cohort, in which the clinician was blinded to these results and acted according to usual clinical practice (CP). The randomization was carried out through a centralized system with a computer-generated sequence by a person from the Research Unit of the Basurto Hospital who was not involved in the clinical care of patients. The randomization process was performed in blocks and weighted to a 1:1 ratio of IFX/ADA, which is used in the usual clinical practice of the participating hospitals, to ensure a homogeneous distribution in the groups. Finally, the group to which the selected patient corresponded was communicated to the clinician. Procedures As in usual clinical practice, patients were assessed every 3 months (range 2–4 months) according to their clinical situation. At each visit, clinical activity was recorded through the CDAI, HBI or PMS, also IBDQ-9 quality-of-life [ 17 ] and the EuroQol-5D [ 18 ] assessments were completed. Blood samples were taken from all patients prior to drug administration to perform hemogram, biochemistry, C-reactive protein (CRP) and fecal calprotectin (FC) analyses. Three 1 ml aliquots of serum were preserved and stored in the biobank at -80° until they were subsequently sent to Progenika, where the determination of IFX and ADA levels was performed with ELISA (LISA-TRACKER ELISA kits, IDK monitor ELISA kits and Promonitor ELISA kits) [ 11 ]. For antibodies, we followed the reflex method, which consists of determining plasma levels of anti-TNFa antibodies only when a substantial decrease in plasma drug levels is observed, as indicated by antibodies (AAAs) (+), values > 10 AU/ml and high-level values > 100 AU/ml. The results were entered into the electronic CDR through the Xolomon platform. Intervention For patients in the TDM group, the dose was adjusted at each visit. In the case of IFX, according to the algorithm of the TAXIT(10) study, a range of 3–7 pg/ml was established. If the levels exceeded that range, the administration time was increased by two weeks at the next dose (up to 12 weeks). If the levels were lower than that range, the administration time was shortened by two weeks (down to 4 weeks). For patients with ADA, the range was 5–8 µg/ml (5). To adjust drug levels, drug administration time was increased or shortened by one week (range, 1–4 weeks). In the CP cohort, although the plasma levels of the drug were determined at each visit, the results were not known by the clinician. The patients in this group were treated exclusively according to usual clinical practice. Finally, the clinician was responsible for modifying the treatment or changing the drug. Outcomes The primary endpoint was to assess whether, for patients with CD/UC in remission who were treated with IFX or ADA to remain in clinical remission after 12 months of follow-up, a strategy based on the optimization of doses and plasma drug levels was superior to another strategy based on usual clinical practice. The secondary endpoints were as follows: the number of outbreaks/months of follow-up; the time at which the patient remained in clinical remission during the study; the rate of hospital admissions in relation to IBD or the treatment followed; and whether the patient’s quality of life was related to the type of patient management. Finally, the adverse events associated with IFX and ADA use were recorded. Statistical Analysis The calculation of the sample size was based on the TAXIT study [ 10 ]. A 65% remission rate at 1 year was estimated in the CP group, and an additional 16% difference was assumed in the proportion of patients who achieved the primary endpoint in the TDM group. For a difference of 16% with a power of 80% at 0.05 significance, a power of 80% and a significance level of 0.05, approximately 120 patients per branch were estimated to be necessary. The analysis of the main variable was by intention to treat and included all the randomized subjects. Patients who ended the study early, either by treatment failure or for safety reasons (adverse effects), were considered as failure in the ITT analysis. For the remaining reasons for abandonment, the last observation was carried forward. At an exploratory level, the relationship between the use of the test and the response variable of each objective (quality of life, number of days in remission/low activity) were analyzed, adjusted by possible confounding variables that were related to the response variable (association with a p < 0.20). The specific multivariate regression technique used (OLS, GLM or GEE) was selected on the basis of the data distribution of the variable response in the analysis sample. Categorical or qualitative variables are described as proportions, and continuous variables are presented as the mean and standard deviation or median and interquartile interval, depending on whether they followed the normal distribution (analyzed by the Kolmogorov‒Smirnov test or the D´Agostino‒Pearsons test for continuous variables). The differences between the groups were compared with the X2 test for categorical dependent variables and the Student´s t test or the Mann‒Whitney U test for quantitative dependent (unpaired) variables, as appropriate. To quantify the correlation between continuous variables, the Pearson correlation coefficient or the Spearman range coefficient was calculated, as appropriate. To model the evolution of remission percentages over time, survival analysis (time to event) was used together with Kaplan–Meier graphs, the log-rank test and Cox regression. A 95% confidence level and a significance level of p < 0.05 were used. The SPSS23 and Stata 14 programs were used for data analysis. RESULTS Baseline Characteristics A total of 227 patients were screened at 3 hospitals between January 2017 and October 2020, and 209 were randomized: 105 were included in the Clinical Practice (CP) group, and 104 were included in the TDM group (Fig. 1 . Patients screening and randomization). Among the 209 patients included (156 with CD and 53 with UC.), IFX was administered to 105 patients, and ADA was administered to 104 patients. The main characteristics of the entire cohort and of both groups are summarized in Table 1 . Among the total patients, 119 (56.9%) were males. The average age was 51.4 years (± 13,2), and the duration of IBD was 18.97 years (± 8.88). Among those in the CD group, 81 patients (51.9%) had inflammatory CD and the ileum was the most common location (69 patients, 44.2%). In the UC group, more than half of the patients had extensive colitis (31 [58.5%]). Almost half of the patients (102 [48.8%]) received combined treatment with immunomodulators. The average remission time in years was 3.08 ± 2.68 years. The time since the first IFX infusion was 4.84 years (4.08–5.61), and the time since the first ADA infusion was 4.46 years (3.03–5.01). The clinical activity in CD patients according to the CDAI was 44.88 (40.51), and that according to the HBI was 1.1 (± 1.35). The PMS for UC patients was 0.3 (± 0.61). The most frequent comorbidity was hepatic disease in 44 (21.2%) patients. The most common number of visits per patient per year was 3 (131 patients), followed by 4 (53 patients) (Table 1 ). Outcomes Remission at the end of the study in the 209 patients was achieved in 94 (90.3%) of the TDM group and 86 (81.9%) of the CP group, with a difference of 8.4% (p = 0.079) (95%-17.7-0.91) (Fig. 2 . Primary endpoints). There were no differences between the two types of management, neither among patients with CD or UC nor between patients treated with IFX or ADA (Fig. 3 . Loss of treatment response in patients during the maintenance phase according to the following: A: Type of anti-TNF, B: CP or TDM group, C: to Crohn´s or ulcerative colitis). The time in remission during the 12 months of follow-up was 45.69 (14.21) weeks in the CP group and 48.04 (10.76) weeks in the TDM group. Compared with the CP group, the TDM group remained in clinical remission significantly longer (96.7% versus 91.5%, p = 0.03) during the 12-month follow-up. Patients who did not require drug intensification (n = 162) remained in remission longer than those who did require drug intensification (n = 47) (p = 0.01). In terms of the type of anti-TNF agent used, the incidence rate ratio (IRR) was 0.56 (95% CI 0.08–3.81) in patients who used IFX and 0.78 (95% CI 0.29–2.16) in patients who used ADA. In total, 39 flares were recorded. The IRR of flares throughout the study was 0.71 (95% CI 0.32–1.55). In the TDM group, 15 flares were reported. In the CP group, there were 24 flares (Fig. 3 . Loss of treatment response in patients during the maintenance phase according to the following: A: Type of anti-TNF, B: CP or TDM group, C: to Crohn´s or ulcerative colitis), which represented 1.3/10 patient-years in the TDM group and 2.4/10 patient-years in the CP group. Considering the whole group of patients, men had more flares than women did, but the differences were not significant (p = 0.88). Hospital admissions were recorded for 21 patients over 12 months, with a rate of 0.14 hospitalizations/patient/year in the CP group and 0.07 hospitalizations/patient/year in the TDM group (p = 0.13). With respect to quality of life, we did not find differences between the two groups during the follow-up period (Fig. 4 . Patients with flares according to the group). IFX and ADA Concentrations IFX levels at the beginning of the study were in the optimal range in 51 patients (48,5%), and in the ADA group, they were 36 (35.3%). There were no differences between the two groups for either of the two drugs (Table 2 ). The changes in the drug dose throughout the study are shown in Fig. 5 (Quality of life recorded with the IBDQ at each clinical visit of the study). More than half of the patients in the TDM group (57, 54.8%) underwent modification of the drug dose, whereas 18 (17.1%) in the CP group underwent modification. In 29 patients (13.9%), the dose was intensified (11 in the CP group and 18 in the TDM group). During the study, antibodies were detected in a total of 22 patients (10.5%). Thirteen (12.1%) patients had ATIs against IFX, and 9 (8.8%) had ATIs against ADA. There were no differences between the groups (Fig. 6 . Dose modifications infliximab and adalimumab according to the group during the study). Adverse Events Adverse events were observed in 47 patients (22.48%) during the study, the most frequent of which were infections. Most cases were mild and affected the upper respiratory tract, followed by the gastrointestinal tract. For 4 patients (2 in each group), treatment had to be stopped. Two patients, both from the CP group (one with pneumonia and another with meningitis due to Listeria), required hospitalization and treatment withdrawal. The remaining adverse events are shown in Table 3 . DISCUSSION In this prospective and randomized study, which was carried out in patients with IBD treated with anti-TNFa drugs (IFX or ADA), we compared the clinical remission rates at 12 months between the group controlled with drug determination and the group followed according to usual clinical practice. There was no significant difference in the remission rate between the groups (8.4%, p = 0.07). We did not reach the preestablished target of 16% in favor of the proactive management of the drug. The results for both IFX and ADA did not differ, which supports the hypothesis of the TAXIT study that there is a class effect that is applicable to other anti-TNF agents. Since these patients were in clinical remission with a low number of flares/year, a greater number of patients or a longer follow-up time may be needed, as suggested in the PAILOX study, which lasted up to 72 weeks and was found to favor proactive management in children with CD treated with IFX (19). In this study, the remission rate in both groups was high compared with that in the TAXIT study, despite the optimization of IFX levels in all patients in a preliminary phase. The prolonged remission time in both groups at the time of their inclusion in the study could be a favorable factor in our case (these data are not included in the TAXIT study). Second, the long duration of previous treatment with ant-TNF agents could be another favorable factor since the loss of response (20–40%) occurs mainly in the first year of treatment (3) (20). Another factor to consider is the high incidence of combined treatment with immunosuppressants in almost half of the patients, compared with the 5% reported in the TAXIT study. On the other hand, it cannot be ruled out that some episodes of clinical activity were not detected at the clinical visits. In the TAILORIX trial (21), which was carried out in patients with CD who were treated with IFX during maintenance phases, no differences in study outcomes were found between proactive drug management and typical clinical practice. The results of that study significantly differed from those of ours, likely because the randomization was performed very early (week 14) and therefore, most of the patients remained in an inflammatory state. Although those authors also implemented a minimum plasma IFX level of 3 µg/ml, the management of the drug in each of the three groups was different. Although numerous studies have reported an association between drug concentration and clinical outcome, the optimal range of plasma ADA levels is poorly defined. For example, it differs according to the therapeutic objective and the inflammatory burden of the disease. In the IBD remission phase, some expert consensuses establish minimum plasma levels of > 3 µg/ml for IFX and between 5-7.5 for ADA and recommend the determination of this value at least once in the maintenance phase (22) (23). Other consensuses, such as the AGA, do not establish recommendations for patients in remission regarding drug monitoring (24). In this study, the optimal plasma levels for patients in clinical remission were 3–7 µg/ml for IFX and 5–8 µg/ml for ADA. The drug dose was modified in more than half of the patients (n = 57, 55.8%) in the proactive group, which was similar for both the intensification and the spacing phases. In the CP group, in which intensification was performed if symptoms persisted or there was evidence of active inflammation using biomarkers, the drug dose was modified in only 18% of patients (17.1%). This difference between the two groups suggests that the early detection of low drug concentrations, which is related to immunogenicity and a lower risk for loss of response to anti-TNF, may be possible in some cases (25). It is also important to determine the optimal time at which the drug should be used. This method has been shown to be useful before the withdrawal of immunosuppressants in patients receiving combined treatment (26). To determine the antibody concentrations, we established a cutoff (+) > 10. On the basis of this criteria, we estimated that 10.5% of patients (12.1% with IFX and 8.8% with ADA) had antibody positivity; these results were lower than those described in other studies (26). It is possible that combined treatment with immunomodulators in almost half of the patients, as described, was associated with lower immunogenicity to both drugs (27). In addition, in most cases, the levels were low; therefore, withdrawal of the drug was not necessary, since with the intensification or combination of immunosuppressants, it is expected that the antibody levels will disappear in ¾ of cases (28). We cannot rule out that the use of the reflex method, according to which the determination of antibodies was carried out only in patients with low levels of the drug, resulted in some cases having been undetected. For the secondary endpoint, the time in remission throughout the study was greater in the TDM group than in the PC group, and the difference was significant (p = 0.03). We also detected fewer hospitalizations related to the disease and fewer flares in the group with controlled drug levels, which coincides with what is described in the TAXIT study. This trend was more favorable in patients with IFX than in those treated with ADA. Some studies have also shown that in patients with CD who were treated with IFX for more than 10 years, the proactive strategy was associated with fewer surgical interventions, fewer hospitalizations and a lower risk of infusion reactions than the reactive strategy was (23). However, in this study, we did not find differences in quality of life or adverse effects, which generally had a low incidence but forced the cessation of treatment in 2 patients in each group. The low number of events throughout the study could explain the absence of differences between the groups. Moreover, we did not detect a relationship between plasma drug levels and the biomarkers FC and CRP, possibly because in both cases and in general, the levels remained in a low range and were insufficient to show differences. This study has several limitations since it addresses two pathologies, CD and UC, and uses two types of anti-TNF agents, IFX and ADA. Although on the one hand, it is a novel approach, on the other hand, this design can be a factor that makes it difficult to interpret the results obtained. Moreover, we did not collect endoscopic data regarding mucosal healing, an element of significant value in the long-term evolution of patients that is related to higher plasma drug levels (28). It would also be advisable, given that these are patients in remission and therefore stable, to increase the follow-up time and/or the number of patients to better study the differences between the strategies. In conclusion, and on the basis of the results of the present study, a clinical management strategy with plasma drug level determination in patients with CD or UC in clinical remission and maintenance treatment with IFX or ADA could be recommended. More evidence and broader studies that confirm this benefit and that establish the most appropriate time for its determination are needed. Abbreviations Abbreviations used in this paper: UC, Ulcerative Colitis; CD, Crohn’s disease; CDAI, Crohn’s disease activity index; HBI, index Harvey-Bradshaw; PMS, partial Mayo score; CI, Informed Consent;CRP, C-reactive protein; CF, calprotectin fecal; IFX , Infliximab; ADA, Adalimumab; TDM, therapeutic drug monitoring; anti-TNF, tumor necrosis factor.IBDQ: Inflammatory Bowel Disease Questionnaire. Declarations Ethics statements Patient consent for publication: Not applicable Ethics approval and consent to participate: All data were anonymised and de-identified, and no extra intervention was conducted. All patients were given a study information sheet and voluntarily signed their participation in the study. The investigation conformed with the principles outlined in the Declaration of Helsinki (as revised in Brazil 2013). All procedures were performed in compliance with relevant laws and institutional guidelines. The study was aprobed by “ Comité de Ética de la Investigación con medicamentos de Euskadi (CEIm-E)”, in 07 Nov 2016. Availability of data and materials Data are available upon reasonable request. Competing interests C.M-V: consultant: Glaxosmith-Kline (GSK); grant support from Janssen. O.M: No conflict of interest. P.A: Grant support from Abbvie, Janssen, Takeda, Pfizer, MSD, Abbot. L.B: grant support from Abbvie, Janssen, Takeda, Pfizer, MSD. L.G.: consultant: Abbvie, Janssen, Tillots, Ferring and Dr. Falk Pharma Spain. J.OZ.: consultant: Abbvie, Janssen and fresenius; grant supprot Abbvie, Janssen, Takeda. R.H: consultant: Abbvie, Janssen, Takeda, Falk, Chiesi, Shire; grant support from Abbvie, Janssen, Takeda, Pfizer, MSD, Abbot, Chiesi, Falk, Tillotts, FAES, Ferring, Lilly. L.D.N. and B.R-A. declare to be full-time employees of Progenika Biopharma SA. Funding This project has been funded by “MINISTERIO DE ECONOMÍA Y COMPETITIVIDAD” from Spain. Contract RTC-2015-4004-1, from 2015 through 2018. Authors’ contribution All authors have contributed and designed the study and to data collection and have approved the final version of the study. CM-V has written the manuscript. CM-V, RH, L.G, JOZ, P.A, S.I, and O.M contributed to data analysis and interpretation. D.N and B.R-A have contributed in designer of the study. I.G. has carried out the statistical analyse. Acknowledgements The authors are grateful to the patients who participated in this study. 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Increasing Infliximab Dose Based on Symptoms, Biomarkers, and Serum Drug Concentrations Does Not Increase Clinical, Endoscopic, and Corticosteroid-Free Remission in Patients With Active Luminal Crohn’s Disease. Gastroenterology 2018;154:1343–1 Rodríguez-Moranta F, Argüelles-Arias F, Hinojosa del Val J, Iborra Colomino M, M. Martín-Arranz D, Menchén Viso L et al. Monitorización terapéutica de los fármacos biológicos en la enfermedad inflamatoria intestinal. Documento de Posicionamiento del Grupo Espanol ˜ de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU). Gastroenterología y Hepatología 47 (2024) 522---552 Papamichael K, Chachu KA, Vajravelu RK, Vaughn BP, Ni J, Osterman MT, et al. Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Com pared With Reactive Monitoring of Serum Concentrations of Infliximab. Clin Gastroenterol Hepatol. 2017;15:1580---8. Feuerstein JD, Geoffrey GC,. Kupfer SS, Falck-Ytter Y and Singh S. American Gastroenterological Association Institute Guideline on Therapeutic Drug Monitoring in Inflamador Bowel Disease. Gastroenterology 2017;153:827–834 Kennedy N, Heap GA, D Green H, Hamilton B, Bewshea C, Walker GJ et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn’s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol 2019;4(5):341-353. Battat R, Lukin D, Scherl E J, Pola S, Kumar A, Okada L et al. Immunogenicity of Tumor Necrosis Factor Antagonists and Effect of Dose Escalation on Anti-Drug Antibodies and Serum Drug Concentrations in Inflammatory Bowel Disease. Inflamm Bowel Dis ,202,7(9): 1443-1451 Steenholdt C, Magid Al-khalaf M, Brynskov JO, Bendtzen K, Thomsen O, MD, and Ainsworth, MA. Clinical Implications of Variations in Anti-infliximab Antibody Levels in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis Volume 2012,18(12): 2209-2217 Yarur AJ, AJain A, Hauenstein S I, Quintero AM, Barkin JS,Deshpande AR, et al . Higher Adalimumab Levels Are Associated with Histologic and Endoscopic Remission in Patients with Crohn’s Disease and Ulcerative Colitis. Inflamm Bowel Dis Volume, 2016, 22(2): 409-415 Tables Tables 1 to 3 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files TABLES.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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2","display":"","copyAsset":false,"role":"figure","size":72673,"visible":true,"origin":"","legend":"\u003cp\u003ePrimary endpoint.Clinical remission rates at the end of follow up at week 5\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7537370/v1/86ce287a01e37ee8c0b3cdcd.png"},{"id":94049358,"identity":"d775eb50-5703-4aa4-b0a8-ab85e21a6e8e","added_by":"auto","created_at":"2025-10-21 23:32:43","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":88858,"visible":true,"origin":"","legend":"\u003cp\u003eLoss of response of patients in maintenance phase according to:\u003c/p\u003e\n\u003cp\u003eA.-Loss of response of patients in maintenance phase according to the type of Anti-TNF\u003c/p\u003e\n\u003cp\u003eB.- Loss of response of patients in maintenance phase according Clinical practice or Therapeutic Drug Monitoring\u003c/p\u003e\n\u003cp\u003eC- Loss of response of patients in maintenance phase according Crohn’s Disease or Ulcerative Colitis\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7537370/v1/fc972e2ac4b6b32e26ecaae0.png"},{"id":94049361,"identity":"13fd62fc-ff1d-4129-84f4-ee1af786679c","added_by":"auto","created_at":"2025-10-21 23:32:44","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":62278,"visible":true,"origin":"","legend":"\u003cp\u003ePatients with flares up according to the group\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-7537370/v1/0006354a77afa6aa4853f20b.png"},{"id":94048735,"identity":"dcb9f822-964f-4033-8275-20e8e642be7f","added_by":"auto","created_at":"2025-10-21 23:24:44","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":67395,"visible":true,"origin":"","legend":"\u003cp\u003eQuality of life recorded by IBDQ at each clinical visit of study\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-7537370/v1/0b6428266a7f5c73b07b350f.png"},{"id":94048734,"identity":"01a2d9e9-80f0-4f40-95af-9f8f31ab2fc6","added_by":"auto","created_at":"2025-10-21 23:24:43","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":84622,"visible":true,"origin":"","legend":"\u003cp\u003eDose modifications Infliximab and Adalimumab according to the group during the study\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-7537370/v1/d1fd8d77b4881ac553d0d66c.png"},{"id":94984992,"identity":"bbd65994-8b9b-4f6d-9e90-f4be3a82edc0","added_by":"auto","created_at":"2025-11-03 06:57:09","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":850337,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7537370/v1/c453481a-55b8-4554-9ba5-d87053342ae0.pdf"},{"id":94048732,"identity":"0d11d35c-46cb-445f-bf3a-c06d819082fa","added_by":"auto","created_at":"2025-10-21 23:24:43","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":31909,"visible":true,"origin":"","legend":"","description":"","filename":"TABLES.docx","url":"https://assets-eu.researchsquare.com/files/rs-7537370/v1/71457e8d1c77573add70cb37.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Infliximab and Adalimumab Monitoring versus Clinical Control during Maintenance Therapy in Randomized Patients with Inflammatory Bowel Disease","fulltext":[{"header":"BACKGROUND","content":"\u003cp\u003eThe high efficacy of the anti-TNF, infliximab(IFX) and later adalimumab(ADA) in the treatment of Inflammatory Bowel Disease (IBD): Crohn\u0026acute;s Disease (CD) and Ulcerative Colitis (CU) is well known [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However,10\u0026ndash;30% of patients have a lack of primary response [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and 20\u0026ndash;40% of those who respond, lose this response after one year of treatment [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. There is evidence that the presence of low plasma levels of anti-TNF agents and/or antidrug antibodies, is related to the loss of response[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough different studies have shown that there is a relationship between the levels of IFX and/or ADA and clinical outcomes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], most of the available data are from post hoc analyses or retrospective studies, data regarding ADA are even scarcer than are those for I than are those for IFX. Questions remain to be answered, such as what are the optimal ranges of plasma levels for these drugs or what is the most appropriate time for their determination.\u003c/p\u003e\u003cp\u003eIn the Classic I study, a higher percentage of remission at week 4 was described in patients with CD treated with a higher dose of ADA [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. However, in week 56 of the Classic II study, no relationship was found between plasma ADA levels and clinical remission status [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. In other studies, endoscopic and histological remission have been shown to be related to higher plasma levels of ADA [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Similarly, the ACT-1 and ACT-2 studies have shown that both the clinical response and mucosal healing are more favorable in patients with higher plasma levels of IFX[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Some factors that can modify the pharmacokinetics of drugs have also been identified [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe place of drug monitoring in the induction phase of the treatment is better established, whereas in the maintenance phase, the timing or the clinical usefulness of its determination is poorly understood. The TAXIT study included patients who were in the maintenance phase, and the usual management of the patients according to clinical parameters and usual biomarkers were compared with therapeutic monitoring of IFX levels. First, they performed an optimization phase with respect to the IFX levels of all patients, which reached a range of 3\u0026ndash;7 ng/ml, which are considered optimal values. They did not find differences in terms of clinical remission after a year of follow-up between the two groups, but they did find a lower relapse rate in the control group [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eCurrently, various organizations, including the NICE Guide, have considered monitoring biological drugs in the management of IBD as a new tool, which can help optimize the treatment of these patients [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe available data seem to indicate that optimizing the dose of the drug on the basis of plasma levels could improve the response and avoid some losses. The aim of this study was to compare the effects of proactive management of plasma IFX and ADA with those of usual clinical management in patients with CD or UC who are in the clinical remission phase of the disease.\u003c/p\u003e"},{"header":"MATERIAL AND METHODS","content":"\u003cp\u003eStudy Design and Population\u003c/p\u003e\u003cp\u003eThis is a multicenter, randomized open\u0026ndash;label study of superiority with equal monitoring conducted at University Hospital of Basurto and two other hospitals in the Basque Country (Spain). The study was designed by investigators of the participating centers in conjunction with the sponsors (Progenika S.A.), and its adheres to CONSORT guidelines. The protocol was approved by the Clinical Research Ethics Committee (CEIC) of the Basque Country, and all patients signed informed consent (IC) forms.\u003c/p\u003e\u003cp\u003eWe recruited patients who were adults with a previously confirmed diagnosis of CD or UC [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e][\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], in the remission phase with respect to disease activity for at least the previous 12 weeks, and in maintenance treatment with IFX or ADA at a stable dose (for the previous 3 months). Patients with positive antibody levels (\u0026gt;\u0026thinsp;10 AU/ml) at baseline were excluded.\u003c/p\u003e\u003cp\u003eTo evaluate the clinical activity of patients, different assessments used in routine clinical practice have been used, such as: the partial Mayo score (PMS), with a total score ranging between 0 and 9 [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Clinical remission was considered a PMS\u0026thinsp;\u0026lt;\u0026thinsp;2, and blood in feces was 0. In patients with CD, the CD Activity Index (CDAI) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] was used at the baseline visit and after 12 months. For the remaining visits, the Harvey‒Bradshaw index (HBI) was used [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. CDAI values\u0026thinsp;\u0026lt;\u0026thinsp;150 or HBI\u0026thinsp;\u0026lt;\u0026thinsp;4 were considered to indicate clinical remission.\u003c/p\u003e\u003cp\u003eAt screening, the IFX dosing regimen ranged from the standard dosing regimen of 5 mg/kg every 8 weeks to 5 mg/kg every 4 weeks or 10 mg/kg every 6 or 8 weeks. ADA was increased from 40 mg every two weeks to 40 mg per week. Treatment with immunosuppressants (azathioprine, mercaptopurine or methotrexate) and/or corticosteroids at low levels (\u0026lt;\u0026thinsp;10 mg of prednisone) was allowed at the beginning.\u003c/p\u003e\u003cp\u003eRandomization and Masking\u003c/p\u003e\u003cp\u003e The patients were randomly assigned to one of two cohorts: the therapeutic drug monitoring (TDM) cohort, in which the clinician had information on drug levels as support for decision-making, and the second cohort, in which the clinician was blinded to these results and acted according to usual clinical practice (CP).\u003c/p\u003e\u003cp\u003eThe randomization was carried out through a centralized system with a computer-generated sequence by a person from the Research Unit of the Basurto Hospital who was not involved in the clinical care of patients. The randomization process was performed in blocks and weighted to a 1:1 ratio of IFX/ADA, which is used in the usual clinical practice of the participating hospitals, to ensure a homogeneous distribution in the groups. Finally, the group to which the selected patient corresponded was communicated to the clinician.\u003c/p\u003e\u003cp\u003eProcedures\u003c/p\u003e\u003cp\u003eAs in usual clinical practice, patients were assessed every 3 months (range 2\u0026ndash;4 months) according to their clinical situation. At each visit, clinical activity was recorded through the CDAI, HBI or PMS, also IBDQ-9 quality-of-life [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and the EuroQol-5D [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e] assessments were completed.\u003c/p\u003e\u003cp\u003eBlood samples were taken from all patients prior to drug administration to perform hemogram, biochemistry, C-reactive protein (CRP) and fecal calprotectin (FC) analyses. Three 1 ml aliquots of serum were preserved and stored in the biobank at -80\u0026deg; until they were subsequently sent to Progenika, where the determination of IFX and ADA levels was performed with ELISA (LISA-TRACKER ELISA kits, IDK monitor ELISA kits and Promonitor ELISA kits) [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. For antibodies, we followed the reflex method, which consists of determining plasma levels of anti-TNFa antibodies only when a substantial decrease in plasma drug levels is observed, as indicated by antibodies (AAAs) (+), values\u0026thinsp;\u0026gt;\u0026thinsp;10 AU/ml and high-level values\u0026thinsp;\u0026gt;\u0026thinsp;100 AU/ml. The results were entered into the electronic CDR through the Xolomon platform.\u003c/p\u003e\u003cp\u003eIntervention\u003c/p\u003e\u003cp\u003eFor patients in the TDM group, the dose was adjusted at each visit. In the case of IFX, according to the algorithm of the TAXIT(10) study, a range of 3\u0026ndash;7 pg/ml was established. If the levels exceeded that range, the administration time was increased by two weeks at the next dose (up to 12 weeks). If the levels were lower than that range, the administration time was shortened by two weeks (down to 4 weeks). For patients with ADA, the range was 5\u0026ndash;8 \u0026micro;g/ml (5). To adjust drug levels, drug administration time was increased or shortened by one week (range, 1\u0026ndash;4 weeks).\u003c/p\u003e\u003cp\u003eIn the CP cohort, although the plasma levels of the drug were determined at each visit, the results were not known by the clinician. The patients in this group were treated exclusively according to usual clinical practice. Finally, the clinician was responsible for modifying the treatment or changing the drug.\u003c/p\u003e\u003cp\u003eOutcomes\u003c/p\u003e\u003cp\u003eThe primary endpoint was to assess whether, for patients with CD/UC in remission who were treated with IFX or ADA to remain in clinical remission after 12 months of follow-up, a strategy based on the optimization of doses and plasma drug levels was superior to another strategy based on usual clinical practice.\u003c/p\u003e\u003cp\u003eThe secondary endpoints were as follows: the number of outbreaks/months of follow-up; the time at which the patient remained in clinical remission during the study; the rate of hospital admissions in relation to IBD or the treatment followed; and whether the patient\u0026rsquo;s quality of life was related to the type of patient management. Finally, the adverse events associated with IFX and ADA use were recorded.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\u003cp\u003eThe calculation of the sample size was based on the TAXIT study [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. A 65% remission rate at 1 year was estimated in the CP group, and an additional 16% difference was assumed in the proportion of patients who achieved the primary endpoint in the TDM group. For a difference of 16% with a power of 80% at 0.05 significance, a power of 80% and a significance level of 0.05, approximately 120 patients per branch were estimated to be necessary.\u003c/p\u003e\u003cp\u003eThe analysis of the main variable was by intention to treat and included all the randomized subjects. Patients who ended the study early, either by treatment failure or for safety reasons (adverse effects), were considered as failure in the ITT analysis. For the remaining reasons for abandonment, the last observation was carried forward. At an exploratory level, the relationship between the use of the test and the response variable of each objective (quality of life, number of days in remission/low activity) were analyzed, adjusted by possible confounding variables that were related to the response variable (association with a p\u0026thinsp;\u0026lt;\u0026thinsp;0.20). The specific multivariate regression technique used (OLS, GLM or GEE) was selected on the basis of the data distribution of the variable response in the analysis sample.\u003c/p\u003e\u003cp\u003eCategorical or qualitative variables are described as proportions, and continuous variables are presented as the mean and standard deviation or median and interquartile interval, depending on whether they followed the normal distribution (analyzed by the Kolmogorov‒Smirnov test or the D\u0026acute;Agostino‒Pearsons test for continuous variables).\u003c/p\u003e\u003cp\u003eThe differences between the groups were compared with the X2 test for categorical dependent variables and the Student\u0026acute;s t test or the Mann‒Whitney U test for quantitative dependent (unpaired) variables, as appropriate. To quantify the correlation between continuous variables, the Pearson correlation coefficient or the Spearman range coefficient was calculated, as appropriate. To model the evolution of remission percentages over time, survival analysis (time to event) was used together with Kaplan\u0026ndash;Meier graphs, the log-rank test and Cox regression. A 95% confidence level and a significance level of p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were used. The SPSS23 and Stata 14 programs were used for data analysis.\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eBaseline Characteristics\u003c/p\u003e\n\u003cp\u003eA total of 227 patients were screened at 3 hospitals between January 2017 and October 2020, and 209 were randomized: 105 were included in the Clinical Practice (CP) group, and 104 were included in the TDM group (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Patients screening and randomization). Among the 209 patients included (156 with CD and 53 with UC.), IFX was administered to 105 patients, and ADA was administered to 104 patients.\u003c/p\u003e\n\u003cp\u003eThe main characteristics of the entire cohort and of both groups are summarized in Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. Among the total patients, 119 (56.9%) were males. The average age was 51.4 years (\u0026plusmn;\u0026thinsp;13,2), and the duration of IBD was 18.97 years (\u0026plusmn;\u0026thinsp;8.88).\u003c/p\u003e\n\u003cp\u003eAmong those in the CD group, 81 patients (51.9%) had inflammatory CD and the ileum was the most common location (69 patients, 44.2%). In the UC group, more than half of the patients had extensive colitis (31 [58.5%]). Almost half of the patients (102 [48.8%]) received combined treatment with immunomodulators. The average remission time in years was 3.08\u0026thinsp;\u0026plusmn;\u0026thinsp;2.68 years. The time since the first IFX infusion was 4.84 years (4.08\u0026ndash;5.61), and the time since the first ADA infusion was 4.46 years (3.03\u0026ndash;5.01).\u003c/p\u003e\n\u003cp\u003eThe clinical activity in CD patients according to the CDAI was 44.88 (40.51), and that according to the HBI was 1.1 (\u0026plusmn;\u0026thinsp;1.35). The PMS for UC patients was 0.3 (\u0026plusmn;\u0026thinsp;0.61). The most frequent comorbidity was hepatic disease in 44 (21.2%) patients. The most common number of visits per patient per year was 3 (131 patients), followed by 4 (53 patients) (Table \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eOutcomes\u003c/p\u003e\n\u003cp\u003eRemission at the end of the study in the 209 patients was achieved in 94 (90.3%) of the TDM group and 86 (81.9%) of the CP group, with a difference of 8.4% (p\u0026thinsp;=\u0026thinsp;0.079) (95%-17.7-0.91) (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e. Primary endpoints). There were no differences between the two types of management, neither among patients with CD or UC nor between patients treated with IFX or ADA (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. Loss of treatment response in patients during the maintenance phase according to the following: A: Type of anti-TNF, B: CP or TDM group, C: to Crohn\u0026acute;s or ulcerative colitis).\u003c/p\u003e\n\u003cp\u003eThe time in remission during the 12 months of follow-up was 45.69 (14.21) weeks in the CP group and 48.04 (10.76) weeks in the TDM group. Compared with the CP group, the TDM group remained in clinical remission significantly longer (96.7% versus 91.5%, p\u0026thinsp;=\u0026thinsp;0.03) during the 12-month follow-up.\u003c/p\u003e\n\u003cp\u003ePatients who did not require drug intensification (n\u0026thinsp;=\u0026thinsp;162) remained in remission longer than those who did require drug intensification (n\u0026thinsp;=\u0026thinsp;47) (p\u0026thinsp;=\u0026thinsp;0.01).\u003c/p\u003e\n\u003cp\u003eIn terms of the type of anti-TNF agent used, the incidence rate ratio (IRR) was 0.56 (95% CI 0.08\u0026ndash;3.81) in patients who used IFX and 0.78 (95% CI 0.29\u0026ndash;2.16) in patients who used ADA.\u003c/p\u003e\n\u003cp\u003eIn total, 39 flares were recorded. The IRR of flares throughout the study was 0.71 (95% CI 0.32\u0026ndash;1.55). In the TDM group, 15 flares were reported. In the CP group, there were 24 flares (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. Loss of treatment response in patients during the maintenance phase according to the following: A: Type of anti-TNF, B: CP or TDM group, C: to Crohn\u0026acute;s or ulcerative colitis), which represented 1.3/10 patient-years in the TDM group and 2.4/10 patient-years in the CP group. Considering the whole group of patients, men had more flares than women did, but the differences were not significant (p\u0026thinsp;=\u0026thinsp;0.88).\u003c/p\u003e\n\u003cp\u003eHospital admissions were recorded for 21 patients over 12 months, with a rate of 0.14 hospitalizations/patient/year in the CP group and 0.07 hospitalizations/patient/year in the TDM group (p\u0026thinsp;=\u0026thinsp;0.13). With respect to quality of life, we did not find differences between the two groups during the follow-up period (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e. Patients with flares according to the group).\u003c/p\u003e\n\u003cp\u003eIFX and ADA Concentrations\u003c/p\u003e\n\u003cp\u003eIFX levels at the beginning of the study were in the optimal range in 51 patients (48,5%), and in the ADA group, they were 36 (35.3%). There were no differences between the two groups for either of the two drugs (Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eThe changes in the drug dose throughout the study are shown in Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e (Quality of life recorded with the IBDQ at each clinical visit of the study). More than half of the patients in the TDM group (57, 54.8%) underwent modification of the drug dose, whereas 18 (17.1%) in the CP group underwent modification. In 29 patients (13.9%), the dose was intensified (11 in the CP group and 18 in the TDM group). During the study, antibodies were detected in a total of 22 patients (10.5%). Thirteen (12.1%) patients had ATIs against IFX, and 9 (8.8%) had ATIs against ADA. There were no differences between the groups (Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e. Dose modifications infliximab and adalimumab according to the group during the study).\u003c/p\u003e\n\u003cp\u003eAdverse Events\u003c/p\u003e\n\u003cp\u003eAdverse events were observed in 47 patients (22.48%) during the study, the most frequent of which were infections. Most cases were mild and affected the upper respiratory tract, followed by the gastrointestinal tract. For 4 patients (2 in each group), treatment had to be stopped. Two patients, both from the CP group (one with pneumonia and another with meningitis due to Listeria), required hospitalization and treatment withdrawal. The remaining adverse events are shown in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eIn this prospective and randomized study, which was carried out in patients with IBD treated with anti-TNFa drugs (IFX or ADA), we compared the clinical remission rates at 12 months between the group controlled with drug determination and the group followed according to usual clinical practice. There was no significant difference in the remission rate between the groups (8.4%, p\u0026thinsp;=\u0026thinsp;0.07). We did not reach the preestablished target of 16% in favor of the proactive management of the drug. The results for both IFX and ADA did not differ, which supports the hypothesis of the TAXIT study that there is a class effect that is applicable to other anti-TNF agents.\u003c/p\u003e\u003cp\u003eSince these patients were in clinical remission with a low number of flares/year, a greater number of patients or a longer follow-up time may be needed, as suggested in the PAILOX study, which lasted up to 72 weeks and was found to favor proactive management in children with CD treated with IFX (19).\u003c/p\u003e\u003cp\u003eIn this study, the remission rate in both groups was high compared with that in the TAXIT study, despite the optimization of IFX levels in all patients in a preliminary phase. The prolonged remission time in both groups at the time of their inclusion in the study could be a favorable factor in our case (these data are not included in the TAXIT study). Second, the long duration of previous treatment with ant-TNF agents could be another favorable factor since the loss of response (20\u0026ndash;40%) occurs mainly in the first year of treatment (3) (20). Another factor to consider is the high incidence of combined treatment with immunosuppressants in almost half of the patients, compared with the 5% reported in the TAXIT study. On the other hand, it cannot be ruled out that some episodes of clinical activity were not detected at the clinical visits.\u003c/p\u003e\u003cp\u003eIn the TAILORIX trial (21), which was carried out in patients with CD who were treated with IFX during maintenance phases, no differences in study outcomes were found between proactive drug management and typical clinical practice. The results of that study significantly differed from those of ours, likely because the randomization was performed very early (week 14) and therefore, most of the patients remained in an inflammatory state. Although those authors also implemented a minimum plasma IFX level of 3 \u0026micro;g/ml, the management of the drug in each of the three groups was different.\u003c/p\u003e\u003cp\u003eAlthough numerous studies have reported an association between drug concentration and clinical outcome, the optimal range of plasma ADA levels is poorly defined. For example, it differs according to the therapeutic objective and the inflammatory burden of the disease. In the IBD remission phase, some expert consensuses establish minimum plasma levels of \u0026gt;\u0026thinsp;3 \u0026micro;g/ml for IFX and between 5-7.5 for ADA and recommend the determination of this value at least once in the maintenance phase (22) (23). Other consensuses, such as the AGA, do not establish recommendations for patients in remission regarding drug monitoring (24).\u003c/p\u003e\u003cp\u003eIn this study, the optimal plasma levels for patients in clinical remission were 3\u0026ndash;7 \u0026micro;g/ml for IFX and 5\u0026ndash;8 \u0026micro;g/ml for ADA. The drug dose was modified in more than half of the patients (n\u0026thinsp;=\u0026thinsp;57, 55.8%) in the proactive group, which was similar for both the intensification and the spacing phases. In the CP group, in which intensification was performed if symptoms persisted or there was evidence of active inflammation using biomarkers, the drug dose was modified in only 18% of patients (17.1%). This difference between the two groups suggests that the early detection of low drug concentrations, which is related to immunogenicity and a lower risk for loss of response to anti-TNF, may be possible in some cases (25). It is also important to determine the optimal time at which the drug should be used. This method has been shown to be useful before the withdrawal of immunosuppressants in patients receiving combined treatment (26).\u003c/p\u003e\u003cp\u003eTo determine the antibody concentrations, we established a cutoff (+)\u0026thinsp;\u0026gt;\u0026thinsp;10. On the basis of this criteria, we estimated that 10.5% of patients (12.1% with IFX and 8.8% with ADA) had antibody positivity; these results were lower than those described in other studies (26). It is possible that combined treatment with immunomodulators in almost half of the patients, as described, was associated with lower immunogenicity to both drugs (27). In addition, in most cases, the levels were low; therefore, withdrawal of the drug was not necessary, since with the intensification or combination of immunosuppressants, it is expected that the antibody levels will disappear in \u0026frac34; of cases (28). We cannot rule out that the use of the reflex method, according to which the determination of antibodies was carried out only in patients with low levels of the drug, resulted in some cases having been undetected.\u003c/p\u003e\u003cp\u003eFor the secondary endpoint, the time in remission throughout the study was greater in the TDM group than in the PC group, and the difference was significant (p\u0026thinsp;=\u0026thinsp;0.03). We also detected fewer hospitalizations related to the disease and fewer flares in the group with controlled drug levels, which coincides with what is described in the TAXIT study. This trend was more favorable in patients with IFX than in those treated with ADA. Some studies have also shown that in patients with CD who were treated with IFX for more than 10 years, the proactive strategy was associated with fewer surgical interventions, fewer hospitalizations and a lower risk of infusion reactions than the reactive strategy was (23). However, in this study, we did not find differences in quality of life or adverse effects, which generally had a low incidence but forced the cessation of treatment in 2 patients in each group. The low number of events throughout the study could explain the absence of differences between the groups.\u003c/p\u003e\u003cp\u003eMoreover, we did not detect a relationship between plasma drug levels and the biomarkers FC and CRP, possibly because in both cases and in general, the levels remained in a low range and were insufficient to show differences.\u003c/p\u003e\u003cp\u003eThis study has several limitations since it addresses two pathologies, CD and UC, and uses two types of anti-TNF agents, IFX and ADA. Although on the one hand, it is a novel approach, on the other hand, this design can be a factor that makes it difficult to interpret the results obtained. Moreover, we did not collect endoscopic data regarding mucosal healing, an element of significant value in the long-term evolution of patients that is related to higher plasma drug levels (28).\u003c/p\u003e\u003cp\u003eIt would also be advisable, given that these are patients in remission and therefore stable, to increase the follow-up time and/or the number of patients to better study the differences between the strategies.\u003c/p\u003e\u003cp\u003eIn conclusion, and on the basis of the results of the present study, a clinical management strategy with plasma drug level determination in patients with CD or UC in clinical remission and maintenance treatment with IFX or ADA could be recommended. More evidence and broader studies that confirm this benefit and that establish the most appropriate time for its determination are needed.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAbbreviations used in this paper: UC, Ulcerative Colitis; CD, Crohn\u0026rsquo;s disease; CDAI, Crohn\u0026rsquo;s disease activity index; HBI, index Harvey-Bradshaw; PMS, partial Mayo score; CI, Informed Consent;CRP, C-reactive protein; CF, calprotectin fecal; IFX , Infliximab; ADA, Adalimumab; TDM, therapeutic drug monitoring; anti-TNF, tumor necrosis factor.IBDQ: Inflammatory Bowel Disease Questionnaire.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics statements\u003c/p\u003e\n\u003cp\u003ePatient consent for publication: Not applicable\u003c/p\u003e\n\u003cp\u003eEthics approval and consent to participate: All data were anonymised and de-identified, and no extra intervention was conducted. All patients were given a study information sheet and voluntarily signed their participation in the study. The investigation conformed with the principles outlined in the Declaration of Helsinki (as revised in Brazil 2013). All procedures were performed in compliance with relevant laws and institutional guidelines.\u0026nbsp;The study was aprobed by \u0026ldquo;\u003cstrong\u003eComit\u0026eacute; de \u0026Eacute;tica de la Investigaci\u0026oacute;n con medicamentos de Euskadi (CEIm-E)\u0026rdquo;, in 07 Nov 2016.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials\u003c/p\u003e\n\u003cp\u003eData are available upon reasonable request.\u003c/p\u003e\n\u003ch4\u003eCompeting interests\u003c/h4\u003e\n\u003cp\u003eC.M-V: consultant: Glaxosmith-Kline (GSK); grant support from Janssen. O.M: No conflict of interest. P.A: Grant support from Abbvie, Janssen, Takeda, Pfizer, MSD, Abbot. L.B: grant support from Abbvie, Janssen, Takeda, Pfizer, MSD. L.G.: consultant: Abbvie, Janssen, Tillots, Ferring and Dr. Falk Pharma Spain. \u0026nbsp;J.OZ.: consultant: Abbvie, Janssen and fresenius; grant supprot Abbvie, Janssen, Takeda. R.H: consultant: Abbvie, Janssen, Takeda, Falk, Chiesi, Shire; grant support from Abbvie, Janssen, Takeda, Pfizer, MSD, Abbot, Chiesi, Falk, Tillotts, FAES, Ferring, Lilly. L.D.N. and B.R-A. declare to be full-time employees of Progenika Biopharma SA.\u003c/p\u003e\n\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eThis project has been funded by \u0026ldquo;MINISTERIO DE ECONOM\u0026Iacute;A Y COMPETITIVIDAD\u0026rdquo; from Spain. Contract RTC-2015-4004-1, from 2015 through 2018.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contribution\u003c/p\u003e\n\u003cp\u003eAll authors have contributed and designed the study and to data collection and have approved the final version of the study. CM-V has written the manuscript. CM-V, RH, L.G, JOZ, P.A, S.I, and O.M contributed to data analysis and interpretation. D.N and B.R-A have contributed in designer of the study. I.G. has carried out the statistical analyse.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors are grateful to the patients who participated in this study. To the IBD nurses: M.A Fuente and A.Villar for their help with questionnaires and serum sample collection; to I.Filimon for completing the data collection; to I.Alzaga for assisting in the preparation of the document and to N. Rivera, as clinical coordinator, for her guidance and support in the management of the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLichtenstein GR, Yan S, Bala M, Blank M, Sands BE. Infliximab maintenance treatment reduces hospitalizations, surgeries, and procedures in fistulizing Crohn\u0026apos;s disease. Gastroenterology. 2005 Apr; 128(4):862-9\u003c/li\u003e\n\u003cli\u003eSprakes MB, Ford AC, Warren L, Greer D, Hamlin J. Efficacy, tolerability, and predictors of response to infliximab therapy for Crohn\u0026apos;s disease: a large single centre experience. J Crohns Colitis. 2012 Mar; 6(2):143-53.\u003c/li\u003e\n\u003cli\u003eBen-Horin S, Chowers Y. Review article: loss of response to anti-TNF treatments in Crohn\u0026rsquo;s disease. Aliment Pharmacol Ther 2011; 33: 987\u0026ndash;95\u003c/li\u003e\n\u003cli\u003ePaul S, Del Tedesco E, Marotte H, et al. Therapeutic drug monitoring of infliximab and mucosal healing in inflammatory bowel disease: a prospective study. Inflamm Bowel Dis 2013;19:2568\u0026ndash;2576.\u003c/li\u003e\n\u003cli\u003eHanauer SB, Sandborn WJ, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh D, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn\u0026apos;s disease: the CLASSIC-I trial. Gastroenterology. 2006 Feb; 130(2):323-33\u003c/li\u003e\n\u003cli\u003eSandborn WJ, Hanauer SB, Rutgeerts P, Fedorak RN, Lukas M, MacIntosh DG, et al. Adalimumab for maintenance treatment of Crohn\u0026apos;s disease: results of the CLASSIC II trial. Gut. 2007 Sep; 56(9):1232-9\u003c/li\u003e\n\u003cli\u003eYarur AJ, Jain A, Hauenstein SI, Quintero MA, Barkin JS, Deshpande AR, et al. Higher Adalimumab Levels Are Associated with Histologic and Endoscopic Remission in Patients with Crohn\u0026apos;s Disease and Ulcerative Colitis. Inflamm Bowel Dis. 2016 Feb; 22(2):409-15\u003c/li\u003e\n\u003cli\u003eAdedokun OJ, Sandborn WJ, Feagan BG, Rutgeerts P, Xu Z, Marano CW, et al. Association between serum concentration of infliximab and efficacy in adult patients with ulcerative colitis. Gastroenterology. 2014 Dec; 147(6):1296-307.\u003c/li\u003e\n\u003cli\u003eLopez-Ibanez M, Marin-Jimenez I. [Drugs and anti-drug antibody levels in the management of patients with inflammatory bowel disease]. Gastroenterol Hepatol. 2016 Apr; 39(4):265- 72\u003c/li\u003e\n\u003cli\u003eVande Casteele CN, Ferrante M, Van AG, Ballet V, Compernolle G, Van SK, et al. Trough concentrations of infliximab guide dosing for patients with inflammatory bowel disease. Gastroenterology. 2015 Jun; 148(7):1320-9.\u003c/li\u003e\n\u003cli\u003eNational Institute for Health and Care Excellence (NICE). Therapeutic Monitoring of TNF-alpha Inhibitors in Crohn\u0026rsquo;s Disease (LISA-TRACKER ELISA Kits, IDKmonitor ELISA Kits, and Promonitor ELISA kits) [DG22]. London: NICE; 2016. Available on: https://www.nice.org.uk/guidance/dg22 \u003c/li\u003e\n\u003cli\u003eLennard-Jones JE. Classification of inflammatory bowel disease. Scand J Gastroenterol Suppl. 1989; 170:2-6.\u003c/li\u003e\n\u003cli\u003eSilverberg MS, Satsangi J, Ahmad T, Arnott ID, Bernstein CN, Brant SR, et al. Toward an integrated clinical, molecular and serological classification of inflammatory bowel disease: report of a Working Party of the 2005 Montreal World Congress of Gastroenterology. Can J Gastroenterol. 2005 Sep; 19 Suppl A:5A-36A.\u003c/li\u003e\n\u003cli\u003eRoth LS, Chande N, Ponich T, Roth ML, Gregor J. Predictors of disease severity in ulcerative colitis patients from Southwestern Ontario. World J Gastroenterol. 2010 Jan 14; 16(2):232-6.\u003c/li\u003e\n\u003cli\u003eVan AG, Dignass A, Panes J, Beaugerie L, Karagiannis J, Allez M, et al. The second European evidence-based Consensus on the diagnosis and management of Crohn\u0026apos;s disease: Definitions and diagnosis. J Crohns Colitis. 2010 Feb; 4(1):7-27\u003c/li\u003e\n\u003cli\u003eHarvey RF, Bradshaw JM. A simple index of Crohn\u0026apos;s-disease activity. Lancet. 1980 Mar 8; 1(8167):514.\u003c/li\u003e\n\u003cli\u003eLopez-Vivancos J, Casellas F, Badia X, Vilaseca J, Malagelada JR. Validation of the spanish version of the inflammatory bowel disease questionnaire on ulcerative colitis and Crohn\u0026apos;s disease. Digestion. 1999; 60(3):274-80.\u003c/li\u003e\n\u003cli\u003eKonig HH, Ulshofer A, Gregor M, et al. Validation of the EuroQol questionnaire in patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2002;14: 1205\u0026ndash;1215.\u003c/li\u003e\n\u003cli\u003eAssa A , Matar M, Turner D, Broide E, Weiss B,2, Ledder O et al. Proactive Monitoring of AdalimumabTrough Concentration Associated With Increased Clinical Remission in Children With Crohn\u0026rsquo;s Disease Compared With Reactive Monitoring. Gastroenterology 2019,157(4): 985\u0026ndash;996\u003c/li\u003e\n\u003cli\u003eKarmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Cro hn\u0026rsquo;s disease. Gastroenterology 2009; 137: 1628\u0026ndash;40.\u003c/li\u003e\n\u003cli\u003eD\u0026rsquo;Haens G, Vermeire S, Lambrecht G, Baert F, Bossuyt P, Pariente B et al. Increasing Infliximab Dose Based on Symptoms, Biomarkers, and Serum Drug Concentrations Does Not Increase Clinical, Endoscopic, and Corticosteroid-Free Remission in Patients With Active Luminal Crohn\u0026rsquo;s Disease. Gastroenterology 2018;154:1343\u0026ndash;1\u003c/li\u003e\n\u003cli\u003eRodr\u0026iacute;guez-Moranta F, Arg\u0026uuml;elles-Arias F, Hinojosa del Val J, Iborra Colomino M, M. Mart\u0026iacute;n-Arranz D, Mench\u0026eacute;n Viso L et al. Monitorizaci\u0026oacute;n terap\u0026eacute;utica de los f\u0026aacute;rmacos biol\u0026oacute;gicos en la enfermedad inflamatoria intestinal. Documento de Posicionamiento del Grupo Espanol \u0026tilde; de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa (GETECCU). Gastroenterolog\u0026iacute;a y Hepatolog\u0026iacute;a 47 (2024) 522---552\u003c/li\u003e\n\u003cli\u003ePapamichael K, Chachu KA, Vajravelu RK, Vaughn BP, Ni J, Osterman MT, et al. Improved Long-term Outcomes of Patients With Inflammatory Bowel Disease Receiving Proactive Com pared With Reactive Monitoring of Serum Concentrations of Infliximab. Clin Gastroenterol Hepatol. 2017;15:1580---8.\u003c/li\u003e\n\u003cli\u003eFeuerstein JD, Geoffrey GC,. Kupfer SS, Falck-Ytter Y and Singh S. American Gastroenterological Association Institute Guideline on Therapeutic Drug Monitoring in Inflamador Bowel Disease. Gastroenterology 2017;153:827\u0026ndash;834\u003c/li\u003e\n\u003cli\u003eKennedy N, Heap GA, D Green H, Hamilton B, Bewshea C, Walker GJ et al. Predictors of anti-TNF treatment failure in anti-TNF-naive patients with active luminal Crohn\u0026rsquo;s disease: a prospective, multicentre, cohort study. Lancet Gastroenterol Hepatol 2019;4(5):341-353.\u003c/li\u003e\n\u003cli\u003eBattat R, Lukin D, Scherl E J, Pola S, Kumar A, Okada L et al. Immunogenicity of Tumor Necrosis Factor Antagonists and Effect of Dose Escalation on Anti-Drug Antibodies and Serum Drug Concentrations in Inflammatory Bowel Disease. Inflamm Bowel Dis ,202,7(9): 1443-1451\u003c/li\u003e\n\u003cli\u003eSteenholdt C, Magid Al-khalaf M, Brynskov JO, Bendtzen K, Thomsen O, MD, and Ainsworth, MA. Clinical Implications of Variations in Anti-infliximab Antibody Levels in Patients with Inflammatory Bowel Disease. Inflamm Bowel Dis Volume 2012,18(12): 2209-2217\u003c/li\u003e\n\u003cli\u003eYarur AJ, AJain A, Hauenstein S I, Quintero AM, Barkin JS,Deshpande AR, et al . Higher Adalimumab Levels Are Associated with Histologic and Endoscopic Remission in Patients with Crohn\u0026rsquo;s Disease and Ulcerative Colitis. Inflamm Bowel Dis Volume, 2016, 22(2): 409-415\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 3 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Inflammatory Bowel Disease, Adalimumab, Infliximab, Therapeutic Drug Monitoring, Clinical Remission","lastPublishedDoi":"10.21203/rs.3.rs-7537370/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7537370/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAlthough the serum levels of infliximab (IFX) and adalimumab (ADA) are correlated with the clinical response in patients with inflammatory bowel disease (IBD), the optimal management strategy during maintenance therapy remains controversial. We performed a randomized trial to determine whether proactive monitoring drug in patients with inflammatory bowel disease is better than control clinical to keep clinical remission\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a randomized, prospective, multicenter trial involving 209 patients with Crohn's disease (CD) or ulcerative colitis (UC) who had been in clinical remission for at least 12 weeks. Patients were randomized into two groups: 104 in the TDM group and 105 in the clinical practice (CP) group. In the TDM group, the dosing and intervals of IFX and ADA were adjusted at each visit to maintain optimal serum concentrations (3–7 μg/mL for IFX and 5–8 μg/mL for ADA). The primary endpoint was the proportion of patients who remained in clinical remission at 12 months of follow-up. The secondary endpoints included the number of disease flares, duration of clinical remission, rate of hospital admissions related to IBD, and quality of life.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint of remission was achieved in 94 patients (90.3%) in the TDM group and 86 patients (81.9%) in the CP group, with a difference of 8.4% between the groups (p = 0.079; 95% CI: –17.70.91). The mean duration of remission over the 12-month follow-up was significantly longer in the TDM group [48.04 ± 10.76 weeks] than in the CP group [45.69 ± 14.21 weeks] (p = 0.03). The number of disease flares was lower in the TDM group (15 flares) than inthe CP group (24 flares). At baseline, optimal IFX levels were present in 51 patients (48.5%), and optimal ADA levels were present in 36 patients (35.3%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this prospective randomized trial of patients with CD or UC in clinical remission receiving IFX or ADA, compared withstandard clinical management, proactive TDM did not significantly increase the overall remission rate at one year. However, patients in the TDM group remained in clinical remission for a significantly longer duration.\u003c/p\u003e\n\u003cp\u003eClinicalTrials.gov Identifier: NCT06666569. (30 oct 2024). Retrospectively registered.\u003c/p\u003e","manuscriptTitle":"Infliximab and Adalimumab Monitoring versus Clinical Control during Maintenance Therapy in Randomized Patients with Inflammatory Bowel Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 23:24:38","doi":"10.21203/rs.3.rs-7537370/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"db3ee39c-69e8-4430-b9fc-63cc6bd2c318","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-31T08:24:07+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 23:24:38","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7537370","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7537370","identity":"rs-7537370","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}