How We Can Personalize the Infliximab Use in Ulcerative Patients

• Abstract
• Introduction
• Subjects and Methods
• Definitions of Clinical and Endoscopic Remission
• Predictors of Response
• Outcomes
• Statistical Analysis
• Results
• Discussion
• Conclusion
• References

Abstract

Objective

We aimed to assess the predictors of response to infliximab treatment in individuals with ulcerative colitis to personalize its use.

Methods

This study included the initial 100 UC patients who were administered Infliximab. We Excluded individuals under 18 years old, primary non-responders, and those who declined participation or measurement of their IFX trough levels. We evaluated laboratory tests conducted within 3 months of assessing clinical and endoscopic remission for patients who already started infliximab. Laboratory data, including albumin and C-reactive protein (CRP) test results, and PANCA were collected. We observed the patients for any clinical changes or problems while they had Infliximab treatment.

Result

mean age was 34.36 ± 15.5. 73 cases were male while 27 were female. 36 were smokers. In Multivariate correlation regression, there were strong significant correlations between good response and PANCA, Pan-ulcerative, CRP, ESR, NAR, and Fecal calprotectin.

Conclusion

PANCA, Pan-ulcerative colitis (E3), CRP, ESR, NAR and Fecal calprotectin are good predictors of infliximab response

Introduction

Ulcerative colitis (UC) is a chronic inflammatory condition of the gastrointestinal system with unknown causes. The utilization of anti-tumor necrosis factor [anti-TNF] medications has significantly transformed the management of inflammatory bowel disease [IBD]. Using them eliminates the necessity for steroid treatment, encourages the recovery of mucosal tissue, decreases hospitalizations and operations, and significantly enhances the quality of life for people with inflammatory bowel disease.1 Approximately two-thirds of patients with inflammatory bowel disease (IBD) who are treated with anti-tumor necrosis factor (anti-TNF) medications experience an initial positive response to the therapy.[1] Anti-TNF drugs were the exclusive biologics utilized for IBD treatment for an extended period. Two novel biologic medicines, vedolizumab and ustekinumab, which target distinct inflammatory pathways, have been licensed for IBD in recent years. Similar to anti-TNF medications, a considerable number of patients do not respond to these drugs, and their position in relation to anti-TNF therapy is uncertain.[2] Unlike Crohn's disease, ulcerative colitis has traditionally been viewed as a disease driven by T helper 2 cells, with tumor necrosis factor playing a less significant role. Two pieces of evidence indicate a significant involvement of TNF in the development of UC.[3] [4] Initially, multiple researchers discovered elevated TNF levels in various body fluids and tissues of patients with active colitis.[5] [6]

The early open-label and small randomized controlled clinical studies of infliximab produced contradictory results due to the absence of a placebo-controlled group, insufficient statistical power, or variations in the patient populations investigated (steroid-refractory versus moderate-to-severe UC patients). The ACT1 and ACT2 trials, which were randomized, double-blind, and multicenter placebo-controlled studies, demonstrated a notable advantage of infliximab (IFX) in patients with moderate-to-severe active UC.[7] [8] Patients were given either a placebo or IFX at doses of 5 or 10 mg/kg body weight at weeks 0, 2, and 6 as part of the induction scheme. Following this, they received maintenance medication (placebo or IFX) every 8 weeks for a total duration of 22 weeks (ACT2) or 46 weeks (ACT1). At 8 weeks, the placebo had a clinical response rate of 29–37%, whereas IFX 5 mg/kg had a rate of 64–69%, and IFX 10 mg/kg had a rate of 61–69%. The clinical response rates were significantly superior in the IFX-treated group at 30 and 54 weeks. Moreover, individuals treated with IFX exhibited significantly greater rates of clinical remission, and mucosal healing, and were more successful in discontinuing corticosteroid use.[9]

Currently, the sole randomized-controlled trial conducted on patients with severe steroid-refractory UC, sponsored by Jarnerot et al, revealed a notable decrease in colectomy rates 3 months following IFX treatment (29% versus 67%). In addition, the administration of infliximab did not impact postoperative complications. Although IFX has shown clear benefits in ulcerative colitis patients in the ACT1 and ACT2 trials and the study by Jarnerot et al, concerns concerning its long-term safety, immunogenicity, and cost-effectiveness are still relevant. Identifying indicators of response to infliximab (IFX) is crucial for selecting UC patients who do not benefit from the medicine, which is costly and may have adverse effects.[10]

We wanted to evaluate factors that predict the response to infliximab treatment in patients with ulcerative colitis, both before and after the initial loading dose.

Subjects and Methods

This study included the initial 100 UC patients who were administered IFX. All patients underwent their initial IFX infusion at our facility. Exclusion criteria were individuals under 18 years old, primary non-responders, and those who declined participation or measurement of their IFX trough levels. Primary non-response was characterized by the absence of improvement in clinical signs and symptoms while undergoing induction therapy. Patients who have ostomy, total colectomy, or those receiving oral systemic and local corticosteroids were also ineligible. The diagnosis of IBD was confirmed using clinical, endoscopic, imaging, and histological examinations. Data regarding sex, body mass index (BMI), age, diagnosis date, disease duration, location, behavior, smoking history, comorbidities, duration of current biological therapy, IFX dosage (in mg/kg), dosing interval, IFX standard or escalation dose, concomitant immunomodulators, prior IBD treatments, and surgical procedures (such as enterectomy, right hemicolectomy, and perianal approaches) was extracted from electronic medical records at the time of measuring IFX trough levels. Immunomodulators such as 6-mercaptopurine, azathioprine, and methotrexate were used. Laboratory data, including albumin and C-reactive protein (CRP) test results, were collected from medical records. They were measured in the nearby area. We observed the patients for any clinical changes or problems while they had IFX treatment. We evaluated the IFX level test and other laboratory tests conducted within 3 months of assessing clinical and endoscopic remission.

Definitions of Clinical and Endoscopic Remission

Clinical remission was evaluated simultaneously with the IFX measurement, while the endoscopic assessment was conducted within a 3-month window before and after the IFX measures. We assessed clinical remission using the Harvey Bradshaw Index (HBI) for Crohn's disease (CD) and the partial Mayo score (PMS) for ulcerative colitis (UC). Clinical remission was defined as having an HBI score below 5 and a PMS score below 2. Endoscopic data were utilized to evaluate endoscopic recovery. We utilized the endoscopic Mayo score of 0 and 1 to determine endoscopic remission in patients with UC. We exclusively applied Rutgeerts' score to individuals who had undergone hemicolectomy in the past (i0 or i1). In this study, we equated endoscopic remission with endoscopic healing.

Predictors of Response

In addition to demographic data such as gender, age at diagnosis, length of disease before IFX, and age at first IFX infusion, we also evaluated markers of disease severity. The degree of inflammation was categorized as proctitis, left-sided colitis, or pancolitis, based on Montreal classification. The chronic inflammatory infiltrate was evaluated as 1, lamina propria infiltration with neutrophils or eosinophils as 2, cryptitis as 3, and crypt destruction as 4. Grade 5 was tasked with analyzing biopsies showing erosion, ulceration, or healing epithelium with nearby inflammation. Serum samples were collected from UC patients during their initial IFX infusion, and ELISA tests were conducted to detect pANCA antibodies. We investigated the prognostic significance of the pANCA because of its great specificity. The study also considered the initial dose of the first IFX (5 or 10 mg/kg body weight), the implementation of an IFX induction regimen, C-reactive protein levels during the first IFX infusion, smoking habits, and concurrent treatment with corticosteroids or immunomodulators.

Outcomes

The focus was on achieving clinical remission while on maintenance treatment with IFX, with the secondary focus being on achieving endoscopic healing.

Statistical Analysis

The data was collected, organized, and statistically analyzed using SPSS 26.0 for Windows (SPSS Inc., Chicago, IL, USA). Qualitative data were represented using numerical values and percentages. Quantitative data were summarized using range (minimum and maximum), mean, standard deviation, and media. Logistic regression was employed to assess the impact of various explanatory variables. We updated the multiple logistic regression model by including variables with a bivariate p-value less than 0.10 using the backward stepwise selection approach with the entry and exit criterion set at 5%. Analyses were conducted for the entire patient population and separately for each condition.

Results

[Table 1] shows that the mean age was 34.36 ± 15.5. 73 cases were male while 27 were female. 36 were smokers. 85% were below 30 years old at Diagnosis. 76 cases were rural. 12 cases had E1, 15 cases had E2, and 73 cases had E3. The pulse was 84.22 ± 6.84.

[Table 2] shows that the mean Bowel movement /day was 3.98 ± 1.17. 100 cases had Diarrhea, 86 had Blood in stool, 8 had Abdominal pain, 6 had Fever and 12 had Extra intestinal symptoms.

[Table 3] shows that 100 continued 5-ASA, 4 had Azathioprine continuation, and 93 cases had more than 3 years. 100 cases had previously conservative treatment, and 76 had clinical improvement after loading dose. 51 cases had endoscopic healing after loading the dose.

[Table 4] shows that there was a highly significant difference between before and after loading dose according to laboratory data.

[Table 5] In Multivariate correlation regression, there were strong significant correlations between good response and pANCA, Pan ulcerative, CRP, ESR, NAR, and Fecal calprotectin.

Discussion

The etiology of ulcerative colitis (UC) remains incompletely elucidated. Personalization of infliximab treatment in patients with ulcerative colitis involves tailoring therapy based on individual patient characteristics, responses, and clinical factors. Patients experience enhanced quality of life, less reliance on steroids, repair of mucosal tissue, and reduced hospitalizations and surgeries.[1] Initially, anti-TNF drugs provide benefits to approximately two-thirds of persons with ulcerative colitis.[11] The introduction of specific inhibitors of tumor necrosis factor (TNF) is a groundbreaking achievement, enabling long-standing remission, and modification of the IBD course in a significant fraction of patients.[12] However, primary non-response to TNF inhibitors was observed in up to 40% of patients in clinical trials and 10–20% of patients in clinical series; secondary loss of response occurred in ∼23–46% of patients after 1 year of treatment[13]

Our study showed that the mean age was 34.36 ± 15.5. 73 cases were male while 27 were female. 36 were smokers. 85% were below 30 years of diagnosis. This concordant with other studies showed that the age of registration for UC was mostly between 30- and 49-years old Male to female ratio for UC was 1.64.[3]

According to our study, 12 cases had E1, 15 cases had E2 and 73 cases had E3, this is partially disconcordant with a study conducted by Rawal and his colleague who reported that E1 (Ulcerative proctitis) Approximately 33.92% of UC patients have disease limited to the rectum, E2 (Left-sided colitis) Around 36.56% of patients have disease extending up to the splenic flexure, E3 (Extensive colitis) About 29.50% of patients have disease extending beyond the splenic flexure.[4]

Personalization of biologics, the therapeutic objectives of IBD have been changed and mucosal healing has become targeted. Endoscopy maintains a key role in monitoring mucosal healing nowadays. In the study, patients' clinical improvement was achieved after loading dose in 76 cases. Also, 64 percent of patients received 5 mg of infliximab. Fifty-one cases had endoscopic healing after the loading dose. This is also concordant with the study conducted by Rutgeerts and his colleague which mentioned that early endoscopic assessment (within 12 weeks) yields mucosal healing rates varying between 25% and 50% only.[6]

The severity of ulcerative colitis increases the response to infliximab, so infliximab drives more effectively in severe ulcerative colitis, so, the results of our study showed strong and statistically significant associations between a good response and indicators of activity and severity (PANCA, Pan ulcerative, CRP, ESR, NAR, and Fecal calprotectin). Different studies provide strong evidence for the efficacy of infliximab in UC, but they may not explicitly address the impact of disease severity on treatment response, below are some of them: -

• Gisbert et al. (2020) have shown that C-reactive protein (CRP), a laboratory biomarker of inflammation, has been the most used biomarker in clinical practice over the years. However, it is unclear whether pre-treatment CRP alone is a dependable predictor of the effectiveness of antiTNF medication. Thus, it remains uncertain whether an increased CRP level is a reliable predictor of a patient's response to anti-TNF medication or if it just signifies that symptoms are caused by an ongoing inflammatory condition.[1]

• Several investigations, including those conducted by Ferrante et al. and Dahlén et al., have confirmed a correlation between low CRP levels and a more favorable response to anti-TNF medicine, such as infliximab and adalimumab. Individuals diagnosed with ulcerative colitis have been the focus of these research studies. In addition, other researchers, such as Gonzalez et al., found no link between CRP levels and the responsiveness to anti-TNF treatment in individuals with UC. C-reactive protein, or CRP, is a laboratory biomarker that is commonly used in clinical practice to measure inflammation. It is one of the most frequently utilized biomarkers among many others. However, it is unclear whether pre-treatment CRP alone is a dependable predictor of the effectiveness of anti-TNF medication. Thus, it remains uncertain whether an increased CRP level is a reliable predictor of a patient's response to anti-TNF medication or if it just serves as an indicator that symptoms are caused by an ongoing inflammatory condition.[2] [7]

• Several investigations, including those conducted by Sandborn et al. and Peters et al., have confirmed a correlation between elevated CRP levels and the effectiveness of anti-TNF treatment in CD, such as infliximab, adalimumab, and certolizumab. However, several studies, including the one conducted by Arias et al., have shown a link between low CRP levels and a stronger response to anti-TNF treatment, which involves giving infliximab and adalimumab to patients with UC.[10]

• In addition, some investigations, such as the one conducted by Gonzalez et al., found no association between CRP levels and the effectiveness of anti-TNF treatment in patients diagnosed with either Crohn's disease (CD) or ulcerative colitis (UC). Gisbert et al. (2020) showed that these differences can be ascribed to the fact that CRP is associated not only with an inflammatory phenotype but also with a more severe form of disease. Therefore, it has been theorized that an increased baseline CRP can have both positive and negative effects. While a high baseline CRP level may exclude patients with non-inflammatory functional complaints and predict a better overall response, it may also suggest a greater inflammatory load, leading to faster elimination of the drug. This can lead to a diminished response in specific patients with a high C-reactive protein (CRP) level.[1]

• In 2020, Gisbert and his colleagues did research that showed a connection between two serological markers, perinuclear anti-neutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA), with ulcerative colitis (UC) and Crohn's disease (CD) respectively.[1]

• These antibodies have been studied as potential indicators of how likely someone is to respond to anti-TNFs in the latest advancements. Previous studies have indicated that a positive pANCA test may serve as a predictive factor for the response to infliximab treatment in patients with UC. However, additional studies have failed to confirm this correlation in patients with CD. Nevertheless, the outcomes were underwhelming: The serological testing for pANCA+ in predicting nonresponse to infliximab therapy showed a sensitivity of 25%, specificity of 85%, positive predictive value of 41%, and negative predictive value of 74%.[8] [14]

• A meta-analysis revealed that patients who tested positive for pANCA had a much lower response rate compared with patients who tested negative for pANCA, with the former group achieving a response rate that was nearly half that of the latter group.

• Gisbert et al. (2020) discovered that faecal calprotectin and lactoferrin can be used as substitute indicators of disease activity within the intestinal lumen. These markers have been suggested as indicators that can indicate how well a patient would respond to anti-TNF. Conversely, in some studies, a higher calprotectin level was found to be indicative of a favorable reaction, whereas in other investigations, the relationship was the opposite. Furthermore, some studies have failed to validate any of the associations.[1]

Conclusion

In conclusion, the response of infliximab more in patients with severe disease, personalized medicine in ulcerative colitis can be depended upon the following predictors pANCA, extension of the disease (Pan ulcerative), CRP, ESR, NAR and fecal calprotectin.

Conflict of Interest

The authors declare that they have no conflicts of interest.

Acknowledgment

To our families.

• References

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Address for correspondence

Publication History

Received: 11 March 2025

Accepted: 22 May 2025

Article published online:
02 July 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit (https://creativecommons.org/licenses/by/4.0/)

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• References

• 1 Gisbert JP, Chaparro M. Predictors of primary response to biologic treatment [anti-TNF, vedolizumab, and ustekinumab] in patients with inflammatory bowel disease: from basic science to clinical practice. J Crohns Colitis 2020; 14 (05) 694-709
  PubMedSearch in Google Scholar
• 2 Ferrante M, Vermeire S, Fidder H. et al. Long-term outcome after infliximab for refractory ulcerative colitis. J Crohns Colitis 2008; 2 (03) 219-225
  CrossrefPubMedSearch in Google Scholar
• 3 Wei SC, Lin MH, Tung CC. et al A nationwide populationbased study of the inflammatory bowel diseases between 1998 and 2008 in Taiwan. BMC Gastroenterol 2013; ; page 13: 166
  PubMedSearch in Google Scholar
• 4 Rawal KK, Shukla VP, Chikani S, Thakkar M, Ruparelia M, Chudasama RK. Prevalence of extraintestinal manifestations in ulcerative colitis and associated risk factors. Indian J Gastroenterol 2021; 40 (05) 477-482
  CrossrefPubMedSearch in Google Scholar
• 5 Gonzalez-Lama Y, Fernandez-Blanco I, Lopez-SanRoman A. et al; Group for the Study of Inflammatory Bowel Diseases from Madrid. Open-label infliximab therapy in ulcerative colitis: a multicenter survey of results and predictors of response. Hepatogastroenterology 2008; 55 (86-87): 1609-1614
  PubMedSearch in Google Scholar
• 6 Rutgeerts P, Sandborn WJ, Feagan BG. et al. Infliximab for induction and maintenance therapy for ulcerative colitis. N Engl J Med 2005; 353 (23) 2462-2476 Erratum in: N Engl J Med. 2006 May 18;354(20):2200. PMID: 16339095
  CrossrefPubMedSearch in Google Scholar
• 7 Dahlén R, Magnusson MK, Bajor A. et al. Global mucosal and serum cytokine profile in patients with ulcerative colitis undergoing anti-TNF therapy. Scand J Gastroenterol 2015; 50 (09) 1118-1126
  PubMedSearch in Google Scholar
• 8 Grasmeier MK, Langmann AF, Langmann P, Treiber M, Thaler MA, Luppa PB. Dynamics of serum concentrations of antibodies to infliximab: a new approach for predicting secondary loss of response in inflammatory bowel diseases. Therap Adv Gastroenterol 2021; Aug 19; page 14: 17 562848211037849
  CrossrefPubMedSearch in Google Scholar
• 9 Sandborn WJ, Regula J, Feagan BG. et al. Delayed-release oral mesalamine 4.8 g/day [800-mg tablet] is effective for patients with moderately active ulcerative colitis. Gastroenterology 2009; 137: 1934-43.e1–3
  PubMedSearch in Google Scholar
• 10 Peters CP, Eshuis EJ, Toxopeüs FM. et al; North Holland GUT club. Adalimumab for Crohn's disease: long-term sustained benefit in a population-based cohort of 438 patients. J Crohns Colitis 2014; 8 (08) 866-875
  PubMedSearch in Google Scholar
• 11 Martins CA, de Azevedo MFC, Carlos AS, Damião AOMC, Sobrado Junior CW, Nahas SC, Queiroz NSF. Predictive factors of response to infliximab therapy in Brazilian inflammatory bowel disease patients. Therap Adv Gastroenterol 2023; Nov 15; page 16: 17 562848231210053 . PMID: 38026104; PMCID: PMC10652804
  CrossrefPubMedSearch in Google Scholar
• 12 Nielsen OH, Ainsworth MA. Tumor necrosis factor inhibitors for inflammatory bowel disease. N Engl J Med 2013; 369 (08) 754-762
  CrossrefPubMedSearch in Google Scholar
• 13 Ben-Horin S, Kopylov U, Chowers Y. Optimizing anti-TNF treatments in inflammatory bowel disease. Autoimmun Rev 2014; 13 (01) 24-30
  CrossrefPubMedSearch in Google Scholar
• 14 Ben-Horin S, Kopylov U, Chowers Y. Optimizing anti-TNF treat ments in inflammatory bowel disease. Autoimmun Rev 2014; 13 (01) Page 24-30
  CrossrefPubMedSearch in Google Scholar