Ahmed Khalid Mohammed¹, Huda I. Al-Qadhi², Nawal Mehdi Alkhalidi³, Hayder Adnan Fawzi⁴*

¹ Department of pharmacology, Faculty of Medicine, University of Baghdad, Baghdad, Iraq‎. ² Assistant Professor, Department of Pharmacology, Faculty of ‎Medicine, ‎University ‎of Baghdad, Baghdad, Iraq. ³ Consultant gastroenterologist, Baghdad Medical City, Ministry of ‎Health and Environment, Baghdad, Iraq. ⁴ Associate professor, Department of Pharmacy, Al-Rasheed University College, Baghdad, Iraq.

Correspondence: Hayder Adnan Fawzi, Associate professor, Department of Pharmacy, University of Al-Rasheed, Baghdad, Iraq.

 Email: Hayder.adnan2010 @ gmail.com.

Introduction  

Ulcerative colitis refers to an inflammatory bowel disease (IBD) that results in persistent inflammation and ulcers (lesions) in the large bowel. Ulcerative colitis affects the colon and the rectum. ‎Symptoms appear over a long period ^[1]. There is no real reason for the occurrence of ulcerative ‎colitis, although there is linkage to the immunity of the body ^[2].

Patients need awareness of inflammatory disease and anti-inflammatory remedies. ^{[3, 4]} Ulcerative colitis is an autoimmune condition which studied by many researchers. ^[5] However, inflammation of ulcerative colitis is due to the stimulation of white cells to eliminate the infection resulting in bacterial infection ^[6]. With infection dismissal, retaliation of the immune system proceeds, however, failure would result in a struggle for infections that are not existing leading to continuous inflammation ^[7].

Ulcerative colitis mainly begins in the rectum. It may stay in the rectum (ulcerative proctitis) or exceed contiguously, occasionally spreading wholly to the colon. Patients suffer from diarrhea, rectal bleeding, lower abdominal pain, and tenesmus (dire need to excrete the bowels however less little movement of stool).  ^[8].

There is a lack of head to head randomized clinical trial (RCT) comparing both infliximab (IFX) and adalimumab (ADA) in the literature, most of these studies performed in Western countries ^[9-12], with few studies examined Asian populations. This study aimed to evaluate the effect of Infliximab and Adalimumab in patients with ulcerative colitis in the Real-world setting.

Methods

Study design

One hundred patients who had previously diagnosed with UC at least 3 months had received treatment protocols prescribed by physicians at the GIT center and had received biological treatment (all patients received no previous TNF inhibitor). The patients were divided into two groups; The first group (70 UC patients) received Infliximab and the second group (30 UC patients) received Adalimumab. All patients were followed up for 6 months after the onset of biological agents.

Study setting

The study was conducted at the Baghdad Medical City –‎Gastroenterology and Hepatology Training Hospital in Baghdad/Iraq. The study was conducted from December 2018 to July 2019.‎

Patients with congestive heart failure, viral hepatitis, active bacterial infection (e.g. tuberculosis [TB]), and pregnant women were excluded from the study.

Baseline assessment

Screening of all patients before the onset of TNF inhibitors includes a physical examination, endoscopic examination, Mayo subscore, and TB screening.

Participants

Adults between the ages of 18 – 70 years were eligible for inclusion, patients with mild to severe UC (based on Mayo subscore), patients who did not receive previous anti-TNF treatment.

Data collection

Detailed history regarding the following points was taken:

1. The type of biological treatment according to the treatment ‎protocol schedule.‎
2. Response (including remissions and relapses) these parameters were calculated and compared before and after the start of treatment (clinically and colonoscopically)
3. Any symptoms that indicate side effects

Patients were examined for signs of fever, tachycardia, pallor, abdominal pain, blood on rectal exam, joints' inflammation and diarrhea with or without blood. These physical symptoms and complications may present related to UC reported and studied before and after the biologic ‎treatment. ‎

Treatment protocol

‎Infliximab IFX (REMICADE® brand name of Janssen CarePath Company) at the recommended dose of 5 mg/kg intravenous infusion with induction regimen at 0, 2 and 6 weeks followed by a 5 mg/kg maintenance regimen every 8 weeks ‎for 1 year or accordingly.‎

Adalimumab (HUMIRA® brand name of Abbvie Company) subcutaneously with a recommended dose regimen of 160 mg initially on day 1 (given on a single day or split over two consecutive days), followed by 80 mg two weeks later than 40 mg every two weeks.

Evaluation of study parameters

Relapse: relapse UC (flare) is an acute worsening of the symptoms of bowel inflammation. Disease relapse was diagnosed clinically and endoscopically by the Mayo sub-score with the exclusion of other causes of relapse, i.e. infection and ‎interruption of treatment ^[13].

Clinical relapse symptoms include cramps or abdominal pain that can't be managed by ordinary antispasmodic or pain killer drugs, bloody stool, dehydration, diarrheal symptoms, decrease appetite leading to loss of weight, and abnormal bowel motion. These symptoms and others are evaluated and compared between groups before and after 6 months of treatment.

Mayo Endoscopic sub-score

This score was used to assess mucosal healing (MH) ^[14], then recorded by specialists and compared to before and after 6 months of treatment, for severity grade (see Table 1) ^[13]. MH is defined as a score of 0 or 1 ^[14].

Figure 1: endoscopic images

Ethical approval

All procedures in the study are following the ethical standards of the institutional research committee at the Faculty of Medicine – University of Baghdad (Code: 2019/0263) and with the 1964 ‎Helsinki declaration and subsequent amendments.

Informed consent

Written Informed consent was obtained from all study participants separately.

Statistical analysis

Wilcoxon Median rank test, logistic regression were used to calculate odds ratios (OR) ‎and ‎ 95% confidence intervals were used for statistical analysis. GraphPad Prism version ‎‎8.0.0 used for statistical analysis, p-value <0.05 was considered significant.

Results

The study included 100 UC patients, mean age 34.2 ± 12.1 years, with slightly higher female subjects, 70% of them received IFX, and 30% received ADA, as shown in Table 2.

At baseline, 45% of patients had endoscopy subscore 1, after 6 months only 26 (57.8%) remained with the same score, also 18 of them (40%) reduced their score to zero, and only 1 patient had increased to 3. Initially, 55% of patients had endoscopy subscore 2 and 3, after 6 months only 3 of them remained with the same score, the rest of them reduce at least one level, as shown in Table 3.

Infliximab showed slightly better conversion from moderate-severe Mayo endoscopic sub-score to mucosal healing (MH), 97.3%, compared with adalimumab (83.3%), however, the difference did not appear to be significant between the two drugs, as shown in Table 4.

There was a significant decrease in the relapse rate (both drugs reduced the relapse rate to a similar degree), as shown in Table 5.
 

Palpitation was the most common side effect caused by IFX during the study, followed by blurred vision, while headache was the most common side effect affect patients received ADA, the rest of the side effects are illustrated in table 6.

Discussion

Anti-TNF therapy is one of the most effective agents for UC. They are used when the other treatment fails to improve the signs and symptoms of the disease, by blocking the activity of TNF, a substance that causes immune-system diseases and inflammation ^[15]. Limited observational studies are comparing the effectiveness of anti-TNF agents on IBD ^[16].

In the present study, the number of relapses decreased significantly for both IFX and ADA from baseline to 6 months of treatment, but there was no significant difference in the number of relapses treated with IFX or ADA after 6 months of therapy (median relapse was 0 for both IFX and ADA).

In Ananthakrishnan et al., they show moderate symptomatic improvement for IFX compared to ADA ^[17]. In Sandborn et al. study, both drugs were effective for the management of moderate-severe UC patients with no significant difference between the two drugs ^[18]. Other studies reported similar findings ^[9-12], most of these studies have been reported from Western countries. Few studies performed in Asia that compared both medications, in a recent study (2020) Han et al. examined 862 UC patients, 630 patients receiving IFX 232, and also ADA, There was no significant difference between the two drugs, despite both were clinically effective in treating UC ^[19]. Several meta-analyses indirectly compared these two anti-TNF, their result was in agreement with our findings ^[20-22].

In the present study, after 6 months of treatment, most UC patients achieved or maintained 95% mucosal healing. Infliximab showed slightly better conversion from moderate-severe Mayo endoscopic sub-score to mucosal healing (MH), 97.3%, compared with adalimumab (83.3%), however, the difference between the two drugs did not appear to be significant.

contrary to these studies, two meta-analyses showed that IFX is better than ADA, Danese et al. showed that IFX is better in inducing and maintaining remission in UC ^[23], Cholapranee et al. showed that IFX is better in inducing mucosal healing in UC ^[24]. These findings were somewhat similar to our findings.

There is a decrease in the number of relapses using biologic agents because these biologic agents ‎bind with high affinity to TNF-α (a key proinflammatory cytokine in UC patients), neutralizing its biologic activity. Thus, these two agents are effective for maintaining clinical remission ^[25].

Study limitation

The small sample size of this study is a potential bias, in addition, the short duration of prospective follow-up (i.e. six months) also limits the number of events observed by the researcher.

Conclusion

In this Real-World study, there was no significant difference between the most commonly used anti-TNF medications for the treatment of UC, namely infliximab and adalimumab, in their effect on decreasing relapse rate and mucosal healing after 6 months of follow-up.

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