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 Table of Contents  
CASE REPORT
Year : 2022  |  Volume : 55  |  Issue : 6  |  Page : 229-233

Life-threatening bowel complications following anti-tumor necrosis factor antibody therapy for patients with inflammatory bowel disease: A report of three cases in Taiwan


1 Division of Colon and Rectal Surgery, Department of Surgery, Mackay Memorial Hospital; Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei; Department of Surgery, Mackay Medical College, New Taipei, Taiwan
2 Division of Colon and Rectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei; Department of Surgery, Mackay Medical College, New Taipei, Taiwan
3 Division of Colon and Rectal Surgery, Department of Surgery, Mackay Memorial Hospital, Taipei, Taiwan
4 Division of Gastroenterology, Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan

Date of Submission24-Mar-2022
Date of Decision09-Jun-2022
Date of Acceptance05-Jul-2022
Date of Web Publication22-Nov-2022

Correspondence Address:
Tzu-Chi Hsu
No. 92, Section 2, Chung-San North Road, Taipei
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/fjs.fjs_73_22

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  Abstract 


Incidence of inflammatory bowel disease (IBD) in Taiwan and the experience of the management of serious complications is much lower than in Western countries. The authors just want to alert readers that anti-tumor necrosis factor (TNF) is not without life-threatening complications. Three serious complications were described, including surgical management and outcomes following the application of anti-TNF monoclonal antibody therapy for IBD. Case 1 involved a 25-year-old man treated with five doses of adalimumab for moderate control of Crohn's disease (CD). Six months later, he experienced severe intestinal obstruction, which necessitated right hemicolectomy with ileocolic anastomosis. He recovered postsurgery. Case 2 involved a 54-year-old man treated with adalimumab for intractable ulcerative colitis. Ten days after the second dose of adalimumab, an emergent subtotal colectomy with ileostomy was performed for a transverse colon perforation with peritonitis. The patient underwent an ileal pouch operation a year later. Case 3 was based on a 16-year-old male patient treated with six doses of an infliximab biosimilar for CD; thereafter, an emergent subtotal colectomy with ileostomy and Hartmann's pouch was performed for peritonitis with the presence of a perforated gastrocolic fistula tract. He had no serious complications following an uneventful recovery period. Creating awareness of serious complications associated with biologic treatments and offering appropriate patient management, including surgical treatment, is beneficial to patients.

Keywords: Anti-TNF antibody, colectomy, inflammatory bowel disease, perforation


How to cite this article:
Hsu TC, Chen MJ, Tsai PL, Sun WC, Lin PW, Lin WC, Wang HY. Life-threatening bowel complications following anti-tumor necrosis factor antibody therapy for patients with inflammatory bowel disease: A report of three cases in Taiwan. Formos J Surg 2022;55:229-33

How to cite this URL:
Hsu TC, Chen MJ, Tsai PL, Sun WC, Lin PW, Lin WC, Wang HY. Life-threatening bowel complications following anti-tumor necrosis factor antibody therapy for patients with inflammatory bowel disease: A report of three cases in Taiwan. Formos J Surg [serial online] 2022 [cited 2022 Nov 26];55:229-33. Available from: https://www.e-fjs.org/text.asp?2022/55/6/229/361706




  Introduction Top


The incidence and prevalence of inflammatory bowel disease (IBD) are increasing worldwide.[1],[2],[3] This condition is usually treated conventionally; surgery is only performed if complications arise due to IBD. The incidence of IBD in Taiwan is much lower than that in Western countries;[4] hence, most of the physicians' experience for treating IBD is relatively limited. Recently, biologics have become one of the standard treatments for IBD;[5] however, the use of biologics is not without complications.[6],[7],[8] We report three cases of serious complications, two of Crohn's disease (CD), and one of ulcerative colitis (UC), while the patient was still in the earlier stage of anti-tumor necrosis factor (TNF) monoclonal antibody therapy. All patients signed an informed consent form before receiving the anti-TNF treatment.


  Case Report Top


Case 1

A 23-year-old man with a history of active psychosis, neurotic depression, schizophrenia, and secondary parkinsonism presented to our colorectal surgery clinic on December 16, 2007, with a chief complaint of perineal and scrotal induration being experienced for the past few months; an anal fistula was found postexamination. The patient visited a gastroenterologist on March 10, 2008, with a complaint of chronic left lower quadrant pain and diarrhea that lead to the prognosis of UC. The patient was emaciated. He underwent a colonoscopy (completed to the cecum) that revealed friable, edematous colonic mucosa with multiple pseudopolyps and ulcerations; terminal ileum intubation was difficult to perform because of fibrosis.

A nonspecific chronic inflammation was reported in the biopsy. Small bowel series were negative for typical findings of IBD. The patient was administered five doses of adalimumab (anti-TNF monoclonal antibody) from April 1, 2008, to May 29, 2008. He was treated with mesalazine, prednisolone, tinidazole, ferrous, and mosapride until admission on February 17, 2009. During hospitalization, the patient experienced worsening of abdominal pain with abdominal fullness and poor appetite for few days. A computed tomography (CT) scan on January 9, 2009, revealed dilatation of the colon without identifiable obstructive lesion. A plain abdominal CT scan on February 17, 2009, revealed the presence of few intestinal loops, representing a partial ileus. Six months later, severe intestinal obstruction was detected. The patient was suspected to have developed tuberculosis (TB) owing to its high prevalence in Taiwan. He underwent right colectomy with ileocolic anastomosis on February 20, 2009 [Figure 1]. Pathological findings were compatible with CD (noted on February 24, 2009). He recovered well after surgery. The patient last visited the clinic on November 18, 2021, and was followed up with mesalazine to maintain disease remission.
Figure 1: Gross specimen revealed severe stricture of the ileum with proximal dilatation of the bowel

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Case 2

A 54-year-old man with chronic UC (experienced for 20 years) was initially treated with mesalazine, fludiazepam, and prednisolone. A CT scan on November 31, 2015, revealed diffused colonic wall thickening, an irregular mucosal pattern, and peripheral fat stranding that was compatible with the clinical impression of UC. The patient was eventually treated with adalimumab for intractable UC in January 2017. Ten days after the second dose of adalimumab, he visited the emergency room (ER) with a chief complaint of abdominal pain and distension that had been occurring for a few days. Fever and leukocytosis were observed. A CT scan revealed massive intra-abdominal free air with ascites. On January 23, 2017, emergent laparotomy detected at least 3000 cc of purulent ascites and fibropurulent coating of the entire peritoneal surface, with edematous; thickened, friable small intestine; and a perforated hole in the transverse colon. Dilation was observed, particularly in the right colon. A subtotal colectomy with ileostomy was performed. Pathological examination revealed chronic ulcers with perforations [Figure 2]. The postoperative course was complicated by a wound infection. A year later, restorative proctocolectomy ileal pouch-anal anastomosis with ileostomy was performed in the distal colon and rectum for persistent colitis on February 20, 2018. The ileostomy was closed 3 months later on May 15, 2018. The patient was last examined on January 21, 2021, which revealed the improved function of the ileal pouch.
Figure 2: Gross specimen showed severe colitis with a perforation hole in the transverse colon

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Case 3

A 16-year-old male patient with chronic diarrhea (developed for the past 2 years) presented to the CRS clinic on April 28, 2014. Perianal swelling with purulent discharge was noted in the right anterolateral anal area. Antibiotics were administered to the patient; an incision was made and the anal fistulous abscess was drained. The patient underwent a colonoscopy on June 10, 2014, that revealed multiple pseudopolyps in the entire colon, suggestive of UC. Pathological examination revealed a chronic ulcer with granulation tissue. The patient was periodically treated by a few surgeons for the next few years, until he was visited by the senior author Tzu-Chi Hsu on September 27, 2018. CD was suspected postflexible sigmoidoscopy that revealed multiple pseudopolyps with friable edematous mucosa, longitudinal ulceration, and easy contact bleeding. The patient was treated with steroids and mesalazine for CD. A CT scan on October 6, 2018, revealed diffused wall thickening of the colon, adjacent fat stranding, and prominent mesenteric veins. An infliximab biosimilar (known as Remsima) was administered on December 20, 2018, because the patient showed a poor response to steroids and mesalazine. Following injection of biologics, the patient experienced a reduced intensity of abdominal pain, decreased number of bowel movements (from 8 to 10 BM/day–3 to 4 BM/day), and felt of more energetic. Post six doses of biologics administration, the patient visited another hospital on October 1, 2019, for sudden onset of high fever and severe abdominal pain; laboratory data revealed leukocytosis with a left shift of leukocytes. Abdominal CT revealed gas in the biliary tract and portal vein, with a suspected diagnosis of ischemic bowel or severe enteritis [Figure 3]. An emergent laparotomy revealed severe adhesions inside the abdominal cavity, especially in the transverse colon on October 1, 2019. The entire colon was edematous and congested with fat wrap. A gastrocolic fistula was also observed. Pathological examination of the serosal surface revealed hemorrhagic and inflammatory areas with perforated holes. Subtotal colectomy with ileostomy and Hartmann's pouch was performed. The postoperative course was uneventful, and the patient's body weight gradually increased. The patient's body mass index was noted to be 20 in the last examination (January 6, 2022). He received continuous injections of biologics; further evidence of serious complications was not attained.
Figure 3: Abdominal CT revealed gas in the biliary tract and portal vein, with suspicious diagnosis of possible ischemic bowel or severe enteritis. CT: Computed tomography

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  Discussion Top


CD and UC are immune-mediated disorders characterized by alternating periods of active disease and remission, which can affect segments of the gastrointestinal tract.[1],[2],[3] Both CD and UC cause considerable morbidity; mortality in CD is higher than expected in some population-based studies, including one conducted in Taiwan.[4] The goals of CD and UC therapy include inducing and maintaining remission, reducing the risk of complications, and improving quality of life. The incidence and prevalence of CD have been steadily rising in Taiwan and other Asian countries, although the rates are still lower than that of Western countries.[5]

The goal of this treatment was to achieve and sustain clinical remission, confirmed by the disappearance of clinical symptoms and endoscopic mucosal healing.

The chimeric monoclonal antibody TNF-α, infliximab, has been used as a treatment for CD since 1997,[5] and is now used for induction and maintenance therapy in both CD and UC. Two other anti-TNF agents, adalimumab and certolizumab pegol, have also proven efficacious in the treatment of CD.[6] Previous studies reported that anti-TNF antibody (infliximab and adalimumab) treatment for IBD could be promising for patients with CD; in addition, few patients could also have their operation delayed for a certain period of time. However, infection and neoplasm might increase leading to the prognosis of TB even in areas of low TB prevalence.[7],[8] Immunosuppressive medications, particularly when used in combination, and older age are associated with an increased risk of opportunistic infections. The absolute risk of opportunistic infections in patients with IBD remains elusive, as does any potential benefit of any preventive strategy. The incidence of TB is <10 cases/100,000 in North American and Western Europe;[7] however, the incidence of TB is 20+ cases/100,000 in Japan and 70+ cases/100,000 in Taiwan.[9] Active TB may develop soon after the initiation of infliximab treatment. Before prescribing a drug, physicians should screen patients for latent TB infection or disease. The patient in case 1 was also suspected to have developed TB before surgery.

A recent study from Mount-Sinai Medical Center by Toy et al. reported a newly described complication in a patient with complete bowel obstruction following an initial response to infliximab response therapy for CD in the journal of gastroenterology.[10] Case 1 in our study is similar to the description of cases reported by Toy et al.[10]

Burmester reported the long-term safety of adalimumab in 29,967 adult patients, representing 6916 patient-years of exposure. The most frequently reported serious adverse effects of interest were infections (with the highest incidences in CD), rheumatoid arthritis, noninfectious uveitis, and UC; fewer incidences of serious infections in plaque psoriasis and hidradenitis suppurativa were observed. The observed number of deaths was less than expected in an age- and sex-adjusted population of most adalimumab-treated patients (including Ps). The lack of real-life data and limited long-term data (>5 years) for most patients is a limitation of this analysis.[11]

Common side effects of adalimumab affecting the gastrointestinal system include diarrhea, nausea, abdominal pain, vomiting, stomatitis, and mouth ulceration (1%–10%), whereas cholecystitis, cholelithiasis, gastroenteritis, gastrointestinal hemorrhage, gastritis, dyspepsia, gastrointestinal disorder, gastrointestinal hemorrhage, rectal hemorrhage, and abdominal bloating are the uncommon side effects (0.1%–1%); in addition, esophagitis, intestinal stenosis, colitis, and enteritis are the rare side effects (<0.1%). The frequencies not reported included diverticulitis and large bowel perforations, including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis and pancreatitis.

Závada et al. reported the risk of gastrointestinal perforation (GIP) in patients with rheumatoid arthritis who were treated with anti-TNF therapy; these data were acquired from the British Society for Rheumatology Biologics Register in Rheumatoid Arthritis. There were 42 GIPs: 5 in the nonbiological disease-modifying antirheumatic drug cohort and 37 in the anti-TNF cohort. After adjustment, treatment with TNF antagonists was associated with a hazard ratio (HR) of 1.6 for all gastrointestinal performations, 2.7 for lower GIP, and 0.9 for upper GIPs. The current use of steroids was the single most important predictor of GIPs with an adjusted HR of 2.9; however, this risk was confined to lower GIPs. In univariate analyses, higher age, use of steroids at baseline, higher health assessment questionnaire scores, the presence of renal disease, history of hypertension, and smoking were significantly associated with the risk of lower GIP, while the use of nonselective nonsteroidal anti-inflammatory drugs at baseline and low weight were significantly associated with the risk of upper GIP.[12] Large intestine perforation was found majorly among the female population administered with adalimumab, particularly for people over 60 years of age who have been taking the drug for 1–6 months along with methotrexate medication and have high blood pressure.

Although our experience of using biologics is much lower than that of Western countries, we observed three cases of serious life-threatening complications, which prompted us to ensure that all patients undergoing treatment with biologics should be carefully monitored and followed up. Early detection with appropriate management of complications might be able to save the lives of few patients at the least.[12]


  Conclusions Top


Biologics are not conventional drugs. Although biologic therapy might offer the most effective means to treat a variety of medical illnesses and conditions, it may also cause serious complications. Awareness of the serious complications associated with biologics and offering appropriate patient management, including surgical treatment, are best for the patient's interest.

Ethical approval

This study was approved by the Institutional Review Board of Mackay Memorial Hospital (approval number: 19MMHIS195e).

Declaration of patient consent

The authors certify that they have obtained appropriate patient consent form. In the form, the patients have given their consent for the images and other clinical information to be reported in the journal. The patients understand that their name and initial will not be published and due efforts will be made to conceal the identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Molodecky NA, Soon IS, Rabi DM, Ghali WA, Ferris M, Chernoff G, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology 2012;142:46-54.e42.  Back to cited text no. 1
    
2.
Cosnes J, Gower-Rousseau C, Seksik P, Cortot A. Epidemiology and natural history of inflammatory bowel diseases. Gastroenterology 2011;140:1785-94.  Back to cited text no. 2
    
3.
Feuerstein JD, Cheifetz AS. Ulcerative colitis: Epidemiology, diagnosis, and management. Mayo Clin Proc 2014;89:1553-63.  Back to cited text no. 3
    
4.
Wei SC, Lin MH, Tung CC, Weng MT, Kuo JS, Shieh MJ, et al. A nationwide population-based study of the inflammatory bowel diseases between 1998 and 2008 in Taiwan. BMC Gastroenterol 2013;13:166.  Back to cited text no. 4
    
5.
Mouser JF, Hyams JS. Infliximab: A novel chimeric monoclonal antibody for the treatment of Crohn's disease. Clin Ther 1999;21:932-42.  Back to cited text no. 5
    
6.
Peyrin-Biroulet L, Deltenre P, de Suray N, Branche J, Sandborn WJ, Colombel JF. Efficacy and safety of tumor necrosis factor antagonists in Crohn's disease: Meta-analysis of placebo-controlled trials. Clin Gastroenterol Hepatol 2008;6:644-53.  Back to cited text no. 6
    
7.
Keane J, Gershon S, Wise RP, Mirabile-Levens E, Kasznica J, Schwieterman WD, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha-neutralizing agent. N Engl J Med 2001;345:1098-104.  Back to cited text no. 7
    
8.
Toruner M, Loftus EV Jr., Harmsen WS, Zinsmeister AR, Orenstein R, Sandborn WJ, et al. Risk factors for opportunistic infections in patients with inflammatory bowel disease. Gastroenterology 2008;134:929-36.  Back to cited text no. 8
    
9.
Tuberculosis Diagnosis and Treatment Guidelines (version 5.1). Centers for Disease Control, R.O.C. (Taiwan). Available from: https://www.cdc.gov.tw/En/InfectionReport/Info/9YUAXbFsmorP5T10V8qvMA?infoId=2yN3cpsgj5HkfGwHioZKwA. [Last updated on 2015 Dec 17; last accessed on 2017 Mar 03].  Back to cited text no. 9
    
10.
Toy LS, Scherl EJ, Kornbluth AA, Marion JF, Greenstein AJ, Agus SG, et al. Complete bowel obstruction following initial response to infliximab therapy for Crohn's disease: A series of a newly described complication. Gastroenterology 2000;118:A569.  Back to cited text no. 10
    
11.
Burmester GR, Gordon KB, Rosenbaum JT, Arikan D, Lau WL, Li P, et al. Long-term safety of adalimumab in 29,967 adult patients from global clinical trials across multiple indications: An updated analysis. Adv Ther 2020;37:364-80.  Back to cited text no. 11
    
12.
Závada J, Lunt M, Davies R, Low AS, Mercer LK, Galloway JB, et al. The risk of gastrointestinal perforations in patients with rheumatoid arthritis treated with anti-TNF therapy: Results from the BSRBR-RA. Ann Rheum Dis 2014;73:252-5.  Back to cited text no. 12
    


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