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 Table of Contents  
CASE REPORT
Year : 2021  |  Volume : 10  |  Issue : 3  |  Page : 212-214

Infliximab (an antitumor necrosis factor) induced lupus in a patient with inflammatory bowel disease


Department of Internal Medicine, King Fahad Specialized Hospital, Buraydah, Saudi Arabia

Date of Submission05-Aug-2021
Date of Acceptance05-Nov-2021
Date of Web Publication6-Dec-2021

Correspondence Address:
Khaled M Alsubiaee
Department of Internal Medicine, King Fahad Specialized Hospital, Buraydah
Saudi Arabia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjhs.sjhs_110_21

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  Abstract 


Infliximab is a monoclonal antibody that works by inhibiting the proinflammatory cytokine and tumor necrosis factor-alpha. Systemic lupus erythematosus is an autoimmune disease that affects multiple organs, and its pathogenesis involves abnormal immune complexes, environment factors, and genetics. Several reports have documented a controversy regarding infliximab-induced lupus disease. This paper reports on infliximab-induced lupus in an 18-year-old Saudi female having short stature, hypogonadism, and Crohn's disease with ileocolonic fistula. The patient developed reactive arthritis, and serology showed positive anti-double strand DNA and antihistone antibodies after infliximab administration, suggesting drug-induced lupus. More cohort studies are recommended to monitor the presentation and reversibility of infliximab-induced lupus disease.

Keywords: Antitumor necrosis factor agent, drug-related side effects, and adverse reactions, inflammatory bowel disease, lupus erythematosus, lupus erythematosus, systemic/chemically induced, systemic/drug therapy


How to cite this article:
Alsubiaee KM, Alharbi NT, Almutairi NH. Infliximab (an antitumor necrosis factor) induced lupus in a patient with inflammatory bowel disease. Saudi J Health Sci 2021;10:212-4

How to cite this URL:
Alsubiaee KM, Alharbi NT, Almutairi NH. Infliximab (an antitumor necrosis factor) induced lupus in a patient with inflammatory bowel disease. Saudi J Health Sci [serial online] 2021 [cited 2022 Jan 26];10:212-4. Available from: https://www.saudijhealthsci.org/text.asp?2021/10/3/212/331768




  Introduction Top


Infliximab is a monoclonal antibody that works by inhibiting the proinflammatory cytokine and tumor necrosis factor-alpha (TNF-α).[1] The TNF-α gene is located on chromosome 6 and initiates neutrophil activation, adhesion molecules, T-cell activation, and antibody production.[2] Ethnicity is a risk factor associated with TNF-α polymorphism; studies have revealed an association between systemic lupus erythematosus (SLE), and 308G/A higher than 238G/A polymorphism.[3]

SLE is an autoimmune disease with multifactorial pathogenesis involves abnormal immune complexes, environmental factors, and genetics. Apoptosis dysfunction with a decrease in the number of dendritic cells and diminished capability of macrophages to engulf apoptotic cells induces immunological changes in SLE.[4] The anti-TNF-α antibody, infliximab, is not related to SLE activity but elevates the levels of the autoantibodies, anti-double strand DNA (dsDNA), and cardiolipin.[5] Some of these cases may develop rare immunological features resemble SLE manifestations (skin rash, polysynovitis, and myalgias) interpreted as either anti-TNF-induced lupus or not related which requires supportive laboratory confirmation.[6],[7]

This paper reports on a young female having Crohn's disease (CD) with ileocolonic fistula that developed laboratory and clinical SLE manifestations postinfliximab administration.


  Case Report Top


In 2017, an 18-year-old Saudi female with short stature and hypogonadism (low follicle-stimulating hormone, luteinizing hormone, and testosterone levels) was admitted to King Fahad Specialized Hospital on suspicion of having CD complicated with ileocolonic fistula. Computed tomography (CT) of the abdomen with contrast showed thickened terminal ilium and skin involvement of the colon associated with pericolonic abscess [Figure 1]. The radiologist recommended magnetic resonance cholangiopancreatography (MRCP) to rule out primary sclerosing cholangitis. MRCP showed active CD involving the colon with perianal abscess. The patient had left knee swelling, and aspiration showed a high white blood cell count (3000 cells), mainly polymorph with negative fluid culture. The patient was diagnosed with reactive arthritis, and treatment was commenced with 5 mg/kg infliximab (100 mg). One week later, the patient still had left knee swelling, and CD symptoms improved with a weight gain of 5 kg after the administration of infliximab and 25 mg azathioprine once daily. Laboratory investigations showed high ESR, negative anti-dsDNA, anti-Smith, and anti-SSA antibodies, and positive ANA, with normal C3 and C4 levels.
Figure 1: Computed tomography with contrast, 2017. Active Crohn's disease with terminal ileum thickening and skip involvement of the colon associated with pericolonic abscess. Multiple abdominal lymph nodes. A small abscess measuring 2 cm × 1 cm at transverse colon and adjacent phlegmonous change along with inflammation

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The dose of infliximab was increased to 200 mg, and that of azathioprine was increased to 50 mg once daily with calcium and vitamin D supplements, after the patient presented with frequent diarrhea associated with colicky abdominal pain and extraintestinal manifestations (inflamed right eye, sacroiliitis, and knee arthritis). Repeated abdominal CT with contrast showed an improvement in mucosal thickening with complete resolution of the left mesenteric pathological lymph nodes [Figure 2]. The dose of infliximab was then intensified to 300 mg every 6 weeks and that of azathioprine was increased to 75 mg once daily following colonoscopy results of multiple ulcers along with transverse colon strictures. The infliximab dose was then increased to 400 mg to control the active symptoms of the patient. Later, infliximab failure was confirmed based on colonoscopy results, which showed evidence of a fistula opening in the cecum.
Figure 2: Computed tomography with contrast, 2020. Significant improvement in previously noted mucosal thickening and enhancement of small and large bowel. Reduced mucosal thickening and complete resolution of left mesenteric pathological lymph nodes. No newly developed active lesion, abscess, or fistula

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Furthermore, magnetic resonance imaging of the pelvis revealed an inactive perianal abscess. Laboratory investigations showed positive ANA, anti-dsDNA, and anti-histone antibody, and negative anti-Smith antibody, high C3 levels, and normal C4 levels [Table 1]. Infliximab-induced lupus was suspected.
Table 1: Laboratory results before and after infliximab administration

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Subsequently, administration of infliximab was switched to that of 90 mg ustekinumab every 8 weeks and 20 mg prednisolone once daily for a month and then tapered. The symptoms of the patient improved after the third dose of ustekinumab. Azathioprine was discontinued, and the patient was administered 10 mg methotrexate weekly with a tapering prednisolone dose. Recently, the patient improved clinically in terms of signs and symptoms of CD.


  Discussion Top


There are controversies regarding the association between infliximab and complications that induce lupus-like features. In this case study, the patient was monitored for 5 years from the initiation of infliximab therapy for refractory CD. The patient developed clinical and laboratory manifestations of anti-TNF-induced lupus. Clinically, the patient had myalgias (sacroiliitis and knee arthritis) after administration of infliximab. In terms of laboratory findings, posttreatment with infliximab, the patient developed positive anti-dsDNA and positive anti-histone antibody which is more specific to drug-induced lupus.

A retrospective study conducted in Korea reviewing patients with inflammatory bowel disease (IBD) receiving anti-TNF using the American College of Rheumatology criteria found that about 1% diagnosed, and 3.7% suspected with anti-TNF-induced lupus, respectively. A precaution ought to be undertaken in patients with IBD who develop a cutaneous rash and arthralgia during infliximab treatment.[8]

Some studies have shown no statistical significance for infliximab-induced lupus. A pilot study compared SLE with nonSLE patients for infliximab-related symptoms and found that infliximab improves manifestations of SLE, with an acceptable safety profile in nonSLE patients.[9] Moreover, a cohort study that assessed the long-term complications of infliximab concluded that there were no clinical symptoms that indicated infliximab-induced lupus.[10] Recently, some studies have suggested that infliximab-induces lupus, which includes cutaneous and joint arthritis,[11] is comparable to the clinical manifestations observed in this case study. This case report finding adds to the available literature that a correlation between infliximab and lupus as an adverse effect is evident with both clinical and laboratory outcomes. Therefore, in cases of IBD during treatment with infliximab; a suspicion of anti-TNF-induced lupus should be considered. The benefits outweigh the risks is accounted in the decision of infliximab withdrawal, especially in the presence of other alternative management options. The mechanism of infliximab-induced lupus is still unknown, a future experimental research to investigate the exact mechanism of lupus induction is recommended.

As there is no strong consensus on the diagnostic criteria for drug-induced lupus, more cohort studies are recommended to monitor the presentation and reversibility of infliximab-induced lupus disease and determine more precise diagnostic criteria.

Acknowledgments

We would like to acknowledge and thank Dr. Mazen Alsagri, a consultant radiologist, for his cooperation.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Lichtenstein L, Ron Y, Kivity S, Ben-Horin S, Israeli E, Fraser GM, et al. Infliximab-related infusion reactions: Systematic review. J Crohns Colitis 2015;9:806-15.  Back to cited text no. 1
    
2.
Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol 2016;12:49-62.  Back to cited text no. 2
    
3.
Chen L, Huang Z, Liao Y, Yang B, Zhang J. Association between tumor necrosis factor polymorphisms and rheumatoid arthritis as well as systemic lupus erythematosus: A meta-analysis. Braz J Med Biol Res 2019;52:e7927.  Back to cited text no. 3
    
4.
Crispín JC, Liossis SN, Kis-Toth K, Lieberman LA, Kyttaris VC, Juang YT, et al. Pathogenesis of human systemic lupus erythematosus: Recent advances. Trends Mol Med 2010;16:47-57.  Back to cited text no. 4
    
5.
Aringer M, Graninger WB, Steiner G, Smolen JS. Safety and efficacy of tumor necrosis factor alpha blockade in systemic lupus erythematosus: An open-label study. Arthritis Rheum 2004;50:3161-9.  Back to cited text no. 5
    
6.
Almoallim H, Al-Ghamdi Y, Almaghrabi H, Alyasi O. Anti-tumor necrosis factor-α induced systemic lupus erythematosus. Open Rheumatol J 2012;6:315-9.  Back to cited text no. 6
    
7.
Costa MF, Said NR, Zimmermann B. Drug-induced lupus due to anti-tumor necrosis factor alpha agents. Semin Arthritis Rheum 2008;37:381-7.  Back to cited text no. 7
    
8.
Choi SJ, Ahn SM, Oh JS, Hong S, Lee CK, Yoo B, et al. Anti-tumor necrosis factor-induced lupus in patients with inflammatory bowel disease: A hospital-based cohort study from Korea. Therap Adv Gastroenterol 2021;14:1756284821997794.  Back to cited text no. 8
    
9.
Uppal SS, Hayat SJ, Raghupathy R. Efficacy and safety of infliximab in active SLE: A pilot study. Lupus 2009;18:690-7.  Back to cited text no. 9
    
10.
Aringer M, Houssiau F, Gordon C, Graninger WB, Voll RE, Rath E, et al. Adverse events and efficacy of TNF-alpha blockade with infliximab in patients with systemic lupus erythematosus: Long-term follow-up of 13 patients. Rheumatology (Oxford) 2009;48:1451-4.  Back to cited text no. 10
    
11.
Mudduluru BM, Shah S, Shamah S, Swaminath A. TNF-alpha antagonist induced lupus on three different agents. Postgrad Med 2017;129:304-6.  Back to cited text no. 11
    


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