Leflunomide-induced colitis with clinical, endoscopic & microscopic findings: a case report

Introduction

Background

Leflunomide is a medication used to treat rheumatoid arthritis (RA) among other types of inflammatory arthritis. While the gastrointestinal symptoms of this medication are common and approximately 17% of patients reported diarrhea in clinical trials, leflunomide-induced colitis remains a rare entity (1). Acute diarrhea must prompt an investigation for infectious or medication related etiologies while chronic diarrhea may encompass inflammatory causes or conditions such malabsorption, celiac disease, bile acid malabsorption, pancreatic exocrine insufficiency, or functional disorders. Meanwhile, drug induced colitis encompasses a variety of macroscopic and microscopic findings. Non-steroidal anti-inflammatory drug (NSAID) medications are the most common cause of drug induced colitis, including microscopic, inflammatory, and ischemic colitis phenotypes (2). In addition, many common medications including proton pump inhibitors, selective serotonin reuptake inhibitors, angiotensin-converting enzyme inhibitors, and beta-blockers, may have increased risk of microscopic colitis (2). Immune checkpoint inhibitors and a variety of chemotherapy agents have been associated with both colitis and diarrhea (2).

Rational and knowledge gap

The late onset of symptoms with a range of endoscopic and histologic findings makes leflunomide colitis a challenging diagnosis to make, especially when not all investigations are performed, such as in cases missing endoscopic findings. The exact mechanism of how leflunomide causes colitis also deems investigation. We present a case of an elderly woman with RA treated with leflunomide who was hospitalized for diarrhea.

Objective

This case includes a clinical presentation coupled with clear endoscopic and microscopic findings that helped make a diagnosis. Having endoscopic findings allows us to differentiate this drug induced colitis from microscopic colitis. Additionally, the histologic findings may point to a possible way the immunomodulatory effects of leflunomide leads to colitis. We hope to aid in the recognition of this drug-induced colitis to reduce hospitalization length and improve outcomes. We present this article in accordance with the CARE reporting checklist (available at https://amj.amegroups.com/article/view/10.21037/amj-23-37/rc).

Case presentation

A 79-year-old Caucasian woman with medical history of RA, chronic obstructive pulmonary disease (COPD) and gout presented to the hospital on April 4^th 2022, with 7 days of non-bloody, watery diarrhea. Two months ago, she started taking leflunomide 10 mg once daily for RA. She reported more than six bowel movements daily for multiple days. The diarrhea was not related to food. She reported nothing had made it better. She denied recent travel history, sick contacts, NSAID use and did not recall recent changes in diet. There was no known family history of inflammatory bowel disease, RA, or colorectal malignancy. Her other medications included albuterol and budesonide inhalers and denosumab injection every 6 months. The vitals on admission included blood pressure of 99/51 mmHg, heart rate of 85 beats per minute, respiratory rate of 15 breaths per minute, breathing 92% O₂ on room air. Her physical exam was benign. There was no prior colonoscopy on record. Computed tomography (CT) abdomen/pelvis demonstrated mild wall thickening of the distal colon from the splenic flexure to the rectum. The complete blood count, basic metabolic panel and hepatic function panel were within normal limits. Coronavirus disease 2019 (COVID-19) testing was negative. The patient had a lipase of 236 U/L, C-reactive protein of 40.7 mg/L, erythrocyte sedimentation rate of 58% with a negative C. difficile toxin. A fecal lactoferrin was positive. The patient was kept on intravenous fluid maintenance and started on ceftriaxone and metronidazole at admission. Leflunomide was held on the second day of hospitalization. Stool studies were eventually negative for Salmonella, Shigella, Campylobacter, E. coli, and ova and parasites. A colonoscopy was performed and found a diffuse area of congested, erythematous granular mucosa with some areas of vascular effacement in the rectum, sigmoid colon and transverse colon (Figure 1). Biopsies of those areas demonstrated increased lymphocytic infiltration of the lamina propria with a thickened epithelial layer and crypts with increased intraepithelial lymphocytes (Figure 2A). A trichrome stain showed a clearly thickened subepithelial layer of collagen measuring up to 25 µm in thickness at the ascending colon and rectum (Figure 2B). The patient continued to have 2–3 episodes of diarrhea daily upon hospital discharge. On an outpatient follow up, after more than 14 days since leflunomide cessation, there was resolution of diarrhea and the patient stated she felt better. She was prescribed hydroxychloroquine for RA by her outpatient rheumatologist.

Figure 1 Timeline of clinical course with endoscopic findings.

Figure 2 Histopathology slides from biopsies include hematoxylin and eosin stain indicating lymphocytic infiltration present in the lamina propria and crypts with increased intraepithelial lymphocytes (A) and trichrome stain representing thickened subepithelial layer of collagen in blue (B). Original magnification ×200.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). While verbal consent was obtained via phone by author, K.F.K., on Friday 4/22/2022 at 16:14, written informed consent for publication of this case report and accompanying images could be not obtained from the patient or the relatives after all possible attempts were made.

Discussion

Key findings

This case represents clear clinical, endoscopic and, histologic findings of leflunomide induced colitis. This patient’s symptoms improved with resolution of the drug but complete resolution took more than 14 days. Since she did not present until 2 months after leflunomide onset, this case exemplifies the importance of knowing that leflunomide induced colitis may present much later after medication onset, thus a thorough home medicine review must be completed. Other types of drugs induced colitis must be ruled out as well. Additionally, we present endoscopic findings of vascular effacement and inflammation alongside biopsy findings that are typical of microscopic colitis more so, but these findings are also present in leflunomide colitis. However, the clinical presentation with endoscopic findings coupled with biopsy results point towards this particular drug induced colitis.

Strengths and limitations

This is a report of a single patient, so it is predisposed to some limitations. While it may add to the description of leflunomide colitis, it may not be generalizable to a larger population. Moreover, our patient did not require additional therapies such as cholestyramine washout or steroids, so we cannot comment on the efficacy of these treatments. Leflunomide drug levels are not an available lab at our institution. It would have been helpful to have drug levels to correlate with patient’s diarrheal illness. On the other hand, this case report has multiple strengths including a single report where clinical, endoscopic and histologic findings of leflunomide colitis are presented. Very few reports in the literature have all of this in one place and allows for characterization of this condition and comparison to the other cases published.

Comparison to similar research

Generally, drug-induced colitis has been described in few case reports, and even fewer endoscopic descriptions exist. Paucity of this diagnosis may be attributed to its nebulous presentation and since leflunomide colitis is a rare occurrence, very few case reports include full endoscopic and biopsy findings. Currently, there remains no definitive diagnostic criteria for leflunomide colitis but case reports have demonstrated improvement of diarrhea within 14 to 20 days after drug cessation (3-5). Leflunomide colitis is known for its late onset after initiation of the medication. Colitis related symptom onset can range anywhere from 18 months to 2 years after starting the drug (5). Symptoms commonly improve to about 1–2 more formed bowel movements daily after 2 weeks (3). The timeline of symptom onset and resolution as mentioned above is very similar to our case. Furthermore, prior published cases with biopsy findings mention luminal subepithelial collagenous bands and colonic crypt formation including crypt abscesses (4-6). Others may demonstrate biopsy findings that resemble a combination of both lymphocytic and collagenous types of microscopic colitis (3). The latter is most similar to this case. There have been instances of microscopic colitis associated with leflunomide as well (6).

Explanation of findings

Leflunomide is known as a disease modifying antirheumatic drug (DMARD) which has anti-inflammatory and immunomodulatory properties, yet the exact pathogenesis of leflunomide colitis has yet to be elucidated (1,3). Leflunomide’s active metabolite, A771726, selectively inhibits the enzyme dihydroorotate dehydrogenase, a key enzyme in the synthesis of pyrimidines (1,3). The activated T-lymphocyte is a cell type that predominantly synthesizes pyrimidines, and its activity is sensitive to leflunomide (1). It is from this relationship that leflunomide causes alterations in the immune system (1). Perhaps this may play a role in the development of colitis. Common gastrointestinal adverse effects such as nausea, abdominal pain, diarrhea and unintentional weight loss can occur for up to 20% of patients with RA on this medication, many of which are apparent in short term studies, from 6 months to 2 years (3,4). The major distinction between microscopic colitis and, a drug induced colitis is that microscopic colitis by definition will present with normal mucosa on colonoscopy (3). The lymphocytic predominance in the biopsy findings may relate back to the possible effects leflunomide has on the activated T lymphocytes, begetting a pathophysiological mechanism to this condition. There remains a range of endoscopic findings associated with leflunomide colitis, including mucosal hyperemia, ulceration and vasculature effacement similar to this patient’s colonoscopy (4,5). The delayed symptom onset of leflunomide colitis may be explained by its extended half-life and A771726’s tendency to be recycled in the enterohepatic system. Additionally, the immune system may take time to have such a response that leads to colitis symptomology. The reasons why there is such a variable time frame between patients from the initiation of leflunomide and this drug induced colitis is not known. For severe colitis with more life-threatening symptoms, steroids, cholestyramine washout, and, biologics may be considered (3,4). Cholestyramine, a bile acid sequestrant, can bind A771726, prevent its recycling and facilitate its biliary excretion instead (3,7). The utility of a cholestyramine washout has been demonstrated in cases of severe sepsis with renal failure and refractory wound healing (7). If the patient presented more critically ill this could be considered an adjunct therapy.

Implications and actions needed

As this case exemplifies, the delay in presentation can lead to unnecessary testing and prolonged hospitalization when inflammatory, infectious, or other drug induced etiologies may be on the differential. Due to this patient’s clinical improvement with supportive care, drug cessation was enough. More vigilance is necessary when evaluating patient’s on leflunomide presenting with colitis. While it may not always be necessary to investigate with endoscopy and perform biopsies if a direct connection is made, it is important to rule out other etiologies of diarrhea and colitis. Expanding knowledge of the mechanism of this drug is important and obtaining a full medication list upon admission to the hospital or at an outpatient clinic must be done.

Conclusions

In summary, we report a case with full endoscopic and histologic findings for leflunomide induced colitis, which has been a rarity in the currently published work. This can be a difficult diagnosis to make as the onset of colitis can be 18 to 24 months from starting the medication. While there may be overlapping symptoms with other drug induced colitis, leflunomide colitis is strongly suggested when symptoms improve after stopping the medication within two weeks. The microscopic findings of lymphocytic infiltration in the biopsy may point towards the mechanism of leflunomide’s induction of colitis, as this medication affects activated T lymphocytes. To synthesize the clinical, endoscopic, and microscopic findings, characterizes this condition better and, ideally, may allow for better recognition and effective patient treatment.

Acknowledgments

A special thank to Mike Kelly MD, and Melissa Klimes, of Ascension Macomb Oakland Pathology and Lab Department for providing images of biopsies.

The abstract for this case report was accepted for a poster in the American College of Gastroenterology National Conference on October 2022 and only the abstract was published in the October supplement of the American Journal of Gastroenterology.

Funding: None.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://amj.amegroups.com/article/view/10.21037/amj-23-37/rc

Peer Review File: Available at https://amj.amegroups.com/article/view/10.21037/amj-23-37/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://amj.amegroups.com/article/view/10.21037/amj-23-37/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration (as revised in 2013). While verbal consent was obtained via phone by author, K.F.K., on Friday 4/22/2022 at 16:14, written informed consent for publication of this case report and accompanying images could be not obtained from the patient or the relatives after all possible attempts were made.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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