Review Article

Drug-induced Small Bowel Injury

Shadi Hamdeh; Dejan Micic; Stephen Hanauer

Disclosures

Aliment Pharmacol Ther. 2021;54(44512):1370-1388. 

In This Article

Histology

Histological patterns of injury may include mucosal erosions and ulcerations, focal active enteritis, villous atrophy mimicking celiac disease, epithelial apoptosis or necrotising enteritis/enterocolitis. More than one histological pattern can be seen with a single medication (eg NSAIDs, potassium chloride, MMF).[10] It is extremely important for physicians to be aware of the early clinical and endoscopic manifestations of DIE as early recognition can lead to prompt discontinuation of the offending therapy and therefore a reduction in the risk of future complications.

Drug Classes Linked to SB Injury

Medications associated with drug-induced small bowel injury are summarized in Table 1.

NSAIDs. Non-steroidal anti-inflammatory drugs are amongst the most commonly used and prescribed medications with more than 30 million people worldwide using NSAIDs on a daily basis, and accounting for 60% of over-the-counter analgesics used in the United States.[11]

Epidemiology: The incidence of overall GI events (both complicated and uncomplicated) was studied in the EVIDENCE study, the largest European prospective study to date.[12] The incidence rate of adverse GI events was 19 (17.3–20.8) per 100 person-years. The incidence was the highest in Sweden, the Netherlands and Spain, with events localising to the upper GI tract more commonly than the lower GI tract (12% vs 1%).[12] NSAID-induced enteropathy has been seemingly under-reported due to a limited ability to assess the SB mucosa.[13] With the introduction of newer modalities allowing for direct visualisation of the SB (ie video capsule endoscopy) and direct evaluation of the SB to allow for biopsy sampling (ie balloon enteroscopy), NSAID-induced enteropathy is becoming increasingly recognised.[14] Numerous studies have demonstrated a risk of SB injury in up to 75% in healthy volunteers with both short-term (2 weeks) courses of oral NSAIDs[15] and long-term use (>3 months) when compared to placebo (71% vs 10%, P < 0.001).[16] This suggests an increased risk of bowel injury amongst both short and long term users. Moreover, short-term use resulted in an increased intestinal permeability within 12 hours of NSAID use and development of bowel injury within 10 days.[15] However, a linear cumulative incidence was observed over 6-month period suggestive of higher incidence among long-term users.[17] This effect was also dose dependent but the lowest dose associated with GI toxicity is not known.[17] In an autopsy report of 713 patients, 8.4% of individuals using NSAIDs in the 6-month period before death were found to have non-specific SB ulcerations as compared to 0.6% of individuals not using NSAIDs, although this rate was less than that of ulcers found in the stomach or duodenum in NSAID users (21.7%).[18]

Pathophysiology: Although significant advances have been made involving the pathophysiology of NSAID-induced SB injury, gaps remain in our understanding of the development and evolution of DIE. A variety of mechanisms have been suggested to include: (1) COX-inhibition that results in decreased prostaglandin (PG) production and therefore a reduction in SB mucosal integrity; (2) alterations in bile acid production and signalling; (3) modulation of enteric bacteria; (4) enterocyte mitochondrial dysfunction and (5) alterations in the innate immune system to include tumour necrosis factor (TNF) activation.[19,20]

Risk Factors: Risk factors for NSAID-induced enteropathy are not well-established, especially when trying to differentiate SB injury from upper GI adverse effects. Age over 65 years, simultaneous use of anti-platelet agents, and genetic polymorphisms are common risk factors for both NSAID-induced upper GI and SB injury.[13] However, in contrast with the protection afforded by proton pump inhibitors against upper gastroduodenal injury with NSAID use, proton-pump inhibitors (PPI) were found to increase the incidence of SB injury, potentially due to alterations in the small intestinal microbiome.[13,19,21,22] Wallace et al conducted a RCT in a rat model that demonstrated exacerbation of NSAID-related SB damage with PPI use secondary to changes in the microbiota, specifically due to a reduction in jejunal Actinobacteria and Bifidobacteria spp.[23] Multiple clinical studies have supported the role of acid suppression resulting in SB damage associated with NSAID use. A randomised, placebo-controlled trial by Washio et al showed a higher incidence of SB injury when celecoxib was administered concomitantly with a PPI as compared to placebo (44% vs 16.7%, RR 2.67, 95% CI 1.08–6.58).[21] In another prospective, multicenter capsule endoscopy registry, PPI use was associated with an increased risk for SB mucosal breaks (OR 2.04, 95% CI 1.05–3.97).[22]

Other risk factors identified in a case-control study by Ishihara et al[24] included the presence of comorbidities (AOR 2.97, 95% CI 1.05–8.41) and the use specifically of oxicams or diclofenac (AOR 7.05, 95% CI 2.04–24.40). Concomitant use of PPI, indication or duration of NSAID use and CYP2C9*2, *3 or *13 polymorphisms were not associated with an increased risk in this study.[24] However, meloxicam use and CYP2C9*3 were associated with an increased risk of diaphragm disease. A subsequent study found that the CYP2C19 polymorphism was a risk factor for SB damage in subjects using celecoxib with rabeprazole but not celecoxib alone.[25] Lastly, CYP4F11 and CYP2D6 were found to increase risk of ASA-induced SB bleeding.[26]

Clinical Presentation: Symptoms of NSAID-induced enteropathy are non-specific and can range from asymptomatic to serious complications including SB bleeding as a result of ulcerations, perforation and obstruction. Patients may present with abdominal pain, nausea, vomiting, diarrhoea, distension or dyspepsia. NSAID-induced bleeding may present with either melena, hematochezia or clinical symptoms associated with iron deficiency anaemia. Iron deficiency anaemia may occur due to either occult or overt blood loss associated with NSAID related SB lesions (erosions or ulcers), or due to poor intestinal iron absorption as a result of NSAID interference with enteric iron absorption.[27] In fact, NSAID-induced enteropathy was the most common cause of obscure GI bleeding as shown in a prospective study by Kameda et al[28] Protein losing enteropathy as a result of SB ulcers resulting in hypoalbuminemia is a rare presentation of SB injury.[13,19]

Direct visualisation of the SB injury via capsule endoscopy or balloon enteroscopy is considered the gold standard of diagnosis of NSAID-induced enteropathy. However, due to its cost or limited availability, the need for non-invasive markers of SB injury has increased. Chromium-51-labeled ethylenediaminetetraacetic acid urinary excretion and faecal indium-111-labeled neutrophils have been studied but need more comparative studies.[19] While faecal calprotectin (FC) has been found to be elevated in NSAID-induced enteropathy, studies have failed to show a correlation between FC and abnormal capsule endoscopy findings; therefore, it cannot be currently used as a screening tool for SB injury or to monitor for disease improvement after medication discontinuation.[19]

Endoscopy: In a quantitative analysis of NSAID-induced enteropathy in healthy volunteers after NSAID administration for 14 days, Maiden et al[15] categorised capsule endoscopy findings into: mucosal breaks (mucosal erosions or ulcers), denuded mucosa (loss of villi), reddened folds, petechiae or red spots and presence of blood without a visualised source. Abnormalities were demonstrated in 68% of the video capsule studies with mucosal breaks being the most common pattern of drug injury accounting for 40% of the abnormal video capsules.[15,29]

Patterns of drug-induced injury to the small intestine can differ based on the location within the small intestine. Fujimori et al[30] reported denuded lesions more commonly in the proximal SB, ulcers in the distal SB and erosions scattered throughout.[30] More mucosal breaks were seen in the jejunum than in the ileum in patients with long-term NSAID use[31] suggesting a possible correlation with duration of NSAID use and the distribution of injury. Mucosal and submucosal fibrosis secondary to chronic NSAID use leads to strictures resulting in diaphragm disease, which can be pathognomonic for NSAID-induced enteropathy.[13] In the aforementioned study by Maiden et al,[15] 2% of chronic NSAID users developed diaphragm disease on capsule endoscopy. Although it can occur throughout the SB, the ileum was the most common location in 67% of the cases.[32] Long-term use remains one of the major risk factors to develop diaphragm disease, while the CYP2C9*3 polymorphism was also found to be associated with an increased risk in the study conducted by Ishihara et al[24] Bowel perforation is uncommon.

Aspirin: Growing evidence indicates that aspirin, even at low doses, can be harmful to the SB mucosa. Endo et al in a retrospective study demonstrated a significant increase in SB injury among healthy volunteers taking low dose enteric-coated aspirin (ASA) for 14 days as compared to placebo (80% vs 20%, P = 0.023).[33] Low dose enteric-coated ASA resulted in mucosal breaks in 10/11 patients in another prospective study.[34] Several other studies[35,36] reported similar findings of increased SB mucosal breaks with the use of low dose ASA for at least 2 weeks and the reported rates of SB injury were as high as those with non-selective NSAIDs.[19]

Selective COX-2 Inhibitors: While the use of selective COX-2 inhibitors resulted in less duodenal ulcers[37–39] or lower GI tract ulcers[39,40] in several large-scale, RCTs, long-term use for more than 3 months showed no difference when compared to conventional NSAIDs with respect to SB injury.[41,42] However, several other large-scale RCTs revealed a decreased risk with COX-2 inhibitor use when compared to conventional NSAIDs. In a large RCT conducted at 301 centres in 22 countries, Bombardier et al demonstrated a decreased risk of complicated bleeding beyond the duodenum with the use of rofecoxib vs naproxen with a relative risk (RR) of 0.5 (0.2–0.9, P = 0.03).[37] Similarly the risk of duodenal ulcer was lower with the use of celecoxib compared to diclofenac (5% vs 11%, P < 0.009) in another large RCT involving 132 centres and 655 adult patients.[38] Chan et al conducted another large double-blind RCT that included 196 centres in 32 countries and demonstrated more adverse events throughout the GI tract with the use of diclofenac plus omeprazole vs celecoxib (HR 4.3, 95% confidence interval [CI]: 2.6–7).[39] However, no statistically significant decrease was seen in lower GI events with the long-term use of COX-2 inhibitor (etoricoxib) compared to traditional NSAID (diclofenac) in another large RCT involving 34 701 patients,[41] or in a cross-sectional study in rheumatoid arthritis (RA) patients.[43]

Adverse upper GI events that include duodenal injury were observed with the use of every type of NSAID, including COX-2 inhibitors, in a population-based, case-control analysis of the UK QRESEARCH database.[44] The unadjusted OR showed an increased risk among all NSAID users whether the medication was prescribed within 90 days, more than 90 days or even prescribed more than three years prior to the GI event.[44] Once adjustment for confounding factors was added to the analysis, naproxen was found to be associated with the highest risk (OR 2.12, 95% CI 1.73–2.58), followed by diclofenac (OR 1.96, 95% CI 1.78–2.15), other COX-2 inhibitors (OR 1.75, 95% CI 1.41–2.15), other conventional NSAIDs (OR 1.67, 95% CI 1.43–1.94), aspirin (OR 1.60, 95% CI 1.49–1.72), rofecoxib (OR 1.56, 95% CI 1.30–1.87) and lastly ibuprofen (OR 1.42, 95% CI 1.27–1.59).[44] To summarise, COX-2 inhibitor use may be associated with a decreased risk of SB injury if used for short term but this effect might decrease with the long-term use for more than 3 months.

Approach to Treatment and Prevention: While medication discontinuation is the mainstay treatment for NSAID-induced enteropathy, their cessation may not be feasible and can result in worse patient clinical outcomes, to include increased mortality in cardiovascular patients after discontinuation of ASA.[45] Therefore, identifying prophylactic therapies or targeted drugs that allow for mucosal healing in the SB while on NSAIDs is essential. There is yet no well-established protocol for prophylaxis of SB injury. As discussed earlier, PPIs, while useful at preventing gastroduodenal lesions from NSAIDs are ineffective in prophylaxis and in fact may be associated with an increased risk of adverse outcomes related to distal enteropathies.[21,22] Medications, most commonly PG analogues, targeting mucosal protective properties have been found to be effective in both prevention and treatment of NSAID-induced enteropathy.[19] Misoprostol, a synthetic PG analogue that is only available in North America and Europe was proven effective in prevention[46] and treatment[47] of SB mucosal injury related to NSAIDs. In a recent RCT, Kyaw et al found misoprostol superior to placebo in improving SB ulcers among ASA users (28.6% vs 9.5%, P = 0.026).[48] Therefore, misoprostol can be considered as a first-line treatment option in patients with SB injury due to NSAIDs or ASA, bearing in mind the abortigenic potential.[7] Similar to misoprostol, other muco-protective drugs have also demonstrated efficacy in prevention and treatment of NSAID-induced enteropathy. However, these medications are only available in Asia at the current time. Rebamipide[49,50] and irsogladine[50,51] have demonstrated superiority to placebo in both prevention and treatment of NSAID-induced enteropathy, whereas polaprezinc showed efficacy only in ulcer healing[52] and teprenone (geranylgeranylacetone)[53] and ecabet sodium only in prevention.[54] Nevertheless, none of these medications have been proven to be effective in SB bleeding ulcers outside of misoprostol.[19,48]

The variety of mechanisms of DIE related to NSAID use has recently shed light on the importance of the SB microbiome in the development of DIE. Antibiotic use has been shown to reduce the severity and the inflammatory burden related to NSAID use in the SB in multiple animal and human studies.[55,56] Metronidazole reduced SB inflammation and blood loss in NSAID users in one study,[55] while rifaximin was found to decrease the number and severity of NSAID-induced SB lesions on capsule endoscopy in another RCT.[56] Several RCTs have demonstrated the potential for probiotics to limit NSAID-induced enteropathy.[57–59]

As NSAIDs have demonstrated abilities to increase TNF-alpha production,[60] anti-TNF agents have also been studied and have shown a reduction in NSAID-induced SB damage in a cohort of RA patients requiring NSAID therapy.[61] This is in line with prior studies supporting NSAID use as a risk factor for IBD exacerbations.[61,62] Albeit it is very difficult to differentiate NSAID induced enteropathy from CD, Table 2 provides few differential points to help clinicians differentiate between the two entities.

Biologic Therapies

While biologic therapies are used to treat inflammatory conditions, their use has also been linked to the development of paradoxical autoimmune diseases including IBD that can affect the small intestine. In the early 1990s, infliximab (IFX) was the first biologic agent in the anti-TNF class of therapies. Several studies have reported an increased risk of de novo IBD or worsening existing IBD with the use of anti-TNF therapy; the majority of cases have been related to etanercept (ETN) use. Anti-TNF use in rheumatoid disorders resulted in the development of de novo IBD in 16 patients in a nationwide French series.[63] The incidence of de novo IBD was estimated to be 0.15% over a 2-year period. Etanercept was the offending agent in the majority of the cases (14/16) and IFX was implicated in the other two (2/16).[63] The mean timeframe between initiation of anti-TNF agents and development of IBD was 29.3 ± 20.1 months. Switching ETN to another anti-TNF agent showed no recurrence among all reported cases. In another report from an IBD referral centre and the FDA Adverse Event Reporting System (FAERS), a total of 443 IBD cases were suspected to be provoked by ETN.[64] Among 49 patients with complete data, 43% of cases reported overlapping NSAID use. Eventually, 34 patients required complete discontinuation of ETN and 19 required initiation of a new anti-TNF agent. Crohn's disease (CD) was the most common phenotype of clinical presentation in 297 patients. Use of concomitant methotrexate was found to be protective and not associated with IBD development based on a German biologic registry that included 3071 patients with IBD development in 11 patients.[65] To evaluate a potential association between anti-TNF use and IBD, Krishnan et al analysed the FAERS data between 2003 and 2011.[66] One hundred fifty-eight reported cases of IBD development after anti-TNF initiation were analysed. A weak association between anti-TNF use and development of new-onset IBD was observed, with a moderately strong association specific to use of ETN.[66] The underlying mechanism is still not fully elucidated, but is thought to be related to cytokine imbalance, or an unmasking of an underlying IBD as a result of anti-TNF use or concomitant medications (ie NSAIDS).[8,67]

Crohn's disease has also been linked to the use of other biologic therapies including interleukin (IL)-17A inhibitors including secukinumab, ixekizumab and brodalumab. Secukinumab use has been associated with development of CD as shown in the MEASURE 1 and 2 RCTs, with a pooled exposure-adjusted incidence rate (IR) of 0.7 per 100 patient-years.[68] However, this correlation was found to be less significant and minimal based on a pooled analysis of 10 phase II and III clinical studies in plaque psoriasis with an IR of 0.1 per 100 patient-years. During 52 weeks of treatment with secukinumab, only 3/3430 patients had CD.[69] Two of these three patients had a known underlying history of CD and the third patient had baseline GI symptoms prior to initiating therapy.[69] Similarly, ixekizumab, another IL-17A inhibitor has been shown to carry an increased risk to develop CD with an IR of 1.1/1000 patient-exposure years based on an integrated database of seven randomised trials.[70] More recently, Fauny et al reviewed the literature from both clinical trials and real world (case reports) experiences about the correlation between IL-17 inhibitors and the risk of IBD.[71] In this review, total of 11 studies including two phase 2 and nine phase 3 trials were included. IL-17 inhibitor use was associated with an increased the risk of development of IBD in nine trials and one systematic review.[71] The real world experience demonstrated 19 cases of IBD with the use of secukinumab and two cases with ixekizumab.[71] The authors concluded that, while the risk of IBD is increased among IL-17 inhibitor users (and should not be neglected), the absolute risk is low (2.4 per 1000 patient-years).[71]

Other Immunosuppressive Agents

Transplant Medications. Mycophenolate Mofetil: Mycophenolate mofetil is a pro-drug of mycophenolic acid, commonly used in solid organ transplant for prevention and treatment of organ rejection. By inhibiting purine synthesis, MMF has both B and T cell anti-proliferative effects. Diarrhoea is one of most common adverse events (AEs) and was found to have an incidence as high as 40% in renal transplant patients.[72] Other AEs include nausea, vomiting, abdominal pain and bleeding. In one study, a dose reduction or discontinuation of MMF was required in 40%-50% of patients due to GI AEs.[73] Moreover, medication discontinuation due to diarrhoea was needed in 3.6% and 8.4% of patients taking MMF 2 and 3 g, respectively, suggesting a dose related effect as shown in the US Renal Transplant Mycophenolate Mofetil Study Group.[74] Mycophenolate-induced colitis accounted for 76.6% of all cases in one study by Liapis et al,[75] which was discussed thoroughly in our recent review.[8] However, drug toxicity can result in injury to any part of the GI tract. Parfitt et al conducted a study where 75 biopsies (including 16 duodenal and 5 ileal) from 46 transplant recipients between 2002 and 2006 were obtained and assessed histologically.[76] Graft–versus-host-disease (GVHD) features were only seen in MMF patients (four duodenal and one ileal).[76] This included crypt architectural distortion, lamina propria edema and/or inflammation, and increased crypt apoptosis.[76] In addition, dilated crypts with eosinophils and neutrophils can be seen.[77] Moreover, SB villous atrophy was reported in four case reports for patients presenting with severe diarrhoea 4–66 months after starting MMF.[78] Typical celiac histological features to include intra-epithelial lymphocytes were not present and the specific anti-endomysial antibody testing was negative in all cases. Diarrhoea resolved within one month of MMD discontinuation.

Switching to enteric-coated mycophenolate sodium (EC-MPS) resulted in a significant improvement in GI related toxicities based on prospective study that involved 34 liver transplant recipients.[79] Similar results were seen in an open label study including 278 renal transplant patients who switched from MMF to EC-MPS.[80] On the contrary, no difference in incidence of GI AEs was seen between MMF vs EC-MPS groups at 3 and 12 months in a RCT that included 322 renal transplant patients.[81]

Calcineurin and mTOR Inhibitors. Diarrhoea is commonly reported with the use of calcineurin inhibitors including tacrolimus and cyclosporin occurring in up to 43%-72% and 40%-47% of individuals, respectively.[82,83] Three RCTs compared tacrolimus to cyclosporin following renal and liver transplant with a total of 1338 patients.[82–84] Tacrolimus use carried a 1.5–2.2 fold increased risk of diarrhoea when compared to cyclosporin.[82,84] Most cases of diarrhoea were mild, self-limited and only required medication dose reduction.[85] None of the patients in the Mayer et al[84] study (0/303) required medication discontinuation, and only 3/205 (1.5%) in Pirsch et al study[83] required switching tacrolimus to cyclosporin.[85]

Similarly, sirolimus use has a known association with diarrhoea. In a large controlled trial that included 719 renal transplant recipients, the incidence of diarrhoea was 20% and 32% at doses of 2 and 5 mg, respectively, suggesting a dose-related effect.[86] The exact mechanism of diarrhoea with calcineurin and mTOR inhibitors is not fully understood. However, infectious etiologies, polypharmacy, a direct effect on the SB and colonic mucosa, or an effect on intestinal motilin receptors has been previously suggested.[87] The higher incidence of diarrhoea with tacrolimus use was thought also to be partially due to its macrolide structure in comparison to cyclosporin.[87]

Tacrolimus also been attributed to a case of intestinal angioedema in a single case report of a kidney transplant recipient.[88] Abdominal cross-sectional imaging revealed thickened loops of proximal SB, followed by capsule endoscopy that showed severe edema and congestion of several loops of SB. Diagnosis was confirmed by histology that revealed edema of the villi.[88] Symptoms completely resolved within 3 weeks of tacrolimus discontinuation. A re-challenge of tacrolimus resulted in a rapid-onset diarrhoea that resolved within 48 hours after drug stoppage.

Chemotherapeutic Agents. Gastrointestinal toxicity as a result of chemotherapeutic agents is common, and can affect any part of the GI tract. The SB is one of the most frequently affected sites, which can result in a significant healthcare burden due to the increased risk of hospitalisation and reductions in patient quality of life.[7] Due to the rapidity of enterocyte turnover (occurring approximately every 4–5 days), the SB epithelium is rapidly affected by chemotherapeutic agents resulting in ulceration and alterations in the integrity (and permeability) of the mucosa.[89] In one study by Dore et al, capsule endoscopy was performed 3–14 days following chemotherapy for solid tumours in 20 patients. A quarter of patients developed widespread ulcerations in the SB.[89] Risk factors associated with severe mucosal injury included the chemotherapeutic delivery route, dosage and number of prior cycles, and concomitant use of radiotherapy.[89]

Multiple factors likely play a role in chemotherapy-induced diarrhoea including inflammatory changes of the intestine, changes of the SB microbiota, mucin composition alterations, increased intestinal permeability and goblet cell distribution.[90] 5-Fluorouracil (5-FU) and irinotecan are the most studied therapies with well-known associations with SB injury. Both 5-FU and irinotecan can result in intestinal mucosal damage leading to an increase in fluid transmission from SB to the colon and therefore diarrhoea.[91] This is also true for a delayed onset irinotecan-induced enteropathy, which appears to be related to an inflammatory process with direct toxicity to mucosal cells. However, early onset irinotecan induced diarrhoea is thought to be cholinergic mediated and is often can be accompanied by lacrimation, salivation, rhinitis and other symptoms of excessive cholinergic stimulation.[92] Several randomised trials evaluated the risk of diarrhoea in patients receiving 5-FU including: FIRE-3 (FOLFIRI + cetuximab),[93] VELOUR (FOLFIRI + aflibercept)[94] and the TRIBE trial (FOLFOX and bevacizumab).[95] The risk of any grade of diarrhoea ranged from 46% to 69.2%[93,94] and severe diarrhoea (grade III-IV) ranged from 10.6% to 19.3% of included patients.[94,95] The onset of diarrhoea and GI AEs can be associated with a notable increase in morbidity. In a retrospective study by Dranitsaris et al, grade III-IV diarrhoea occurred in 54.2% of patients after the first chemotherapy cycle with 5-FU, irinotecan or oxalipatin.[96] One-third of patients required hospitalisation (2–28 days, median: 8 days), with a median cost of $2559 per patient.[96] Common terminology criteria for adverse events (CTCAE) is used to grade diarrhoea. Grade III diarrhoea involves having seven or more bowel movements over baseline, the need of intravenous fluids for ≥24 hours or the need for hospitalisation, whereas grade IV indicates life threatening complications. Grade I and II indicates having ≤4 or 4–6 bowel movements daily, respectively.

A possible association between irinotecan-induced enteropathy and UGT1A1*1/*28 genotype has been suggested in a meta-analysis by Liu et al (OR 1.84, 95% CI 1.24–2.72).[97] However, a subgroup analysis showed a possible correlation between the genotype and irinotecan-induced enteropathy only at higher doses or when combined with 5-FU.[97]

Docetaxel is a cytotoxic chemotherapeutic commonly used in a variety of cancer therapies to include: breast, prostate, stomach, lung and head and neck. In a retrospective study included 1227 patients, 13.4% experienced diarrhoea.[98] Among these patients, 27 developed enterocolitis with three deaths (0.8%).[98] Higher doses of docetaxel, and the first cycle were the risk factors associated with worse outcomes in a multivariate analysis.

Diarrhoea due to bile salt malabsorption has been linked to lenalidomide use for treatment of myeloma.[99] Other cytotoxic agents with reported possible AEs of diarrhoea include cisplatin, cytosine arabinoside, doxorubicin, vincristine, mercaptopurine and dasatinib.[100,101]

With respect to the management of SB ulcers and DIE, omeprazole was found to be effective in preventing chemotherapy-induced gastroduodenal injury in one RCT that included 228 patients, although specific injury to the mid and distal SB was not assessed.[102] Lactobacillus may reduce the frequency of severe diarrhoea and severe abdominal pain in one RCT.[103] Octreotide did not show efficacy in preventing chemotherapy-induced diarrhoea in the LARCID trial.[104] Treatment usually involves supportive care with intravenous fluids, loperamide or atropine-diphenoxylate. In grade III-IV cases or persistent grade I-II cases octreotide can be considered to reduce the secretions arising from the SB. Octreotide should be considered in patients who are refractory to loperamide escalation after 48 hours. While one RCT showed a superiority of octreotide compared to loperamide (90% vs 15%) in terms of diarrhoea discontinuation by day 3, cost is a limiting factor.[105] The recommended starting dose of octreotide is 100–150 μg subcutaneous (sc) or IV three times daily, but in refractory cases, dose escalation up to 500 μg three times daily either sc or IV, or even continuous infusion 25–50 μg/h can be considered.[105]

Monoclonal Antibodies (Immunotherapy). Monoclonal antibodies are among a class of novel therapies targeting specific immune molecules that can increase the immune systems response directed at tumours. Their use has been associated with rapid improvements in survival for a number of malignancies. However, as the promising therapies up-regulate immune-mediated activity, their use has also been associated with AEs referred to as immune related adverse events (irAE) that can affect several target organs, to include the GI tract.

Checkpoint inhibitors (CPI) are relatively new therapies targeting cytotoxic T-lymphocyte associated protein-4 (CTLA-4), programmed death-1 (PD-1) or PD1 ligand 1 (PD-L1) molecules and are now approved by the FDA and European medicine agencies to treat melanoma, renal cell carcinoma (RCC), urothelial carcinoma, non-small cell lung cancer, hepatocellular carcinoma, squamous cell carcinoma of head and neck and Hodgkin's lymphoma.[106] Ipilumumab represents the first approved CPI in 2011 and the only approved CTLA-4. Nivolumab, pembrolizumab, durvalumab and cemipilmab are the approved PD-1 inhibitors and atezolizumab and avelumab are the approved PD-L1 inhibitors. CPI-induced GI toxicity is relatively common, and up to 30% of patients can develop diarrhoea.[107,108]

Enterocolitis is the most frequent GI irAE associated with CPI use with an incidence of 21% in a single centre study including 198 patients on ipilumumab.[109] The incidence and severity of GI irAE including diarrhoea and enterocolitis are higher with anti-CTLA-4 use when compared to anti PD-1 therapy.[106] The incidence of diarrhoea was 30.2%-35.4% with anti-CTLA-4 therapy as compared to 12.1%-13.7% with anti-PD-1 use in a systematic review by Soularue et al[106] Combination therapy increases the risk of diarrhoea and enterocolitis when compared to monotherapy (combination: 44%, CTLA-4:35%, PD-1:17%-20%).[110] These results were reinforced in a recent report by Reese et al evaluating reports of AEs from the World Health Organisation's Global Individual Case Safety Report database (ICSR) that contains over 20 million anonymised reports submitted from over 130 countries.[111] All CPIs were found to have an association with enterocolitis with the strongest association with ipilumumab (reporting odds ratio [ROR] 99.83, 95% CI: 99.64–106.44).[111] Other agents related to the development of enterocolitis included: nivolumab (ROR 18.06, 95% CI: 16.70–19.52), atezolizumab (ROR 14.95, 95% CI: 11.59–19.28), durvalumab (ROR 22.21, 95% CI: 16.12–30.35), and pembrolizumab (ROR: 19.04, 95% CI 17.35–20.89).[111]

Diarrhoea and enterocolitis occurs earlier with anti-CTLA-4 therapies as compared to anti-PD-1 therapy (1 vs 2–4 months), and can also resolve more quickly (0.5–1.6 vs 1.1–4.2 months).[106] The median time to the development of enterocolitis was 51 days (22–98) in the recent aforementioned report by Reese et al[111] Checkpoint inhibitor-induced enterocolitis is mostly recognised as a colitis in a continuous pattern in 45%-79% of patients with at least two thirds of patients have extensive colitis proximal to splenic flexure.[110] Ileal involvement is also demonstrated in up to 12% of patients.[112]

Isolated SB involvement has been described resulting in an enteropathy and severe electrolyte disturbances with ipilimumab,[113] and pembrolizumab has been linked to a severe proximal enteropathy resulting in scattered erosions throughout the duodenum.[114] In a study by Tang et al, among 38 patients undergoing both upper endoscopy and colonoscopy, 38% demonstrated histological inflammation in the duodenum. A single case report of de-novo vs previously unrecognised celiac disease has been described with ipilimumab use[115] and the second case report demonstrated a celiac disease-mimicking enteropathy with nivolumab where celiac serologies were negative.[116]

Endoscopic features include erythema, erosions, bleeding and mucosal edema. Within the SB, features mimicking celiac disease can be observed to include scalloping of folds and a reduction in fold number. Histology usually shows a predominance of CD4-positive T cells in the colonic mucosa when anti CTLA-4 therapy is used.[7]

The presence of pre-existing IBD is a risk factor for CPI-related enterocolitis. In a recent meta-analysis of 12 studies, 40% of IBD patients experienced IBD relapse with the use of CPI. The majority of individuals required steroids for the management of the IBD exacerbation and over one-third of individuals required biologics.[117] In a single study, the risk of IBD relapse was higher with anti-CTLA-4 therapy when compared to PD-1/PD-L1 inhibitors.[118]

There appears to be a role of microbiota in pathogenesis of checkpoint-induced enterocolitis dysbiosis leads to intestinal inflammation or results from it.[119] Analysis of gut bacteria in patients with malignancies taking CPIs has shown an association between different gut bacteria with response to CPI and/or toxicity in humans.[119] For example, bifidobacterium, ruminococcaceae and faecalibactrium are associated with an increased response to anti-PD-1 therapy whereas bacteroidales decreases the response to anti-PD-1 therapy.[119] It is unlikely that the development of CPI-induced enterocolitis is dependent on specific bacteria but it may be that the diversity of gut commensals impacts this development. Further research is needed to better understand the role of gut microbiome in the development of CPI-related bowel injury, and potentially its role in prevention.

The mainstay of treatment of CPI-induced enterocolitis is corticosteroids except for mild cases with grade I diarrhoea based on CTCAE where symptomatic management can be sufficient. In refractory cases, infliximab, vedolizumab can be considered. Faecal microbiota transplant (FMT) was investigated in two cases for severe disease refractory to steroids, infliximab and vedolizumab and both patients were able to achieve clinical and endoscopic remission.[8] This again suggests a correlation between microbiota and the pathogenesis of CPI-induced enterocolitis. Ustekinumab was also able to achieve disease remission in two patients refractory to other agents in a recently published report of two patients,[120] and surgery may be required in refractory or complicated cases. A detailed management algorithm has been previously presented in the prior work on drug-induced colitis by Hamdeh et al[8]

Other Monoclonal Antibodies. Vascular endothelial growth factor (VEGF) inhibitors are monoclonal antibodies that target VEGF and therefore play a central role in the management of cancer angiogenesis. Bevacizumab was the first VEGF inhibitor that was approved by the FDA in 2011 and several agents have been approved since then for treatment of non-small cell lung cancer, renal cell cancer, ovarian cancer and glioblastoma multiforme. Albeit uncommon, GI perforation is a well-documented AE associated with VEGF inhibitors and has potential catastrophic outcomes including death. Thirty-seven of 1953 (1%-2%) of patients treated with bevacizumab in the BRITE registry developed GI perforation.[121] Similarly other large trials including the OCEANS trial and AURELIA trial reported an incidence of perforation of 0.8% and 2.2%, respectively.[122,123] This resulted in black box warning issued by the FDA. Hapani et al conducted a meta-analysis study that demonstrated an increased risk of GI perforation (RR 2.14, 95% CI 1.19–3.85),[124] and a meta-analysis by Qi et al that included 33 RCTs with a total of 26 833 patients demonstrated an increased risk of fatal GI perforation in both the SB and colon (RR 3.08, 95% CI 1.04–9.08, P = 0.042).[125]

Antibodies against the anti-epidermal growth factor (EGFR) include cetuximab and panitumumab are increasingly utilised in non-small cell lung cancer and colon cancer. Several case reports link cetuximab use to SB injury, including pneumatosis intestinalis[126,127] and ileal peforation.[128,129] This association with SB injury has been emphasised in a meta-analysis study by Miroddi et al including 18 clinical trials enrolling 13 958 patients which found an association with diarrhoea (grade 3–4) (RR 1.66, CI: 1.52–1.80) and mucositis (RR 3.44, CI: 2.66–4.44).[130] Subgroup analysis showed no significant difference between the AEs and the studied anti-EGFR agent.[130]

Pertuzumab is another monoclonal antibody that inhibits human epidermal growth factor 2 (HER-2) receptors. Pertuzumab was associated with a significant increased risk of diarrhoea in a large phase III CLEOPATRA trial that reported a 66.8% incidence of all diarrhoea grades, and grade III/IV diarrhoea occurring in 7.9% of individuals. However, included patients also received docetaxel, and after docetaxel was discontinued, 28.1% in pertuzumab group as compared to 14.2% in placebo had diarrhoea suggesting a pertuzumab-specific etiology.[131]

Tyrosine Kinase Inhibitors. Similar to cetuximab, erlotinib inhibits EGFR, although the mechanism of action is different and includes tyrosine kinase inhibition. Erlotinib is approved for treatment of lung and pancreatic cancer. Erlotinib use has led to SB perforation in two case reports, occurring 3 weeks to 6 months after therapy initiation.[132,133] Other tyrosine kinase inhibitors (TKIs) linked to SB perforation in sporadic case reports include nilotinib,[134] nintedanib,[135] pazopanib,[136] gefitinib,[137,138] osmirtinib,[139] lenvatinib[140] and regofarnib.[141] Tyrosine kinase inhibitors that also inhibit VEGF can also lead to GI toxicities with perforation, SB bleeding[142] and pneumatosis[143] linked to sorafenib use. Similar AEs were reported with the therapies axitinib,[144] and sunitinib[145] in case reports.

Diarrhoea is also a common adverse event of TKI use, seen in 79.2% with bosutinib and 28.1% with dasatinib in a recent meta-analysis of 43 studies including 10 769 patients.[146] However, severe grade III-IV diarrhoea was only seen in ≤3% except for bosutinib (9.5%).[146]

Rituximab. Rituximab is a chimeric anti-CD20 monoclonal antibody that has been linked to spontaneous SB perforation when used for the treatment of post-transplant lymphoproliferative disorder (PTLD). Several published cases reported bowel perforation with rituximab use warranting further investigations. Roche pharmaceutical identified 37 cases of GI perforations resulted in four fatalities among 730 000 patients received rituximab and a warning was sent about this potential risk.[147] Also a pooled analysis showed higher risk of bowel perforation when rituximab was added to chemotherapy regimen vs no rituximab (0.38% vs 0.15%).[147]

Phosphoinositide-3 Kinase (PI-3K) Inhibitors. Idelalisib, a PI-3K inhibitor, has been associated with the development of diarrhoea and enterocolitis in clinical trials. In a retrospective analysis of nine clinical trials, 15% of patients on idelalisib developed grade III-IV diarrhoea and/or colitis.[148] A total of 29 eligible patients with reported abdominal pain and diarrhoea were included in the analysis, with colonic involvement in all cases and five with simultaneous SB involvement.[148] Mild (grade I-II) diarrhoea occurs within months of therapy initiation and more severe diarrhoea (grade III-IV) can occur later. Histology demonstrated an inflammatory pattern with attenuated glands (12 cases), apoptosis (two cases), mixed apoptotic and inflammatory pattern, and/or attenuated glands (12 cases), and normal pattern without architectural abnormalities (two cases). Twenty of the 29 cases demonstrated an increased percentage of T cells positive for FOXP3, of which, eight were also positive for infectious pathogens.[148]

Anti-hypertensives. Drug-induced SB injury has been reported with several anti-hypertensive (HTN) medication classes, of which angiotensin converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) have the most established association with SB injury. This AE has been linked to use of any HTN medication in the respective classes. However, olmesartan, a long-acting, selective ARB, seems to carry the highest risk. Apart from the known association with enteropathy with olmesartan, intestinal angioedema has been reported with the use of ACEIs and ARBs in a few case reports in the literature.[149–151]

Olmesartan. Sprue-like enteropathy associated with olmesartan use was first described in 2012 when Rubio-Tapia et al reported a series of 22 cases of diarrhoea and weight loss associated with olmesartan use.[152] Fourteen patients (64%) required hospitalisation, and none of the patients had positive celiac serologies. Interestingly, 2 years prior to the recognition of olmesartan-associated enteropathy (OAE), the Mayo clinic group found that olmesartan use was common in a cohort study describing the management of collagenous sprue, which was present in one-third of cases.[153] Several case reports,[154,155] original studies and systematic reviews have since been published.[156,157]

The pathophysiology of OAE is not fully understood. Marietta et al reviewed duodenal biopsies from 28 patients with OAE before and after discontinuation of the drug, including seven paired samples.[158] The study concluded that olmesartan shares features with celiac disease including an increase in CD8+ T cells and IL-15 overexpression in the SB epithelium.[158] Scialom et al described a histological pattern in OAE patients mimicking autoimmune enteritis suggesting possible immune dysregulation.[159]

Risk factors for OAE include older age (>50 years old), Caucasian race and obesity.[152] Genetic predisposition could also play a role pathogenesis as patients with HLA-DQ2 antigens were found to have an increased risk of OAE.[6]

Although olmesartan carries an increased risk for the development of OAE, the absolute risk is still low. The incidence rate over 3.2 years was 1/2232 individuals (<0.05%) in the ROADMAP (Randomised Olmesartan And Diabetes Micro Albuminuria Prevention) study.[160] Patients with OAE can present with abdominal pain, nausea, vomiting, weight loss and severe diarrhoea.[6] The onset of diarrhoea after starting Olmesartan is usually several months but symptoms may develop after several (mean duration 3.1 years (0.5–7 years)].[152] Complications include malnutrition, dehydration and acute kidney injury, at times requiring parenteral nutrition support. Patients with severe complications may require hospitalisation with an increased morbidity and mortality.[6] The diagnostic approach includes a detailed history with a positive correlation between the start of the symptoms and medication initiation, negative celiac serologies and inadequate to no response to a gluten free diet.[152] In the Rubio et al study, 14/22 patients had histological features similar to celiac disease including complete villus atrophy and increased intraepithelial lymphocytes.[152]

In a cohort study using France's health insurance system, olmesartan increased the risk of hospitalisation due to enteropathy 10-fold compared to other ACEIs or ARBs.[161] Similarly, Basson et al assessed the French national health insurance claim database that included 4 546 680 patients with 218 events. Olmesartan was associated with an increased risk of hospitalisation due to intestinal malabsorption compared to ACEIs (ARR 2.49, 95% CI 1.73–3.57) and ARBs (ARR 3.17, 95% CI 2.22–4.53). This difference was not statistically significant with treatment duration less than 1 year, but significant with 1–2 years and over 2 years duration with an increased risk with treatment duration.[156] Olmesartan was also associated with an increase in hospitalisations for the diagnosis of 'celiac disease' (ARR 4.39, 95% CI 2.77–6.96, P < 0.0001).

Although most studies associated olmesartan specifically with enteropathy, a recent large observational cohort study using data from a large German database and Italian local health care units including 465 443 patients showed no specific difference in intestinal malabsorption between olmesartan and ACEIs. Interestingly, the study also demonstrated a higher risk of malabsorption when comparing other ARBs to olmesartan (RR 2.50, 95% CI 1.21–5.19). The unadjusted incidence rate of intestinal malabsorption per 100 000 patient-years was 12.49, 14.62 and 9.05 for olmesartan, ARBs and ACEIs, respectively, concluding that DIE is the result of drug class exposure to ARBs rather than to a specific olmesartan drug effect.[157]

Medication discontinuation is the mainstay of therapy, and in the initial Rubio et al study, clinical and histological improvement was achieved in all patients who had follow-up biopsies (18/18).[152]

Calcium Channel Blockers. Bezoar formation in the duodenum secondary to extended release nifedipine, although rare, has been described in the literature.[162] To compare this risk with another calcium channel blocker, Juurlink et al conducted a population-based study that identified 103 657 patients treated with extended-release nifedipine versus 204 733 patients treated with amlodipine over a 6-year period.[163] The risk of bowel obstruction was found to be 0.6% in both groups with no statistically significant difference.[163] Although this risk is low, physicians should be aware of it when encountering patients with recurrent bowel obstruction utilising calcium channel blockers.

Antimicrobials. Antibiotic-induced diarrhoea and specific to enterocolitis was discussed exhaustively in our recent review.[8]

Diabetes Medications. An association between dipeptidyl peptidase-4 (DPP-4) inhibitors and IBD was shown in a population-based study by Abrahami et al utilising data from 141 170 patients obtained from the United Kingdom Clinical Practice Research Datalink over a 10-year period.[164] The study concluded that DPP-4 inhibitors were associated with an increased risk of IBD (HR 1.75, 95% CI 1.22–2.49) with gradual increase in incidence with longer duration of use and a peak at 3–4 years (HR 2.90, 95% CI 1.31–6.41), with a subsequent decline after 4 years.[164] A subsequent meta-analysis that included 16 studies with total of 198 404 patients (largely driven by the inclusion of the previous study by Abrahami et al) showed an association between DPP-4 inhibitors and CD risk using a fixed-effect model (RR 2.47, 95% CI 1.36–4.48), but failed to show an association when a random effect model was applied.[164] The study authors concluded that DPP-4 inhibitors did not increase IBD risk but post-marketing surveillance is warranted.

Acarbose. By inhibiting a-glucosidase, acarbose delays carbohydrate absorption, and therefore results in abdominal bloating, flatulence and at times diarrhoea, which are well-known AEs, related to acarbose use. A rare side effect of acarbose is pneumatosis cystoid intestinalis as reported in several case reports.[165,166] Pneumatosis intestinalis refers to presence of intramural gas in the intestine but can also involve any part of the GI tract. Most of the reported very few cases of pneumatosis cystoid intestinalis due to acarbose use affected the colon, but SB involvement has been reported.[166]

Metformin. Diarrhoea is one of the most common side effects of metformin and occurs in up to 30% of patients leading to medication discontinuation in approximately 4% of patients.[167] Increased glucagon like peptide 1 (GLP-1), increased gut exposure to bile acids and altering the microbiome are thought to be the underlying mechanisms of diarrhoea among metformin users.[168] GI symptoms are usually mild, self limited and occur shortly after starting metformin, however, delayed GI symptoms (1.5–2 years) after initiating metformin have been reported.[167] Diarrhoea can be minimised by taking starting metformin at lower doses (eg 500 mg once or twice daily) with gradual up-titration of doses and administration with meals.

Oral Contraceptives/Hormonal Therapies. The association between oral contraceptives (OCP) use and IBD has been controversial with conflicting data in the literature. Many studies found an increased incidence of de-novo IBD in women taking OCPs. Ortiz et al conducted a meta-analysis of 20 case controlled and cohort studies and found a 24% increased risk of CD development in women exposed to OCPs when compared non-exposed individuals (OR 1.24 95% CI: 1.09–1.40).[169] The analysis showed an increased risk of IBD while receiving OCPs that was no longer significant when OCPs were discontinued.[169] In another large study that included two large prospective US cohorts from the Nurse Health Study I (NHS I) and Nurse Health Study II (NHS II) comprising 232 452 female participants with over 5 030 196 person-years of follow-up, a total of 315 cases of de-novo CD were reported through 2008.[170] The multivariate-adjusted analysis demonstrated a HR for CD of 2.82 (95% CI 1.65–4.82).[170] Importantly, not all studies have reached the same conclusion. The same authors, when conducting a study limited to the NHS I study and including 108 844 postmenopausal women utilising hormone therapy found no increased risk of CD.[171] Moreover, a protective effect was shown with the use of hormonal therapies (HT) in postmenopausal women in a study conducted by Kane et al, suggesting an age modifier on the risk of OCPs/HT with respect to the development of CD.[172] With respect to IBD relapse, Timmer et al followed 152 patients for up to 48 weeks and found a threefold increased risk of CD relapse in current and previous OCP users.[173] However, there was no significant increased risk in four other cohort studies.[174–177]

Isotretinoin: A possible correlation between isotretinoin and IBD was suggested by Reddy et al in 2006 after reviewing the FAERS. Four "highly probable" and 58 "probable" associations with IBD was reported.[178] Following this several case reports were published in addition to an increase in the number of reported cases to the FDA leading to a lawsuit against the pharmaceutical company Hoffman La Roche.[179] The FDA issued a warning and eventually the medication was recalled. However, in 2013 Stobaugh et al found disproportionate reporting by attorneys compared to physicians and consumers (total of 2214 cases of IBD, of which 1944 were reported by attorneys, 132 reported by physicians and 112 reported by consumers).[180] This inflated the pharmacovigilance signal of isotretinoin-associated IBD in the FAERS. However, this association has been discredited by subsequent studies, including a population-based case-control Canadian study by Bernstein et al[181] and a French nationwide study by Racine et al[182] Moreover, two meta-analyses of five and six studies published in 2013 and 2016 showed no increased risk of IBD among isotretinoin users.[183,184]

Potassium Supplementation: The association between potassium supplementation and SB ulceration has been established since the 1960s with an estimated risk of 40–50 cases per 10 000 patient/years.[7] Although still controversial, the suggested pathogenesis include direct contact of potassium with the intestinal mucosa, and local interference with the blood flow provoked by a rapid release and absorption of high concentrations of potassium in the SB.[185] Ulcers usually occur in mid and distal jejunum and ileum, and are usually isolated and rarely up to three ulcers can be seen.[185] The presence of narrow band-like circular lumen, with a proximal dilation is a distinguishing feature of the late stenotic phase of disease. This can eventually progress to intestinal obstruction, necrosis and perforation. The risk of potassium induced SB injury is significantly decreased with the use of the newer slow-release tablets but not absent in the reported literature.[186]

Iron Supplementation: Gastrointestinal adverse events including SB injury are common with iron supplementation, occurring in 32.3%, 30.9% and 47% of users with the use of ferrous sulphate, ferrous gluconate and ferrous fumarate, respectively.[187] A meta-analysis of 43 RCTs comprising 6831 patients by Tolkien et al showed a statistically significant increased GI AEs with the use of ferrous sulphate vs placebo with OR of 2.32, 95% CI 1.74–3.08, and when compared to intravenous iron (OR 3.05, 95% CI 2.07–4.48).[188] A subgroup analysis of IBD patients showed a higher incidence of GI AE (OR3.14, 95% CI 1.34–7.366).[188] This effect was thought to be related to direct toxicity to the SB mucosa by unabsorbed iron.[7]

Cholinesterase Inhibitors (ChEI): An increased risk of GI bleeding with the use of ChEI has been suggested. Thirty eight cases of peptic ulcers, and 30 reports of GI bleed secondary to donepezil were received by the Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card Data.[189] However, a population-based Canadian cohort study using healthcare administrative claims data showed no statistically significant increased risk of upper GI bleeding with ChEI users, although 34.4% of patients received gastroprotective therapy.[190] Kok et al reported a case of upper GI bleeding secondary to a duodenal ulcer due to donepezil use.[189] Physicians should be aware of these potential AE especially since most of these patients have other risk factors for ulcer disease besides polypharmacy.

Miscellaneous. Several reports suggested a possible link between nicorandil, an anti-anginal medication used in Japan and Europe, and GI ulceration and fistulas. These ulcers can affect any part of the GI tract but mostly the distal two ends (oral and anal ulcers).[191] Rare case reports described jejunal[192] and ileal[193] ulcerations with nicoradil use. Also, sporadic cases of enteropathy were reported with the use of alendronate (four reported cases of de-novo celiac disease or exacerbation),[194] clozapine (one case of necrotising enterocolitis).[195] Moreover, enterocolitis was reported with the use of gold compounds in a literature review of 29 cases.[196] Abdominal pain and diarrhoea were reported in nearly half of the patients on gold preparation,[197] leading to medication discontinuation in approximately 4% of patients.[7] Increased intestinal permeability and protein losing enteropathy were also found in these patients.[7]

Clofazimine, a medication used to treat leprosy was associated with enteropathy.[7] SB histology revealed clofazimine birefringent crystal deposition in the mucosa, submucosa and also mesenteric lymph nodes.l Radiologically, the appearance can mimic infiltrative diseases including lymphoma.

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