Researchers at the Emory Eye Center (Atlanta, GA) studying retinal eye disease have made another remarkable finding, that some IC/BPS patients using pentosan polysulfate (PPS, Elmiron®)  are struggling with inflammatory bowel disease, some so severe that colectomy (removal of a section of the colon) was required.(1) 

Elmiron® is the only FDA approved medication for IC/BPS. Approved by the FDA in 1996, it was the primary treatment given to patients for many years. In 2018, Emory Eye researchers discovered a new retinal disease associated with its use, pigmentary maculopathy.(2) Multiple studies in the past four years have established a strong association between the medication and eye disease, resulting in a black box warning that retinal disease is a potential adverse effect.(3)

In the performance of that research, Emory researchers also began tracking inflammatory bowel disease in the same population of patients. In May 2023, they released their first case series, a study of 13 patients of whom eleven (84.6%) developed symptoms (abdominal pain, cramping, diarrhea, etc.) suggestive of IBD or IBS after beginning pentosan therapy. Ten patients had abnormal mucosal changes (colopathy) in their colon and six had abnormal-appearing colonic mucosa in endoscopy. Notably, after Elmiron®/pentosan use was stopped, all patients had improvement in both their symptoms and the lining of their colon. 

Early Studies Report Bowel Symptoms and Colitis

In 2005, gastroenterologists in the Texas A&M University Health System published two case studies which they believed showed a causal relationship between PPS use and colitis.(4) 

  1. A 29 year old woman developed bloody diarrhea and cramping abdominal pain one month after starting PPS. A sigmoidoscopy, a test that looks at the rectum and lower intestine, found small ulcers and friable tissue (i.e. red, bleeding tissue). A colonoscopy revealed colitis extending from her rectum to the transverse colon. Biopsies confirmed active colitis. Her symptoms completely resolved when she discontinued PPS use. A repeat endoscopy and biopsies found a total resolution of the colitis. 
  2. A 59 year old female with a history of IBS developed increased diarrhea and lower left quadrant abdominal pain two weeks  after starting PPS. A colonoscopy also revealed ulcerations. Biopsies confirmed moderately active colitis, with some fibrosis (thickening) and necrosis (tissue death). Treatments commonly used for colitis (i.e. mesalamine, prednisone) were not effective. Her abdominal pain and diarrhea improved after PPS was stopped and, like the previous case, further testing revealed a resolution of the colitis. 

In 2015, researchers at the University of Missouri and UC Irvine published a case study of a 32 year old female with IC who had struggled with diarrhea for seven months.(5) She had abdominal cramping and loose bloody stools with approximately 20 bowel movements per day. They attempted treatment with several medications (mesalamine, prednisone, rifaximin, dicyclomine, amitryptiline) over a year with no improvement. However, when Elmiron® was discontinued, her symptoms resolved over a few weeks. A new colonoscopy found normal tissue. They concluded that “Elmiron may rarely induce colitis and rectal bleeding. Providers should be aware of this potential side effect, especially at higher doses.” 

Worrisome Colonic Dysplasia Reported

In 2022, researchers at the Oregon Health and Science University, searched electronic medical records at two care centers to identify patients using PPS and who had a diagnosis of Crohn’s disease or ulcerative colitis(6). They found thirty patients who met their criteria, ten of whom had colonic dysplasia. Dysplasia is an area of the lining of the colon where the cells become abnormal and could become cancerous over time. Six (60%) of these patients required colectomy while three discontinued the drug and achieved healing.  

These authors said “The presence of mucosal inflammation is a known risk for the development of colorectal cancer. Dysplasia is a precursor for IBD-related colorectal neoplasia; thus, early identification is critical.” They note that in their study PPS users have a significantly higher rate dysplasia at 33% than the 4% observed in the general IBD population.

2023 Emory Studies Suggest Strong Association

In May 2023, the original team at Emory released two concerning studies (currently in peer review).(1) Their first study involves fourteen IC/BPS patients with pigmentary maculopathy who had enrolled in a four year prospective study of their ocular and systemic health prior to any concerns about bowel disease. They each had a high, cumulative exposure to pentosan. 

One patient withdrew from the study. The remaining 13 all experienced GI symptoms while on PPS. Twelve were female, one was male. Median age was 62 years. Median duration of use of PPS was 14 years (9 to 18).  Eleven patients (84.6%) experienced  bowel symptoms after beginning PPS use with a median time of 4.9 years (3.5 to 6.2).  Symptoms included diarrhea, abdominal pain, stool with mucus and blood, tenesmus (feeling like you need to have a bowel movement even when the bowel is empty), fecal urgency and fecal incontinence.  Only two of these participants had bowel symptoms prior to starting PPS… one with lactose intolerance and the other with IBS. 

All 11 underwent at least one colonoscopy and all received a diagnosis of IBD or IBS. Biopsy and microscopic examination found abnormal mucosal changes.

This group of patients have now reported that their IBD symptoms have improved. Seven received medical therapy, including mesalamine, balsalazine and budesonide. Two underwent a colectomy (bowel removal) for dysplasia. Patient 11 had a colectomy one year after being diagnosed with UC, 15 years after starting PPS use with a cumulative exposure of 2.42kg of PPS. Patient 2 was diagnosed with UC 4.9 years into treatment with PPS but had been off the medication for 3.2 years before a colectomy was performed. A third patient is being monitored for dysplasia and may require a partial colectomy. 

Their second study evaluated 219 patients with IC who were seen at the Emory Eye Center and PPS use was a statistically significant predictor of IBD or IBS/IBD. No other medications were associated with this risk. 

Method of Injury

It is unclear whether PPS itself or a metabolite is causing both the eye and gut effects. One theory suggests that it could be a chemical injury. In animal studies on IBD, researchers use the drug dextran sodium sulfate to artificially induce intestinal inflammation. Pentosan polysulfate is also a sulfated polysaccharide with a similar structure. Could this be injuring tissue over time?  This must be confirmed in additional research.

Conclusion

The researchers at Emory state that more research is needed to establish a causal relationship between PPS and colopathy. Yet, they do suggest that their data is concerning if not just for the fact that prior IC studies only found a prevalence rate of 2% of IBD while their study shows an 85% rate. Further research is currently underway to explore the relationship between PPS and bowel disease. 

If you are taking Elmiron®/pentosan and struggling with bowel symptoms, we suggest that you discuss this new research with your doctor. It may be reasonable to stop using the medication for a period of time to see if your bowel symptoms resolve, as they found in these prior studies and case reports.  

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References: 

  1. Jung E, et al. Colopathy Associated with Pentosan Polysulfate Use – Currently in peer review prior to publication =. June 2023. 
  2. Pearce, et al. Pigmentary Maculopathy Associated with Chronic Exposure to Pentosan Polysulfate Sodium. Ophthalmology. 2018 May 22.
  3. Osborne, J. Elmiron Label in USA Now Includes New Warning About Eye Disease. IC Network. June 17, 2020. Accessed 6/19/23 – https://www.ic-network.com/elmiron-label-has-been-changed-to-include-a-warning-about-eye-disease/
  4. Conkling B, et al. Pentosan Drug Induced Colitis. Am J Gastroenterol. 100:S202. September 2005
  5. Almashhrawi, A, et al. Elmiron-induced Colitis: A Rare Complication. Am J Gastrolenterol. 11;S151, October 2015. 
  6. Anderson J, et al. Pentosan Polysulfate-Associated Dysplasia in Inflammatory Bowel Disease: A Case Series. Am J Gastroenterol. 117:S15, December 2022