Stefan Holubar, MD, on Advances in the Management of Fistulizing CD

Stem-cell therapies show promise in the management of perianal fistulizing Crohn disease (CD), Stefan Holubar, MD, noted during his presentation at the Advances in Inflammatory Bowel Disease virtual meeting. However, he cautioned against overenthusiasm, due to the limited data and availability outside of clinical trials at present.

Dr Holubar is the inflammatory bowel disease (IBD) surgery section chief and director of research in the department of colorectal surgery at Cleveland Clinic in Cleveland, Ohio.

“The key is to focus on combined medical-surgical therapy with tumor necrosis factor inhibitors, seton drainage, and attempts at definitive closure in order to improve quality of life for many,” Dr Holubar said during his presentation on emerging therapies and patient-centric management strategies in the field of fistulizing CD. “Some patients may also require proctectomy to achieve optimal quality of life,” he added.

To estimate the cumulative incidence and the risk factors of perianal CD, Dr Holubar referenced a systematic literature review that showed  “approximately 1 in 5 patients with CD develops perianal disease within 10 years of CD diagnosis, including 11.5% who have perianal disease at presentation.” The findings also revealed that two-thirds of the patients opted for perianal surgery, with a smaller group of patients requiring major abdominal surgery.

The burden of disease has far-reaching effects. The manifestations of the symptoms could lead to pain and discharge among patients, with cases of restricted mobility and constant fatigue. The disease could also have a negative and long-lasting impact on the patients’ physical, emotional, and mental well-being. And then there are challenges to treatment, Dr Holubar said. The interventions often have side effects, and patients may not completely understand the treatment plans or even tolerate them. Finally, access to treatment remains a major hurdle for many patients.

Dr Holubar stressed that improving quality of life for patients with IBD is a primary goal of surgery. "Controlling life-threatening complications and preserving the bowel/sphincter are the overarching goals of IBD surgery,” he added.

He also identified that surgical outcomes are different for patients with CD compared to those of patients with ulcerative colitis (UC). For patients with CD, surgery is not a curative solution for the underlying disease. Surgery can be targeted to combat the complications of the disease, such as fistulization, abscess, bleeding, and neoplasia, while surgery may be curative among patients with UC.

Dr Holubar explained the importance of referring patients to surgery for medically refractory disease, and “not for failure of medical therapy.” Also, “surgery is not a failure,” he insisted, and should not be treated as a therapy of last resort.

For a disease phenotype as aggressive as perianal fistulizing CD, the current biological understanding of diagnosis and treatment is inadequate, he said. Improving upon the previous classification system, Jeroen Geldof, MD, and colleagues arrived at a new expert consensus to guide decision-making in daily practice and clinical trials.

The new guide identifies 4 groups of patients with perianal fistulizing CD. Key elements include “stratification according to disease severity as well as disease outcome; synchronization of patient and clinician goals in decision making, with a proactive, combined medical and surgical approach, on a treat to target goal basis; and identification of indications for curative fistula treatment, diverting ostomy, and proctectomy,” Dr Holubar explained.

Perhaps the most important feature of the new system is that it allows a certain level of flexibility “in which patients can cycle through different classes over time,” he noted.

For diagnosis, examination under anesthesia (EUA) has been considered the gold standard. However, recent studies comparing visual inspection, palpation, and the passage of metal probes into fistula tracks under general anesthesia to a newer method using pelvic magnetic resonance imaging (MRI) or anorectal endoscopic ultrasound (EUS), suggested flaws in the long-approved method. While EUS, MRI, and EUA are all known to provide accurate diagnosis of fistula among patients with perianal CD, the optimal approach would in fact be “to combine any 2 of these 3 methods,” Dr Holubar said.

What about the role of antibiotics in the treatment of fistulizing CD? A small, randomized trial including 25 patients revealed no statistically significant difference in the use of metronidazole or ciprofloxacin vs placebo. The efficacy of treatment increased significantly when antibiotics were used in conjunction with biologics. Fistula response at week 18 for patients on a combination of ciprofloxacin and infliximab was 73.0% vs those on infliximab alone at 39.0% (P=0.12). Similarly, fistula response at week 12 for patients on ciprofloxacin and adalimumab was 70.6% vs those on adalimumab alone at 47.2% (P=0.05) 

Dr Holubar said evidence is limited that immunomodulators help fistula healing. A study published in the Annals of Internal Medicine to assess the effectiveness of azathioprine and 6-mercaptopurine in inducing remission of active CD and the effectiveness of azathioprine in maintaining remission of quiescent disease found that “compared to placebo, azathioprine or 6-mercaptopurine therapy had an odds ratio of response of 3.09 (95% CI, 2.45 to 3.91) in patients with active CD.” For active disease, continuation of therapy for at least 17 weeks improved response (P = 0.03). For quiescent disease, a higher dose improved response (P = 0.008).

Another study published in Gastroenterology found oral tacrolimus 0.2mg to be more effective in fistula improvement, but not fistula remission. While 43.0% of tacrolimus-treated patients had fistula improvement compared with 8.0% of placebo-treated patients (P = 0.004); only 10.0% of tacrolimus-treated patients had fistula remission compared with 8.0% of placebo-treated patients (P = 0.86). “Lower doses of tacrolimus should be evaluated,” he said.

In the surgical management of perianal CD, Dr Holubar said the ultimate goals should be source control, inflammation control, and local repair. While draining setons, fistulotomy, and mushroom catheters are traditional methods of treating fistulae, some newer therapies and clinical trials include stem cell-based therapies. “Cell transplantation to overcome healing problems is a new surgical tool,” Dr Holubar noted.

A French pilot study found that deep remission improved the quality of life for many patients with CD and anoperianal fistula who were treated with darvadstrocel. Similarly, autologous platelet-rich plasma proved to be generally safe among patients with perianal CD “with an acceptable healing rate over a medium-term follow-up, particularly if biological therapies are used concomitantly.”

Dr Holubar said the efficacy results from trials with adipose-derived stem cells (ASCs) demand serious consideration. ASCs are a subset of mesenchymal stem cells (MSCs) that can be obtained easily from adipose tissues and possess many of the same regenerative properties as other MSCs. A study of 21 patients followed for 6 months revealed “injection of recently collected autologous adipose tissue to be safe and to result in complete fistula healing in 57% of patients.”

In summary, Dr Holubar stated, optimal management of perianal fistulizing CD requires “careful patient assessment, evidence-based use of existing therapies, and thorough assessment to define treatment success,” as is stated in the Toronto Consensus Clinical Practice Guidelines. Medical therapy should be optimized and informed by therapeutic drug monitoring before patients are considered refractory to treatment.

Reference:

Holubar S. Advances in fistulizing Crohn disease: Emerging therapies and patient-centric management strategies. Presented at: Advances in Inflammatory Bowel Disease virtual meeting. April 20, 2023.