There is significant interest in optimizing medical treatments of Crohn disease (CD) in hopes of preventing complications and the need for surgery. According to a 2010 study, up to 50% of patients with CD will develop disease complications including abscesses, strictures or fistulas1. In addition, 50% of patients with CD will require surgery within 10 years of diagnosis2,3.

There are several classes of biologics available for the treatment of CD, including the tumor necrosis factor alpha (TNF-α) antagonists (adalimumab, infliximab, certolizumab, golimumab), α4β7 integrin inhibitors (vedolizumab), and interleukin-12 and -23 inhibitors (ustekinumab). Although combination therapy with biologics and immunomodulators such as azathioprine is relatively well studied, there is a lack of research on the real-world use of dual biologic therapy (DBT) in patients with CD. A group led by Yang et al recently evaluated the safety and efficacy data of DBT in patients with refractory CD. Results of this study were published in Alimentary Pharmacology and Therapeutics4.

The authors retrospectively reviewed data on patients with refractory CD receiving DBT with TNF-α antagonists, vedolizumab, natalizumab, and/or ustekinumab at 2 centers in North America. The primary outcome was endoscopic improvement, determined by >50% improvement in Simplified Endoscopic Score-Crohn’s Disease [SES-CD] or explicit statement on an endoscopy report. Secondary endpoints included endoscopic remission (SES-CD < 3 or stated in report), clinical response (Crohn’s Disease-patient reported outcome-2 score [PRO2] reduction by 8), clinical remission (PRO2 < 8), C-reactive protein, and adverse events.  Patients, who required surgery while receiving DBT, were considered treatment failures for all outcomes. 

The authors identified 22 patients with CD who had undergone a total of 24 DBT therapeutic trials.  Most of the patients had a history of CD complications, including prior surgery (91%), stricturing (59%), penetrating disease (36%), and/or fistulas (55%). The median number of failed biologic treatments was 4, and there was a total of 94 failed single biologic trials among the patient cohort.  The most common reasons for failure were: secondary non-response without immunogenicity, primary non-response, immunogenicity and AE.  Prior to starting DBT treating, 79% of patients were receiving immunodulators, 33% receiving steroids, and 33% receiving antibiotics. The 3 most common DBT combinations included vedolizumab with either ustekinumab, infliximab or adalimumab.


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Although the number of DBT trials was relatively low, a number of promising findings were made. The authors of found endoscopic improvement in 43% of DBT trials and endoscopic remission in 26% of trials. Median SES-CD was reduced from 14.0 (IQR, 12.0-17.5) to 6.0 (IQR, 2.5-8.0) (P =.0005). Secondary endpoints showed promising results as well. There was clinical response in 50% of all DBT trials, clinical remission in 41%, and steroid-free clinical remission in 36%. The presence of peri-anal fistulas decreased from a baseline level of 50% to 33% after DBT use. In total, 33% of DBT trials required surgery and were thus considered treatment failures. Median CRP decreased from 17 mg/L at baseline to 9 mg/L post-treatment.

The median treatment time with DBT was 274 days and patients had up to 1 year of follow-up data. At 1 year, 38% of patients continued DBT treatment. The most frequently used therapeutic class was TNF-α antagonists. In total, 13% of DBT trials had adverse events, including drug-induced lupus and pneumonia. A patient had a series of complications including basal cell skin cancer, recurrent C. difficile infection, and Acinetobacter bacteremia, though they also had a history of all 3 prior to DBT initiation.

The authors concluded that DBT use led to improvement in clinical, endoscopic and biomarker outcomes in patients with complicated CD and a prior history of failing treatment with multiple biologics. Although DBT trials included a considerably low number of patients with complicated CD, the safety and efficacy data appeared encouraging. Based on the limited number of patients, it is challenging to determine the exact effect of concurrent steroid, immunomodulatory and antibiotic use. Some of the key concerns of using DBT are its potential safety implications. However, the safety profiles of trials in this study do not preclude future investigation. The best combination of therapeutic classes could not be determined based on the small sample size, though it appears that a TNF-α antagonist with vedolizumab/ustekinumab are attractive options based on their efficacy and safety profiles. 

Future studies are needed to prospectively evaluate DBT in a larger group of patients with CD over a prolonged period of time to determine which combinations of biologics display the best outcomes.  Even if positive data continues to accumulate, it remains to see if insurance companies will authorize and subsequently agree to cover DBT. How novel oral agents such as the JAK-2 inhibitor tofacitinib factor into the dual therapy paradigm will need to be considered as well.

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References

1.     Thia KT, Sandborn WJ, Harmsen WS, Zinsmeister AR, Loftus EV Jr. Risk factors associated with progression to intestinal complications of Crohn’s disease in a population-based cohort. Gastroenterology. 2010;139(4):1147‐1155. doi:10.1053/j.gastro.2010.06.070

2.     Bernell O, Lapidus A, Hellers G. Risk factors for surgery and postoperative recurrence in Crohn’s disease. Ann Surg. 2000;231:38-45

3.     Frolkis AD, Lipton DS, Fiest KM, et al. Cumulative incidence of second intestinal resection in Crohn’s disease: a systematic review and meta-analysis of population-based studies. Am J Gastroenterol.  2014;109:1739-1748

4.      Yang E, Panaccione N, Whitmire N, et al. Efficacy and safety of simultaneous treatment with two biologic medications in refractory Crohn’s disease. Aliment Pharmacol Ther. 2020;51(11):1031‐1038. doi:10.1111/apt.15719