Mentoring in IBD is an innovative and successful educational program for Canadian gastroenterologists that includes an annual national meeting, regional satellites in both official languages, www.mentoringinibd.com, an educational newsletter series, and regular electronic communications answering key clinical questions with new research. This issue is based on the presentation made by Dr. Vipul Jairath, at the 22nd annual national meeting, Mentoring in IBD XXII: The Master Class, held virtually, November 5, 2021.
The objective of this presentation was to discuss sequencing of therapies incorporating new molecules and new strategies in IBD with emphasis on combination biologics. The rationale for dual biologic therapy is that multiple pathways drive inflammatory process and that remission rates for currently available biologics remain limited when used as single agents. Furthermore, mechanistic failure can lead to secondary loss of response with single biologic agents, biologics used second- or third-line tend to be less effective, and agents effective for luminal disease may not be as effective for extraintestinal manifestations or other concomitant immune-mediated inflammatory diseases (IMIDs). This is particularly relevant given the burden of IBD often goes beyond the gut, and studies have shown that IBD patients have a 7.5 times higher risk of developing another IMID compared with non-IBD patients.(1)
Theoretical advantages of combined therapy include greater efficacy, prevention of immunogenicity, and increased drug concentrations. Potential disadvantages of combined therapy include increased adverse effects, unknown safety risks, the complexity and cost of the regimen, and an increased need for patient monitoring.
Clinical scenarios where combination strategies may be appropriate include refractory IBD or well-controlled IBD with an uncontrolled concomitant IMID. As the different mechanistic pathways underlying immune-modulated diseases are becoming better understood, there has been a shift towards a biology- and system-mediated approach to treatment selection, which may aid in selection of therapies with a common mechanism to one or more conditions. For example, when treating ulcerative colitis (UC) and ankylosing spondylitis (AS), an anti-TNF or tofacitinib may be the most appropriate choices (See Table 1).
The notion of combined therapy in IBD is not new. For example, in 2007 a trial of infliximab and natalizumab in combination was completed in patients with moderately to severely active Crohn’s Disease (CD). Results showed a non-significant efficacy trend in favor of combination therapy and found the combination well tolerated with no new safety signals, though the follow-up period was short.(3)
In addition, combination therapy with thiopurines is well established and data from the SONIC trial showed that the use of infliximab plus thiopurine in CD led to significantly more patients achieving steroid-free remission at week 26 than either therapy alone.(4) Further post hoc analysis investigating the exposure-response relationships determined that the benefit of combination therapy may be due to azathioprine’s influence on the pharmacokinetics of infliximab, in addition to an additive effect and reducing immunogenicity.(5)
In addition to efficacy, safety is a common concern associated with combination therapy. This was investigated within the TREAT Registry, which revealed no increased risk of infection associated with combination therapy. Risks of infection attributed to therapy may be offset by reduced susceptibility to infection with better disease control. (6)
There are data on combination therapy from the rheumatology experience that may be of relevance to IBD. For example, a randomized-controlled trial (RCT) investigated the use of etanercept plus anakinra combination in patients with active rheumatoid arthritis (RA) despite methotrexate treatment. Results showed that the combination therapy for 6 months provided no additional treatment benefit nor immunogenicity. However, more serious infection, neutropenia, and injection site reactions occurred in the combination group leading the authors to recommend against the use of this combination in RA.(7)
Similar results were seen with an RCT of etanercept and abatacept in RA, showing no additional treatment benefits of combination therapy after 12 months but more serious adverse events (SAEs) and serious infections (SIs), again leading the authors to recommend against the use of this combination in RA.(8) Similar results were seen in another RCT that looked at anti-TNF/methotrexate combined with rituximab in RA.(9)
Lastly, a study on ABT-122, a bispecific variable domain immunoglobulin targeting TNF and interleukin (IL)-17A, in patients with RA with inadequate response to methotrexate (n=22) showed no meaningful efficacy benefit and no new safety signals up to 12 weeks over adalimumab alone.(10) Given the safety questions arising from these studies, a meta-analysis focusing on the safety of combination disease-modifying anti-rheumatic drugs (DMARDS) in RA concluded that there is no added benefit, while there is an increased risk of SAEs during the first twelve months of combination treatment.(11)
In IBD, data on combination therapy thus far are mainly from retrospective cohort studies or case reports. A recent review found that in all studies to date, combination therapy had positive outcomes, with only one study reporting an increased risk of infection.(12)
Specifically, a retrospective cohort study investigated the use of combination biologic or small molecule therapy in 50 patients with either IBD in remission and continued joint or skin inflammation or joint or skin in remission, but ongoing IBD activity. The study included a variety of combinations in UC and CD, most commonly with the base drug being vedolizumab. Results showed a significant increase in clinical and endoscopic remission rates with the introduction of combination therapy that was paralleled by improvement in biomarkers. Nothing atypical was observed in terms of safety.(13)
Another retrospective cohort study described 22 refractory patients with CD for whom a second biologic was added sequentially. In the majority of cases the baseline biologic was vedolizumab or ustekinumab and add-on was mainly anti-TNF. The results showed a significant improvement in endoscopic, clinical, and biomarker outcomes, and 38% of patients remained on dual therapy at 1 year. Surgery was needed in 33% of cases and nothing atypical was noted in terms of adverse events.(14)
Also relevant to this discussion is a study that looked at the safety of combination biologic and anti-rejection therapy in 20 IBD patients post liver transplantation. The case series combined with available literature concluded that there were no serious infections aside from C. difficile, which may be due to concurrent antibiotic use.(15)
To summarize the data available to date on combination therapy in IBD, possible combinations to consider are summarized in Table 2.
In terms of the future of combination therapy in IBD, there are some trials underway to help guide clinical practice:
To summarize, case series of combination therapy in IBD are generally positive, but our understanding of safety outcomes is limited by short follow-up durations. Furthermore, it can be debated whether observational studies from rheumatology that show no impact on efficacy and compromised safety can be extrapolated to IBD.
When facing patients with IBD that are refractory to treatments, it is important to review their medical records in detail to understand whether reported prior biological failures were indeed true failures and to characterize the nature of the failures. Some therapies can be re-introduced, combination therapies with different immunomodulators can be tried, trial eligibility can be assessed, and surgery can be considered.
Failing these steps, combination biologic/small molecule therapy could be carefully considered with clear counselling regarding off-label use and unknown safety concerns. In terms of risk, it is important to weigh against the risk of untreated disease (recurrent surgery, total parenteral nutrition, etc.). Furthermore, a defined timeframe (e.g., 6 months) should be agreed upon for re-assessment. Data thus far best support the use of vedolizumab or ustekinumab as anchor biologic.
Jacqueline is a 32-year-old female working as a paramedic with an eight-year history of ileocolonic CD. She initiated azathioprine soon after diagnosis, then transitioned to methotrexate. Adalimumab was commenced 5 years ago but concomitant methotrexate subsequently stopped at her request after 1 year of combination therapy. Her CD has been ‘controlled’ with 40 mg of adalimumab every 2 weeks as monotherapy for the last 4 years.
She reports increasing symptoms over the last 6 months, during which time she had the initial COVID vaccine, the second dose and most recently a booster dose. She currently has three semi-formed bowel movements (BMs) per day, abdominal cramps and feels fatigued.
Her investigations reveal:
With regard to COVID vaccination in patients with IBD(20):
Management strategies in this patient include optimization of her current treatment or switching to another treatment:
You advise Jacqueline that the frequency of adverse effects to the COVID vaccine in individuals with IBD is similar to that reported in the general population, and of note, IBD patients on biologic therapy were less likely to experience an adverse effect. You decide to check an adalimumab level while on 40 mg every other week, which returns at 12.3 mcg/mL.
Bowel ultrasound reveals prominence of the terminal ileum and sigmoid. After discussion, you decide to dose escalate to 40 mg weekly for three months, then reevaluate. Unfortunately, her symptoms progress and she requests to change therapies, also mentioning new perianal discomfort.
In terms of therapeutic options to consider next for this patient:
Colonoscopy reveals moderate inflammation with occasional ulceration in the terminal ileum, the descending colon and the sigmoid without rectal involvement. Perianal examination is non-contributory, but digital rectal examination reveals moderate hemorrhoids, which you believe are contributing to her perianal discomfort.
Jacqueline declines any further anti-TNF therapy after reading reports of waning antibodies to COVID and is not reassured by her recent booster COVID vaccination. She requests a ‘gut-specific’ option that will not affect her ‘immune system’, so intravenous induction and subcutaneous maintenance doses of vedolizumab are provided.
At her 3 and 6-month follow-up appointments Jacqueline states she is far less fatigued and has an overall improved sense of well-being. She reports that she has been wearing a pad because of blood and “pus” leakage from her “hemorrhoids”. MRI demonstrates a small trans-sphincteric tract leading out to the gluteal skin corresponding to an updated perianal physical examination.
You increase the vedolizumab dosing to q4w for 6 months. There is further improvement in her bowel frequency and abdominal pain, and she achieves mucosal healing as evidenced by colonoscopy. You had hoped there may be some effect on her perianal disease, but the discomfort worsens, with the development of complex branching perianal fistulae.
The 2021 AGA Technical Review on the Medical Management of Moderate to Severe Luminal and Perianal Fistulizing Crohn’s Diseases recommends the following for adults with symptomatic fistulizing CD:(22,25)
You ponder whether to:
While you are scratching your head over these complex decisions, Jacqueline calls your office about a new skin rash on her neck, behind her ears, and on her lower limbs.
John K. Marshall, MD MSc FRCPC AGAF, Director, Division of Gastroenterology, Professor, Department of Medicine, McMaster University, Hamilton, ON
Vipul Jairath, MBChB (hons) DPhil MRCP FRCPC, Professor of Medicine, Division of Gastroenterology, Western University, London Health Sciences Centre, London, ON
Alain Bitton, MD FRCPC, McGill University, Montreal, QC
Anne M. Griffiths, MC FRCPC, University of Toronto, Toronto, ON
Karen I. Kroeker, MD MSc FRCPC, University of Alberta, Edmonton, AB
Cynthia Seow, MBBS (Hons) MSc FRACP, University of Calgary, Calgary, AB
Jennifer Stretton, ACNP MN BScN, St. Joseph’s Healthcare, Hamilton, ON
Published by Catrile & Associates Ltd., 167 Floyd Avenue, North York, ON M4J 2H9
(c) Catrile & Associates Ltd., 2022. All rights reserved. None of the contents may be reproduced in any form without prior written permission from the publisher. The opinions expressed in this paper are those of the authors and do not necessarily reflect the opinions or recommendations of the sponsors, the grantor, or the publisher.