De-escalation of IBD Combination Therapy In Patients with Crohn’s Disease

Waseem Ahmed, MD
Assistant Professor of Medicine
University of Colorado Crohn’s and Colitis Center
Division of Gastroenterology & Hepatology 
University of Colorado School of Medicine
@Waseem_AhmedMD

Shomron Ben-Horin, MD
Chief, Gastroenterology Department
Sheba Medical Center
Tel-Aviv University
Israel
@ShomronH

Aline Charabaty, MD, AGAF, FACG
Assistant Professor of Medicine
Johns Hopkins School of Medicine
Clinical Director, IBD Center
Johns Hopkins–Sibley Memorial Hospital
Washington, DC
@DCharabaty

Combination therapy with anti-TNF therapy and a thiopurine has been shown to be superior to a monotherapy approach to induce and maintain remission in moderate to severe Crohn’s disease. However, the long-term use of this approach carries some significant risks and may not be cost- and risk-effective for many patients.

We review here a @MondayNightIBD discussion looking at the case of a young patient with ileal CD in clinical and endoscopic remission who is on combination therapy and wants to de-escalate medical therapy. The majority of clinicians participating agreed that de-escalation of therapy was appropriate for the patient, noting the different factors that need to be considered when this approach is used and the need for subsequent monitoring. Conversely, in our patient poll, the majority of respondents favored continuing all their current medications and not changing their regimen if they are doing well on it. De-escalation of combination therapy is a complex topic, and in the absence of formal guideline-based recommendations, requires careful shared decision making between each patient and the treating medical team. After reviewing the available data on de-escalating therapy from combination to thiopurine or anti-TNF monotherapy, we propose an #IBDAlgorithm to guide clinicians in their de-escalation strategy for patients with CD (Figure 1).

Figure 1. #IBD Algorithm for de-escalation of therapy in IBD.

6-TG, 6-thioguanine; CRP, C-reactive protein; FCP, fecal calprotectin; IFX, infliximab; IUS, intestinal ultrasound; MRE, magnetic resonance enterography; MTX, methotrexate; TDM, therapeutic drug monitoring; TL, trough level; TNFi, tumor necrosis factor inhibitor; TP, thiopurine; VCE, video capsule endoscopy.

Clinical Case Scenario

A 32-year-old woman with a 5-year history of ileal CD has been receiving a regimen of infliximab (IFX) (5 mg/kg every 6 weeks) and azathioprine (AZA) (1.8 mg/kg daily) for 2 years and is in clinical remission, with an occasional anal fissure. Colonoscopy 6 months ago was consistent with endoscopic remission. Complete blood count and C-reactive protein levels are normal. Fecal calprotectin (FCP) is 89 mcg/g. The patient’s IFX trough level is 4 mcg/mL, and there is no evidence of antibodies to infliximab. She notes that her brother recently was diagnosed with melanoma and asks if she can stop her IFX infusions.

Our IBD poll asked gastroenterologists and other healthcare professionals how they would advise the patient in this case (Figure 2).

Figure 2. Healthcare professionals poll: What is your recommendation for the patient in endoscopic remission on IFX+AZA who wishes to stop one or both medication?^a

^a 306 votes by poll participants.

Scope of the Problem With Combination Anti-TNF + Thiopurine

The pivotal SONIC trial demonstrated the improved efficacy of combination therapy with IFX and AZA over either monotherapy in CD, and this combination strategy remains a mainstay regimen for most patients initiating anti-TNF (particularly IFX) for moderate to severe CD.¹ Indeed, adding an antimetabolite (thiopurines or methotrexate) to anti-TNF decreases the risk for development of anti-drug antibodies and increases the anti-TNF drug level, both of which contribute to improved response and duration of response.² However, long-term use of combination therapy with both an anti-TNF and a thiopurine confers an increased risk for infection and lymphoma compared with each therapy alone.^3,4 In addition, both therapy classes increase the risk for skin cancer (with anti-TNF increasing the risk for melanoma and thiopurines the risk for non-melanoma skin cancers), and thiopurines increase the risk for HPV-associated cervical cancer and urinary tract malignancy in elderly patient.^5-7 Moreover, the costs of drugs and monitoring as well as access issues remain significant individual and population-level barriers.⁸

Data on Anti-TNF Withdrawal With Maintainance of Thiopurine Monotherapy

Anti-TNF therapy cost and access can vary, with some populations particularly vulnerable to out-of-pocket expenses or having limited access to infusion centers.⁹ Thus, an important question is whether de-escalation to thiopurine monotherapy is an acceptable alternative to combination therapy in patients with cost and access hurdles or those who value the convenience of oral therapy.⁷ The landmark STORI trial was a prospective cohort study of 115 patients with CD in steroid-free clinical remission for at least 6 months on combination therapy with IFX and an antimetabolite. Patients underwent de-escalation of IFX and continued antimetabolite monotherapy. Approximately 50% of patients relapsed within 1 year of discontinuation of IFX. Long-term follow-up of this cohort has demonstrated a 20% rate of biologic-free survival at 7 years. Predictors of relapse included upper gastrointestinal CD, anemia, leukocytosis, and biochemical disease at the time of IFX discontinuation.^10,11 The STOP-IT trial was a randomized, double-blind, placebo-controlled withdrawal study of patients with CD who were on standard IFX for at least a year, approximately 50% of whom also received a thiopurine. All the patients were in clinical, biochemical, and endoscopic remission before they stopped IFX. The rate of relapse-free survival at 1 year was 51% in patients who discontinued IFX, including those who were maintained on thiopurine, versus 100% in those who did not stop IFX.¹²

Data on Antimetabolite Withdrawal With Maintainance of Anti-TNF Monotherapy

Part of the conundrum of combination therapy lies in the debate over whether its benefit is due to a separate or synergistic effect of anti-TNF and thiopurines. Although both drug classes demonstrate steroid-free efficacy in maintenance of remission for both CD and ulcerative colitis, post-hoc analysis of the SONIC trial showed that the primary benefit of a combination approach is due to the effect of AZA on IFX pharmacokinetics, ie, thiopurines decreasing IFX clearance and increasing IFX drug level.¹³ This raises the possibility that anti-TNF monotherapy strategy with adequate biologic exposure (therapeutic anti-TNF drug level) may be associated with equal outcomes and can be used in lieu of a combination based-strategy.

Conversely, the main concerns with stopping the antimetabolite in a patient previously in remission on combination therapy, are the risk for developing antibodies to anti-TNF and/or losss of adequate anti-TNF drug level and subsequent loss of response to the anti-TNF. In an open-label prospective controlled trial, investigators randomized IBD patients who were in durable remission (clinical and biomarkers and/or endoscopic) on combination IFX and full-dose of AZA (2-2.5 mg/kg per day) to discontinue AZA, decrease the dose of AZA by half, or continue full-dose AZA with IFX. Patients who continued the full dose or halved the dose of AZA had similar rates of relapse at 1 year (17.8% and 11.5%, respectively), similar mean trough levels of IFX, and similar rates of antibodies to anti-TNF formation at 1 year (14.2% and 18.5%). However, patients who completely discontinued AZA had a 30.8% relapse rate at 1 year, as well as a higher rate of decrease in the mean trough IFX level and formation of antibodies to anti-TNF, compared with the two other groups (53.8%).¹⁴

The recent open-label SPARE trial randomized individuals with CD on combination therapy for over a year and in sustained steroid-free remission for at least 6 months to either continue combination therapy, stop IFX, or stop the antimetabolite. The relapse rate at 2 years for individuals stopping IFX was 40%, whereas it was not different between individuals who stopped the antimetabolite (10%) and those who continued combination therapy (14%). Of note however, patients in the SPARE trial had a nearly equal mean time spent in remission over 2 years, regardless of relapsing during the study. Finally, what is reassuring, and in line with retrospective studies where IFX was stopped but thiopurine maintained, is that response was recaptured by re-initiating IFX in nearly all patients who flared when they were switched to antimetabolite monotherapy.^11,15 Overall, these results suggest that once sustained remission is achieved on combination therapy, discontinuing the antimetabolite and maintaining the patient on IFX monotherapy provides long-term remission rates comparable to combination therapy.

Recommended Strategy For MNIBD Participants

Some conclusions can be drawn from the available data and the discussion on @MondayNightIBD to help guide clinicians in their decision when they are considering de-escalating therapy in a patient with CD from combination anti-TNF and thiopurines to monotherapy.

1.Good candidates for therapy de-escalation are patients who have been in steroid-free and sustained clinical AND biomarker and/or endoscopic remission on a stable regimen of anti-TNF and thiopurine.

2.Clinical remission alone is not a sufficient to allow consideration of de-escalation, and objective evidence of biomarker and/or endoscopic remission should be obtained before de-escalation.

3.Stopping the antimetabolite, not the anti-TNF, is the most effective strategy to maintain remission. In other words, withdrawal of anti-TNF carries a high risk for relapse even when patients are maintained on a thiopurine.

4.However, several health care practitioners (HCPs)recognized the cost burden of biologics and access limitations in certain areas of the world and for underinsured patients, and subsequently recommend thiopurine maintenance after initial combination therapy.

5.While most discussants agreed that it is important to check anti-TNF level and check for the presence of antibodies to anti-TNF before withdrawing thiopurines, there was controversy as to what level is considered adequate or therapeutic in a patient in remission. Most HCPs considered an IFX trough level of 4 mcg/mL to be adequate in this case, although data show that a higher drug level is associated with endoscopic remission.¹⁶ Many HCPs reflected on the fact that anti-TNF target trough levels should be individualized to the patient’s disease phenotype and severity and how long the patient has been in remission on the current level.

6.Several participants recommended optimizing the IFX dose before discontinuation of the thiopurine, and most agreed that, whether anti-TNF dosing is adjusted or not before de-escalation, it is important to check levels a few months after decreasing the dose and/or discontinuation of the thiopurine. Keeping the antimetabolite on board should be considered in patients who are not able to optimize their anti-TNF dose or frequency (because of payor or access issues) to keep their drug level adequate.

7.Some HCPs are in favor of keeping the patient on combination therapy and suggested substituting methotrexate for thiopurine, noting it has less of an association with lymphomas but maintains optimized IFX pharmacokinetics.¹⁷

8.Proactive and close disease monitoring should be done after de-escalation of therapy, with periodic evaluation of symptoms and biomarkers as well as endoscopy.

9.The decision about therapy de-escalation has to consider both disease and patient characteristics, including the disease phenotype and extent, presence of perianal disease, history of a relapsing disease course, need for treatment intensification, prior therapy failures, prior history of immunogenicity on anti-TNF, history of CD surgeries, patient’s age and fitness, comorbidities, contraindications to certain drug classes, intolerance to therapies, and history of recurrent infections.

10.A rescue strategy should be discussed ahead of time, to be implemented in case the patient relapses on monotherapy. Having a plan ready can decrease the duration of disease flare and the risks for steroid exposure, surgery, hospitalization, and ineffective recapturing of remission.^18,19

11.Shared decision making is a vital component when discussing de-escalation of combination therapy. Patients need to be aware of the risks and benefits of switching to anti-TNF or AZA monotherapy, and they must agree to monitoring after such a strategy is implemented. The patient poll results re-enforced this paradigm, with the majority of patient responders voicing their preference to continue on their current medicines as long as their disease was in remission and “not rock the boat” (Figure 3). The risk for relapse was a strong deterrent for many patients, but they acknowledged a desire to minimize medications if possible.

Figure 3. Patients with IBD poll: When doing well on more than one IBD medication, what would you prefer to do with your treatment regimen?^a

^a 173 votes by poll participants.

12.HCPs and polled patients agreed that withdrawal of therapy altogether should be avoided in the vast majority of patients. This @MondayNightIBD discussion and this review focused on withdrawal strategies of a single agent for patients on combination therapy. Data about discontinuing therapy altogether in selected patients on monotherapy with anti-TNF is anecdotal in nature (no RCTs), making it hard to draw any firm conclusions.

Conclusion

De-escalation from combination therapy (anti-TNF and antimetabolite) to monotherapy is a reasonable consideration for a significant proportion of patients with CD, but should be implemented only in patients with confirmed, stable steroid-free endoscopic remission. The risks and benefits of de-escalation should be discussed with the patient, with acknowledgement of the available data and knowledge gaps, as well as the need for close monitoring and a rescue plan in case of relapse. The decision should be individualized based on the patient’s preference, medical history, and disease characteristics. Certain high-risk patients, such as those with prior exposure to multiple prior biologics, a history of multiple surgeries, severe penetrating or perianal disease, a history of immunogenicity to anti-TNF, or an inability to achieve therapeutic biologic drug level without an immunomodulator, may benefit remaining on combination therapy. Withdrawal of the antimetabolite and maintenance on anti-TNF is the most effective strategy to maintain remission. Ideally, the monotherapy should be optimized, and drug levels adjusted in accordance to the patient-specific treatment goals.

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This article is from the June 2023 print issue.