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Optimized Remicade monotherapy effective for IBD induction
Remicade monotherapy with optimized dosing was an effective treatment for patients with inflammatory bowel disease beginning induction therapy, according to data published in Alimentary Pharmacology & Therapeutics.
David Drobne, MD, PhD, of the department of gastroenterology at University Medical Centre Ljubljana in Slovenia, and colleagues wrote that combination therapy with azathioprine has been the preferred method of Remicade (infliximab, Janssen) induction because of improved pharmacokinetics and lower drug consumption. However, monotherapy has become increasingly common as the addition of infliximab biosimilars has lowered treatment costs.
“It is unclear whether substituting the 612 months of combination treatment with optimized infliximab monotherapy results in equal short and longterm clinical effectiveness,” they wrote. “It is also unknown to what extent the optimized infliximab monotherapy increases the consumption of costly infliximab in comparison to combination treatment, which is currently the preferred strategy in most IBD centers.”
Researchers studied the clinical success and infliximab consumption of both strategies in 149 patients with IBD starting induction and undergoing intensive drug monitoring assisted treatment optimization.
They found that patients in the mono and combination therapy groups had similar drug retention rates after induction (96% vs. 97%), after the first year (90% vs. 83%) and at the end of follow-up (74% vs. 75%). Both groups also had similar rates of steroid use at one year (5% vs. 14%; P = .08) and mucosal healing at the end of follow-up (64% vs. 67%)
Investigators found that the monotherapy group had higher infliximab consumption (7.6 mg/kg every 8 weeks; interquartile range [IQR], 5.9-10.3 vs. 6.4 mg/kg every 8 weeks; IQR, 5.28; P = .019) and lower trough levels (1.7 µg/mL; IQR, 0.36.6 vs. 5 µg/mL; IQR, 2.58.7; P = .012) compared with the combination therapy at year one. However, once patients in the combination group discontinued azathioprine for a median of 14 months, the differences disappeared.
Drobne and colleagues wrote that patients receiving optimized infliximab monotherapy can achieve similar outcomes as patients who also receive azathioprine as long as they receive higher doses of drug during the first year of treatment.
“Azathioprine cotreatment had no impact on the longterm clinical outcome of patients and only a transient infliximabsparing effect for the duration of azathioprine cotreatment,” they wrote. “Our results, together with the findings of others, indicate that routine use of azathioprine cotreatment during introduction of infliximab in patients who previously failed azathioprine is questionable. The efficacy, safety and costeffectiveness of optimized infliximab monotherapy should be evaluated in a prospective study.” – by Alex Young
Disclosures: Drobne reports serving as a speaker, consultant and advisory board member for AbbVie, Janssen, Krka, MSD, Pfizer and Takeda. Please see the full study for all other authors’ relevant financial disclosures.
Perspective
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Combination therapy with infliximab and thiopurines is currently the standard of care for treating patients with IBD. Based primarily on the SONIC trial, combination therapy is more effective than infliximab monotherapy or azathioprine. This combination leads to higher infliximab concentrations and less formation of antibodies to infliximab which are treatment failure and infusion reactions. However, combination therapy can increase the risk for serious and opportunistic infection, lymphoma and hepatosplenic T-cell lymphoma. Further, higher infliximab concentrations can also be achieved by increasing the dose and/or shortening the interval.
A recent post-hoc analysis of the randomized controlled trial SONIC showed that among patients with Crohn’s disease and similar serum concentrations of infliximab, combination therapy with azathioprine was not significantly more effective than infliximab monotherapy. It was the concentration of infliximab that mattered, not whether the patient was on combination therapy. The concept of ‘optimized monotherapy’ was introduced 5 years ago in a retrospective pilot study that compared proactive therapeutic drug monitoring (TDM) to standard of care. A more recent single-center retrospective pediatric study showed that infliximab durability did not differ between patients on infliximab monotherapy dosed based on proactive TDM and patients receiving combination therapy. Proactive TDM is defined as the evaluation of drug concentrations and anti-drug antibodies with the goal of adjusting to dose to aim for a target therapeutic drug concentration.
Drobne and colleagues conducted a well-designed retrospective cohort study and compared the clinical success of combination vs. optimised monotherapy strategies in 149 patients with IBD (94 CD) starting infliximab and undergoing intensive TDM assisted treatment optimization. They found that these therapeutic strategies had similar drug retention rates after induction, after the first year, and at the end of follow-up (median 19 months; IQR: 12‐40 months). Moreover, both groups also had similar rates of steroid use at 1 year and mucosal healing at the end of follow-up. However, the monotherapy group had higher infliximab consumption and lower trough levels compared with the combination therapy at 1 year; although, at the end of follow‐up, when azathioprine had been discontinued for a median of 14 months (IQR: 3‐33), these differences disappeared. The authors concluded that azathioprine cotreatment had no impact on the long-term clinical outcome of patients and only a transient infliximab sparing effect for the duration of azathioprine co-treatment.
Nevertheless, this study is limited by the retrospective design and the potential allocation bias for choosing a short‐term combination strategy over infliximab monotherapy for patients with a more severe disease phenotype. Another limitation, as pointed out also by the authors, could be the short duration (6-12 months) of azathioprine cotreatment. Finally, as the authors also suggest, prospective studies are needed to evaluate the efficacy, safety and cost-effectiveness of optimized infliximab monotherapy. However, if patients or physicians choose not to use combination therapy, optimized infliximab monotherapy with proactive TDM appears to be a viable alternative.