Frequency and Effectiveness of Empirical Anti-TNF Dose Intensification in Inflammatory Bowel Disease: Systematic Review with Meta-Analysis

Abstract

Loss of response to antitumor necrosis factor (anti-TNF) therapies in inflammatory bowel disease occurs in a high proportion of patients. Our aim was to evaluate the loss of response to anti-TNF therapy, considered as the need for dose intensification (DI), DI effectiveness and the possible variables influencing its requirements. Bibliographical searches were performed. Selection: prospective and retrospective studies assessing DI in Crohn’s disease and ulcerative colitis patients treated for at least 12 weeks with an anti-TNF drug. Exclusion criteria: studies using anti-TNF as a prophylaxis for the postoperative recurrence in Crohn’s disease or those where DI was based on therapeutic drug monitoring. Data synthesis: effectiveness by intention-to-treat (random effects model). Data were stratified by medical condition (ulcerative colitis vs. Crohn’s disease), anti-TNF drug and follow-up. Results: One hundred and seventy-three studies (33,241 patients) were included. Overall rate of the DI requirement after 12 months was 28% (95% CI 24–32, I2 = 96%, 41 studies) in naïve patients and 39% (95% CI 31–47, I2 = 86%, 18 studies) in non-naïve patients. The DI requirement rate was higher both in those with prior anti-TNF exposure (p = 0.01) and with ulcerative colitis (p = 0.02). The DI requirement rate in naïve patients after 36 months was 35% (95% CI 28–43%; I2 = 98%; 18 studies). The overall short-term response and remission rates of empirical DI in naïve patients were 63% (95% CI 48–78%; I2 = 99%; 32 studies) and 48% (95% CI: 39–58%; I2 = 92%; 25 studies), respectively. The loss of response to anti-TNF agents―and, consequently, DI―occurred frequently in inflammatory bowel disease (approximately in one-fourth at one year and in one-third at 3 years). Empirical DI was a relatively effective therapeutic option.

Primary Failure to an Anti-TNF Agent in Inflammatory Bowel Disease: Switch (to a Second Anti-TNF Agent) or Swap (for Another Mechanism of Action)?

“…Finally, a significant proportion of patients lost the response to the second anti-TNF in the long term, although increasing the dose was an effective strategy for regaining response in some cases. Dose escalation in patients who lose the response to anti-TNF drugs is effective and common in clinical practice [40,41]. However, there are insufficient data to recommend dose optimisation strategies in patients who do not respond to the second anti-TNF drug and experienced primary failure with the first one.…”

Monitoring of infliximab treatment in inflammatory bowel diseases – basic knowledge and current data based on clinical trials in a population of Polish patients

“…14 A recent analysis of numerous studies examining the need for IFX dose escalation in IBD showed that patients with UC more often required dose escalation than patients with Crohn's diseas. 15 However, attempts to alter the dosing regimen and accelerate the induction strategy in severe UC have produced inconclusive results. A small retrospective analysis of 50 patients with severe UC showed that the accelerated induction strategy of IFX reduces the need for an early colectomy.…”

“…49 An alternative to reactive monitoring is empirical dose escalation based on clinical symptoms alone and this has also been shown to be relatively beneficial. 50 However, reactive TDM of biologics is ultimately recommended as the new standard of care as it enables the most rational therapeutic decisions to be undertaken. 37 An important advantage of TDM is not only the possibility to determine the extent to which treatment should be escalated but also to identify patients who will not benefit from dosage increase due to normal drug levels or the presence of high antibody titers.…”

Systematic review and meta-analysis: evaluating response to empiric anti-TNF dose intensification for secondary loss of response in Crohn’s disease

“…Two recent systematic reviews, one of which also undertook a meta-analysis, evaluated the clinical effectiveness of anti-TNF dose intensification to address LOR across Crohn’s disease and ulcerative colitis. 8,9 While comprehensive in their approach, neither review distinguished between anti-TNF dose intensification undertaken to address secondary LOR and anti-TNF dose intensification undertaken to address pooled primary non-response and secondary LOR. It is, however, important to differentiate between both of these entities, given the disparate clinical effectiveness of anti-TNF dose intensification between primary responders and primary non-responders.…”