Editorial: Time to EXIT? When Less Is More in IBD Management. Authors' Reply

We thank Drs. Asonuma and Kobayashi [1] for highlighting our publication on long-term outcomes following anti-TNF withdrawal in patients with inflammatory bowel disease in remission [2].

As they noted, our randomised controlled trial (EXIT) and its extended follow-up study found no significant differences in relapse rates at 1 year and over the longer term between patients who discontinued or continued anti-TNF therapy [2, 3]. We acknowledge that these results contrast with previous randomised trials such as HAYABUSA, STOP-IT, and SPARE, which reported higher relapse rates following anti-TNF withdrawal [4-6].

Several key differences distinguish EXIT from these earlier trials. Primarily, EXIT included only highly selected patients who had maintained deep, stable remission for at least 6 months on standard-dose anti-TNF combined with immunomodulators, without prior risk factors such as intestinal resection or significant endoscopic lesions [2]. Conversely, the cohorts of HAYABUSA, STOP-IT, and SPARE enrolled more heterogeneous patient populations, had shorter anti-TNF exposure times, did not uniformly include concomitant immunomodulator therapy, and only STOP-IT was double-blinded [4-6]. Moreover, all participants in EXIT continued stable immunomodulator therapy before and after randomisation. While retrospective studies have suggested a protective role for immunomodulators post-withdrawal of a biologic, prospective randomised data are limited [2, 4-8]. In EXIT and EXIT long-term, the consistent use of immunomodulators potentially mitigated post-withdrawal flares, thereby minimising differences in relapse rates between treatment arms.

Our findings suggest that a carefully monitored anti-TNF discontinuation strategy, with planned treatment resumption upon relapse, is effective in carefully selected patients. This aligns with real-world evidence, which also reported high remission recapture rates after treatment resumption [9, 10].

We agree with Drs. Asonuma and Kobayashi that future research should focus on identifying optimal candidates for anti-TNF withdrawal and retreatment. Planned anti-TNF withdrawal may be safe in highly selected patients in stable, deep remission on combined therapy, provided rigorous biomarker monitoring (faecal calprotectin and C-reactive protein) is conducted, especially during the first year after discontinuation. Moreover, rapid access to anti-TNF therapy upon relapse is crucial to successfully recapturing remission. This strategy should not be routinely applied but should rather be individualised, carefully weighing patient preferences, risk profiles, and commitment to frequent monitoring.

Crucially, this “exit” strategy should be reserved for motivated patients willing to undergo stringent monitoring. However, for broader IBD populations—especially those with previous surgeries, anti-TNF dose escalation, monotherapy, or elevated biomarkers—the risk of withdrawal probably outweighs potential benefits.

EXIT and EXIT-long term studies thus contribute to a paradigm shift: anti-TNF withdrawal is not categorically unsafe but is contingent on precise patient selection, sustained immunomodulator co-therapy, and vigilant follow-up. Future studies must clarify optimal monitoring intervals, define precise biomarker thresholds, and explore whether similar withdrawal strategies are applicable with other biological agents or JAK inhibitors.

In summary, the findings of EXIT [2] and EXIT long-term [3] advance the discussion from uncertainty to a measurable risk–benefit calculation demonstrating that, under strict conditions, less treatment can indeed achieve more.