Old and Novel Therapies in Inflammatory Bowel Disease

Treatment of acute flare in IBD relies on corticosteroids (Cs). In patients with acute severe UC (ASUC) failing to respond to Cs, Cyclosporine A (CyA) is used as a rescue therapy to avoid colectomy. For patients responding to CyA, thiopurines are used as maintenance therapy. In some, response to thiopurines is lost in long- term and some patients prove intolerant of or unresponsive to therapy. For these, biologicals have proven to be an efficient alternative. However, the response to biologicals, if achieved, is frequently lost over time. In CD, surgery is rarely curative. In UC, surgical treatment is considered a curative therapy but some patients are reluctant to undergo colectomy. In treatment-refractory IBD, dual biological therapy (DBT) has emerged as a new treatment option.

Data on the effects of intravenous (iv) Cs and CyA rescue therapy in the long-term disease evolution of ASUC are scarce and partly inconsistent and evidence on the perioperative safety of CyA in IBD patients is lacking. In addition, there is a lack of long-term real-world data on the disease course after the first course of biologicals. DBT is a novel form of treatment. Published data on the safety and effectiveness of DBT are still rare and official guidelines are lacking.

All patients 16 years or over treated for UC in Tampere University Hospital between the years 2006-2020 were identified from patient records. UC patients treated with first intravenous Cs, CyA rescue therapy, or first course of biologicals were included. In the multicentre study, we contacted all Finnish centres treating IBD patients with DBT between the years 2015 and 2020. Of the six centres, four participated.

Of the 217 ASUC patients treated with first course of iv Cs, 85% responded to treatment. Of the responders, 21% had long-term response with no need for enhancement of therapy during median 7.5 years of follow-up. Of all patients, 69% required further Cs and 48% re-hospitalization due to a new flare during follow-up. Altogether 71% of patients used thiopurines as maintenance therapy, of whom in 72% of cases treatment was initiated within one year from admission to index flare. Biologicals were initiated in 17% of patients. In this series five (2.3%) patients needed emergency surgery and altogether 56 (26%) were operated on during long-term follow-up. Clinical and endoscopic severity predicted poorer outcome while patients with onset of UC at index flare were more likely to benefit from treatment. Of those 182 UC patients treated with CyA rescue therapy, 76% had short-term response and 23% achieved long-term remission during media follow-up of 3.8 years. Of all patients, 29% were taking thiopurines at the end of follow-up. Altogether, 46% required further Cs due to a new flare and 33% biologicals or small molecules for enhancement of treatment. Of the responders, 32% needed colectomy. Of those not responding to CyA, 55% needed surgery between admission and index flare and 86% during follow-up. IFX was used as third-line rescue therapy in 16 patients, of whom 37% benefitted. The overall colectomy rate in this series was 45%. When comparing CyA-treated patients to all UC patients operated on, CyA did not increase the risk for postoperative complications when compared to Cs alone. In 2% of patients, anaphylaxis was reported as a severe adverse event (AE) while significant AEs were reported in 8%. The extent of the disease seemed to predict the need for colectomy in this series.

Altogether 192 UC patients were treated with biologicals, of whom 96% received anti-TNFs as the first course and others were treated with vedolizumab. Of all patients, 40% continued with the first course of biologicals at the end of follow- up while 36% needed at least one consecutive therapy trial with biologicals or small molecules. The overall colectomy rate in this series was 30%. Two patients had anaphylaxis as a severe AE (SAE) while 11 trials reported significant AEs. We found no difference in terms of treatment duration when comparing different agents or when comparing IFX alone or in combination with immunomodulators.

Twenty-two therapeutic trials of DBT were initiated among 16 patients (15 CD and one UC). Adalimumab and ustekinumab were the most common and efficient combination during median follow-up of nine months. Remission was achieved in seven trials and in two response was evaluated as partial with symptom relief. DBT reduced the need for Cs in 40% while two out of three patients reported response in active perianal disease. When evaluating changes in biochemical markers significant reductions in faecal calprotectin levels were observed. Infection complications were reported in 19% of the trials.

In conclusion, ASUC patients should be closely monitored after admission and optimization of maintenance therapy should be evaluated early on after acute flare. Despite the wider range of different therapy options, colectomy rates in severe UC remain high. Educating ASUC patients about the possibility of surgery is advised, especially when rescue therapy is needed. DBT may benefit some patients with treatment refractory IBD. However, in those UC patients with recurring relapses and persistent disease activity surgery should not be considered as a failure.