Y-ECCO Literature Review: Aamir Saifuddin

The commonest strategy to avoid colectomy has been infliximab escalation. Despite some evidence for its benefit [4, 5], along with British Society of Gastroenterology recommendation [6] for those without a convincing initial response to 5 mg/kg infliximab, many will still require colectomy. This is partly explicable by proteolytic degradation of infliximab molecules and serum and faecal drug loss [5].

There is interest in the role of tofacitinib in severe UC given its novel JAK1/3 inhibition, particularly in anti-TNF non-responders; indeed, potential benefit has been noted in some small studies [7–9]. This recently reported multicentre observational study by Uzzan et al., published in Alimentary Pharmacology and Therapeutics, describes outcomes in this regard.

Methods

Data from patients who were >16 years old and received tofacitinib during hospitalisation for UC were collected through retrospective (between January 2017 and May 2020) and prospective (June 2020 to April 2021) enrolment from the French multicentre GETAID IBD database. All the patients had previously failed and/or been intolerant to anti-TNF medication, vedolizumab and/or ustekinumab. The primary objective was to determine colectomy-free survival following tofacitinib commencement. Secondary objectives included investigation of factors associated with colectomy, clinical outcomes during tofacitinib treatment and drug safety. The primary endpoint was colectomy. Clinical response and remission were defined in the standard way based on reductions in the partial Mayo score compared to the score at inclusion.

Key Findings

Demographics

In total, 55 patients were included from 14 centres, 31 (56.4%) retrospectively and 24 (43.6%) prospectively. The median age was 27.6 years (IQR 21.8–42.5), with 18 patients over 50 years old; 45.5% were female. The median duration of disease was 4.4 years (IQR 2.4–7.1). Most had received at least one anti-TNF drug previously (98.2%) and the median number of previous biologics used was 2.5 per patient.

During the current flare, 29 (52.7%) patients were unsuccessfully initially treated with intravenous steroids and ten had attempted rescue with infliximab (two patients, 3.6%) or ciclosporin (eight patients, 14.5%). Median CRP at tofacitinib initiation was 17.2 mg/L (IQR 7.3–66.3) and 37 (67.2%) patients had a Mayo endoscopic score of 3, whilst the rest scored 2. The median Lichtiger score (where a score >10 defines ASUC) was 12 (IQR 9.5–13).

Tofacitinib was initiated a median of 3 days (IQR 1–6) after admission and 36 (65.5%) patients were on corticosteroids at this time.

Outcomes

Follow-up continued for a median of 6.5 (IQR 3–12.3) months. Fifteen patients (27.3%) had undergone colectomy. Colectomy-free survival was estimated at 85.2% (95% CI 76.3%–95.2%) at 1 month, 78.9% (95% CI 68.5%–90.9%) at 3 months and 73.6% (95% CI 61.9%–87.3%) at 6 months. This compares to roughly 80% colectomy-free survival at 3 months in the CONSTRUCT trial. No specific factors were significantly associated with colectomy, though pancolitis, higher CRP and Lichtiger scores, and deep ulcers tended towards significance.

At week 6, 43/55 patients were still taking tofacitinib, all 10 mg twice daily. From the overall cohort, 33 patients (60%) had a clinical response, 25 (45.5%) were in clinical remission and 20 (37.5%) achieved clinical steroid-free remission. Follow-up CRP was available for 36 patients: the median was 4 mg/L (IQR 1.5–9.5) vs 15 mg/L (IQR 9.5–44.8) at enrolment (p=0.047, paired Student’s t test).

At week 14, 31 patients remained on tofacitinib, with 24 (77.4%) taking 10 mg twice daily and the remainder on 5 mg twice daily. Of the overall cohort, 23 (41.8%) had a clinical response, 19 (34.5%) were in clinical remission and 18 (32.7%) achieved steroid-free clinical remission. CRP also significantly decreased for the 22 patients with available measurements [3 mg/L (IQR 2.3–5) vs 14.5 mg/L (IQR 6.9–50.3) at enrolment; p=0.01].

At the end of follow-up, 28 patients (50.9%) remained on tofacitinib. It was estimated that, at 1 month, 3 months and 6 months from initiation, 81.8% (95% CI 72.2%–92.7%), 68.1% (95% CI 56.6%–81.9%) and 44.9% (95% CI 32.6%–61.8%] remained on treatment, respectively. The main reason for withdrawal was primary non-response (17/27, 63%).

Adverse events occurred in six patients (10.3%) and drug was ceased in three cases. The latter included an episode of herpes zoster (shingles) with bullous lesions, recurrent viral pneumonia complicating bronchiectasis and unusual abdominal pain; another patient also had shingles but the drug was continued. There were no cardiovascular or venothromboembolic adverse events.

Discussion

In their particularly hard-to-treat cohort with severe UC, the authors found that tofacitinib treatment led to colectomy-free survival comparable to previous outcomes seen in unselected patients treated with conventional rescue therapy. There was a favourable safety profile, though herpes zoster reactivation occurred in two patients over 60.

This is the largest reported cohort of hospitalised patients treated with tofacitinib. In the pre-existing literature, 11 such patients in total have been prescribed tofacitinib [7–9]. Of these, six underwent colectomy. A more recent retrospective case-control study found that 10 mg three times per day may be beneficial and safe in ASUC [10].

The major benefits of tofacitinib lie in its quick action, so necessary colectomy is not delayed whilst evaluating response, and probably its ability to block multiple immune pathways, likely a feature of refractory IBD [11]. The difficulty in treating severe disease has been underlined recently by the IASO trial [12]. looking at anakinra (IL-1 blockade) in ASUC, which unfortunately had to stop recruitment due to lack of effectiveness.

The strengths of this study lie in its relatively large numbers and the inclusion of a refractory, unwell group of patients nearing colectomy. The multicentre nature also demonstrates potential wide applicability. The limitations include the lack of an internal matched control group of patients who did not receive tofacitinib, which may have strengthened the findings, and the likely heterogeneity of standard care between patients, particularly given that many were included retrospectively. Biochemical and post-treatment endoscopic data are also incomplete. Furthermore, no separate data are available for those specifically diagnosed with ASUC.

In conclusion, this study suggests that tofacitinib may be useful in reducing the need for colectomy in patients admitted acutely with refractory UC. Future prospective trials will determine its more widespread role in both anti-TNF-resistant and -naïve patients in severe UC.

References

1. Dinesen LC, Walsh AJ, Protic MN, et al. The pattern and outcome of acute severe colitis. J Crohns Colitis. 2010;4:431–7.
2. Truelove SC, Witts LJ. Cortisone in ulcerative colitis. BMJ. 1955;2(4947):1041–8.
3. Aratari A, Papi C, Clemente V, et al. Colectomy rate in acute severe ulcerative colitis in the infliximab era. Dig Liver Dis. 2008;40:821–6.
4. Gibson DJ, Doherty J, McNally M et al. Comparison of medium to long-term outcomes of acute severe ulcerative colitis patients receiving accelerated and standard infliximab induction. Frontline Gastroenterol. 2020;11:441–7.
5. Fiske J, Conley T, Sebastian S, Subramanian S. Infliximab in acute severe colitis: getting the right dose. Frontline Gastroenterol. 2020;11:427–9.
6. Lamb CA, Kennedy NA, Raine T, et al. British Society of Gastroenterology consensus guidelines on the management of inflammatory bowel disease in adults. Gut. 2019;68:s1–106.
7. Honap S, Pavlidis P, Ray S, et al. Tofacitinib in acute severe ulcerative colitis – a real-world tertiary center experience. Inflammatory Bowel Dis. 2020;26:E147–9.
8. Berinstein JA, Steiner CA, Regal RE, et al. Efficacy of induction therapy with high-intensity tofacitinib in 4 patients with acute severe ulcerative colitis. Clin Gastroenterol Hepatol. 2019;17:988–990.e1.
9. Kotwani P, Terdiman J, Lewin S. Tofacitinib for rescue therapy in acute severe ulcerative colitis: a real-world experience. J Crohns Colitis 2020;14:1026–8.
10. Berinstein JA, Sheehan JL, Dias S, et al. Tofacitinib for biologic-experienced hospitalized patients with acute severe ulcerative colitis: a retrospective case-control study. Clin Gastroenterol Hepatol 2021;19:2112–20.e1.
11. Atreya R, Neurath MF. Mechanisms of molecular resistance and predictors of response to biological therapy in inflammatory bowel disease. Lancet Gastroenterol Hepatol 2018;3:790–802.
12. Thomas MG, Bayliss C, Bond S, et al. Trial summary and protocol for a phase II randomised placebo-controlled double-blinded trial of Interleukin 1 blockade in acute severe colitis: the IASO trial. BMJ Open 2019;9:e023765.

Aamir Saifuddin - Short Biography

Aamir Saifuddin is a senior gastroenterology registrar in Kent and London. He is currently an IBD Clinical Research Fellow at St Mark’s Hospital and Imperial College London, supervised by Professor Ailsa Hart and Dr Nick Powell. His main area of interest is precision medicine in IBD and transcriptomic predictors of biologic resistance, particularly relating to the matrisome.