Safety and Effectiveness of Janus Kinase Inhibitors in the Management of Inflammatory Bowel Disease Following Liver Transplantation

Abstract

1. Introduction

Primary sclerosing cholangitis [PSC] represents the most common indication for liver transplantation in patients with inflammatory bowel disease [IBD].¹ A proportion of these patients require advanced medical therapies to manage their IBD following transplantation. Whereas the safety of using anti-tumour necrosis factor [TNF] and anti-integrin therapies to treat IBD following liver transplantation has been described, data pertaining to the safety of newer therapies, including small molecule janus kinase [JAK] inhibitors, remain limited.²

JAK inhibitors, such as tofacitinib and upadacitinib, have emerged as novel, orally administered, small molecules with a rapid onset of action achieved through modulation of intracellular JAK signalling pathways.³ Both of these agents are efficacious for the treatment of ulcerative colitis, with upadacitinib also efficacious in luminal Crohn’s disease.^4–6 Safety considerations, including an increased risk of serious infection, accentuates concerns regarding the use of JAK inhibitors in high-risk patient populations such as transplant recipients.⁷ Moreover, advanced IBD therapies are typically co-prescribed with post-transplant immunosuppression, highlighting the need to examine the safety of such therapeutic combinations.⁸

Only a single case report has documented the safe and effective use of tofacitinib in a liver transplant recipient with ulcerative colitis.⁹ This highlights the need to verify these findings across larger cohorts. Here, we present state-wide data from three states within Australia on the safety and clinical effectiveness of prescribing tofacitinib and upadacitinib for the management of IBD in liver transplant recipients.

2. Methods

Adult liver transplant recipients who received at least one dose of tofacitinib or upadacitinib for the management of Crohn’s disease [CD] or ulcerative colitis [UC] were identified from two Australian quaternary liver transplant centres, which collectively manage all liver transplant recipients in the states of Victoria, New South Wales, and Tasmania, and represent 60% of Australia’s population. Patients were identified from the respective prospective liver transplant databases. The decision to prescribe JAK inhibition in each patient was made through collaborative discussion between the IBD and liver transplant teams, with individual patients counselled regarding potential risks. The decision to prescribe long-term vancomycin for PSC-associated colitis was made by the treating IBD physician.^10,11 At our centres, patients are generally managed with combination corticosteroids, tacrolimus, and mycophenolate mofetil [MMF] immediately following liver transplantation. However, due to its well-known gastrointestinal side effects, MMF is typically avoided in post-transplant patients with active IBD. Baseline data regarding patient demographics, disease characteristics, IBD co-therapy, and anti-rejection transplant medications were collected. The follow-up period was defined as the earlier of either time from first dose of JAK inhibitor to the cessation of JAK inhibitor, or time of last follow-up. Adverse events were defined as one or more of any infection [including shingles], venous thromboembolism [VTE], major adverse cardiovascular events [MACE], or malignancy, with interruption to therapy on account of these events also recorded. Disease activity was recorded at baseline and last follow-up, with clinical remission defined as a Harvey Bradshaw–Index less than 5 or a partial Mayo Score of less than 2 in Crohn’s disease and ulcerative colitis, respectively. Biochemical activity and endoscopic disease activity, where available, were recorded at baseline and last follow-up. Data availability statement: requests for sharing of de-identified data by third parties will, after written request to the corresponding author, be considered subject to approval from our Institutional Review Board.

3. Results

Eight liver transplant recipients with IBD [ulcerative colitis: n = 6; Crohn’s disease: n = 1; chronic immune-mediated pouchitis: n = 1] were included in this series, seven of whom received first-line JAK inhibition with tofacitinib [see Table 1]. The median age at initiation of JAK inhibition was 30 years, and all patients had failed one or more biologic therapies prior to commencing JAK inhibition, including six patients who had failed two or more biologic agents. JAK inhibition was initiated following objectively confirmed loss of response to one or more biologic therapies, and was initiated in the outpatient setting in all cases. The indication for liver transplantation was PSC in all patients, with co-existing autoimmune hepatitis also present in one patient. The median time from liver transplantation to commencement of JAK inhibition was 7.1 years, with JAK inhibition continued for a median of 17 months and 143 patient-months of cumulative follow-up. Long-term anti-rejection medication regimens included tacrolimus monotherapy in five patients, tacrolimus with prednisolone in one patient due to chronic rejection, tacrolimus with prednisolone and everolimus due to chronic rejection in another patient, and tacrolimus with azathioprine due to concurrent autoimmune hepatitis in one patient.

3.1. Safety

Tofacitinib was commenced at standard induction dosing of 10 mg twice daily [b.i.d], which was continued for the duration of treatment in six of seven patients, with the dose reduced to 5 mg b.i.d in the remaining patient after 9 months. Upadacitinib was also commenced at standard induction doses of 45 mg daily for 8 weeks followed by 30 mg daily maintenance therapy thereafter for the duration of therapy in all four patients. One patient [patient B] required trimethoprim-sulphamethoxezole prophylaxis throughout treatment owing to concurrent prednisolone use.

JAK inhibition was continued with anti-rejection medicines, which included tacrolimus, in all eight patients. Two patients also received concurrent everolimus and low-dose prednisolone, and another patient received low-dose azathioprine co-therapy in the context of their history of autoimmune hepatitis [see Table 2]. The median tacrolimus level prior to initiation of JAK inhibition was 7.4 µg/L (interquartile range [IQR] 5.6–8.1), with levels observed to remain stable following JAK inhibition at 7.5 µg/L [IQR 6.0–9.2]. Notably, dose adjustment of tacrolimus was not required in any patient following initiation of JAK inhibition.

Three patients developed mild Covid-19 and one patient developed bacterial pharyngitis, all of which were managed in the outpatient setting with anti-viral and antibiotic therapy, respectively. JAK inhibition was withheld for 1 week in all cases, with uneventful reintroduction. There were no other cases of serious infection, venous thromboembolism, shingles, or MACE during the 143 patient-months of follow-up.

3.2. Clinical effectiveness

All patients had evidence of clinical, biochemical, and endoscopic disease activity at the time of commencing JAK inhibition [median faecal calprotectin 677 µg/g, IQR 498–1421] [see Table 2]. Of the seven patients who commenced tofacitinib, three [43%] were in clinical remission by 6 months, including two who were additionally in endoscopic remission by 6 months. Of the remaining four patients treated with tofacitinib, one patient required a colectomy after 4 weeks, and three were switched to upadacitinib owing to inadequate response. Of the four patients treated with upadacitinib, all four achieved disease remission, evidenced by a combination of clinical and either biochemical or endoscopic remission by 6 months.

4. Discussion

This case series highlights that JAK inhibition may be safe and clinically effective for the management of IBD in liver transplant recipients. No serious adverse events, including shingles, VTE, or MACE, were documented, nor were any interactions with transplant medications observed. Apart from four of eight patients who developed mild infections, all of which were unlikely to be directly attributable to JAK inhibition, there were no concerning safety signals over 143 patients-months of follow-up. This is supported by all four patients being able to resume JAK inhibition after 7 days without recurrence of infection.

Overall, seven [88%] patients achieved clinical remission with JAK inhibition, including all three patients who were switched from tofacitinib to upadacitinib. JAK inhibitors are efficacious for the management of IBD in both biologic-naïve and biologic-experienced patients. This is particularly relevant to our cohort, wherein six of eight patients had failed two or more biologic therapies. The decision to prescribe tofacitinib ahead of upadacitinib in seven patients was driven by the local availability of tofacitinib ahead of upadacitinib, with upadacitinib only becoming available more recently. Notably, all four patients treated with upadacitinib appeared to achieve clinical remission, including those switched from tofacitinib, potentially signalling that there may be advantages in prescribing upadacitinib ahead of tofacitinib.¹² We do, however, acknowledge that these findings need to be explored across larger cohorts before definitive conclusions can be made.

The management of IBD is complicated in patients with prior liver transplantation, due to the requirement for multiple immunosuppressive therapies. The common anti-rejection medication MMF has a well-known risk of causing gastrointestinal side effects, and is typically avoided in patients with active IBD. Tacrolimus may have some efficacy in IBD, given its mechanism of action as a calcineurin inhibitor, but additional IBD-specific immunosuppression is frequently still required. Moreover, from a transplant immunosuppression perspective, although tacrolimus monotherapy is frequently used in the post-transplant setting, additional immunosuppression may still be required in patients at high risk of rejection, such as our patient B who required tacrolimus, everolimus, and long-term prednisolone. The use of concurrent vedolizumab is generally considered to be safe, given its gut-selective immunosuppressive properties, with limited case series and emerging data regarding the safety of infliximab and ustekinumab, respectively.^2,13,14 However, in the setting of multiple biologic failures, IBD patients are typically left with limited medical options. Ultimately, long-term safety of multiple immunosuppressive agents should be compared with conventional liver transplant therapy.

As the largest case series to-date, these data indicate that combining JAK inhibition with post-transplant immunosuppression may be a safe and clinically effective method of treating IBD in patients with prior biologic failure. However, despite the absence of any significant adverse events across this cohort, it is important to acknowledge that safety concerns associated with longer-term use of this combination needs to be evaluated across larger cohorts with a longer duration of follow-up. Our findings also suggest that the comparative safety and clinical effectiveness of tofacitinib and upadacitinib, particularly when co-prescribed with transplant immunosuppression following multiple biologic failures, may be important in establishing whether one agent should be positioned ahead of the other.

Funding

This study was not directly funded.

Conflict of Interest

PDC has served as a consultant, an advisory board member, or a speaker for AbbVie, Baxter, Ferring, Janssen, Celltrion, Emerge Health, Shire, and Takeda. PDC is supported by an NHMRC Emerging Leader 2 Fellowship and has received research support from AbbVie, Ferring, Shire, Janssen, Pfizer, and Takeda. AS has served as a speaker for Arrotex Pharmaceuticals and received advisory fees from AstraZeneca, AbbVie, and Takeda Pharmaceuticals. CC has received travel support from Takeda, Pfizer, Janssen, Abbvie, Ferring, and Celltrion; unrestricted educational grants from Janssen, Abbvie, and Ferring; speaker fees and advisory board fees from Takeda, Pfizer, Janssen, Abbvie, Ferring, Celltrion, and Chiesi. SC has received conference sponshorship from Janssen and Sandoz. For the remaining authors, no conflict of interest is declared.

Author Contributions

Study concept, design, and supervision: AS, MC. Acquisition and analysis of data: PH, DC, SC, BH, AS. Drafting of manuscript: DC, AS, PH, SC. Critical revision of manuscript: AS, MC, PDC, CC, AT.

REFERENCES