An Old Bridge to the Newer Biologics: Cyclosporine for Rescue Therapy in Acute Severe Ulcerative Colitis

CASE PRESENTATION

A 45-year-old man with an 11-year history of extensive ulcerative colitis (UC) was evaluated for acute severe UC (ASUC), manifest as increased stool frequency, urgency, hematochezia, and left-sided abdominal pain. He had previously been well-controlled with vedolizumab infusions every 4 weeks for 2 years, but he self-discontinued this therapy in the setting of clinical and endoscopic remission. Therapies utilized prior to vedolizumab included infliximab and azathioprine combination therapy (initiated during a prior admission for ASUC) that were discontinued due to loss of insurance.

A flexible sigmoidoscopy revealed Mayo 3 colitis in the visualized rectosigmoid (Figure 1). Biopsies were read as moderate-severe chronic active colitis that was with no immunohistochemical evidence of cytomegalovirus. Laboratory evaluation demonstrated anemia (hemoglobin 9.8 g/dL, total iron 30 μg/dL, total iron binding 199 μg/dL, iron saturation 15%, ferritin 167.7 ng/mL)low albumin (2.0 g/dL) and an elevated C-reactive protein (220 mg/L [normal 10 mg/L]). The patient was initiated on methylprednisolone 20 mg intravenously three times daily, but he had no clinical response after 48 hours.

Figure 1:

Flexible sigmoidoscopy on admission demonstrating severe (Mayo 3) colitis

Within the first 24 hours of admission he was evaluated by the colorectal surgery service although the patient desired further medical management rather than colectomy. Given his prior treatment with infliximab and prior remission with vedolizumab monotherapy, a decision was made to proceed with cyclosporine rescue therapy as a bridge to vedolizumab re-induction. Risk factors for cyclosporine toxicity including hypomagnesemia, hypocholesterolemia, and renal insufficiency were not present. Cyclosporine was initiated at 2 mg/kg/day IV. He was also transitioned to oral prednisone at the time of cyclosporine induction. Over the next 48–72 hours, significantly improvement was noted in both his colitis symptoms and objective markers of inflammation (Figure 2). Cyclosporine trough levels were checked every 48 hours with the aim to achieve a level of 200 – 300 ng/mL. [1] He was eventually switched to oral cyclosporine at 5 mg/kg in two divided doses. Cyclosporine trough levels were checked every 48 hours for dose adjustments until a steady trough level was achieved. The patient was ultimately discharged on hospital day 8.

Figure 2:

Patient’s C-reactive protein (CRP) and cyclosporine trough levels during and after hospitalization for acute severe ulcerative colitis. Vedo – vedolizumab.

One week after discharge, the patient received his initial vedolizumab infusion, followed by two additional loading doses and then maintenance infusions every 4 weeks, in light of his prior regimen. His prednisone was tapered from 40 mg daily at discharge to 30 mg daily after 1 week, and then tapered by 5 mg per week over the next 7 weeks. Serum creatinine, potassium, uric acid, magnesium, liver function tests, and cyclosporine trough levels were monitored weekly for 2 weeks, then every other week until cyclosporine was discontinued. After 3 months of concomitant therapy with cyclosporine and vedolizumab, cyclosporine was tapered slowly over 6 weeks. The patient remained in clinical remission on vedolizumab monotherapy with a colonoscopy at 6 months post-induction demonstrating Mayo 0 colitis.

DISCUSSION

Our case highlights an emerging role of calcineurin inhibitor therapy (CNI) in the current treatment paradigm of inflammatory bowel disease (IBD), particularly ASUC. CNIs such as cyclosporine and tacrolimus are rapid-acting immunosuppressants that have proven efficacy as induction therapy in ASUC across several studies. [2] Current guidelines recommend the use of either cyclosporine or infliximab as “second-line rescue” therapies. A recent meta-analysis demonstrated no significant differences in efficacy in inducing remission, rates of colectomy, or safety when comparing the two agents in the treatment of ASUC. [3]

The utility of CNI in ASUC is typically restricted to short-term use for induction or rescue therapy, since maintenance data are less encouraging in terms of efficacy and safety. [2] CNI can serve as a rapid induction option in patients with contraindications to steroid therapy or steroid-refractory disease, as well as those patients with prior exposure, non-response, or contraindications to anti-tumor necrosis factor (TNF) therapy. Deciding on a transition strategy from CNI to a long-term maintenance agent is essential prior to initiating therapy with a CNI. Induction with cyclosporine in the rescue setting for ASUC has traditionally been followed by transition to a thiopurine for long-term maintenance therapy in patients without prior thiopurine treatment failure. [2] In recent years, newer approaches have emerged that incorporate cyclosporine as the induction agent with newer biologics such as vedolizumab and ustekinumab serving as the maintenance agent. [4–10] A typical treatment strategy (as described in the above case) involves initiation of intravenous cyclosporine as an inpatient, followed by measurement of trough concentrations until a therapeutic level is achieved. Once clinical improvement is noted, the patient is then transitioned to oral cyclosporine with dose adjustments to maintain a therapeutic cyclosporine level. Immediately following discharge, vedolizumab or ustekinumab therapy is initiated. Cyclosporine trough levels and maintenance labs are checked every 1–2 weeks to assess for any signs of drug toxicity. Prednisone is tapered over several weeks. After approximately 3 months of combination therapy with cyclosporine and vedolizumab or ustekinumab, tapering of cyclosporine begins, with close monitoring of the patient’s clinical status.

Vedolizumab is a gut-specific biologic (anti-α4β7 integrin) approved in the treatment of moderate to severe UC and Crohn’s disease (CD).[2, 11] Particularly in anti-TNF exposed patients, it has been associated with longer times to induction of remission, and therefore requires the addition of a rapid-acting agent for induction in certain settings such as ASUC.[12] In the past several years, multiple retrospective studies and case series have described experience using CNI as induction therapy as a bridge to vedolizumab maintenance therapy [4–8] (Table 1). A total of 148 patients are described in the literature with the majority of patients (135/148) having UC. The patient population in these studies was mostly steroid-refractory and most had a prior exposure to an anti-TNF agent. One year after CNI induction, 43–63% of UC patients had steroid-free clinical remission and 28–67% had colectomy-free survival. In these studies, up to 59% of patients continued vedolizumab without needing steroids or a CNI at 1 year. There were no major adverse events seen from the CNI-vedolizumab sequential therapy. In our case, the patient’s history included steroid-refractory UC, prior infliximab exposure, and prior successful use of vedolizumab. We were able to use cyclosporine successfully as a rescue therapy and transition to vedolizumab infusions for maintenance with durable effect for greater than 6 months.

Table 1.

Published literature on calcineurin inhibitors as a ‘bridge’ to novel biologics in inflammatory bowel disease

Author Year (Reference)	Study design	Number of patients (IBD subtype)	CNI therapy	Biologic therapy	Key results
Szántó et al. 2018 [4]	Case series	6 (2 UC; 4 CD)	Cyclosporine	Vedolizumab	• 100% responded to cyclosporine-vedolizumab induction. • Colonoscopy after induction showed mucosal healing in 1, significant regression in 1 and moderate regression of mucosal inflammation in 3 patients. • 1 patient eventually underwent colectomy.
Christensen et al. 2019 [5]	Retrospective observational	20 (11 UC; 9 CD)	11 Cyclosporine 9 Tacrolimus	Vedolizumab	• At 1 year, 33% (CD) and 45% (UC) were in steroid-free clinical remission. • At 1 year, 59% remained on vedolizumab.
Pellet et al. 2019 [6]	Retrospective observational	39 (39 UC)	37 Cyclosporine 2 Tacrolimus	Vedolizumab	• At 1 year, 68% had colectomy-free survival. • At 1 year, 44% remained on vedolizumab.
Ollech et al. 2019 [7]	Retrospective observational	71 (71 UC)	48 Cyclosporine 23 Tacrolimus	Vedolizumab	• At 1 and 2 years, 43% and 76% had steroid-free remission respectively. • At 1 and 2 years, 67% and 55% had colectomy-free survival respectively. • At 1 and 2 years, 43% and 28% remained on vedolizumab respectively. • At 1 year, 21% had endoscopic remission.
Resál et al. 2020 [8]	Case series	13 (13 UC)	Cyclosporine	Vedolizumab	• At 1 year, 63% had steroid-free remission. • At 21 months, 100% had colectomy-free survival. • Until last follow-up, 77% were still on vedolizumab.
Ganzleben et al. 2020 [9]	Case report	1 (1 UC)	Cyclosporine	Ustekinumab	• At ~5 months (139 days), patient was in clinical and endoscopic remission. • At ~7 months (195 days), patient was in sustained clinical remission.
Shaffer et al. 2021 [10]	Case series	2 (2 UC)	Cyclosporine	Ustekinumab	• At 4 months, both patients were in clinical remission.

CNI: Calcineurin inhibitors; CD: Crohn’s disease; IBD: Inflammatory bowel disease; UC: Ulcerative colitis

Ustekinumab is a systemic biologic (p-40 inhibitor of IL-12/23) approved for the treatment of both moderate to severe UC and CD [2, 11] although there is currently little evidence regarding its use as an induction therapy in ASUC. [13] It is possible that CNI induction therapy could also be used as a bridge to ustekinumab maintenance therapy in the setting of ASUC. Published data for this approach are limited to case reports among patients with ASUC who received cyclosporine induction and were bridged to ustekinumab maintenance [9, 10] (Table 1).

Despite recent advances in IBD therapy, the management of severe presentations including ASUC remain challenging, with a significant proportion of patients undergoing colectomy. Many patients in modern practice have already been exposed to thiopurines and/or anti-TNF therapies. In such situations, alternative management strategies are needed. The evolving use of cyclosporine as a rescue induction therapy with transition to vedolizumab or ustekinumab maintenance therapy offers a novel therapeutic paradigm for patients. Moreover, vedolizumab and ustekinumab are appealing long-term maintenance therapies given their favorable safety profiles when compared with thiopurines or anti-TNF agents. [14] When considering safety, initiating cyclosporine after anti-TNF therapy may be less risky than prior data have suggested, offering further reassurance to the use of cyclosporine as an induction therapy. [15] Nevertheless, there are some notable limitations in the use of vedolizumab or ustekinumab as maintenance options when compared with thiopurines (if there was no prior thiopurine failure): biologic medications may be associated with substantially higher costs than thiopurines, and some patients may prefer the oral dosing of thiopurine medications compared with intravenous infusions or subcutaneous injections for the biologic medications.

In the present era, CNI continue to remain a valuable rescue option in the treatment of ASUC. Though patients with ASUC have a high risk of medical treatment failure during the initial admission and subsequent disease course, cyclosporine and tacrolimus offer potential benefits to those patients with contraindications to systemic steroids or anti-TNFs, steroid-refractory disease, or prior non-response or loss of response to anti-TNFs. Moreover, the ability to combine cyclosporine or tacrolimus with novel biologic therapies such as vedolizumab or ustekinumab broadens the therapeutic landscape and offers new potential mechanisms for combination therapies in the treatment of IBD refractory to more conventional therapies. Although induction therapies remain limited for ASUC, these new methods of utilizing cyclosporine warrant further consideration by all gastroenterologists in the treatment of ASUC.

KEY POINTS.

• Calcineurin inhibitors (CNIs) are valuable, rescue therapies in the treatment of refractory UC or CD, particularly in patients who are steroid-refractory or who have already failed an anti-TNF treatment.

• If CNI rescue is pursued, it is essential to have an exit strategy for maintenance in the form of immunomodulator or biologic therapy.

• Use of cyclosporine as a bridge to vedolizumab or ustekinumab maintenance in the treatment of ASUC is a promising emerging management strategy. Although available data thus far are retrospective, these data demonstrate potential efficacy and safety of this strategy.