Abstract

Background and aims: Approximately 15% of patients with ulcerative colitis will have a severe flare requiring hospitalisation at some stage. For those who fail to respond to intravenous steroids Cyclosporin A (CyA) therapy is one option. We have evaluated the management of such patients in our centre and present the long term colectomy avoidance rates.

Methods: 38 consecutive patients receiving CyA for an acute, steroid-refractory flare of colitis were retrieved from our database. Records were unavailable for 2 patients and 2 received therapy twice, hence 38 episodes were analysed.

Results: 24/36 patients were male; median age 37 years. On admission 20 patients were taking oral steroids; 8 were taking a thiopurine and 7 patients were on no treatment. CyA was started a median of 8 days after admission (range 1–28) and most patients (32/38) received this orally at doses of 4.5–8.3 mg/kg. 15 patients have undergone colectomy, 11 of these during the same admission for lack of response to CyA. Of the patients who were discharged without surgery, 84% have still not required colectomy after a median follow-up of 3.8 years. Adverse effects were mostly minor, though two patients developed neutropenia on dual immunosuppression.

Conclusions: CyA can be administered orally with good tolerability. We use it as a bridging therapy to Azathioprine. In our population, 84% of those who responded to CyA have not required surgery.

Introduction

It has been well-established that approximately 15% of patients with ulcerative colitis (UC) will require admission to hospital for an acute flare at some point. 1 Cyclosporin A (CyA) is a calcineurin inhibitor which suppresses T lymphocyte responses by blocking production of IL-2 and other cytokines at a pretranslational level. It has been used to treat steroid-refractory acute flares of UC since the early 1990s as an alternative to colectomy. 2 , 3 Previously published data have shown variable short and long term results, with 74–91% of patients avoiding colectomy in the short term and 42–70% avoiding this in the long term (with a range of 18 months to 12.6 years follow-up). 412 This variability of response rates reflects not only the small patient numbers in each study but also the variability in dosing and route of administration of CyA. Despite the availability of CyA, it remains underused, as shown in the UK National IBD Audit of 2008 13 where only 31% of those patients eligible for CyA actually received it. This may reflect concerns over toxicity and perceived poor long term outcomes, with many Gastroenterologists believing CyA use merely delays the inevitable colectomy. We do not agree, and present the Cambridge data regarding response rates and long term colectomy-free survival following use of CyA in acute steroid-refractory colitis.

Materials and methods

From internal audit data we know our hospital admits approximately 25 patients per year meeting Truelove and Witts criteria for acute severe ulcerative colitis, 14 and that the colectomy rate varies between 30 and 44% in any one year. From our inflammatory bowel disease (IBD) database we retrospectively extracted details of all patients receiving CyA for UC between January 2000 and July 2009 in Cambridge University Hospital. 44 patients had received CyA, 37 for acute flares refractory to intravenous corticosteroid therapy. The other 7 patients were excluded as they received CyA for other indications (including outpatient treatment for chronic active colitis or Crohn's disease, post-liver transplant for primary sclerosing cholangitis, and as treatment for psoriasis). Hospital records were unavailable for 2 patients and 2 received this treatment twice. We also included one patient who was initially treated in another hospital then transferred to our unit for CyA. Hence 38 episodes of CyA use in 36 patients were analysed. The data collected included patient demographics, preadmission treatment, indication for CyA, dose, and route of administration, duration as inpatient and outpatient and adverse effects. The primary outcome was colectomy-free survival.

24/36 patients were male; age range of 17–72 years (median 37.5 years). At the time of admission 21 patients were on oral prednisolone (at doses of 10–60 mg); 3 were established on immunomodulator therapy at therapeutic doses, with five others having started within 3 weeks of admission. 7 patients were on no treatment at admission, 2 being new diagnoses of UC ( Table 1 ).

Results

Cyclosporin therapy

All patients received intravenous steroids (hydrocortisone 100 mg QDS or methylprednisolone 40 mg BD). In 9 episodes of CyA use patients fulfilled the Travis criteria for rescue therapy (stool frequency > 8 per day or frequency > 3 per day and C-Reactive Protein > 45 mg/L on day 3) 15 whereas the others had achieved partial response or became more unwell after Day 3. CyA was started a median of 8 days after admission (range 1–28 days). Most patients (32/38) received CyA orally from outset at a starting dose of 4.5–8.3 mg/kg daily in divided doses (the patient receiving 4.5 mg/kg was pregnant). Doses were adjusted to achieve a trough level of 150–250ug/l. The other 6 patients received intravenous CyA at 2–5 mg/kg and were changed to oral CyA 2-8 days after starting. 5/6 were treated before 2004 after which time our policy changed to use of oral CyA from outset, with daily monitoring of drug levels. Almost all patients continued a weaning course of oral prednisolone during CyA use. In 28/38 episodes patients received PCP prophylaxis with co-trimoxazole or pentamidine, with the majority of cases where this was not given occurring before 2004 when it became part of our standard protocol. No opportunistic infections were identified.

Colectomy rates

Of the 36 patients who received CyA for acute UC, 15 have undergone colectomy during median follow-up of 45 months/3.8 years (Range 11 to 118 months). 11 of these surgeries were carried out due to lack of response in the acute phase after mean 6.1 days (range 2–12) from starting CyA ( Fig. 1 ).

21/25 patients (84% of those who responded and were discharged on CyA) have not required colectomy. For the 4 patients requiring surgery this occurred 3–8 months post-discharge with identifiable reasons in 3 cases. One of these had stopped all medication to seek ‘alternative’ therapies, and then required emergency colectomy; one was intolerant of immunomodulators, flared again and elected for surgery; a third had CyA twice at 4 year intervals, having responded well first time, then developed neutropenia with thiopurines and central serous retinopathy due to steroids, hence a joint decision was made for elective surgery.

Monitoring and subsequent treatment

All patients were monitored by our IBD nurses, with initially daily and subsequently weekly drug levels while on CyA. This does represent a considerable workload after hospital discharge, with an average of 5 clinic appointments (range 1–9) and 7 email or telephone contacts (range 1–20) with our IBD nurses needed during this time. 15 side effects occurred in 12 patients including headache (11%), paraesthesia and hypertension (8.5%) each. The latter, as well as renal impairment (5.7%) were treated with dose reduction. 5.7% of patients complained of tremors and 2 patients (5.6%) developed neutropenia on combination CyA and azathioprine. No opportunistic infections occurred.

As per our protocol, 85% (23/27 episodes) were started on a thiopurine (mostly azathioprine) at a median of 5 weeks post-discharge from hospital (range 0–34 weeks) once the oral prednisolone dose was below 15 mg.

Discussion

Initial uncontrolled studies in the early 1990s showed that 80% of patients with acute severe colitis refractory to intravenous steroid therapy responded to CyA given as an intravenous infusion of 4 mg/kg 2 . A further small (n = 20) randomised comparison of CyA (4 mg/kg/day continuous intravenous infusion) versus placebo for 14 days in steroid-refractory patients confirmed a response rate of 82% in the CyA group compared to 0% in the placebo group. This study was terminated early due to the obvious difference between the treatment and placebo groups. 3

Based on the observation that doses of CyA used in the transplant population were lower than 4 mg/kg and that the most concerning adverse effects of CyA (hypertension and renal toxicity) were dose dependent, Actis et al. 1993 and later Van Assche et al. 2003 4 , 16 showed that 2 mg/kg was as effective in the short term.

An oral microemulsion form of CyA (Neoral®, Novartis) with high bioavailability was first used in the transplant population then subsequently tested in the setting of steroid refractory acute colitis following demonstrations that the pharmacokinetics were similar in patients with inflammatory bowel disease and controls. Actis et al 1998 17 compared oral to intravenous formulations and showed superior response rates in the oral group. However, this was a heterogeneous patient population including chronic non-responders as well as those with refractory acute colitis. Weber et al 18 considered 20 episodes of steroid-refractory UC treated with oral CyA with a 75% remission rate at 13 days and a 74% colectomy-free survival after a median follow-up of 8 months. Given that oral CyA is logistically easier to administer, and that doses are adjusted to daily drug levels whether given orally or intravenously, we switched over in 2004 to oral dosing from the time of initiation of CyA therapy.

A national audit of IBD management in the UK in 2008 13 included analysis of 2981 emergency inpatient admissions for acute ulcerative colitis. Overall, 7% of these received CyA. Of the 30% who failed to respond to steroids, 31% received CyA while 55% proceeded to surgery. Of those who received CyA 52% were reported to have achieved remission.

Most UC patients requiring CyA in our centre received this orally with good tolerability and safety. Of patients who responded in the acute setting and were discharged on Cyclosporin 84% have avoided colectomy. We attribute this success to careful management of the transition from CyA to azathioprine. We also believe (though have no direct proof) that the close monitoring by our IBD nurses, with careful adjustment of drug doses according to drug levels, colitis symptoms and signs of toxicity, significantly contributed to the favourable outcomes. Our data suggest that in those who respond to the acute treatment CyA does not simply ‘delay the inevitable colectomy’.

Author contributions

LS and FB carried out the database search and data analysis. FB and AN maintain the database. MP conceived the study and participated in its design and co-ordination and helped to draft the manuscript with LS. All authors read and approved the final manuscript.

Acknowledgements

We thank the patients and staff at Addenbrooke's Hospital who contributed to this study.

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Figures

Figure 1

Kaplan-Meier curve showing colectomy-free survival in patients requiring Cyclosporin therapy following discharge.

Figure 1

Kaplan-Meier curve showing colectomy-free survival in patients requiring Cyclosporin therapy following discharge.

Tables

Table 1

Summary of patient characteristics.

Age Median 37.5 years 
(Range 17–72 years) 
Disease distribution Pancolitis 43% 
Extensive 26% 
Left sided or distal 31% 
Medications on admission Steroids 60.5% of episodes 
Immunomodulators 18.4% (but only 7.8% established) 
Mesalazine 21% 
Sulphasalazine 5.3% 
Admission CRP Median 70 
(Range 6 to > 250) 
Admission bowel frequency Median 10 
(Range 0–30) 
Follow-up Median 45 months 
(Range 11–118 months) 
Age Median 37.5 years 
(Range 17–72 years) 
Disease distribution Pancolitis 43% 
Extensive 26% 
Left sided or distal 31% 
Medications on admission Steroids 60.5% of episodes 
Immunomodulators 18.4% (but only 7.8% established) 
Mesalazine 21% 
Sulphasalazine 5.3% 
Admission CRP Median 70 
(Range 6 to > 250) 
Admission bowel frequency Median 10 
(Range 0–30) 
Follow-up Median 45 months 
(Range 11–118 months)