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Keywords:

  • refractory;
  • ulcerative colitis;
  • cyclosporin;
  • long-term outcome

Abstract

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

Objectives

IV cyclosporin A (CSA) is an effective therapy in patients with severe ulcerative colitis (UC). It remains unclear if this treatment affects the course of the disease in the long run. We investigated the long-term efficacy and safety in 86 patients with ulcerative colitis treated with IV CSA at our center.

Methods

The records of all patients treated with IV CSA between 11/1992 and 11/2000 were reviewed.

Results

Seventy-two of 86 patients (83.7%) responded to IV CSA therapy, administered for a mean of 9 ± 2 days. Following the initial treatment, 69 patients (96%) were discharged on oral CSA with mean blood CSA concentrations of 192 ± 55 ng/mL. Azathioprine was added in 64 (89%) patients. A second treatment with CSA was necessary in 11 patients; 1 patient received three courses of IV treatment.

The duration of follow-up averaged 773 ± 369 days. Patients who were responders but were still having certain symptoms at discharge had a higher incidence of colectomy during follow-up. Of all initial responders, 18 (25%) underwent colectomy after a mean interval of 178 ± 141 days. The life-table predicts that of all treated patients, 55% will avoid a colectomy during a period of 3 years.

Complications of CSA treatment were mostly reversible, but 3 patients (3.5%) died of opportunistic infections (1 of Pneumocystis carinii pneumonia and 2 of Aspergillus fumigatus pneumoniae). One patient with anaphylactic shock caused by the CSA solvent was successfully resuscitated.

Conclusions

CSA is an effective treatment of the majority of patients with severe attacks of UC, although the toxicity and even mortality associated with its use necessitates careful evaluation, selection, and follow-up.

Approximately 10% to 15% of patients with ulcerative colitis (UC) have a severe attack requiring hospitalization at some time point during the course of the disease. 1 Standard treatment of severe exacerbations of UC generally consists of intravenous glucocorticosteroids, but this approach fails to induce improvement in up to 40% of patients. Colectomy is then often necessary. 2 Besides glucocorticosteroids, cyclosporin A (CSA) is the only medication that has affected the outcome of severe acute UC. CSA is a potent immunosuppressor used in the prevention of organ graft rejection. It is a fungal metabolite, which acts as a calcineurin inhibitor, reducing the production of interleukin-2 and, hence, interfering with T lymphocyte function.

Lichtiger and colleagues performed the first double-blind, placebo-controlled trial demonstrating the efficacy of intravenous CSA in hospitalized patients. Nine of 11 patients (82%) in the CSA group improved and avoided colectomy, versus none in the placebo-group. 3 Since then, CSA has become standard therapy for steroid-refractory UC. In a controlled trial by D'Haens and colleagues it was even shown that therapy with CSA alone (without glucocorticosteroids) was as effective as glucocorticosteroids. 4 The goal of the current analysis was to study the efficacy and side effects in all patients treated with CSA at a single center.

Methods

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

Patients

We carried out a retrospective survey of all patients admitted to the Gastroenterology Departments of the university hospitals of Leuven (Belgium) with a severe attack of ulcerative colitis treated with IV CSA between November 1992 and December 2000. Medical charts and progress notes were reviewed, with specific attention to side effects and laboratory changes. Patients with Crohn's disease or indeterminate colitis were excluded. If there was no recent contact (less than 3 months), the patient was evaluated by telephone.

Treatment Regimen

Each patient was treated with IV steroids (minimum 40 mg methylprednisolone/day) before a treatment with CSA was initiated. All had an objective or subjective deterioration or a lack of response to steroids. The decision to start CSA was made after discussion with surgical colleagues. All patients received CSA at 4 mg/kg/d starting dose as a continuous intravenous infusion. Fifteen patients who were enrolled in a prospective study comparing different doses of CSA received 2 mg/kg/d. Blood CSA levels were measured every other day or more frequently if considered necessary. This analysis was done with a monoclonal assay utilizing Fluorescence Polarization Immunoassay technology (Abbott Laboratories, Abbott Park, IL 60064, USA). During intravenous treatment, CSA blood levels were kept between 250 and 450 ng/mL. IV glucocorticosteroids were continued at a stable dose. Patients who had a response were switched to oral treatment with Neoral (Novartis, Basel, Switzerland) at a dose of 8 mg/kg/d, adjusted to blood levels between 150 and 250 ng/mL in combination with azathioprine at a dose of 2.5 mg/kg or 6-mercaptopurine at a dose of 1.5 mg/kg (except in patients with earlier intolerance). CSA levels were assessed before the oral intake of Neoral. Prophylactic treatment with trimethoprim-sulfamethoxazole for Pneumocystis carinii pneumonia was not routinely given during the study period.

After 3 to 4 months, CSA was discontinued if the patient was in remission. Glucocorticosteroids were tapered over a 3-month period following hospitalization. Patients taking aminosalicylates continued this therapy.

Statistical Analysis

Quantitative variables were compared with two-tailed Student t test. Qualitative variables and differences were compared with χ2 analysis. For survival analysis, the methods of Kaplan and Meier were applied.

Results

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

Patients' Demographics

Eighty-six patients were included in the analysis—33 female (37%), 53 male (63%), mean age 40.9 ± 11.8 years. As already stated, 15 patients received 2 mg/kg/d of CSA and all other patients 4 mg/kg/d. Among the latter, 15 patients received CSA without concomitant glucocorticosteroids.

Short-term Response to IV CSA (Up to 1 Week After Discharge)

Seventy-two of the initial 86 patients (83.7%) had a response and avoided colectomy during their initial hospitalizations. Ten of these 72 patients, however, remained symptomatic with bloody stools and abdominal cramps, but could nonetheless be discharged from the hospital. The duration of intravenous CSA administration averaged 9 ± 2 days, with mean CSA blood levels of 324 ± 63.4 ng/mL. Although this study was not powered to detect differences in CSA levels, blood levels were comparable in responders and non-responders. The mean interval to surgery in patients not responding to CSA (n = 14) was 12 ± 4 days.

Table 1 demonstrates comparable characteristics in (initial) responders and non-responders.

Table 1. Patient Characteristics—No Significant Differences Were Noted Between Patients Who Underwent Colectomy Until 1 Week After the End of IV CSA and Those Who Responded to Medical Therapy (P = NS for all variables)
 No ColectomyColectomy PatientsAll Patients
N (male/female)72 (46/26)14 (8/6)86 (54/32)
Age (mean ± SEM)39.9 ±12.746.0 ± 6.540.9 ± 11.8
Disease duration (yrs)6.2 ±5.25.2 ±4.15.9 ± 4.9
Disease location   
 Pancolitis41.7%64.3%45.4%
 Left–sided colitis58.3%35.7%54.6%
Duration IV CSA (days)8.9 ±1.710.0 ±3.29.1 ±2.0
CSA blood   
 concentration (ng/mL)322 ± 66339 ± 54324 ± 63

All but 3 patients (69/72) who avoided colectomy were switched to oral CSA (Neoral). The first of these 3 patients was not in complete remission and was further successfully treated with oral glucocorticosteroids and azathioprine. The second patient did not respond and underwent colectomy 2 weeks later and the third had renal insufficiency and arterial hypertension caused by IV CSA.

After discharge from the hospital, glucocorticosteroids were gradually tapered over a period of 3 months. Oral CSA was simultaneously continued in the 69 patients for a mean period of 108 ± 50 days with a mean CSA blood concentration of 192 ± 55 ng/mL. In 62 of the 72 responders, azathioprine or methotrexate was continued or initiated. Two patients (2/72) with intolerance to azathioprine were given methotrexate. One patient was immediately treated with methotrexate. Only 7 patients were discharged on aminosalicylates, glucocorticosteroids, and oral CSA without azathioprine or MTX.

A second intravenous treatment with CSA was necessary in 11 patients, and 1 patient even received three IV courses of CSA. They were all treated with AZA before the second IV CSA treatment was given. One patient was treated immediately with IV CSA without clinical improvement, but after IV steroids were infused, his condition improved, although only temporarily. During the same hospitalization, the CU attack was resolved after a combination therapy for IV steroids and a second trial of CSA. AZA was not started between the two CSA treatment periods. The mean interval between the first and second treatment with CSA was 251 ± 233 days. In 3 patients, a colectomy was necessary despite a second IV CSA treatment with intervals of 10,108 and 966 days. The other 8 patients did not necessitate surgery with a mean follow up of 802 ± 393 days.

Long-term Response and Colectomy Rates

Of the 72 patients with complete or partial response, 18 underwent colectomy during further follow-up, after an average period of 178 ± 141 days (range 16–966) for a mean total follow up time of 773 ± 369 days (range 43–2929 days). Life table analysis of avoidance of colectomy is shown in Figure 1. The probability to avoid colectomy following successful CSA therapy was 64% at 1 year and 55% at 3 years of follow-up.

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Figure FIGURE 1. The time-related freedom from surgery after initiation of CSA.

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Table 2a shows the characteristics of the patients who avoided colectomy and those who did not. None of the parameters were predictive of failure of medical therapy. The outcome of the 10 patients who remained symptomatic was significantly worse than that of the patients who had a complete remission (P < 0.01). Six of these 10 patients (60%) underwent colectomy after a mean interval of 67 ± 35 days, versus time to colectomy of 234 ± 175 days in 12 of the 62 patients (19.4%) who had a “complete” response to CSA. Fifteen of 65 patients on maintenance therapy with azathioprine or methotrexate (23%) had a colectomy after an interval of 180 ± 140 days. Three out of the 7 patients who received no immunosuppressive treatment other than glucocorticosteroids and oral CSA were operated on after 28, 35, and 385 days (Table 2b). Since the majority of patients in remission were using azathioprine, we were unable to statistically demonstrate an additional benefit from this treatment.

Table TABLE 2a.. Patient Characteristics: Longterm
 No ColectomyColectomy
N (male/female)54(33/21)18(13/5)
Age (mean ± SHM)39.5 ± 12.640.4 ± 11.5
Disease duration (yrs)6.9 5.85.1 ±3.6
Disease location  
 Pancolitis40.7%53.1%
 Left–sided colitis59.3%46.9%
Duration IV CSA (days)8.9 ± 1.79.2 ± 1.8
CSA blood concentration  
 (ng/mL) IV phase307 ± 63360 ± 66
Duration oral CSA118 ± 4785 ± 39
CSA blood concentration  
 (ng/mL) oral phase193 ± 56185 ± 52
Table TABLE 2b.. Effect of Azathioprine/6 MP on the Prevention of a Colectomy
 Azathioprine/6 MP (65 pts)No Azathioprine/6 MP (7 pts)
Colectomy153
No Colectomy504

Not all patients who successfully avoided colectomy remained in remission. During follow-up, a substantial percentage of the responders relapsed and needed treatment with steroids or CSA again. Figure 2 shows the proportion of patients without relapse (no need for restarting glucocorticosteroids or CSA) of all patients who became asymptomatic after IV CSA. Of the 54 patients who avoided colectomy up to end 2000, 15 (27.8%) had a relapse of UC after an interval of 387 ± 122 days following CSA treatment. Life table predicts a relapse of 50% within 3 years.

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Figure FIGURE 2. Patients in remission after CSA treatment.

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Adverse Events: Mortality

Three patients died during or shortly after treatment with CSA (3.5%) because of opportunistic infections. All 3 patients received triple combined immunosuppressive treatment. The first patient was a 60-year-old male with diabetes and a 2-year history of UC, which was successfully treated with glucocorticosteroids and IV CSA for 12 days. Azathioprine was added at discharge. Two weeks later this patient developed Aspergillus pneumonia. Despite discontinuation of immunosuppressive therapy and initiation of antifungal agents, the patients died in septic shock. The second patient was a 57-year-old male relapsing under maintenance treatment with azathioprine. After 20 days of IV steroids, IV CSA was added for 15 days without clinical improvement. He then underwent colectomy, shortly after the intervention complicated by pneumonia with Aspergillus fumigatus. He died 1 week later. The third patient was a 32-year-old young male with an 8-year history of UC. He was using azathioprine maintenance when he presented with a relapse of UC, successfully treated with IV CSA IV and IV steroids for 9 days. During follow-up, 3 months later and still on azathioprine, glucocorticosteroids and oral CSA he developed a lethal pneumonia due to a Pneumocystis carinii infection.

Adverse Events: Other Problems

Six percent of all patients developed renal insufficiency, reflected as a rise (of ≥ 20%) in serum creatinine, most frequently during the administration of IV CSA. Arterial hypertension was present in 40% of these patients. In 50% of the patients, the mean concentration of CSA was considered too high.

The most common other side effects were infections associated with the use of combined immunosuppressive treatment or deep venous catheters. Eight patients suffered from catheter sepsis, 3 had a pneumocystic carinii pneumonia and 2 patients had an Aspergillus infection. One patient had a pneumothorax while placing a central line. Two patients developed an anal abscess.

One patient had an anaphylactic cardiac arrest due to the solvent in the CSA solution. After successful cardiopulmonary resuscitation, he recovered with minor cognitive dysfunction. In Table 3, a number of other side effects by CSA are mentioned, including hypertrichosis, arterial hypertension, headache, tremor, gingival hyperplasia, and elevation of liver function tests.

Table 3. Adverse Reactions Occurring During CSA Therapy
Infections1618.6%
Tremor/paresthesia89.3%
Arterial hypertension67.0%
Renal insufficiency55.8%
Hypertrichosis55.8%
Gingival hyperplasia55.8%
Headache33.5%
Mortality (infections)33.5%
Elevated liver tests (>2X)22.4%
Anaphylaxis (cardiac arrest)11.2%
Seizure00.0%

Discussion

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References

Severe attacks of UC are most frequently treated with IV glucocorticosteroids, although CSA mono-therapy has also been effective. Several papers have reported success with CSA, reflected as 56% to 100% of patients avoiding colectomy. (Table 4) 11–25 Our short-term success rate of 84% is consistent with other published data. After a mean follow-up of more than 2 years and with the majority of patients on maintenance immunomodulators, 62.7% (54/86) of our patients have avoided colectomy so far. Within this group, up to date, only 15 patients (27.7%) have developed a relapse of their UC. Overall, 39/86 patients (45%) have remained in remission without relapse. The life-table predicts that after 3 years, 55% of all treated patients will maintain their colon and, of these patients, 50% will develop a relapse.

Table 4. Short- and Long-Term Results of CSA IV in the Treatment of Severe Ulcerative Colitis Based on Literature Data
StudyStart Dose mg/kg/dBlood Cone. ng/mlNumber PatientsShort–Term ResponseLong–Term Response (Mean Follow–up Period)
Lichtiger114482982%64.2% (6m)
Liditiger1243280%60%
Cohen134360 ±1264285.7%61.9% (5.5 years)
Actis142216±39887.5%62.5% (3–18m)
Stack1542290.9%54.5% (39m)
Carbonnel163.21 ±0.95279 ± 963262.5%31.3% (190d)
Gurudu174550785.7% 0.0% (1 year)
Wenzl1851478.6%50.0% (48m)
Van Gossum1942969.0%44.8% (12m)
Ferandez2041392.3%91.7% (16.3m)
Ramkrishna212683.3%66.7% (6m)
Svanoni2243090%   –
Hyde2345056.0%40.0% (19m)
Rowe242.53669.4%33.3% (9m)
Rosselli2522483.3%30.4% (20.5m)

Several minor and major complications have been reported with the use of CSA. Minor complications such as tremor, paresthesia, headache, hypertrichosis, and gingival hyperplasia are common and certainly impair the quality of life of the patients. The incidence of these side effects was lower in the current series than in other papers, but the retrospective character of the study may explain this; many minor side effects may not have been recorded in the medical charts.

Since a number of adverse events may be related to the dose of CSA, 5 we recently performed a comparative trial with CSA doses of 2 and 4 mg/kg/d. The results of this trial suggest that both doses are equally effective, although patients treated with 4 mg/kg had a more rapid response than with 2 mg/kg. 6 It can therefore be recommended to use doses of 2 or 3 mg/kg/d, especially in patients carrying a high risk of adverse events.

Several complications originated from IV lines, including 1 case of pneumothorax and several documented cases of catheter sepsis. This type of complications could be avoided by using oral instead of IV loading doses of CSA, as it was done by Actis and colleagues. They obtained identical results with both routes of administration. The study was unblinded and included only a small number of patients not responding to oral steroids. 7 These data need confirmation before oral CSA can be used as an alternative for IV CSA.

One patient in our study had anaphylactic shock caused by the solvent of CSA. When switched to oral CSA, complete remission of his colitis was achieved.

The most concerning issue of the current series is mortality. Three patients (3.5%) died of opportunistic infections. These patients were deeply immunosuppressed, having received high doses of IV glucocorticosteroids for more than 7 days before starting IV CSA, followed by oral glucocorticosteroids, oral CSA, and azathioprine. We believe that the risk of opportunistic infections can be reduced by using the lowest effective dose of CSA, tapering glucocorticosteroids as soon as possible, and adding prophylactic treatment of Pneumocystis pneumonia with trimethoprim-sulfamethoxazole. This strategy is now routinely being used in patients treated with CSA in our department, and no further mortality has occurred since. It is even questionable if IV CSA has to be switched to oral CSA. Preliminary Greek data suggest maintenance success with steroids, azathioprine, and 5-ASA comparable with steroids, oral CSA, and 5-ASA during 6 months after successful induction therapy with IV CSA + IV steroids. 8 This was evaluated in a small group of patients and larger studies are needed before we can recommend that oral CSA can be replaced by azathioprine. We do not believe, however, that CSA can be advocated as a long-term maintenance option, given the significant toxicity profile.

Cohen and colleagues showed a significantly better quality of life in patients responding to CSA than patients after a colectomy. 9 Another element to be aware of is that patients who keep their colon have an enhanced risk of developing dysplasia or cancer in the colon.

Our study reveals a number of pros and cons of CSA therapy for severe UC. The better quality of life without colectomy has to be balanced against the risk of minor and major toxicity and even mortality. We believe, however, that with better knowledge of the potential risks, maximal prevention of opportunistic infections, earlier initiation of IV CSA in patients not responding to IV glucocorticosteroids (as reported by Travis et al 10) and probably also lower doses of CSA, the mortality risk will further be reduced. At this moment we suggest to start with IV CSA 2 mg/kg to continue IV steroids and to start azathioprine/6MP from the moment a clinical response is observed. During the treatment period with triple immunosuppression, all patients should receive trimethoprim-sulfamethoxazole to prevent Pneumocystis pneumonia. If there is no clinical response after a maximum of 1 to 2 weeks, colectomy should be performed. For patients relapsing after CSA withdrawal, a second IV treatment with CSA can be considered.

References

  1. Top of page
  2. Abstract
  3. Methods
  4. Results
  5. Discussion
  6. References
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