Immunosuppressants and operation in ulcerative colitis1

Immunosuppressants and Operation in Ulcerative Colitis Alon Pikarsky, MD, Oded Zmora, MD, Steven D Wexner, MD, FACS, FRCS, FRCSEd Ulcerative colitis (UC) has many pathophysiologic features characteristic of immune diseases. These features provide the rationale for immunomodulatory therapy offered for treatment of UC in recent years. The association between UC and other autoimmune diseases, such as autoimmune anemia, pernicious anemia, systemic lupus erythematosus, and Hashimoto’s thyroiditis, has been previously described but there is no increase in the incidence of these disorders in patients with UC.1-4 Both UC and Crohn’s disease are characterized by a production of mucosal immunoglobulin G, T- and B-cell mucosal lymphocytosis, and macrophage activation during exacerbation of the disease.5,6 Autoantibodies are known to be present in UC, the most common being antineutrophil cytoplasmic antibody (ANCA).7 In UC, the staining pattern is perinuclear (pANCA), as opposed to Wegner’s granulomatosis, which has a cytoplasmic staining pattern.8 pANCA is expressed by 60% to 80% of patients with UC and by only 20% to 30% of patients with Crohn’s disease.9,10 Of interest is the fact that the vast majority of patients with pouchitis express pANCA.11 Antibody-producing cells are synthesized in reaction to intestinal antigens. T helper cells and B cells regulate the immune response, activating cytokines and resulting in altered immunoglobulin production. Importantly, the absolute number of lymphocytes in UC is normal,12,13 as are both delayed hypersensitivity and the subset of circulating T cells.14-17 The ratio of CD4 (helper) to CD8 (suppressor) T cells is the variable factor, and although the ratio is normal in remission, it is altered in exacerbation with T helper predominance.13,18-22 The B-cell population is less affected in

UC, and natural killer cells are not defective, but there is an increase in lymphocyte production of interleukin2.23-27 The peripheral lymphocytes of UC patients have cytotoxic properties; this cytotoxicity is non–complement-dependent and is completely eliminated after colectomy.28-34 In summary, the immunopathology of UC involves an initiating antigen triggering a disproportionate inflammatory cascade. This cascade consists of inflammatory cell recruitment from the colonic blood supply with resultant release of inflammatory mediators.35-37 Mucosal function is altered by these changes, with increased permeability, mucous secretion, platelet activation, and tissue damage.38 Immunosuppressive agents are known to affect T-cell function and modulate cytokine function.39 This is the basis for the addition of cyclosporine, azathioprine, and 6-mercaptopurine to the conservative armamentarium for treating UC. The impact of prolonged steroid treatment as another indication for operation was evaluated by Sher and colleagues.40 They compared a matched group of patients treated either medically or surgically. Each group consisted of 20 patients matched for duration and severity of disease. Medically treated patients who required at least one hospital admission were compared with patients treated by a three-stage restorative proctocolectomy. Weight loss and transfusion requirements were both notably increased in the medically treated group. Sixty-five percent of patients in this group had major steroid-related complications, but the major surgical complication rate was only 15%. INDICATIONS FOR SURGICAL TREATMENT Indications for operation in UC include perforation, toxic megacolon, uncontrolled hemorrhage, and the possibility of malignancy. Additionally, because proctocolectomy cures UC, intractability is considered an indication even in the absence of complications. The last indication is by far the most common, mainly because of the existence of restorative procedures. Other indications include growth retardation in the pediatric popu-

No competing interests declared.

Invited lecture at the American College of Surgeons 86th Annual Clinical Congress, Chicago, IL, October 2000. Received September 26, 2001; Revised January 25, 2002; Accepted February 22, 2002. From the Department of Colorectal Surgery, Cleveland Clinic Florida, Weston, FL. Correspondence address: Steven D Wexner, MD, FACS, FRCS, FRCSEd, Department of Colorectal Surgery, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL 33331.

© 2002 by the American College of Surgeons Published by Elsevier Science Inc.

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lation and extraintestinal manifestations not responding to other areas. There are four basic operations for the surgical treatment of UC: proctocolectomy with a Brooke’s ileostomy, proctocolectomy with continent ileostomy (Kock’s pouch), total colectomy with rectal preservation and ileorectal anastomosis, and restorative proctocolectomy with ileal pouch anal anastomosis. The latter is the procedure most commonly preferred and can be done in one, two, or three stages. A one-stage procedure is reserved for uncomplicated cases, but many authors argue against this form of the procedure because of an increased incidence of pelvic complications. These authors advocate a two-stage procedure in elective cases with a diverting loop ileostomy and future closure. A three-stage procedure is reserved for complicated cases such as acute colitis, perforation, and hemorrhage. A subtotal colectomy with end ileostomy is done as the first stage, followed by completion proctectomy and a diverting loop ileostomy, and finally closure of the loop ileostomy. COMPLICATIONS OF POUCH OPERATION Mortality rates after restorative proctocolectomy are remarkably low, despite the magnitude of the operation. Researchers from the Mayo Clinic reported a mortality rate of 0.2% in more than 1,600 patients,41 and a similar rate of 0.4% was reported by the Cleveland Clinic after 1,005 procedures.42 Despite the low mortality, morbidity is a major concern after pouch operation, with complications in the range of 20% to 50%. Anastomotic leak occurs in 10% to 15% of cases, leading to future development of anal stricture. Fleshman and colleagues43 reported a 10% incidence of anastomotic leak in 179 patients. In a review from the Mayo Clinic, radiologic or clinical leak from the pouch or the ileoanal anastomosis occurred in 14% of patients.44 Fazio and colleagues42 reported a rate of 3% in 1,005 patients (including familial polyposis). Fear of anastomotic leak and resultant stricture formation is perhaps the main reason for using a protective ileostomy. After the double-stapled technique began being used, prognosis after anastomotic leak improved, and its occurrence does not always mean pouch failure.45 One of the most common complications after pouch operation is small bowel obstruction. Incidence rates of 15% to 25% are reported.43,46-48 Obstruction is usually caused by adhesions, but internal hernias and outlet obstruction of the diverting ileostomy

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can also lead to bowel obstruction.43,49,50 The use of sodium hyaluronate bioresorbable membrane (Seprafilm, Genzyme Corp, Cambridge, MA) markedly reduces the incidence and severity of adhesions after this operation.51 Stomal complications in the period before closing the ileostomy also lead to considerable morbidity. Stomal retraction, parastomal hernias, and dehydration because of high stomal output can all complicate this procedure, leading to avoidance of diversion by some authors,47,52-54 but patients with incomplete fecal diversion have higher incidences of pelvic complications.53 Fistulas from the pouch to the perianal skin or vagina are related to technical problems during anastomosis construction or the incorrect diagnosis of UC versus Crohn’s disease.55 Rates of fistula formation range from 4% to 7%, and multiple procedures are required to cure the problem, leading to a 30% rate of pouch loss.56-59 Pouchitis, a term originally used by Kock, is a wellrecognized complication occurring in 15% to 20% of patients after operation and probably reaching a rate of up to 50% at 10 years after operation. Stasis and bacterial overgrowth are considered causative, but the infrequent occurrence in familial polyposis patients suggests an autoimmune etiology, as is found in UC.60-63 Patients usually report diarrhea, bloody stools, low-grade fever, and malaise. Those with extraintestinal manifestations of UC, particularly sclerosing cholangitis, are more likely to suffer from these complications.62 Treatment is usually a course of oral antibiotics (metronidazole) or salicylate/steroid enemas. Recurrent pouchitis should always lead to pouch biopsy to exclude the possibility of Crohn’s disease. Several other complications can follow pouch operation, including pouch perforation, perianal skin irritation, evacuation problems, erectile dysfunction, and reduced fertility in both men and women.63-67 These complications, coupled with patients’ reluctance for a stoma, are the main reasons for conservative management of UC with primarily fulminant colitis. Importantly, 10% of patients with fulminant colitis experience a severe flare at initial disease presentation. In these traditionally young patients with no earlier health problems, operation can seem an extreme solution.68 In the last decade, immunosuppressants have become the hallmark of treatment in this group of patients with severe steroid-refractory UC. These medications are used in an attempt to avoid colectomy or, at the very least, to delay

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urgent subtotal colectomy allowing for an elective restorative proctocolectomy. IMMUNOSUPPRESSIVE DRUGS’ MODE OF ACTION Cyclosporine A (CSA), an amino acid cyclic polypeptide, is a metabolite of the fungus species Beauveria nivea. CSA has long been known to suppress some humoral immunity and, to a greater extent, cell-mediated immunity such as allograft rejection and delayed type hypersensitivity69; the exact mechanism of action is unknown. Specific reversible inhibition of immunocompetent lymphocytes in the G0 or G1 phase of the cell cycle has been found to be responsible for its action.69,70 T helper cells are the primary target of CSA, but they also inhibit production and release of interleukin (T-cell growth factor) and decrease the expression of interleukin-2 receptors in target cells without interleukin-2; T helper cells remain inactive and undifferentiated, rendering these cells, which are critical in the inflammatory process, incapable of supporting the inflammatory cascade. Absorption of CSA from the gastrointestinal tract is incomplete and variable, even in the presence of a healthy gastrointestinal tract.71 Compared with IV administration, the absolute bioavailability of the oral solution is approximately 30%.69,72 Drug elimination is primarily biliary, with only 6% excreted in the urine. The main adverse reactions of CSA are renal dysfunction, tremor, hirsutism, hypertension, and gingival hyperplasia. Azathioprine (Imuran, Prometheus Laboratories, Inc, San Diego, CA), an immunosuppressive antimetabolite, is an imidazolyl derivative of 6-mercaptopurine, so many of its biologic effects are similar to those of the parent compound.73 It is well absorbed after oral administration, and maximum availability occurs 1 to 2 hours after ingestion.74 Blood levels are of no predictive value because the clinical effects correlate with nucleotide levels in the tissues rather than in the plasma. Azathioprine is cleaved in vivo to mercaptopurine. Both compounds are oxidized or methylated in the liver with no kidney metabolism. Inactivation by xanthine oxidase is the important degradative pathway and is the reduction necessary in patients receiving allopurinol. The drug acts by suppressing hypersensitivity reactions of the cell-mediated type and causing variable alterations in antibody production. When used in organ

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transplantation, T-cell effects on suppression depend on its relationship to antigenic stimulators or engraftment.75,76 Azathioprine has a minimal effect in established graft rejection. The mechanism by which azathioprine affects autoimmune response is still unknown. In rat models of arthritis, azathioprine has been shown to inhibit lymph node hyperplasia, which precedes onset of the disease. Main side effects include severe leukopenia and thrombocytopenia. These side effects are dose related and account for persistent blood counts necessary while using the drug. Gastrointestinal hypersensitivity with severe nausea and vomiting has also been reported.74,77,78 6-Mercaptopurine (6-MP; Purinethol, GlaxoSmithKline, Research Triangle Park, NC) is an analogue of the purine bases adenine and hyperanthine.79 Primarily, it is one of a series of purine analogues that interferes with nucleic acid biosynthesis. Found to be active against human leukemias, 6-MP competes with hypoxanthine and guanine for the enzyme hypoxanthine-guanine phosphoribosyl transferase and interferes with the de novo pathway for purine ribonucleotide synthesis.80 It is not known which of the biochemical effects of 6-MP and its metabolites is predominantly responsible for cell death.81 6-MP, like azathioprine, is metabolized by xanthine oxidase in the liver, accounting for dose reduction with concomitant use of allopurinol.81 Immunosuppressive effects are similar to those of azathioprine. 6-MP is hepatotoxic, it is a dose-dependent bone marrow suppressor, and it has been reported to cause intestinal ulcerations.82-84 When used in conjunction with UC, it is associated with increased risks of acute pancreatitis.85-87 IMMUNOSUPPRESSIVES IN UC Patients with UC have a 15% to 20% chance of developing acute colitis requiring hospitalization and use of IV steroids.88 The course of these patients varies. Remission can be achieved in about 60% of patients with this mode of therapy. Those patients who do not respond to IV steroids require emergent colectomy.89,90 Twenty percent of UC patients suffer from pancolitis, and the risk of complications such as fulminant colitis, toxic megacolon, perforation, and bleeding increases when the colon is more diseased, increasing the chance for urgent colectomy.91-93 Gupta and colleagues94 were the first to report successful treatment with CSA of a patient with acute UC.

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Table 1. Early Outcomes of Intravenous Cyclosporine A for Acute Colitis First author

n

Early response n %

Lichtiger96 Carbonnel100 Cohen101 Kozarek98 Gurundu102 Fleshner103 Stack104 Pinna-Pintor105

11 32 42 30 7 45 22 46

9 20 36 17 6 — 20 29

82 62 86 56 86 — 91 63

Duration of IV therapy (d)

Followup (mo)

Colectomy (at 6 mo)

2 (range 3–14) — 10.3 ⫾ 5.4 6.5 10.5 (range 4–14) 10.9 (range 5–23) 7 —

— 12 (range 25–32) 23 (range 6–65) 6 (range 1–16) 6.6 (range 1–12) — 39 (range 31–59) —

— 22 (69%) 16 (38%) 22 (73%) 5 (71%) 14 (31%) 10 (45%) 25 (54%)

Dash indicates that the author did not report that information.

Subsequently, another report described 15 patients with acute colitis who were not cured by at least 10 days of IV steroids. These patients were given IV CSA (4 mg/kg/d), and 11 (73%) responded in a mean time of 5.8 days. Responders were then switched to maintenance oral CSA for 6 months, and colectomy was avoided in all but one patient; six patients (55%) were weaned completely from steroids.95 After this pilot study, the same group from Mount Sinai Hospital in New York conducted a prospective randomized study of CSA versus placebo for steroid-resistant acute colitis. An 82% response rate was noted in the 11 patients enrolled in the treatment arm (mean time to response 2 days) versus no response in the placebo group. A clinical activity index was used to determine response to treatment, which included parameters such as frequency of diarrhea, rectal bleeding, general well-being, and incontinence. Of the 11 patients in the CSA arm, 2 did not respond to CSA and underwent colectomy. Of the nine patients who responded to therapy, all but one were managed successfully with oral CSA. In the placebo group (nine patients), four underwent urgent colectomy, and five received open-label CSA; all successfully went ahead to maintenance oral CSA.96 This prospective randomized study led to a rapid increase in the use of CSA for acute steroid-resistant colitis. A collective review of 11 uncontrolled studies revealed an 80% initial response to IV CSA,97 but 50% of these initial responders required colectomy within the first 6 months. Members of the Pacific Northwest Gastroenterology Society evaluated their results with this treatment regimen.98 Overall, 30 patients were treated by this group, and 13 (43%) required urgent colectomy. Nine of the remaining 17 (53%) patients required subsequent colectomy at a mean of 6 months after initial treatment; altogether, colectomy was prevented in 8

(27%) patients at a mean followup of 6 months. These discouraging results were attributed to lack of a uniform treatment protocol and learning curve of the physicians. In response, a “user’s guide” was published by Kornbluth and colleagues99 to standardize CSA treatment for acute colitis. Table 1 summarizes the early outcomes of IV CSA for acute colitis. With continued use of this regimen, a variety of drugrelated complications arose in these patients. In the randomized study of Lichtiger and colleagues,96 one patient of the treatment group had a grand mal seizure 13 hours after beginning therapy; after drug discontinuation, this patient, who had hypocholesterolemia, underwent emergent colectomy. In their guidelines for CSA use for acute colitis, these authors caution that hypocholesterolemia and hypomagnesemia are risk factors for seizures in these patients.99 In a collected series from the Mayo Clinic, 243 patients developed 246 CSA-related side effects, most commonly paresthesias and hypertrichosis.97 Of note, all these side effects were reversible on drug discontinuation. Sepsis because of colonic perforation after IV CSA administration was reported by Gurundu and colleagues,102 Kozarek and colleagues,98 and Carbonnel and colleagues,100 in all cases leading to urgent operation. Perforation occurred also in the series reported by Cohen and colleagues.101 In this series, major complications were attributed to CSA in 3 of 42 patients, leading to cessation of treatment. These included, in addition to the perforation, Pneumocystis carinii pneumonia and a grand mal seizure. A summary of complications after CSA treatment is presented in Table 2. Overall, a low rate of major complications and a high rate of minor side effects are related to treatment with CSA. These complications are usually reversible and of note is the fact that no case of renal failure has been reported; nevertheless, more than 50% of patients expe-

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Table 2. Complications with Cyclosporine A Treatment Sepsis

Seizures

Hypertension

Renal impairment

Infectious complications

Paresthesias tremor

Headaches

First author

n

n

%

n

%

n

%

n

%

n

%

n

%

n

%

Lichtiger96 Gurundu102 Carbonnel100 Kozarek98 Cohen101 Stack104

11 13 32 30 42 22

— 1 1 1 1 —

— 7 3 3 2 —

1 — — — 1 —

9 — — — 2 —

4 1 4 1 10 4

38 7 12 3 24 18

— — 1 1 — 2

— — 3 3 — 9

— — 3 1 8 —

— — 9 3 19 —

4 3 4 2 3 4

36 23 12 7 7 18

2 — — — 1 6

18 — — — 2 27

Dash indicates that the author did not report that information.

rience side effects related to the drug use. Consequently, many authors are reluctant to continue treatment with oral CSA, even in patients who respond, to prevent acute exacerbation of the disease.105-107 Attempts were made to predict patients with high chances of good response to CSA treatment with endoscopic and radiologic assessments of disease extent, but characterizing the severity of disease failed to predict response to treatment.100 Even more discouraging is the fact that even initial responders end up undergoing colectomy in 30% to 70% of cases within 6 months. OPERATION IN PATIENTS RECEIVING IMMUNOSUPPRESSIVE AGENTS Three retrospective studies addressed the role of CSA treatment on surgical outcomes (Tables 3, 4). Fleshner and colleagues103 were the first to report the morbidity of operation for UC associated with CSA therapy. In this series, patients unresponsive to CSA who underwent operation while on the medication were evaluated. Fourteen patients with severe UC who did not respond to treatment (31% of 45 patients entering CSA protocol) entered this retrospective review. Thirteen patients also received high-dose steroids, 6 were also receiving 6-MP, and 10 were on 5-aminosalicylic products. Overall, the mean duration of CSA treatment before operation was 35.1 days, and the mean length of inpatient IV CSA treatment was 10.9 days. Cyclosporine toxicity was observed in three patients (21%). Two patients developed transaminase elevations, and one patient had nausea related to CSA. All patients underwent subtotal colectomy with end ileostomy, closure of the Hartmann’s stump, and transanal rectal catheter for drainage. No mortality was encountered. Complications occurred in eight patients (57%), including ileus/small bowel obstruction in three patients, all of which were successfully conserva-

tively managed; deep vein thrombosis in two; wound infection in two; and partial dehiscence of the rectal stump in one patient, which was conservatively treated. There is a known association between CSA treatment and increased incidence of postoperative thrombosis107-109 that can account for the complications seen in the series of Fleshner and colleagues.103 The authors concluded that CSA itself did not change the outcomes of operation in these patients, although complications did occur in a relatively high number of patients, some of which can be attributed to CSA. Pinna-Pintor and colleagues,105 from Torino, Italy, reported their experience over a 5-year period with outcomes of restorative procedures in patients not responding to CSA treatment. Overall, this was a very low response rate. Colectomy was avoided in only 10 patients (22%). One patient died from pulmonary embolism during IV CSA treatment and was not considered a mortality in this series. Seventeen patients were initially nonresponders and underwent operation during the same hospitalization; the remaining 8 (32%) patients relapsed as outpatients on oral CSA and were readmitted for operation. All 25 patients underwent restorative proctocolectomy: 21 (84%) in three stages (Group I) and 4 (15%) in two stages (Group II). Nine patients (36%) had perioperative complications, and there was no mortality. In Group I, two major complications ocTable 3. Retrospective Series Assessing CSA Treatment on Surgical Outcomes: Demographics

First author

n

Mean age (y)

Mean disease duration (mo)

Fleshner103 Pinna-Pintor105 Hyde68

14 25 19

34.6 32.7 33

20 41 48

CSA, cyclosporine A.

Mean intravenous CSA treatment (d)

11 14 4

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Table 4. Retrospective Series Assessing Cyclosporine A Treatment on Surgical Outcomes: Surgical Procedure and Outcomes

First author

Fleshner103 Pinto-Pintor105 Hyde68

Subtotal colectomy

Total proctocolectomy

Rehospitalization after colectomy (d)

Major complications, n (%)

Minor complications, n (%)

14 21 19

0 4 0

8.8 15.2 —

0 3 (12) 2 (10.5)

8 (57) 6 (24) 2 (10.5)

*Dash indicates that the author did not report that information.

curred: abdominal wound dehiscence and ileal volvulus, both of which required immediate reoperation. Two patients with bowel obstruction were conservatively managed, and two other patients had minor infectious complications. In Group II, three of four patients had major complications: two had anastomotic dehiscence, and one had suture line bleeding. Longterm complications in the entire series included one pouch-perianal fistula, five cases of anastomotic stricture, three cases of pouchitis, and two cases of bowel obstruction. There was no need for pouch excision in this series, and mean bowel frequency 1 year after operation was 4.8 per day. The authors concluded that, in this setting, restorative proctocolectomy should be performed only as a three-stage procedure; like the previously mentioned series, these authors state that CSA treatment does not negatively affect the outcomes of operation for UC. Recently, Hyde and colleagues68 compared the surgical outcomes in patients treated with CSA and steroids to outcomes in those treated with steroids alone. During a 7-year period, 44 patients who did not respond to medical therapy were retrospectively reviewed. Twentyfive patients were treated with steroids alone, and 19 were also treated with IV CSA. During the study period, 28 patients (56%) responded to CSA and avoided colectomy. In the CSA group, the rectal stump was managed as a Hartmann’s pouch in eight patients, left closed within the abdominal wall in nine, and left as a mucous fistula in the remaining two patients. There was no mortality in this series, and morbidity was not markedly different between the two groups. Two patients (10.5%) in the CSA group had complications requiring operation: one patient had a necrotic mucosal fistula, and the other had a postoperative small bowel obstruction. Two other patients had minor surgical complications that were conservatively managed. Additionally, medical complications occurred in eight (42%) patients in the CSA group. This series led the authors to conclude that CSA does not increase morbidity in this group of patients. Importantly, these patients do suffer from a high

morbidity rate, and timely surgical intervention is crucial. Procedures and outcomes of these three series are outlined in Table 4. DRUG MAINTENANCE WITHOUT OPERATION IV CSA is an effective treatment for rapid improvement and for avoiding urgent operation in UC, but in addition to a high complication rate, a high relapse rate has been noted, even when patients are maintained on oral CSA. These results suggest that oral CSA is not an effective drug for remission maintenance. Fernandez-Banares and colleagues110 and Hinojosa and colleagues111 were the first to report better longterm outcomes with maintenance oral azathioprine and 6-MP compared with oral CSA therapy. In the first reports, patients had a mean response time to these drugs of 3.4 months, with complete or partial response achieved in 80% of patients.110,111 Azathioprine and 6-MP are not new drugs in the armamentarium of UC treatment. These drugs have long been used for the treatment of steroid-refractory UC with response rates of 60% to 70%.112-114 The main problem with these immunomodulators is a 3-month delay in response, limiting their use in acutely ill patients.115,116 George and colleagues117 evaluated the longterm outcomes of 105 UC patients treated with 6-MP. Forty-seven of these patients had pancolitis; complete remission was achieved in 62% and partial remission in another 23%. Patients were followed for a mean duration of 5 years: the relapse rate while on 6-MP therapy was 35%; the median time to relapse was 14 months; and overall, 10 patients required colectomy. There were adverse outcomes to this treatment regimen. Twentyone patients experienced leukopenia (counts of less than 3,000), which was reversible in all cases. Two patients were hospitalized for infectious complications, five had abnormal liver function tests (one requiring drug withdrawal), and two patients had severe arthritis requiring discontinuation of therapy. Of special concern is the fact that three patients with chronic colitis (of 17, 14, and

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22 years’ duration) developed colonic neoplasia while on the treatment regimen for durations of 1.5, 0.5, and 3.1 years, respectively. Cohen and colleagues101 combined IV CSA with maintenance 6-MP or azathioprine. Twenty-seven (64%) of the patients initially treated with CSA were also treated with these drugs. Seven of these patients were treated with 6-MP/azathioprine before IV CSA was started. Treatment outcomes in these 27 patients resulted in an operation rate of 62%, compared with 60% in patients not receiving 6-MP/azathioprine. Life-table analysis revealed that the probability of avoiding colectomy in patients who received CSA and 6-MP/ azathioprine was 66% at 5.5 years, compared with 40% in those who received CSA alone. This study, together with the previously described series, supports the regimen of adding maintenance 6-MP/azathioprine after acute intervention with IV CSA for patients with acute colitis. In this manner, complications of longterm treatment with CSA are avoided, and the delay in effect of 6-MP/azathioprine is overcome during the treatment period with CSA. Operation, when necessary, is delayed for 10 to 14 months, allowing replenishment of nutritional status and an elective setting, avoiding a three-stage procedure. This regimen is not risk free, because complications were noted with all three medications. The three patients who developed colonic neoplasia while being treated117 raises another concern, especially with the availability of a restorative procedure that both eliminates the disease and allows an excellent quality of life.

CONCLUSIONS In conclusion, IV CSA is effective in remission induction in those patients unresponsive to steroids. The drug is less effective in maintenance of remission and is associated with a large variety of complications with chronic use. For these reasons, 6-MP/azathioprine should be initiated for maintenance of remission and therapy with CSA stopped. This combination therapy delays operation and should be regarded as a “bridge” to operation so that the patient’s nutritional status can be improved and an elective procedure performed. In cases of treatment failure with CSA, operation should be contemplated. Patients can be reassured that outcomes of operation in these cases are not worsened because of the immuno-

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