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- MATERIALS AND METHODS
Background: To determine the long-term outcome of patients admitted with acute severe colitis (ASC) who avoided colectomy on the index admission, a retrospective cohort study was performed.
Methods: Patients admitted for intensive treatment of ASC in 1992–1993 previously described for a predictive index of short-term outcome in severe ulcerative colitis (UC) were followed for a median 122 months (range 3–144). Complete responders (CR) to intensive therapy had <3 nonbloody stools/day on day 7 of the index admission; incomplete responders (IR) were all others who avoided colectomy on that admission. Main outcome measures were colectomy-free survival, time to colectomy, and duration of steroid-free remission.
Results: In all, 6/19 CR (32%) came to colectomy compared to 10/13 IR (P = 0.016; relative risk 3.33, 95% confidence interval [CI] 1.12–9.9). The median ± interquartile range time to colectomy was 28 ± 47 months (range 6–99) for CR who came to colectomy versus 7.5 ± 32 (3–72) months for IR (P = 0.118). Among the IR, 7/13 came to colectomy within 12 months, and all within 6 years from the index admission. The longest period of steroid-free remission was 42 ± 48 (0–120) months for CR, but 9 ± 20 (1–35) months for IR (P = 0.011).
Conclusions: One week after admission with ASC in the prebiologic era, IRs had a 50% chance of colectomy within a year and 70% within 5 years, despite cyclosporin and azathioprine where appropriate. The maximum duration of remission in CRs was almost 5 times longer than IRs. It is unknown whether biologics change the long-term outcome.
Acute severe ulcerative colitis (UC) requiring hospital admission affects about 15% of patients during the course of their illness.1 The mortality from severe attacks of UC has declined from 7% after the introduction of steroids in 19552 to <1% in specialist centers today.3 Nevertheless, the response to intensive treatment with steroids has remained unchanged for almost 50 years. A systematic review of 32 studies of severe UC involving 1991 patients shows that the colectomy rate did not change between 1974 and 2006 (29%, 95% confidence interval [CI] 28–31).4
With the advent of cyclosporin, first used to treat intravenous steroid-refractory UC in 1984,5 70%–80% of such patients show a short-term response, but by 12 months 65% have relapsed and by 7 years 58%–88% have come to colectomy.6, 7 Alternative rescue therapies include tacrolimus8 and infliximab,9 which makes the difficult decision between continued medical therapy and colectomy yet more challenging. The long-term outcome of patients presenting with a severe attack, who either respond completely or incompletely to therapy, remains unclear.
In 1992–1993 a prospective study was performed on 49 patients admitted with 51 episodes of severe UC to examine clinical and biochemical factors that might predict short-term outcome.10 It was found that the simple measures of a C-reactive protein (CRP) >45 mg/L and stool frequency 3–8/day, or a stool frequency >8/day on day 3 of intensive treatment were associated with an 85% chance of colectomy on that admission. The short-term outcome was defined according to the treatment response on day 7 of the index admission: complete responders, incomplete responders, and colectomy on that admission. In this patient cohort, 14/51 episodes were treated with cyclosporin in addition to intravenous steroids. The purpose of the current study was to use this cohort to examine the long-term outcome of those making a complete or incomplete response to medical therapy for severe UC. This provides a measure of the burden of disease among patients admitted with severe colitis.
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- MATERIALS AND METHODS
In a group of consecutive patients admitted with acute severe UC, our data show that about two-thirds (65%) will come to colectomy within 12 years. The numbers were small, but these are the longest outcome data yet presented and have clinical credibility. Just 7 days after admission to hospital with acute severe UC, patients can be divided into 3 groups, according to treatment response to intensive medical therapy with intravenous steroids and cyclosporin: CRs who have ≤3 stools/day and no visible blood in the stools, the IRs who have >3 stools/day or visible blood in the stools on day 7, and those heading for colectomy on that admission. At that 7th day it may not be possible to discriminate precisely between IRs and those who will have a colectomy on that admission, but this discrimination still has practical value even when applied retrospectively. This is because the symptoms on the 7th day have a bearing on the long-term outcome, which informs both patients and physicians when deciding on future therapy. The questions that matter to patients are the likelihood of colectomy, the likelihood of relapse or a further severe attack needing hospital admission, and the expectation of an extended period of remission.
The 5-, 10-, and 25-year cumulative colectomy rates in the largest population-based study of 1586 patients with UC was 20% (95% CI 18%–22%), 28% (95% CI 26%–30%), and 45% (95% CI 41%–49%), respectively.12 Other population-based studies of UC have reported similar figures (24% after 10 years and 31% after 18 years),13, 14 although colectomy rates may be decreasing in the Copenhagen population in recent years.15 These studies do not discriminate between degrees of severity and reported colectomy rates, for severe UC remain unchanged over 30 years4 in spite of the introduction of cyclosporin as rescue therapy 20 years ago. It is too early to determine the impact of infliximab, but unpublished data from the Swedish-Danish study9 suggest that only a third come to colectomy even after 3 years. Kohn et al16 showed that among 83 patients with severe UC treated with infliximab, 15% underwent colectomy within 2 months and about 60% (of which most were on immunosuppressive therapy) avoided colectomy during a median 23 months' follow-up. On the other hand, Jakobovits et al17 reported that 16/30 (53%) patients treated with infliximab for refractory UC came to colectomy after a median 140 days from their first infusion. Only 17% (5/30) achieved steroid-free remission after a median follow-up of 13 months and there is no doubt from the patient profiles that these had more treatment-refractory disease than the Kohn et al study.16 Biologics have the potential to change disease activity and colectomy-free or steroid-free remission in severe UC, but the magnitude of that impact in the long term remains to be tested.
Those with the highest risk of colectomy in the current study (77%) were the IRs (RR 3.3, 95% CI 1.1–9.9; P = 0.016). It is remarkable that it may be possible to indicate the likely need for colectomy over the succeeding decade just 7 days after admission with severe UC. Those with an IR to intensive therapy had a more rapid progression to colectomy than CRs. Within a year of the index admission, 54% of IRs underwent colectomy, while only 5% of those with a CR came to colectomy (P = 0.005). The median time to colectomy among CRs who came to colectomy was over 2 years, compared to 7 months for IRs. Even though this difference did not reach significance when only patients who had a colectomy were analyzed, 2 further analyses suggest that the difference is real. There was a highly significant difference when the groups as a whole were analyzed for the whole follow-up period (P = 0.006; Table 3) and a test to analyze the expected direction of travel of the 2 groups (the Moses extreme reaction test) also showed a highly significant difference (P = 0.003). Factors influencing this disease behavior remain to be established. Extensive disease was associated with the need for colectomy on the index admission, but not during follow-up. The numbers, however, were small, even if the point is made that distal colitis can be just as refractory to medical treatment as more extensive disease. It is notable that the need for surgery in UC appears to be highest within the first few years of diagnosis.18 In contrast, 13 of the 30 patients who came to colectomy (43%) in our cohort had been diagnosed with UC 10 or more years before entering the study. This suggests that short disease duration may not be a predictive factor for colectomy in the context of severe UC. This is consistent with the finding that there was no difference between CRs and IRs in disease duration measured by time from index diagnosis to index surgery.
The pattern of disease as determined by the number of relapses, median number of relapses per patient, number of courses of steroids, and median number of hospital readmissions for acute severe colitis did not show differences between CRs and IRs. However, the observation period for CRs was much longer, because of the high colectomy rate among IRs. The impact of immunomodulation is difficult to evaluate. The median number of relapses for CRs and IRs on AZA was almost identical. This could mean that AZA corrects for the impact of IR, potentially changing the natural course of disease. It could also mean that AZA is not that effective in UC. The most likely explanation, however, is that treatment with AZA identifies the most refractory group of patients and that small numbers should not be overinterpreted.
The maximum interval between relapses was different for CRs and IRs. The longest period of steroid-free remission was 3.5 years for CRs, but less than a year (median 9 months, P = 0.011) for IRs. This is useful information when advising patients who are recovering from a severe attack of UC, since a patient with an IR on that admission can expect to relapse sooner than CRs.
The key weakness of this study is the small sample size and retrospective nature that limit the applicability of these results, but patients admitted with severe UC are relatively uncommon in individual practice. The key strength is the long follow-up period and the fact that the study comes from a single center with a special interest in the management of severe UC. The outcomes in Oxford most closely match the median colectomy rate of all published series over a period of 30 years.4
The poor long-term outcome of IRs to intensive treatment should be recognized. Two-thirds of a series of consecutive patients admitted to the hospital with severe UC came to colectomy within the next decade. Just 7 days after admission it may be possible to predict the likelihood of colectomy among responders in whom a severe attack was treated with corticosteroids and/or cyclosporin, but not infliximab. IRs to medical treatment seem to be at particular risk. This includes anyone who has >3 stools/day or visible bleeding on day 7, but who avoids colectomy on that admission. These patients had a 70% chance of colectomy within the next 5 years. In contrast, the maximum duration of remission in CRs was almost 5 times longer than for IRs. These are material facts that help inform clinicians' decision-making and are relevant to patient care, albeit from the prebiologic era. The long-term effect of biologics as rescue and maintenance therapy in acute severe UC remains to be tested.