Inflammatory bowel disease (IBD) is classically characterized by periods of remission and clinical relapse. In some patients disease may take an aggressive course that involves frequent relapses, continued active disease, intensified medical treatment, or even a surgical approach. It is important to determine clinical factors that predict the aggressive course of disease to implement appropriate therapy to prevent patients from developing complications and to improve their quality of life. This review discusses clinical factors that have been suggested to predict an aggressive course of disease in patients with ulcerative colitis (UC) and Crohn disease (CD).
Ulcerative Colitis
Introduction
UC is a chronic inflammatory disorder involving the colon. The cause of UC remains unknown; however, it has been suggested that genetic, immunologic, and environmental factors may play a role. Patients with UC may present with varied clinical presentations and extraintestinal manifestations. It has been estimated that there are 1 million people afflicted with IBD in the United States, with approximately half attributable to UC, and similar numbers in Europe.
Over 50% of patients using corticosteroids and 15% using immunomodulators and infliximab may experience adverse events. It is thus appropriate for physicians and other health care providers who treat them to recognize which patients have a high propensity for having disease that will be active and aggressive in the near future. In such patients, other therapeutic interventions may modify disease activity. The term disabling or aggressive UC has not been specifically defined in the literature. For this review the authors have defined aggressive or disabling UC as disease with frequent clinical relapses that require intensification in medical treatment or surgical approach.
Thus, a pressing question that remains largely unanswered is which specific variables predict the presence of UC with an aggressive course. The most commonly cited variables predictive of relapse have been severity of disease at time of initial presentation, younger patient age, female sex, time from recent relapse, lack of primary sclerosing cholangitis (PSC) diagnosis, therapy with mesalamine or systemic corticosteroids, nonadherence to mesalamine, and having had a recent colonoscopy. However, there are several limitations to these studies. There has not been one single study that has conclusively demonstrated which variables accurately predict patient clinical relapse.
Natural history
The disease course is characterized typically by periods of active and inactive disease, a pattern reported to occur in 80% to 90% of UC patients. Data from a large, long-duration population-based cohort study has demonstrated that 9% of patients have severe, 71% of patients moderate, and 20% of patients mild disease activity of UC at the time of presentation. An intermittent course of the disease after the first flare was observed in 40% to 65% of patients, whereas a continuous course was present in 5% to 10% of patients. Among 1161 patients with UC evaluated in years 3 to 7 after initial diagnosis, 25% were in remission, 18% had continuously active disease every year, and 57% had intermittent relapses. After 25 years of follow-up, an intermittent course was observed in 90% of patients ( Fig. 1 ).
Population-based studies have also observed that approximately 50% of patients were symptom-free at any time during follow-up. Disease activity in the preceding years and the duration of activity were predictive of the subsequent clinical course in the following years ( Fig. 2 ) . There was a significant correlation observed between the activity of UC in the first 2 years after initial diagnosis with an increased chance of 5 consecutive years with active disease ( P <.00001). There was a 30% probability of a 1-year remission-free course in patients after the relapse. On the other hand, an annual risk of relapse for patients in remission for 1 year was estimated at 20%. Patients who experienced relapse had a 10% to 20% risk of yearly relapse 10 years after the first relapse.
Predictors of colectomy
According to the most recent guidelines by the American College of Gastroenterology, absolute indications for surgery in UC include presence of exsanguinating hemorrhage, perforation of the colon, and documented or strongly suspected colon cancer (high grade dysplasia, low grade dysplasia in flat mucosa). Colectomy is also recommended in patients with severe UC with or without toxic megacolon who do not respond to conventional medical therapy, or in those with a less severe form of UC but with symptoms that are medically intractable or with intolerable medication side effects. The rates of colectomy differ among studies, in part because of different proportions of patients with extensive and limited disease. A population-based cohort study from Denmark observed that the rate of colectomy decreased with every year of disease, with the highest rate of 10% during the first year after diagnosis, 3% in the second year after diagnosis, and a constant 1% rate per year after 4 years of disease duration. Another population-based study reported a 10-year cumulative rate of colectomy of 24%, 15-year rate of 30%, and a 25-year rate of 30%.
Several studies attempted to determine factors predictive of colectomy in patients with UC and suggested that increased number of stools (>8 per day) or 3 to 8 stools along with increased serum C-reactive protein (CRP >45 mg/L) on the third day of hospitalization, the endoscopic appearance of rectal mucosa (deep ulcerations) upon hospital admission, and disease extent (pancolitis) at diagnosis were predictors of colectomy. A multivariate regression model of the data from the population-based study after stratification according to the initial extent of UC determined that patients at initial presentation of UC with mucopus in the stool (relative hazard coefficient 2.53, 95% confidence interval [CI] 1.16–5.53), fever (relative hazard coefficient 2.87, 95% CI 1.44–5.69) or poor general condition (relative hazard coefficient 2.54, 95% CI 1.22–1.66) were at an increased risk of colectomy. Another model from a multicenter prospective inception cohort study of 617 UC patients determined that extensive colitis increased the risk of colectomy fourfold (hazard ratio [HR] = 4.1, 95% CI, 2.0–8.4). Data from population-based inception IBD cohort from southeastern Norway (the IBSEN cohort) determined that extensive colitis and increased erythrocyte sedimentation rate (ESR ≥30 mm/h) at the time of diagnosis were independent factors that increased the risk of requiring a future colectomy threefold (HR = 2.98, 95% CI 1.25–7.08 and HR = 2.94, 95% CI 1.58–5.46, respectively). It should be noted that this result is before the era of anti-tumor necrosis factor α (anti-TNF) therapy. It is uncertain what effect treatment with anti-TNF therapy would have on this patient population.
A retrospective case-control study of 246 patients with UC done in the era of anti-TNF therapy for UC found that the requirement to hospitalize a patient to control disease (odds ratio [OR] = 5.37, 95% CI 2.00–14.46) and the use of infliximab (OR = 3.12, 95% CI 1.21–8.07) were independent predictors of future colectomy.
Mortality
The risk of death from UC decreased significantly after introduction of glucocorticosteroids. Published in 2007, a metaanalysis of 10 population-based inception cohort studies highlighted that patients with UC had a risk of death that is similar to people in the general population, noting a standardized mortality ratio (SMR) of 1.1 (95% CI, 0.9–1.2, P = .42). Overall, among all deaths in patients with UC, the disease itself only accounted for 17%. The most common causes of UC-related morality were colorectal cancer (37%) and complications during or after surgery (44%). Recent data from IBSEN study with 10-year follow-up also did not observe a significant increased risk of death in patients with UC, with an overall SMR of 1.24 (95% CI 0.93–1.62).
Clinical Predictors of Aggressive/Disabling Disease
Clinical predictors of extent of progression of disease
Disease extent (as measured endoscopically) may progress over the 10-year time period after initial diagnosis in 10% to 30% of patients experiencing proctitis or proctosigmoiditis at the first recurrence of previously diagnosed disease. According to the population-based study, the cumulative probability of progression of proctosigmoiditis was 53% after 25 years of disease. Disease progression was seen in 9% within the first year of disease, with a constant intensity of 5% per year during subsequent 10 years, and then with subsequent decrease to a stable rate of 2.5% per year.
The severity of UC is roughly proportionate to the amount of colon that is involved with macroscopically visible inflammation as determined endoscopically. In four studies it was observed that anywhere from 14% to 37% of patients with UC have pancolitis, 36% to 41% have disease extending beyond the rectum, and about 44% to 49% have disease confined to the rectum at the time of disease diagnosis.
An analysis of data from a cohort of 470 patients who were seen at the Cleveland Clinic in a referral-based center presenting with either proctitis or left-sided colitis at initial diagnosis determined that 53.8% of patients had an extension of their disease over time. Patients were followed for at least 5 years with a mean duration of 12.7 years. Clinical factors present at the time of diagnosis that were associated with an increased risk of disease extension included younger age (20–30 years) (OR 0.886, 95% CI 0.78–1.0), presence of toxic, fulminant, or severe colitis (OR = 14.8, 95% CI 3.5–63.1), left-sided colitis (OR = 2.5, 95% CI 1.6–3.9) and presence of joint symptoms (OR = 3.7, 95% CI 1.6–8.6). Patients with pancolitis ( P <.001) and left-sided ( P <.002) UC had significantly greater frequencies of observed complications: toxic, fulminant, or severe colitis (24% and12.6% vs 3.7%), toxic dilatation (21.1% and 9.5% vs 2.9%), bleeding (25.2% and 17.9% vs 9.5%), and undergoing surgery (60.7% and 51.6% vs 14.2%) compared with those with proctitis. Data from multivariable logistic regression analysis from a Scandinavian population-based cohort study indicated that abdominal pain (relative hazard coefficient of 3.59, 95% CI 1.76–7.35) and diarrhea (relative hazard coefficient of 5.54, 95% CI 2.25–13.64) when present at diagnosis were two independent predictors of progression of disease extent.
Primary sclerosing cholangitis
Several studies observed that patients with UC who had concurrent PSC had a milder clinical course of UC than those with UC but without PSC. Patients with UC only had received treatment with systemic and local corticosteroids significantly more often and were hospitalized more frequently because of disease activity than UC patients with PSC. Another study evaluating 30 patients with PSC who underwent orthotopic liver transplantation and survived more than 12 months observed that among 16 patients who had concomitant UC, the activity of UC worsened in 50% of cases in the posttransplant period when compared with the pretransplant UC course; on the other hand, de novo UC developed after liver transplantation in 25% of patients without pretransplant IBD and follows a mild course. However, studies have suggested that patients with UC and PSC are at increased risk of colon cancer when compared with those with UC only. Patients with both UC and PSC had 48.1% cumulative incidence of colorectal cancer and dysplasia after 28 years. A case-control study of 40 patients with extensive UC and PSC matched 1:2 to patients with extensive UC alone and determined that there is a significantly increased absolute cumulative risk of developing colorectal dysplasia/carcinoma in the former when compared with the latter group of patients after 10 (9% vs 2%), 20 (31% vs 5%), and 25 (50% vs 10%) ( P <.001 for all comparisons) years from diagnosis.
Medications
Corticosteroids
A population-based study from Olmsted County, Minnesota, described the natural history of treatment with corticosteroids in patients with UC. It was observed that among patients treated with corticosteroids, 54% achieved complete remission, 30% partial response, and 16% no response over first 30 days. An analysis of the course of disease over 1 year showed that 49% of patients achieved prolonged response, 22% became corticosteroid-dependent, and 29% required colectomy. Because of the frequent occurrence of corticosteroid dependence and need of surgery, treatment with corticosteroids has been considered a marker of poor prognosis.
Patients with a severe flare of UC are usually treated initially with intravenous glucocorticosteroids. Retrospective analysis of data from four hospital centers in Scandinavia obtained from 97 patients with severe UC who received corticosteroids intravenously determined that increased CRP level (≥25 mg/L) ( P = .012) and the presence of increased bowel movement frequency (>4 per day) ( P <.001) on the third day of treatment with high dose corticosteroids were independent predictors of corticosteroids resistance and colectomy within 30 days after admission to the hospital. Multivariable logistic regression analysis of clinical, biological, or endoscopic factors gathered from 53 patients with UC and 1 patient with CD identified that the presence of an increased number of bowel movements (>7 per day) on the third day of hospitalization (adjusted OR 21.0, 95% CI 3.6–124.3) and male sex (adjusted OR 8.2, 95% CI 1.2–55.5), were independent factors predictive of corticosteroid failure in patients with severe IBD colitis.
Azathioprine
Azathioprine is recommended in patients with UC as a maintenance treatment in those with inadequately sustained remission on 5-aminosalicylic acid agents or in corticosteroid-dependent patients allowing for corticosteroid sparing. Data from a multicenter retrospective study of 127 patients with UC illustrated that withdrawal of azathioprine in patients with UC in remission is associated with an increased risk of relapse. Multivariable logistic regression analysis determined clinical predictors of disease relapse after discontinuation of azathioprine. Lack of remission during treatment with azathioprine (HR = 2.4, 95% CI 1.4–3.9), extensive disease beyond splenic flexure versus left-sided colitis (HR = 1.8, 95% CI 1.1–3.0) or versus distal colitis (HR = 2.0, 95% CI 1.1–3.7), and short duration (3–6 months) of treatment with azathioprine (HR = 2.8, 95% CI 1.3–6.1) increased the risk of UC relapse by a factor of two- to threefold.
Nonsteroidal antiinflammatory drugs
Several studies assessed an association between the use of nonsteroidal antiinflammatory drugs (NSAIDs) and the course of IBD. A prospective case-control analysis determined that current (within 45 days) and recent (within 45 and 180 days) use of NSAIDs was associated with a significantly increased risk of emergency admissions to the hospital because of exacerbation of UC with a respective unadjusted odds ratios of 2.54 (95% CI 1.09–5.91) and 2.45 (95% CI 1.19–5.03). Another prospective case-control study observed 20-fold increased odds of exacerbation or new onset of disease among IBD patients when compared with controls with irritable bowel syndrome (IBS) who were taking NSAIDs less than 1 month before onset of symptoms with confirmed association between NSAID use and disease activity (OR = 20.3, 95% CI 2.6–159.7). The relationship between the use of NSAIDs and disease activity was found in 31% and 2% of IBD and IBS patients, respectively. Data from retrospective analyses determined a significant association between IBD relapse and use of NSAIDs (adjusted OR = 6.31, 95% CI, 1.16–34.38, P = .03). Early clinical relapse of IBD within 9 days of NSAIDs ingestion was observed in 17% to 28% of users of nonselective NSAIDs (23% of UC patients and 20% of CD patients, P >.6). A randomized double blind placebo controlled trial with celecoxib showed no risk of UC flare after 2 weeks of use when compared with placebo with similar respective relapse rates of 3% and 4% ( P = .719).
Nonadherence to mesalamine
Nonadherence to mesalamine has been found to increase the risk of UC recurrence fivefold (HR 5.5, 95% CI 2.3–13) based on data from a prospective cohort study of 99 patients. A systematic review of the literature determined that nonadherence to mesalamine was associated with increased morbidity and greater risk of symptomatic relapse, reduced quality of life, and possible increased risk of colorectal cancer.
Nonsmoking status
Recent metaanalysis of 12 case-control studies and 1 prospective cohort study that examined the relationship between UC and smoking when compared with non-IBD controls indicated that current smoking had a protective effect on the development of UC (OR = 0.58, 95% CI 0,45–0.75) by reducing the risk of UC by 42%. Patients who quit smoking were found to be at an increased risk of UC compared with current smokers (OR 1.79, 95% CI 1.37–2.34). Small studies and case reports observed that intermittent smokers may experience symptomatic improvement during smoking and that nonsmokers with UC who start smoking may achieve remission. An analysis of the effect of smoking habits on the course of UC performed in 209 patients showed that current smoking status after disease onset was associated with a decreased risk of hospitalization when compared with nonsmoking status (less than 100 cigarettes in the lifetime) (adjusted relative risk [RR] = 0.5, 95% CI 0.3–0.8). On the contrary, the adjusted risk of colectomy was similar between current smokers and nonsmokers (RR = 1.1, 95% CI 0.4–2.8). Those who stopped smoking before the disease onset were 1.5-fold more likely to be hospitalized because of disease activity than nonsmokers (adjusted RR = 1.5, 95% CI 1.0–2.2), and the odds were particularly increased in those who smoked at least 21 pack-years (adjusted RR = 2.4, 95% CI 1.3–4.6). A nonsignificantly increased risk of colectomy was found in patients who stopped smoking after UC diagnosis when compared with nonsmokers (adjusted RR = 2.2, 95% CI 0.8–6.3). However those who smoked at least 41 pack-years had significant and nearly 18-fold higher risk of colectomy than nonsmokers (adjusted RR = 17.9, 95% CI 2.4–131.7). A group of French researchers observed significantly increased rates of duration of time with active UC (54 vs 35 per 100 person-years, P <.01), years with hospital admissions (9 vs 4 per 100 person-years, P <.05), and years with medical therapy with oral (13 vs 3 per 100 person-years, P <.01) or intravenous (4 vs 0 per 100 person-years, P <.01) corticosteroids and azathioprine (5 vs 0 per 100 person-years, P <.01) after cessation of smoking when compared with these parameters measured before discontinuation of smoking in 32 patients.
Colonoscopy
A significant association between performing colonoscopy and developing a subsequent increase in UC disease activity as measured by the UC Simple Clinical Colitis Activity Index (SCCAI) was recently suggested based on a multivariate mixed modeling performed in 51 patients with UC in remission. It was observed that shorter time from colonoscopy preparation (week 1 vs week 4, P = .0127), higher baseline SCCAI ( P <.0001) and the use of prednisone ( P = .0120) were factors predictive of increased disease activity after colonoscopy. However, the use of thiopurines ( P = .0045) was protective against an increase in disease activity following colonoscopy. It should be noted that 6 of 51 patients (12%) experienced relapse within a week after colonoscopy with only 1 of them continuing to relapse 4 weeks after the colonoscopy.
Clinical factors predictive of relapse in patients with UC determined by multivariate logistic regression analyses
Several prospective studies have identified multiple clinical factors affecting the probability of UC relapse using multivariable logistic regression analysis during follow-up ranging from 6 months to 10 years ( Table 1 ).
| Author and Year Study Design | Design | Patients (n) | Risk Factors | Hazard Ratio (95% CI) | Comment |
|---|---|---|---|---|---|
| Hoie et al 2007 | Population-based inception cohort | 771 | Female sex High level of education Mesalamine rx during follow-up Corticosteroids rx during follow-up | 1.2 (1.0–1.5) 1.4 (1.1–1.8) 2.1 (1.7–2.7) 7.1 (5.1–9.7) | Factors predictive of first clinical relapse within 10-year follow-up |
| Female sex Smoking cessation during study vs never smoking Mesalamine rx during follow-up Corticosteroids rx during follow-up | 1.2 (1.1–1.3) 1.3 (1.1–1.6) 1.9 (1.6–2.2) 5.6 (4.5–6.9) | Factors predictive of all clinical relapses within 10-year follow-up Clinical relapse: increase in disease symptoms causing changes in medical treatment or necessitating surgery | |||
| Bitton et al 2001 | Prospective longitudinal | 74 | Younger age (20–30 y) (per decade) Basal plasmacytosis on rectal biopsy Greater number of prior relapses in women (per prior relapse) | 0.4 (0.2–0.7) 4.5 (1.7–11.9) 1.6 (1.2–1.9) | Factors predictive of shorter time to clinical relapse: worsening of bowel function and rectal bleeding within 12-month follow-up |
| Nishio et al 2006 | Prospective cohort | 113 | Pit patterns in rectal mucosa on magnifying colonoscopy | 2.06 (1.53–3.17) | Factors predictive of clinical relapse within 12-month follow-up Remission: Disease Activity Index ≤3 |
| Fujiya et al 2002 | Prospective cohort | 18 | Absence of minute defects of colonic epithelium on magnifying colonoscopy | 0.24 (0.072–0.801) | Factors predictive of clinical relapse within 6-month follow-up Relapse: Rachmilewitz score ≥5 |
| Watanabe et al 2009 | Prospective longitudinal | 57 | Regular findings on magnifying colonoscopy | 0.03 (0.01–0.24) | Factors predictive of clinical relapse within 12-month follow-up Relapse: presence of diarrhea, bloody stool, abdominal pain |
The identified clinical factors that were considered independent predictors of disease relapse included younger age (20–30 years old) (HR = 0.4, 95% CI 0.2–0.7), history of multiple relapses in women (HR = 1.6, 95% CI 1.2–1.9), plasmacytosis on rectal biopsy specimens (HR = 4.5, 95% CI 1.7–11.9), use of mesalamine (HR = 1.9, 95% CI, 1.6–2.2), use of glucocorticosteroids (HR = 5.6, 95% CI, 4.5–6.9), female sex (HR = 1.2, 95% CI, 1.1–1.3), cessation of smoking during the study period (HR = 1.3, 95% CI, 1.1–1.6), presence of pit patterns in rectal mucosa (RR = 2.06, 95% CI 1.34–3.17), or absence of minute defects of colonic epithelium (HR = 0.24, 95% CI 0.072–0.801) on magnifying colonoscopy or regular magnifying colonoscopy findings (OR = 0.03, 95% CI 0.01–0.24. A recent prospective population-based study of 354 patients with UC who were evaluated after 1 year and 5 years of follow-up periods determined based on multivariable logistic regression analysis that factors predictive of mucosal healing after 1 year of follow-up included duration of education greater than 12 years (OR = 2.08, 95% CI 1.27–3.43) and extensive disease at the time of initial diagnosis (OR = 2.56, 95% CI 1.38–4.75). It was also determined that the presence of mucosal healing at 1 year was associated with decreased risk of future colectomy at 5 years (RR = 0.22, 95% CI 0.06–0.79).
Summary
Controlled data focusing on factors that predict an aggressive course of UC are limited. In the medical literature there is a lack of consistent definition of aggressive and disabling UC. Most patients with UC have an intermittent, relapsing-remitting course, with a minority of patients having continuous disease activity. Therapy with rectal mesalamine and systemic immunomodulators has greatly reduced the relapse rate and has lowered the necessity of using systemic corticosteroids, agents which may actually increase the relapse rate.
Patients with PSC and patients who are taking azathioprine tended to have a lower relapse rate, whereas those patients who were ex-smokers, female, or of younger age have been shown to have an elevated risk of relapse. Additionally, patients who have basal plasmacytosis on rectal biopsy or abnormal endoscopic findings on magnifying colonoscopy also tended to have increased risk of relapse. There are still not enough data to conclusively judge which factors are responsible for greater relapse rates, however. Significant limitations exist because of shortcomings of the studies that have been published. Therefore, a large multicenter prospective study, as well as additional other studies, are required to conclusively assess such factors.
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