Robert Löfberg

A comparison of budesonide with prednisolone for active Crohn's disease

BACKGROUND Patients with active Crohns disease are often treated with corticosteroids, but the treatment has many side effects. Budesonide is a potent, well-absorbed corticosteroid, but because of a high rate of first-pass metabolism in the liver, its systemic bioavailability is low. METHODS We conducted a randomized, double-blind, 10-week trial comparing the efficacy and safety of an oral controlled-release form of budesonide with the efficacy and safety of prednisolone in 176 patients with active ileal or ileocecal Crohns disease (88 patients in each treatment group). The dose of budesonide was 9 mg per day for eight weeks and then 6 mg per day for two weeks. The dose of prednisolone was 40 mg per day for two weeks, after which it was gradually reduced to 5 mg per day during the last week. RESULTS At 10 weeks, 53 percent of the patients treated with budesonide were in remission (defined as a score < or = 150 on the Crohns disease activity index), as compared with 66 percent of those treated with prednisolone (P = 0.12). The mean score on the Crohns disease activity index decreased from 275 to 175 in the budesonide group and from 279 to 136 in the prednisolone group (P = 0.001). Corticosteroid-associated side effects were significantly less common in the budesonide group (29 vs. 48 patients, P = 0.003). Two patients in the prednisolone group had serious complications (one had intestinal perforation and one an abdominal-wall fistula). The mean morning plasma cortisol concentration was significantly lower in the prednisolone group than in the budesonide group after 4 weeks (P < 0.001) and 8 weeks (P = 0.02) of therapy, but not after 10 weeks. CONCLUSIONS Among patients with active Crohns disease, both controlled-release budesonide and prednisolone are effective in inducing remission. In this trial, prednisolone reduced scores on the Crohns disease activity index more, whereas with budesonide there were fewer glucocorticoid-associated side effects and less suppression of pituitary-adrenal function.

A reproducible grading scale for histological assessment of inflammation in ulcerative colitis

BACKGROUND Evaluation of histological activity in ulcerative colitis needs to be reproducible but has rarely been tested. This could be useful both clinically and in clinical trials. AIM To develop reproducible criteria which are valid in the assessment of acute inflammation (activity) and chronicity, and to evaluate these features in an interobserver variability study. METHODS A six grade classification system for inflammation was developed which could also be fine tuned within each grade. The grades were: 0, structural change only; 1, chronic inflammation; 2, lamina propria neutrophils; 3, neutrophils in epithelium; 4, crypt destruction; and 5, erosions or ulcers. Ninety nine haematoxylin-eosin sections from endoscopically inflamed and non-inflamed mucosa from patients with distal ulcerative colitis were assessed in two separate readings by three pathologists independently and without knowledge of the clinical status. Interobserver agreement was compared pairwise using kappa statistics. RESULTS Initially, kappa values between the observers were 0.20, 0.42, and 0.26, which are too low to be of value. Following development of a semiquantitative pictorial scale for each criterion, kappa values improved to 0.62, 0.70, and 0.59. For activity defined by neutrophils between epithelial cells, kappa values were 0.903, 1.000, and 0.907. Complete agreement was reached in 64% of samples of endoscopically normal and in 66% of endoscopically inflamed tissue. Neutrophils in epithelium correlated with the presence of crypt destruction and ulceration. CONCLUSION A histological activity system was developed for ulcerative colitis that showed good reproducibility and modest agreement with the endoscopic grading system which it complemented. It has potential value both clinically and in clinical trials.

The London Position Statement of the World Congress of Gastroenterology on Biological Therapy for IBD With the European Crohn's and Colitis Organization: When to Start, When to Stop, Which Drug to Choose, and How to Predict Response?

The advent of biological therapy has revolutionized inflammatory bowel disease (IBD) care. Nonetheless, not all patients require biological therapy. Selection of patients depends on clinical characteristics, previous response to other medical therapy, and comorbid conditions. Availability, reimbursement guidelines, and patient preferences guide the choice of first-line biological therapy for luminal Crohns disease (CD). Infliximab (IFX) has the most extensive clinical trial data, but other biological agents (adalimumab (ADA), certolizumab pegol (CZP), and natalizumab (NAT)) appear to have similar benefits in CD. Steroid-refractory, steroid-dependent, or complex fistulizing CD are indications for starting biological therapy, after surgical drainage of any sepsis. For fistulizing CD, the efficacy of IFX for inducing fistula closure is best documented. Unique risks of NAT account for its labeling as a second-line biological agent in some countries. Patients who respond to induction therapy benefit from systematic re-treatment. The combination of IFX with azathioprine is better than monotherapy for induction of remission and mucosal healing up to 1 year in patients who are naïve to both agents. Whether this applies to other agents remains unknown. IFX is also effective for treatment-refractory, moderate, or severely active ulcerative colitis. Patients who have a diminished or loss of response to anti-tumor necrosis factor (TNF) therapy may respond to dose adjustment of the same agent or switching to another agent. Careful consideration should be given to the reasons for loss of response. There are insufficient data to make recommendations on when to stop anti-TNF therapy. Preliminary evidence suggests that a substantial proportion of patients in clinical remission for >1 year, without signs of active inflammation can remain in remission after stopping treatment.

Infliximab in inflammatory bowel disease: clinical outcome in a population based cohort from Stockholm County

Background: Several placebo controlled studies have demonstrated the efficacy of infliximab in inflammatory bowel disease (IBD) but the potential toxicity of this new biological compound has been less studied. Aim: To assess the use of infliximab in IBD in a population based cohort, with special emphasis on the occurrence of severe adverse events and mortality. Patients: All patients with IBD treated with infliximab between 1999 and 2001 in Stockholm County were evaluated. Methods: Prospective registration of clinical data was carried out. Retrospective analyses were made of possible adverse events occurring in relation to infliximab treatment. Adverse events requiring pharmacological treatment or hospitalisation were defined as severe. Clinical response was assessed as remission, response, or failure. Results: A cohort comprising 217 patients was assembled: 191 patients had Crohn’s disease (CD), and infliximab was used off label for ulcerative colitis (UC) in 22 patients. Four patients were treated for indeterminate colitis (IC). Mean age was 37.6 (0.9) years (range 8–79). The mean number of infliximab infusions was 2.6 (0.1) (range 1–11). Forty two severe adverse events were registered in 41 patients (CD, n = 35). Eleven of the severe adverse events occurred postoperatively (CD, n = 6). Three patients with CD developed lymphoma (of which two were fatal), opportunistic infections occurred in two patients (one with UC, fatal), and two patients with severe attacks of IBD died due to sepsis (one with CD, one postoperatively with UC). One additional patient with UC died from pulmonary embolism after colectomy. Mean age in the group with fatal outcome was 62.7 years (range 25–79). The overall response rate was 75% and did not differ between the patient groups. Conclusions: Infliximab was efficacious as an anti-inflammatory treatment when assessed in a population based cohort of patients with IBD. However, there appear to be a significant risk of deleterious and fatal adverse events, particularly in elderly patients with severe attacks of IBD. Off label use of infliximab in UC and IC should be avoided until efficacy is proven in randomised controlled trials. The underlying risk of developing malignancies among patients with severe or chronically active CD in need of infliximab treatment is not known but the finding of a 1.5% annual incidence of lymphoma emphasises the need for vigilant surveillance with respect to this malignant complication.

Is colonoscopic surveillance reducing colorectal cancer mortality in ulcerative colitis? A population based case control study

Background—Colonoscopic surveillance is a standard procedure in many patients with long standing, extensive ulcerative colitis (UC), in order to avoid death from colorectal cancer. No conclusive proof of its benefits has been presented however. Aims—To evaluate the association between colonoscopic surveillance and colorectal cancer mortality in patients with UC. Patients—A population based, nested case control study comprising 142 patients with a definite UC diagnosis, derived from a study population of 4664 patients with UC, was conducted. Methods—Colonoscopic surveillance in all patients with UC who had died from colorectal cancer after 1975 was compared with that in controls matched for age, sex, extent, and duration of the disease. Information on colonoscopic surveillance was obtained from the medical records. Results—Two of 40 patients with UC and 18 of 102 controls had undergone at least one surveillance colonoscopy (relative risk (RR) 0.29, 95% confidence interval 0.06 to 1.31). Twelve controls but only one patient with UC had undergone two or more surveillance colonoscopies (RR 0.22, 95% confidence interval 0.03 to 1.74), indicating a protective dose response relation. Conclusion—Colonoscopic surveillance may be associated with a decreased risk of death from colorectal cancer in patients with long standing UC.

Oral budesonide for prevention of postsurgical recurrence in Crohn's disease

BACKGROUND & AIMS Prevention of postoperative recurrence after resection for Crohns disease (CD) would be of great clinical benefit. The efficacy of oral budesonide for prevention of endoscopic recurrence was evaluated in patients undergoing resection for ileal or ileocecal CD. METHODS Sixty-three patients received budesonide and 66 received placebo in a double-blind, randomized trial with parallel groups. Ileocolonoscopy, including biopsy, was performed after 3 and 12 months. Indications for surgery were fibrostenosis (78 patients), disease activity (41), and other reasons (10). RESULTS The frequency of endoscopic recurrence did not differ between the groups at 3 and 12 months. In patients with disease activity as indication for surgery, the endoscopic recurrence rate at the anastomosis was lower in the budesonide group at 3 months, although not significantly (21% vs. 47%; P = 0.11), and at 12 months (32% vs. 65%; P = 0.047). There was no such difference with respect to fibrostenosis as indication for surgery. No differences in adverse event patterns were found between the two groups. CONCLUSIONS Oral budesonide, 6 mg daily, offered no benefit in prevention of endoscopic recurrence after surgery for ileal/ileocecal fibrostenotic CD but decreased the recurrence rate in patients who had undergone surgery for disease activity.

Adacolumn, an adsorptive carrier based granulocyte and monocyte apheresis device for the treatment of inflammatory and refractory diseases associated with leukocytes

Abstract:  Apheresis has been recognized both economically and therapeuticallyas a novel approach for the treatment of inflammatory diseases,and certain others, which respond poorly to drug therapy. This reportis about Adacolumn, an adsorptive carrier based granulocyteand monocyte apheresis device with a volume of 335 mL,filled with about 220 g of cellulose acetate beads of 2 mmdiameter as the column adsorptive carriers. Pre‐ and post‐columnleukocyte counts have shown that the carriers adsorb about 65% ofgranulocytes, 55% of monocytes and 2% of lymphocytesfrom the blood in the column. Additionally, after apheresis, thereis a marked decrease in inflammatory cytokines (TNF‐α,IL‐1β, IL‐6 and IL‐8) produced by blood leukocytes,together with down‐modulation of l‐selectinand the chemokine receptor CXCR3. Adacolumn has been used to treatpatients with rheumatoid arthritis, ulcerative colitis and HIV infection. Typicalapheresis sessions have been 4–10, at a frequency of oneor two sessions per week. Treatment of patients with Adacolumn hasbeen associated with very promising efficacy and safety data. Accordingly,in Japan, Adacolumn has been approved by the Ministry of Healthfor the treatment of ulcerative colitis. Furthermore, Adacolumnmet the required quality and safety standards for medical devices andreceived an EC certification (CE‐mark) from TUV in 1999. However,although Adacolumn carriers are very efficient in depleting excessand activated granulocytes and monocytes/macrophages, theclinical efficacy associated with Adacolumn apheresis cannot befully explained on the basis of reducing granulocytes and monocytesper se. Hence, a long lasting effect on inflammatory cytokine generation,chemokine activities or immunomodulation is likely, but the precisemechanisms involved are not fully understood yet.

Risk of haematopoietic cancer in patients with inflammatory bowel disease

Background and aims: Several chronic inflammatory conditions are associated with an increased risk of lymphoma. Whether this applies to inflammatory bowel disease (IBD) is still unclear but of paramount interest, particularly in the safety evaluation of newer immunosuppressive drugs. Reports also indicate a possible increase in the risk of leukaemia in IBD. We therefore assessed the risk of haematopoietic cancers in a large cohort of patients with IBD. Subjects and methods: We performed a population based cohort study using prospectively recorded data, including 47 679 Swedish patients with Crohn’s disease (CD) or ulcerative colitis (UC) assembled from regional cohorts of IBD from 1955 to 1990 (n = 8028) and from the Inpatient Register of 1964–2000 (n = 45 060), with follow up until 2001. Relative risks were expressed as standardised incidence ratios (SIR). Results: Overall, we observed 264 haematopoietic cancers during follow up, which corresponded to a borderline significant 20% increased risk in both UC and CD. In UC, lymphomas occurred as expected (SIR 1.0, n = 87) but myeloid leukaemia occurred significantly more often than expected (SIR 1.8, n = 32). In CD, there was a borderline significant increased lymphoma risk (SIR 1.3, n = 65), essentially confined to the first years of follow up. Proxy markers of disease activity had little impact on lymphoma risk. Conclusion: On average, patients with IBD have a marginally increased risk of haematopoietic cancer. In UC, this is accounted for by an excess of myeloid leukaemia. In CD, a modest short term increase in the risk of lymphoma of unknown significance cannot be excluded but any long term risk increase seems unlikely.

Clinical course of colorectal Crohn's disease: A 35-year follow-up study of 507 patients

BACKGROUND & AIMS Crohns disease (CD) confined to the colon and rectum is an increasing clinical entity. The aim of this study was to assess the features and clinical course of colorectal CD. METHODS This was a retrospective cohort study of 507 patients in whom colonic or rectal CD had been diagnosed between 1955 and 1989. RESULTS Colonic distribution was segmental in 40%, total in 31%, and left-sided in 26%. Perianal/rectal fistulas occurred in 37%. In patients who attained clinical remission, the 5-year cumulative relapse rate after diagnosis was 67% (95% confidence interval [CI], 62-72). At the initial presentation of CD, the frequency of major surgery decreased from 24% to 14% (P < 0.005) over time. Still, the overall long-term probability of major surgery after 10 years was unaltered (49% vs. 47%). The presence of fistulas increased the probability of surgical resection (relative risk [RR], 1.7 [95% CI, 1.3-2.2]), whereas left-sided disease was associated with a decrease (RR, 0.6 [95% CI, 0.4-0.8]). Twenty-four percent of the patients developed inflammation in the small bowel. The cumulative risk for a permanent ileostomy was 25% (95% CI, 21-29) 10 years after diagnosis. CONCLUSIONS Colorectal CD is an increasing entity carrying substantial morbidity. Half of the patients will undergo surgical resection within the first 10 years, and half of those will ultimately undergo ileostomy. Changed management at diagnosis has not affected the long-term probability of resection.

Increased risk of cancer in ulcerative colitis: a population-based cohort study

OBJECTIVE:There is an increased risk of colorectal cancer among patients with ulcerative colitis (UC). However, the overall and site specific cancer risks in these patients have been investigated to a limited extent. To study the association between UC and cancer, a population-based study of 1547 patients with UC in Stockholm diagnosed between 1955 and 1984 was carried out.METHODS:The patients were followed in both the National Cancer Register and the National Cause of Death Register until 1989. For comparisons, regional cancer incidence rates in Stockholm County were used together with individually computed person-years at risk in the UC disease cohort.RESULTS:A total of 121 malignancies occurred among 97 individuals as compared with 89.8 expected (standardized morbidity ratio [SMR] = 1.4; 95% confidence interval (CI), 1.1–1.6). Overall, an excess number of colorectal cancers (SMR, 4.1; 95% CI, 2.7–5.8), and hepatobiliary cancers in men (SMR = 6.0; 95% CI, 2.8–11.1) associated with primary sclerosing cholangitis, was observed. The risk of pulmonary cancer was decreased (SMR = 0.3; 95% CI, 0.1–0.9). In all, 91 extracolonic malignancies were observed, compared with the 82.3 expected (SMR = 1.11; 95% CI, 0.9–1.3).CONCLUSIONS:In UC patients, the overall cancer incidence is increased mainly because of an increased incidence of colorectal and hepatobiliary cancer. This increase is partly counterbalanced by a decreased risk of pulmonary cancer compared with that in the general population.