Per Karlén

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.

Crohn's disease and cancer: A population-based cohort study

BACKGROUND/AIMS To study the association between Crohns disease and cancer, we performed a population-based study of 1251 subjects with Crohns disease diagnosed in Stockholm from 1955 to 1984 and followed in both the National Cancer Register and the National Cause-of-Death Register until 1989. METHODS For comparisons, regional cancer incidence rates in Stockholm County were used together with individually computed person-years at risk in the Crohns disease cohort. RESULTS Overall, 69 malignancies occurred among 67 individuals as compared with 59.80 expected malignancies (standardized morbidity ratio [SMR] = 1.15; 95% confidence interval, 0.90-1.46). An excess number of cancers of the upper gastrointestinal tract (SMR, 3.05; 95% confidence interval, 1.67-5.11) was observed, mainly because of an increased number of cancers of the small intestine (SMR, 15.64; 95% confidence interval, 4.26-40.06). An increased occurrence of urinary bladder cancer was also observed (SMR, 2.68; 95% confidence interval, 1.08-5.53). CONCLUSIONS The occurrence of colorectal cancer was not increased.

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.

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.

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.

Clinical trial: colectomy after rescue therapy in ulcerative colitis-3-year follow-up of the Swedish-Danish controlled infliximab study

Aliment Pharmacol Ther 2010; 32: 984–989

DNA aneuploidy in ulcerative colitis: Reproducibility, topographic distribution, and relation to dysplasia

Fifty-nine patients with longstanding, total ulcerative colitis were followed up in a prospective colonoscopic surveillance program. Biopsy specimens were sampled from predetermined locations of the colon and rectum at regular intervals. All specimens were assessed for histological dysplasia and, by flow cytometry, for detection of DNA aneuploidy during 8 years of follow-up. Special emphasis was made to correlate the findings of DNA aneuploidy with findings of dysplasia at colonoscopy or, in case proctocolectomy was performed, in the surgical specimen. Fifteen patients (25.4%) had DNA aneuploidy detected at least once during the follow-up. Eight of 10 patients with repeated findings had consistent ploidy level of the aneuploid peaks from one examination to another. Ten patients had multiple peaks. DNA aneuploidy tended to become more widespread in the bowel during the follow-up but persisted in the same part(s) of the colon and rectum. DNA aneuploidy occurred before development of definite dysplasia in 6 patients, simultaneously with development of dysplasia in 6 patients, and after the development of dysplasia in 1 patient only. In 2 patients, single aneuploid peaks were detected once but could not be found again at subsequent examinations. Dysplasia correlated closely topographically to DNA aneuploidy, but the latter finding was more common without concomitant dysplasia. Only in 1 patient, and at one examination, definite dysplasia was recorded without findings of DNA aneuploidy. Detection of DNA aneuploidy in patients with ulcerative colitis is persistent and reproducible and closely correlated to dysplasia. Widespread changes indicate that the entire colorectal mucosa is at increased risk of malignant transformation. Changes in nuclear DNA content appear to be an earlier phenomenon than dysplasia in the malignant transformation of the colorectal mucosa in ulcerative colitis, and the use of flow cytometry in surveillance programs may be of value for selection of patients at high risk of developing colorectal carcinoma.

Inflammatory Bowel Disease Confers a Lower Risk of Colorectal Cancer to Females Than to Males

BACKGROUND & AIMS Reported differences in cancer risk between male and female animals after chronic inflammation suggest that estrogen has inflammation-modifying properties. Little is known about these effects in human beings. Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer (CRC); we studied differences in inflammation-associated CRC between men and women patients with IBD. METHODS By using a large population-based cohort (n = 7607) of individuals diagnosed with IBD from 1954 to 1989, we assessed the sex-specific incidence of CRC from 1960 to 2004. Incidence was determined within the cohort (modeled using Poisson regression) and compared with the general population (assessed as standardized incidence ratios) using data from national Swedish health and census registers. RESULTS During 171,000 person-years of follow-up evaluation, 196 new cases of CRC were observed (123 in males, 73 in females). Males with IBD had a 60% higher risk of CRC (relative risk [RR], 1.6; 95% confidence interval [CI], 1.2-2.2) than females (cumulative incidence 40 years after IBD diagnosis, 8.3% vs 3.5%). Compared with the rate of CRC among the general population, in males with IBD the RR was 2.6 and the 95% CI was 2.2-3.1, whereas in females the RR was 1.9 and the 95% CI was 1.5-2.4. The effect of sex was limited to the period after 10 years of follow-up evaluation (RR, 0.8 before vs 2.2 after), and to patients diagnosed before age 45 (RR, 2.1 before vs 1.0 after). CONCLUSIONS IBD confers a lower risk of CRC to females than to males.

A randomized controlled trial of the efficacy and safety of CCX282-B, an orally-administered blocker of chemokine receptor CCR9, for patients with Crohn's disease.

CCX282-B, also called vercirnon, is a specific, orally-administered chemokine receptor CCR9 antagonist that regulates migration and activation of inflammatory cells in the intestine. This randomized, placebo-controlled trial was conducted to evaluate the safety and efficacy of CCX282-B in 436 patients with Crohn’s disease. Crohn’s Disease Activity Index (CDAI) scores were 250–450 and C-reactive protein >7.5 mg/L at study entry. In addition to stable concomitant Crohn’s medication (85% of subjects), subjects received placebo or CCX282-B (250 mg once daily, 250 mg twice daily, or 500 mg once daily) for 12 weeks. They then received 250 mg CCX282-B twice daily, open-label, through week 16. Subjects who had a clinical response (a ≥70 point drop in CDAI) at week 16 were randomly assigned to groups given placebo or CCX282-B (250 mg, twice daily) for 36 weeks. Primary endpoints were clinical response at Week 8 and sustained clinical response at Week 52. During the 12-week Induction period, the clinical response was highest in the group given 500 mg CCX282-B once daily. Response rates at week 8 were 49% in the placebo group, 52% in the group given CCX282-B 250 mg once daily (odds ratio [OR] = 1.12; p = .667 vs placebo), 48% in the group given CCX282-B 250 mg twice daily (OR = 0.95; p = .833), and 60% in the group given CCX282-B 500 mg once daily (OR = 1.53; p = .111). At week 12, response rates were 47%, 56% (OR = 1.44; p = .168), 49% (OR = 1.07; p = .792), and 61% (OR = 1.74; p = .039), respectively. At the end of the Maintenance period (week 52), 47% of subjects on CCX282-B were in remission, compared to 31% on placebo (OR = 2.01; p = .012); 46% showed sustained clinical responses, compared to 42% on placebo (OR = 1.14; p = .629). CCX282-B was well tolerated. Encouraging results from this clinical trial led to initiation of Phase 3 clinical trials in Crohn’s disease. Trial Registration ClinicalTrials.gov NCT00306215.

Colorectal cancer rates among first-degree relatives of patients with inflammatory bowel disease: a population-based cohort study

BACKGROUND Inflammatory bowel disease (IBD) and colorectal cancer might share a common cause and, therefore, relatives of patients with IBD could be at increased risk of this malignant disease. We aimed to assess cancer rates among first-degree relatives of patients with IBD to try to determine whether an association between the two diseases exists. METHODS In a population-based study, we identified 114,102 first-degree relatives by registry linkage and followed them up for cancer occurrence. We used standardised incidence ratio (SIR) of cancer as relative risk. FINDINGS 560 colorectal cancers were identified among relatives. First-degree relatives of patients with Crohns disease or ulcerative colitis were not at increased risk of cancer (SIR 0.90, 95% CI 0.82-0.97). The relative risk was 0.96 (0.87-1.06, n=379) for colon cancer and 0.78 (0.68-0.91, 181) for rectal cancer. The SIRs were not affected by age, relation to patient, or type or extent of IBD in the patient. Relatives of patients with both IBD and colorectal cancer had an 80% increased risk of colorectal cancer. INTERPRETATION Our results do not endorse a common cause of IBD and colorectal cancer. The slightly decreased relative risk for colorectal cancer among relatives could indicate the proportion of all colorectal cancer cases attributable to IBD.