Mikael Andersson

Changes in medical treatment and surgery rates in inflammatory bowel disease: a nationwide cohort study 1979–2011

Introduction Treatment possibilities have changed in inflammatory bowel disease (IBD). We assessed changes in medical treatment and surgery over time and impact of medications on risk of surgery in a population-based cohort. Methods 48 967 individuals were diagnosed with IBD (Crohns disease (CD), 13 185; ulcerative colitis (UC), 35 782) during 1979–2011. Cumulative probability of receiving 5-aminosalicylic acids (5-ASA), topical, oral corticosteroids, thiopurines, and tumour necrosis factor-α (TNF-α) blockers, and of first minor or major surgery according to period of diagnosis, was estimated. Medication use and risk of surgery was examined by Cox regression. Results 5-year cumulative probability of first major surgery decreased from 44.7% in cohort (1979–1986) to 19.6% in cohort (2003–2011) (p < 0.001) for CD, and from 11.7% in cohort (1979–1986) to 7.5% in cohort (2003–2011) (p < 0.001) for UC. Minor surgery risk decreased significantly in CD. From cohort (1995–2002) to cohort (2003–2011), a significant increase in use of thiopurines and TNF-α blockers was observed, paralleled by a significant decrease in use of 5-ASA and corticosteroids. Comparing use of azathioprine (or oral corticosteroids) to never-use, no convincing surgery-sparing effect was found. Comparing use in 3+ months of a given drug with use <3 months, only 3+ months use of oral corticosteroids reduced the risk of surgery in patients with disease duration of >1 year. Conclusions Parallel to an increasing use of thiopurines and TNF-α blockers in IBD over time, a persistent significant decrease in surgery rates was observed along with a significant decrease in use of 5-ASA and corticosteroids. However, no convincing surgery-sparing effect of newer medications was found.

Disease Course and Surgery Rates in Inflammatory Bowel Disease: A Population-Based, 7-Year Follow-Up Study in the Era of Immunomodulating Therapy

Objectives:In this population-based 7-year follow-up of incident patients with ulcerative colitis (UC) or Crohns disease (CD), we aimed to describe disease progression and surgery rates in an era influenced by the increased use of immunosuppressants and the introduction of biological therapy.Methods:From 1 January 2003 to 31 December 2004, all incident cases (562) of patients diagnosed with UC, CD, or inflammatory bowel disease unclassified in a well-defined Copenhagen area were registered. Medical records were reviewed from 1 November 2011 to 30 November 2012, and clinical data were registered. Clinical data on surgery, cancer, and death were cross-checked with register data from national health administrative databases in order to include missed data.Results:In total, 513 patients (213 CD and 300 UC) entered the follow-up study. Twenty-six patients changed diagnosis during the follow-up. Changes in disease localization and behavior in CD according to the Vienna classification were observed in 23.9% and 15.0% of the patients, respectively, during follow-up. In total, 28.3% of the 300 UC patients had disease progression during the follow-up. The overall use of systemic steroids, immunomodulators, and anti-tumor necrosis factor agents in CD was 86.4%, 64.3%, and 23.5%, respectively. The rate of first-time intestinal resection in CD was 29.1% (n=62), and the 7-year cumulative risk was 28.5%. The cumulative risk of colectomy in UC was 12.5% at 7 years.Conclusions:UC and CD are dynamic diseases that progress in extent and behavior over time. The resection rate in CD and the colectomy rate in UC are still relatively high, although the rates seem to have decreased compared with historic data, which could be due to an increase in the use of immunomodulating therapy.

Association Between Tumor Necrosis Factor-α Antagonists and Risk of Cancer in Patients With Inflammatory Bowel Disease

IMPORTANCE A Cochrane review and network meta-analysis concluded that there is need for more research on adverse effects, including cancer, after treatment with tumor necrosis factor α (TNF-α) antagonists and that national registries and large databases would provide relevant sources of data to evaluate these effects. OBJECTIVE To investigate whether patients with inflammatory bowel disease (IBD) exposed to TNF-α antagonists were at increased risk of developing cancer. DESIGN, SETTING, AND PARTICIPANTS Nationwide register-based cohort study in Denmark, 1999-2012. Participants were 56,146 patients 15 years or older with IBD identified in the National Patient Registry, of whom 4553 (8.1%) were exposed to TNF-α antagonists. Cancer cases were identified in the Danish Cancer Registry. MAIN OUTCOMES AND MEASURES Rate ratios (RRs) for incident cancer (overall and site-specific) comparing TNF-α antagonist users and nonusers, estimated using Poisson regression adjusted for age, calendar year, disease duration, propensity scores, and use of other IBD medications. RESULTS During 489,433 person-years of follow-up (median, 9.3 years [interquartile range, 4.2-14.0]), 81 of 4553 patients exposed to TNF-α antagonists (1.8%) (median follow-up, 3.7 years [interquartile range, 1.8-6.0]) and 3465 of 51,593 unexposed patients (6.7%) developed cancer, yielding a fully adjusted RR of 1.07 (95% CI, 0.85-1.36). There was no significantly increased risk of cancer in analyses according to time since first TNF-α antagonist exposure (less than 1 year: RR, 1.10 [95% CI, 0.67-1.81]; 1 to less than 2 years: RR, 1.22 [95% CI, 0.77-1.93]; 2 to less than 5 years: RR, 0.82 [95% CI, 0.54-1.24]; 5 or more years: RR, 1.33 [95% CI, 0.88-2.03]) and in analyses according to the number of TNF-α antagonist doses received (1 to 3 doses: RR, 1.02 [95% CI, 0.71-1.47]; 4 to 7 doses: RR, 0.89 [95% CI, 0.55-1.42]; 8 or more doses: RR, 1.29 [95% CI, 0.90-1.85]). No site-specific cancers were in significant excess in fully adjusted models. CONCLUSIONS AND RELEVANCE In this Danish nationwide study, exposure to TNF-α antagonists among patients with IBD was not associated with an increased risk of cancer over a median follow-up of 3.7 years among those exposed. An increased risk associated with longer-term accumulated doses and follow-up cannot be excluded.

Both high and low serum vitamin D concentrations are associated with tuberculosis: a case–control study in Greenland

Vitamin D deficiency has been associated with increased risk of tuberculosis (TB). Changes from a traditional to a Westernised diet among Greenlanders have resulted in reduced serum vitamin D, leading to considerations of whether preventive vitamin D supplementation should be introduced. The association between vitamin D status and TB was examined to assess the feasibility of vitamin D supplementation in Greenland. This was examined in a case-control study involving seventy-two matched pairs of TB patients (cases) and controls aged 8-74 years. Cases were diagnosed with TB during 2004-6 based on clinical findings in combination with either (1) positive Mycobacterium tuberculosis culture, (2) characteristic X-ray abnormalities together with a positive tuberculin skin test or a positive interferon-γ release assay or (3) characteristic histology. Controls were individually matched on age ( ± 5 years), sex and district. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were measured and OR of TB were the outcome. Compared with individuals with 25(OH)D concentrations between 75 and 140 nmol/l, individuals with concentrations < 75 nmol/l (OR 6.5; 95% CI 1.8, 23.5) or > 140 nmol/l (OR 6.5; 95% CI 1.9, 22.2) had higher risks of active TB (P = 0.003; adjustment for alcohol and ethnicity). Supplementing individuals with low vitamin D to normalise serum 25(OH)D concentrations was estimated to result in a 29% reduction in the number of TB cases. The study indicated that vitamin D supplementation may be beneficial to individuals with insufficient vitamin D concentrations but may increase the risk of TB among individuals with normal or high concentrations.

Body mass index and risk of autoimmune diseases: a study within the Danish National Birth Cohort.

BACKGROUND A possible aetiological link between obesity and certain autoimmune diseases (ADs) has been suggested. We investigated the associations between body mass index (BMI, kg/m2) and 43 ADs. METHODS 75,008 women participating in the Danish National Birth Cohort were followed during a median time of 11 years. Diagnoses on ADs were retrieved from the Danish National Patient Register. Cox proportional hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated adjusting for potential confounders (smoking, alcohol, parity and socio-occupational status). RESULTS During follow-up, 2430 women (3.2%) developed a total of 2607 new-onset ADs. Risk of any autoimmune disease was increased in obese women (HR, 1.27; 95% CI, 1.11 to 1.46) compared with normal weight women (18.5-≤25 kg/m2). Obese women (BMI≥30 kg/m2) were at increased risk of sarcoidosis (HR 3.59; 95% CI, 2.31 to 5.57) and type 1 diabetes mellitus (HR 2.67; 95% CI, 1.71 to 4.17). Risk of dermatitis herpetiformis increased by 14% (95% CI, 1% to 30%) per BMI unit. Conversely, risk of celiac disease and Raynauds phenomenon decreased by 7% (95% CI, 1% to 13%) and 12% (95% CI, 4% to 19%) per BMI unit, respectively. Further associations between BMI and risk of psoriasis, rheumatoid arthritis and Crohns disease were suggested. CONCLUSIONS BMI was found to be associated with several Ads. This was most pronounced between obesity and risk of sarcoidosis and and risk of type 1 diabetes mellitus. These novel findings need confirmation and the possible role of adipose tissue-derived immunological changes in the development of autoimmune reactions needs consideration.

Incidence of Otitis Media in a Contemporary Danish National Birth Cohort

Objectives In recent years welfare in Denmark has increased which might be expected to reduce otitis media (OM) incidence. We examined the age-specific incidence of OM in a nation-wide cohort of children aged 0–7 years born in 1996–2003 (Danish National Birth Cohort, DNBC). Only selection was ability to understand and speak Danish. Methods Information of OM and ventilation tubes (VT) was collected through three maternal interviews at 6-month, 18-month and 7-years of age and based on this age-specific and cumulative incidence of OM was calculated. As different numbers of the total population answered the different interviews, the calculations are done with different denominators. The information in DNBC was validated against two population based registries containing information of VT insertions. Results Cumulative incidence of OM at 7 years was 60.6% (31,982/52,755). For children with OM, 16.2% (7143/44194) had their first OM episodes between 0–6 months of age, 44.3% (19579/44194) between 7–18 months, and 39.5% (17472/44194) between 19 months and 7 years. Four or more OM episodes before 7 years were reported by 39.5% (12620/31982) and by 64.0% (2482/3881) of those who had their OM debut between 0–6 months; by 48.2% (4998/10378) with debut between 7–18 months; and by 28.7% (4996/17344) with debut between 19 months and 7 years. These figures are essentially unchanged from earlier figures from Denmark. VT insertion at least once was reported by 26,1% in the 7-year interview. Assuming recordings in the Danish National Patient Registry to be gold standard, maternal self-reportings in DNBC of insertion of VT showed high sensitivity (96.4%), specificity (98.2%), and positive (94.8%) and negative predictive values (98.8%). Conclusion OM affects nearly 2/3 of preschool children in Denmark despite reduction in known OM risk factors.

Association between tumour necrosis factor-α inhibitors and risk of serious infections in people with inflammatory bowel disease: nationwide Danish cohort study.

Objective To investigate whether people with inflammatory bowel disease treated with tumour necrosis factor-α (TNF-α) inhibitors are at increased risk of serious infections. Design Nationwide register based propensity score matched cohort study. Setting Denmark, 2002-12. Participants The background cohort eligible for matching comprised 52 392 people with inflammatory bowel disease, aged 15 to 75 years, of whom 4300 were treated with TNF-α inhibitors. To limit confounding, a two stage matching method was applied; firstly matching on age, sex, disease duration, and inflammatory bowel disease subtype, and secondly matching on propensity scores (1:1 ratio); this yielded 1543 people treated with TNF-α inhibitors and 1543 untreated to be included in the analyses. Main outcome measures The main outcome was any serious infection, defined as a diagnosis of infection associated with hospital admission. Cox regression was used to estimate hazard ratios for two risk periods (90 and 365 days after the start of TNF-α inhibitor treatment). Hazard ratios of site specific serious infections were obtained solely for the 365 days risk period. Results Within the 90 days risk period, 51 cases of infection were observed in users of TNF-α inhibitors (incidence rate 14/100 person years), compared with 33 cases in non-users (9/100 person years), yielding a hazard ratio of 1.63 (95% confidence interval 1.01 to 2.63). Within the risk period of 365 days, the hazard ratio was 1.27 (0.92 to 1.75). In analyses of site specific infections, the hazard ratio was above 2 for several of the subgroups but only reached statistical significance for skin and soft tissue infections (2.51, 1.23 to 5.12). Conclusions This nationwide propensity score matched cohort study suggests an increased risk of serious infections associated with use of TNF-α inhibitors within the first 90 days of starting treatment and a subsequent decline in risk. This calls for increased clinical awareness of potential infectious complications among people with inflammatory bowel disease using these drugs, especially early in the course of treatment.

Long-term follow-up of chronic suppurative otitis media in a high-risk children cohort

OBJECTIVE Chronic suppurative otitis media (CSOM) is the leading cause of mild to moderate hearing impairment in children worldwide and a major public health problem in many indigenous populations. There is a lack of basic epidemiological facts and knowledge on the development of CSOM, as the disease primarily affects developing countries where research capacities often are limited. The purpose of this study was to determine the long-term outcome of CSOM in a high-risk population and to identify risk factors. METHODS Follow-up study (2008) on a population-based cohort of 465 children in Greenland, initially examined (1996-8) between the ages 0 and 4 years. Follow-up was attempted among 307 children living in the two major towns. Binomial logistic regression analysis was made to identify risk factors for developing CSOM and for maintaining disease in to adolescence (odds ratios). Log linear binomial regression was used to estimate risk ratios and absolute risks. RESULTS At follow-up 236 participated (77% of those available). The prevalence of CSOM was 32/236 (14%) at age group 0-4 years and 21/236 (9%) at age group 11-15 years. Thirteen had disease debut after the initial study. Of those with CSOM in the initial study 24/32 (75%) healed spontaneously. Risk factors for the development of CSOM at any time in childhood was the mothers history of CSOM OR 2.55 (95% CI 1.14-5.70; p=0.02), and mothers with low levels of schooling OR 1.57 (1.03-2.40; p=0.04). Once CSOM had developed boys were more likely to have persistent disease OR 5.46 (95% CI 1.47-20.37; p=0.01). The absolute risk of CSOM if the mother had both a history of CSOM and low schooling was for boys 45.4% (95% CI 26.5-77.7) and for girls 30.7% (95% CI 17.8-53.10). The cumulative risk of CSOM was 19% at follow-up. CONCLUSIONS Even though a large number of CSOM cases seemed to heal spontaneously, the prevalence of untreated CSOM among school-age children in Greenland remained high as new cases were found at follow-up. Increased focus on prevention and identification of children at special risk could reduce the high prevalence of CSOM.

Hospitalisation, surgical and medical recurrence rates in inflammatory bowel disease 2003-2011—A Danish population-based cohort study

OBJECTIVE The aim of this study is to evaluate the cumulative probability of recurrence and admission rates in an inflammatory bowel disease (IBD) inception cohort diagnosed in 2003-2004. METHODS Data on medications, phenotypes and surgery for 513 individuals with ulcerative colitis (UC, n=300) and Crohns disease (CD, n=213) were obtained from medical records and linked to population-based health administrative database information. The admission rates and cumulative probability of recurrences were estimated, and the association with the baseline factors and medication was tested. RESULTS The cumulative risk of first recurrence after 1, 5 and 7 years was 40%, 63%, and 66% in CD patients and 51%, 75%, and 79% in UC patients, respectively. The cumulative risk of first surgical relapse was 6%, 18%, and 23% at 1, 5 and 7 years in CD respectively. One hundred and CD patients (66%) and 142 UC patients (47%) had at least one IBD-related hospitalisation. The hospitalisation rate decreased from 7.0 days/person-year in year one to 0.9 day at year 5 in CD, and from 4.7 days to 0.4 days for UC patients. Age above 40, current smoking, stricturing behaviour, and disease localisation (colonic, ileocolonic, and upper-GI) at diagnosis were predictors of recurrence in CD. In UC, age above 40 and former smoker status were predictors of recurrence and left-sided and extensive colitis were predictors of first-time hospitalisation. CONCLUSION In an era of improved treatment options, the recurrence rates, but not the surgery or hospitalisation rates, have decreased for CD but not for UC. The phenotypic characteristics at diagnosis predict the risk of recurrence and hospitalisation.

Ongoing tuberculosis transmission to children in Greenland

Inuit in the Arctic are experiencing an increase in tuberculosis cases, reaching levels in Greenland comparable to high-incidence countries. This prompted us to study the level of tuberculosis transmission to Greenlandic children. Specifically, we estimated the current prevalence of Mycobacterium tuberculosis infection (MTI) and the underlying annual risk of MTI. 2,231 Greenlandic school children aged 5–17 yrs (∼25% of the Greenlandic population in the relevant age group) were tested for MTI using the tuberculin skin test and the QuantiFERON®-TB Gold in-tube test. Subjects with dual-positive results were considered infected and subjects with dual-negative results uninfected. The children with discordant test results were classified as probably having MTI and analysed separately. 8.1% of the children had dual-positive test results. The annual risk of MTI was estimated as 0.80% (95% CI 0.67–0.92%) giving a cumulative risk at the 18th birthday of 13.4%. The annual risk of MTI varied substantially by ethnicity (0.87% in Inuit children, 0.02% in non-Inuit children; p<0.001) and by location (0.13% on the west coast, 1.68% on the south coast; p<0.001). M. tuberculosis transmission occurs at a very high level in Inuit children with pronounced geographic differences emphasising the need for immediate public health interventions.