Nete Munk Nielsen

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.

Cancer risk among patients with multiple sclerosis: A population-based register study

Cancer occurrence in patients with multiple sclerosis (MS) has been little studied, but associations with brain tumours, breast cancer, Hodgkin lymphoma and nasopharyngeal carcinoma have been suggested. We took advantage of population‐based registers of MS and cancer to assess the risk of cancer following diagnosis of MS. Patients registered in the Danish Multiple Sclerosis Register were linked with the Danish Cancer Register to obtain information on cancer occurrence. The ratio of the observed to the number of expected cancers based on population‐based incidence rates, i.e., the standardised incidence ratio (SIR), served as measure of the relative cancer risk. A database comprising all Danish women born after April 1, 1935, with information on all live‐born children, was used in the analyses of breast cancer to adjust for reproductive factors. Overall 1,037 cancers were observed in 11,817 MS patients during 153,875 person‐years of follow‐up vs. an expected number of 1,098 (SIR = 0.94 [95% confidence interval CI: (0.89–1.00)]. The risk of brain tumours and Hodgkin lymphoma was not increased. A 16% overall reduced cancer risk in men with MS was explained by reduced numbers of cancers of the digestive, respiratory and genital organs. Though the overall cancer risk was not increased [SIR = 1.01(0.94–1.09), n = 676], female MS patients had an increased risk of breast cancer [SIR = 1.21 (1.05–1.39), n = 193]. Adjusting for parity and age at first child delivery did not change this risk estimate materially. In general MS patients are not at increased risk of cancer. Women with MS, however, seem to have a small excess risk of breast cancer, which cannot be attributed to reduced parity or delayed first child birth.

Enteric Salmonella or Campylobacter infections and the risk of inflammatory bowel disease

Objective Enteric pathogens have been implicated in the aetiology of inflammatory bowel disease (IBD), but increased rates of stool testing of patients with unclear gastrointestinal symptoms might cause detection bias. Hence, the objective of this study was to analyse incidence rates of Crohns disease and ulcerative colitis among patients with Salmonella- or Campylobacter-positive and negative stool tests and to study the incidence of positive and negative stool tests among patients already diagnosed with IBD. Methods The Danish population was followed for 94.3 million person-years during 1992–2008 using national registers to identify persons with positive and negative stool tests and patients with IBD. Using Poisson regression, incidence rate ratios (IRRs) for IBD after positive or negative stool tests and, conversely, IRRs for positive and negative stool tests following IBD, were calculated. Results IRRs for IBD were significantly high in the first year after Salmonella- or Campylobacter-positive stool tests (IRRs 5.4–9.8), and they remained moderately increased 1–10 years later (IRRs 1.6–2.2), and less so >10 years later (IRRs 0.8–1.8). However, IRRs for IBD <1 year after a negative stool test were several-fold higher (IRRs 53.2–57.5), and a decreasing incidence pattern over time was parallel to that following positive test results. Among patients with IBD, IRRs for subsequent positive and—most notably—negative stool test results were also significantly high. Conclusion Similarities in temporal risk patterns for IBD following positive or negative stool tests indicate that the increased occurrence of Salmonella- or Campylobacter-positive results around the time of first IBD hospitalisation results from detection bias.

Use of Calcium Channel Blockers and Parkinson’s Disease

Experimental evidence and case-control studies suggest that dihydropyridine calcium channel blockers (DiCCBs) may protect against Parkinsons disease. The authors conducted a historical cohort study in Denmark to investigate the association between DiCCB use and risk of Parkinsons disease (1998-2006). Individual-level data on filled drug prescriptions, diagnostic information, and covariates were linked between nationwide registries. Among DiCCB users, 173 incident cases of Parkinsons disease were detected during 461,984 person-years of follow-up, compared with 5,538 cases during 17,343,641 person-years of follow-up among nonusers. After adjustment for age, sex, year, propensity score, and use of other antihypertensive drugs and statins, DiCCB use was associated with a reduced risk of Parkinsons disease (rate ratio (RR) = 0.71, 95% confidence interval (CI): 0.60, 0.82). This association was not present in patients who had previously used DiCCBs (RR = 1.04, 95% CI: 0.87, 1.24). DiCCB users aged ≥65 years were at lower risk of Parkinsons disease than DiCCB users aged <65 years (RR = 0.59, 95% CI: 0.40, 0.85). Among patients with Parkinsons disease, DiCCB use was associated with reduced risk of death (adjusted RR = 0.66, 95% CI: 0.47, 0.91) but not dementia (adjusted RR = 0.97, 95% CI: 0.60, 1.56). In conclusion, DiCCB exposure was associated with a reduced risk of incident Parkinsons disease, particularly in older patients, and with reduced mortality among patients with Parkinsons disease.

Cesarean section and offspring's risk of inflammatory bowel disease: a national cohort study.

Background: Intestinal bacteria have been implicated in the etiology of the common inflammatory bowel diseases (IBD) ulcerative colitis and Crohns disease. Because delivery by cesarean section disturbs the normal bacterial colonization of the newborns intestine, we determined the risk of IBD according to mode of delivery. Methods: A register‐based national cohort study of 2.1 million Danes born 1973–2008. The effect of mode of delivery on IBD incidence in the age‐span 0–35 years was estimated by means of confounder‐adjusted incidence rate ratios (IRRs) with 95% confidence intervals (CIs) obtained in Poisson regression analysis. Information on mode of delivery was obtained from the Danish Medical Birth Registry and cases of IBD were identified in the Danish National Patient Registry 1977–2008. Results: During 32.6 million person‐years of follow‐up, a total of 8142 persons were diagnosed with IBD before age 36 years. Cesarean section was associated with moderately, yet significantly, increased risk of IBD at age 0–14 years (IRR 1.29, 95% CI 1.11–1.49), regardless of parental disposition to IBD. Assuming causality, an estimated 3.2% of IBD cases before age 15 years were attributable to cesarean section. Conclusions: Rates of IBD with onset in childhood are moderately increased after birth by cesarean section but underlying mechanisms remain unclear. Even if the association is causal, the possible impact of increasing cesarean section practices on the overall burden of IBD in childhood is small. (Inflamm Bowel Dis 2011;)

Autoimmune diseases in women with Turner's Syndrome

OBJECTIVE In terms of number of X chromosomes, women with Turners syndrome cytogenetically resemble men. An increased risk of autoimmune diseases has been observed among women with Turners syndrome. This study was undertaken to investigate whether the autoimmune disease profile in women with Turners syndrome is characterized by diseases with a female or male predominance. METHODS Using the Danish Cytogenetic Central Register, the Danish National Patient Register, and the Danish Civil Registration System, we estimated relative risk of 46 different autoimmune diseases in a cohort of 798 Danish women with Turners syndrome followed up for 12,461 person-years between 1980 and 2004. Standardized incidence ratios (SIRs) of first hospitalization for autoimmune disease and 95% confidence intervals (95% CIs) were used as measures of relative risk. RESULTS The overall risk of autoimmune disease among women with Turners syndrome was twice that among Danish women in general (SIR 2.1 [95% CI 1.6-2.7]). For autoimmune diseases with a female predominance, the SIR among women with Turners syndrome was 1.7 (95% CI 1.2-2.4), whereas the SIR for autoimmune diseases with a male predominance among these women was 3.9 (95% CI 2.5-5.8). Associations were strongest for Hashimoto thyroiditis (SIR 14.6 [95% CI 6.7-27.1]), a strongly female-predominant condition, and type 1 diabetes mellitus (SIR 4.1 [95% CI 2.5-6.3]). CONCLUSION Women with Turners syndrome are at excess risk of autoimmune diseases, notably autoimmune diseases characterized by male predominance.

HPV DETECTION IN CHILDREN PRIOR TO SEXUAL DEBUT

Knowledge of the epidemiology of infection with human papillomavirus (HPV) in childhood is important, since HPV infection early in life could represent a risk factor for later development of anogenital cancer. A random sample of Danish children aged 0 to 17 years was tested for the presence of HPV in the anal region and the oral cavity by the polymerase chain reaction using a consensus HPV L1 primer. Only 4 of 249 anal beta‐globin‐positive samples and one of 392 oral beta‐globin‐positive samples were HPV‐positive. All HPV‐positive samples were of unknown types. We conclude that the prevalence of anogenital HPV infection in childhood is very low indeed and that the oral cavity does not seem to act as a reservoir for HPV infection in childhood. This indicates that anogenital types of HPV are not transmitted to any measureable degree by non‐sexual routes and further supports the notion that HPV infection takes place mainly later in life. Int. J. Cancer73:621–624, 1997.

Increased risk of inflammatory bowel disease in women with endometriosis: a nationwide Danish cohort study

Background An association between endometriosis and certain autoimmune diseases has been suggested. However, the impact of endometriosis on risk of inflammatory bowel disease (IBD) remains unknown. Objective To assess the risk of Crohns disease (CD) and ulcerative colitis (UC) in an unselected nationwide Danish cohort of women with endometriosis. Design By use of national registers, 37 661 women hospitalised with endometriosis during 1977–2007 were identified. The relative risk of developing IBD after an endometriosis diagnosis was calculated as observed versus expected numbers and presented as standardised incidence ratios (SIRs) with 95% CIs. Results Women with endometriosis had a increased risk of IBD overall (SIR=1.5; 95% CI 1.4 to 1.7) and of UC (SIR=1.5; 95% CI 1.3 to 1.7) and CD (SIR=1.6; 95% CI 1.3 to 2.0) separately, even 20 years after a diagnosis of endometriosis (UC: SIR=1.5; 95% CI 1.1 to 2.1; CD: SIR=1.8; 95% CI 1.1 to 3.2). Restricting analyses to women with surgically verified endometriosis suggested even stronger associations (UC: SIR=1.8; 95% CI 1.4 to 2.3; CD: SIR=1.7; 95% CI 1.2 to 2.5). Conclusion The risk of IBD in women with endometriosis was increased even in the long term, hence suggesting a genuine association between the diseases, which may either reflect common immunological features or an impact of endometriosis treatment with oral contraceptives on risk of IBD.

Characterization of Rotavirus Strains in a Danish Population: High Frequency of Mixed Infections and Diversity within the VP4 Gene of P[8] Strains

ABSTRACT We characterized the G and P types from 162 rotavirus-positive stool specimens collected from 162 persons in Denmark (134 children and 28 adults) with acute diarrhea in 1998, 2000, and 2002. Samples were obtained during outpatient consultations (73%) and from hospitalized patients (27%). Although more than 20 different G-P combinations were identified, only 52% represented the globally most common types G1P[8], G2P[4], and G4P[8]. The G9 genotype, which is emerging worldwide, was identified in 12% of all samples. Twenty-one percent of the samples were of mixed genotypic origin, which is the highest frequency reported in any European population. The standard reverse transcription-PCR methods initially failed to identify a considerable fraction of the rotavirus P strains due to mutations at the VP4 primer-binding sites of P[8] strains. The application of a degenerate P[8] primer resulted in typing of most VP4 strains. There was considerable year-to-year variation among the circulating G-P types, and whereas G1P[8] was predominant in 1998 (42% of samples) and 2002 (26%), G2P[4] was the strain that was most frequently detected in 2000 (26% of samples). Our findings might implicate challenges for rotavirus vaccine implementation in a European population and underscore the importance of extensive strain surveillance prior to, during, and after introduction of any vaccine candidate.

The co-occurrence of endometriosis with multiple sclerosis, systemic lupus erythematosus and Sjögren syndrome

BACKGROUND In a previous study, women with endometriosis were found to be at a 7-24-fold increased risk of multiple sclerosis (MS), systemic lupus erythematosus (SLE) and Sjögren syndrome (SS). We examined these associations in a large population-based cohort study. METHODS We followed 37 661 women registered with endometriosis in the Danish Hospital Discharge Register 1977-2007 for subsequent hospitalizations with MS, SLE or SS. As measures of relative risk, we used ratios of observed to expected incidence rates of first hospitalizations for MS, SLE and SS among women with endometriosis, i.e. standardized incidence ratios (SIR) with accompanying 95% confidence intervals (CIs). RESULTS During slightly more than 456 000 person-years of follow-up, we identified 130, 54 and 86 cases of MS, SLE and SS, respectively, yielding SIRs of 1.2 (95% CI 1.05-1.5) for MS, 1.6 (1.2-2.1) for SLE and 1.6 (1.3-2.0) for SS. In a supplementary analysis restricted to 9191 women with laparoscopy or laparotomy confirmed endometriosis, associations were unchanged for MS (SIR = 1.4; 1.04-1.9), but lost statistical significance for SLE (SIR = 1.1; 0.6-2.1) and SS (SIR = 1.4; 0.9-2.3). CONCLUSIONS Our national cohort-based findings do not support prior claims of markedly increased risks of MS, SLE and SS in women with endometriosis. However, whether women with endometriosis are truly at a modestly (20-60%) elevated risk of one or more of the studied autoimmune diseases must await clarification in future large-scale prospective studies.