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The aim of this study was to examine the cancer pattern in a large group of patients with rheumatoid arthritis (RA). A follow-up study of cancer incidence in RA was conducted within a cohort of 20,699 patients recorded in the Danish Hospital Discharge Register during 1977-1987 by linkage with the Danish Cancer Registry through 1991. There were consistent excesses of non-Hodgkin's lymphoma and Hodgkin's disease in both sexes and during both early and late periods of follow-up. Risks for lung cancer and non-melanoma skin cancer were also increased, with no predilection for any specific histological subtype, while risks for colorectal cancer and female breast cancer were reduced. The cancer pattern seen among Danish RA patients largely supports findings from two earlier Nordic investigations. Thus, there seem to be consistent positive associations between RA and non-Hodgkin's lymphoma, Hodgkin's disease and lung cancer and a consistent negative association with colorectal cancer.

There are several reports of familial testicular cancer in the literature but few systematic attempts have been made to estimate the risk of testicular cancer in first-degree relatives of patients with this neoplasm, and the risk remains to be fully assessed in population-based studies. By means of data from the Danish Cancer Registry, we identified all testicular cancer patients (index cases) born and diagnosed during 1950–1993 in Denmark. Their fathers were identified from national registries, as were the brothers of a subcohort of these patients. Familial cancer occurrence was determined through linkage with the cancer registry and compared with the cancer incidence in the general male population in Denmark. The ratio of observed to expected cancers generated the measure used for the relative risk. Fathers of 2,113 index cases with testicular cancer experienced an almost 2-fold risk of developing testicular cancer themselves (RR = 1.96; 95% CI: 1.01–3.43). Overall, the fathers had a decreased relative cancer risk (RR = 0.84; 95% CI: 0.74–0.95) with a significantly decreased risk of cancers of the lung and digestive organs. Brothers of a subcohort of 702 index cases showed a markedly increased risk of testicular cancer (RR = 12.3; 95% CI: 3.37ndash;31.5). In conclusion, we documented a significantly increased familial risk of testicular cancer which was relatively more pronounced between brothers than between fathers and sons. These findings support the possible involvement of a genetic component in the aetiology of testicular cancer, but also leave room for a hypothesized influence of in-utero exposures, such as specific maternal hormone levels, that might be shared by brothers. © 1996 Wiley-Liss, Inc.

BACKGROUND Studies have suggested that the incidence of classic Kaposi's sarcoma (KS) varies considerably within Europe. The epidemiology of classic KS in Denmark was described for the period between 1970 and 1992 and association with marital status and country of origin were evaluated. METHODS A descriptive epidemiology study was carried out using data from the Danish Cancer Registry and from all Danish pathology departments. The effects of marital status and of immigration were evaluated in a case–control study with sex- and age-matched controls for 50 cases of classic KS. RESULTS A total of 59 patients with classic KS, 34 men, 25 women, were identified between 1970 and 1992, yielding world standardized incidence rates of 0.40 and 0.22 per 1,000,000 population among men and women, respectively. Among men, a larger proportion of the patients with classic KS were of non-Danish origin [odds ratio (OR) = 3.8, 95% confidence interval (CI) = 1.5–9.6]. No excess of foreign born persons was observed among women with KS. Never-married men were at a markedly increased risk for classic KS (OR = 2.8, 95% CI = 1.2–6.7). This risk was, however, restricted to men younger than 60 years (OR = 18.8, 95% CI = 3.4–104.8), whereas no increased risk was observed in men age 60 years or older nor was there an increased risk observed in women. CONCLUSIONS Classic KS is a rare disease in Denmark. However, men, immigrants and never-married men age 60 years or younger experienced an excess risk. Even though the latter finding might reflect an association with male homosexuality, the observation should be interpreted with caution due to the limited number of observations. Cancer 1996;77:1373-8.

Time-related trends in the incidence of non-Hodgkin's lymphoma (NHL) in Denmark were analysed for the period 1943-89. A total of 13 822 patients (7565 men and 6257 women) were included in the study. In men, world-standardised incidence rates per 100 000 population increased from 2.5 in 1943-47 to 9.3 in 1988-89. In women, a similar increase was seen, i.e. from 1.9 in 1943-47 to 6.5 per 100 000 population in 1988-89. For all birth cohorts, the male-to-female incidence ratio was highest among young subjects and fell significantly after the age of 29 years. Trends in age-specific incidence were analysed separately for two periods, i.e. 1943-77 and 1978-89, reflecting an early, pre-AIDS period and a later period possibly influenced by AIDS. In both periods, the incidence of NHL increased in all age groups. However, in recent years a noticeable increase in incidence averaging 8% annually was observed in men and women aged 40-49 years. A number of factors including changes in the perception of NHL and in the diagnostic methods available are considered insufficient to explain the observed increase. The remarkable and parallel time trends observed in young men and women in recent years indicate that factors other than AIDS must be considered.

This report presents the unusual occurrence of metachronous perianal and penile carcinomas in a young, immunosuppressed man. Both anogenital cancers were HPV-16-DNA-positive by the polymerase chain reaction. DNA in situ hybridization analysis of the penile carcinoma revealed HPV-16 in most neoplastic cells. HPV-16 appears to have played a central role in both anogenital cancers in this patient, suggesting that, like in immunologically susceptible women, a carcinogenic 'field effect' may exist in the anogenital area of the immunosuppressed male.

Previous studies suggest that spouses of cancer patients are at increased risk for several chronic diseases. We investigated mortality in relation to cancer morbidity in the stable female partner.We established a national retrospective cohort study of 1,422,131 men who had lived continuously with the same partner for at least 5 years and used Cox regression analysis to assess the association between experiencing cancer in a cohabiting partner and all-cause mortality.The risk for death was only slightly elevated among men whose partner had cancer than for men whose partner remained free of cancer (hazard ratio = 1.03; 95% confidence interval = 1.01-1.05).Although a cancer diagnosis in a spouse might be associated with considerable distress, our study indicates that the risk for death differs only slightly between men living with a partner with cancer and those living with a partner without cancer.

Few population-based studies have investigated the relation between living arrangements and risk of invasive penile squamous cell carcinoma (iP-SCC). Using long-term national cancer registry data in Denmark we examined incidence trends of iP-SCC. Furthermore, we examined the relation between marital status, cohabitation status and risk of iP-SCC using hazard ratios (HRs) with 95% confidence intervals (CIs) obtained in Cox proportional hazards regression analyses as our measure of relative risk. Overall, 1,292 cases of iP-SCC were identified during 65.6 million person-years of observation between 1978 and 2010. During this period, the WHO world age-standardized incidence remained relatively stable (p-trend = 0.41) with an average incidence of 1.05 cases per 100,000 person-years. When compared to married men, those who were unmarried (HR 1.37; 95% CI: 1.13-1.66), divorced (HR 1.49; 95% CI: 1.24-1.79) or widowed (HR 1.36; 95% CI: 1.13-1.63) were at increased risk of iP-SCC. Regarding cohabitation status, single-living men were at increased risk of iP-SCC compared to men in opposite-sex cohabitation (HR 1.43; 95% CI: 1.26-1.62). Risk increased with increasing numbers of prior opposite-sex (p-trend = 0.02) and same-sex (p-trend 0.001) cohabitations. In conclusion, single-living Danish men and men who are not currently married are at increased risk of iP-SCC, and the risk increases with the number of prior cohabitations, perhaps reflecting less stable sexual relations in these subgroups.

OBJECTIVE--To investigate a possible link between exposure to ultraviolet light and the almost epidemic increase in non-Hodgkin's lymphoma worldwide. Because ultraviolet light is known to cause skin cancers, the association between non-Hodgkin's lymphoma and skin cancer was studied. DESIGN--Secondary occurrence of either malignant melanoma or squamous cell skin cancer in cohorts of patients with a first diagnosis of either non-Hodgkin's lymphoma or chronic lymphocytic leukaemia, and vice versa, were studied. Expected numbers of subsequent cancers were calculated by sex, age, and period specific national incidence rates multiplied by the person years under observation in the cohorts. SETTING--Denmark (1943-89) and Sweden (1958-89). SUBJECTS--Four population based cohorts identified in the nationwide cancer registries (34,641 people with non-Hodgkin's lymphoma, 17,400 with chronic lymphocytic leukaemia, 34,989 with malignant melanoma, 25,980 with squamous cell skin cancer). A total of 562,085 person years were accrued for the analysis. MAIN OUTCOME MEASURES--The ratios of observed to expected cancers (the standardised incidence ratio) served as a measure of the relative risk. RESULTS--The relative risk for developing squamous cell skin cancer was 5.5 (95% confidence interval 4.6 to 6.6) among patients with non-Hodgkin's lymphoma and 8.6 (7.2 to 10.3) among patients with chronic lymphocytic leukaemia. The relative risks remained high over more than 15 years of follow up. Relative risks for malignant melanoma were 2.4 (1.8 to 3.2) for patients with non-Hodgkin's lymphoma and 3.1 (2.1 to 4.4) for patients with chronic lymphocytic leukaemia. After squamous cell skin cancer had been diagnosed there was a twofold excess risk for non-Hodgkin's lymphoma and chronic lymphocytic leukaemia. By contrast, in each of the cohorts the general cancer risks excluding skin and lymphoproliferative malignancies were close to the expected. CONCLUSIONS--The occurrence of non-Hodgkin's lymphoma and skin cancer are strongly associated; this supports the hypothesis that the secular increase in exposure to ultraviolet light may have contributed to the increasing incidence of non-Hodgkin's lymphoma in recent decades.

In a search for clues to the origin of squamous cell skin cancer (SCC), the authors investigated the pattern of new cancers in a cohort of 5,100 SCC patients whose tumors were diagnosed during the years 1978-1989 and recorded in the Danish Cancer Registry. Subsequent cancer experiences in SCC patients were compared with the cancer incidence in the Danish population using ratios of observed cancers to expected cancers as a measure of the relative risk. Overall, patients with SCC were at increased risk of new malignancies (relative risk (RR) = 1.6, 95% confidence interval (CI) 1.5-1.7). Significantly elevated risks were found for cancers of the respiratory organs (RR = 1.7, 95% CI 1.4-2.0); cancers of the lip, buccal cavity, and pharynx (RR = 3.1, 95% CI 2.1-4.5); non-Hodgkin's lymphoma (RR = 2.3, 95% CI 1.4-3.5); leukemia (RR = 2.5, 95% CI 1.7-3.5); malignant melanoma (RR = 2.6, 95% CI 1.5-4.3); and cancer of the small intestine in men (RR = 4.1, 95% CI 1.1-10.6). The risk of new cancers (other than nonmelanoma skin cancers) was higher in patients diagnosed with SCC before the age of 60 years (RR = 1.9, 95% CI 1.5-2.5) than in those diagnosed with SCC at or after that age (RR = 1.3, 95% CI 1.2-1.4). The data confirmed previous strong associations between SCC and malignant melanoma and cancers of the major salivary glands. A previously undocumented significant excess of smoking-related cancers was observed after an SCC diagnosis, suggesting that smoking may be involved in the development of SCC. Since a variety of other squamous cell cancers have already been linked to smoking, the authors speculate that some general effect of smoking might act on all human squamous epithelia. The observed significant associations with lymphoma and leukemia and the high risk of subsequent malignancies in young SCC patients merit further attention.

A cohort of 5,546 ulcerative colitis patients was identified from the Danish Hospital Discharge Register for 1977-1989. Patients not included in the cohort comprised those with proctitis, those treated in outpatient clinics and those for whom follow-up was less than 1 year. The cohort was linked to the Danish Cancer Registry in order to assess the risks for colorectal and other cancers. The linkage revealed a significant increase in the number of colorectal cancers over that in the general population (RR = 1.8; n = 42; 95% CI = 1.3-2.4) with consistent relative risks during early and late follow-up. The relative risk was considerably higher among younger (20-39 years: RR = 22; n = 8; 95% CI = 9.7-44) than older patients (> or = 60 years: RR = 1.3; n = 25; 95% CI = 0.8-1.9), but the risk difference between patients and the general population was approximately constant across all ages. In addition, we observed a significant increase in the relative risk of hepatobiliary cancers (RR = 2.3; n = 9; 95% = 1.0-4.3) and a slight but significant increase in the relative risk of non-melanoma skin cancer (RR = 1.4; n = 37; 95% CI = 1.0-1.9). In summary, our population-based study confirms the increased risk of colorectal cancer among patients with ulcerative colitis and provides new leads suggesting that hepatobiliary cancer and non-melanoma skin cancer should be considered as possible sites for future patient monitoring.

Anal cancer has been hypothesized to be associated with a sexually transmitted agent and, more recently, with the epidemic of human immunodeficiency virus (HIV). The authors used a descriptive incidence study to evaluate these hypotheses based on US data from the Surveillance, Epidemiology, and End Results (SEER) program for 1973-1989 and from the Connecticut Tumor Registry for 1940-1988. Since 1960, anal cancer incidence in Connecticut increased 1.9-fold among men and 2.3-fold among women. Based on information from SEER, the incidence was lowest among white men (1973-1989 average: 0.41/100,000) and highest among black women (1973-1989 average: 0.74/100,000). Residents of the metropolitan areas had a twofold risk of anal cancer compared with populations in less densely populated areas. The most dramatic change in incidence was observed for white men in the San Francisco Bay area, among whom the incidence increased from 0.5/100,000 in 1973-1975 to 1.2/100,000 in 1988-1989 (p trend < 0.001). The relative risks (95% confidence intervals) of anal cancer among never married men compared with ever married men in the urban areas rose from 5.8 (0.9-8.7) in 1973-1978 to 6.7 (4.7-9.5) in 1979-1984 and 10.3 (7.5-14.1) in 1985-1989 (p trend = 0.02). No significant difference was observed among women. In conclusion, anal cancer incidence in the United States has increased significantly during the past 30 years and is now higher in women than men, in blacks than whites, and in residents of metropolitan rather than rural areas. Some of this changing pattern clearly relates to the period prior to the acquired immunodeficiency syndrome (AIDS) epidemic and argues that behavioral changes are important in anal cancer development. However, the recent remarkable change in rates among never married men and men living in the San Francisco Bay area suggests that homosexual men are at special and increasing risk. The authors speculate whether part of this recent increase could be attributed to the AIDS epidemic.

There is controversy as to whether appendectomy protects against the development of ulcerative colitis, but the possible impact of appendectomies performed in adulthood has not been systematically investigated.We conducted a large case-control study based on inpatient records from Veterans Affairs hospitals in the United States for the period 1969-96. We identified 6,172 male patients with ulcerative colitis (age range 19-101 years, mean 57.4 years) and 4,498 male patients with Crohn disease (age range 18-99 years, mean 52.9 years). Each of these case patients was individually age- and race-matched to five other male veterans without recorded history of inflammatory bowel disease. We compared records of prior appendectomies in adulthood for the matched case-control sets using conditional logistic regression.Overall, both ulcerative colitis (odds ratio (OR) = 1.6, 95% confidence interval (CI): 1.3-2.1) and Crohn disease (OR = 2.5, 95% CI: 2.0-3.3) were significantly and positively associated with history of appendectomy in adulthood. However, risks were not increased at intervals of 15 years or more between appendectomy and inflammatory bowel disease (ulcerative colitis: OR = 0.9, 95% CI: 0.4-2.1; Crohn disease: OR = 1.2. 95% CI: 0.5-2.5).The elevated risk of inflammatory bowel disease, notably Crohn disease, after appendectomy probably reflects differential diagnostic difficulties in patients with abdominal pain. Appendectomy carried out during adulthood seems not to confer protection against ulcerative colitis.

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 Crohn9s 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.

In agreement with the findings in two prior Danish studies, which together covered the period 1943–2003 [1, 2], Baldur-Felskov et al. [3] provided compelling evidence of a stable incidence of invasive penile cancer in Denmark during 1978–2008, as judged from data in the Danish Cancer Registry (DCR) [4]. However, after adding pathology data that are notoriously incomplete before 1998, the authors reported a statistically significant rising trend in penile cancer incidence over the 31-year period. In other incidence studies of human papillomavirus-associated invasive cancers from the same group [5–7], the authors relied exclusively on DCR data. However, for unstated reasons, Baldur-Felskov et al. chose to search for additional invasive penile cancers in the Danish Pathology Data Bank (DPDB) [8], to ‘increase completeness of data’. Adding penile cancers recorded only in the DPDB is problematic, because this data source is unable to make comparable corrections of potentially missing DCR data for all 31 years under study. The authors may well have identified some missing cases of penile cancer in recent years that could not be identified under penile cancer codes in the DCR (e.g., penile skin cancers inaccurately recorded as skin cancers), but the DPDB data did not permit similar corrections before 1998. Consequently, the apparent longterm trend of increasing penile cancer incidence based on the combined dataset most likely represents an artifact resulting from selective addition in recent years of penile cancer cases identified only in the DPDB. Moreover, Fig. 1 in Baldur-Felskov et al.’s paper provides no evidence to support the claim of increasing penile cancer incidence in the most recent decade, whether based on DCR data alone, DPDB data alone, or the two combined. With respect to precancerous lesions, the authors rightly point out that the observed increase in incidence of highgrade penile intraepithelial neoplasia (PIN 2/3) during 1998–2008 might, at least in part, be ‘explained by increasing knowledge about and greater awareness of HPV-associated diseases’. Also, the reported increase in PIN 2/3 incidence should be viewed in the light of the way the authors treated recurrent episodes in the analysis. Counting recurrences more than 24 months after a prior episode as new incident cases of PIN 2/3 most likely contributed importantly to the observed doubling in incidence. Such analyses may be relevant in attempts to estimate the PIN 2/3-associated burden to the healthcare system. However, to learn if, and to what extent, the annual number of newly affected men with PIN 2/3 is truly increasing, it would be informative if the authors presented a graph of the PIN 2/3 incidence during 1998–2008 in which they counted only the first recorded episode of PIN 2/3 in each patient. As a minor point, it is unclear why the authors deliberately excluded the relatively few cases of penile cancer recorded under ICD-O3 topography code C60.8. Such cancers include lesions that overlap the boundaries of two or more anatomical sublocalizations on the penis (e.g., cancers involving both the glans and the prepuce) and penile cancers whose exact point of origin on the penis cannot be determined. Despite difficulties in determining their exact point of origin on the penis, such cancers are nevertheless penile cancers and should be included in the definition of penile cancer. The authors refer to similar findings in a recent Dutch study [9] to add credence to their claim of increasing invasive penile cancer rates in Denmark. Indeed, findings M. Frisch (&) C. J. Ulff-Moller J. Simonsen Department of Epidemiology Research, Statens Serum Institut, 2300 Copenhagen S, Denmark e-mail: mfr@ssi.dk

It is well accepted that patients with antibodies against cyclic citrullinated peptides (anti-CCP) and rheumatoid arthritis (RA) suffer from more severe forms of RA in terms of clinical presentation and radiographic destruction at long term compared to anti-CCP-negative patients. The purpose of this cross-sectional study was to investigate whether the measures of self-reported health among patients with RA of5 years of duration are influenced by anti-CCP status. Additionally, we aimed to determine whether the measures of self-reported health among the two patient groups differ from those of a control group. Telephone interviews were conducted with 464 patients with RA and 637 population controls, who reported educational level, income, smoking habits and lifestyle 10 years before the interview and completed the Health Assessment Questionnaire and the Short-Form Health Survey Questionnaire, version 2 (SF-36v2); 424 (91%) patients submitted a blood sample for analysis. Patients with anti-CCP-positive and anti-CCP-negative RA showed no significant differences in self-reported disability and physical health after adjustment for age, gender, socioeconomic factors, lifestyle and disease-related variables (p0.05). Both groups of RA patients reported significantly more physical disabilities in everyday life and significantly poorer physical health than the controls (both p0.001). A similar pattern was seen for self-reported mental health (both p0.05). Patients with RA of5 years of duration report significantly more disability and poorer physical health than the general population of Denmark, but these reports were independent of anti-CCP status.

The risk of some female predominant autoimmune diseases (ADs) has previously been shown to be higher in women who experience hyperemesis, gestational hypertensive disorders and idiopathic pregnancy losses. This study assessed the association between such pregnancy-related experiences and the subsequent risk of female predominant and other ADs. Our study cohort comprised 1.6 million Danish women born since 1955 for whom we had information about hyperemesis, gestational hypertensive disorders and pregnancy losses and subsequent hospital contacts for 31 ADs between 1982 and 2008. Ratios of first hospitalization rates (RRs) with 95% confidence intervals (CIs) were calculated using Poisson regression, adjusting for age, birth cohort, calendar period, marital status and childbirths. During 27.0 million person-years of follow-up 51,732 women were hospitalized with one or more ADs. Overall, compared with women without the specific pregnancy experiences, the risk of any AD was significantly increased for women with hyperemesis (RR = 1.41; 95% CI 1.30-1.51), gestational hypertensive disorders (1.21; 1.16-1.26), spontaneous abortions (1.10; 1.07-1.14), missed abortions (1.09; 1.04-1.13), stillbirths (1.25; 1.12-1.40), ectopic pregnancies (1.08; 1.02-1.14) and induced abortions (1.07; 1.04-1.09). Associations with female predominant ADs (i.e., ADs with a female:male ratio >2:1) were strongest in the first five years after the studied pregnancy experiences, but overall there was little difference between the RRs for groups of female predominant ADs and other ADs. Strong and potentially biological associations were observed for a number of specific ADs; including systemic lupus erythematosus, Graves' disease, type 1 diabetes mellitus and pernicious anemia, and for some specific ADs associations persisted even more than five years after the abnormal pregnancy experience. Abnormal pregnancies are associated with increased risk of certain ADs, possibly because of underlying immunologic or hormonal factors that predispose to both adverse pregnancy experiences and AD development.

Background: Intestinal bacteria have been implicated in the etiology of the common inflammatory bowel diseases (IBD) ulcerative colitis and Crohn's disease. Because delivery by cesarean section disturbs the normal bacterial colonization of the newborn's 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;)

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 Sjogren 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 sub- sequent 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% con- fidence 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, respect- ively, 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 ¼ 1.4; 1.04 -1.9), but lost statistical significance for SLE (SIR ¼ 1.1; 0.6 -2.1) and SS (SIR ¼ 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.

Objective To determine the incidence of vulvar carcinoma in situ (CIS) and cancer of squamous cell (SC) origin in Denmark in the period 1978–2007. Methods Using the nationwide Danish Cancer Registry, we identified 980 women diagnosed with vulvar CIS 1978–2003 (67.8% were SC) and 2455 women diagnosed with vulvar cancer 1978–2007 (76.0% were SC). Analysis was restricted to vulvar CIS and cancer of SC origin. We assessed age-specific incidence rates, age-standardized incidence rates, and distribution of stage at diagnosis. Poisson regression analysis was used to estimate the average annual percentage change. Results During the study period the age-standardized incidence rate of vulvar SC CIS increased by 1.97% per year (95% CI: 0.99% to 2.96%) with a tendency toward a steeper increase among women younger than 50years. The age-standardized incidence rate of vulvar SC cancer showed a stable or slightly increasing pattern. However, among women below 60years of age a significantly increasing trend was observed (1.60% per year; 95% CI: 0.50% to 2.71%). The distribution in the extent of vulvar SC cancer at diagnosis showed a tendency toward a higher proportion being diagnosed with localized disease in the more recent calendar years. Conclusions The incidence rates of vulvar SC CIS and vulvar SC cancer among women below the age of 60years have increased since 1978. Human papillomavirus (HPV) could explain the increase and thus, the recent introduction of HPV vaccination may in the future result in a notable reduction of vulvar malignancies.

Introduction Studies have shown a high prevalence of sexual dysfunctions among individuals with a variety of health problems. Aim To obtain a population-based assessment of these matters, we studied associations between indicators of physical and mental health problems and sexual dysfunctions in Denmark. Methods We used questionnaire data from 4,415 sexually active men (mean age 48 years) and women (mean age 45 years) who participated in a nationally representative survey in 2005. Cross-sectional associations of overall health and physical and mental health problems with sexual dysfunctions in the last year were estimated by logistic regression-derived, confounder-adjusted odds ratios (ORadj). Main Outcome Measures We calculated ORadj with 95% confidence intervals (CI) for erectile dysfunction, anorgasmia, premature ejaculation, and dyspareunia in men, for lubrication insufficiency, anorgasmia, dyspareunia, and vaginismus in women, and for sexual dysfunction and sexual difficulties overall in both sexes. Results Sexual dysfunction was significantly more common among participants with poor self-rated health (ORadj 1.86, 95% CI 1.05-3.33 in men, ORadj 1.91, 1.08–3.37 in women). Physical health problems were significantly associated with male sexual dysfunctions (ORadj 1.75, 1.18–2.61), whereas mental health problems were significantly associated with female sexual dysfunctions (ORadj 2.59, 1.60–4.22). Conclusion Among sexually active Danes, poor self-reported overall health is associated with increased rates of sexual dysfunction in both sexes, with physical health problems mainly affecting men's sex lives, and mental health problems being strongly associated with female sexual dysfunction.

Ulcerative colitis (UC) is believed to carry a predisposition to colorectal cancer (CRC) development. International clinical guidelines suggest that UC patients should have a colonoscopy performed every year or up to every third year from approximately eight years after diagnosis for early detection of CRC/dysplasia. However, according to the Danish epidemiological data available, such recommendations are dubious. The present mini review focuses on this matter for the UC population in Denmark.

Objective.The female predominance in systemic lupus erythematosus (SLE) suggests the possible involvement of reproductive factors in its etiology. We evaluated the relationship between parity and pregnancy losses and subsequent risk of SLE in a population-based cohort study.Methods.We followed 4.4 million Danes aged 15–69 years for first inpatient hospitalizations for SLE between 1977 and 2004. As measures of relative risk, we used Poisson regression-derived hospitalization rate ratios (RR) with 95% confidence intervals (CI) for cohort members with different reproductive histories.Results.Overall, 1614 women and 274 men were hospitalized with SLE during 88.9 million person-years of followup. Number of children was unrelated to SLE risk in men, but women with at least one liveborn child were at lower risk than nulliparous women (RR 0.74; 95% CI 0.64–0.86), and women with 2 or more children were at lower risk than 1-child mothers. Recurrent idiopathic pregnancy losses, including spontaneous abortions, missed abortions, and stillbirths, were associated with markedly increased SLE risk (RR 3.50; 95% CI 2.38–4.96, for 2+ vs none; p < 0.001).Conclusion.Nulliparous women, 1-child mothers, and women who experience spontaneous abortions, missed abortions, or stillbirths are at increased SLE risk. Theoretically, immunological processes involved in subfertility or idiopathic pregnancy losses might act as initiating or contributing factors in some cases of SLE. However, considering the well established excess of pregnancy complications in women with established SLE, the observed associations more likely reflect the effect of subclinical immunological processes in women destined to develop SLE.

Sexual dysfunctions and difficulties are common experiences that may impact importantly on the perceived quality of life, but prevalence estimates are highly sensitive to the definitions used. We used questionnaire data for 4415 sexually active Danes aged 16-95 years who participated in a national health and morbidity survey in 2005 to estimate the prevalence of sexual dysfunctions and difficulties and to identify associated sociodemographic factors. Overall, 11% (95% CI, 10-13%) of men and 11% (10-13%) of women reported at least one sexual dysfunction (i.e., a frequent sexual difficulty that was perceived as a problem) in the last year, while another 68% (66-70%) of men and 69% (67-71%) of women reported infrequent or less severe sexual difficulties. Estimated overall frequencies of sexual dysfunctions among men were: premature ejaculation (7%), erectile dysfunction (5%), anorgasmia (2%), and dyspareunia (0.1%); among women: lubrication insufficiency (7%), anorgasmia (6%), dyspareunia (3%), and vaginismus (0.4%). Highest frequencies of sexual dysfunction were seen in men above age 60 years and women below age 30 years or above age 50 years. In logistic regression analysis, indicators of economic hardship in the family were positively associated with sexual dysfunctions, notably among women. In conclusion, while a majority of sexually active adults in Denmark experience sexual difficulties with their partner once in a while, approximately one in nine suffer from frequent sexual difficulties that constitute a threat to their well-being. Sexual dysfunctions seem to be more common among persons who experience economic hardship in the family.

Objectives. We studied overall mortality in a demographically defined, complete cohort of gay men and lesbians to address recent claims of markedly shorter life spans among homosexual persons. Methods. We calculated standardized mortality ratios (SMRs) starting 1 year after the date of same-sex marriage for 4914 men and 3419 women in Denmark who married a same-sex partner between 1989 and 2004. Results. Mortality was markedly increased in the first decade after same-sex marriage for men who married between 1989 and 1995 (SMR = 2.25; 95% confidence interval [CI] = 2.01, 2.50), but much less so for men who married after 1995, when efficient HIV/AIDS therapies were available (SMR = 1.33; 95% CI = 1.04, 1.68). For women who married their same-sex partner between 1989 and 2004, mortality was 34% higher than was mortality in the general female population (SMR = 1.34; 95% CI = 1.09, 1.63). For women, and for men marrying after 1995, the significant excess mortality was limited to the period 1 to 3 years after the marriage. Conclusions. Despite recent marked reduction in mortality among gay men, Danish men and women in same-sex marriages still have mortality rates that exceed those of the general population. The excess mortality is restricted to the first few years after a marriage, presumably reflecting preexisting illness at the time of marriage. Although further study is needed, the claims of drastically increased overall mortality in gay men and lesbians appear unjustified.

A high prevalence of cervical cancer associated high-risk types of human papillomavirus (hrHPV) has been demonstrated in premalignant and invasive squamous cell lesions of the penis, but large studies correlating histological characteristics with HPV status are few in number. Tumour tissues from 145 patients with invasive (n = 116) or in situ (n = 29) penile squamous cell carcinoma were subjected to systematic histological evaluation and were PCR-tested for 14 hrHPV types and 23 low-risk HPV types. Around half (52%) of invasive and nine-tenths (90%) of in situ lesions were positive for an hrHPV type, of which HPV 16 was by far the predominant type (91% of hrHPV-positive lesions). In relation to histological characteristics, hrHPV positivity was statistically significantly more common in high-grade tumours, lesions dominated by small tumour cells, lesions with a high number of multinucleated cells and mitoses, and lesions with a small amount of parakeratosis. In conclusion, about half of invasive penile squamous carcinomas in this study were hrHPV-positive, most notably to HPV 16, and probably arose through in situ lesions whereas the other half of invasive penile lesions appeared to be unrelated to hrHPV. A number of histological characteristics differed significantly between hrHPV-positive and -negative invasive penile carcinomas.

Studies exploring the association between appendectomy and Crohn's disease (CD) have reported conflicting findings. We conducted a systematic review of the literature and a meta-analysis to assess the risk of CD following an appendectomy and determine the effect of time between appendectomy and CD diagnosis.MEDLINE was used to identify observational studies evaluating the association between appendectomy and CD. Authors were contacted when data were insufficient. Relative risks (RR) with 95% confidence intervals (CI) were calculated using a random effects model. Studies that analyzed their data by the interval between the appendectomy and the diagnosis of CD were assessed separately. The Woolf chi(2) statistic was used to test for homogeneity. Egger's test was used to evaluate publication bias.The summary RR estimate for CD following an appendectomy was significantly elevated (RR 1.61, 95% CI 1.28-2.02), though heterogeneity was observed (P0.0001). The risk was elevated within the first year following the operation (RR 6.69, 95% CI 5.42-8.25). The risk of CD was also significantly increased 1-4 yr following an appendectomy (RR 1.99, 95% CI 1.66- 2.38); however, after 5 yr or more, the risk fell to baseline levels (RR 1.08, 95% CI 0.99-1.18). Publication bias was not detected (P = 0.2).The meta-analysis demonstrated a significant risk of CD following an appendectomy, though heterogeneity was observed between the studies. The elevated risk early after an appendectomy, which diminishes thereafter, likely reflects diagnostic problems in patients with incipient CD.

Objectives:To determine the association between risk of rheumatoid arthritis (RA) and alcohol consumption in combination with smoking and HLA-DRB1 shared epitope (SE).Methods:Data from two independent case–control studies of RA, the Swedish EIRA (1204 cases and 871 controls) and the Danish CACORA (444 cases and 533 controls), were used to estimate ORs of developing RA for different amounts of alcohol consumed.Results:Alcohol consumption was significantly more common in controls (pConclusions:The observed inverse association between alcohol intake and risk of RA and the recent demonstration of a preventive effect of alcohol in experimental arthritis indicate that alcohol may protect against RA. This highlights the potential role of lifestyle in determining the risk of developing RA, and emphasises the advice to stop smoking, but not necessarily to abstain from alcohol in order to diminish risk of RA. The evidence of potential RA prevention should prompt additional studies on how this can be achieved.

Prostate cancer is the third most common cancer in men and the most common male cancer in Europe and North America [1,2], but little is known about the etiology of this malignancy. Currently, the only well-established risk factors include advanced age, race (higher incidence in blacks than whites) and having a first-degree relative with prostate cancer. Recent studies have provided evidence that fatherhood and prostate cancer risk are somehow associated. A Swedish register-based case–control study with 48,850 prostate cancer patients and an equal number of controls reported that childless men were at 17% reduced risk for prostate cancer compared with men fathering two or more children [3]. Last year, a cohort study of 38,934 fathers in Israel reported an association between absence of sons and increased risk of prostate cancer based on the observation that cohort members who subsequently developed prostate cancer had fathered significantly fewer sons than other men in the cohort [4]. In 2008, a Danish cohort study with 3400 cases of prostate cancer occurring during 51.6 million person-years of follow-up reported that childless men were at 16% reduced risk of prostate cancer compared with men with children. Among men with children, the risk of prostate cancer declined significantly with the number of offspring, regardless of the sex of the children [5]. Having children is an integral and central part of the lives of most men. Thus, the finding that fathers are at an increased risk of prostate cancer compared with men who remain childless is disturbing and the subject of broad public and scientific interest. However, at present it remains unclear whether biological or environmental factors are to explain the observed difference in risk between fathers and childless men. Likewise, the observed ‘dose-dependent’ risk reduction associated with the number of offspring in Danish fathers has no obvious explanation. Here, we will discuss some of the current ideas linking fatherhood status to prostate cancer risk.

The etiology of vulvar and vaginal squamous cell carcinoma (VV-SCC) has received little attention. A total of 182 women with invasive VV-SCC (116 with VV-SCC(vulva), 66 with VV-SCC(vagina)), 164 uterine corpus cancer controls and 518 population controls were interviewed in a population-based case-control study in Denmark, and 87 (48%) of the VV-SCC cases had tissue samples examined for human papillomavirus (HPV) DNA using the GP5+/6+ PCR-EIA assay and subsequent reverse line blotting for HPV typing. Logistic regression-derived odds ratios with 95% confidence intervals served as relative risks. Cervical cancer-associated high-risk HPVs (hrHPVs) were detectable in most (89%) examined cases of VV-SCC(vagina) and in half (50%) of cases of VV-SCC(vulva) (p < 0.001). In site-specific multivariate logistic regression analyses, statistically significant risk factors for both VV-SCC(vulva) and VV-SCC(vagina) included measures of hrHPV exposure (anogenital warts for VV-SCC(vulva); cervical neoplasia and poor genital hygiene for VV-SCC(vagina)), tobacco smoking and alcohol consumption. Furthermore, socioeconomic variables (marital status and years at school) were associated with risk of VV-SCC(vulva). Comparing hrHPV-positive and hrHPV-negative VV-SCCs in polytomous logistic regression analysis revealed that tobacco smoking and cervical neoplasia were significant risk factors only for hrHPV-positive VV-SCCs. Our study shows that VV-SCC(vulva) and VV-SCC(vagina) share measures of prior hrHPV exposure, tobacco smoking and alcohol consumption as statistically significant risk factors. HPV vaccination programs aimed at reducing the burden of cervical cancers are likely to also provide considerable protection against VV-SCCs.

BACKGROUND. Whether fatherhood status affects prostate cancer risk remains controversial. Recently, it was proposed that childless men are at lower prostate cancer risk than men with children and that men with sons may be at lower risk than men with daughters only. METHODS. National population-based register data were used to address these associations between fatherhood status and prostate cancer risk. The cohort comprised all men born in Denmark between 1935 and 1988, among whom 3400 developed prostate cancer during a total of 51.6 million person-years of follow-up between 1968 and 2003. RESULTS. Childless men were found to be at a 16% reduced risk of prostate cancer compared with fathers (rate ratio [RR] of 0.84; 95% confidence interval [95% CI], 0.73–0.95). The sex of the offspring did not affect prostate cancer risk (fathers with sons vs fathers without sons: RR of 0.99; 95% CI, 0.90–1.08). Among fathers, a significant trend was observed of gradually reduced prostate cancer risk with increasing number of children (P = .009), a pattern applying to both sons (P = .01) and daughters (P = .04). CONCLUSIONS. Our national cohort study corroborates the view that men without children constitute a group that is at a moderately reduced risk of prostate cancer. Among men with children, there appears to be a linear decline in prostate cancer risk with increasing number of children that is independent of the sex of the offspring. Cancer 2008. © 2008 American Cancer Society.

Background Multiple sclerosis (MS) and other autoimmune diseases might cluster. Our aim was to estimate the relative risk (RR) of other autoimmune diseases among MS patients and their first-degree relatives in a population-based cohort study. Methods Using the Danish Multiple Sclerosis Register, the Danish Hospital Discharge Register, and the Danish Civil Registration System, we estimated RRs for 42 different autoimmune diseases in a population-based cohort of 12 403 MS patients and 20 798 of their first-degree relatives. Ratios of observed to expected numbers of autoimmune diseases, based on national sex-, age-, and period-specific incidence rates, served as measures of the RRs. Results Compared with the general population, MS patients were at an increased risk of developing ulcerative colitis (RR = 2.0 (95% confidence interval (CI): 1.4–2.8), n = 29) and pemphigoid (RR = 15.4 (CI: 8.7–27.1), n = 12) but at reduced risk of rheumatoid arthritis (RR = 0.5 (CI: 0.4–0.8), n = 28) and temporal arteritis (RR = 0.5 (CI: 0.3–0.97), n = 11). First-degree relatives of MS patients were at increased risks of Crohn’s disease (RR = 1.4 (CI: 1.04–1.9), n = 44), ulcerative colitis (RR = 1.3 (CI: 0.99–1.7), n = 51), Addison’s disease (RR = 3.4 (CI: 1.3–9.0), n = 4), and polyarteritis nodosa (RR = 3.7 (CI: 1.4–10.0), n = 4). Conclusion Patients with MS and their first-degree relatives seem to be at an increased risk of acquiring certain other autoimmune diseases.

Objective To study the role of shared epitope (SE) susceptibility genes, alone and in combination with tobacco smoking and other environmental risk factors, for risk of subtypes of rheumatoid arthritis (RA) defined by the presence or absence of serum antibodies against cyclic citrullinated peptides (CCPs). Methods To address these issues, a nationwide case–control study was conducted in Denmark during 2002–2004, comprising incident cases of RA or patients with recently diagnosed RA (309 seropositive and 136 seronegative for IgG antibodies against CCP) and 533 sex- and age-matched population controls. Associations were evaluated by logistic regression analyses, in which odds ratios (ORs) served as measures of relative risk. Results Compared with individuals without SE susceptibility genes, SE homozygotes had an elevated risk of anti-CCP–positive RA (OR 17.8, 95% confidence interval [95% CI] 10.8–29.4) but not anti-CCP–negative RA (OR 1.07, 95% CI 0.53–2.18). Strong combined gene–environment effects were observed, with markedly increased risks of anti-CCP–positive RA in SE homozygotes who were heavy smokers (OR 52.6, 95% CI 18.0–154), heavy coffee drinkers (OR 53.3, 95% CI 15.5–183), or oral contraceptive users (OR 44.6, 95% CI 15.2–131) compared with SE noncarriers who were not exposed to these environmental risk factors. Conclusion Persons who are homozygous for SE susceptibility genes, notably those who are also exposed to environmental risk factors, have a markedly and selectively increased risk of anti-CCP–positive RA. A distinction between anti-CCP–positive RA and anti-CCP–negative RA seems warranted, because these RA subtypes most likely represent etiologically distinct disease entities.

Background The capsular polysaccharide of group B meningococci (GBM) is structurally identical to a polysaccharide found on neural cell adhesion molecules in humans. This structural identity has raised concern that a vaccine based on the GBM capsular polysaccharide might induce autoimmune disease in vaccinated persons. Because systemic infection with GBM induces serum antibody in adults, we investigated whether persons with a history of GBM disease are at increased risk of developing autoimmune diseases. Methods The entire Danish population constituted our study cohort of 7,467,001 individuals, who were observed for autoimmune diseases from 1977 through 2004. At-risk years were counted as the number of uninfected years prior to the first recorded diagnosis of meningococcal disease but changed to person-years at risk at the diagnosis of GBM disease (2984 subjects) or group C meningococcal disease (914 patients). Ratios of incidence rates of autoimmune disease served as measures of the relative risk. Results Persons with a history of GBM disease experienced a total of 37,290 person-years at risk, ranging from 11 days to 31 years at risk after the onset of GBM disease, during which 49 cases of autoimmune disease occurred. Persons with GBM disease had no increased risk of autoimmune diseases, either compared with persons with a history of group C meningococcal disease (incidence rate ratio, 0.9; 95% confidence interval, 0.5-1.4) or compared with persons without a history of meningococcal disease (incidence rate ratio, 1.1; 95% confidence interval, 0.8-1.5). Conclusions Our findings suggest that invasive disease caused by GBM is not associated with autoimmune diseases in humans for up to 31 years after meningococcal disease and should lessen concerns regarding the development of a capsular-based GBM vaccine.

BACKGROUND & AIMS: We examined the risk of cervical neoplasia (dysplasia or cancer) in women with ulcerative colitis (UC) or Crohn's disease (CD). We also calculated the reverse, the risk for diagnosis with cervical neoplasia before development of inflammatory bowel disease (IBD).METHODS: We established a national cohort of women diagnosed with UC (n = 18,691) or CD (n = 8717) between 1979 and 2011 and a control cohort of individually matched women from the general population (controls, n = 1,508,334). Incidence rate ratios (IRRs) of screening activity and diagnosis of cervical neoplasia in women with IBD were assessed by Cox proportional hazards regression analysis. Odds ratios (ORs) of cervical neoplasia before diagnosis of IBD were calculated by using conditional logistic regression.RESULTS: Women with CD underwent cervical cancer screening as often as women in the general population (IRR, 0.99; 95% confidence interval [CI], 0.96-1.02), whereas screening frequency was slightly increased in women with UC (IRR, 1.06; 95% CI, 1.04-1.08). A total of 561 patients with UC were diagnosed with dysplasia during a median follow-up time of 7.8 years, and 28 patients with UC developed cervical cancer, compared with 1918 controls. A total of 407 patients with CD were diagnosed with dysplasia during a median follow-up time of 8.3 years, and 26 patients with CD developed cervical cancer, compared with 940 controls. Patients with UC had increased risk of low-grade (IRR, 1.15; 95% CI, 1.00-1.32) and high-grade (IRR, 1.12; 95% CI, 1.01-1.25) squamous intraepithelial lesions (SILs), whereas patients with CD had increased risks of low-grade SIL (IRR, 1.26; 95% CI, 1.07-1.48), high-grade SIL (IRR, 1.28; 95% CI, 1.13-1.45), and cervical cancer compared with controls (IRR, 1.53; 95% CI, 1.04-2.27). ORs for cervical cancer were also increased 1-9 years before diagnosis of UC, compared with women without UC (OR, 2.78; 95% CI, 2.12-3.64) or CD (OR, 1.85; 95% CI, 1.08-3.15).CONCLUSIONS: In a population-based nationwide cohort study, we found a 2-way association between IBD, notably CD, and neoplastic lesions of the uterine cervix. This observation is not explained by differences in screening activity.

Children who experience parental divorce are less likely to marry heterosexually than those growing up in intact families; however, little is known about other childhood factors affecting marital choices. We studied childhood correlates of first marriages (heterosexual since 1970, homosexual since 1989) in a national cohort of 2 million 18–49 year-old Danes. In multivariate analyses, persons born in the capital area were significantly less likely to marry heterosexually, but more likely to marry homosexually, than their rural-born peers. Heterosexual marriage was significantly linked to having young parents, small age differences between parents, stable parental relationships, large sibships, and late birth order. For men, homosexual marriage was associated with having older mothers, divorced parents, absent fathers, and being the youngest child. For women, maternal death during adolescence and being the only or youngest child or the only girl in the family increased the likelihood of homosexual marriage. Our study provides population-based, prospective evidence that childhood family experiences are important determinants of heterosexual and homosexual marriage decisions in adulthood.

Variants of invasive squamous carcinoma of the anal canal and perianal skin, referred to collectively as anal cancers, are rare malignancies constituting approximately 2% of all intestinal cancers. of a crude estimate of 35,000–40,000 new anal cancers worldwide, approximately 3,300 cases are diagnosed in the United States each year. This chapter reviews the epidemiology of anal cancer. Topics covered include classification, demographic patterns, lifestyle and environmental factors, host factors, pathogenesis, and preventive measures.

To examine whether markers of socioeconomic status (SES) are associated with risk of rheumatoid arthritis (RA), and if so, whether selected lifestyle-related factors could explain this association.We conducted a frequency matched case-control study; subjects comprised 515 patients (participation rate 83%) attending rheumatology and internal medicine departments in Denmark, with recently diagnosed RA according to the American College of Rheumatology (ACR) 1987 classification criteria for RA (mean disease duration 2.3 yrs), and 769 frequency-matched population controls (participation rate 64%). Information about SES and environmental exposure was obtained by structured telephone interview. Logistic regression analyses evaluated the role of markers of SES.Level of education was significantly inversely associated with risk of RA, with a 2-fold lower risk of RA among those with the longest formal education compared with those having the lowest level of education (multivariate odds ratio = 0.43, 95% confidence interval 0.24-0.76, p trend = 0.001). None of a series of studied lifestyle factors could explain this finding in multivariate logistic regression analyses. When dividing the RA cases into clinical subgroups, the inverse association with level of education was found to apply predominantly to rheumatoid factor (RF)-positive RA.The inverse association between level of education and risk of RF-positive RA was not explained by any of the examined lifestyle factors. RF-positive and RF-negative RA may be 2 distinct diseases with different etiologies, with unmeasured factors related to educational level predominantly associated with the risk of RF-positive RA. However, because mechanisms underlying referral to a hospital might be linked to educational level, our observation based on hospital-referred RA patients should be evaluated cautiously. The study stresses the importance of taking SES measures into account in studies that aim at identifying environmental risk factors for RA.

Udgivelsesdato: 2006-Jul BACKGROUND: Type 1 diabetes mellitus (T1D) and multiple sclerosis (MS) contribute considerably to the burden of autoimmune diseases in young adults. Although HLA patterns of T1D and MS are considered mutually exclusive, individual and familial co-occurrence of the 2 diseases has been reported. OBJECTIVE: To assess the co-occurrence of T1D and MS by estimating the risk for MS in patients with T1D and the risk for T1D in first-degree relatives of patients with MS. DESIGN, SETTING, AND PARTICIPANTS: Two population-based disease registers, the Danish Hospital Discharge Register and the Danish Multiple Sclerosis Register were used to identify patients with T1D, defined as patients in whom diabetes was diagnosed before age 20 years (N = 6078), and patients with MS (N = 11 862). First-degree relatives (N = 14,771) of patients with MS were identified from family information in the Danish Civil Registration System. MAIN OUTCOME MEASURE: Patients with T1D and first-degree relatives of patients with MS were followed up for occurrence of MS and T1D, respectively, and the relative risks were expressed as standardized incidence ratios, that is, ratios of observed to expected numbers of outcomes based on national age, sex, and period-specific MS and T1D incidence rates. RESULTS: Patients with T1D were at more than 3-fold increased risk for development of MS (relative risk, 3.26; 95% confidence interval, 1.80-5.88; n = 11). First-degree relatives of patients with MS were at 63% increased risk (relative risk, 1.63; 95% confidence interval, 1.26-2.12; n = 56) for development of T1D. However, adjusting for familial relationship to patients with T1D reduced the excess risk to 44% (relative risk, 1.44; 95% confidence interval, 1.11-1.88; n = 56). CONCLUSION: The present nationwide cohort study demonstrates an intraindividual and, to a lesser degree, an intrafamilial co-occurrence of MS and T1D.

Multiple sclerosis (MS) is known to accumulate within families. The magnitude of the familial risk, however, remains uncertain. Using a nationwide MS register and other national registers, the authors estimated relative and absolute risks of MS in a population-based cohort that included 19,615 first-degree relatives of 8,205 Danish MS patients followed from 1968 to 1997. The ratio of observed to expected numbers of MS cases served as the measure of the relative risk of MS. Lifetime risks of MS in first-degree relatives were estimated as the product of the relative risk and the national lifetime risk of MS. Overall, first-degree relatives had a sevenfold increased risk of MS (relative risk ¼ 7.1, 95% confidence interval: 5.8, 8.8) (n ¼ 90) compared with the background population. By modeling the individual incidence rate of MS as the sum of a familial component and a sporadic risk component, the familial excess lifetime risk was found to be 2.5% (95% confidence interval: 2.0, 3.2) among firstdegree relatives of MS patients, irrespective of the gender of the proband and the relative. This percentage should be added to a sporadic absolute risk in the general population of 0.5% in women and 0.3% for men. Spouses of MS patients did not experience an increased risk of MS, suggesting no major role for environmental factors acting in adulthood. cohort studies; Denmark; family; multiple sclerosis; risk

To assess the association between dietary factors and risk of rheumatoid arthritis (RA) in a large prospective cohort.Information about dietary intake was obtained from a detailed self-administered food frequency questionnaire completed by 57,053 individuals who participated in a prospective cohort. Linking the cohort to the Danish National Patient Registry we identified patients who developed RA. A rheumatologist scrutinized original medical records for these individuals in order to confirm the diagnosis of RA. Cox proportional hazards regression analyses were performed for dietary and lifestyle factors.The average time of followup in the cohort was 5.3 years (range1 mo to 7.7 yrs). Sixty-nine individuals were identified with confirmed incident RA. In multivariate models each increase in intake of 30 g fat fish (or = 8 g fat/100 g fish) per day was associated with 49% reduction in the risk of RA (p = 0.06), whereas medium fat fish (3-7 g fat/100 g fish) was associated with significantly increased risk of RA. Intake of fruit and coffee was not associated with risk of RA. Furthermore, no associations were found between risk of RA and intake of a range of other dietary factors including long chain fatty acids, olive oil, vitamins A, E, C, D, zinc, selenium, iron, and meat.The limited number of patients who developed RA during followup of our large cohort prevented us from concluding that dietary factors are unimportant as risk factors for RA. It appears, however, that if dietary factors are important modifiers of RA risk, they must play a role more than a few years before clinical diagnosis.

The belief that oestrogens are involved in the pathogenesis both of testicular cancer in young men and of cancers of the endometrium and female breast has become widespread. In a search for possible hormonal links between these cancers, we investigated the cancer pattern in a cohort of women who had given birth to sons who developed testicular cancer. Particular focus was given to oestrogen-related cancers. The present retrospective population-based cohort study is based on data from the Danish Cancer Registry. Mothers of 2,204 testicular-cancer patients were followed for the occurrence of cancer over a total of 70,063 person years. The ratio of observed cancers in the cohort over the expected numbers based on cancer incidence in the underlying female population served as measure of the relative risk (RR). The RR of developing breast cancer among mothers of testicular-cancer patients was 0.8 (95% confidence interval 0.6–1.1), the relative risk of endometrial cancer 0.6 (0.3–1.0) and of ovarian cancer 1.0 (0.6–1.6). Mothers of testicular-cancer patients are not at increased risk of developing oestrogen-related cancers. © 1996 Wiley-Liss, Inc.

Infectious mononucleosis-related Epstein-Barr virus (EBV) infection has been associated with an increased risk of Hodgkin's lymphoma in young adults. Whether the association is causal remains unclear.We compared the incidence rates of Hodgkin's lymphoma in two population-based Danish cohorts of patients who were tested for infectious mononucleosis: 17,045 with serologic evidence of having had acute EBV infection, and 24,614 with no such evidence. We combined the cohort of patients who had serologically verified infectious mononucleosis with a cohort of 21,510 Swedish patients with infectious mononucleosis (combined total, 38,555). Biopsy specimens of Hodgkin's lymphomas occurring during follow-up in this combined cohort were tested serologically for the presence of EBV. Using this information, we modeled the relative risk of EBV-negative and EBV-positive Hodgkin's lymphoma in different periods after the diagnosis of infectious mononucleosis and estimated the median incubation time for mononucleosis-related EBV-positive Hodgkin's lymphoma.Only serologically confirmed infectious mononucleosis was associated with a persistently increased risk of Hodgkin's lymphoma. Sixteen of 29 tumors (55 percent), obtained from patients with infectious mononucleosis, had evidence of EBV. There was no evidence of an increased risk of EBV-negative Hodgkin's lymphoma after infectious mononucleosis. In contrast, the risk of EBV-positive Hodgkin's lymphoma was significantly increased (relative risk, 4.0; 95 percent confidence interval, 3.4 to 4.5). The estimated median incubation time from mononucleosis to EBV-positive Hodgkin's lymphoma was 4.1 years (95 percent confidence interval, 1.8 to 8.3).A causal association between infectious mononucleosis-related EBV infection and the EBV-positive subgroup of Hodgkin's lymphomas is likely in young adults.

Persons with acquired immunodeficiency syndrome (AIDS) have increased risk for non-Hodgkin's lymphoma (NHL). Recent studies have reported the detection of DNA sequences from simian virus 40 (SV40), a macaque polyomavirus that contaminated early poliovirus vaccines, in a large proportion of AIDS-associated NHLs. To examine the association between SV40 exposure and NHL risk, we analyzed data from a U.S. registry-based cohort study of persons with AIDS (1980–96). We calculated NHL incidence in persons born in 1958–61 (exposed to SV40-contaminated poliovirus vaccine as children, n = 39,468) and in 1964–67 (born after vaccines were cleared of SV40 and thus unexposed, n = 17,340). Among persons with AIDS, NHL incidence was 11.7 per 1,000 person-years in SV40-exposed individuals (616 NHL cases) and 10.1 per 1,000 person-years in SV40-unexposed individuals (230 cases; unadjusted relative risk 1.15, 95% CI 0.99–1.34, p = 0.06). Because of differences in cohorts' birth years and the evolving demographics of the AIDS epidemic, SV40-exposed subjects were older at AIDS onset than unexposed subjects (mean age 32.0 vs. 27.2 years, p < 0.0001), and the cohorts differed by sex (p < 0.0001) and ethnic group (p < 0.0001). Since NHL incidence was relatively high among whites (p < 0.0001) and homosexual males (p < 0.0001) and increased with age (p = 0.09), comparisons required adjustments for these factors. After adjustment, SV40 exposure was not associated with NHL incidence (adjusted relative risk 0.97, 95% CI 0.79–1.20, p = 0.80). We conclude that childhood exposure to SV40 through receipt of contaminated poliovirus vaccine was not associated with increased risk for AIDS-associated NHL. Our findings do not support a role for SV40 in lymphomagenesis among immunosuppressed persons. © 2003 Wiley-Liss, Inc.

Background: Early poliovirus vaccines were accidentally contaminated with simian virus 40 (SV40). In Denmark, poliovirus vaccine was administered to most children from 1955 through 1961. SV40 DNA sequences have been detected in several human malignancies, including mesothelioma, ependymoma, choroid plexus tumors, and non-Hodgkin's lymphoma. To clarify whether SV40 infection increases risk of these cancers or of cancers arising in children, we examined cancer incidence in three Danish birth cohorts. Methods: Population-based cancer incidence data from 1943 through 1997 were obtained from the Danish Cancer Registry. The relationship between exposure to SV40-contaminated vaccine and cancer incidence was evaluated by examining incidence in birth cohorts that differed in exposure to SV40-contaminated vaccine. In addition, cancer incidence was examined in children who were 0-4 years of age before, during, and after the period of vaccine contamination. Incidence was compared using Poisson regression, adjusting for age differences. All statistical tests were two-sided. Results: After 69.5 million person-years of follow-up, individuals exposed to SV40-contaminated poliovirus vaccine as infants (i.e., born 1955-1961) or children (i.e., born 1946-1952) had lower overall cancer risk (age-adjusted relative risk [RR] = 0.86, 95% confidence interval [CI] = 0.81 to 0.91 and RR = 0.79, 95% CI = 0.75 to 0.84, respectively; P

Rheumatoid arthritis is a chronic inflammatory joint disease with an annual incidence rate between 25 and 50 per 100,000 individuals. Most likely, a combination of inherited and environmental factors, such as infections, reproductive or hormonal factors, and factors related to life style, is responsible for the disease. Future etiological studies should aim at providing a better insight into the interaction between different risk factors.