Kristian T. Jørgensen

Cytokines, autoantibodies and viral antibodies in premorbid and postdiagnostic sera from patients with rheumatoid arthritis: case–control study nested in a cohort of Norwegian blood donors

Objective: To assess the timing of changes in cytokines, cytokine-related markers, autoantibodies and viral antibodies in the pathogenesis of rheumatoid arthritis (RA). Methods: Case–control study nested in a prospective cohort of 31 330 blood donors in Oslo, Norway. Forty-nine donors developed RA up to 23 years after their most recent blood donation. Stored sera from these donors (case sera) and a sex- and age-matched sample of 245 healthy donors (control sera), and postdiagnostic sera from 33 of the 49 RA cases, were analysed for a panel of cytokines and cytokine-related markers, autoantibodies and antibodies against Epstein–Barr virus and parvovirus B19. Results: Cytokines and cytokine-related markers were generally negative in case sera from >5 years before the diagnosis of RA. In the 5-year interval immediately before the diagnosis of RA, more case than control sera were positive (odds ratios >2) for interleukin (IL)-1α, IL-1β, IL-1 receptor antagonist, IL-4, IL-10, tumour necrosis factor-α and soluble tumour necrosis factor receptor I. In postdiagnostic sera, however, 11 of 16 examined cytokines and cytokine-related markers were statistically significantly elevated compared with control sera. Seropositivity for IgG antibodies against cyclic citrullinated peptides and for IgM and IgA rheumatoid factors were seen in case sera from up to 18 years before the diagnosis of RA. IgG antibodies against Epstein–Barr virus and parvovirus B19 did not differ significantly between case and control sera. Conclusions: Cytokines and cytokine-related markers appear to be upregulated rather late in RA pathogenesis. In contrast, IgM rheumatoid factor and IgG anti-cyclic citrullinated peptide autoantibodies may precede the diagnosis of RA by up to two decades.

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.

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.

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.

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.

Reproductive history and risk of multiple sclerosis.

Background: It has been suggested that reproductive factors may be involved in the etiology of multiple sclerosis (MS). We studied associations of reproductive history with MS risk in a population-based setting. Methods: Using national databases, we established a cohort comprising 4.4 million Danish men and women born between 1935 and 1989 and alive in 1968 or later. We obtained information about their live-born children, pregnancy losses, pregnancy complications, and infertility diagnoses. MS cases in the cohort were identified through 2004 in the Danish Register of Multiple Sclerosis. Associations between reproductive factors and MS risk were evaluated using rate ratios (RRs) obtained in log-linear Poisson regression analysis. Results: MS was diagnosed in 6332 women and 3426 men. In both sexes, parents had a lower risk of MS compared with childless persons (in women, RR = 0.76 [95% confidence interval = 0.71–0.82]; in men, 0.89 [0.80–0.98]). RRs were inversely associated with number of children, age at first childbirth, and proximity in time since most recent birth. Among women, MS risk was unrelated to histories of pregnancy loss, pregnancy complications, or infertility. A supplementary analysis in which the date of MS diagnosis was backdated by 5 years to address the possibility of reverse causality did not confirm a protective effect of parenthood (in women, 0.95 [0.88–1.03]; in men, 1.08 [0.98–1.20]). Conclusions: Similar findings in women and men argue against a biologic role of pregnancy in the etiology of MS. Moreover, the observed differences in childbearing patterns were restricted to the 5 years before MS diagnosis, suggesting that reverse causality (ie, reduced reproductive activity in persons with yet-undiagnosed MS) might explain the observed associations.

Fatherhood status and prostate cancer risk.

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.

Neonatal vitamin D status and risk of multiple sclerosis A population-based case-control study

Objective: As previous research has suggested that exposure to vitamin D insufficiency in utero may have relevance for the risk of multiple sclerosis (MS), we aimed to examine the direct association between level of neonatal vitamin D and risk of MS. Methods: We carried out a matched case-control study. Dried blood spots samples (DBSS) belonging to 521 patients with MS were identified in the Danish Newborn Screening Biobank. For every patient with MS, 1–2 controls with the same sex and birth date were retrieved from the Biobank (n = 972). Level of 25-hydroxyvitamin D (25[OH]D) in the DBSS was measured using liquid chromatography tandem mass spectroscopy. The association between different levels of 25(OH)D and risk of MS was evaluated by odds ratios (OR) calculated in conditional logistic regression models. Results: We observed that lower levels of 25(OH)D in neonates were associated with an increased risk of MS. In the analysis by quintiles, MS risk was highest among individuals in the bottom quintile (<20.7 nmol/L) and lowest among those in the top quintile of 25(OH)D (≥48.9 nmol/L), with an OR for top vs bottom of 0.53 (95% confidence interval [CI] 0.36–0.78). In the analysis treating 25(OH)D as a continuous variable, a 25 nmol/L increase in neonatal 25(OH)D resulted in a 30% reduced risk of MS (OR 0.70, 95% CI 0.57–0.84). Conclusion: Low concentrations of neonatal vitamin D are associated with an increased risk of MS. In light of the high prevalence of vitamin D insufficiency among pregnant women, our observation may have importance for public health.

Socio-demographic factors, reproductive history and risk of osteoarthritis in a cohort of 4.6 million Danish women and men.

OBJECTIVE Studies addressing possible socio-demographic and reproductive factors in the aetiology of osteoarthritis (OA) are few. We studied possible influences of educational level, household income, marital status and parenting patterns on OA risk overall and at anatomical sites. METHOD We linked national register data about socio-demographic variables, reproductive histories and OA hospital contacts to a cohort of 4.6 million Danes. Ratios of first OA hospitalisation rates (RRs) were calculated using Poisson regression. RESULTS Overall, 100,437 women and 92,020 men had a first OA hospital contact during 91.5 million person-years between 1982 and 2008. Short education, low income and married status were significantly associated with increased OA risk, and persons with children were at higher risk of OA(overall) (RR=1.10 in women; RR=1.22 in men), OA(knee) (RRs 1.14; 1.28), OA(back) (RRs 1.18; 1.33), and OA(hand) (RRs 1.21; 1.43), but not of OA(hip) (RRs 0.96; 1.00) than persons without children. The RR of OA(overall) increased by a factor of 1.05 in women and 1.04 in men per additional child, most notably for OA(knee) in women (1.10 per child). CONCLUSION Risk of OA hospitalisation was highest among married persons and persons with short education or low income. The similar or even stronger associations with reproductive factors in men than women suggest that unmeasured lifestyle factors rather than biological factors associated with pregnancy might explain the higher OA risk in persons with children. However, the particularly strong association between parity and risk of OA(knee) in women is compatible with a role of pregnancy-associated factors.

National cohort study of reproductive risk factors for rheumatoid arthritis in Denmark: a role for hyperemesis, gestational hypertension and pre-eclampsia?

Objectives: While reproductive factors might plausibly be involved in the aetiology of rheumatoid arthritis (RA), the female predominance remains unexplained. A study was undertaken to address the possible impact of live births, pregnancy losses and pregnancy complications on the subsequent risk of RA in a nationwide cohort study. Methods: National register data were used to link reproductive histories and later RA hospitalisations in a cohort of 4.4 million Danes. As a measure of relative risk associated with different reproductive histories, ratios of first inpatient RA hospitalisation rates (RRs) were used with 95% confidence intervals (CIs) obtained by Poisson regression analysis. Results: Overall, 7017 women and 3041 men were admitted to hospital with RA in 1977–2004 (88.8 million person-years). The risk of RA was inversely associated with age at birth of first child in both women and men (p for trend <0.001). Overall, nulliparity and a history of pregnancy loss were not associated with RA risk but, compared with one-child mothers, women with two (RR 0.84; 95% CI 0.78 to 0.90) or three (RR 0.83; 95% CI 0.77 to 0.91) children were at reduced risk. The risk of RA was increased in women with a history of hyperemesis (RR 1.70; 95% CI 1.06 to 2.54), gestational hypertension (RR 1.49; 95% CI 1.06 to 2.02) or pre-eclampsia (RR 1.42; 95% CI 1.08 to 1.84). Conclusions: One-child mothers and young parents are at increased risk of RA later in life, possibly due to socioeconomic factors. The novel finding of a significantly increased risk of RA in women whose pregnancies were complicated by hyperemesis, gestational hypertension or pre-eclampsia might reflect reduced immune adaptability to pregnancy in women disposed to RA or a role of fetal microchimerism in the aetiology of RA.