Pregnancies in patients with systemic lupus erythematosus during 2000-2018 in Finland: a case-control study.

OBJECTIVES: The aim was to investigate, how pregnancies proceed in patients with systemic lupus erythematosus (SLE) compared to their individually matched population controls. MATERIAL AND METHODS: Adult incident SLE patients were identified from the register of new special reimbursement decisions for SLE drugs in 2000-2014. For each patient, 1-3 randomly selected controls from the Population Register Centre were matched. Data regarding pregnancies were obtained from the Finnish Medical Birth Register, Care Register and Register of Congenital Malformations until 2018. The study utilized data from the Drug Purchase Register and educational information from Statistic Finland. RESULTS: A total of 163 deliveries for 103 mothers with SLE and 580 deliveries for 371 population controls were identified. The duration of pregnancies in SLE women was significantly shorter compared to controls (38.9 versus 39.6 weeks). There were more urgent Caesarean Sections. (15% versus 9%) and need for care at neonatal intensive care unit (NICU) (21% versus 11%) among deliveries in SLE mothers. No statistical difference was observed between SLE and control groups in the occurrence of preeclampsia or major congenital malformations. Gestational age was 2.5 weeks shorter when the mother experienced pre-eclampsia. Hydroxychloroquine was purchased by 30% of SLE mothers during pregnancy. CONCLUSION: The course of pregnancies in Finnish SLE patients seems to be quite moderate compared to controls, and no new safety issues were detected. The low utilization of hydroxychloroquine indicates that the benefits of the drug to pregnancy and disease course are not optimally recognized by specialists treating SLE mothers.

Risk Factors of Cancer in Pediatric-Onset Inflammatory Bowel Disease in Denmark and Finland.

OBJECTIVES: Pediatric-onset inflammatory bowel disease (pIBD) increases the risk of developing several different cancer forms. In this case-control study, we aimed to assess the impact of medical treatment and disease activity on the risk of developing disease-associated cancer (DAC) and treatment-associated cancer (TAC). METHODS: In a previous study, we identified 27 cases of DAC (colorectal cancer, small bowel cancer, and cholangiocarcinoma) and 28 TAC (lymphoma and skin cancer) in 6689 patients with pIBD in Denmark and Finland during the period 1992-2015. In this study, the patient charts were reviewed manually. Cancer-free patients from another population-based pIBD cohort were included as controls. We recorded data on phenotype, medical treatment, surgery, and relapses. Logistic regression was used to estimate adjusted odds ratios (aOR) with 95% confidence intervals (95% CI) to estimate the relative risk. RESULTS: We included 16 cases with DAC, 21 with TAC, and 331 controls. For DAC, lower frequencies of IBD-relapses were associated with an increased risk of cancer (OR 0.2 [95% CI: 0.04-0.8]). For TAC, we found an increased risk in patients receiving thiopurines at any point during the follow-up period (aOR: 11.7 [95% CI: 2.1-116.2]) and an association with proportion of follow-up time being exposed to thiopurines (aOR 5.6 [95% CI: 1.1-31.5]). CONCLUSIONS: In this nation-wide study, covering all pIBD patients from Denmark and Finland, we found that pIBD patients treated with thiopurines had an increased risk of TAC.

Malignancies among newly diagnosed systemic lupus erythematosus patients and their survival.

The objective of this study was to evaluate the incidence of malignancies among newly diagnosed systemic lupus erythematosus (SLE) patients compared to reference individuals. Another aim was to assess the survival of SLE patients with malignancy compared to references with malignancy. Finnish adult (>17 years) newly diagnosed SLE patients were identified by their drug reimbursement decisions made during 1.1.2000-31.12.2014 from the register of the Social Insurance Institution. For each case, three population controls were individually selected by age, sex and place of residence. Overall, 1006 SLE patients (women 84%), with a mean age of 45.5 years (SD 16 years) and 3005 population controls were linked to Finnish Cancer Registry, and the information about incident malignancies was retrieved from the day the special reimbursement decision for SLE medication was accepted (index day, ID) until 31.12.2018 or until death. The patients diagnosed with malignancy were followed up until 31.12.2019 considering survival. During the follow-up, 85 SLE patients (women 78%) and 192 controls (women 78%) had developed one or more malignancy after the ID. The incidence rate ratio for any malignancy was 1.41 (95% CI 1.08-1.85). The most common malignancy in SLE patients was non-Hodgkin lymphoma, with twelve cases. SLE patients with malignancy had a lower adjusted 15-year survival than controls with malignancy, 27.1% versus 52.4%, and the adjusted hazard ratio for death was 1.68 (95% CI 1.17-2.43). Our results confirm that SLE patients have a higher risk for overall malignancy. The results also suggest that SLE patients with malignancy have lower survival than their references with malignancy.

Usage of drugs for cardiovascular diseases is increased in systemic lupus erythematosus (SLE) patients already before diagnosis of SLE.

OBJECTIVES: Systemic lupus erythematosus (SLE) patients are considered as a high-risk population for cardiovascular diseases (CVDs). To explore whether their risk is increased already in preclinical episodes of the disease, we have studied the usage of CVD drugs in incident SLE cases five years before diagnosis of SLE compared to the population controls. METHODS: Adult SLE incident patients (age ≥18 years) from 2004 through 2014 were identified from a nationwide register. The date of granted reimbursement for SLE medication was defined as the date of diagnosis (index day). For each patient, three population controls were matched for age, sex and residence on the index day. The patients and controls were linked to the drug purchase register. All purchases of CVD drugs (Anatomical Therapeutic Chemical (ATC) - codes of C01-C04, C07-C09) and separately C10 were recorded in half-year periods over five years before the index day. RESULTS: A total of 653 SLE patients (mean age 45.7±15.9 years, 83% females) and 1924 population controls were found. Over five years before the index day, the proportion of SLE patients with purchased CVD drugs (46.7%) was greater compared to the controls (28.5%) (p<0.001). The relative risk for purchases started to increase more steeply during the last half-year period before SLE diagnosis. There was no significant difference in lipid-modifying agents between groups. CONCLUSIONS: Our finding that among SLE patients the use of CVD drugs was more common compared to their control population suggests increased CVD risk already before the diagnosis of SLE.

Mortality in SLE patients compared with population controls in Finland in years 2000-2015.

OBJECTIVE: To estimate the risk of mortality in the Finnish incident SLE cohort in a 16-year period compared with the general population. METHODS: Adults with new-onset SLE between 1 January 2000 and 31 December 2014 identified from the national drug reimbursement register and their individually matched controls from the Population Register Centre were followed up until death or 31 December 2015. Data on deaths were retrieved from the national causes of death register. Comorbidities and education were obtained by linkage to the other national registries. RESULTS: A total of 1006 patients with incident SLE and 3005 population controls were found (mean follow-up 8.6 years). Of these, 98 SLE patients subsequently died. Their 5 -, 10-, and 15-year survival rates were 95.0% (95% CI: 93.3, 96.2), 88.8% (86.2, 91.0), and 82.1% (77.6, 85.8), respectively. Crude hazard ratio (HR) was 1.61 (95% CI: 1.26, 2.06), adjusted for education level was almost the same 1.61 (95% CI: 1.26, 2.05). After adjustment for comorbidities and education at baseline, the difference in mortality disappeared: HR 1.14 (95% CI: 0.88, 1.48). The leading causes of death were cardiovascular diseases (CVDs) (33%), malignancies (27%) and neurological diseases (10%). Subhazard ratio for CVD deaths was 1.28 (95% CI: 0.85, 1.93), adjusted for comorbidities and education 0.88 (95% CI: 0.56, 1.39). CONCLUSIONS: These results suggest that the increased mortality in SLE patients is highly associated with comorbidities present at diagnosis. This underlines the importance to screen and treat comorbidities and disease actively without delays.

Multimorbidity among incident Finnish systemic lupus erythematosus patients during 2000-2017.

The objective of the study was to examine the risk of other morbidities among patients with systemic lupus erythematosus (SLE). A total of 1006 adult new-onset SLE patients were identified during 1.1.2000- 31.12.2014 from the register of Social Insurance Institution. For each case three general population controls matched according to age, sex and place of residence at the index day were sampled from the population register. Both groups were followed up from the index date until the end of 2017 or until death. The national register on specialized care was explored to gather broadly their 12 organ-specific morbidities, which were found among 91.2% of SLE patients and 66.7% of comparators. The rate ratio (RR) was elevated in almost all disease groups. Musculoskeletal, cardiovascular and genitourinary conditions were the most common comorbidities with RRs of 1.82 (1.68 to 1.97), 1.91 (1.76 to 2.08) and 1.91 (1.73 to 2.09), respectively. Men with SLE had a significantly higher risk for diseases of the genitourinary system and endocrine, nutritional and metabolic diseases compared to women with SLE. The risk of concurrent morbidities is essential to note in the care of SLE patients.

Cow's milk allergy in infancy and later development of type 1 diabetes-nationwide case-cohort study.

BAKGROUND: It is suggested that early intake of cow's milk could be a risk factor for type 1 diabetes (T1DM). Further, the different immunological background, gives a suggestion of an inverse relationship for the occurrence of these diseases. The aim of this study was to explore the association between cow's milk allergy (CMA) and the risk of T1DM in a register-based case-cohort study. METHODS: Data were obtained from Finnish nationwide health registers. The study included all children born in Finland between January 01, 1986 and December 31, 2008 and diagnosed with T1DM before the age of 16 years (n = 7754). A 10% random sample from each birth year cohort was selected as a reference cohort (n = 137,798). T1DM, CMA, and asthma were defined based on valid special reimbursements for the costs of drugs/special formulas needed in the treatment of the diseases. Child's sex, birth decade, asthma, maternal diabetes and asthma, smoking during pregnancy, and previous deliveries were considered as confounding factors. Time-dependent, weighted Cox regression was applied for statistical analyses. RESULTS: Children with CMA had an increased risk of developing T1DM in fully adjusted model (HR = 1.17; 95% CI 1.02-1.34), but the association was no longer observed when including the use of special infant formulas in the definition of CMA in the sensitivity analysis (HR = 1.11; 95% CI 0.92-1.32). CMA was associated with an increased risk of T1DM in children without asthma (HR = 1.27; 95%CI 1.10-1.47), but not in children with asthma (HR = 0.80; 95% CI 0.92-1.27). CONCLUSION: Children with CMA may have an increased risk of T1DM.

Use of Antiasthmatic Drugs and the Risk of Type 1 Diabetes in Children: A Nationwide Case-Cohort Study.

Asthma has been reported to be associated with an increased risk of type 1 diabetes mellitus in childhood, but the reasons are unclear. We examined whether the use of antiasthmatic drugs was associated with the development of type 1 diabetes in childhood in a nationwide, register-based case-cohort study. We identified all children who were born January 1, 1995, through December 31, 2008, in Finland and diagnosed with type 1 diabetes by 2010 (n = 3,342). A 10% random sample from each birth-year cohort was selected as a reference cohort (n = 80,909). Information on all dispensed antiasthmatic drugs (Anatomical Therapeutic Chemical classification system code R03) during 1995-2009 was obtained, and associations between the use of antiasthmatic drugs and the development of type 1 diabetes were investigated using time-dependent and time-sequential Cox regression models. Dispensed inhaled corticosteroids and inhaled ß-agonists were associated with an increased risk of type 1 diabetes after adjusting for other antiasthmatic drugs, asthma, sex, and birth decade (hazard ratio = 1.29, 95% confidence interval: 1.09, 1.52, and hazard ratio = 1.22, 95% confidence interval: 1.07, 1.41, respectively). These findings suggest that children using inhaled corticosteroids or inhaled ß-agonists might be at increased risk of type 1 diabetes.

Overall and Cause-Specific Mortality in Adult Celiac Disease and Dermatitis Herpetiformis Diagnosed in the 21st Century.

INTRODUCTION: We assessed whether celiac disease-associated mortality is increased in Finland among patients diagnosed in the 21st century, given recent improvements in diagnostic and treatment facilities. METHODS: Biopsy-proven patients with celiac disease (Marsh III) and dermatitis herpetiformis aged 20-79 years (median 50 years) diagnosed 2005-2014 (n = 12,803) were identified from the national dietary grant registry. Dates and causes of death were obtained from Statistics Finland. Overall mortality and causes of death were compared with reference individuals (n = 38,384) matched for age, sex, and area of residence (at the time of celiac disease diagnosis) selected from the Population Information System. RESULTS: During a mean follow-up of 7.7 years (SD ±3.0 years), 884 (6.9%) and 2,613 (6.8%) deaths occurred among the celiac cohort and reference group, respectively. Overall mortality (hazard ratio [HR] 1.01, 95% confidence intervals [CIs] 0.94-1.09), mortality from all malignancies (HR 1.11, 95% CI 0.96-1.27), gastrointestinal tract malignancies (HR 1.21, 95% CI 0.56-1.71), or cardiovascular diseases (HR 0.91, 95% CI 0.77-1.07) were not increased among patients with celiac disease. Overall, mortality from lymphoproliferative diseases (HR 2.36, 95% CI 1.65-3.39) and nonmalignant digestive diseases (HR 2.19, 95% CI 1.40-3.43) was increased, but HRs decreased after the exclusion of the first 2 years of follow-up (HR 1.71, 95% CI 1.10-2.66 and HR 1.75, 95% CI 1.01-3.05, respectively). DISCUSSION: The overall mortality in adult celiac disease diagnosed 2005-2014 was not increased. Mortality from lymphoproliferative diseases was increased but lower than previously reported.

Perinatal factors and the risk of type 1 diabetes in childhood and adolescence-A register-based case-cohort study in Finland, years 1987 to 2009.

OBJECTIVES: Our aim was to clarify previously reported associations and to explore new ones between various maternal background and perinatal factors and the risk of type 1 diabetes in childhood. METHODS: We identified all children born 1 January 1987 to 31 December 2008 in Finland and diagnosed with type 1 diabetes by age 16 years or end of 2009 from the Special Reimbursement Register (n = 6862). A 10% random sample from each birth year cohort was selected as a reference cohort (n = 127 216). Information on perinatal factors was obtained from the Finnish Medical Birth Register. RESULTS: Maternal diabetes (hazard ratios [HR] = 6.43; 95% confidence interval [CI] 5.35, 7.73), maternal asthma (HR = 1.23; 95% CI 1.06, 1.43), child's high birth length for gestational age (HR = 1.35; 95% CI 1.22, 1.51 highest vs lowest quintile) and premature or early term birth (HR = 1.21; 95% CI 1.05, 1.39 gestational weeks 33-36 and HR = 1.17; 95% CI 1.09, 1.26 gestational weeks 37-38 vs gestational weeks 39-40) was associated with an increased risk of type 1 diabetes when adjusted for several potential confounders. Maternal smoking during pregnancy (HR = 0.72; 95% CI 0.66, 0.77), high number of previous live births (HR = 0.65; 95% CI 0.55, 0.76 ≥ 4 vs 0 live births), and the child being born small for gestational age (HR = 0.80; 95% CI 0.67, 0.96) was associated with a decreased risk of type 1 diabetes. CONCLUSIONS: Findings on maternal asthma and high birth length for gestational age increasing the risk of type 1 diabetes are novel and need to be confirmed. Our findings indicate that perinatal factors may play a role in the development of type 1 diabetes.

Self-certification versus physician certification of sick leave for reducing sickness absence and associated costs.

BACKGROUND: From the societal and employers' perspectives, sickness absence has a large economic impact. Internationally, there is variation in sickness certification practices. However, in most countries a physician's certificate of illness or reduced work ability is needed at some point of sickness absence. In many countries, there is a time period of varying length called the 'self-certification period' at the beginning of sickness absence. During that time a worker is not obliged to provide his or her employer a medical certificate and it is usually enough that the employee notifies his or her supervisor when taken ill. Self-certification can be introduced at organisational, regional, or national level. OBJECTIVES: To evaluate the effects of introducing, abolishing, or changing the period of self-certification of sickness absence on: the total or average duration (number of sickness absence days) of short-term sickness absence periods; the frequency of short-term sickness absence periods; the associated costs (of sickness absence and (occupational) health care); and social climate, supervisor involvement, and workload or presenteeism (see Figure 1). SEARCH METHODS: We conducted a systematic literature search to identify all potentially eligible published and unpublished studies. We adapted the search strategy developed for MEDLINE for use in the other electronic databases. We also searched for unpublished trials on ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP). We used Google Scholar for exploratory searches. SELECTION CRITERIA: We considered randomised controlled trials (RCTs), controlled before-after (CBA) studies, and interrupted time-series (ITS) studies for inclusion. We included studies carried out with individual employees or insured workers. We also included studies in which participants were addressed at the aggregate level of organisations, companies, municipalities, healthcare settings, or general populations. We included studies evaluating the effects of introducing, abolishing, or changing the period of self-certification of sickness absence. DATA COLLECTION AND ANALYSIS: We conducted a systematic literature search up to 14 June 2018. We calculated missing data from other data reported by the authors. We intended to perform a random-effects meta-analysis, but the studies were too different to enable meta-analysis. MAIN RESULTS: We screened 6091 records for inclusion. Five studies fulfilled our inclusion criteria: one is an RCT and four are CBA studies. One study from Sweden changed the period of self-certification in 1985 in two districts for all insured inhabitants. Three studies from Norway conducted between 2001 and 2014 changed the period of self-certification in municipalities for all or part of the workers. One study from 1969 introduced self-certification for all manual workers of an oil refinery in the UK.Longer compared to shorter self-certificationfor reducing sickness absence in workersOutcome: average duration of sickness absence periodsExtending the period of self-certification from one week to two weeks produced a higher mean duration of sickness absence periods: mean difference in change values between the intervention and control group (MDchange) was 0.67 days/period up to 29 days (95% confidence interval (95% CI) 0.55 to 0.79; 1 RCT; low-certainty evidence).The introduction of self-certification for a maximum of three days produced a lower mean duration of sickness absence up to three days (MDchange -0.32 days/period, 95% CI -0.39 to -0.25; 1 CBA study; very low-certainty evidence). The authors of a different study reported that prolonging self-certification from ≤ 3 days to ≤ 365 days did not lead to a change, but they did not provide numerical data (very low-certainty evidence). OUTCOME: number of sickness absence periods per workerExtending the period of self-certification from one week to two weeks resulted in no difference in the number of sickness absence periods in one RCT, but the authors did not report numerical data (low-certainty evidence).The introduction of self-certification for a maximum of three days produced a higher mean number of sickness absence periods lasting up to three days (MDchange 0.48 periods, 95% CI 0.33 to 0.63) in one CBA study (very low-certainty evidence).Extending the period of self-certification from three days to up to a year decreased the number of periods in one CBA study, but the authors did not report data (very low-certainty evidence). OUTCOME: average lost work time per 100 person-yearsExtending the period of self-certification from one week to two weeks resulted in an inferred increase in lost work time in one RCT (very low-certainty evidence).Extending the period of self-certification (introduction of self-certification for a maximum of three days (from zero to three days) and from three days to five days, respectively) resulted in more work time lost due to sickness absence periods lasting up to three days in two CBA studies that could not be pooled (MDchange 0.54 days/person-year, 95% CI 0.47 to 0.61; and MDchange 1.38 days/person-year, 95% CI 1.16 to 1.60; very low-certainty evidence).Extending the period of self-certification from three days up to 50 days led to 0.65 days less lost work time in one CBA study, based on absence periods lasting between four and 16 days. Extending the period of self-certification from three days up to 365 days resulted in less work time lost due to sickness absence periods longer than 16 days (MDchange -2.84 days, 95% CI -3.35 to -2.33; 1 CBA study; very low-certainty evidence). OUTCOME: costs of sickness absence and physician certificationOne RCT reported that the higher costs of sickness absence benefits incurred by extending the period of self-certification far outweighed the possible reduction in costs of fewer physician appointments by almost six to one (low-certainty evidence).In summary, we found very low-certainty evidence that introducing self-certification of sickness absence or prolonging the self-certification period has inconsistent effects on the mean number of sickness absence days, the number of sickness absence periods, and on lost work time due to sickness absence periods. AUTHORS' CONCLUSIONS: There is low- to very low-certainty evidence of inconsistent effects of changing the period of self-certification on the duration or frequency of short-term sickness absence periods or the amount of work time lost due to sickness absence. Because the evidence is of low or very low certainty, more and better studies are needed.

Sustained return to work and work participation after a new legislation obligating employers to notify prolonged sickness absence.

AIMS: Return to work (RTW) after prolonged sickness absence benefits both the individual and society. However, the effectiveness of legislation aiming to improve RTW remains uncertain. We examined whether sustained RTW and work participation were different before and after a legislative change enacted in 2012 (i.e. an intervention) that obligated employers to give notice of prolonged sickness absence to occupational health services. METHODS: Two random samples (2010 and 2013) of the Finnish working aged population (70%, ~2.6 million each) were drawn. Using survival analysis, we assessed sustained RTW (≥28 consecutive working days) during a two-month follow-up after a sickness absence minimum of 30 calendar days in the pre- and post-intervention period. We also identified pathways for RTW with cluster analysis and calculated relative gain in work participation in the total sample and by several population subgroups. RESULTS: In the total sample, sustained RTW was 4% higher and the mean time to sustained RTW was 0.42 days shorter in the post- than in the pre-intervention period. The estimates were larger among women than men and among those with mental disorders compared with other diagnoses. Changes in the pathways for sustained RTW indicated a 4.9% relative gain in work participation in the total sample. The gain was larger among those who lived in areas of low unemployment rate (20.6%) or worked in the public sector (11.9%). CONCLUSIONS: From 2010 to 2013, RTW and work participation increased among the employees with prolonged sickness absence, suggesting that the legislative change enhanced RTW. The change in work participation varied by population subgroup.

Cow's Milk Allergy in Infancy and Later Development of Juvenile Idiopathic Arthritis: A Register-Based Case-Control Study.

We examined the association between cow's milk allergy (CMA) and juvenile idiopathic arthritis (JIA). The material for this case-control study was collected from national registers of all children born in Finland between 2000 and 2010 and diagnosed with JIA (n = 1,298) and age-, sex-, and place-matched controls (n = 5,179). We identified 235 children with CMA; 66 of these children also had JIA. A conditional logistic regression analysis was performed to evaluate the association between CMA and JIA and to test whether exposure to antibiotics would be a covariate for this association. In boys (but not in girls), a diagnosis of CMA and the use of hypoallergenic formula in infancy were associated with the later development of JIA (odds ratio = 2.4, 95% confidence interval: 1.6, 3.6). The association was most evident in boys who were diagnosed with JIA before age 3 years or diagnosed with CMA with predominantly gastrointestinal symptoms. There was no statistically significant additive interaction between CMA and antibiotic exposure in the later development of JIA. These associations may reflect impaired maturation of intestinal immunity and integrity in boys with a risk of JIA. Predisposing factors related to JIA pathogenesis seem to display a sex-linked disparity.

Co-morbidity and clinically significant interactions between antiepileptic drugs and other drugs in elderly patients with newly diagnosed epilepsy.

PURPOSE: A study was conducted to investigate the frequency of potential pharmacokinetic drug-to-drug interactions in elderly patients with newly diagnosed epilepsy. We also investigated co-morbid conditions associated with epilepsy. METHOD: From the register of Kuopio University Hospital (KUH) we identified community-dwelling patients aged 65 or above with newly diagnosed epilepsy and in whom use of the first individual antiepileptic drug (AED) began in 2000-2013 (n=529). Furthermore, register data of the Social Insurance Institution of Finland were used for assessing potential interactions in a nationwide cohort of elderly subjects with newly diagnosed epilepsy. We extracted all patients aged 65 or above who had received special reimbursement for the cost of AEDs prescribed on account of epilepsy in 2012 where their first AED was recorded in 2011-2012 as monotherapy (n=1081). Clinically relevant drug interactions (of class C or D) at the time of starting of the first AED, as assessed via the SFINX-PHARAO database, were analysed. RESULTS: Hypertension (67%), dyslipidemia (45%), and ischaemic stroke (32%) were the most common co-morbid conditions in the hospital cohort of patients. In these patients, excessive polypharmacy (more than 10 concomitant drugs) was identified in 27% of cases. Of the patients started on carbamazepine, 52 subjects (32%) had one class-C or class-D drug interaction and 51 (31%) had two or more C- or D-class interactions. Only 2% of the subjects started on valproate exhibited a class-C interaction. None of the subjects using oxcarbazepine displayed class-C or class-D interactions. Patients with 3-5 (OR 4.22; p=0.05) or over six (OR 8.86; p=0.003) other drugs were more likely to have C- or D-class interaction. The most common drugs with potential interactions with carbamazepine were dihydropyridine calcium-blockers, statins, warfarin, and psychotropic drugs. CONCLUSIONS: Elderly patients with newly diagnosed epilepsy are at high risk of clinically relevant pharmacokinetic interactions with other drugs, especially if exposed to carbamazepine, but these interactions can be controlled via rational drug choices and with prediction of the possible drug-to-drug interactions. Patients on dihydropyridine calcium-channel blockers, statins, warfarin, and risperidone face the highest risk of interactions.

Symptoms suggestive of cow's milk allergy in infancy and pediatric inflammatory bowel disease.

BACKGROUND: Risk factors of pediatric inflammatory bowel disease (PIBD) are incompletely understood. Recently, we reported that among patients with PIBD, a previous diagnosis of cow's milk allergy (CMA) and asthma occurred more frequently than among age- and sex-matched peers. We tested at a national level the hypothesis that CMA is associated with the risk of contracting PIBD. METHODS: A nationwide birth cohort (n = 225,041), including all Finnish children born between 1999 and 2002, was followed up until July 1, 2014. We identified all children with a diagnosis of CMA, asthma, and PIBD from a national register; the data were based on certificates, including diagnostic criteria. The 95% confidence intervals (CI) for the incidence rates per 100,000 person-years were calculated assuming a Poisson distribution. RESULTS: We identified 7,910 infants with CMA yielding a cumulative incidence of 3.5% by 2 years of age. The cumulative incidence of PIBD was 0.14% (n = 316) and that of asthma 6.6% (14,807). Children with CMA were more likely to develop PIBD than non-CMA children, incidence ratio 2.6 (95% CI 1.7-3.8). Children with a diagnosis of CMA contracted PIBD at a younger age than the respective non-CMA group (9 vs. 11 years, p < 0.05). The risk was more evident for ulcerative colitis than for Crohn's disease. The association between CMA and asthma was stronger than that between CMA and PIBD. CONCLUSIONS: CMA in infancy is associated with subsequent development of asthma and PIBD. This suggests that in a subgroup of patients, CMA may share underlying background with PIBD, warranting thorough follow-up.

Maternal dietary folate, folic acid and vitamin D intakes during pregnancy and lactation and the risk of cows' milk allergy in the offspring.

Maternal nutrient intake during pregnancy and lactation potentially influences the development of allergic diseases. Cows' milk allergy (CMA) is often the first manifestation of atopic diseases, but the impact of early nutritional influences on CMA has not been explored. The associations between maternal intakes of folate, folic acid and vitamin D during pregnancy and lactation were addressed in a prospective, population-based birth cohort within the Finnish Type 1 Diabetes Prediction and Prevention Study. Mothers of 4921 children during pregnancy and 2940 children during lactation provided information on maternal dietary intake during the 8th month of pregnancy and the 3rd month of lactation using a detailed, validated FFQ. Information on diagnosed CMA in the offspring was obtained from a medical registry as well as queried from the parents. The Finnish food composition database was used to calculate nutrient intake. Logistic regression was applied for statistical analyses. Folate intake and folic acid and vitamin D supplement use were associated with an increased risk of CMA in the offspring, whereas vitamin D intake from foods during pregnancy was associated with a decreased risk of CMA. Thus, maternal nutrient intake during pregnancy and lactation may affect the development of CMA in offspring. Supplementation with folic acid may not be beneficial in terms of CMA development, especially in children of allergic mothers. The association between dietary supplement use and CMA risk can at least partly be explained by increased health-seeking behaviour among more educated mothers who also use more dietary supplements.

Long-term changes in the incidence of childhood epilepsy. A population study from Finland.

BACKGROUND: The incidence of childhood epilepsy has changed during the past decades, but it is unclear whether it increased or decreased. METHODS: Changes in drug-treated childhood epilepsy between 1968 and 2012 were evaluated using the Finnish nationwide register of all children, aged ≤15years, on antiepileptic drugs (AEDs) prescribed for the treatment of epilepsy. The first registered entitlement to full-refundable AEDs was used as a proxy for newly diagnosed epilepsy. Incidence densities were calculated as ratios of annual new cases per 100,000person-years in each calendar year during 1968 to 2012. RESULTS: The annual incidence density of newly treated childhood epilepsy increased from 35 in the 1960s to 87 per 100,000person-years in the 1990s and decreased thereafter to 61 per 100,000person-years. Since 1996, the incidence density decreased 1-2% per year in children aged <1, 1-5, or 6-10years (all 95% confidence intervals within 0.3%-3%), while no substantial change was seen in older children. CONCLUSION: The incidence of drug-treated childhood epilepsy from the late 1960s to the early 1990s distinctly increased. The reasons for the increase are not fully understood but may include increasing ascertainment through improved diagnosis and a wider acceptance of AED treatment. Since the 1990s, a slight decline can be seen, probably reflecting the recent improvement in child health and safety.

No increased cardiovascular mortality among early rheumatoid arthritis patients: a nationwide register study in 2000-2008.

OBJECTIVES: To assess cardiovascular (CV) mortality in early rheumatoid arthritis (RA), and the impact of RA medications on CV mortality. METHODS: We identified all incident RA patients over 18 years of age diagnosed between 2000 and 2007 in Finland. Causes of death were analysed until the end of the year 2008. We used competing-risks regression models to assess the impact of different variables such as RA medications on CV mortality. CV mortality was compared with that of the age- and sex-specific general population. RESULTS: We identified 14,878 incident RA patients (68% women, 63% rheumatoid factor (RF) positive, mean age 55.8/57.5 years in men/women), of whom more than 80% received RA medications for longer than 90% of their individual patient-years. By the end of 2008, 1,157 patients died, 501 (43%) of whom of CV causes. The standardised mortality ratio (SMR) for CV deaths in the entire RA cohort was 0.57 (95% CI 0.52 to 0.62). Along with traditional CV risk factors, the presence of RF and the use of glucocorticoids was associated with a higher risk of CV death, whereas the use of methotrexate was associated with a lower risk. CONCLUSIONS: These nationwide results suggest that patients with recent-onset RA who receive consistent RA medication have no increased risk for CV mortality compared to the general population, at least in the early years of the disease. The use of methotrexate is associated with lower CV mortality, whereas the use of glucocorticoids is associated with a higher than average CV mortality.

Incidence of malignancies in diagnosed celiac patients: a population-based estimate.

OBJECTIVES: The association between celiac disease and malignancies is well recognized. In Finland, the prevalence of clinically diagnosed adult celiac disease is 0.6%. In this large, population-based cohort, we aimed at a realistic projection of the cancer risk. METHODS: In the period 2002-2011, the register comprised 32,439 adult celiac patients. This was linked with the Finnish Cancer Registry, which covers over 98% of diagnosed malignancies. The standardized incidence ratio (SIR) was calculated for the malignancies, on the basis of incidence figures for the whole population. A time-stratified analysis was made in celiac patients diagnosed after 2004 (n=11,991). Lifestyle factors, including smoking habits and obesity, were not obtainable. RESULTS: The overall incidence ratio of malignant diseases was not increased (SIR 0.94; 95% confidence intervals 0.89-0.98), but it was ≥5 years from the diagnosis of celiac disease (1.31, 1.04-1.63). The SIRs for non-Hodgkin lymphoma (NHL; 1.94; 1.62-2.29), small-intestinal cancer (4.29; 2.83-6.24), colon cancer (1.35; 1.13-1.58), and basal cell carcinoma of the skin (1.13; 1.03-1.22) were increased, whereas those for lung cancer (0.60; 0.48-0.74), pancreatic cancer (0.73; 0.53-0.97), bladder cancer (0.53; 0.35-0.77), renal cancer (0.72; 0.51-0.99), and breast cancer (0.70; 0.62-0.79) were decreased. SIR for NHL immediately after the diagnosis of celiac disease was 2.56 (1.37-4.38). CONCLUSIONS: There was no increased SIR of cancer in the whole series, but SIR was increased after 5 years from the diagnosis of celiac disease. The risk of breast and lung cancers was decreased. The risk of small-intestinal cancer and NHL was increased, but to a lesser extent than previously described.