Objective: To estimate and compare the incidence of overall hematologic malignancy, inclusive of lymphomas, in subjects with EBV-IM diagnosed in the hospital setting (in- and outpatient care) and matched controls. Methods: This was a non-interventional matched cohort study based on secondary use of individual-level data from Danish and Swedish nationwide registers, matching 1:10 on birth date (+/- 6 months) and sex. EBV-IM subjects were identified by ICD diagnosis codes in national patient registers, matched controls in national population registers, and malignancy events in national cancer registers and patient registers (Sweden only) from 1978 to 2021 in Denmark and 1988 to 2022 in Sweden. All patients with a diagnosis of IM were eligible for inclusion, with exclusion of patients with a diagnosis of cytomegalovirus (CMV)-related IM and/or a prior diagnosis of any malignancy. Incidence rates of overall as well as of subtypes of hematologic malignancy were calculated, and Cox proportional hazards models used to estimate hazard ratios (HR) for overall and subtypes of hematologic malignancy, comparing hospital EBV-IM cases to matched controls. A range of lag periods were introduced to take into consideration diagnostic delay and reverse causality, by shifting the start of follow-up to 2, 3, and 5 years after the date of hospital-diagnosed infection. Results: A combined total of 85,874 subjects were identified as eligible for inclusion in Denmark and Sweden and included in the analysis. Baseline characteristics were generally comparable between EBV-IM subjects and matched controls in both countries. Mean (±SD) age at time of EBV-IM diagnosis was 18.2 years (±10.0) (Denmark) and 18.1 years (±10.2) (Sweden) and 47% (Denmark) and 50% (Sweden) of patients were female. We identified 205 (Denmark) and 248 (Sweden) hematologic malignancy events over 728,000 and 752,000 person-years in Denmark and Sweden, respectively, corresponding to incidence rates for any hematologic malignancy of 28.1 (95% CI: 24.3-32.0) per 100,000 person-years (Denmark) and 33.0 (28.9-37.1) (Sweden) among EBV-IM subjects vs 15.5 (14.6-16.4) (Denmark) and 13.3 (12.5-14.1) (Sweden) among matched controls. The corresponding age-sex-calendar-period-adjusted HR (95% CI) for the comparison of EBV-IM subjects with matched controls were 1.77 (1.53-2.06) (Denmark) and 2.49 (2.16-2.86) (Sweden). For sub-groups of hematologic malignancy, HRs (95% CI) were 1.85 (1.49-2.29) (Denmark) and 2.85 (2.37-3.43) (Sweden) for lymphomas, 2.60 (1.78-3.78) (Denmark) and 3.19 (2.41-4.23) (Sweden) for Hodgkin's lymphoma, and 1.62 (1.25-2.10) (Denmark) and 2.60 (2.07-3.27) (Sweden) for non-Hodgkin's lymphoma. For Burkitt's lymphoma, a HR could not be estimated for Denmark due to too few events but was 2.99 (2.22-4.03) in Sweden. Inclusion of lag-periods of 2, 3 and 5 years resulted in lower risk estimates with less precision but that remained significant, with risk patterns consistent with main findings. Conclusion: In this study using nationwide Danish and Swedish data spanning more than 40 years, a diagnosis of EBV-IM was associated with almost two times higher incidence of any hematologic malignancy compared to age and sex matched controls without hospital diagnosed EBV-IM. This association was strongest between EBV-IM infection and Hodgkin's lymphoma in both countries. Understanding the long-term risk of malignancy occurring after EBV-IM in broad populations is crucial for improving patient outcomes.

BACKGROUND AND OBJECTIVES:Teriflunomide is a disease-modifying therapy (DMT) for multiple sclerosis (MS). This post authorisation safety study assessed risks of adverse events of special interest (AESI) associated with teriflunomide use. METHODS:Secondary use of individual data from the Danish MS Registry (DMSR), the French National Health Data System (SNDS), the Belgian national database of health care claims (AIM-IMA) and the Belgian Treatments in MS Registry (Beltrims). We included patients treated with a DMT at the date of teriflunomide reimbursement or initiating another DMT. Adjusted hazard rates (aHR) and 95% confidence intervals were derived from Cox models with time-dependent exposure comparing teriflunomide treatment with another DMT. RESULTS:Of 81 620 patients (72% women) included in the cohort, 22 324 (27%) were treated with teriflunomide. After a median follow-up of 4 years, teriflunomide use compared to other DMT was not associated with a risk of all-cause mortality, severe infection, pneumoniae, herpes zoster reactivation, pancreatitis, cardiovascular condition and cancers. For opportunistic infections, aHR for teriflunomide versus other DMT was 2.4 (1.2-4.8) in SNDS, which was not bound to a particular opportunistic agent. The aHR was 2.0 (1.1-3.7) for renal failures in the SNDS, but no association was found in other data sources. A total of 187 SNDS patients had a history of renal failure prior to cohort entry. None of these patients (0%) had a renal failure recurrence when treated with teriflunomide for 19 (13%) recurrences reported for patients on another DMT. DISCUSSION:We found no evidence that teriflunomide use would be associated with an increased risk of AESI. Trial Registration EUPAS register: EU PAS 19610.

Objective To compare incidences of neuroinflammatory events, including demyelinating disease (DML), inflammatory polyneuropathies (IPN) and multiple sclerosis (MS), in patients with rheumatoid arthritis (RA) or spondyloarthritis (SpA; including psoriatic arthritis) starting a tumour necrosis factor inhibitor (TNFi), investigating whether monoclonal TNFi antibodies (other TNFis (oTNFis)) confer higher risk than etanercept.Methods This is an observational cohort study including patients from the five Nordic countries starting a TNFi in 2001-2020. Time to first neuroinflammatory event was identified through register linkages. We calculated crude incidence rates (cIR) per 1000 person-years and used multivariable-adjusted Cox regression to compare incidences of neuroinflammatory events overall and for DML, IPN and MS with oTNFi versus etanercept. We further examined individual TNFis and indications.Results 33 883 patients with RA and 28 772 patients with SpA were included, initiating 52 704 and 46 572 treatment courses, respectively. In RA, we observed 135 neuroinflammatory events (65% DML) with cIR of 0.38 with oTNFi and 0.34 with etanercept. The HR of oTNFi versus etanercept was 1.07 (95% CI 0.74 to 1.54) for any neuroinflammatory event, 0.79 (95% CI 0.51 to 1.22) for DML, 2.20 (95% CI 1.05 to 4.63) for IPN and 0.73 (95% CI 0.34 to 1.56) for MS. In SpA, we observed 179 events (78% DML) with cIR of 0.68 with oTNFi and 0.65 with etanercept. The HR for any neuroinflammatory event, DML, IPN and MS was 1.06 (95% CI 0.75 to 1.50), 1.01 (95% CI 0.68 to 1.50), 1.28 (95% CI 0.61 to 2.69) and 0.94 (95% CI0.53 to 1.69), respectively.Conclusion The cIRs of neuroinflammatory events are higher in SpA than in RA, but the choice of specific TNFi does not seem to play an important role in the risk of neuroinflammatory events.

Background and purpose Sex differences in multiple sclerosis (MS) prevalence and disease course are thought to be driven by hormones. Exogenous exposure to estrogens may affect MS disease course. Thus, our aim was to investigate the association between hormone therapy (HT) and disease activity and disability accrual among women with MS. Methods A register-based cohort study was conducted with prospectively enrolled cases from the Danish MS registry. Information on hormone exposure was retrieved from the National Prescription Registry. Outcomes were relapse rate, relapse rate ratio, recurrent relapses, 6-month confirmed and sustained Expanded Disability Status Scale (EDSS) milestones 4 and 6, and recurrent EDSS worsening. Results In all, 3325 women were eligible for analyses, of whom 333 (10%) were ever on HT at some time during follow-up. We found no association between HT and disability accrual, although a trend for increasing risk with increasing length of use was seen. The risk of reaching 6-month confirmed and sustained EDSS 4 among users was 0.6 (95% confidence interval [CI] = 0.3-1.2) after <1 year of use and 1.4 (95% CI = 0.9-2.2) after >5 years of HT compared to never use. The risk of recurrent relapse was increased by 20% (95% CI = 1.0-1.4) among current users of HT compared to nonusers. However, the risk of recurrent relapses was driven by the first calendar period (1996-2005) before the introduction of high-efficacy disease-modifying therapy. Conclusions Our findings from this nationwide MS population suggest that HT does not affect disability accrual in women with MS, especially if used for <5 years.

STUDY QUESTION:Is female infertility among women seeking medically assisted reproduction (MAR) associated with prevalent as well as incident multiple sclerosis (MS)?SUMMARY ANSWER:Women with a record of female infertility did not have an increased risk of developing MS compared with apparent fertile women; however, the prevalence of MS was slightly higher among women undergoing MAR compared with women who had a child without MAR, but this was not related to origin of infertility (i.e. male versus female factor infertility).WHAT IS KNOWN ALREADY:Women with MS have fewer children compared with women without MS. Persons with MS more often have other coexisting autoimmune disorders including hypothyroidism compared with the general population. Thyroid dysfunction is associated with ovarian cause of infertility, miscarriage and ovarian failure. Conversely, women with endometriosis, that is highly associated with infertility, also more often have other coexisting autoimmune diseases including MS and hypothyroidism compared with the general population. However, whether the low fertility rate among women with MS is due to a genetically predisposition to other autoimmune and endocrine disorders that leads to reduced fertility, or an active choice of the woman, disease-related pathology or treatment-specific effect on endocrine and/or ovarian function, is not completely understood.STUDY DESIGN, SIZE, DURATION:A register-based cohort study of a total of 310 357 women from 1996 to 2018. A cross-sectional design was used for analysing prevalence of MS, whereas a cohort design with up to 24 years of follow-up was used for analysing incidence of MS.PARTICIPANTS/MATERIALS, SETTING, METHODS:Three cohorts were included in the study (i) 55 404 women with a female infertility diagnosis registered in the Danish IVF register; (ii) 25 096 women with only male factor infertility recorded in the IVF register and thus no female infertility diagnosis and (iii) 229 857 age- and calendar-matched women with a record of first child birth in the Danish Medical Birth Register (DMBR) and no record ever in the IVF register. The prevalence and incidence of MS in the female infertility cohort were compared with the two control cohorts of apparent fertile women using log-binomial regression and Cox proportional hazard regression, respectively.MAIN RESULTS AND THE ROLE OF CHANCE:The crude prevalence of having MS per 1000 persons was 3.2 for women who had undergone MAR treatment regardless of origin of infertility (i.e. male versus female factor infertility) and 2.3 for fertile DMBR controls. The age, calendar and educational level adjusted prevalence ratio of having a diagnosis of MS at the first MAR treatment was 1.27 (95% CI 1.07-1.52) for infertile women compared with fertile DMBR controls, and 1.00 (95% CI 0.77-1.31) for comparison to women with a male partner with infertility who had also undergone MAR treatment. We found no association between incident MS and female infertility compared with either of the control groups of fertile women.LIMITATIONS, REASON FOR CAUTION:The cohort of infertile women is highly selected on the basis of their choice of having fertility treatment and thus does not include women with unestablished infertility or women who, for some reason, have chosen not to have MAR treatment. Additionally, due to the nature of the observational study design, we cannot exclude the possibility of unmeasured and/or residual confounding.WIDER IMPLICATIONS OF THE FINDINGS:Our results suggest that women with MS may undergo MAR treatment more often than women without MS due to more awareness about the possibility of MAR treatments, sexual dysfunction related to MS disease, but also need for timing of the pregnancy to avoid an unnecessary long time period without disease modifying therapy-especially of high efficacy-and hence a wish to conceive quickly. These findings are important for clinicians dealing with women with MS of childbearing age.STUDY FUNDING/COMPETING INTEREST(S):The authors received no financial support for the study. T.I.K. has served on a scientific advisory board for Novartis and has received support for congress participation from Biogen. M.M. has served on scientific advisory boards for Biogen, Sanofi, Roche, Novartis, Merck, Abbvie and Alexion. She has received honoraria for lecturing from Biogen, Merck, Novartis, Sanofi and Genzyme and has received research support and support for congress participation from Biogen, Genzyme, Roche, Merck and Novartis. The remaining authors declare no conflict of interest.TRIAL REGISTRATION NUMBER:N/A.

BACKGROUND AND PURPOSE:Real-world evidence regarding the effectiveness and safety of ocrelizumab for the treatment of multiple sclerosis (MS) is limited. The aim was to evaluate the effectiveness and safety of ocrelizumab treatment for MS in a real-world setting.METHODS:A nationwide population-based cohort study was conducted where clinical and magnetic resonance imaging data of MS patients enrolled prospectively in the Danish Multiple Sclerosis Registry who initiated ocrelizumab treatment between January 2018 and November 2020 were analyzed.RESULTS:A total of 1104 patients (85.7% relapsing-remitting MS [RRMS], 8.8% secondary progressive MS [SPMS], 5.5% primary progressive MS [PPMS]) were included, with a median follow-up period of 1.3 years. At baseline, the mean age was 41.4 years in the RRMS group, 44.5 years in the PPMS group and 50.3 years in the SPMS group. Median Expanded Disability Status Scale score was 2.5, 3.5 and 5.5, respectively. Most RRMS and SPMS patients had received previous disease-modifying therapies (87.5% and 91.8%, respectively), whereas PPMS patients were mostly treatment naïve (78.7%). After ocrelizumab initiation, 9.3% of the patients experienced a relapse and 8.7% a 24 weeks confirmed disability worsening. Conversely, 16.7% showed a 24 weeks confirmed disability improvement. After ~1 year of treatment, most patients (94.5%) were free of magnetic resonance imaging activity. Ocrelizumab was generally well tolerated, as side effects were only reported for 10% of patients, mostly consisting of infusion-related reactions and infections.CONCLUSIONS:It is shown that most MS patients treated with ocrelizumab are clinically stabilized and with an adverse event profile consistent with the experience from the pivotal clinical trials.

To assess the association between early treatment and the risk of disability pension in patients with relapsing-remitting multiple sclerosis (RRMS).

Background: Methotrexate (MTX) is the most commonly recommended disease-modifying anti-rheumatic drug (DMARD) for first-line treatment of rheumatoid arthritis (RA); however, MTX has been suspected to cause lung disease as an adverse effect. Objectives: To investigate the risk of interstitial lung disease (ILD) and acute and chronic respiratory failure in RA patients treated with MTX and other medications. Methods: From the Danish National Patient Register (NPR) and the clinical DANBIO register for rheumatic diseases, we retrieved data on 30,512 RA patients registered between 1997 and 2015. Information on ILD and respiratory failure was obtained from NPR. Information on age and gender for all Danish citizens was obtained from the Danish Civil Registration System. MTX and other medication purchases were retrieved from the Danish Prescription Register. Associations between MTX and lung disease outcomes were analyzed in Cox regression models with adjustment for age, calendar time, gender and other medications. Standardized Incidence Ratios (SIRs) of lung disease were calculated to compare RA patients to the general population. Results: There was no increased risk of lung disease with MTX treatment (one or more purchases compared to no purchases), HR (95% CI) 1.00 (0.78-1.27) for ILD and 0.54 (0.43-0.67) for respiratory failure at 5-year follow-up. SIR was 3-4 times increased for ILD in MTX treated RA patients but at the same level for the whole RA population compared to the background population. Conclusion: RA patients had an increased risk of ILD compared to the general population, but there was no further increased risk associated with MTX treatment.

Prenatal diagnostic methods and screening procedures have changed rapidly in recent years. Previously, only karyotyping was performed prenatally and monitoring was done only for Down syndrome1. Since then, diagnostic possibilities have increased to include quantitative fluorescent polymerase chain reaction, fluorescence in-situ hybridization, multiplex ligation-dependent probe amplification and chromosomal microarray analysis. Simultaneously, the basis of screening criteria has evolved from maternal age1 to biochemistry2 to combined first-trimester screening3. This has resulted in diverse test results and varying indications over time. In Denmark, as in many other countries, there is a professional desire to monitor continuously prenatal diagnostic rates of all chromosomal aberrations4. There is also great public interest in monitoring Down syndrome4. We have, in Denmark, a unique ability to monitor such data using national health registries, like the Danish Cytogenetic Central register5, that feed national pre- and postnatal karyotypes into the Danish Fetal Medicine Database6. However, for those involved in registering patient data, this is a laborious process. It puts daily demands on clinicians' time, requires difficult decisions to be made on how to obtain uniform registrations, and, in spite of these decisions, there are large data cleaning chores after collection to group the data in meaningful ways. We constructed an algorithm to decrease the workload involved in the last of these steps. As part of a study on microcephaly, we obtained data on all Danish pregnancies with normal first-trimester risk assessment, no known anomalies, and that underwent a second-trimester scan including fetal biometry during the period 1 February 2008 to 1 October 2015 (n = 354 544). The data were collected prospectively on pregnancies in all 22 departments of obstetrics and gynecology in Denmark. These data were retrieved from the Danish Fetal Medicine Database, from which pre- and postnatal karyotyping results, fed in from the Danish Cytogenetic Central Register, were extracted. We then constructed an algorithm (Appendix S1) to group karyotypes into normal or abnormal, and to subdivide abnormal ones into type of aneuploidy, translocation, deletion or duplication (Table 1). Additional variables defined fetal sex, mosaicism and whether the aberration is known to have low penetrance7. After constructing this algorithm, we applied it to the entire 2008–2015 prenatal karyotype data extracted from the Danish Fetal Medicine Database. It instantly produced a grouping of results that would allow the database to monitor Down syndrome pre- and postnatally without much additional work (Table 1). Previously, a clinical geneticist would have had to review manually all abnormal karyotypes to identify trisomy 21 karyotypes for detailing in annual reports. We are, of course, aware that some of the subgroups are relatively inhomogeneous (e.g. the deletion and/or duplication subgroup). According to the International System for Human Cytogenetic Nomenclature, only karyotypes presumed abnormal on the basis of clinical findings should be reported as abnormal, whereas familial copy number variants should result in a normal karyotype. Here, variants of unknown significance, susceptibility variants and pathogenic variants are grouped together. If karyotype data are to be used for research, data cleaning should be done with more scrutiny, and often one should return to the reporting laboratory to receive full insight into the analyses performed. We hope that the algorithm can be of use in other settings after local adaptations are made, and for additional purposes other than in the Danish Fetal Medicine Database. Funding from the Novo Nordic Foundation (NNF16OC0018772) for I.V. is greatly appreciated. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.