Long-Term Safety of Teriflunomide in Multiple Sclerosis Patients: Results of Prospective Comparative Studies in Three European Countries.

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.

Time to first treatment and risk of disability pension in relapsing-remitting multiple sclerosis.

Background Initiation of disease-modifying therapy early in the disease course of relapsing-remitting multiple sclerosis (RRMS) has demonstrated beneficial effects on clinical outcomes, but socioeconomic outcomes remain largely unexplored. Objective To investigate the association between the delay from disease onset to first treatment and the hazard of disability pension. Methods We performed a population-based cohort study with data from the nationwide Danish Multiple Sclerosis Registry and Danish nationwide registries. Patients with a disease onset between 1 January 1996 to 5 April 2016 were followed until disability pension or a competing risk/censoring event. 7859 patients were assessed for eligibility of which 5208 were included in the final cohort. Key inclusion criteria were: a diagnosis of multiple sclerosis, relapsing-remitting phenotype, treatment in history, age 18-65 years and an Expanded Disability Status Scale≤4. Patients were categorised according to time from onset to first treatment: within 1 year (early), between 1 and 4 years (intermediate) and from 4 to 8 years (late). Results Of the 5208 patients, 1922 were early, 2126 were intermediate and 1160 were late. Baseline clinical and socioeconomic variables were well balanced. The hazard of receiving disability pension increased with increasing delay of treatment initiation compared with the early group. Cox regression estimates adjusted for clinical and socioeconomic confounders: intermediate (HR, 1.37; 95% CI, 1.12 to 1.68) and late (HR, 1.97; 95% CI, 1.55 to 2.51). Conclusion Early treatment initiation is associated with a reduced risk of disability pension in patients with RRMS. This finding underlines the importance of early diagnosis and treatment on a patient-centred, socioeconomic disability milestone.

Changes in prognosis of the Danish multiple sclerosis population over time.

BACKGROUND: The course of multiple sclerosis (MS) appears to be milder in recent decades. OBJECTIVE: To investigate how time from onset to disability milestones and how demographic and clinical characteristics have changed through subsequent onset cohorts of patients with MS. METHODS: In the nationwide Danish Multiple Sclerosis Registry, we have registered all 13,562 Danish patients with onset of MS or clinically isolated syndrome from 1996 through 2020. For the analyses of prognosis, we used all cases with relapsing onset (N = 11,669). After stratification into 5-year onset cohorts, we computed the hazard ratios for disability endpoints for all cohorts having at least 10 years of follow-up and the oldest 1996-2000 onset cohort as reference. RESULTS: Patients in more recent MS onset cohorts have a shorter diagnostic delay and more of them start disease-modifying treatment within 1 year since diagnosis. The prognosis was better for later onset cohorts. For the 2001-2005 cohort, the hazard ratio for confirmed Expanded Disability Status Scale (EDSS) 4 was 0.85 (95% confidence interval (CI), 0.76-0.95) and for confirmed EDSS 6: 0.76 (95% CI, 0.65-0.88). For the more recent 2006-2010 cohort, the corresponding hazard ratios were 0.70 (95% CI, 0.62-0.79) and 0.60 (95% CI, 0.50-0.71). CONCLUSION: We observed a considerable improvement of the prognosis in recent onset cohorts of relapsing-onset MS.

Hormone therapy and disease activity in Danish women with multiple sclerosis: A population-based cohort study.

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.

Methotrexate and risk of interstitial lung disease and respiratory failure in rheumatoid arthritis: a nationwide population-based study.

OBJECTIVES: MTX is the most commonly recommended DMARD for first-line treatment of RA, however, it has been hypothesized to cause lung disease as an adverse effect. We investigated the risk of interstitial lung disease (ILD) and acute and chronic respiratory failure in persons with RA treated with MTX and other medications. METHODS: From the Danish National Patient Register (NPR) and the DANBIO register for rheumatic diseases, we retrieved data on 30 512 persons with RA registered in 1997-2015. Information on ILD and respiratory failure was obtained from the NPR. Information on age and sex for all Danish citizens was obtained from the Danish Civil Registration System. MTX and other medication purchases were retrieved from the Danish Prescription Registry. Associations between MTX and lung disease outcomes were analysed in Cox regression models with adjustment for age, calendar time, sex and other medications. Standardized incidence ratios (SIRs) of lung disease were calculated to compare the RA population with the general population. RESULTS: There was no increased risk of lung disease with MTX treatment [one or more purchases compared with no purchases; HR 1.00 (95% CI 0.78, 1.27) for ILD and 0.54 (95% CI 0.43, 0.67) for respiratory failure] at the 5 year follow-up. The SIR was three to four times higher for ILD in MTX-treated persons with RA, but similar to the whole RA population compared with the background population. CONCLUSION: Persons with RA had an increased risk of ILD compared with the general population, but there was no further increased risk associated with MTX treatment.

Risk of neuroinflammatory events in arthritis patients treated with tumour necrosis factor alpha inhibitors: a collaborative population-based cohort study from Denmark and Sweden.

OBJECTIVES: To investigate whether tumour necrosis factor alpha inhibitors (TNFis) are associated with an increased risk of neuroinflammatory diseases among patients with arthritic diseases. METHODS: Cohorts of patients with rheumatoid arthritis (RA, n=25 796), psoriatic arthritis (PsA, n=8586) and ankylosing spondylitis (AS, n=9527) who initiated a TNFi treatment year 2000-2017 were identified from nationwide clinical rheumatology registers in Sweden and Denmark. Information on demyelinating disease and inflammatory neuropathy diagnoses was retrieved from prospective linkage to National Patients Register. A Cox proportional hazard model was used to estimate HRs and 95% CI comparing TNFi exposed and non-exposed, by disease and country. RESULTS: Among 111 455 patients with RA, we identified 270 (Sweden) and 51 (Denmark) events (all types of neuroinflammatory diseases combined), corresponding to crude incidence rates (per 1000 person-years) of 0.37 (Sweden) and 0.39 (Denmark) in TNFi-treated patients vs 0.39 (Sweden) and 0.28 (Denmark) in unexposed patients, and an age-sex-calendar-period-adjusted HR (95% CI) of 0.97 (0.72 to 1.33) (Sweden) and 1.45 (0.74 to 2.81) (Denmark) in TNFi exposed compared with non-exposed patients. For a total of 64 065 AS/PsA patients, the corresponding numbers were: 196 and 32 events, crude incidence rates of 0.59 and 0.87 in TNFi-treated patients vs 0.40 and 0.19 in unexposed patients, and HRs of 1.50 (1.07 to 2.11) and 3.41 (1.30 to 8.96), for Sweden and Denmark, respectively. For multiple sclerosis, the patterns of HRs were similar. CONCLUSIONS: Use of TNFi in AS/PsA, but not in RA, was associated with increased risk of incident neuroinflammatory disease, though the absolute risk was below one in 1000 patients/year.

Predictors of treatment outcome in patients with paediatric onset multiple sclerosis.

BACKGROUND: Disease-modifying therapies (DMT) are increasingly used for children with multiple sclerosis (MS) even though most double-blinded randomized controlled trials evaluating efficacy, safety and dosing strategy of a specific drug have included adults. OBJECTIVE: To investigate predictors of treatment outcomes in patients with paediatric onset MS treated with DMTs. METHODS: Prospective cohort study from the nationwide Danish Multiple Sclerosis Registry including all patients with a MS diagnosis who initiated treatment with an approved DMT before the age of 18 (N = 137) and followed until their 25th birthday. Selected baseline predictors were tested in univariate and multivariate regression models. RESULTS: Multivariate analyses showed that being female and having disease duration for 2 or more years prior to DMT initiation predicted a higher relapse rate. In addition, disease duration and baseline expanded disability status scale (EDSS) predicted both confirmed disability worsening and improvement. We found no difference in treatment outcome between children with MS onset before and after the age of 13 years. CONCLUSIONS: The efficacy of DMT in paediatric onset MS patients is comparable to that seen in adult onset MS patients. Earlier treatment start is associated with a beneficial prognosis in the paediatric cohort.

Intake of dietary fibre, red and processed meat and risk of late-onset Chronic Inflammatory Diseases: A prospective Danish study on the "diet, cancer and health" cohort.

Background: Human and animal studies support the involvement of diet in the development of CID -chronic inflammatory diseases such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, psoriatic arthritis, and multiple sclerosis. Objective: This cohort study aimed to investigate the association between intake of fibre, red and processed meat, and occurrence of late-onset CID (50+ years of age) in the DCH: Danish Diet, Cancer and Health cohort. We hypothesised that risk of late-onset CID would be lower among those with high intake of fibre and/or low intake of meat compared to individuals with low fibre and/or high meat intake. Methods: The DCH recruited 56,468 individuals, aged 50-64 years, between 1993 and 1997. At recruitment, diet intake was registered using food frequency questionnaires as well as lifestyle factors in 56,075 persons. Exposure variables were generated as sex-adjusted tertiles of fibre and meat (g/day). Development of CIDs was identified in national registries. Hazard ratios (HR) of late-onset CIDs (adjusted for age, sex, energy intake, alcohol, smoking, education, comorbidity, and civil status) were estimated for all three exposure variables. Results: During follow-up of 1,123,754 years (median (Interquartile range) = 22.2 (20.1-23.1)), 1,758 (3.1%) participants developed at least one CID. The adjusted HRs for developing CID (low fibre 1.04 [0.89-1.22] and medium fibre 1.04 [0.91-1.18] (high fibre as reference), and medium meat 0.96 [0.86-1.09] and high meat 0.94 [0.82-1.07] (low meat as reference)) or the individual diseases were not statistically significant. Conclusion: This large study did not support that a high intake of fibre and/or a low intake of meat had a high impact on the risk of late-onset CID.

Reduced Complications Following Implementation of Laparoscopic Hysterectomy: A Danish Population-based Cohort Study of Minimally Invasive Benign Gynecologic Surgery between 2004 and 2018.

STUDY OBJECTIVE: To monitor and report nationwide changes in the rates of and complications after different methods for benign hysterectomy, operative hysteroscopy, myomectomy, and embolization in Denmark. To report the national mortality after benign hysterectomy DESIGN: National prospective, observational cohort study. SETTING: The Danish Hysterectomy and Hysteroscopy Database. PATIENTS: Women undergoing surgery for benign gynecologic diseases: 64 818 hysterectomies, 84 175 hysteroscopies, 4016 myomectomies, and 1209 embolizations in Denmark between 2004 and 2018. INTERVENTIONS: National meetings with representatives from all departments, annual working reports of institutional complication rates, workshops, and national guideline initiative to improve minimally invasive surgical methods. MEASUREMENTS AND MAIN RESULTS: Rates of the different methods and complications after each method with follow-up to 5 years as recorded by the database directly in the National Patient Registry. Nationwide, a decline in the use of hysterectomy, myomectomy, embolizations, and endometrial ablation. The total short-term complications were 9.8%, 7.5%, 8.9%, and 2.7% respectively, however, with a persistent risk of approximately 20% for recurrent operations within 5 years after endometrial ablation. Initially, we urged for increased use of vaginal hysterectomy, but only reached 36%. From 2010, we urged for reducing abdominal hysterectomies by implementing laparoscopic hysterectomy and reached 72% laparoscopic and robotic procedures. Since 2015, we used coring or contained morcellation for removal of large uterus at laparoscopic hysterectomy. The major and minor complication rates (modified Clavien-Dindo classification) were reduced significantly from 8.1% to 4.1% and 9.9% to 5.7% respectively. Mortality after benign hysterectomy was 0.27‰. The odds ratio for major complications after abdominal hysterectomy was 1.66 (1.52-1.81) compared to minimally invasive hysterectomy independent of the length of stay, high-volume departments, indications, comorbidity, age, and calendar year. CONCLUSION: Fifteen years with a national database has resulted in a marked quality improvement. Denmark has 85% minimally invasive hysterectomies and has reduced the number of major complications by 50%.

Intake of Red and Processed Meat, Use of Non-Steroid Anti-Inflammatory Drugs, Genetic Variants and Risk of Colorectal Cancer: A Prospective Study of the Danish "Diet, Cancer and Health" Cohort.

Red and processed meat have been associated with increased risk of colorectal cancer (CRC), whereas long-term use of non-steroid anti-inflammatory drugs (NSAIDs) may reduce the risk. The aim was to investigate potential interactions between meat intake, NSAID use, and gene variants in fatty acid metabolism and NSAID pathways in relation to the risk of CRC. A nested case-cohort study of 1038 CRC cases and 1857 randomly selected participants from the Danish prospective "Diet, Cancer and Health" study encompassing 57,053 persons was performed using the Cox proportional hazard model. Gene variants in SLC25A20, PRKAB1, LPCAT1, PLA2G4A, ALOX5, PTGER3, TP53, CCAT2, TCF7L2, and BCL2 were investigated. CCAT2 rs6983267 was associated with the risk of CRC per se (p < 0.01). Statistically significant interactions were found between intake of red and processed meat and CCAT2 rs6983267, TP53 rs1042522, LPCAT1 rs7737692, SLC25A20 rs7623023 (pinteraction = 0.04, 0.04, 0.02, 0.03, respectively), and the use of NSAID and alcohol intake and TP53 rs1042522 (pinteraction = 0.04, 0.04, respectively) in relation to the risk of CRC. No other consistent associations or interactions were found. This study replicated an association of CCAT2 rs6983267 with CRC and an interaction between TP53 rs1042522 and NSAID in relation to CRC. Interactions between genetic variants in fatty acid metabolism and NSAID pathways and the intake of red and processed meat were found. Our results suggest that meat intake and NSAID use affect the same carcinogenic mechanisms. All new findings should be sought replicated in independent prospective studies. Future studies on the cancer-protective effects of aspirin/NSAID should include gene and meat assessments.

The Manchester-Fothergill procedure versus vaginal hysterectomy with uterosacral ligament suspension: a matched historical cohort study.

INTRODUCTION AND HYPOTHESIS: This study compares vaginal hysterectomy with uterosacral ligament suspension (VH) with the Manchester-Fothergill procedure (MP) for treating pelvic organ prolapse (POP) in the apical compartment. METHODS: Our matched historical cohort study is based on data from four Danish databases and the corresponding electronic medical records. Patients with POP surgically treated with VH (n = 295) or the MP (n = 295) in between 2010 and 2014 were matched for age and preoperative POP stage in the apical compartment. The main outcome was recurrent or de novo POP in any compartment. Secondary outcomes were recurrent or de novo POP in each compartment and complications. RESULTS: The risk of recurrent or de novo POP in any compartment was higher after VH (18.3%) compared with the MP (7.8%) (Hazard ratio, HR = 2.5, 95% confidence interval (CI): 1.3-4.8). Recurrence in the apical compartment occurred in 5.1% after VH vs. 0.3% after the MP (hazard ratio (HR) = 10.0, 95% confidence interval (CI) 1.3-78.1). In the anterior compartment, rates of recurrent or de novo POP were 11.2% after VH vs. 4.1% after the MP (HR = 3.5, 95% CI 1.4-8.7) and in the posterior compartment 12.9% vs. 4.7% (HR = 2.6, 95% CI 1.3-5.4), respectively. There were more perioperative complications (2.7 vs. 0%, p = 0.007) and postoperative intra-abdominal bleeding (2 vs. 0%, p = 0.03) after VH. CONCLUSIONS: This study shows that the MP is superior to VH; if there is no other indication for hysterectomy, the MP should be preferred to VH for surgical treatment of POP in the apical compartment.

Alcohol-related breast cancer in postmenopausal women - effect of CYP19A1, PPARG and PPARGC1A polymorphisms on female sex-hormone levels and interaction with alcohol consumption and NSAID usage in a nested case-control study and a randomised controlled trial.

BACKGROUND: Alcohol consumption is associated with increased risk of breast cancer (BC), and the underlying mechanism is thought to be sex-hormone driven. In vitro and observational studies suggest a mechanism involving peroxisome proliferator-activated receptor gamma (PPARγ) in a complex with peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) and interaction with aromatase (encoded by CYP19A1). Use of non-steroidal anti-inflammatory drugs (NSAID) may also affect circulating sex-hormone levels by modifying PPARγ activity. METHODS: In the present study we assessed whether genetic variation in CYP19A1 is associated with risk of BC in a case-control study group nested within the Danish "Diet, Cancer and Health" cohort (ncases = 687 and ncontrols = 687) and searched for gene-gene interaction between CYP19A1 and PPARGC1A, and CYP19A1 and PPARG, and gene-alcohol and gene-NSAID interactions. Association between the CYP19A1 polymorphisms and hormone levels was also examined among 339 non-HRT users. Incidence rate ratios were calculated based on Cox' proportional hazards model. Furthermore, we performed a pilot randomised controlled trial to determine the effect of the PPARG Pro(12)Ala polymorphism and the PPARγ stimulator Ibuprofen on sex-hormone levels following alcohol intake in postmenopausal women (n = 25) using linear regression. RESULTS: Genetic variations in CYP19A1 were associated with hormone levels (estrone: P rs11070844 = 0.009, estrone sulphate: P rs11070844 = 0.01, P rs749292 = 0.004, P rs1062033 = 0.007 and P rs10519297 = 0.03, and sex hormone-binding globulin (SHBG): P rs3751591 = 0.03) and interacted with alcohol intake in relation to hormone levels (estrone sulphate: P interaction/rs2008691 = 0.02 and P interaction/rs1062033= 0.03, and SHBG: P interaction/rs11070844 = 0.03). CYP19A1/rs3751591 was both associated with SHBG levels (P = 0.03) and with risk of BC (Incidence Rate Ratio = 2.12; 95 % Confidence Interval: 1.02-4.43) such that homozygous variant allele carriers had increased levels of serum SHBG and were at increased risk of BC. Acute intake of alcohol decreased blood estrone (P = <0.0001), estrone sulphate (P = <0.0001), and SHBG (P = 0.009) levels, whereas Ibuprofen intake and PPARG Pro(12)Ala genotype had no effect on hormone levels. CONCLUSIONS: Our results suggest that genetically determined variation in CYP19A1 is associated with differences in sex hormone levels. However, the genetically determined differences in sex hormone levels were not convincingly associated with BC risk. The results therefore indicate that the genetically determined variation in CYP19A1 contributes little to BC risk and to alcohol-mediated BC risk. TRIAL REGISTRATION: NCT02463383, June 3, 2015.

Polymorphisms in ATP-binding cassette transporter genes and interaction with diet and life style factors in relation to colorectal cancer in a Danish prospective case-cohort study.

BACKGROUND AND AIMS: The ATP-binding cassette (ABC) transporter family transports various molecules across the enterocytes in the gut protecting the intestine against potentially harmful substances. Moreover, ABC transporters are involved in mucosal immune defence through interaction with cytokines. The study aimed to assess whether polymorphisms in ABCB1, ABCC2 and ABCG2 were associated with risk of colorectal cancer (CRC) and to investigate gene-environment (dietary factors, smoking and use of non-steroidal anti-inflammatory drugs) and gene-gene interactions between previously studied polymorphisms in IL1B and IL10 and ABC transporter genes in relation to CRC risk. MATERIALS AND METHODS: We used a Danish prospective case-cohort study of 1010 CRC cases and 1829 randomly selected participants from the Danish Diet, Cancer and Health cohort. Incidence rate ratios were calculated based on Cox' proportional hazards model. RESULTS: None of the polymorphisms were associated with CRC, but ABCB1 and ABCG2 haplotypes were associated with risk of CRC. ABCB1/rs1045642 interacted with intake of cereals and fiber (p-Value for interaction (P(int)) = 0.001 and 0.01, respectively). In a three-way analysis, both ABCB1/rs1045642 and ABCG2/rs2231137 in combination with IL10/rs3024505 interacted with fiber intake in relation to risk of CRC (P(int) = 0.0007 and 0.009). CONCLUSIONS: Our results suggest that the ABC transporters P-glycoprotein/multidrug resistance 1 and BRCP, in cooperation with IL-10, are involved in the biological mechanism underlying the protective effect of fiber intake in relation to CRC. These results should be replicated in other cohorts to rule out chance findings.

No association between HMOX1 and risk of colorectal cancer and no interaction with diet and lifestyle factors in a prospective Danish case-cohort study.

Red meat is a risk factor for colorectal cancer (CRC). We wanted to evaluate whether a functional polymorphism in the HMOX1 gene encoding heme oxygenase modifies risk of CRC or interacts with diet or lifestyle factors because this would identify heme or heme iron as a risk factor of CRC. The HMOX1 A-413T (rs2071746) was assessed in relation to risk of colorectal cancer (CRC) and interactions with diet (red meat, fish, fiber, cereals, fruit and vegetables) and lifestyle (use of non-steroidal anti-inflammatory drug and smoking status) were assessed in a case-cohort study of 928 CRC cases and a comparison group of 1726 randomly selected participants from a prospective study of 57,053 persons. No association between HMOX1 A-413T and CRC risk was found (TT vs. AA + TA; IRR = 1.15, 95% CI: 0.98-1.36, p = 0.10 for the adjusted estimate). No interactions were found between diet or lifestyle and HMOX1 A-413T. HMOX1 A-413T was not associated with CRC risk and no interactions with diet or lifestyle were identified in this large, prospective cohort with high meat intake. The results reproduced the previous findings from the same cohort and did not support a link between heme or heme iron and colorectal cancer. These results should be sought and replicated in other well-characterized cohorts with high meat intake.

Assisted reproductive technology treatment and risk of multiple sclerosis - a Danish cohort study.

OBJECTIVE: To compare the incidence of multiple sclerosis (MS) among women who had undergone assisted reproductive technology (ART) treatment with the women who had conceived a child without previous ART treatment. DESIGN: A register-based nationwide cohort study. PATIENT(S): Women with a first ovarian stimulation cycle before in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) (i.e., ART treatment) recorded in the Danish IVF register between 1996 and 2018; and women recorded in the Danish Medical Birth Register with the birth of their first child where date of conception is between 1996 and 2018. The cohort was observed until March 10, 2021. INTERVENTION(S): Mainly included IVF, ICSI, and fresh embryo transfer with hormone stimulation. MAIN OUTCOME MEASURES: A diagnosis of MS recorded in the Danish Multiple Sclerosis Registry. Crude and adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs) were calculated. RESULTS: A total of 585,716 women were included in the cohort of which 63,791 (11%) were exposed to at least one initiated IVF or ICSI cycle during the study period. Cycles with oocyte donation were excluded. The median follow-up time for the entire cohort was 12.4 years (Q1-Q3= 6.6-18.1). Compared with women conceiving without previous ART, ART treated women were older (31.8 years vs. 27.5 years), more often had a university degree (45% vs. 36%), and more often had received other fertility treatments than IVF or ICSI before cohort entry (26% vs. 3%). We found no association between incident MS and exposure to ART compared with non-ART pregnancy (aHR=1.08; 95 % CI, 0.93-1.25). An analysis following intention-to-treat principle on a propensity score matched sub cohort confirmed our results. In subgroup analysis including all ART cycles among the ART treated women, we found no increased risk of MS within 2 years of ART cycle start for successful ART cycles (pregnancy) compared with failed ART cycles (no pregnancy) (aHR=1.01; 95% CI, 0.58-1.76). We found a non-significant trend toward increased risk of MS with increasing numbers of ART cycles although based on small numbers. CONCLUSION(S): Women treated with ART do not seem to be at increased risk of developing MS compared with the women not exposed to ART.

Exposure to specific tumour necrosis factor inhibitors and risk of demyelinating and inflammatory neuropathy in cohorts of patients with inflammatory arthritis: a collaborative observational study across five Nordic rheumatology registers.

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.

Pregnancy-Related and Perinatal Outcomes in Women With Multiple Sclerosis: A Nationwide Danish Cross-sectional Study.

OBJECTIVE: To investigate differences in pregnancy-related and perinatal outcomes in women with multiple sclerosis (MS) compared with the general population. METHODS: We conducted a cross-sectional study including pregnancies from January 1, 1997, to December 31, 2016, to women registered in the Danish Multiple Sclerosis Registry (the study cohort). Pregnancy-related and perinatal outcomes were compared with a randomly selected subcohort of pregnancies from the general population (the comparison cohort) using logistic regression adjusted for possible confounders. RESULTS: In total, 2,930 pregnancies were included in the study cohort and 56,958 pregnancies in the comparison cohort. No differences were found in pregnancy-related complications (preeclampsia/gestational diabetes or placenta complications), emergency caesarean section (c-section), instrumental delivery, low Apgar score, stillbirth, preterm birth, or congenital malformations. Elective c-section (odds ratio [OR] 1.89 [95% confidence interval (CI) 1.65-2.16]), induced delivery (OR 1.15 [95% CI 1.01-1.31]), and being born small for gestational age (SGA) (OR 1.29 [95 %CI 1.04-1.60]) had a higher prevalence in the study cohort, whereas the prevalence of signs indicating asphyxia was lower in the study cohort (OR 0.87 [95% CI 0.78-0.97]) relative to the comparison cohort. CONCLUSION: We found a higher prevalence of elective c-sections, induced delivery, and infants being SGA among newborns to women with MS, whereas the prevalence of asphyxia was lower in the study cohort. There were no significant differences in severe adverse perinatal outcomes when comparing women with MS and their newborns with those of the general population.

Age and sex as determinants of treatment decisions in patients with relapsing-remitting MS.

BACKGROUND: . Most patients with relapsing-remitting multiple sclerosis (RRMS) are initially treated with moderate efficacy disease-modifying therapies (meDMTs), and only a smaller group of highly active patients are initiated on a high efficacy disease-modifying therapy (heDMT). Real-world data have shown that choosing a heDMT as the initial therapy in highly active RRMS patients is more effective than using a meDMT, and that in patients with breakthrough disease on a meDMT escalation of treatment to a heDMT is more effective than staying on the same or switching to another meDMT. The role of age and sex as determinants for selection of the initial treatment intensity, and for using escalation of treatment intensity in patients with relapse activity on treatment with meDMTs, is only partially known. METHODS: . We included all Danish patients with RRMS registered in The Danish Multiple Sclerosis Registry who began a DMT since 2014 and stratified the cohort according to sex and age < 40 and ≥ 40 years at first DMT treatment. We studied determinants, with emphasis on age and sex, for the primary choice of therapy, for adherence to the initial therapy and for treatment escalation. Based on existing literature and clinical relevance, we included the following potential confounders in the analyses: DMT efficacy, pre-treatment relapse activity, disease duration, Expanded Disability Status Scale (EDSS) score, and, in a subgroup, MRI activity. RESULTS: . With all covariates mutually adjusted, patient age was a strong decisive factor for choosing a heDMT with odds ratio 1.69 for starting a heDMT in patients < 40 years compared with patients ≥ 40 years. Men had odds ratio 1.53 for starting with a heDMT compared with women. The odds ratio of heDMT in patients with EDSS > 3 vs ≤ 3 was 3.49, and every additional relapse was associated with increased odds ratio 2.33 for heDMT. Patients were more adherent to the initial heDMTs than to the initial meDMTs. Patients above 40 years were more prone to stay on the initial treatment compared to patients below 40, regardless of whether the initial treatment was meDMT (p<0.001) or heDMT (p=0.008) (covariates mutually adjusted). Relapse activity resulted in escalation of therapy to a heDMT in 67% of patients aged < 40 years (N=273) and in 56% patients aged 40 years or above (N=159) (p=0.008), and younger patients had odds ratio 1.46 of escalating therapy compared to older patients. Male patients were more likely to have treatment escalation to heDMTs than female patients (odds ratio 2.03). CONCLUSION: . Age and sex appear to be independent determinants for the choice of the initial DMT and for the decision of treatment escalation in patients with breakthrough disease on a meDMT. It is unfortunate, if older age is a factor that make choice of a heDMT more unlikely, as many DMTs seems to be less efficacious in older patients.

Application of definitions for conversion to secondary progressive MS in a Danish nationwide population.

BACKGROUND: The number of patients with relapsing remitting multiple sclerosis (RRMS) who convert to secondary progressive (SP) MS is uncertain, and with emerging treatment options for SPMS, it is important to identify RRMS patients in transition to the SP phase. The objective of the present study was to characterize clinical parameters and use of disease modifying therapies in patients diagnosed with SPMS and RRMS patients already entered the SP phase by use of the Danish Multiple Sclerosis Registry (DMSR). METHODS: We used a cross-sectional design, including all living patients with MS as of June 30, 2020 from DMSR. First, we applied the MSBase definition of SPMS on all RRMS patients. Second, we applied the slightly modified inclusion criteria from the EXPAND clinical trial on patients with clinically confirmed SPMS and patients with RRMS fulfilling the MSBase definition of SPMS to identify SPMS patients recently progressed who may benefit from treatment with disease modifying therapy. We compared clinical characteristics and disease-modifying therapy use in the different patient groups. RESULTS: Among patients with clinically confirmed SPMS, application of a slightly modified EXPAND trial inclusion criteria for SPMS (m-EXPAND) captured patients who had converted to SPMS more recently and who had relapsed and initiated high-efficacy treatment more frequently. Moreover, our RRMS patients fulfilling the "SPMS"-criteria according to MSBase and recently progression according to m-EXPAND had similar characteristics and remarkably resembled the SPMS population in the EXPAND trial. CONCLUSION: Our results indicate that data-driven diagnostic definitions might help identify RRMS patients at risk for SPMS and we highlight the challenges and reluctance in diagnosing SPMS in clinical practice.