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Jan Hillert,1 Helmut Butzkueven,2,3 Melinda Magyari,4 Stig Wergeland,5,6 Nicholas Moore,7 Merja Soilu-Hänninen,8 Tjalf Ziemssen,9 Jens Kuhle,10 Luigi Pontieri,11 Lars Forsberg,1 Jan Harald Aarseth,5 Chao Zhu,2 Nicholas Sicignano,12 Vasili Mushnikov,13 Irene Bezemer,14 Meritxell Sabidó15 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 2Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; 3The Alfred Hospital, Melbourne, Victoria, Australia; 4Danish Multiple Sclerosis Center and Danish Multiple Sclerosis Registry, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 5Norwegian MS Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway; 6Department of Clinical Medicine, University of Bergen, Bergen, Norway; 7Bordeaux PharmacoEpi (BPE), Université de Bordeaux, Bordeaux, France; 8Turku University Hospital Neurocenter and Division of Clinical Neurosciences, University of Turku, Turku, Finland; 9Center of Clinical Neuroscience, Department of Neurology, University Clinic Carl Gustav Carus, Dresden University of Technology, Dresden, Germany; 10MS Centre and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Neurology, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland; 11Danish Multiple Sclerosis Registry, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 12Health ResearchTx LLC, Trevose, PA, USA; 13IQVIA, Helsinki, Finland; 14IQVIA, Amsterdam, the Netherlands; 15Merck Healthcare KGaA, Darmstadt, GermanyCorrespondence: Meritxell Sabidó, Merck Healthcare KGaA, Frankfurter Str. 250, Darmstadt, 64293, Germany, Email meritxell.sabido-espin@merckgroup.comPurpose: Understanding the long-term safety of disease-modifying therapies for multiple sclerosis (MS) in routine clinical practice can be undertaken through registry-based studies. However, variability of data quality across such sources poses the challenge of data fit for regulatory decision-making. CLARION, a non-interventional cohort safety study of cladribine tablets, combines aggregated data from MS registries/data sources, except in Germany (which utilizes primary data collection). We describe the application of key data quality indicators (DQIs) within CLARION to evaluate data quality over time, as recommended by the European Medicines Agency (EMA) guideline on registry-based studies.Methods: DQIs were defined with participating registries/sources; they were used to assess data quality according to the EMA Data Quality Framework, addressing consistency, accuracy, completeness, and study representativeness. DQIs were associated with potential remedial measures if data quality was not met. DQIs were summarized overall and for individual MS registries/data sources to November 1, 2022.Results: A total of 28 DQIs were analyzed using data from 5069 patients arising from eight MS registries/data sources and 14 countries. The Representativeness DQIs showed that 72.0% of patients were female, median age at MS diagnosis was 29.0 to 43.3 years, and 93.5% had relapsing-remitting MS. Consistency DQIs showed a total of 2899 patients had achieved at least two years of follow-up; 6.9% did not have any recorded visits during this timeframe. Discrepant values were assessed as part of Accuracy DQIs, and improvements over time were noted for recorded dates of MS onset and diagnosis. Regarding Completeness DQIs, 191/5069 (3.8%) patients were lost to follow-up.Conclusion: The application of 28 DQIs within the CLARION study has helped with understanding, not only intrinsic and question-specific determinants of data quality, but also tracking the quality of post-authorization safety data obtained from MS registries/data sources, thereby providing a foundation for the regulatory decision-making process.Keywords: cladribine tablets, multiple sclerosis, safety, fingolimod

Background: Interest in research on migrant health is increasing. The aim of this study is to review sample characteristics, study design, and outcomes (participation and retention rate) of longitudinal studies of the health of migrant populations, and to evaluate whether there are differences in outcomes related to study population and methodology. Methods: A literature search of prospective longitudinal studies on migrant health was performed in Medline and Web of Science, with 545 articles retrieved. Key informants were contacted when needed. After identification, screening, and eligibility, nine articles were included. Results: The most commonly studied topics were occupational and mental health (44.4%). Two studies had sample sizes of >5000 subjects, and 4 studies recruited families. One study targeted undocumented workers. Study duration was 2 years in 4 studies with 1 follow up wave. Two studies collected biological samples, and 2 used incentives. Higher participation (PR) and retention (RR) rates were found in studies of families, studies of groups perceived to be at high risk, studies where the researchers had close community ties, and studies where complete contact information had been obtained by the researchers. Lower PR and RR were associated with large time delays between waves and targeting irregular workers. Respondent driven sampling (RDS) was successful in reaching hidden populations. Conclusions: Identification of documented migrants through governmental records, early follow up, use of a variety of strategies (including digital technologies) to locate participants and maintaining personal relationships are the main factors influencing PR and RR. It is essential to consider them when planning research and to foresee and plan for the difficulties that might arise during a longitudinal study. [ABSTRACT FROM AUTHOR]

Background: As of September 2022, there was no globally recommended set of core data elements for use in multiple sclerosis (MS) healthcare and research. As a result, data harmonisation across observational data sources and scientific collaboration is limited., Objectives: To define and agree upon a core dataset for real-world data (RWD) in MS from observational registries and cohorts., Methods: A three-phase process approach was conducted combining a landscaping exercise with dedicated discussions within a global multi-stakeholder task force consisting of 20 experts in the field of MS and its RWD to define the Core Dataset., Results: A core dataset for MS consisting of 44 variables in eight categories was translated into a data dictionary that has been published and disseminated for emerging and existing registries and cohorts to use. Categories include variables on demographics and comorbidities (patient-specific data), disease history, disease status, relapses, magnetic resonance imaging (MRI) and treatment data (disease-specific data)., Conclusion: The MS Data Alliance Core Dataset guides emerging registries in their dataset definitions and speeds up and supports harmonisation across registries and initiatives. The straight-forward, time-efficient process using a dedicated global multi-stakeholder task force has proven to be effective to define a concise core dataset., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: T.P. has no other conflicts of interests to disclose than that she is funded by the Flemish Government under the ‘Special Research Fund (Bijzonder Onderzoeksfonds, BOF)’: BOF22OWB01. L.G. has no other conflicts of interests to disclose than that she is funded by the Flemish Government under the ‘Onderzoeksprogramma Artificiële Intelligentie Vlaanderen’. A.H. has no personal pecuniary interests to disclose, other than being an employee of the MS International Federation, which receives income from a range of corporate sponsors, recently including: Biogen, BristolMyersSquibb, Coloplast, Janssen, Merck, Viatris (formerly Mylan), Novartis, Roche and Sanofi – all of which is publicly disclosed. J.H. has received honoraria for serving on advisory boards for Biogen, Bristol-Myers-Squibb, Sanofi-Genzyme, Merck KGaA, Novartis, and Sandoz and speaker’s fees from Biogen, Novartis, Merck KGaA, Teva and Sanofi-Genzyme. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Bristol-Myers-Squibb, Merck KGaA, Novartis, Roche and Sanofi-Genzyme. His MS research was funded by the Swedish Research Council and the Swedish Brain foundation. H.S. works for the Accelerated Cure Project for MS (ACP), which has received grants, collaboration funding, payments for use of assets, or in-kind contributions from the following companies: EMD Serono, Sanofi/Genzyme, Biogen, Genentech, AbbVie, Octave, GlycoMinds, Pfizer, MedDay, AstraZeneca, Teva, Mallinckrodt, MSDx, Regeneron Genetics Centre, BC Platforms, and Celgene. A.C.P. has also received funding from the Patient-Centred Outcomes Research Institute (PCORI) and the National MS Society (NMSS). A.S. is on the editorial board for Neurology and serves as a consultant for Gryphon Bio, LLC. She has received research funding from the Department of Defence, MS Society of Canada, National MS Society and the Consortium of MS Centres. A.S. works for the NARCOMS Registry which is supported by the Consortium of MS Centres (CMSC) and the Foundation of the CMSC. R.M. has received no personal funding from any sources, the UK MS Register is funded by the MS Society, and has received funding for specific projects from Novartis, Sanofi-Genzyme, and Merck KGaA. A.S. has no personal pecuniary interests to disclose, other than being the lead of the German MS-Registry, which receives funding from a range of public and corporate sponsors, recently including: The German Innovation Fund (G-BA), The German MS Trust, The German Retirement Insurance, German MS Society, Biogen, Celgene (BMS), Merck, Novartis, Roche and Sanofi. P.D. is a full-time employee and a shareholder of Biogen. E.H.M.-L. and K.P. have no conflicts of interest to disclose. The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the EMA or one of its committees or working parties. P.I. has served on scientific advisory boards for Biogen Idec, Bayer, Teva, Roche, Merck Serono, Novartis and Genzyme and has received funding for travel and/or Speaker honoraria from Sanofi Aventis, Genzyme, Biogen Idec, Teva, Merck Serono, Alexion and Novartis. J.I.R. has received honoraria from Novartis as a scientific advisor. He has received travel grants and attended courses and conferences on behalf of Merck-Serono Argentina, Novartis, Roche, Sanofi-Genzyme, Biogen, Bayer and Teva. He receives unrestricted research funding from Novartis, Biogen, Roche, Merck and Sanofi. M.M. has served in scientific advisory board for Sanofi, Novartis, Merck, and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, Bristol-Myers Squibb. She received research support and support for congress participation from Biogen, Genzyme, Roche, Merck, Novartis. A.v.d.W. has received honoraria and unrestricted research funding from Novartis, Biogen, Roche, Merck and Sanofi. G.C. reports that he has received consulting and speaking fees from Novartis, Teva Pharmaceutical Industries Ltd, Teva Italia Srl, Sanofi-Genzyme Corporation, Genzyme Europe, Merck KGgA, Merck Serono SpA, Celgene Group, Biogen Idec, Biogen Italia Srl, F. Hoffman-La Roche, Roche SpA, Almirall SpA, Forward Pharma, Medday, and Excemed. L.M.P. has no conflict to report related to this work other than being the chair and the coordinator of the MSDA initiative, receiving funding from a range of corporate sponsors, including Biogen, Bristol-Myers Squibb, Janssen Pharmaceuticals, Merck, Novartis, and Roche. All other co-authors have no relevant competing interests to report. The authors declare that the funding sources did not influence the content of this work.

Introduction and Objective: The ConcePTION project aims to improve the way medication use during pregnancy is studied. This includes exploring the possibility of developing a distributed data processing and analysis infrastructure using a common data model that could form a foundational platform for future surveillance and research. A prerequisite would be that data from various data access providers (DAPs) can be harmonised according to an agreed set of standard rules concerning the structure and content of the data. To do so, a reference framework of core data elements (CDEs) recommended for primary data studies on drug safety during pregnancy was previously developed. The aim of this study was to assess the ability of several public and private DAPs using different primary data sources focusing on multiple sclerosis, as a pilot, to map their respective data variables and definitions with the CDE recommendations framework., Methods: Four pregnancy registries (Gilenya, Novartis; Aubagio, Sanofi; the Organization of Teratology Information Specialists [OTIS]; Aubagio, Sanofi; the Dutch Pregnancy Drug Register, Lareb), two enhanced pharmacovigilance programmes (Gilenya PRIM, Novartis; MAPLE-MS, Merck Healthcare KGaA) and four Teratology Information Services (UK TIS, Jerusalem TIS, Zerifin TIS, Swiss TIS) participated in the study. The ConcePTION primary data source CDE includes 51 items covering administrative functions, the description of pregnancy, maternal medical history, maternal illnesses arising in pregnancy, delivery details, and pregnancy and infant outcomes. For each variable in the CDE, the DAPs identified whether their variables were: identical to the one mentioned in the CDE; derived; similar but with a divergent definition; or not available., Results: The majority of the DAP data variables were either directly taken (85%, n = 305/357, range 73-94% between DAPs) or derived by combining different variables (12%, n = 42/357, range 0-24% between DAPs) to conform to the CDE variables and definitions. For very few of the DAP variables, alignment with the CDE items was not possible, either because of divergent definitions (1%, n = 3/357, range 0-2% between DAPs) or because the variables were not available (2%, n = 7/357, range 0-4% between DAPs)., Conclusions: Data access providers participating in this study presented a very high proportion of variables matching the CDE items, indicating that alignment of definitions and harmonisation of data analysis by different stakeholders to accelerate and strengthen pregnancy pharmacovigilance safety data analyses could be feasible., (© 2023. The Author(s).)

Purpose: Studies focusing on safety outcomes typically require large populations to comprehensively characterise the patient groups exposed to the medicines under investigation. However, there is often less information for subpopulations, such as pregnant or breastfeeding women, particularly when new medicines are considered. It is important to understand what information can be obtained from drug utilization studies (DUS) involving pregnant women in the early years postmarketing to provide supportive information for safety studies. The aims of this literature review are to (1) identify and review DUS for new medicines in pregnancy and breastfeeding and (2) list and summarise key information items to be reported in a DUS for new medicines in pregnancy., Methods: To identify postmarketing DUS of new prescription medicines or enantiomers in pregnancy, a systematic literature review was undertaken in PubMed and Embase between January 2015 and June 2022. In addition, the complete database of the ENCePP EU PAS Register was systematically searched to June 2022., Results: We identified 11 published DUS on new medicines in pregnancy from the ENCePP EU PAS Register and none from other sources. No studies on breastfeeding were identified. The 11 identified publications reported the medicine's use for the first 3 to 5 years after marketing approval. No reports assessed utilization in the first 3 years of approval. It was usual to issue interim reports annually (7 studies). All studies concerned conditions managed in ambulatory care (primary care and outpatient facilities) and included some primary care prescribing. Most ( n = 8) only had prescribing/dispensing data available at individual level for ambulatory care; outpatient prescribing was included in three of these studies Three studies held a limited amount of in-hospital prescribing data. A DUS can confirm at an early stage whether there are sufficient exposed pregnancies in available data sources to ensure a safety study is powered to detect a difference in the prevalence of adverse pregnancy or infant outcomes or if additional data from other databases are needed. A DUS may also help address methodological considerations such as selection of comparators. DUS can be performed embedded in a DUS in the general population, in a cohort of women of childbearing age, or in a cohort of pregnant women., Conclusion: This review summarises key aspects of a DUS for new medicines in pregnancy. DUS for new medicines in pregnancy should be planned before marketing, scheduled for the first 3 to 5 years after release, with annual interim/progress reports, and reported in peer-reviewed journals. By offering detailed information on data sources, exposure timing, prevalence and location, coprescribing, comorbidities, coexposures, and demographics, a DUS will offer a firm foundation for safety studies and will help to contextualize spontaneous reporting of serious adverse events., Competing Interests: S.L.L. is an employee of Novartis Pharmaceutical Company, A.G. of Janssen Biologics, J.S. of Bristol Myers Squibb, K.W. of GlaxoSmithKline, M.S. of Merck Healthcare, J.M. of Pfizer, and D.M.N. of Novo Nordisk., (Copyright © 2024 Sandra Lopez-Leon et al.)

Objective: The aim of this study was to assess the prevalence of low bone mass (osteopenia/osteoporosis), the factors associated with low bone mass, and the risk of fractures in Brazilian postmenopausal women living with HIV (WLH) in the Amazon region., Methods: This is a cohort study with a cross-sectional assessment at baseline conducted between March 2021 to August 2022 with 100 postmenopausal WLH undergoing antiretroviral therapy (ART) between 45 and 60 years of age and 100 age-matched HIV-negative women. Data on bone mineral density in the lumbar spine (LS) and femoral neck (FN) were collected using dual x-ray absorptiometry and the 10-year risk of hip and major osteoporotic fractures was assessed using the Fracture Risk Assessment tool (FRAX)., Results: The age of menopause onset occurred earlier in WLH ( P < 0.001). No differences in prevalence of osteoporosis and osteopenia in LS and FN were observed except for a lower T score in FN in WLH ( P = 0.039). The FRAX for major osteoporotic fracture and hip fracture were low in both groups, despite the mean of both FRAX scores was higher in WLH ( P < 0.001). Multivariate analysis showed that years since menopause onset, higher body mass index and higher FRAX major osteoporotic fracture were associated with the WLH group, while a higher frequency of physical activity was registered in the HIV-negative group. Multivariate analysis also showed that in WLH, a lower T score in FN was associated with years since menopause onset and body mass index and that the number of years since menopause onset was associated with a lower T score in the LS and a higher score in the FRAX hip fracture., Conclusions: Our findings show a high prevalence of low bone mass (osteopenia/osteoporosis) in Brazilian postmenopausal women from the Amazon region. Women living with HIV have higher FRAX scores than HIV-negative women and a lower T score in the FN., Competing Interests: Financial disclosures/conflicts of interest: None reported., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The Menopause Society.)

Purpose: The objective was to compare the risk of malignancies in real-world settings between exclusive immunosuppressant (IS) and immunomodulator (IM) use in multiple sclerosis (MS)., Methods: A nested case-control study was designed within a new-user cohort of all patients with MS who initiated a first IM or IS between 2008 and 2014, and without cancer history, using the information of the SNDS nationwide French claims database. Incident cancer cases were matched with up to six controls on year of birth, sex, initiation date, and disease risk score of cancer. A conditional logistic regression (odds ratio [95% confidence interval]) was used to compare exclusive IS versus IM use during follow-up and according to three use durations., Results: From 28 720 newly treated patients with MS, 407 incident cancers were observed during the follow-up with 2324 matched controls. A significant increase in cancer risk was observed for IS compared with IM (1.36 [1.05, 1.77]), with similar increases for the first 2 years of use but not for ≥2 years (1.06 [0.65, 1.75]). Similar increase was also observed for IS with indications other than MS (1.37 [1.04, 1.81]) but not for IS indicated only in MS (1.03 [0.45, 2.34])., Conclusions: Compared with IM, a 37% increase in cancer risk was observed for IS with indications other than MS and used for a short duration (≤2 years) but not for IS indicated only in MS. The absence of risk for prolonged exposure of IS with indications other than MS is not in favor of a causal relation with these drugs., (© 2023 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons Ltd.)

Objectives: As part of the CLARION study: (1) characterize the incidence of severe infections, herpes zoster, and malignancies in patients newly initiating cladribine or fingolimod for relapsing multiple sclerosis (MS); (2) estimate the incidence of severe lymphopenia among cladribine users; and (3) describe prior/subsequent disease-modifying therapy (DMT) in both cohorts., Methods: Patients were identified from seven participating MS registries/data sources. The incidence rate (IR) of each outcome per 1000 patient-years and its 95% confidence interval (95%CI) were estimated for cohorts using Poisson regression., Results: By cut-off date (01-April-2020), 742 cladribine and 867 fingolimod users were included. Mean follow-up was ∼1 year. The IR for severe infections from all contributing sources (except Denmark) was: cladribine, 7.37 (2.76,19.6); fingolimod, 6.55 (2.46,17.4). The corresponding IR for herpes zoster was 5.51 (1.78,17.1) and 3.27 (0.82,13.1), respectively, while values for opportunistic infections were 0 (0,6.76) and 1.63 (0.23,11.6), respectively. There were no events of progressive multifocal leukoencephalopathy in either cohort. The IR of severe lymphopenia was 63.9 (40.7,100.1) in 349 cladribine users from contributing sources. The IR of malignancies (cut-off date 01-April-2022) was 3.55 (1.59,7.90) for the cladribine cohort ( n  = 1035) and 3.55 (1.48,8.52) for the fingolimod cohort ( n  = 843) from three MS registries/data sources. In the combined data sources, 36.8% of cladribine and 27.4% of fingolimod users were DMT-naïve; after initiation of study treatment, 2.5% and 20.2% switched to another DMT, respectively., Conclusion: No new safety signal was observed in patients treated with cladribine tablets, although results are limited by a relatively short duration of follow-up.

This study estimated the incidence of malignancy in patients with multiple sclerosis (MS) versus a matched general population cohort in the Netherlands. Adults with a diagnosis of MS between 2006 and 2014 in the General Practitioner (GP) Database of the PHARMO Database Network with ≥ 1 year of patient history were matched to four non-MS individuals based on year of birth, sex, and GP practice. Patients were followed-up until the earliest malignancy diagnosis, death, or end of data collection. Age-adjusted incidence rates (IR) were measured overall and by cancer type. Standardized incidence ratios (SIR) were calculated as the ratio of stratification-specific IRs in the MS and non-MS cohorts. A total of 1,692 MS patients were matched to 6,768 non-MS patients. Age-adjusted IR of any malignancy, excluding non-melanoma skin cancer (n = 27), in the MS cohort was 48.3 (95%CI:30.1-66.5) per 10,000 PY. An increased incidence of any malignancy was observed in the MS cohort versus the non-MS cohort (SIR 1.8 [95%CI:1.1-2.5]). The most commonly observed malignancies in the MS cohort were breast cancer (n = 8; IR 20.4 [95%CI:6.3-34.5] per 10,000 PY) and melanoma (n = 6; IR 14.8 [95%CI:3.0-26.7] per 10,000 PY). The corresponding SIR observed between cohorts was 1.4 (95%CI:0.4-2.4) and 3.4 (95%CI:0.7-6.2), respectively. While the small increased incidence of malignancy in the MS cohort could be an artefact created by a different distribution of risk factors, an increased incidence of malignancy in MS patients in the Netherlands cannot be excluded., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: To describe the design of the CLARION post-approval safety study (EU PAS Register number, EUPAS24484) and provide a status update, including characteristics of patients included up to 1 May 2021., Methods: CLARION aims to further evaluate adverse events of special interest in patients who are newly initiating treatment with cladribine tablets for relapsing multiple sclerosis (MS). The study population consists of two cohorts: patients newly initiating cladribine tablets (cladribine cohort) and patients newly initiating oral fingolimod tablets (comparator fingolimod cohort), with an aim to include 8000 patients (4000 patients per cohort). The study relies on secondary use of data from pre-existing MS registries/data sources (except in Germany, where primary data collection is performed). The study is projected to last 15 years, with an anticipated 5-year inclusion period. Study outcomes are: malignancies; severe infections; tuberculosis; progressive multifocal leukoencephalopathy; other opportunistic infections; herpes zoster; severe lymphopenia (Grade ≥ 3); and treatment discontinuation., Results: As of 1 May 2021, 2393 patients were included in CLARION from seven participating MS registries/data sources (cladribine cohort, n  = 1266; fingolimod cohort, n  = 1127). The majority of patients are female (cladribine cohort, 72.5%; fingolimod cohort, 68.0%), with mean age at onset of MS of 31.5 years for the cladribine cohort and 30.9 years for the fingolimod cohort. The majority of patients in both cohorts had relapsing MS (cladribine cohort, 92.1%; fingolimod cohort, 93.5%)., Conclusion: By providing further information on adverse events of special interest during long-term follow-up, CLARION will assist neurologists and patients regarding treatment decision-making for management of relapsing MS.

Background and Purpose: Studies have not yet found conclusive results on the risk of cancer in patients with multiple sclerosis (MS). This study aimed to compare the incidence of all cancers and of specific types of cancer between MS patients and the general population by age and by sex., Methods: All prevalent MS patients identified between 2008 and 2014 in the nationwide French health care database (Système National des Données de Santé) and without history of malignancy were included in a cohort study and followed up until cancer occurrence, date of death, or 31 December 2015, whichever came first. MS patients were matched based on sex and year of birth to non-MS controls from the general population without cancer before index date. Incidence rate was reported per 100,000 person-years (PY), and risk of cancer was estimated by type of cancer, age, and sex using a Cox model (hazard ratio [HR] and its 95% confidence interval [CI])., Results: Overall, 576 cancers per 100,000 PY were observed in MS patients versus 424 per 100,000 PY in the control population. The risk of cancer was higher among MS patients than among population controls whether considered overall (HR = 1.36, 95% CI = 1.29-1.43) or for prostate (HR = 2.08, 95% CI = 1.68-2.58), colorectal and anal (HR = 1.35, 95% CI = 1.16-1.58), trachea, bronchus, and lung (HR = 2.36, 95% CI = 1.96-2.84), and to a lesser extent, breast cancer (HR = 1.12, 95% CI = 1.03-1.23)., Conclusions: MS patients were associated with increased risk of cancer compared to population controls., (© 2021 European Academy of Neurology.)

Background: The association between multiple sclerosis and malignancy is controversial and a current appraisal is needed., Objective: To determine the incidence of malignancy in patients with multiple sclerosis compared with the general population and in relation to disease-modifying therapy., Methods: Patients with multiple sclerosis (1995 - 2015) were matched by birth year and sex to individuals without multiple sclerosis in the general population. Patients with multiple sclerosis initiating disease-modifying therapy were evaluated using landmark period analysis. Malignancy risk was assessed by incidence rates, incidence rate ratios, and standardised incidence ratios., Results: The standardised incidence ratio of any malignancy (excluding non-melanoma skin cancer) in patients with multiple sclerosis ( n  = 10,557) was 0.96 (95% CI 0.88 - 1.06), and there was no increased incidence of specific malignancy types compared with the general population cohort ( n  = 103,761). At the 48-month landmark period, the age-adjusted incidence per 100,000 person-years of any malignancy (excluding non-melanoma skin cancer) was 436.7 (95% CI 361.0 - 512.4) in patients newly treated with immunomodulator-only and 675.1 (95% CI 130.4 - 1219.9) in patients newly treated with immunosuppressant-only., Conclusions: There was no increased incidence of malignancy overall or by type in patients with multiple sclerosis compared neither with the general population nor in relation to disease-modifying therapy., Competing Interests: Declaration of conflicting interests: MN, KV and LSS are salaried employees of Aarhus University/Aarhus University Hospital. The study was partially funded by the healthcare business of Merck KGaA, Darmstadt, Germany as a research grant given to and administered by Aarhus University, Denmark. CF, EB and MS are full-time employees of the healthcare business of Merck KGaA, Darmstadt, Germany. FS has served on scientific advisory boards, been on the steering committees of clinical trials, served as a consultant, received support for congress participation, received speaker honoraria, or received research support for his laboratory from Biogen, the healthcare business of Merck KGaA (Darmstadt, Germany), Novartis, Roche, Sanofi-Genzyme and Teva. MM has served on the scientific advisory board for AbbVie, Alexion, Biogen, the healthcare business of Merck KGaA (Darmstadt, Germany), Novartis, Roche and Sanofi, and has received honoraria for lecturing from Biogen, the healthcare business of Merck KGaA (Darmstadt, Germany), Novartis and Sanofi, and has received support for congress participation from Biogen, Genzyme, the healthcare business of Merck KGaA (Darmstadt, Germany) and Roche., (© The Author(s), 2021.)

Introduction: Pregnancy is widely accepted as a period when relapses of multiple sclerosis (MS) are decreased, with an increased risk of relapse in the first months postpartum. This systematic review evaluated relapses during pregnancy and postpartum, according to disease-modifying therapy (DMT) exposure before, during, and after pregnancy, and the influence of DMT on these outcomes., Methods: We searched Medline and EMBASE to identify relevant publications from November 2009 to 2019 along with references lists of selected articles. Publications were filtered and assessed by two independent reviewers to ensure appropriate data extraction., Results: Of 469 articles identified, 28 were included for analysis including 4739 pregnancies in 5324 patients. All five studies comparing natalizumab or fingolimod (high-efficacy DMTs) use preconception versus interferon beta, glatiramer acetate, or dimethyl fumarate, or no DMT suggested that there was a greater risk of relapse during pregnancy following withdrawal of the high-efficacy DMTs. Of 10 studies evaluating relapses during pregnancy, five studies found that continuing DMTs into early pregnancy reduced relapses compared to discontinuing treatment. DMT exposure preconception generally had no effect on postpartum relapses versus no DMT; however, natalizumab or fingolimod use preconception was associated with postpartum relapse versus no high-efficacy DMT in one study. DMT exposure during pregnancy was associated with fewer postpartum relapses versus no DMT exposure in four of seven studies, while three found no difference between groups., Conclusion: Results of this systematic review concerning women with relapsing MS show a complex and often conflicting picture regarding DMT exposure and relapses during and after pregnancy. Although our data are limited by variability between studies, there is some evidence suggesting the use of natalizumab or fingolimod preconception is associated with increased risk of relapses during pregnancy, highlighting the need for effective disease-management strategies in these especially high-risk patients., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: KH has received honoraria and research support from Bayer, Biogen, Merck Healthcare KGaA (Darmstadt, Germany), Novartis, Sanofi-Genzyme, and Teva. EVDC is an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA. MS is an employee of Merck Healthcare KGaA, Darmstadt, Germany., (© The Author(s), 2021.)

Background: Previous studies reported no increase in the prevalence of adverse pregnancy outcomes after exposure to interferon-beta (IFN-beta). However, no study has investigated if the prevalence of these outcomes after IFN-beta exposure is modified by maternal and newborn characteristics. Our objective was to describe the stratified prevalence of adverse pregnancy outcomes among women with multiple sclerosis (MS) exposed only to IFN-beta or unexposed to any MS disease modifying drugs (MSDMDs)., Methods: This population-based cohort study using Finnish (1996-2014) and Swedish (2005-2014) register data included pregnancies of women with MS exposed only to IFN-beta 6 months before or during pregnancy (n=718) or unexposed to MSDMDs (n=1397). The outcome prevalences were described stratified by maternal and newborn characteristics, with 95% confidence intervals (CIs). Confounder-adjusted analyses were performed if the prevalence results indicated modified effect of IFN-beta in specific strata., Results: The stratified analysis indicated that the prevalence of serious (anomaly or stillbirth) and other adverse pregnancy outcomes was similar among the exposed and unexposed, with no statistically significant difference. Among women treated for MS >5 years, serious adverse pregnancy outcomes occurred in 4.3% (95%CI: 1.9-8.3%) of pregnancies exposed only to IFN-beta 6 months before or during pregnancy and in 2.7% (95%CI: 1.2-5.0%) of unexposed pregnancies. The confounder adjusted analyses did not support the hypothesis that MS treatment duration before pregnancy would modify the risk of adverse pregnancy outcomes after exposure to IFN-beta 6 months before or during pregnancy., Conclusion: The prevalence of adverse pregnancy outcomes was not increased after IFN-beta exposure, when pregnancies of women with MS were stratified by maternal and newborn characteristics. The stratified results were similar to the unstratified results in the same population., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Achieving viral suppression (VS) in children is challenging despite the exponential increase in access to antiretroviral therapy (ART). We evaluated VS in children >1 year of age and adolescents 5 years after they had begun ART, in Manaus, Amazonas state, Brazil., Methods: HIV-infected, ART-naive children >1 year of age between 1999 and 2016 were eligible. Analysis was stratified by age at ART initiation: 1-5 y, >5-10 y, and >10-19 y. CD4+ T-cell count and viral load were assessed on arrival at the clinic, on ART initiation, and at 6 months, 1 year, 2 years, and 5 years after ART initiation. The primary outcome was a viral load <50 copies/mL 5 years after ART initiation., Results: Ultimately, 121 patients were included. The mean age at diagnosis was 4.8 years (SD 3.5), mean CD4% was 17.9 (SD 9.8), and mean viral load was 4.6 log10 copies/ml (SD 0.8). Five years after ART initiation, the overall VS rate was 46.9%. VS by patient age group was as follows: 36.6% for 1-5 y, 53.3% for >5-10 y, and 30% for >10-19 y. Almost all children (90,4%) showed an increase in CD4%+ T cell count. There were no statistically significant predictors for detecting children who do not achieve VS with treatment. VS remained below 65% in all the evaluated periods., Conclusions: Considerable immunological improvement is seen in children after ART initiation. Further efforts are needed to maintain adequate long-term VS levels and improve the survival of this vulnerable population.

Background: Our aim was to estimate and compare the prevalence of adverse pregnancy outcomes among pregnant women with multiple sclerosis (MS) exposed to interferon beta (IFNB) and among women with MS unexposed to any MS disease-modifying drug (MSDMD)., Methods: This cohort study used Finnish (1996-2014) and Swedish (2005-2014) national register data. Women with MS having IFNB dispensed 6 months before or during pregnancy as the only medication were considered as IFNB exposed (only IFNB-exposed), whereas women with MS unexposed to any MSDMD were considered unexposed (MSDMD-unexposed). Prevalence was described and compared using log-binomial or logistic regression and adjusted for potential confounders including maternal age and comorbidity., Results: Among 2831 pregnancies, 2.2% of the only IFNB-exposed and 4.0% of the MSDMD-unexposed women had serious adverse pregnancy outcomes [elective termination of pregnancy due to foetal anomaly (TOPFA), major congenital anomaly (MCA) in live, or stillbirth]. After adjustments, the prevalence of serious adverse pregnancy outcomes was lower among the only IFNB-exposed compared with the MSDMD-unexposed [relative risk 0.55, 95% confidence interval (CI) 0.31-0.96]. The prevalence of individual outcomes, including MCA, spontaneous abortions, and stillbirths was not increased with IFNB exposure. Women with MS exposed to IFNB appeared more likely to terminate their pregnancy for reasons other than foetal anomaly, compared with MSDMD-unexposed pregnant MS patients (odds ratio 1.71, 95% CI 1.06-2.78)., Conclusion: In this large cohort study, no increase in the prevalence of adverse pregnancy outcomes was observed in women with MS exposed to IFNB compared with MS patients unexposed to any MSDMDs. This study together with other evidence led to a change in the labels of the IFNB products in September 2019 in the European Union, and IFNB use today may be considered during pregnancy, if clinically needed., Competing Interests: Conflict of interest statement: Katja Hakkarainen is an employee of StatFinn & EPID Research which performs commissioned pharmacoepidemiological studies for several pharmaceutical companies. Rosa Juuti was at the time of conducting the study an employee of StatFinn & EPID Research which performs commissioned pharmacoepidemiological studies for several pharmaceutical companies. Sarah Burkill was at the time of conducting the study an employee at the Centre for Pharmacoepidemiology, which receive grants from several entities including pharmaceutical companies. Yvonne Geissbühler is an employee of Novartis Pharma AG. Meritxell Sabidó is an employee of Merck KGaA, Darmstadt, Germany. Catrinel Popescu is an employee and stockholder of Biogen. Kiliana Suzart-Woischnik is an employee of Bayer AG. Jan Hillert received unrestricted grants, honoraria for serving on advisory boards and/or speaker honoraria from Biogen, Sanofi-Genzyme, Novartis, Merck-Serono, Bayer-Schering, Teva and Biogen Idec. This MS research was funded by the Swedish Research Council and the Swedish Brain foundation. Miia Artama reports no disclosures. Auli Verkkoniemi-Ahola received investigator fees (Sanofi) and congress fee covering or honoraria for lectures or advisory boards (Biogen, Merck, Novartis, Roche, Sanofi-Genzyme, Grifols). Kjell-Morten Myhr received unrestricted grants and/or speaker honoraria and/or scientific advisory board honoraria from Almirall, Biogen, Genzyme, Merck, Novartis, Sanofi-Aventis, Roche and the Norwegian MS Society. Juha Mehtälä was at the time of conducting the study an employee of StatFinn & EPID Research which performs commissioned pharmacoepidemiological studies for several pharmaceutical companies. Shahram Bahmanyar is an employee at the Centre for Pharmacoepidemiology, which receives grants from several entities including pharmaceutical companies. Scott Montgomery received funding for MS research in the last 5 years from Roche, Novartis and AstraZeneca; and speaker’s honoraria, including from Teva. Pasi Korhonen was at the time of conducting the study an employee of StatFinn & EPID Research which performs commissioned pharmacoepidemiological studies for several pharmaceutical companies., (© The Author(s), 2020.)

Neurologists managing women with Multiple Sclerosis (MS) need information about the safety of disease modifying drugs (DMDs) during pregnancy. However, this knowledge is limited. The present study aims to summarize previous studies by performing a systematic review and meta-analyses. The terms "multiple sclerosis" combined with DMDs of interest and a broad profile for pregnancy terms were used to search Embase and Medline databases to identify relevant studies published from January 2000 to July 2019.1260 studies were identified and ten studies met our inclusion criteria. Pooled risk ratios (RR) of pregnancy and birth outcomes in pregnancies exposed to DMDs compared to those not exposed were calculated using a random effects model. For spontaneous abortion RR = 1.14, 95% CI 0.99-1.32, for preterm births RR = 0.93, 95% CI 0.72-1.21 and for major congenital malformations RR = 0.86, 95% CI 0.47-1.56. The most common major congenital malformations reported in MS patients exposed to MS drugs were atrial septal defect (ASD) (N = 4), polydactyly (N = 4) and club foot (N = 3), which are among the most prevalent birth defects observed in the general population. In conclusion, interferons, glatiramer acetate or natalizumab, do not appear to increase the risk for spontaneous abortions, pre-term birth or major congenital malformations. There were very few patients included that were exposed to fingolimod, azathioprine and rituximab; therefore, these results cannot be generalized across drugs. Future studies including internal comparators are needed to enable treating physicians and their patients to decide on the best treatment options.

Background: Family planning is an important consideration for women with multiple sclerosis (MS), who are often diagnosed during their reproductive years. Currently, limited data are available on pregnancy outcomes in patients exposed to interferon-beta (IFN-beta) before or during pregnancy. Here, we present the cumulative pregnancy exposure data and prevalence of pregnancy and infant outcomes in IFN-beta-exposed pregnant women with MS from the European IFN-beta Pregnancy Registry., Methods: Using spontaneous and solicited reports, the registry collected data from 26 countries of the European Economic Area, consisting of information on women with MS identifying themselves to one of the Marketing Authorisation Holders (Bayer, Biogen, Merck KGaA, and Novartis) or healthcare professionals as pregnant and exposed to IFN-beta during pregnancy or within 1 month before conception. The outcomes collected by the registry included ectopic pregnancies, spontaneous abortions, elective terminations, live, and stillbirths with or without congenital anomalies. The prevalence of pregnancy outcomes was put in context with those reported in the general population., Results: Between 2009 and 2017, the registry collected 948 pregnancy reports with a known pregnancy outcome. Overall, 82.0% (777/948) of pregnancies resulted in live birth without congenital anomaly. When comparing IFN-beta-exposed pregnancies with the general population, the prevalence of spontaneous abortions (10.7% vs. 10-21%) and congenital anomalies in live births (2.1% vs. 2.1-4.1%) were found to be within reported ranges., Conclusions: The data gathered from these pregnancy cases suggest no evidence that IFN-beta exposure before conception and/or during pregnancy adversely increases the rate of congenital anomalies or spontaneous abortions.

Objectives: International spread has contributed substantially to the high prevalence of antimicrobial resistant (AMR) Neisseria gonorrhoeae infections worldwide. We compared the prevalence of AMR gonococcal isolates among native persons to foreign-born (reporting country different from country of birth) persons, and describe the epidemiological and clinical characteristics of foreign-born patients and their associations to AMR., Methods: We analysed isolates and patient data reported to the European Gonococcal Antimicrobial Surveillance Programme (Euro-GASP) 2010-2014 (n=9529)., Results: Forty-three per cent of isolates had known country of birth and 17.2% of these were from persons born abroad. Almost 50% of foreign-born were from the WHO European Region (13.1% from non-European Union [EU] and the European Economic Area [EEA] countries). Compared with isolates from natives, isolates from foreign-born had a similar level (p>0.05) of azithromycin resistance (7.5% vs 7.2%), ciprofloxacin resistance (50.0% vs 46.3%) and of decreased susceptibility to ceftriaxone (1.9% vs 2.8%); a lower rate of cefixime resistance (5.7% vs 3.6%, p=0.02), and a higher proportion of isolates producing penicillinase (8.4% vs 11.7%, p=0.02). Among isolates from persons born outside EU/EEA, the level of decreased susceptibility to ceftriaxone was higher (1.8% vs 3.5%, p=0.02), particularly in those from the WHO Eastern Mediterranean Region and non-EU/EEA WHO European countries (1.9% vs 9.6% and 8.7%, respectively, p<0.01). In multivariable analysis, foreign-born patients with AMR isolates were more likely to be from non-EU/EEA WHO European countries (adjusted OR [aOR]: 3.2, 95% CI 1.8 to 5.8), WHO Eastern Mediterranean countries (aOR: 1.8, 95% CI 1.1 to 3.3) and heterosexual males (aOR: 1.8, 95% CI 1.2 to 2.7)., Conclusions: Importation of AMR strains remains an important threat in the EU/EEA. Research to improve understanding of sexual networks within foreign born and sexual tourism populations could help to inform effective tailor-made interventions. The Euro-GASP demonstrates the public health value of quality-assured surveillance of gonococcal AMR and the need for strengthened AMR surveillance, particularly in the non-EU/EEA WHO European Region., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Most metastatic colorectal cancer (mCRC) patients are elderly. This systematic review identifies and describes observational studies evaluating the influence of age on first-line treatment effectiveness in real-world practice., Methods: Medline and EMBASE were searched up to May 2016. The included studies were those that investigated first-line treatment of mCRC and reported age groups and overall survival (OS), progression-free survival (PFS) or overall response rate (ORR) were included. Studies published before 2008 were excluded. Study quality was assessed using the Newcastle-Ottawa Scale. Data were evaluated by age group (< 70 vs. ≥ 70 years; 65-75 vs. ≥ 75 years) and outcome. A pooled survival median was calculated for patients (cutoff = 70 years)., Results: In total, 11 articles with 11,063 patients were included. Four studies using a cutoff of 70 years of age reported OS and PFS, and two studies reported ORRs. In terms of OS, all studies showed a higher OS for those < 70 years of age than for those ≥ 70 years of age. PFS did not find differences by age. For ORRs, one study favoured the younger group, while the second study did not differ by age. Based on three studies, the pooled medians for  < 70 years of age and ≥ 70 years of age were the same for PFS (10.2) and were 27.0 and 22.9 for OS, respectively. All included studies were of high or acceptable quality., Conclusions: The results suggest that age has no effect on PFS. For ORR, the results were inconsistent between studies. Younger patients in general had better OS, which might be partly explained by more aggressive treatment. This treatment seemed not to be guided by performance status or number of metastatic sites.

Background: To evaluate the trends in AIDS detection and the AIDS-attributed death rate in Brazil between 2007 and 2015 and to determine the population characteristics associated with AIDS detection., Methods: Surveillance data including demographics, mode of HIV transmission, AIDS cases, and AIDS-attributed deaths were analysed. A logistic regression model was fitted to assess the trends in AIDS cases by mode of HIV transmission throughout the study period. A segmented Poisson regression model was used to assess changes in the trends of AIDS detection and mortality rates before (2007-2014) and after (2015) the introduction of the Test and Treat Initiative., Results: In the segmented Poisson regression, the decline in the AIDS detection rate from 2007 to 2014 was 2.0% annually (i.e., the odds ratio (OR) for annual decline was 0.98 (95% [CI: 0.98-1.00, p-value < 0.001). The observed AIDS detection rate in 2015 was 7.7 cases per 100,000, which was 60% lower than the regression estimate of 19.8 for the hypothetical absence of the Test and Treat Initiative. The reduction in AIDS-attributed deaths from 2007 to 2014 was 8.0% annually (i.e., the OR for annual decline was 0.92 (95% [CI: 0.91-0.95, p-value < 0.001). The observed AIDS mortality rate in 2015 was 0.49 cases per 100,000, which was 73% lower than the regression estimate of 2.1 for the hypothetical absence of the Test and Treat Initiative in 2015., Conclusions: Our results reveal a fairly stable AIDS detection rate from 2007 to 2014, with a sudden significant drop in 2015. This drop may be related to the increasing trends in rapid testing, the number of new HIV diagnoses, the number of patients on antiretroviral therapy (ART), and a median CD4 count at ART enrolment. Further evaluation of the effects of the Test and Treat Initiative on AIDS diagnosis and mortality is needed and must be strengthened with additional data from subsequent years.

Background: Relapsing-remitting multiple sclerosis (RRMS) has a major impact on affected patients; therefore, improved understanding of RRMS is important, particularly in the context of real-world evidence., Objectives: To develop and validate algorithms for identifying patients with RRMS in both unstructured clinical notes found in electronic health records (EHRs) and structured/coded health care claims data., Methods: US Integrated Delivery Network data (2010-2014) were queried for study inclusion criteria (possible multiple sclerosis [MS] base cohort): one or more MS diagnosis code, patients aged 18 years or older, 1 year or more baseline history, and no other demyelinating diseases. Sets of algorithms were developed to search narrative text of unstructured clinical notes (EHR clinical notes-based algorithms) and structured/coded data (claims-based algorithms) to identify adult patients with RRMS, excluding patients with evidence of progressive MS. Medical records were reviewed manually for algorithm validation. Positive predictive value was calculated for both EHR clinical notes-based and claims-based algorithms., Results: From a sample of 5308 patients with possible MS, 837 patients with RRMS were identified using only the EHR clinical notes-based algorithms and 2271 patients were identified using only the claims-based algorithms; 779 patients were identified using both algorithms. The positive predictive value was 99.1% (95% confidence interval [CI], 94.2%-100%) for the EHR clinical notes-based algorithms and 94.6% (95% CI, 89.1%-97.8%) to 94.9% (95% CI, 89.8%-97.9%) for the claims-based algorithms., Conclusions: The algorithms evaluated in this study identified a real-world cohort of patients with RRMS without evidence of progressive MS that can be studied in clinical research with confidence., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Introduction: Previous studies suggest that multiple sclerosis (MS) patients have a greater stroke risk than the general population but there is limited evidence of stroke risk in patients receiving disease-modifying treatment. We assessed stroke risk in MS patients treated with subcutaneous interferon-β1a (sc IFN-β1a) using pooled data from clinical trials and post-marketing surveillance., Methods: Seventeen phase II-IV Merck KGaA-sponsored trials of sc IFN-β1a were assessed to estimate the stroke incidence rate (IR) and IR ratio (IRR) per 100 patient-years (PY), and associated 95% confidence intervals (CI). The association of treatment duration with stroke was assessed through a Cox model. IR, IRR, and hazard ratio (HR) were adjusted by age, sex, presence of any comorbidity, and MS duration. Individual case safety reports were retrieved from the Global Patient Safety Database. The reporting rates of stroke were calculated and classified as medically confirmed or non-medically confirmed according to the source of each report., Results: In 17 clinical trials, 4412 patients were treated with sc IFN-β1a for a total of 10,622 PY and 1055 patients with placebo for 2005 PY. The IR/100 PY (95% CI) of stroke was 0.025 (0.004, 0.150) in sc IFN-β1a patients and 0.051 (0.008, 0.349) in placebo patients. The IRR for sc IFN-β1a vs placebo was 0.486 (0.238, 0.995) and the HR was 0.496 (0.235, 1.043) for time to stroke-related event for sc IFN-β1a treatment at any dose compared with placebo. Among sc IFN-β1a patients, the IRR in those treated for < 2 years was 0.602 (0.159, 2.277) and for ≥ 2 years 0.469 (0.196, 1.124). Analysis of the safety database showed that the overall reporting rate for stroke was 13.286/10,000 PY., Conclusion: Safety data from both clinical trial and post-marketing settings indicate that treatment with sc IFN-β1a does not increase stroke risk in patients with MS., Funding: Merck KGaA, Darmstadt, Germany.