Association between clinic-level quality of care and patient-level outcomes in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) quality of care guidelines are consensus-based. The effectiveness of the recommendations is unknown. OBJECTIVE: To determine whether clinic-level quality of care affects clinical and patient-reported outcomes. METHODS: This nationwide observational cohort study included patients with adult-onset MS in the Swedish MS registry with disease onset 2005-2015. Clinic-level quality of care was measured by four indicators: visit density, magnetic resonance imaging (MRI) density, mean time to commencement of disease-modifying therapy, and data completeness. Outcomes were Expanded Disability Status Scale (EDSS) and patient-reported symptoms measured by the Multiple Sclerosis Impact Scale (MSIS-29). Analyses were adjusted for individual patient characteristics and disease-modifying therapy exposure. RESULTS: In relapsing MS, all quality indicators benefitted EDSS and physical symptoms. Faster treatment, frequent visits, and higher data completeness benefitted psychological symptoms. After controlling for all indicators and individual treatment exposures, faster treatment remained independently associated with lower EDSS (-0.06, 95% confidence interval (CI): -0.01, -0.10) and more frequent visits were associated with milder physical symptoms (MSIS-29 physical score: -16.2%, 95% CI: -1.8%, -29.5%). Clinic-level quality of care did not affect any outcomes in progressive-onset disease. CONCLUSION: Certain quality of care indicators correlated to disability and patient-reported outcomes in relapse-onset but not progressive-onset disease. Future guidelines should consider recommendations specific to disease course.

A comparative study of teriflunomide and dimethyl fumarate within the Swedish MS Registry.

BACKGROUND: Teriflunomide and dimethyl fumarate (DMF) are first-line disease-modifying treatments for multiple sclerosis with similar labels that are used in comparable populations. OBJECTIVES: The objective of this study was to compare the effectiveness and persistence of teriflunomide and DMF in a Swedish real-world setting. METHODS: All relapsing-remitting multiple sclerosis (RRMS) patients in the Swedish MS registry initiating teriflunomide or DMF were included in the analysis. The primary endpoint was treatment persistence. Propensity score matching was used to adjust comparisons for baseline confounders. RESULTS: A total of 353 teriflunomide patients were successfully matched to 353 DMF. There was no difference in the rate of overall treatment discontinuation by treatment group across the entire observation period (hazard ratio (HR) = 1.12; 95% confidence interval (CI) = 0.91-1.39; p = 0.277; reference = teriflunomide). Annualised relapse rate (ARR) was comparable (p = 0.237) between DMF (0.07; 95% CI = 0.05-0.10) and teriflunomide (0.09; 95% CI = 0.07-0.12). There was no difference in time to first on-treatment relapse (HR = 0.78; 95% CI = 0.50-1.21), disability progression (HR = 0.55; 95% CI = 0.27-1.12) or confirmed improvement (HR = 1.17; 95% CI = 0.57-2.36). CONCLUSION: This population-based real-world study reports similarities in treatment persistence, clinical effectiveness and quality of life outcomes between teriflunomide and dimethyl fumarate.

Increased rate of hospitalisation for COVID-19 among rituximab-treated multiple sclerosis patients: A study of the Swedish multiple sclerosis registry.

BACKGROUND: The primary objective of this study was to analyse the association between multiple sclerosis (MS) disease-modifying therapy (DMT) exposure and hospitalisation in patients infected with COVID-19. METHODS: Associations between MS DMT exposure and COVID-19 hospitalisation were analysed using univariable and multi-variable-clustered propensity score weighted logistic regression, where the models were clustered on the individual patients to control for patients contributing multiple COVID-19 episodes. FINDINGS: As of 18 January 2021, a total of 476 reported COVID-19 cases had been recorded in MS patients in the Swedish MS registry. Of these, 292 (61.3%) had confirmed COVID-19. The mean value (standard deviation (SD)) age at infection was 44.0 years (11.6). Of the 292 confirmed infections, 68 (23.2%) required hospitalisation. A total of 49 of the 164 confirmed COVID-19 patients on rituximab at baseline (29.9%) required hospitalisation, compared to a rate of 12.7% for all other DMTs combined. Rituximab in confirmed COVID-19 patients was associated with 2.95 times the odds of hospitalisation relative to any other DMT combined (odds ratio = 2.95; 95% confidence interval (CI) = 1.48-5.87). INTERPRETATION: Rituximab treatment, known to increase the risk of severe infections in general, also confers such a risk for MS patients with COVID-19, in comparison with other MS DMTs.

Cognitive function is a major determinant of income among multiple sclerosis patients in Sweden acting independently from physical disability.

BACKGROUND: In multiple sclerosis (MS), various aspects of cognitive function can be detrimentally affected, thus patients' employment and social functioning is commonly impacted. OBJECTIVE: To analyse income among MS patients in relation to cognitive function, assessed with the Symbol Digit Modalities Test (SDMT). METHODS: A cross-sectional study including 2080 MS patients was conducted linking national register-based data. Descriptive statistics and a two-part model were used to estimate differences in earnings and social benefits. RESULTS: MS patients in the highest SDMT score quartile earned more than twice annually compared to patients in the lowest quartile, whereas patients in the lowest quartile received three times more income through social benefits. The difference in earnings and benefits across the SDMT performance quartiles remained statistically significant after adjusting for various clinical and socio-demographic variables, including physical disability. The corrected prevalence ratios for MS patients in the highest quartile for having income from earnings and benefits were 1.40 (95% confidence interval (CI): 1.29-1.49) and 0.81 (95% CI: 0.71-0.90), respectively, when compared to the patients in the lowest quartile. CONCLUSION: Cognitive function affects the financial situation of MS patients negatively and independently of physical disability. This warrants cognitive testing as a routine measure in health care services for MS patients.

Predicting risk of secondary progression in multiple sclerosis: A nomogram.

OBJECTIVES: We aimed at designing a nomogram, a prediction tool, to predict the individual's risk of conversion to secondary progressive multiple sclerosis (SPMS) at the time of multiple sclerosis (MS) onset. METHODS: One derivation and three validation cohorts were established. The derivation cohort included 8825 relapsing-onset MS patients in Sweden. A nomogram was built based on a survival model with the best statistical fit and prediction accuracy. The nomogram was validated using data from 3967 patients in the British Columbia cohort, 176 patients in the ACROSS and 2355 patients in FREEDOMS/FREEDOMS II extension studies. RESULTS: Sex, calendar year of birth, first-recorded Expanded Disability Status Scale (EDSS) score, age at the first EDSS and age at disease onset showed significant predictive ability to estimate the risk of SPMS conversion at 10, 15 and 20 years. The nomogram reached 84% (95% confidence intervals (CIs): 83-85) internal and 77% (95% CI: 76-78), 77% (95% CI: 70-85) and 87% (95% CI: 84-89) external accuracy. CONCLUSIONS: The SPMS nomogram represents a much-needed complementary tool designed to assist in decision-making and patient counselling in the early phase of MS. The SPMS nomogram may improve outcomes by prompting timely and more efficacious treatment for those with a worse prognosis.

Multiple sclerosis treatment effects on plasma cytokine receptor levels.

Genetic variants within some cytokine receptor genes have been associated with MS susceptibility, including IL7RA and IL2RA. As these genes are expressed by cells targeted by immune-modulatory drugs, we explored the potential role of their gene products as biomarkers in monitoring MS treatment. We assessed the impact of natalizumab followed by fingolimod on the intra-individual changes of plasma protein levels of sIL-7Rα, sIL-2Rα and also sIL-6R and sgp130 in MS patients. During natalizumab treatment we observed a decline in sgp130 and sIL-7Rα levels, while subsequent fingolimod treatment lead to increased sgp130 and sIL-7Rα and decreased sIL-2Rα levels. In addition, during fingolimod treatment sIL-7Rα levels were increasing significantly more in patients homozygous for the MS risk genotype of rs6897932. We also observed an effect of the MS associated rs71624119 on sgp130 levels. These results may elucidate the pharmacodynamics of treatments and help identify biomarkers for MS outcomes.

Neutrophil activation signature in juvenile idiopathic arthritis indicates the presence of low-density granulocytes.

Objective: JIA is an autoimmune, inflammatory disease with involvement of innate and adaptive immune responses. However, the role of neutrophils in JIA pathogenesis remains unclear. This study aimed to identify and validate neutrophil gene expression signatures in JIA using public microarray datasets and new clinical samples. Methods: Three suitable datasets were analysed by significance analysis of microarray and Ingenuity. Neutrophils and peripheral blood mononuclear cells (PBMCs) were isolated from a new cohort of JIA patients and healthy paediatric controls (HCs). Gene expression was validated using quantitative PCR. Serum concentrations of proteins were measured using ELISA. Low-density granulocytes (LDGs) in JIA and HC PBMCs were quantified by flow cytometry using forward/side-scatter properties. Results: Ingenuity identified transcriptional regulation (false discovery rate < 0.05) by G-CSF, GM-CSF and IL-8 along with expression of neutrophil granule protein genes including ELANE, MPO, MMP8 and MMP9 in datasets from JIA PBMCs. LDG counts were elevated in JIA compared with HCs (2.5% vs 1.4%; P = 0.007). Transcripts for MMP8 (P = 0.005), MPO (P = 0.0124) and Fcγ Receptor 1B (FCγR1B) (P = 0.0417) were significantly higher in JIA compared with HC neutrophils. MMP9 protein levels were lower in systemic JIA patient sera [355.95 ng/ml (s.d. 250.03)] compared with HCs [675.41 ng/ml (s.d. 181.17); P = 0.007], but levels of elastase, MPO and MMP8 were not significantly different. Conclusion: LDGs are elevated in JIA and contribute to the transcriptomic profile of JIA PBMCs. JIA neutrophils express higher levels of MMP8 and FCGR1B, which may be implicated in disease pathology through the release of proteases and reactive oxygen metabolites, causing systemic inflammation and damage to joints.

A rare P2X7 variant Arg307Gln with absent pore formation function protects against neuroinflammation in multiple sclerosis.

Multiple sclerosis (MS) is a chronic relapsing-remitting inflammatory disease of the central nervous system characterized by oligodendrocyte damage, demyelination and neuronal death. Genetic association studies have shown a 2-fold or greater prevalence of the HLA-DRB1*1501 allele in the MS population compared with normal Caucasians. In discovery cohorts of Australasian patients with MS (total 2941 patients and 3008 controls), we examined the associations of 12 functional polymorphisms of P2X7, a microglial/macrophage receptor with proinflammatory effects when activated by extracellular adenosine triphosphate (ATP). In discovery cohorts, rs28360457, coding for Arg307Gln was associated with MS and combined analysis showed a 2-fold lower minor allele frequency compared with controls (1.11% for MS and 2.15% for controls, P = 0.0000071). Replication analysis of four independent European MS case-control cohorts (total 2140 cases and 2634 controls) confirmed this association [odds ratio (OR) = 0.69, P = 0.026]. A meta-analysis of all Australasian and European cohorts indicated that Arg307Gln confers a 1.8-fold protective effect on MS risk (OR = 0.57, P = 0.0000024). Fresh human monocytes heterozygous for Arg307Gln have >85% loss of 'pore' function of the P2X7 receptor measured by ATP-induced ethidium uptake. Analysis shows Arg307Gln always occurred with 270His suggesting a single 307Gln-270His haplotype that confers dominant negative effects on P2X7 function and protection against MS. Modeling based on the homologous zP2X4 receptor showed Arg307 is located in a region rich in basic residues located only 12 Å from the ligand binding site. Our data show the protective effect against MS of a rare genetic variant of P2RX7 with heterozygotes showing near absent proinflammatory 'pore' function.

Importance of early treatment initiation in the clinical course of multiple sclerosis.

OBJECTIVES: The aim of this study was to identify factors influencing the long-term clinical progression of multiple sclerosis (MS). A special objective was to investigate whether early treatment decisions influence outcome. METHODS: We included 639 patients diagnosed with MS from 2001 to 2007. The median follow-up time was 99 months (8.25 years). Cox regression models were applied to identify factors correlating with the outcome variable defined as time from treatment start to irreversible score 4 of the Expanded Disability Status Scale (EDSS). RESULTS: Patients initiated on treatment later had a greater risk of reaching EDSS 4 (hazard ratio of 1.074 (95% confidence interval (CI), 1.048-1.101)), increased by 7.4% for every year of delay in treatment start after MS onset. Patients who started treatment after 3 years from MS onset reached the outcome sooner with hazard ratio of 2.64 (95% CI, 1.71-4.08) compared with the patients who started treatment within 1 year from MS onset. Baseline EDSS and age at onset were found to be predictive factors of disability progression. CONCLUSION: Early treatment initiation was associated with a better clinical outcome. In addition, we confirmed the well-established prognostic factors of late age at onset and early disability.

Age Related Multiple Sclerosis Severity Score: Disability ranked by age.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS) is obtained by normalising the Expanded Disability Status Scale (EDSS) score for disease duration and has been a valuable tool in cross-sectional studies. OBJECTIVE: To assess whether use of age rather than the inherently ambiguous disease duration was a feasible approach. METHOD: We pooled disability data from three population-based cohorts and developed an Age Related Multiple Sclerosis Severity (ARMSS) score by ranking EDSS scores based on the patient's age at the time of assessment. We established the power to detect a difference between groups afforded by the ARMSS score and assessed its relative consistency over time. RESULTS: The study population included 26058 patients from Sweden ( n = 11846), Canada ( n = 6179) and the United Kingdom ( n = 8033). There was a moderate correlation between EDSS and disease duration ( r = 0.46, 95% confidence interval (CI): 0.45-0.47) and between EDSS and age ( r = 0.44, 95% CI: 0.43-0.45). The ARMSS scores showed comparable power to detect disability differences between groups to the updated and original MSSS. CONCLUSION: Since age is typically unbiased and readily obtained, and the ARMSS and MSSS were comparable, the ARMSS may provide a more versatile tool and could minimise study biases and loss of statistical power caused by inaccurate or missing onset dates.

Hereditary diffuse leukoencephalopathy with spheroids with phenotype of primary progressive multiple sclerosis.

BACKGROUND AND PURPOSE: Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is a devastating, hereditary white matter (WM) disorder with heterogeneous neuropsychiatric features. Colony stimulating factor 1 receptor (CSF1R) mutations were looked for in primary progressive multiple sclerosis (PPMS) patients and the clinical features of a family with a novel CSF1R mutation are reported. METHODS: CSF1R exons 12-22 in a cohort of 220 PPMS patients from the Swedish and Norwegian national multiple sclerosis registries were sequenced. RESULTS: One patient had a novel mutation, c.2562T>A; p.Asn854Lys, in the CSF1R gene. Her symptoms started at the age of 29 years with insidious onset of pyramidal weakness in the left leg. The cerebrospinal fluid examination showed four intrathecal immunoglobulin G bands. A magnetic resonance imaging scan performed 4 years after symptom onset demonstrated patchy deep WM lesions. She was diagnosed as having PPMS and treated with intramuscular interferon beta 1a. Due to slow disease progression, the development of memory decline and cerebellar signs, she was given subcutaneous interferon beta 1a without any benefit. The updated pedigree indicated that five siblings also had the CSF1R gene mutation; one was diagnosed with PPMS. Six more distant relatives also had a neurological disorder; four were clinically diagnosed with PPMS. CONCLUSIONS: Our study indicates that a chronic course of HDLS may mimic PPMS. Genetic testing for CSF1R gene mutations in PPMS cases with a positive family history of neurological disorders may establish the diagnosis of HDLS.

The influence of immunomodulatory treatment on the clinical course of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease of the central nervous system. One of the major questions concerning the clinical progression of MS, still insufficiently elaborated or confirmed, is if it can be slowed down or augmented by external factors. Immunomodulatory treatment is a disease modifiable factor shown to influence disease progression of various medical conditions. OBJECTIVE: To investigate if treatment affects the long-term clinical progression of MS, measured as time from diagnosis to score of 4 or higher of Expanded Disability Status Scale (EDSS). METHODS: Longitudinal, prospective data concerning treatment status and EDSS were collected by health professionals in the Swedish MS Registry. Study cohort comprised new diagnosed MS patients at Karolinska Hospital between 2001 and 2005. Survival analysis adjusted for suspected confounders was used with the outcome variable time from diagnosis to EDSS ≥ 4. RESULTS: Early treatment was correlated with longer time from diagnosis to EDSS ≥ 4 (HR: 1.77; 95 % CI: 1.15-2.73; p = 0.01). Additionally, the influence of the covariates-age at onset and the baseline EDSS, which were statistically significant with hazard ratios of 1.03 and 2.1, respectively, was found. CONCLUSION: Early treatment was associated with a better clinical outcome.

Multiple sclerosis registries in Europe - results of a systematic survey.

BACKGROUND: Identification of MS registries and databases that are currently in use in Europe as well as a detailed knowledge of their content and structure is important in order to facilitate comprehensive analysis and comparison of data. METHODS: National MS registries or databases were identified by literature search, from the results of the MS Barometer 2011 and by asking 33 national MS societies. A standardized questionnaire was developed and sent to the registries' leaders, followed by telephone interviews with them. RESULTS: Twenty registries were identified, with 13 completing the questionnaire and seven being interviewed by telephone. These registries differed widely for objectives, structure, collected data, and for patients and centres included. Despite this heterogeneity, common objectives of the registries were epidemiology (n=10), long-term therapy outcome (n=8), healthcare research (n=9) and support/basis for clinical trials (n=8). While physician-based outcome measures (EDSS) are used in all registries, data from patients' perspectives were only collected in six registries. CONCLUSIONS: The detailed information on a large number of national MS registries in Europe is a prerequisite to facilitating harmonized integration of existing data from MS registries and databases, as well as comprehensive analyses and comparison across European populations.

Co-morbidities increase the risk of disability pension among MS patients: a population-based nationwide cohort study.

BACKGROUND: Multiple sclerosis (MS) is a chronic and often disabling disease. In 2005, 62% of the MS patients in Sweden aged 16-65 years were on disability pension. The objective of this study is to investigate whether the presence of common co-morbidities increase MS patients' risk for disability pension. METHODS: This population-based cohort study included 4 519 MS patients and 4 972 174 non-MS patients who in 2005 were aged 17-64 years, lived in Sweden, and were not on disability pension. Patients with MS were identified in the nationwide in- and outpatient registers, while four different registers were used to construct three sets of measures of musculoskeletal, mental, and cardiovascular disorders. Time-dependent proportional hazard models with a five-year follow up were performed, adjusting for socio-demographic factors. RESULTS: All studied disorders were elevated among MS patients, regardless of type of measure used. MS patients with mental disorders had a higher risk for disability pension than MS patients with no such co-morbidities. Moreover, mental disorders had a synergistic influence on MS patients' risk for disability pension. These findings were also confirmed when conducting sensitivity analyses. Musculoskeletal disorders appeared to increase MS patients' risk for disability pension. The results with regard to musculoskeletal disorders' synergistic influence on disability pension were however inconclusive. Cardiovascular co-morbidity had no significant influence on MS-patients' risk for disability pension. CONCLUSIONS: Co-morbidities, especially mental disorders, significantly contribute to MS patients' risk of disability pension, a finding of relevance for MS management and treatment.

Identification of mutations in CUL7 in 3-M syndrome.

Intrauterine growth retardation is caused by maternal, fetal or placental factors that result in impaired endovascular trophoblast invasion and reduced placental perfusion. Although various causes of intrauterine growth retardation have been identified, most cases remain unexplained. Studying 29 families with 3-M syndrome (OMIM 273750), an autosomal recessive condition characterized by severe pre- and postnatal growth retardation, we first mapped the underlying gene to chromosome 6p21.1 and then identified 25 distinct mutations in the gene cullin 7 (CUL7). CUL7 assembles an E3 ubiquitin ligase complex containing Skp1, Fbx29 (also called Fbw8) and ROC1 and promotes ubiquitination. Using deletion analysis, we found that CUL7 uses its central region to interact with the Skp1-Fbx29 heterodimer. Functional studies indicated that the 3-M-associated CUL7 nonsense and missense mutations R1445X and H1464P, respectively, render CUL7 deficient in recruiting ROC1. These results suggest that impaired ubiquitination may have a role in the pathogenesis of intrauterine growth retardation in humans.

Socioeconomic status and quality of multiple sclerosis care in Sweden.

In Sweden's universal healthcare system, it is unknown whether people of higher socioeconomic status receive higher quality multiple sclerosis (MS) care. Using linked clinical and administrative data, we investigated the quality of care received by 4426 adults aged 23-60 with relapsing-remitting MS. In adjusted analyses, we demonstrated that higher premorbid educational attainment is associated with 4-12 % more frequent neurologist visits and MRI scans in the first four years post diagnosis, while higher premorbid income was associated with faster diagnosis-to-treatment times by 34-64 days. Neither education nor income were associated with time to diagnosis. This suggests that the more favourable MS outcomes observed for people of higher socioeconomic status may in part be related to higher quality care.

Big Multiple Sclerosis Data network: an international registry research network.

BACKGROUND: The Big Multiple Sclerosis Data (BMSD) network ( https://bigmsdata.org ) was initiated in 2014 and includes the national multiple sclerosis (MS) registries of the Czech Republic, Denmark, France, Italy, and Sweden as well as the international MSBase registry. BMSD has addressed the ethical, legal, technical, and governance-related challenges for data sharing and so far, published three scientific papers on pooled datasets as proof of concept for its collaborative design. DATA COLLECTION: Although BMSD registries operate independently on different platforms, similarities in variables, definitions and data structure allow joint analysis of data. Certain coordinated modifications in how the registries collect adverse event data have been implemented after BMSD consensus decisions, showing the ability to develop together. DATA MANAGEMENT: Scientific projects can be proposed by external sponsors via the coordinating centre and each registry decides independently on participation, respecting its governance structure. Research datasets are established in a project-to-project fashion and a project-specific data model is developed, based on a unifying core data model. To overcome challenges in data sharing, BMSD has developed procedures for federated data analysis. FUTURE PERSPECTIVES: Presently, BMSD is seeking a qualification opinion from the European Medicines Agency (EMA) to conduct post-authorization safety studies (PASS) and aims to pursue a qualification opinion also for post-authorization effectiveness studies (PAES). BMSD aspires to promote the advancement of real-world evidence research in the MS field.

High prevalence of sickness absence and disability pension among multiple sclerosis patients: a nationwide population-based study.

INTRODUCTION: Although multiple sclerosis (MS) often implies substantial disability, there is little knowledge about sick leave and disability pension among MS patients. OBJECTIVES: The purpose of this study was to estimate the prevalence rates of sick leave and disability pension among MS patients and to explore how socio-demographics are associated with such rates. METHODS: The register data of all people who lived in Sweden in 2005 and were 16-64 years old was used to identify 9721 MS patients and matched controls. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated and effect modifications were evaluated with Wald X(2) tests. RESULTS: In 2005, 61.7% of the MS patients were on partial or full disability pension compared to 14.2% among the controls. Of the others, 36.8% had ≥ 1 sick-leave spell for >14 days during that year. Socio-demographics were similarly associated with sick leave and disability pension among MS patients and controls, with the noteworthy exceptions that female gender and immigration status were less potent risk factors in the MS population (p<0.05). CONCLUSION: In spite of widespread access to modern health care including disease-modifying drugs, the majority of MS patients of working ages were on a disability pension. Strategies enabling MS patients to retain their footing in the labour market are needed.

Premorbid Sociodemographic Status and Multiple Sclerosis Outcomes in a Universal Health Care Context.

Importance: Multiple sclerosis (MS) severity may be informed by premorbid sociodemographic factors. Objective: To determine whether premorbid education, income, and marital status are associated with future MS disability and symptom severity, independent of treatment, in a universal health care context. Design, Setting, and Participants: This nationwide observational cohort study examined data from the Swedish MS Registry linked to national population registries from 2000 to 2020. Participants included people with MS onset from 2005 to 2015 and of working age (aged 23 to 59 years) 1 year and 5 years preceding disease onset. Exposures: Income quartile, educational attainment, and marital status measured at 1 and 5 years preceding disease onset. Main Outcome and Measures: Repeated measures of Expanded Disability Status Scale (EDSS) scores and patient-reported Multiple Sclerosis Impact Scale (MSIS-29) scores. Models were adjusted for age, sex, relapses, disease duration, and treatment exposure. Secondary analyses further adjusted for comorbidity. All analyses were stratified by disease course (relapse onset and progressive onset). Results: There were 4557 patients (mean [SD] age, 37.5 [9.3] years; 3136 [68.8%] female, 4195 [92.1%] relapse-onset MS) with sociodemographic data from 1-year preonset of MS. In relapse-onset MS, higher premorbid income and education correlated with lower disability (EDSS, -0.16 [95% CI, -0.12 to -0.20] points) per income quartile; EDSS, -0.47 [95% CI, -0.59 to -0.35] points if tertiary educated), physical symptoms (MSIS-29 physical subscore, -14% [95% CI, -11% to -18%] per income quartile; MSIS-29 physical subscore, -43% [95% CI, -35% to -50%] if tertiary educated), and psychological symptoms (MSIS-29 psychological subscore, -12% [95% CI, -9% to -16%] per income quartile; MSIS-29 psychological subscore, -25% [95% CI, -17% to -33%] if tertiary educated). Marital separation was associated with adverse outcomes (EDSS, 0.34 [95% CI, 0.18 to 0.51]; MSIS-29 physical subscore, 35% [95% CI, 12% to 62%]; MSIS-29 psychological subscore, 25% [95% CI, 8% to 46%]). In progressive-onset MS, higher income correlated with lower EDSS (-0.30 [95% CI, -0.48 to -0.11] points per income quartile) whereas education correlated with lower physical (-34% [95% CI, -53% to -7%]) and psychological symptoms (-33% [95% CI, -54% to -1%]). Estimates for 5-years preonset were comparable with 1-year preonset, as were the comorbidity-adjusted findings. Conclusions and relevance: In this cohort study of working-age adults with MS, premorbid income, education, and marital status correlated with disability and symptom severity in relapse-onset and progressive-onset MS, independent of treatment. These findings suggest that socioeconomic status may reflect both structural and individual determinants of health in MS.

Trajectories of disease-modifying therapies and associated sickness absence and disability pension among 1923 people with multiple sclerosis in Sweden.

BACKGROUND: There is limited information on the trajectories of disease-modifying therapy (DMT) use and their association with sickness absence and/or disability pension (SADP) among people with multiple sclerosis (PwMS). The objective of the study was to identify trajectories of DMT use over 10 years among PwMS, identify sociodemographic and clinical factors associated with the trajectories, and to assess the association between identified trajectories and SADP days. METHODS: A longitudinal register-based study was conducted, on a prospective data set linked across six nationwide registers, assessing treatment courses of PwMS with DMTs for the 10 years following multiple sclerosis (MS) onset. The study included 1923 PwMS with MS onset in 2007-2010, when aged 19-56 years. In each 6-month-period, their treatment was categorized as before treatment, high-efficacy, non-high-efficacy, or no DMT. Sequence analysis was performed to identify sequences of the treatment categories and cluster them into different DMT trajectories. Cluster belonging, in relation to demographic and clinical characteristics, was assessed through log-multinomial regression analysis. The association of trajectories/cluster-belonging with SADP net days was assessed using generalized estimating equation (GEE) models. RESULTS: Cluster analyses identified 4 trajectories of DMT use: long-term non-high-efficacy DMTs (38.6%), escalation to high-efficacy DMTs (31.2%), delayed start and escalation to high-efficacy DMTs (15.4%), and discontinued/ no DMT (14.2%). Age, MS type, expanded disability status scale (EDSS) score and the number of DMT switches were associated with cluster belonging. The youngest age group (18-25) were more likely to be in the escalation to high-efficacy cluster. People with primary progressive MS were more likely to be in the delayed start or discontinued/ no DMT cluster. Higher EDSS scores were associated to being in the other three clusters than in the long-term non-high-efficacy DMTs cluster. Higher number of DMT switches were associated with being in the escalation to high-efficacy DMTs cluster but less likely to be in the delayed start or discontinued/ no DMT clusters. Descriptive analyses showed a trend of fewer mean SADP days among PwMS using non-high-efficacy DMT than the other clusters about 9 years after onset. PwMS in the escalation to high-efficacy and discontinued/no DMT clusters had more SADP days. PwMS in the delayed start and escalation to high-efficacy DMTs cluster, started with fewer SADP days which increased over time. SADP days adjusted through GEE models showed trends comparable with the descriptive analysis. CONCLUSION: This study described the long-term real-world trajectories of DMT use among PwMS in Sweden using sequence analysis and showed the association of the trajectories with SADP days as well as sociodemographic and clinical characteristics.