Prevalence and Associated Clinical Characteristics of Walking-Related Motor, Cognitive, and Fatigability in Progressive Multiple Sclerosis: Baseline Results From the CogEx Study.

BACKGROUND: People with progressive multiple sclerosis (PMS) present motor (eg, walking) and cognitive impairments, and report fatigue. Fatigue encompasses fatigability which is objectively measured by the capacity to sustain a motor or cognitive task. OBJECTIVE: To investigate the prevalence of walking and cognitive fatigability (CF) and the associated clinical characteristics in a large sample of PMS patients. METHODS: PMS patients (25-65 years old) were included from 11 sites (Europe and North America), having cognitive impairment (1.28 standard deviation below normative data for the symbol digit modality test [SDMT]). Walking fatigability (WF) was assessed using the distance walk index (DWI) and CF using the SDMT (scores from the last 30 seconds compared to the first 30 seconds). Additional measures were: cognitive assessment-Brief International Cognitive Assessment for multiple sclerosis (MS), cardiorespiratory fitness, 6-minute walk, physical activity, depressive symptoms, perceived fatigue-Modified Fatigue Impact Scale (MFIS), MS impact-MSIS-29, and walking ability. RESULTS: Of 298 participants, 153 (51%) presented WF (DWI = -28.9 ± 22.1%) and 196 (66%) presented CF (-29.7 ± 15%). Clinical characteristics (EDSS, disease duration, and use of assistive device) were worse in patients with versus without WF. They also presented worse scores on MSIS-29 physical, MFIS total and physical and reduced physical capacity. CF patients scored better in the MSIS-29 physical and MFIS psychosocial, compared to non-CF group. Magnitude of CF and WF were not related. CONCLUSIONS: Half of the cognitively-impaired PMS population presented WF which was associated with higher disability, physical functions, and fatigue. There was a high prevalence of CF but without strong associations with clinical, cognitive, and physical functions. TRIAL REGISTRATION NUMBER: The "CogEx-study," www.clinicaltrial.gov identifier number: NCT03679468.

Time interval between the onset of symptoms and diagnosis of multiple sclerosis and the influential factors: A national registry-based study.

OBJECTIVE: The time to diagnosis of multiple sclerosis (MS) is of great importance for early treatment, thereby reducing the disability and burden of the disease. The purpose of this study was to determine the time from the onset of clinical symptoms to the diagnosis of MS and to evaluate the factors associated with a late diagnosis in Iranian MS patients. METHODS: The present cross-sectional study was conducted on patients with MS who were registered in the National MS Registry System of Iran (NMSRI). RESULTS: Overall, 23291 MS patients registered in 18 provinces of Iran were included in this study. The mean (standard deviation) interval between the onset of the disease and diagnosis of MS was 13.42 (32.40) months, and the median was one month. The diagnostic interval of 41.6% of patients was less than one month, and 14.8% of them had a one-month time to diagnosis. Patients with an age of onset below 18 years and those diagnosed after the age of 50 years had a longer time to diagnosis (P<0.001). Patients with primary progressive MS (PPMS) had the longest time to diagnose and those with relapsing-remitting MS (RRMS) had the shortest time (P<0.001). The results of negative binominal regression showed that the average rate of delay in diagnosis in women was 12% less than that in men. The average delay in diagnosis in patients with a positive family history of MS was 23% more than that in others. The rate of delay in the diagnosis of patients with PPMS and secondary progressive MS was 2.22 and 1.66 times higher, respectively, compared with RRMS. CONCLUSION: The findings of the present study revealed that more than half of the MS patients were diagnosed within a one-month interval from the symptom onset, which is an acceptable period. More attention should be paid to patients' access to medical facilities and MS specialists.

A national registry-based study of ethnic differences in people with multiple sclerosis in Iran.

OBJECTIVE: The relationship between MS and ethnicity has been understudied in the Middle East compared to the United States and Europe. As Iran as the highest prevalence of MS in the Middle East, we decided to investigate the demographic and clinical differences in people with MS (pwMS) from major ethnicities Iran. METHODS: In a cross-sectional study using data from National Multiple Sclerosis Registry in Iran. PwMS from six provinces were chosen and interviewed for determining their ethnicity. Persians (Fars), Kurds, Lurs, Azeris and Arabs with a clear ethnic background were included. Recorded data from the registry was used to compare the demographic and clinical features. RESULTS: A total of 4015 pwMS (74.2% female) were included in the study with an average age of 36.76 ± 9.68 years. Persians and Kurds had the highest percentage of pwMS in youngest and oldest age groups, respectively, with 2.9% and 5.7% (p<0.01). The highest average age of onset was seen in Persians (29.47 ± 8.89) and the lowest observed in Mazandaranis (26.82 ± 7.68, p<0.01). Azeris and Kurds had the highest proportions of pwMS diagnosed <18 and >55, at rates of 12% and 1.6%, respectively (p<0.01). There were statistically significant differences in distribution of phenotypes (p<0.01) and time to progression to secondary progressive MS (p<0.01) such that Persians had the highest rate of clinically isolated syndrome (CIS) at 19.3% and Arabs had highest rates of relapsing-remitting MS (86.2%) and secondary progressive MS (16.4%). Lurs, Azeris and Mazandaranis had significantly more patients progressing to secondary-progressive MS <5 years from diagnosis (p<0.01). There was a significant difference in number of relapses between the ethnicities (p<0.01) with Lurs having the highest proportion of participants reporting >4 relapses with 23.0% and Azeris having the highest percentage of pwMS reporting no relapse (53.0%). Kurds had the highest Expanded Disability Status Scale (EDSS) average at 2.93 ± 1.99 and Lurs had the lowest with 1.28 ± 1.25 (p<0.01). The differences in prevalence of positive family history for the whole cohort between ethnicities were significant (P=0.02), ranging from 12.8% in Kurds to 19.6% in Persians. CONCLUSION: We found Persians to have higher rates of pediatric MS and higher rates of CIS. Kurds and Lurs had higher and lower EDSS scores, respectively. Lurs and Persian had higher annual relapse rates. We also found lower rates of SPMS among Arabs and earlier progression to SPMS in Lurs, Azeris and Mazandaranis. Such differences highlight the importance of the potential role of ethnicities in diagnosis and prognosis of MS, especially considering their observation within the geographical limits of a single country.

Clinical characteristics and dynamics of disability progression in a cohort of patients with multiple sclerosis in Latvians.

There is wide variation in the time from the onset to secondary progressive multiple sclerosis (MS) and some controversy regarding the clinical characteristics of the courses (phenotypes) of MS. The present study aimed to characterize demographic and clinical factors that potentially influence long-term disability progression in the cohort of Latvian MS patients. A descriptive longitudinal incidence study was conducted using a cohort of 288 MS patients beginning in 2011 (disease duration from 1 to 51 years). Socio-demographic and clinical information from the first visit to 15/20 years was analysed in groups stratified by gender and visits at five-time points (the first visit; after a year or 2; after 5 ± 1 year; after 10 ± 2 years; after 15-20 years). Our study was dominated by patients from urban areas and non-smokers. The female/male ratio was 2.4:1; the distribution of clinical courses at the first visit was consistent with most European studies. The most common symptom at presentation in our study was optic manifestations, followed by sensory disturbances and motor deficits. In the Latvian study, gender was not a significant influencing factor on the rate of disease progression; however, patient age was statistically significantly associated with EDSS (Expanded Disability Status Scale) value at the first visit. Early clinical features of MS are important in predicting the disability accumulation of patients. Despite the small differences regarding the first MS symptoms, the disability outcomes in the cohort of Latvian patients are similar to other regions of the world.

Clinical and demographic characteristics of late-onset multiple sclerosis: LOMS-TR study.

OBJECTIVES: Multiple sclerosis (MS), which is known as a young-adult age disease, is called late-onset MS (LOMS) when it occurs at the age of 50 and older. In our study, we aimed to analyse the clinical and demographic characteristics, comorbidities, diagnostic and treatment challenges and prognosis of LOMS. METHODS: In a retrospective analysis of 136 patients diagnosed with multiple sclerosis (MS) after the age of 50, based on the 2017 McDonald criteria, and who were under observation in eight distinct MS centers across Turkey; demographic information, clinical characteristics of the disease, oligoclonal band (OCB) status, initial and current Expanded Disability Status Scale (EDSS) values, administered treatments, and the existence of spinal lesions on magnetic resonance imaging (MRI) were investigated. RESULTS: The mean age of the 136 patients was 60.96±6.42 years (51-79), the mean age at diagnosis was 54.94±4.30 years, and 89 (65.4 %) of the patients were female. Most of the cases, 61.1 % (83) had at least one comorbidity. In 97 patients who underwent lumbar puncture (LP), OCB positivity was observed in 63.6 %. In 114 patients (83.8 %), spinal lesions were detected on MRI. Eighty-seven patients had relapsing-remitting MS (RRMS) (64 %), 27 patients had secondary progressive MS (SPMS) (19.9 %), and 22 patients had primary progressive MS (PPMS) (16.2 %). The mean EDSS at the time of diagnosis was 2.44±1.46, and the mean current EDSS was 3.15±2.14. CONCLUSIONS: In LOMS patients, the rates of delay in the diagnostic process, treatment disruption and progressive disease are higher than in the general MS population. The high rates of LP applying and OCB positivity of this study may indicate the habit of looking for clear evidences in advanged age in our country. This situation and comorbidities may cause a delay in diagnosis and eliminates the window of opportunity for early diagnosis. Although the high number of spinal lesions is a known marker for progressive disease, it is an issue that needs to be discussed whether the increased frequency of progressive course at older ages is due to the nature of the disease or immune aging itself.

Clinical characterization of long-term multiple sclerosis (COLuMbus) patients in Argentina: A cross-sectional non-interventional study.

BACKGROUND: Most Multiple Sclerosis (MS) clinical trials fail to assess the long-term effects of disease-modifying therapies (DMT) or disability. METHODS: COLuMbus was a single-visit, cross-sectional study in Argentina in adult patients with ≥10 years of MS since first diagnosis. The primary endpoint was to determine patient disability using the Expanded Disability Status Scale (EDSS). The secondary endpoints were to evaluate the distribution of diagnoses between relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS), patient demographics, disease history, and the risk of disability progression. The relationship between baseline characteristics and the current disability state and the risk of disability progression was assessed. RESULTS: Out of the 210 patients included, 76.7 % had a diagnosis of RRMS and 23.3 % had been diagnosed with SPMS, with a mean disease duration of 17.9 years and 20.5 years, respectively. The mean delay in the initial MS diagnosis was 2.6 years for the RRMS subgroup and 2.8 years for the SPMS subgroups. At the time of cut-off (28May2020), 90.1 % (RRMS) and 75.5 % (SPMS) of patients were receiving a DMT, with a mean of 1.5 and 2.0 prior DMTs, respectively. The median EDSS scores were 2.5 (RRMS) and 6.5 (SPMS). In the RRMS and SPMS subgroups, 23 % and 95.9 % of patients were at high risk of disability, respectively; the time since first diagnosis showed a significant correlation with the degree of disability. CONCLUSIONS: This is the first local real-world study in patients with long-term MS that highlights the importance of recognizing early disease progression to treat the disease on time and delay disability.

Examining the environmental risk factors of progressive-onset and relapsing-onset multiple sclerosis: recruitment challenges, potential bias, and statistical strategies.

It is unknown whether the currently known risk factors of multiple sclerosis reflect the etiology of progressive-onset multiple sclerosis (POMS) as observational studies rarely included analysis by type of onset. We designed a case-control study to examine associations between environmental factors and POMS and compared effect sizes to relapse-onset MS (ROMS), which will offer insights into the etiology of POMS and potentially contribute to prevention and intervention practice. This study utilizes data from the Primary Progressive Multiple Sclerosis (PPMS) Study and the Australian Multi-center Study of Environment and Immune Function (the AusImmune Study). This report outlines the conduct of the PPMS Study, whether the POMS sample is representative, and the planned analysis methods. The study includes 155 POMS, 204 ROMS, and 558 controls. The distributions of the POMS were largely similar to Australian POMS patients in the MSBase Study, with 54.8% female, 85.8% POMS born before 1970, mean age of onset of 41.44 ± 8.38 years old, and 67.1% living between 28.9 and 39.4° S. The POMS were representative of the Australian POMS population. There are some differences between POMS and ROMS/controls (mean age at interview: POMS 55 years vs. controls 40 years; sex: POMS 53% female vs. controls 78% female; location of residence: 14.3% of POMS at a latitude ≤ 28.9°S vs. 32.8% in controls), which will be taken into account in the analysis. We discuss the methodological issues considered in the study design, including prevalence-incidence bias, cohort effects, interview bias and recall bias, and present strategies to account for it. Associations between exposures of interest and POMS/ROMS will be presented in subsequent publications.

Treatment reduces the incidence of newly appearing multiple sclerosis lesions evolving into chronic active, slowly expanding lesions: A retrospective analysis.

BACKGROUND AND PURPOSE: Newly appearing lesions in multiple sclerosis (MS) may evolve into chronically active, slowly expanding lesions (SELs), leading to sustained disability progression. The aim of this study was to evaluate the incidence of newly appearing lesions developing into SELs, and their correlation to clinical evolution and treatment. METHODS: A retrospective analysis of a fingolimod trial in primary progressive MS (PPMS; INFORMS, NCT00731692) was undertaken. Data were available from 324 patients with magnetic resonance imaging scans up to 3 years after screening. New lesions at year 1 were identified with convolutional neural networks, and SELs obtained through a deformation-based method. Clinical disability was assessed annually by Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test, Timed 25-Foot Walk, and Paced Auditory Serial Addition Test. Linear, logistic, and mixed-effect models were used to assess the relationship between the Jacobian expansion in new lesions and SELs, disability scores, and treatment status. RESULTS: One hundred seventy patients had ≥1 new lesions at year 1 and had a higher lesion count at screening compared to patients with no new lesions (median = 27 vs. 22, p = 0.007). Among the new lesions (median = 2 per patient), 37% evolved into definite or possible SELs. Higher SEL volume and count were associated with EDSS worsening and confirmed disability progression. Treated patients had lower volume and count of definite SELs (ß = -0.04, 95% confidence interval [CI] = -0.07 to -0.01, p = 0.015; ß = -0.36, 95% CI = -0.67 to -0.06, p = 0.019, respectively). CONCLUSIONS: Incident chronic active lesions are common in PPMS, and fingolimod treatment can reduce their number.

The familial risk and heritability of multiple sclerosis and its onset phenotypes: A case-control study.

BACKGROUND: The two main phenotypes of multiple sclerosis (MS), primary progressive (PPMS) and relapsing Onset (ROMS), show clinical and demographic differences suggesting possible differential risk mechanisms. Understanding the heritable features of these phenotypes could provide aetiological insight. OBJECTIVES: To evaluate the magnitude of familial components in PPMS and ROMS and to estimate the heritability of disease phenotypes. METHODS: We used data from 25,186 MS patients of Nordic ancestry from the Swedish MS Registry between 1987 and 2019 with known disease phenotype (1593 PPMS and 16,718 ROMS) and 251,881 matched population-based controls and 3,364,646 relatives of cases and controls. Heritability was calculated using threshold-liability models. For familial odds ratios (ORs), logistic regression with robust sandwich estimator was utilized. RESULTS: The OR of MS diagnosis in those with a first-degree family member with ROMS was 7.00 and 8.06 in those with PPMS. The corresponding ORs for having a second-degree family member with ROMS was 2.16 and 2.18 in PPMS. The additive genetic effect in ROMS was 0.54 and 0.22 in PPMS. CONCLUSION: Risk of MS increases by several folds in those with a relative with MS. The likelihood of developing either disease phenotype appears independent of genetic predisposition.

The natural history of primary progressive multiple sclerosis: insights from the German NeuroTransData registry.

BACKGROUND: Primary progressive multiple sclerosis (PPMS) is characterised by gradual worsening of disability from symptom onset. Knowledge about the natural course of PPMS remains limited. METHODS: PPMS patients from the German NeuroTransData (NTD) MS registry with data from 56 outpatient practices were employed for retrospective cross-sectional and longitudinal analyses. The cross-sectional analysis included a contemporary PPMS cohort with a documented visit within the last 2 years before index date (1 Jan 2021). The longitudinal analysis included a disease modifying therapy (DMT)-naïve population and focused on the evolution of expanded disability status scale (EDSS) from the first available assessment at or after diagnosis within the NTD registry to index date. Outcome measures were estimated median time from first EDSS assessment to first 24-week confirmed EDSS ≥ 4 and ≥ 7. Besides EDSS change, the proportion of patients on disability pension were described over time. RESULTS: The cross-sectional analysis included 481 PPMS patients (59.9% female, mean [standard deviation, SD] age 60.5 [11.5] years, mean [SD] EDSS 4.9 [2.1]). Estimated median time from first EDSS assessment after diagnosis to reach 24-week confirmed EDSS ≥ 4 for DMT-naïve patients was 6.9 years. Median time to EDSS ≥ 7 was 9.7 years for 25% of the population. Over a decade mean (SD) EDSS scores increased from 4.6 (2.1) to 5.7 (2.0); the proportion of patients on disability pension increased from 18.9% to 33.3%. CONCLUSIONS: This study provides first insights into the German NTD real-world cohort of PPMS patients. Findings confirm the steadily deteriorating course of PPMS accompanied by increasingly limited quality of life.

Risk of secondary progressive multiple sclerosis after early worsening of disability.

BACKGROUND: Whether progression independent of relapse activity (PIRA) heralds earlier onset of secondary progressive multiple sclerosis (SPMS) and more rapid accumulation of disability during SPMS remains to be determined. We investigated the association between early PIRA, relapse-associated worsening (RAW) of disability and time to SPMS, subsequent disability progression and their response to therapy. METHODS: This observational cohort study included patients with relapsing-remitting multiple sclerosis (RRMS) from the MSBase international registry across 146 centres and 39 countries. Associations between the number of PIRA and RAW during early multiple sclerosis (MS) (the initial 5 years of MS onset) were analysed with respect to: time to SPMS using Cox proportional hazards models adjusted for disease characteristics; and disability progression during SPMS, calculated as the change of Multiple Sclerosis Severity Scores over time, using multivariable linear regression. RESULTS: 10 692 patients met the inclusion criteria: 3125 (29%) were men and the mean MS onset age was 32.2 years. A higher number of early PIRA (HR=1.50, 95% CI 1.28 to 1.76, p<0.001) and RAW (HR=2.53, 95% CI 2.25 to 2.85, p<0.001) signalled a higher risk of SPMS. A higher proportion of early disease-modifying therapy exposure (per 10%) reduced the effect of early RAW (HR=0.94, 95% CI 0.89 to 1.00, p=0.041) but not PIRA (HR=0.97, 95% CI 0.91 to 1.05, p=0.49) on SPMS risk. No association between early PIRA/RAW and disability progression during SPMS was found. CONCLUSIONS: Early disability increase during RRMS is associated with a greater risk of SPMS but not the rate of disability progression during SPMS. The deterioration associated with early relapses represents a potentially treatable risk factor of SPMS. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12605000455662).

The risk of secondary progressive multiple sclerosis is geographically determined but modifiable.

Geographical variations in the incidence and prevalence of multiple sclerosis have been reported globally. Latitude as a surrogate for exposure to ultraviolet radiation but also other lifestyle and environmental factors are regarded as drivers of this variation. No previous studies evaluated geographical variation in the risk of secondary progressive multiple sclerosis, an advanced form of multiple sclerosis that is characterized by steady accrual of irreversible disability. We evaluated differences in the risk of secondary progressive multiple sclerosis in relation to latitude and country of residence, modified by high-to-moderate efficacy immunotherapy in a geographically diverse cohort of patients with relapsing-remitting multiple sclerosis. The study included relapsing-remitting multiple sclerosis patients from the global MSBase registry with at least one recorded assessment of disability. Secondary progressive multiple sclerosis was identified as per clinician diagnosis. Sensitivity analyses used the operationalized definition of secondary progressive multiple sclerosis and the Swedish decision tree algorithm. A proportional hazards model was used to estimate the cumulative risk of secondary progressive multiple sclerosis by country of residence (latitude), adjusted for sex, age at disease onset, time from onset to relapsing-remitting phase, disability (Multiple Sclerosis Severity Score) and relapse activity at study inclusion, national multiple sclerosis prevalence, government health expenditure, and proportion of time treated with high-to-moderate efficacy disease-modifying therapy. Geographical variation in time from relapsing-remitting phase to secondary progressive phase of multiple sclerosis was modelled through a proportional hazards model with spatially correlated frailties. We included 51 126 patients (72% female) from 27 countries. The median survival time from relapsing-remitting phase to secondary progressive multiple sclerosis among all patients was 39 (95% confidence interval: 37 to 43) years. Higher latitude [median hazard ratio = 1.21, 95% credible interval (1.16, 1.26)], higher national multiple sclerosis prevalence [1.07 (1.03, 1.11)], male sex [1.30 (1.22, 1.39)], older age at onset [1.35 (1.30, 1.39)], higher disability [2.40 (2.34, 2.47)] and frequent relapses [1.18 (1.15, 1.21)] at inclusion were associated with increased hazard of secondary progressive multiple sclerosis. Higher proportion of time on high-to-moderate efficacy therapy substantially reduced the hazard of secondary progressive multiple sclerosis [0.76 (0.73, 0.79)] and reduced the effect of latitude [interaction: 0.95 (0.92, 0.99)]. At the country-level, patients in Oman, Tunisia, Iran and Canada had higher risks of secondary progressive multiple sclerosis relative to the other studied regions. Higher latitude of residence is associated with a higher probability of developing secondary progressive multiple sclerosis. High-to-moderate efficacy immunotherapy can mitigate some of this geographically co-determined risk.

The prevalence and incidence of multiple sclerosis over the past 20 years in northern Japan.

OBJECTIVES: The prevalence of multiple sclerosis (MS) in East Asia is thought to be lower than in Western countries. Globally, there is a trend of increasing MS prevalence. We investigated the changes in the prevalence and clinical phenotype of MS in the Tokachi province of Hokkaido in northern Japan, from 2001 to 2021. METHODS: Data processing sheets were sent to all related institutions inside and outside the Tokachi area of Hokkaido island in Japan and were collected from April to May 2021. The prevalence according to the Poser's diagnostic criteria for MS was determined on March 31, 2021. RESULTS: In 2021, the crude MS prevalence in northern Japan was 22.4/100,000 (95% confidence interval, 17.6-28.0). The prevalences of MS standardized by the Japanese national population in 2001, 2006, 2011, 2016, and 2021 were 6.9, 11.5, 15.3, 18.5, and 23.3, respectively. The female/male ratio was 4.0 in 2021, increased from 2.6 in 2001. We checked the prevalence using the 2017 revised McDonald criteria, and found only additional male patient who had not fulfilled Poser's criteria. The age- and sex-adjusted incidence of MS per 100,000 individuals increased from 0.09 in 1980-1984 to 0.99 in 2005-2009; since then, it has remained stable. The proportions of primary-progressive, relapsing-remitting, and secondary-progressive MS types in 2021 were 3%, 82%, and 15%, respectively. CONCLUSION: Our results demonstrated a consistent increase in the prevalence of MS among the northern Japanese over 20 years, particularly in females, and consistently lower rates of progressive MS in northern Japan than elsewhere in the world.

The impact of cognitive impairment on disease burden in Chinese patients with multiple sclerosis: A model simulation study.

BACKGROUND: Cognitive impairment (CI) is prevalent in Chinese patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: A decision analytic model was constructed to simulate Chinese patients with newly diagnosed RRMS and their matched control cohort without MS for the risks of developing CI, developing secondary progressive MS (SPMS), and mortality. Both English and Chinese bibliographic databases were searched for evidence to estimate model inputs. Base case analysis and sensitivity analysis were conducted for the point estimations and uncertainty of the measured burden outcomes. RESULTS: Model simulations estimated that the lifetime cumulative risk of CI in newly diagnosed RRMS patients was 85.2%. Relative to the matched control cohort, newly diagnosed RRMS patients were associated with a lower life expectancy (33.2 years vs. 41.7 years, difference: -8.5 years), lower quality-adjusted life years (QALY) (18.4 QALY vs. 38.4 QALY, difference: -19.9 QALY), and higher lifetime medical costs (¥613,883 vs. ¥202,726, difference: ¥411,157) and indirect costs (¥1,099,021 vs. ¥94,612, difference: ¥1,004,410). Patients who developed CI accounted for at least half of the measured burden. The disease burden outcomes were mainly driven by the risk of developing CI, progression risk from RRMS to SPMS, hazard ratios of mortality associated with CI relative to no CI, utility of patients with RRMS, annual relapse risk, and annual costs of personal care. CONCLUSION: Most Chinese patients with newly diagnosed RRMS are likely to develop CI in their lifetime, and such patients that develop CI could significantly contribute to the disease burden of RRMS.

Effectiveness of first generation disease-modifying therapy to prevent conversion to secondary progressive multiple sclerosis.

BACKGROUND: The use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) has been associated with reduced relapse rates and accumulation of disability. However, studies examining impact of DMT on risk of transition to secondary progressive MS (SPMS) leveraging population-based nationwide data are still rare. Here, we determine the population incidence of conversion to SPMS using two consecutive nation-wide cohorts, one immediately before and one after the introduction of DMT in Sweden. METHODS: We included two consecutive population cohorts of relapsing-remitting MS (RRMS) from the Swedish national MS register for the periods 1975-1994 (n = 2161), before DMT availability, and 1995-2011 (n = 3510), in which DMTs, mainly first generation DMT (injectables), became available and eventually were used by 70% of patients. We explored the risk of transition to SPMS as a calendar year function encompassing the two cohorts. In addition, we determined the incidence of transition to SPMS through age strata below and above 50 years in untreated and treated patient subgroups. RESULTS: The risk of conversion to SPMS (adjusted for current age, current time since onset, calendar year and sex) was significantly lower in the second compared with the first population cohort (hazard ratio 0.58; CI 0.48, 0.70). The risk of SPMS conversion per calendar year decreased by 2.6% annually (p < 0.001) after 1995. The risk of SPMS conversion increased with age until age 50. Thereafter, it was unchanged or decreased among those with early MS onset age (<35 years), but continued to increase with onset at higher age, with similar trends in treated and untreated subgroups. CONCLUSION: The incidence of SPMS conversion significantly decreased at the population level after introduction of first generation DMTs by 1995. DMT efficiency was confirmed by a downward turn of the annual trajectory of the risk of SPMS conversion after 1995. An onset age determined pattern of variable SPMS incidence in higher age appeared in both treated and untreated strata. While first generation DMT delayed conversion to SPMS, their long-term effect was only moderate.

Serious infections in patients with relapsing and progressive forms of multiple sclerosis: A German claims data study.

BACKGROUND: People with multiple sclerosis (pwMS) have a higher risk of serious infection (i.e., infection-related hospitalizations) than people without MS. Few studies have explored the risk of serious infections by MS phenotype in a real-world setting. This retrospective study compared the incidence of serious infections among people with relapse remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). METHODS: Adult pwMS were selected from a German claims database, based on one inpatient or two outpatient diagnoses of MS (ICD-10 G35) by a neurologist from 01/01/2016 to 12/31/2018. Three cohorts (RRMS, PPMS, SPMS) were identified based on codes for MS subtypes included in the German Modification of the ICD-10 system. A fourth cohort of unspecified MS patients combined those with conflicting MS subtype diagnoses and multiple unspecified codes for MS. Serious infections were defined as hospitalizations for which infections were selected as the primary inpatient diagnosis. Infections were identified from a basket of ICD-10 codes distributed across 11 main categories, according to possible pathogen (e.g., other bacterial diseases [A30-A49]) or anatomical location (e.g., urinary tract infection [N39.0]). Multiple infections were counted if an interval of at least 60 days was recorded between episodes. Serious infections were counted from index (i.e., first recorded MS code) until the end of the study period or death. Incidence rates (IRs) were reported per 100 patient years (PY). RESULTS: A total of 4,250 pwMS (RRMS: 2,307, PPMS: 282, SPMS: 558, unspecified MS: 1,135) were included; 32 patients progressed from RRMS to SPMS during the follow-up period. Mean (SD) age at baseline was 46.6 (13.6), 61.9 (12.4), and 62.5 (11.8) years in patients with RRMS, PPMS, and SPMS, respectively. Most pwMS were female (RRMS 74.8%, PPMS 62.1%, SPMS 67.4%). Progressive pwMS were more likely to have at least 1 comorbidity (PPMS 87.2%, SPMS 87.5%) compared to those with relapsing MS (61.9%). Most RRMS patients received disease-modifying therapy during follow-up (82.1%), while less than half of progressive MS patients did (PPMS 23.8%, SPMS 31.4%). Over a mean (SD) follow-up period of 3.5 (0.8) years, the IR of serious infections per 100 PY was higher in progressive MS cohorts (PPMS 13.5 [11.3-16.1], SPMS 13.6 [12.0-15.3]) than in the RRMS group (3.4 [3.0-3.7]). Yearly IRs remained stable over time in each cohort. Where anatomical location was specified, respiratory (2.0 per 100 PY) and genitourinary (1.9 per 100 PY) infections were most common. Across all subtypes, higher rates of serious infections were observed in men and older patients. CONCLUSION: Progressive MS, older age and male sex are associated with an increased risk of serious infections. Overall, respiratory and genitourinary infections were the most commonly reported serious infections.

Do patients' and referral centers' characteristics influence multiple sclerosis phenotypes? Results from the Italian multiple sclerosis and related disorders register.

BACKGROUND: Multiple sclerosis (MS) is characterized by phenotypical heterogeneity, partly resulting from demographic and environmental risk factors. Socio-economic factors and the characteristics of local MS facilities might also play a part. METHODS: This study included patients with a confirmed MS diagnosis enrolled in the Italian MS and Related Disorders Register in 2000-2021. Patients at first visit were classified as having a clinically isolated syndrome (CIS), relapsing-remitting (RR), primary progressive (PP), progressive-relapsing (PR), or secondary progressive MS (SP). Demographic and clinical characteristics were analyzed, with centers' characteristics, geographic macro-areas, and Deprivation Index. We computed the odds ratios (OR) for CIS, PP/PR, and SP phenotypes, compared to the RR, using multivariate, multinomial, mixed effects logistic regression models. RESULTS: In all 35,243 patients from 106 centers were included. The OR of presenting more advanced MS phenotypes than the RR phenotype at first visit significantly diminished in relation to calendar period. Females were at a significantly lower risk of a PP/PR or SP phenotype. Older age was associated with CIS, PP/PR, and SP. The risk of a longer interval between disease onset and first visit was lower for the CIS phenotype, but higher for PP/PR and SP. The probability of SP at first visit was greater in the South of Italy. DISCUSSION: Differences in the phenotype of MS patients first seen in Italian centers can be only partly explained by differences in the centers' characteristics. The demographic and socio-economic characteristics of MS patients seem to be the main determinants of the phenotypes at first referral.

A comparison of anxiety symptoms and correlates of anxiety in people with progressive and relapsing-remitting multiple sclerosis.

BACKGROUND: Anxiety appears to be more prevalent in people with multiple sclerosis (MS) than in the general population, though it is unclear if anxiety varies by MS disease course. There are experiences unique to each disease course that might increase the likelihood of anxiety. Additionally, the majority of research in MS has focused on people with relapsing-remitting MS (RRMS), while the experiences of people with progressive forms of MS are understudied. This study examined anxiety in people with progressive MS (PMS) and examined group differences in anxiety compared to people with RRMS, and assessed unique and common correlates of anxiety in people with PMS and RRMS. METHODS: Secondary analysis of data from the fourth survey in a longitudinal study of quality of life in people with physical disabilities. The current study included a subset of participants with MS. Anxiety level was measured by the 4-item Patient-Reported Outcomes Measurement Information System - Anxiety Short Form T-score. T-test and chi-square analyses were used to compare groups. Correlates of anxiety were tested by examining the interaction of MS subtype (PMS and RRMS) and each potential correlate in multiple regression models with bootstrapping. RESULTS: Participants were 464 adults with MS (PMS n = 183; RRMS n = 281) who were predominately female, non-Hispanic white, and not employed with a mean age of 56.9 ± 10.3 years and disease duration of 17.5 ± 9.3 years. On average, participants with PMS reported anxiety symptoms (50.6 ± 8.6) that were comparable to those in the United States general population and statistically lower than participants with RRMS (52.8 ± 9.5; p = .01). Across MS courses, common factors associated with greater anxiety symptoms were shorter disease duration, lower household income, greater speech and/or swallowing problems, and current smoking (tobacco), adjusted R2 = .19, F(4, 391) = 22.68, p < .001. There was no evidence of unique correlates of anxiety symptoms in participants with either MS course. CONCLUSIONS: In this community sample, people with MS, regardless of disease course, reported similar levels of anxiety to the United States general population. This is inconsistent with prior literature that largely involves clinical samples, suggesting a need for further research with community samples of individuals with MS. This discrepancy may also be due to measurement differences between studies (e.g., screen versus symptom measures). Participants with RRMS reported greater average anxiety compared to those with PMS. This statistically significant difference was small and not clinically significant, indicating the need for further examination and replication. Overall, the findings highlight the wide heterogeneity of anxiety presentation within people with MS and identify potential factors to improve conceptualization and treatment of anxiety in this population. Further research is needed with community and clinical samples to understand anxiety in MS as well as risk and protective factors to improve conceptualization and treatment of anxiety in this population.

Multiple Sclerosis Progressive Courses: A Clinical Cohort Long-Term Disability Progression Study.

OBJECTIVES: Improving the understanding of multiple sclerosis (MS) mechanism and disability progression over time is essential to assess the value of healthcare interventions. Poor or no data on disability progression are available for progressive courses. This study aims to fill this gap. METHODS: An observational cohort study of patients with primary MS (PPMS) and secondary progressive MS (SPMS) was conducted on 2 Italian MS centers disease registries over an observational time of 34 years. Annual transition probabilities among Expanded Disability Status Scale (EDSS) states were estimated using continuous Markov models. A sensitivity analysis was performed in relation to clinical characteristic associated to disability progression. RESULTS: The study cohort included 758 patients (274 PPMS and 434 SPMS) with a median follow-up of 8.2 years. Annual transition probability matrices of SPMS and PPMS reported different annual probabilities to move within EDSS levels. Excluding EDSS associated to relapse events or patient with relapses, the annual probability of staying stable in an EDSS level increased in both disease courses even not significantly. CONCLUSIONS: This study provides estimates of annual disability progression as EDSS changes for PPMS and SPMS. These estimates could be a useful tool for healthcare decision makers and clinicians to properly assess impact of clinical interventions.

Multiple sclerosis by phenotype in Germany.

BACKGROUND: A diagnosis of multiple sclerosis (MS) can be categorized based on its disease course into the following phenotypes: relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). With one exception, studies of MS by phenotype either provide only prevalence data or if describing drug utilization, the emphasis is on patients with RRMS; while drug utilization by phenotype tends to be examined over the course of a year. No recent studies have comprehensively evaluated MS phenotypes by prevalence, drug utilization, and comorbidities over time from a population-based perspective, which is essential for understanding the disease burden and identifying unmet needs in MS. Germany is one of the few countries where specific MS phenotypes are commonly recorded in routine clinical practice. The purpose of this study was to compare MS phenotypes with respect to changes in their population-based prevalence rates and the types of MS treatments prescribed over time, as well as the frequency of clinical conditions associated with MS based on data from a German health insurance database. METHODS: This retrospective, observational, cohort study used data from a German health insurance database for the period 2010 to 2017. Patients aged 18+ years with a specified phenotype of MS based on ICD-10 diagnosis coding were included in the analysis. RESULTS: In 2010, RRMS was reported in 73%, PPMS in 8%, and SPMS in 19% of patients with MS with a known phenotype. The mean ages of patients were 41.4, 53.6, and 52.8 years, respectively, and all phenotypes were associated with a female predominance (69%, 63% and 63%, respectively). The prevalence rate of each phenotype markedly increased during the study period (RRMS +113%, PPMS +40%, SPMS +54%; in 2017 the rates were 183, 14, and 34 per 100,000, respectively). The mean age of patients reporting each phenotype also increased (p<0.01), while the female:male proportion remained stable in RRMS and SPMS, the proportion of females significantly declined over time in the PPMS group. The overall percentage of patients prescribed a disease-modifying drug increased across the phenotypes from 51% to 57%. Prescription of interferon-based therapies declined in each phenotype, with the greatest declines observed in RRMS and PPMS. The PPMS and SPMS groups had significantly more prescriptions for symptom management than the RRMS group. Depression was the most prevalent clinical condition associated with each phenotype. There was a significant difference in the percentage of patients with depression across the phenotypes (p = 0.03), with the highest among SPMS (44%) compared with RRMS (35%) or PPMS (37%). Significant differences (p<0.05) across the phenotypes were also observed for the composite prevalence of cardiovascular conditions (highest in PPMS) and cognitive dysfunction (highest in SPMS). CONCLUSION: The increasing numbers of patients across each MS phenotype, aging population in patients with MS regardless of phenotype, gender differences and variations across the types of treatments prescribed, and clinical conditions associated with each MS phenotype present new insight into the disease burden and treatment strategies of MS. These should be considered when developing healthcare strategies and optimizing care for patients with MS.