Epidemiology of multiple sclerosis in Santiago de Compostela (Spain).

OBJECTIVES: To analyze the frequency and demographic characteristics of multiple sclerosis (MS) in the Council of Santiago de Compostela (SPAIN). MATERIAL AND METHODS: The patients diagnosed with MS according to the McDonald 2010 diagnostic criteria were identified within the population of the District of Santiago de Compostela. Several sources were used (records and databases from Hospital, General Practitioners, Private Clinics, and the MS Patients Association). Demographic and clinical data were obtained from the electronic files. RESULTS: The incidence of MS between 2010 and 2015 was 8/100 000/year (95% CI: 6-10), and the prevalence on December 31, 2015, was 152/100 000 (95% CI: 127-176). The age-standardized prevalence (using the European Standard Population 2013) was 137 (95% CI: 114-159) and the incidence of 7 (95% CI: 2-12). The female:male ratio was 1.84, the mean age at the first symptom was 32.23 years, the diagnosis was delayed 3.12 years, and the mean EDSS was 2.82. 71.17% had relapsing-remitting MS, 16.55% secondary progressive MS, 7.59% primary progressive MS, and 0.69% progressive relapsing MS. A disease-modifying treatment was established in 62.76% of patients in a mean of 1.96 years after the diagnosis. CONCLUSIONS: The northwest of Spain is a high-risk area for MS, with frequencies similar to other Atlantic regions and higher than the rest of the country.

Prognostic impact of epilepsy in multiple sclerosis.

BACKGROUND: The incidence of epilepsy, a disease generally associated with increased morbidity and mortality, is increased in multiple sclerosis (MS) but its impact on MS prognosis is largely unknown. OBJECTIVES: To investigate the association between acquired epilepsy and mortality in MS and to examine the occurrence of epilepsy as a stated cause of death in MS. To examine the association between acquired epilepsy and subsequent conversion to secondary progressive MS (SPMS). METHODS: Using the Swedish MS register, we conducted a nationwide register-based cohort study including 10,383 patients with MS onset between 31/12/1991 and 31/12/2014, and with no history of epilepsy before MS onset. Data on epilepsy diagnosis and cause of death (COD) were extracted from comprehensive national registers. Cox regression was used to estimate hazard ratios (HR) of death stratified by MS course, and SPMS conversion after epilepsy diagnosis. The HRs were adjusted for age at MS onset and sex. RESULTS: The adjusted HR of death after epilepsy diagnosis for unselected MS patients was 3.85 (95% CI: 2.53-5.85). Stratifying by disease course, the adjusted HR of death after epilepsy diagnosis in primary progressive MS was 2.28 (95% CI: 0.99-5.26) and in relapsing-onset MS (ROMS), 5.48 (95% CI: 3.33-9.04). Further subdivision of ROMS revealed the adjusted risk of death after epilepsy diagnosis in relapsing remitting MS to be 3.84 (95% CI: 1.57-9.42) and 6.66 (95% CI: 3.18-13.92) in SPMS. Epilepsy was the underlying COD in 4.55% of MS patients with epilepsy. The majority (50%) of MS patients with epilepsy had MS as their stated underlying COD. Adjusted HR of conversion to SPMS after epilepsy diagnosis was 0.83 (95% CI: 0.45-1.56). CONCLUSION: Epilepsy in MS is associated with increased mortality although death from epilepsy is rare. Most MS patients with epilepsy died of MS, and epilepsy was most lethal when developed in SPMS. We thus suggest that development of epilepsy is a marker of severe MS. Despite this, we found no association between epilepsy and conversion to SPMS.

Multiple sclerosis: effect of beta interferon treatment on survival.

Worldwide, the beta interferons remain the most commonly prescribed disease-modifying drugs for multiple sclerosis. However, it is unclear if they alter survival. We investigated the association between beta interferon and mortality in the 'real-world' setting. This was a multi-centre population-based observational study of patients with relapsing-onset multiple sclerosis who were initially registered at a clinic in British Columbia, Canada (1980-2004) or Rennes, France (1976-2013). Data on this cohort were accessed from the clinical multiple sclerosis databases and from individually linked health administrative data; all data were collected prospectively. Participants were followed from the latter of their first multiple sclerosis clinic visit, 18th birthday or 1 January 1996; until death, emigration or 31 December 2013. Only those who were naïve to disease-modifying therapy and immunosuppressant treatment of multiple sclerosis at the start of their follow-up were included in the analysis. A nested case-control approach was used. Up to 20 controls, matched to cases (deaths) by country, sex, age ± 5 years, year and disability level at study entry, were randomly selected from the cohort by incidence density sampling. The associations between all-cause mortality and at least 6 months beta interferon exposure, and also cumulative exposure ('low', 6 months to 3 years; and 'high', >3 years), were estimated by conditional logistic regression adjusting for treatment with other disease-modifying therapies and age in years. Further analyses included separate analyses by sex and country, additional adjustment for comorbidity burden in the Canadian cohort, and estimation of the association between beta interferon and multiple sclerosis-related death in both countries. Among 5989 participants (75% female) with a mean age of 42 (standard deviation, SD 11) years at study entry, there were 742 deaths (70% female) and the mean age at death was 61 (SD 13) years. Of these cases, 649 were matched to between one and 20 controls. Results of the conditional logistic regression analyses are expressed as adjusted odds ratios with 95% confidence intervals. The odds of beta interferon exposure were 32% lower among cases than controls (0.68; 0.53-0.89). Increased survival was associated with >3 years beta interferon exposure (0.44; 0.30-0.66), but not between 6 months and 3 years exposure (1.00; 0.73-1.38). Findings were similar within sex and country, and for multiple sclerosis-related death. Beta interferon treatment was associated with a lower mortality risk among people with relapsing-onset multiple sclerosis. Findings were consistent between two geographically distinct regions in North America and Europe.

Cost-effectiveness analysis of ocrelizumab versus subcutaneous interferon beta-1a for the treatment of relapsing multiple sclerosis.

AIM: To conduct a cost-effectiveness analysis to compare ocrelizumab vs subcutaneous (SC) interferon beta-1a for the treatment of relapsing multiple sclerosis (RMS). METHODS: A Markov cohort model with a 20-year horizon was developed to compare ocrelizumab with SC interferon beta-1a from a US payer perspective. A cohort of patients with relapsing-remitting MS (RRMS) and Expanded Disability Status Scale (EDSS) scores of 0-6, who initiated treatment with ocrelizumab or SC interferon beta-1a, were entered into the model. The model considered 21 health states: EDSS 0-9 in RRMS, EDSS 0-9 in secondary-progressive multiple sclerosis (SPMS), and death. Patients with RRMS could transition across EDSS scores, progress to SPMS, experience relapses, or die. Transition probabilities within RRMS while patients received ocrelizumab or SC interferon beta-1a were based on data from the two SC interferon beta-1a-controlled Phase III OPERA I and OPERA II trials of ocrelizumab in RMS. Transitions within RRMS when off-treatment, RRMS-to-SPMS transitions, transitions within SPMS, and transitions to death were based on the literature. Utilities of health states, disutilities of relapses, costs of therapies, and medical costs associated with health states, relapse, and adverse events were from the literature and publicly available data sources. The model estimated per-patient total costs, incremental cost per life year (LY) gained, and incremental cost per quality-adjusted LY (QALY) gained. Deterministic sensitivity analyses (DSA) and probabilistic sensitivity analysis (PSA) were conducted to evaluate the robustness of the model results. RESULTS: Ocrelizumab was associated with a cost savings of $63,822 and longer LYs (Δ = 0.046) and QALYs (Δ = 0.556) over a 20-year time horizon. The results of the model were robust in the DSA and PSA. LIMITATIONS: The model did not consider subsequent treatments and their impact on disease progression. CONCLUSIONS: The results suggest that ocrelizumab is more cost-effective than SC interferon beta-1a for the treatment of RMS.

Survival and cause of death in multiple sclerosis: a 60-year longitudinal population study.

OBJECTIVE: Survival and causes of death (COD) in multiple sclerosis (MS) provide ultimate endpoints. We aimed to investigate survival and COD in a 60-year population-based MS cohort compared with the general population. METHODS: All patients with incident multiple sclerosis (MS) (N=1388) with onset during 1953-2012 in Hordaland County, Western Norway, were included. Data were obtained from patient records at Haukeland University Hospital and linked to the Norwegian COD registry. Survival adjusted for sex, age and disease course were estimated by Kaplan-Meier analyses from birth and from disease onset. Mortality and COD in MS relative to the general population were examined by standardised mortality ratio (SMR). RESULTS: Of 1388 patients, 291 had deceased, mainly of MS (56.4%). Median life expectancy was 74.7 years for MS and 81.8 years for the general population (p<0.001); 77.2 years for women with MS and 72.2 years for men with MS (p<0.001). Life expectancy for patients with relapsing remitting MS (RRMS) was 77.8 years and -71.4 years for primary progressive MS (PPMS) (p<0.001). Overall SMR was 2.7 (p>0.0001); 2.9 in women and 2.5 in men (p=0.0009). SMR was 2.4 in RRMS and 3.9 in PPMS (p<0.0001). SMR from disease onset during 1953-1974 was 3.1; 2.6 during 1975-1996 and 0.7 during 1997-2012 (p<0.0083). No difference in cause-specific deaths were found (p=0.0871). CONCLUSION: We found a 7-year shorter life expectancy and almost threefold higher mortality in MS compared with the general population. A rise in survival in MS was observed during the entire observation period.

Mortality in Hungarian patients with multiple sclerosis between 1993 and 2013.

OBJECTIVE: We aimed to assess the causes of death, the mortality and survival time of MS patients in Hungary. PATIENTS AND METHODS: Between 1993 and 2013, 740 patients (10,303person-years) were treated at our Outpatients' Clinic, of which 121 died. The causes of death were established from the pathological records or the medical certificates of the cause of death. The standardized mortality ratios (SMR) were calculated. Survival time was assessed with Gehan-Breslow test. RESULTS: Sixty-four percent of our patients died of MS-related causes. The SMR was 2.52. Primary progressive (PPMS) patients' SMR was higher (4.10) than initially relapsing patients' (RR/SPMS) was. There was no difference between the genders (2.46 for men vs 2.57 for women). The median survival time of woman was 3years longer (p<0.001). RR/SPMS patients' median survival (35years) was more than twice as long as PPMS patients' (14years). DISCUSSION: The frequency of the MS-related cause of death, SMR and the median survival times were mostly similar to previous results from Scandinavia and North-America, despite the very different socio-economic backgrounds of these areas which shows that the survival risk can solely be attributed to MS itself. These are the first data on the topic from Central-Eastern-Europe.

Interferon beta 1b following natalizumab discontinuation: one year, randomized, prospective, pilot trial.

BACKGROUND: Natalizumab (NTZ) discontinuation leads to multiple sclerosis reactivation.The objective of this study is to compare disease activity in MS patients who continued on NTZ treatment to those who were switched to subcutaneous interferon 1b (IFNB) treatment. METHODS: 1-year randomized, rater-blinded, parallel-group, pilot study (ClinicalTrial.gov ID: NCT01144052). Relapsing remitting MS patients on NTZ for ≥12 months who had been free of disease activity on this therapy (no relapses and disability progression for ≥6 months, no gadolinium-enhancing lesions on baseline MRI) were randomized to NTZ or IFNB. Primary endpoint was time to first on-study relapse. Additional clinical, MRI and safety parameters were assessed. Analysis was based on intention to treat. RESULTS: 19 patients (NTZ n=10; IFNB n=9) with similar baseline characteristics were included. 78% of IFNB treated patients remained relapse free (NTZ group: 100%), and 25% remained free of new T2 lesions (NTZ group: 62.5%). While time to first on-study relapse was not significantly different between groups (p=0.125), many secondary clinical and radiological endpoints (number of relapses, proportion of relapse free patients, number of new T2 lesions) showed a trend, or were significant (new T2 lesions at month 6) in favoring NTZ. CONCLUSIONS: De-escalation therapy from NTZ to IFNB over 1 year was associated with some clinical and radiological disease recurrence. Overall no major safety concerns were observed.

Patients with neuromyelitis optica have a more severe disease than patients with relapsingremitting multiple sclerosis, including higher risk of dying of a demyelinating disease.

UNLABELLED: Although neuromyelitis optica (NMO) is known to be a more severe disease than relapsing-remitting multiple sclerosis (RRMS), few studies comparing both conditions in a single center have been done. METHODS: Comparison of our previously published cohort of 41 NMO patients with 177 RRMS patients followed in the same center, from 1994 to 2007. RESULTS: Mean age of onset was 32.6 for NMO and 30.2 for RRMS (p=0.2062) with mean disease duration of 7.4 years for NMO and 10.3 years for RRMS. Patients with NMO had a higher annualized relapse rate (1.0 versus 0.8, p=0.0013) and progression index (0.9 versus 0.6, p<0.0001), with more patients reaching expanded disability status scale (EDSS) 6.0 (39 versus 17%, p=0.0036). The odds ratio for reaching EDSS 6.0 and being deceased due to NMO in comparison to RRMS were, respectively, 3.14 and 12.15. CONCLUSION: Patients with NMO have a more severe disease than patients with RRMS, including higher risk of dying of a demyelinating disease.

Patients with neuromyelitis optica have a more severe disease than patients with relapsingremitting multiple sclerosis, including higher risk of dying of a demyelinating disease / Pacientes com neuromielite óptica apresentam doença mais incapacitante que pacientes com esclerose múltipla, incluindo maior chance de falecerem de uma doença desmielinizante

Although neuromyelitis optica (NMO) is known to be a more severe disease than relapsing-remitting multiple sclerosis (RRMS), few studies comparing both conditions in a single center have been done. Methods: Comparison of our previously published cohort of 41 NMO patients with 177 RRMS patients followed in the same center, from 1994 to 2007. Results: Mean age of onset was 32.6 for NMO and 30.2 for RRMS (p=0.2062) with mean disease duration of 7.4 years for NMO and 10.3 years for RRMS. Patients with NMO had a higher annualized relapse rate (1.0 versus 0.8, p=0.0013) and progression index (0.9 versus 0.6, p≪0.0001), with more patients reaching expanded disability status scale (EDSS) 6.0 (39 versus 17%, p=0.0036). The odds ratio for reaching EDSS 6.0 and being deceased due to NMO in comparison to RRMS were, respectively, 3.14 and 12.15. Conclusion: Patients with NMO have a more severe disease than patients with RRMS, including higher risk of dying of a demyelinating disease. .

Embora a neuromielite óptica (NMO) seja reconhecida como mais grave que a esclerose múltipla remitente recorrente (EMRR), existem poucos estudos comparando as duas doenças em um único centro. Métodos: Comparação de nossa coorte publicada de 41 pacientes com NMO com 177 pacientes com EMRR seguidos no mesmo centro, de 1994 a 2007. Resultados: A média de idade inicial foi de 32,6 anos em NMO e 30,2 anos em EMRR (p=0,2062), com tempo médio de doença de 7,4 anos para NMO e 10,3 anos EMRR. Pacientes com NMO apresentaram maior taxa anualizada de surtos (1,0 versus 0,8, p=0,0013) e índice de progressão (0,9 versus 0,6, p≪0,0001), com mais pacientes atingindo EDSS 6,0 (39 versus 17%, p=0,0036). Os riscos relativos de se alcançar 6,0 EDSS e falecer em decorrência de NMO em comparação com EMRR, foram, respectivamente, 3,14 e 12,15. Conclusão: Pacientes com NMO têm uma doença mais grave do que os pacientes com EMRR, incluindo maior risco de morrer de uma doença desmielinizante. .

Time to secondary progression in patients with multiple sclerosis who were treated with first generation immunomodulating drugs.

BACKGROUND: It is currently unknown whether early immunomodulatory treatment in relapsing-remitting MS (RRMS) can delay the transition to secondary progression (SP). OBJECTIVE: To compare the time interval from onset to SP in patients with RRMS between a contemporary cohort, treated with first generation disease modifying drugs (DMDs), and a historical control cohort. METHODS: We included a cohort of contemporary RRMS patients treated with DMDs, obtained from the Swedish National MS Registry (disease onset between 1995-2004, n = 730) and a historical population-based incidence cohort (onset 1950-64, n = 186). We retrospectively analyzed the difference in time to SP, termed the "period effect" within a 12-year survival analysis, using Kaplan-Meier and Cox regression analysis. RESULTS: We found that the "period" affected the entire severity spectrum. After adjusting for onset features, which were weaker in the contemporary material, as well as the therapy initiation time, the DMD-treated patients still exhibited a longer time to SP than the controls (hazard ratios: men, 0.32; women, 0.53). CONCLUSION: Our results showed there was a longer time to SP in the contemporary subjects given DMD. Our analyses suggested that this effect was not solely driven by the inclusion of benign cases, and it was at least partly due to the long-term immunomodulating therapy given.

Cost-minimization analysis of fingolimod compared with natalizumab for the treatment of relapsing-remitting multiple sclerosis in Sweden.

BACKGROUND: Fingolimod and natalizumab have the same European Union licence for the treatment of relapsing multiple sclerosis, and are considered by the Committee for Medicinal Products for Human Use (CHMP) to have broadly similar efficacy. OBJECTIVE: A cost-minimization analysis was performed to compare differences in treatment costs between fingolimod and natalizumab from a societal perspective in Sweden. METHODS: This analysis included costs associated with initiating and following treatment (physician visits and monitoring), continuing therapy (drugs and administration), and lost patient productivity and leisure time. Unit costs (in Swedish krona [SEK]) were based on regional data (median prices for physician visits and monitoring sessions). Natalizumab infusion costs were obtained from the national cost-per-patient database. Drug costs for both therapies were 15,651 SEK/28 days. RESULTS: After 3 years, fingolimod use was associated with savings of 124,823 SEK/patient compared with natalizumab (total cost/patient: 566,718 SEK vs 691,542 SEK). Cost savings with fingolimod were 40,402 SEK/patient after 1 year and 301,730 SEK/patient after 10 years. Treatment with natalizumab was 18% more expensive than fingolimod therapy after 1 year and 23% more expensive after 10 years. LIMITATIONS: Based on the CHMP assessment, it was assumed that fingolimod and natalizumab have similar efficacy. The analysis was conducted for Sweden, and caution is needed in extrapolating the results to other countries. CONCLUSION: Fingolimod is cost-saving compared with natalizumab for the treatment of relapsing-remitting multiple sclerosis in Sweden.

Survival in MS: a randomized cohort study 21 years after the start of the pivotal IFNß-1b trial.

OBJECTIVE: To examine the effects of interferon beta (IFNß)-1b on all-cause mortality over 21 years in the cohort of 372 patients who participated in the pivotal randomized clinical trial (RCT), retaining (in the analysis) the original randomized treatment-assignments. METHODS: For this randomized long-term cohort study, the primary outcome, defined before data collection, was the comparison of all-cause mortality between the IFNß-1b 250 µg and placebo groups from the time of randomization through the entire 21-year follow-up interval (intention-to-treat, log-rank test for Kaplan-Meier survival curves). All other survival outcomes were secondary. RESULTS: After a median of 21.1 years from RCT enrollment, 98.4%(366 of 372) of patients were identified, and, of these, 81 deaths were recorded (22.1% [81 of 366]). Patients originally randomly assigned to IFNß-1b 250 µg showed a significant reduction in all-cause mortality over the 21-year period compared with placebo (p = 0.0173), with a hazard ratio of 0.532 (95% confidence interval 0.314-0.902). The hazard rate of death at long-term follow-up by Kaplan-Meier estimates was reduced by 46.8% among IFNß-1b 250 µg-treated patients (46.0% among IFNß-1b 50 µg-treated patients) compared with placebo. Baseline variables did not influence the observed treatment effect. CONCLUSIONS: There was a significant survival advantage in this cohort of patients receiving early IFNß-1b treatment at either dose compared with placebo. Near-complete ascertainment, together with confirmatory findings from both active treatment groups, strengthens the evidence for an IFNß-1b benefit on all-cause mortality. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that early treatment with IFNß-1b is associated with prolonged survival in initially treatment-naive patients with relapsing-remitting multiple sclerosis.

Characteristics of multiple sclerosis in aboriginals living in British Columbia, Canada.

OBJECTIVES: The objectives of this study were to identify and describe the demographic and clinical characteristics of multiple sclerosis (MS) in aboriginals in British Columbia (BC), Canada and compare these findings with non-aboriginal MS patients. METHODS: This retrospective chart and database review accessed patient information from the linked BC-wide MS clinical and genetics databases. Data gathered included: demographics (age, sex and ethnicity); clinical characteristics (MS onset date, disease course and disability scores (Expanded Disability Status Scale [EDSS]). Aboriginals were identified via the database linkage augmented by physician and nurse recall. Two non-aboriginal comparator groups with definite MS were selected. Group one included all definite MS patients in the BC MS database, and group two comprised MS patients matched by sex, age at onset and initial disease course. Patient characteristics were compared using the Student's t-test, chi-squared test, and Kaplan-Meier survival analysis was used to examine disease progression (time to sustained and confirmed EDSS 6) RESULTS: We identified 26 aboriginals with MS, of which 19/26 (73%) were female, 23/26 (89%) had relapsing-onset MS and a mean onset age of 31.1 years. There were no significant differences between the MS aboriginals and the non-matched (n = 5708) comparator group with respect to age, sex or disease course (p > 0.1), However, aboriginals progressed more rapidly to EDSS 6 from disease onset (p < 0.001) when compared with the matched and unmatched comparator groups. CONCLUSION: We identified a small, but important cohort of aboriginals with MS; being the largest identified to date. There was evidence of more rapid MS progression in aboriginals compared with non-aboriginals.

Relative mortality and survival in multiple sclerosis: findings from British Columbia, Canada.

OBJECTIVE: To examine mortality and factors associated with survival in a population based multiple sclerosis (MS) cohort. METHODS: Clinical and demographic data of MS patients registered with the British Columbia MS clinics (1980-2004) were linked to provincial death data, and patients were followed until death, emigration or study end (31 December 2007). Absolute survival and the influence of patient characteristics (sex, disease course (primary progressive (PPMS) vs relapsing onset (R-MS)) and onset age) were estimated by Kaplan-Meier analyses (from birth and disease onset). Mortality relative to the general population was examined using standardised mortality ratios. Excess mortality associated with patient characteristics and time period of cohort entry was assessed by relative survival modelling. RESULTS: Of 6917 patients, 1025 died. Median survival age was 78.6 years (95% CI 77.5 to 79.7) for women and 74.3 years (95% CI 73.1 to 75.4) for men. Survival from onset was longer for R-MS (49.7 years; 95% CI 47.9 to 51.5) than for PPMS (32.5 years; 95% CI 29.5 to 35.7); however, survival age was similar. The overall standardised mortality ratios was 2.89 (95% CI 2.71 to 3.07), and patients survived approximately 6 years less than expected, relative to the general population. PPMS had a higher relative mortality risk compared with R-MS (relative mortality ratio (RMR) 1.52; 95% CI 1.30 to 1.80). Women with PPMS had a relative survival disadvantage compared with men with PPMS (RMR 1.55; 95% CI 1.19 to 2.01). Relative survival within 10 years of cohort entry was similar between time periods. CONCLUSIONS: Some of the longest MS survival times are reported here but the risk of death was still greater than in the age, sex and calendar year matched general population. No evidence of increased survival over time was found when improved survival in the general population was taken into consideration.

Autologous haematopoietic stem cell transplantation with an intermediate intensity conditioning regimen in multiple sclerosis: the Italian multi-centre experience.

BACKGROUND: Over recent years numerous patients with severe forms of multiple sclerosis (MS) refractory to conventional therapies have been treated with intense immunosuppression followed by autologous haematopoietic stem cell transplantation (AHSCT). The clinical outcome and the toxicity of AHSCT can be diverse, depending on the various types of conditioning protocols and on the disease phase. OBJECTIVES: To report the Italian experience on all the consecutive patients with MS treated with AHSCT with an intermediate intensity conditioning regimen, named BEAM/ATG, in the period from 1996 to 2008. METHODS: Clinical and magnetic resonance imaging outcomes of 74 patients were collected after a median follow-up period of 48.3 (range = 0.8-126) months. RESULTS: Two patients (2.7%) died from transplant-related causes. After 5 years, 66% of patients remained stable or improved. Among patients with a follow-up longer than 1 year, eight out of 25 subjects with a relapsing-remitting course (31%) had a 6-12 months confirmed Expanded Disability Status Scale improvement > 1 point after AHSCT as compared with one out of 36 (3%) patients with a secondary progressive disease course (p = 0.009). Among the 18 cases with a follow-up longer than 7 years, eight (44%) remained stable or had a sustained improvement while 10 (56%), after an initial period of stabilization or improvement with median duration of 3.5 years, showed a slow disability progression. CONCLUSIONS: This study shows that AHSCT with a BEAM/ATG conditioning regimen has a sustained effect in suppressing disease progression in aggressive MS cases unresponsive to conventional therapies. It can also cause a sustained clinical improvement, especially if treated subjects are still in the relapsing-remitting phase of the disease.

A Swedish national post-marketing surveillance study of natalizumab treatment in multiple sclerosis.

BACKGROUND: A post marketing surveillance study was conducted to evaluate safety and efficacy of natalizumab in Swedish multiple sclerosis (MS) patients since its introduction in August 2006 until March 2010. METHODS: Patients were registered in the web-based Swedish MS-registry at 40 locations and evaluated every 6 months. Adverse events and clinical outcomes were recorded. RESULTS: One thousand one hundred and fifty-two patients were included (71.4% female) and 149 patients stopped treatment; the main reason was planned pregnancy. Anti-natalizumab antibodies were found in 4.5% (52 patients) of which 1.6% displayed persistent antibodies. Serious adverse events were rare, but included three cases with progressive multifocal leukoencephalopathy (PML). There were seven fatal cases, probably unrelated to the natalizumab treatment. For relapsing-remitting MS patients (n=901), mean Expanded Disability Status Scale (EDSS, -10.7%), Multiple Sclerosis Severity Scale (MSSS, -20.4%), Multiple Sclerosis Impact Scale (MSIS-29, physical -9.9%, psychological -13.3%) and Symbol Digit Modalities Test (SDMT, +10.7%) all showed significant improvements during 24 months of treatment with natalizumab. The Swedish web-based MS quality registry proved to function as a platform for post-marketing MS drug surveillance, providing long-term data regarding drug effects and adverse events beyond clinical trials. CONCLUSIONS: Our results indicate that natalizumab is generally well tolerated and has sustained efficacy for patients with active MS, though the risk of PML is still an important concern.

Primary progressive versus relapsing-onset multiple sclerosis: presence and prognostic value of cerebrospinal fluid oligoclonal IgM.

BACKGROUND: There is increasing evidence on cerebrospinal fluid (CSF) oligoclonal IgM (OCIgM) predicting a more aggressive disease course in relapsing-remitting Multiple Sclerosis (MS), while there is a scarcity of data for primary progressive MS (PPMS). OBJECTIVE: Our aim was to investigate the presence and possible prognostic value of CSF OCIgM in a group of PPMS and in a group of relapsing-onset MS patients. The possible prognostic role of other clinical and biological factors was also evaluated. METHODS: We calculated the impact of single clinical and biological factors, including CSF OCIgM at onset, on the probability of reaching an Expanded Disability Status Scale of 3 and 4 in 45 PPMS and 104 relapsing-onset MS patients. RESULTS: CSF OCIgM were found in only 13% of PPMS patients and did not influence the time taken to reach an Expanded Disability Status Scale of 3 and 4. Conversely, they were present in 46% of relapsing-onset MS patients and increased the risk of reaching an Expanded Disability Status Scale of 4. Clinical factors with a negative prognostic value in PPMS were age at onset <30 years and onset with pyramidal symptoms, while onset with sensory symptoms in relapsing-onset MS predicted a more favourable course. CONCLUSION: This study confirms that, in relapsing-onset MS patients, the presence of CSF OCIgM at onset predicts a worse disease course. In the cohort of PPMS patients, however, CSF OCIgM were rare, suggesting that heterogeneous pathogenetic mechanisms may be involved in the different MS forms.

Cross-sectional study assessing long-term safety of interferon-beta-1b for relapsing-remitting MS.

OBJECTIVE: The 16-Year Long-Term Follow-Up (LTF) to the pivotal interferon-beta-1b (IFNbeta-1b) trial explored clinical, MRI, cognitive, and patient-reported outcomes. Here, we report the safety assessments. METHODS: In the pivotal study, 372 patients were randomized to placebo (n = 123), IFNbeta-1b 50 microg (n = 125), or IFNbeta-1b 250 microg (n = 124) subcutaneously every other day for up to 5 years. Sixteen years later, patients were asked to participate in this cross-sectional follow-up study. No particular therapy was stipulated during follow-up. Adverse events experienced since the pivotal trial were recorded. Neutralizing antibodies (NAbs) to IFNbeta-1b were measured using the myxovirus protein A induction assay. Statistical analyses were descriptive. RESULTS: In total, 88.2% of patients (328/372) were identified. Some centers achieved 100% ascertainment, obviating selection bias. Treatment-related adverse events (e.g., leukopenia and liver and thyroid dysfunction) reported by LTF participants were in keeping with those previously established. Based on a follow-up period that includes 2,000 patient-years of IFNbeta-1b treatment, no new adverse events were observed that were associated with long-term IFNbeta-1b exposure. By LTF, NAbs to IFNbeta-1b disappeared in the majority (76%) of NAb-positive patients. NAb status during the pivotal study appeared to have no impact on long-term clinical and MRI outcomes. There were more deaths among patients assigned to placebo in the pivotal study (20/109 [18.3%]) compared with patients who received IFNbeta-1b 50 microg (9/108 [8.3%]) or IFNbeta-1b 250 microg (6/111 [5.4%]). CONCLUSION: The results from the 16-Year Long-Term Follow-Up study support the long-term safety of interferon-beta-1b therapy in multiple sclerosis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that patients with relapsing-remitting MS taking IFNbeta-1b 50 microg or 250 microg subcutaneously every other day for up to 5 years, with subsequent unspecified treatment, have fewer deaths after 16 years of follow-up than similar patients on placebo for up to 5 years, with subsequent unspecified treatment (risk difference 11.5%, 95% confidence interval 4-19).

Long-term follow-up of the original interferon-beta1b trial in multiple sclerosis: design and lessons from a 16-year observational study.

OBJECTIVE: This article describes the design of and difficulties inherent in the execution of a long-term, observational trial that sought to assess the validity of short-term measures of multiple sclerosis (MS) (eg, relapse rate, inflammatory lesions) for long-term disease outcomes. METHODS: In the original double-blind, placebo-controlled interferon (IFN)-p1b study, 372 patients with relapsing-remitting MS (Expanded Disability Status Scale score 0.0-5.5) were randomly assigned to IFN-beta1b 50 ug (n = 125), IFN-beta1b 250 microg (n = 124), or placebo (n = 123) for 2 years. These patients were recruited 16 years later for participation in this long-term follow-up (LTF) study, which had no exclusion criteria or drug interventions. RESULTS: The 11 centers identified 88.2% (328/372) of the original study patients at LTF; however, 10.8% (n = 40) refused to participate and 9.4% (n = 35) were deceased. Detailed evaluations were available for 260 patients, which included 7 deceased patients. No differences in demographic or baseline disease characteristics were found between individuals who did and did not participate in the LTF. More patients randomly assigned to placebo in the original trial were deceased (20/123 [16.3%]) than those assigned to IFN-beta1b 50 microg (9/125 [7.2%]; uncorrected P = 0.044) or IFN-beta1b 250 microg (6/124 [4.8%]; uncorrected P = 0.003). CONCLUSIONS: Although most patients (88.2%) were identified at LTF, ascertainment was incomplete. This was attributable to patients' refusal to participate, loss to follow-up, or death. Delays in the registration of death data and recent privacy legislation provided further barriers. Mortality was lower for patients originally randomized to receive IFN-beta1b rather than placebo. We recommend that all short-term trials on chronic diseases include provisions for LTF.