Ali Manouchehrinia

A significant decrease in diagnosis of primary progressive multiple sclerosis: A cohort study

Background: Several reports indicate changes to prevalence, incidence, female-to-male ratio in multiple sclerosis. Diagnostic criteria, course definitions and clinical management of the disease have also undergone change during the recent decades. Objective: To investigate temporal trends in the diagnosis of primary progressive multiple sclerosis (PPMS) in Sweden. Methods: Through the Swedish MS registry we investigated the proportion of PPMS diagnosis in birth, diagnosis and age period cohorts using Poisson regression. Results: A total of 16,915 patients were categorised into six birth-cohorts from 1946 to 1975 and seven date-of-diagnosis-cohorts from 1980 to 2014. We observed a decrease in the uncorrected analysis of diagnosis of PPMS from 19.2% to 2.2% and an average decrease of 23% (p < 0.001) per 5-year birth-cohort in the adjusted analysis. An average 21% (p < 0.001) decrease per diagnosis-cohort was seen. In the age-specific diagnosis period cohorts the same decreasing trend of PPMS diagnosis was observed in almost all groups. Conclusion: The diagnosis of PPMS has significantly decreased in Sweden specifically after introduction of disease-modifying treatments. Such decrease can have severe impacts on the future research on PPMS. Our data also suggest that the current trend to emphasise presence or absence of inflammatory activity is already reflected in clinical practice.

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.

Rituximab in multiple sclerosis: Frequency and clinical relevance of anti-drug antibodies:

Background: Rituximab is a chimeric monoclonal anti-CD20 B-cell-depleting antibody increasingly used off-label in multiple sclerosis (MS). The clinical relevance of anti-drug antibodies (ADAs) against rituximab in MS is unknown. Objective: To determine frequency of ADA in relation to B-cell counts, allergic reactions and clinical efficacy in a large cohort of MS-treated patients. Methods: Cross-sectional study with collection of serum samples from 339 MS patients immediately before a scheduled rituximab infusion. ADAs were detected using an in-house–validated electrochemiluminescent immunoassay and a commercial enzyme-linked immunosorbent assay (ELISA) to compare methods. Data on patient demographics and clinical outcomes were retrieved from the Swedish MS Registry and patient records. Results: ADAs were detected in 37% of relapsing–remitting MS and 26% in progressive forms of MS. Presence of ADAs decreased with increasing number of rituximab infusions. There was a significant association between both presence and titres of ADAs and incomplete B-cell depletion, but not with infusion/adverse reactions or clinical outcomes at the group level. Only five patients terminated rituximab during follow-up, four of which were ADA positive. Conclusion: Rituximab treatment is associated with a high degree of ADAs, which correlates with efficacy of B-cell depletion; however, the clinical relevance of ADAs remains uncertain.

Towards personalized therapy for multiple sclerosis: prediction of individual treatment response

&NA; Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease‐modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non‐overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre‐baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2–4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease‐modifying therapies at the time of their commencement.

Clinical course of multiple sclerosis: A nationwide cohort study.

Background: The course of multiple sclerosis (MS) has been studied in several cohorts; however, results have varied significantly. Objective: To describe the clinical course of MS in a nationwide cohort of patients. Method: Data from the Swedish MS register (SMSreg) were used to estimate the median time to the sustained Expanded Disability Status Scale (EDSS) scores 3.0, 4.0 and 6.0, onset of secondary progressive multiple sclerosis (SPMS) and death using Kaplan–Meier method. A possible effect of first-line treatments on age at EDSS 6.0 and SPMS was estimated. Results: In all, 12,703 patients were included. Median ages at EDSS scores 3.0, 4.0 and 6.0 were 55.4 (95% confidence interval (CI): 54.8−55.8), 60.7 (95% CI: 60.1−61.2) and 64.3 (95% CI: 63.6−64.7), respectively. Median age at SPMS was 57.4 (95% CI: 56.9−57.9). The median age at the time of death was 80.5 (95% CI: 79.9−81.1). Males and progressive-onset patients showed higher risks of disability worsening. On average, treated patients gained 1.6 years (95% CI: 0.2−3) to EDSS 6.0 as a result of treatment. Conclusion: Ages at disability milestones in this population-based cohort were higher than previously described in clinic- and regional-based samples. Nevertheless, MS patients die at younger age and live at an average almost 20 years with moderate and 30 years with severe disability.

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.

Income in Multiple Sclerosis Patients with Different Disease Phenotypes

Background Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course. Objective To analyze sources and levels of income among MS patients in relation to disease phenotype with a special focus on identifying differences/similarities between primary progressive MS (PPMS) and secondary progressive MS (SPMS). Methods A total of 6890 MS patients aged 21−64 years and living in Sweden in 2010 were identified for this cross-sectional study. Descriptive statistics, logistic, truncated linear, and zero-inflated negative binomial regression models were used to estimate differences in income between SPMS, PPMS and relapsing-remitting MS (RRMS) patients. Results RRMS patients earned almost twice as much as PPMS and SPMS patients (on average SEK 204,500, SEK 114,500, and SEK 79,800 in 2010, respectively). The difference in earnings between PPMS and SPMS was not statistically significant when analyzed with multivariable regression. The estimated odds ratio for PPMS patients to have income from earnings was not significantly different from SPMS patients (95% CI 0.98 to 1.59). PPMS and RRMS patients were less likely to receive benefits when compared to SPMS patients (by 6% and 27% lower, respectively). Conclusion Our findings argue for similarities between PPMS and SPMS and highlight the socioeconomic importance of preventing RRMS patients convert to SPMS.

The Temporal Retinal Nerve Fiber Layer Thickness Is the Most Important Optical Coherence Tomography Estimate in Multiple Sclerosis

Background Reduced peripapillary retinal nerve fiber layer (pRNFL) and combined ganglion cell and inner plexiform layer (GCIP) thicknesses as measured by optical coherence tomography (OCT) have been observed in multiple sclerosis (MS) patients. The purpose was to determine the most associative OCT measure to level of cognitive and physical disability in MS. Methods Data were collected from 546 MS patients and 175 healthy controls (HCs). We compared the average pRNFL, temporal pRNFL (T-pRNFL), overall inner ganglion cell/inner plexiform layer (GCIP), and the overall ganglion cell complex (GCC) including macular RNFL and GCIP thicknesses measurements in differentiating MS subtypes from HCs. The association between OCT measures, Expanded Disability Status Scale (EDSS), and Symbol Digit Modalities Test (SDMT) were assessed using generalized estimating equations models. Results Both peripapillary and macular OCT measurements could differentiate all MS subtypes from HCs. The SDMT score was significantly associated with reduced thickness of all OCT measures, mostly in average pRNFL (0.14 µm, P = 0.001) and T-pRNFL (0.17 µm, P < 0.001). The EDSS score was significantly associated with reduced inner retinal layer thickness. The largest reduction was seen in T-pRNFL (−1.52 μm, P < 0.001) and inner GCC (−1.78 μm, P < 0.001). Conclusion The T-pRNFL is highly sensitive and associated with level of both cognitive and physical disability.

Characterization of annual disease progression of multiple sclerosis patients: A population-based study

Background: Previous research characterizing factors influencing multiple sclerosis (MS) disease progression has typically been based on time to disease milestones (Kaplan–Meier, Cox hazard regression, etc.). A limitation of these methods is the handling of the often large groups of patients not reaching the milestone. Objective: To characterize clinical factors influencing MS disease progression as annual transitions from each Expanded Disability Status Scale (EDSS). Method: The annual progression of 11,964 patients from the Swedish MS Registry was analysed with 10 multinomial logistic regressions, that is, one for transition from each full EDSS with explanatory variables age, sex, age at onset, time in current EDSS, highest prior EDSS, MS course and treatment. Results: All factors (except sex) investigated had statistically significant impacts on transitions from at least one EDSS. However, significance and size of the effect are dependent on the EDSS state of the patient. Greater age, longer time in a state, highest prior EDSS, having progressive MS and treatment had significant impacts, whereas age at onset had minor impact. Conclusion: Our study confirms that established factors associated with MS disease worsening in time to disease milestones also have impacts on annual progression. This approach adds granularity to what EDSS these factors have an influence.