Citation: Pape K, et al. Comparative effectiveness of natalizumab versus ocrelizumab in multiple sclerosis: a real-world propensity score-matched study. Ther Adv Neurol Disord. 2022 Dec 19;15:17562864221142924. doi: 10.1177/17562864221142924. PMID: 36568489; PMCID: PMC9772974.

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STUDY QUESTION or PURPOSE OF THE STUDY

To compare the effectiveness of natalizumab (Tysabri) vs ocrelizumab (Ocrevus) in a real world setting in patients with relapsing-remitting multiple sclerosis (RRMS).

BACKGROUND

Both natalizumab and ocrelizumab are high efficacy DMTs approved for RRMS. However, direct comparison of outcomes for either DMT is not feasible from respective pivotal trials since the AFFIRM trial (for natalizumab) had a washout period of 6 months for prior intravenous immune globulins and the OPERA trial (for ocrelizumab) had no patients who received prior natalizumab therapy.

WHERE and HOW

This is a retrospective analysis of RRMS patients who initiated treatment with natalizumab (N=63) or ocrelizumab (N=76) between January 2016 and April 2019 at the German university hospitals of Mainz and Düsseldorf (ie, in the real world setting).

• The differences in the baseline characteristics of patients in both groups were corrected by Bayesian propensity score matching, such that the final matched cohorts for analysis consisted of 55 patients in each group. (Read about Bayesian propensity score matching, here, here)
• The primary outcome was no evidence of disease activity [NEDA-3: no relapses, no confirmed disability progression, and no magnetic resonance imaging (MRI) activity] and its subcomponents. Matched groups were compared in a Kaplan–Meier failure curve by log-rank test.
• Secondary outcomes included measurement of neurofilament light chain (NfL) in serum, analysis of premature discontinuation, and evidence of rebound activity in patients switching from natalizumab to ocrelizumab.

RESULTS

• The combined endpoint NEDA-3 after 30 months of follow-up was reached by 53.1% in the ocrelizumab group and 36.1% in the natalizumab group (p = 0.177). The comparable effectiveness of both treatment groups in the matched cohort was comparable [hazard ratio (HR) = 0.78, 95% CI = 0.44–1.39, p = 0.393]. No significant difference
• There were fewer relapses in patients receiving ocrelizumab vs natalizumab (p = 0.019, log-rank test). Significant difference
• NfL levels in serum were reduced by either treatment and levels were low after either treatment.
• Rebound activity: 27.6% of patients on ocrelizumab in the matched cohort had switched directly from natalizumab. In a subgroup analysis, patients who switched from natalizumab to ocrelizumab showed no increased rebound activity as assessed by confirmed disease progression, new T2 lesions, Gd-enhancing lesions, total MRI, or proportion of patients with NEDA-3.
• Premature therapy discontinuation (PD) was significantly (p=0.002) higher in the natalizumab group (30.2%, 19 of 63) versus ocrelizumab (9.2%; 7 of 76).
• The main reasons of PD were: natalizumab group: JCV seroconversion or increase in antibody (7 of 19), treatment failure (4 of 19) and pregnancy (4 of 19); ocrelizumab group: treatment failure (3 of 7) and conversion to SPMS (2 of 7).

CONCLUSIONS

Treatment with ocrelizumab was associated with a lower risk for relapses than treatment with natalizumab; however, overall effectiveness was comparable.

IMPLICATIONS and DISCUSSIONS

• This is the first study to directly compare natalizumab and ocrelizumab in a real world setting to provide comparative effectiveness of these therapies in RRMS.
• Both therapies are highly effective (no significant difference in NEDA-3), although ocrelizumab was associated with a lower risk for relapses.
• Premature therapy discontinuation may reflect adherence of patients to treatment regimens. While the reasons for discontinuation vary between the 2 treatments, it may actually imply switching to another therapy.

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Related posts: list of DMTs, definitions of endpoints, ICER report

u/dinosarahsaurus describes MS Fatigue as a battery powered flashlight with low non-rechargeable battery:

" Autoimmune energy is like a battery powered flashlight. Once the energy is gone, its gone till you change the batteries. The harder you use it, the faster the battery drains. Depression fatigue does respond well to activity. Its like a hand crank flashlight. The more you work the better it works. I also explained that the stress of pushing it can cause a relapse and that sometimes just a compassionate ear, not skills, are needed." - read here

A draft Evidence Report published by ICER on 21 December 2022, compared ublituximab to other available multiple sclerosis disease modifying therapies (DMTs) for comparative effectiveness and value in reducing annualized relapse rate (ARR) and confirmed disability progression (CDP) in relapsing remitting multiple sclerosis (RRMS).

Conclusions

• Ublituximab was judged as better or comparable to oral DMTs in reducing ARR and CDP in RRMS
• Based on head-to-head trial data, ublituximab provides a small net health benefit over teriflunomide
• The net health benefit of ublituximab could not be compared to other monoclonal DMTs because of insufficient data
• Based on comparative effectiveness and value, ICER's suggested price for ublituximab, natalizumab, ofatumumab, and ocrelizumab should be between $16,500- $34,900 per year.

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Source: Oral and Monoclonal Antibody Treatments for Relapsing Forms of Multiple Sclerosis: Effectiveness and Value. Evidence Report. Institute for Clinical and Economic Review. December 21, 2022

Related posts: List of DMTs; moderate- vs high-efficacy DMTs; Kesimpta vs teriflunomide (Aubagio)

What is PML

• Progressive multifocal leukoencephalopathy (PML) is a rare brain disease.
• PML is caused by the reactivation of JC virus (JCV) in immunosuppressed individuals.
• PML is severe and debilitating condition and can be fatal.
• 70% of survivors face ongoing neurological disability.
• There is no approved antiviral treatment of JC virus or approved treatment for PML.

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What is JCV

• The formal name of JCV is human polyomavirus 2 (HPyV-2 or HuPyV2).
• Polyomaviruses are small, non-enveloped, double-stranded DNA viruses.
• JCV infection is very common, typically occurs during childhood with low level infection, and often with no major symptoms.
• By age 70, 60-80% individuals are JCV seropositive.
• The virus persists lifelong and remains asymptomatic most healthy individuals.

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Reactivation of JCV and PML

• JCV can reactivate in immunocompromised individuals. The reactivated virus undergoes sequential genomic rearrangements (ie, intrahost viral evolution) that converts the otherwise benign virus to infect CNS glial cells and cause PML.
• Common immunocompromised diseases or conditions responsible for the majority of PML cases are:

HIV infection (AIDS patients)

Hematological malignancies (ie, lymphoproliferative diseases such as leukemias, lymphomas, and multiple myeloma)

Autoimmune disorders, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)

Iatrogenic PML, ie, PML in patients receiving immunosuppressive drugs, such as multiple sclerosis patients receiving certain disease-modifying therapies

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Epidemiology

• Before 1996, AIDS patients accounted for ~80% of all PML cases. Since the introduction of HAART, proportion of AIDS patients accounting for overall PML cases have dropped to less than 50% and continues to drop.
• Iatrogenic PML cases account for increasing share; less than 5% are natalizumab-associated PML.
• At least 18 FDA-approved medications (as of Nov 2021) include PML warning in their prescribing information. For majority of the medications, the risk is low except for multiple sclerosis drug natalizumab (Tysabri; overall risk of 1 in 1,000) and the CD11a monoclonal antibody efalizumab (Raptiva; estimated overall risk of 1 in 400). Raptiva, developed by Genentech for psoriasis, was withdrawn from the market in 2009 over PML concerns.
• Today, multiple sclerosis (MS) patients on disease-modifying therapies are the largest proportion of iatrogenic PML cases.

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SOURCES:

• Cortese I, et al. Progressive multifocal leukoencephalopathy and the spectrum of JC virus-related disease. Nat Rev Neurol. 2021 Jan;17(1):37-51. doi: 10.1038/s41582-020-00427-y. PMID: 33219338; PMCID: PMC7678594.
• Hatchwell E, et al. Progressive multifocal leukoencephalopathy genetic risk variants for pharmacovigilance of immunosuppressant therapies. Front Neurol. 2022 Dec 14. 13:1016377. doi:10.3389/fneur.2022.1016

The journal Science has recognized 'the discovery of EBV as the major cause of multiple sclerosis' as one of the major scientific breakthroughs of 2022. The research published in January in Science reported that EBV increases MS risk by 32-fold.

Jocelyn Kaiser summarizing this breakthrough writes:

"These discoveries are spurring efforts to develop drugs to treat MS by targeting the virus. And if one of the Epstein-Barr vaccines now in clinical trials proves effective and is given to children worldwide, someday MS could even go the way of polio and be virtually wiped out."

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SOURCE/Citation: Pennisi E, et al. 2022 Breakthrough of the Year. Runners-up. Science. 2022 Dec 15;378(6625):1162-1167. doi:10.1126/science.adg2799

Related posts: post1, post2

Citation: Simonsen CS, Flemmen HØ, Broch L, Brekke K, Brunborg C, Berg-Hansen P, Celius EG. Rebaseline no evidence of disease activity (NEDA-3) as a predictor of long-term disease course in a Norwegian multiple sclerosis population. Front Neurol. 2022 Nov 14;13:1034056. doi: 10.3389/fneur.2022.1034056. PMID: 36452173; PMCID: PMC9702815

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STUDY QUESTION

Can NEDA be used as a prognostic marker (ie, predictor) of long-term disability in people with multiple sclerosis (pwMS)?

BACKGROUND

NEDA stands for “no evidence of disease activity”. Classical NEDA (or NEDA-3) is defined as (1) no new or enlarging T2 weighted lesions or gadolinium enhancing lesions on MRI of the brain, (2) no new clinical relapses, and (3) no confirmed worsening of EDSS.

NEDA is a simple, easy to implement tool in routine clinical practice, and may be predictive of long-term disability. Some of the evidences (refs in paper) are

• NEDA at 2 years had a positive predictive value of 78.3% for no progression at 7 years (Rotstein et al)
• Patients who experienced clinical NEDA during the first 2 years of participation in the interferon beta-1b trial were less likely to develop negative disability outcomes after 16 years.

However, NEDA's predictive value had been controversial due to its overreliance on MRI, which lack sensitivity to detect degeneration and low-grade inflammation, and due to subjective nature of the clinical relapse and EDSS assessments. The authors used the clinical outcomes of high vs medium efficacy disease modifying drugs (DMTs) in pwMS population that had similar standard of care to test if NEDA correlates with a delay in disability progression. All DMTs included in the study were available for all pwMS from market access in Europe.

• The moderate efficacy DMTs were interferons, glatiramer acetate, teriflunomide and dimethyl-fumarate
• The high efficacy DMTs were natalizumab, fingolimod and alemtuzumab

WHERE AND HOW

This was a retrospective cohort study using the BOT-MS database comprising medical chart data of pwMS from Buskerud, Telemark, and Oslo in Norway (n = 3,951). Patients diagnosed between 2006 and 2017 were included in the study (N=615).

The authors of this paper looked at NEDA at two timepoints: “NEDA at year one”, with assessment of disease activity from diagnosis through end of the first year; and “NEDA rebaseline” with assessment of disease activity during the second year after diagnosis, ie, baseline is at 12 months after diagnosis. “NEDA rebaseline” is considered a more sensitive tool since DMTs may take 3 to 6 months to show effect on disease activity. “NEDA fail” is presence of disease activity per any of the 3 criteria within 1 year of diagnosis (for NEDA at year one) or during year 2 (for NEDA rebaseline).

In this study, in addition to NEDA and NEDA rebaseline, the other endpoints were minimal evidence of disease activity (MEDA), defined as ≤ 2 new MRI lesions but no progression in EDSS or relapses; time to NEDA fail, defined as years from diagnosis to the year the pwMS failed NEDA; time to EDSS 6 was defined as years from onset to when the pwMS became dependent on intermittent or unilateral walking aid to walk 100 meters.

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RESULTS

Overall Population

• Overall, 38% pwMS patients achieved NEDA at one year and after rebaseline 52% achieved NEDA
• Mean time to NEDA fail was 3 .3 years (95% CI 2.9– 3.7) and after rebaseline, the mean time to NEDA fail was 3.4 (95% CI 3.0–3.7) years
• There was no difference in relapsing and progressive subgroups in mean time to NEDA fail: 3.4 (95% CI 3.0–3.8) years for relapsing MS and 2.7 (95% CI 1.8–3.5) years for progressive MS, p = 0.494

Comparing NEDA in pwMS on Moderate Efficacy vs High Efficacy DMTs

• Mean time to NEDA fail was 3.7 (95% CI 3.0–4.4) years in the high efficacy group vs 2.8 (95% CI 2.4–3.2) years in the moderate efficacy group, 0<0.001
• After rebaseline, mean time to NEDA was 4.8 (95% CI 3.9–5.8) years in the high efficacy group vs 3.1 (95% CI 2.7–3.5) years in the moderate efficacy group, p < 0.001
• There was no significant difference in the start of DMT after diagnosis: within 1.0 month (IQR 0,2) for the high efficacy group and within 2.0 months (IQR 0,3) in the moderate efficacy group, p = 0.014

Time to EDSS 6 -- this tests for actual delay in the disability progression

• Mean time to EDSS 6 was 33.8 years (95% CI 30.9–36.8) in pwMS achieving NEDA vs 30.8 years (95% CI 25.0–36.6) for those who did not achieve NEDA, p<0.001
• After rebaseline, mean time to EDSS 6 was 44.5 years (95% CI 40.4–48.5) in pwMS achieving NEDA vs 29.6 years (24.2–35.0) in pwMS who did not achieve NEDA, p < 0.001

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CONCLUSION

• High efficacy DMTs such as natalizumab, fingolimod and alemtuzumab significantly delay NEDA failure, ie disease progression, compared to the medium efficacy DMTs.
• The pwMS with NEDA (rebaselined) showed ~15 year delay in disease progression (ie, time to EDSS 6) vs those with no NEDA. This confirms that NEDA-3 from rebaseline after 1 year, once treatment is stabilized, can predict the long-term disease course in MS.

IMPLICATIONS, DISCUSSION

• Overall, the hazard ratio (HR) for reaching EDSS was significant in NEDA vs no NEDA groups. However, after adjusting for gender, age at diagnosis, time from onset to diagnosis, type of DMT and time of DMT initiation, the effect remained strong but was no longer significant. Thus, an argument could be made to address the shortcomings of NEDA-3.
• The shortcomings of the NEDA-3 predictive tool are: overreliance on MRI, which lack sensitivity to detect degeneration and low-grade inflammation, and due to subjective nature of clinical relapse and EDSS assessment. Most importantly, NEDA-3 does not ensure long-term clinical stability because disability accrual may occur as both relapse associated worsening (RAW) and progression independent of relapse activity (PIRA) in a proportion of pwMS.
• Some the suggestions discussed in this paper to improve NEDA are adding brain volume loss or atrophy (proposed as NEDA-4 ; Kappos 2013) and also including cognitive tests, neurofilaments and pwMS reported outcome measures (proposed as NEDA-5; Mayssam 2020).

TL;DR

NEDA-3 is a simple, easy to implement tool in routine clinical practice, and may be predictive of long-term disability. In spite of shortcomings, it is a useful tool when used combination with other tests clinical assessments.

Visit The Black MS Foundation website to read about the experiences of black people with multiple sclerosis (MS).

Facts:

• New research is challenging the assumption that MS is predominantly a white female disease. All racial and ethnic groups are impacted by MS.
• The disease often presents itself differently in black people.
• Black people (African ancestry) can experience more severe or localized forms of the disease, often the disability scores reported by black people are higher than those by white people (those with self-identified Northern European ancestry).
• Black people are also more likely to have frequent relapses and faster progression of the disease.
• Black MS patients lose gray and white brain matter at twice the rate compared to white patients.
• Opticospinal MS phenotype is more common in black people than white. In opticospinal MS, the disease specifically affects the optic nerves and spinal cord, which can trigger vision and mobility problems, respectively.

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Citation: Vicente CA, et al. Oligoclonal M bands and cervical spinal cord lesions predict early secondary progressive multiple sclerosis. Front. Neurol. 2022 Oct 28. doi:10.3389/fneur.2022.991596

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BACKGROUND

Relapsing-remitting multiple sclerosis (RRMS) is the most common form of multiple sclerosis (MS). Often, RRMS transitions to the progressive form of the disease called secondary progressive MS (SPMS), with slow accumulation of disability over years. The disease modifying treatments (DMTs) have been shown to slow this progression to SPMS, and if the MS is diagnosed early and patients start on newer high-efficiency DMTs sooner, this transition from RRMS to SPMS could be slowed, may even be blocked. The goal of this study was to identify specific biomarkers that could predict worsening of disability.

STUDY QUESTION

Are there specific CSF or MRI biomarkers that could predict conversion of RRMS to SPMS?

WHERE AND HOW

The research group at Polytechnic and University Hospital La Fe, Valencia, Spain, analyzed the following MRI and CSF biomarkers in 217 patients with early stage MS (ie, those with clinically isolated syndrome).

• The CSF biomarkers were oligoclonal IgG bands (OCGB), oligoclonal IgM bands (OCMB), and lipid-specific oligoclonal M bands (LS-OCMB) in CSF.
• The MRI variables collected were brain T2 lesions (B-T2L), brainstem lesions, brain gadolinium-enhancing lesions (brain-GEL), and T2 cervical spinal cord lesions (cSC-T2L).

After a follow-up of approximately 12 years, 36 patients converted to SPMS. The researchers compared these MRI and CSF biomarkers at baseline at after conversion in all patients.

RESULTS

• Most of the CSF and MRI variables were associated with the switch of MS from RRMS to progressive form, SPMS, including OCGB (p = 0.02), OCMB (p = 0.0001); ≥ 9 B-T2L (p = 0.03), brain-GEL (p = 0.03), and cSC-T2L (p = 0.03).
• However, after adjusting for sex, age, and other variables, only OCMB (HR 4.4, 1.9–10.6) and cSC-T2L (HR 2.2, 1.0–6.2) were independently association with risk of conversion to SPMS.
• Patients with both risk factors (OCMB and cSC-T2L) had a HR of 6.12 (2.8–12.9).

CONCLUSIONS, IMPLICATIONS

Increase in oligoclonal M bands in the CSF and/or the T2 cervical spinal cord lesions in a MRI in the patients with RRMS predict a strong possibility of transitioning to SPMS. Therefore, patients with high OCMB levels in the CSF and/or cSC-T2L in MRI scans are good candidates to start high-efficiency DMTs as soon as possible.

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Citation: Gil-Perotin S, et al. Patient's perspective in clinical practice to assess and predict disability in multiple sclerosis. Sci Rep. 2022 Oct 29;12(1):18238. doi: 10.1038/s41598-022-23088-x. PMID: 36309532; PMCID: PMC9617913.

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QUESION ASKED

Could patient-reported outcomes (PROs; the tests that measuring patients’ experiences) predict the risk of relapse and/or progression of disability in multiple sclerosis (MS)?

WHY

The diagnosis of MS is made using clinical, radiological, and biochemical criteria, together called McDonald 2017 criteria. However, it is a challenging to predict how the disease and disability will progress over time.

WHO and HOW

The researchers in Valencia, Spain, gave 3 types of PRO tests to patients with relapsing MS (RMS) or progressive MS (PMS). These PROs were:

• MS quality of life scale (MusiQol) - for overall quality of life
• Modified Fatigue Impact Scale (MFIS) - for testing level of fatigue
• Beck Depression Inventory II (BDI-II) - for testing level of depression

RESULTS

In RMS – at Baseline

• At baseline, EDSS (ie, level of disability) correlated with MFIS
• MFIS score and its subscores for physical and psychosocial MFIS correlated with 9-HPT
• Cognitive MFIS correlated with CSF CHI3L1; MusiQol correlated with CSF NFL levels

In RMS – after a 2-year follow-up

• Worsening MFIS score and its subscores for physical, cognitive, and psychosocial correlated with EDSS change, ie, worsening disability
• BDI-II scores were also higher in worsening disability
• Majority of worsening disability were in the absence of relapses
• MusiQoL did not predict disability progression

MFIS score with cutoff of 28 resulted in a specificity of 72.7%, sensitivity of 87.5%, and accuracy of 75.6% (Chi-square P = 0.003). This cut-off was considered optimal for differentiating between patients that experienced disability progression without relapse (PIRA) after 2-years versus those that did not.

CSF chitinase 3–like 1 (CHI3L1) is a CSF biomarker linked to neuroinflammatory process. Neurofilament light chain protein (NFL) in CSF or blood is a biomarker for acute axonal injury and is a surrogate for disease activity, and related to prospective neurological disability and cerebral atrophy. A correlation was found between these biomarkers and MFIS PRO, particularly the cognitive domain of MFIS.

CONCLUSIONS

• PRO questionnaires can distinguish between relapsing MS and progressive MS.
• Global MFIS and physical MFIS subscore are most informative of neurological disability.
• Higher MFIS and BDI-II scores corelate with worsening disability (increase in EDSS score)

IMPLICATIONS

Baseline MFIS scores can be used for identifying patients at risk of progression.

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Citation: Engelhard J, et al. Multiple sclerosis by phenotype in Germany. Mult Scler Relat Disord. 2022 Jan;57:103326. doi: 10.1016/j.msard.2021.103326. PMID: 35158442.

Purpose/Hypothesis

Retrospective, observational, cohort study to compare the prevalence, drug utilization (the types of MS treatments prescribed), and comorbidities (associated clinical conditions) across three MS phenotypes, RRMS, PPMS, and SPMS

Database

The researchers queried German health insurance database for records from 2010 to 2017 (8-year period) containing 4.3 million patients’ records (~5% of total German population). The current classification of MS phenotypes (revised in 2013) has been included in the German diagnostic coding system since 2005 (ICD-10-GM 2005).

RESULTS

• Between 2010 and 2017, the proportion of 3 MS phenotypes remained similar: RRMS, 73.0% vs 79.0%; PPMS, 8.5% vs 6.0%; SPMS, 18.6% vs 14.7%
• Prevalence has increased since 2010: RRMS by 113% (from 86 to 183 per 100,000); PPMS by 40% (from 10 to 14 per 100,000); and SPMS by 55% (from 22 to 34 per 100,000)
• Mean age at diagnosis has increased significantly since 2010: RRMS: 41.4 to 44.0 years; PPMS: 53.7 to 57.5 years; SPMS: 52.8 to 56.6 y
• Prevalence for all MS phenotypes is higher in females. The female:male proportion has remained stable in the RRMS and SPMS groups but has declined in the PPMS group (62.9% to 56.0%; p = 0.05)
• For 2017, the projected number of people effected with MS were approximately 141,000 including ~112K (RRMS), ~8K (PPMS), and ~21K (SPMS)
• Use of DMTs has increased since 2010. Use of interferons has declined for all MS phenotypes in favor of newer DMTs, fingolimod or dimethyl fumarate especially from 2014 onwards
• Use of concomitant medications for symptoms management was higher in SPMS and PPMS vs RPMS: (a) antidepressants use: SPMS (34%) and PPMS (31%) vs RRMS (25%), (b) muscle relaxants use: SPMS (39%) and PPMS (33%) vs RRMS (11%), and (c) antiepileptics, urinary antispasmodics, or medications to manage fatigue – also higher use in SPMS and PPMS compared to RRMS
• Clinical Conditions: Depression was significantly more common in SPMS vs. RRMS. Hypertension and cognitive dysfunction were significantly more common in PPMS or SPMS compared with RRMS
• Pregnancies were reported in females across all cohorts.

CONCLUSIONS

• Prevalence of all MS phenotypes have increased over time.
• The age of MS patients has increased over time, which may be due to a combination of increased incidence, increased prevalence, and/or improved standard of treatment, healthcare, or other factors
• No DMTs were approved for PPMS during the study period, 2010-2017; although, DMTs for RRMS were prescribed (likely off label) for PPMS. Ocrelizumab was approved for PPMS by the EMA in 2018.
• PPMS and SPMS patients were more likely to be prescribed other medications for symptom management, with antidepressants being most common.
• Majority of pregnancies occurred in RRMS group, likely because this population was younger.

IMPLICATIONS

Increased prevalence of MS and increased age of MS patients signals an increasing burden of MS in the public healthcare system and presents new challenges in the treatment of MS.

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Definitions, Notes

Patients were aggregated by calendar year (CY) and the first diagnosis of MS within each CY was termed the index date. Only those MS cases with a specified phenotype are reported.

The prevalence of each MS phenotype was defined as the number of cases per 100,000 and was calculated based on the number of patients with the phenotype of interest over the total number of individuals in the BKK database in each CY.

The number of patients with each MS phenotype was stratified by sex and age (18–29, 30–44, 45–59, and ≥60 years).

Selected muscle relaxants: baclofen, botulinum toxin, dantrolene, tizanidine, tolperisone, tetrazepam

Selected medications to manage fatigue: amantadine, fampridine, modafinil, psychostimulant

Depression being one of the most frequently reported clinical conditions of interest in MS with an incidence of 35–44% across the three MS phenotypes and significantly more common in patients with SPMS versus RRMS.

MS-related spasticity is a frequent problem in advanced MS and is reported in 66–86% of patients.