Background

Alemtuzumab has proven to be an effective treatment for patients with highly active multiple sclerosis (MS). However, its use has been limited by adverse events (AEs) as secondary autoimmunity, being the most frequent those involving the thyroid gland, observed in around 40% of patients.

Objectives

To explore whether patient blood lymphocyte profile before alemtuzumab treatment initiation can identify patients with an increased risk of developing later autoimmunity.

Methods

A multicentre prospective longitudinal study was performed, including fifty‐four Relapsing-Remitting MS (RRMS) patients diagnosed in five Spanish hospitals. Patient blood samples were collected before initiating treatment with alemtuzumab. Autoimmune AEs were defined as the development, at any point within 2 years of follow-up, of any autoimmune thyroid-associated event, immune thrombocytopenia and/or autoimmune nephropathy. Differences were assessed using Man-Whitney U tests. Cut-off values were established using ROC curves to predict autoimmune AEs. Odds ratios were calculated by Fisher tests.

Results

Fifty‐four RRMS patients, 36 (66.7%) women, with a median (range) age of 28 (13–67) years and median (range) follow-up of 6 (0-20) years. Fourteen patients (25.9%) experienced autoimmune AEs, and all of them were dysthyroidism. No immune thrombocytopenia or nephropathies were observed. No statistical differences were found in clinical and demographic characteristics between patients who developed autoimmune AEs and those who did not. Patients who experienced autoimmune AEs before treatment onset had a higher percentage of blood CD19+ B cells (p=0.001), with a higher relative percentage of naïve B cells and plasmablasts. When explored total cell numbers, only plasmablast levels remained significant (p=0.02). A lower risk of autoimmune AEs after alemtuzumab was observed among patients with less than 7.6% of blood CD19+ B cells [odds ratio (OR) 16, confidence interval (CI) 3.86–58.95, p<0.0001] or less than 0.13% of plasmablast cells [OR 9.33, CI 2.17–42.65, p=0.002].

Conclusions

A low percentages of blood CD19+ B cells or plasmablasts before Alemtuzumab treatment predicted a lower risk of autoimmune AEs.

Background

Secondary Progressive Multiple Sclerosis (SPMS) is a clinical form of MS characterized by gradual accrual of disability independent of relapses over time. Limited information is available on decision-making in the management of MS. As a consequence, it is frequently diagnosed retrospectively, thus reducing treatment options.

Objectives

To establish consensus on patient monitoring and definition of relevant clinical variables that can support decision making in the early identification and management of disease progression.

Methods

A two-round RAND-UCLA method was used, involving a panel of 15 MS specialists in Spain. A questionnaire consisting of 72 open-ended questions from 3 dimensions (clinical, radiological and biomarkers) was circulated to the experts in Round I. Eleven additional items were included in Round II based on panel feedback in Round I. Items were rated on a 4-point Likert scale and consensus was defined as ≥66% agreement on an item. Final data are presented.

Results

Panellists agreed on the need of monitoring the patients remaining clinically and radiologically stable while on immunomodulators (93%) or immunosuppressors (73%) every 6 months, leaving the special situations to clinical judgement (80% and 93%, respectively). EDSS is the best variable to define progression (93%); six months is the minimum time to confirm disability progression independent of relapses (87%); a worsening of 2-points in any functional system (except the visual), even without changes in EDSS, suggests progression (80%), regardless of disease duration (> 20 years: 93%; 10-20 years: 87%) and age (87%). 20% time increase in T25-FW and 9HPT, together with an increase in EDSS score, are confirmatory of progression (87%). Panellists agreed to perform an annual cognitive exploration (80%), such as SDMT (100%), BRB-N (93%), BICAMS (93%). Experts agreed to evaluate QoL (80%), depression (73%) and fatigue (73%) once annually. A sustained change in brain atrophy suggests progression (80%) provided major physiological factors have been ruled-out (83%). Sustained medullary atrophy suggests progression (100%) but more precise techniques should be used to confirm a diagnosis (93.3%).

Conclusions

The overall consistency in the level of agreement in the different items is high and reinforces the results obtained. These areas of collective agreement could guide neurologists in anticipating progression and planning informed clinical and therapeutic interventions.

Background

Ocrelizumab is the first drug approved as disease modifying treatment for primary progressive (PP) multiple sclerosis (MS). As a humanized monoclonal antibody targeting CD20 cells, it is widely known that ocrelizumab treatment results in B cells depletion, but less is known about the effects of this drug in other blood leukocyte subsets of PPMS patients.

Objectives

To explore the changes induced by ocrelizumab in blood immune cells of PPMS patients to further understand their effects in the abnormal inflammatory response.

Methods

Multi-centre prospective longitudinal study including fifty‐three PPMS patients who initiated ocrelizumab treatment. Effector, memory, and regulatory cells were analyzed by flow cytometry at baseline and after 6 months of treatment. To assess differences between baseline and after 6 months, Wilcoxon matched paired tests were used and p values were corrected using Bonferroni test.

Results

Ocrelizumab decreased numbers of naïve and memory B cells (p<0.0001) and those of B cells producing interleukin (IL)-6, IL-10, granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha (p<0.0001 in all cases). A reduction of CD20+ T cell numbers (p=0.02) and percentages (p<0.0001) was also observed. We also detected a clear remodelation of the T cell compartment characterized by relative increases of the naïve/effector ratio in CD4+ (p=0.002) and CD8+ (p=0.002) T cells, and relative decreases of CD4+ (p=0.03) and CD8+ (p=0.004) T cells producing interferon-gamma. Total monocyte numbers increased (p=0.002), with no changes in those producing inflammatory cytokines. All these changes resulted in a reduction of serum neurofilament light chain (sNfL) levels (p=0.009).

Conclusions

Effector B cell depletion by ocrelizumab treatment induces changes in the T cell response of PPMS patients towards a low inflammatory profile. This resulted in a decrease of sNfL levels.

Background

Dimethyl fumarate (DMF) treatment can cause sustained severe lymphopenia, which may be associated with an increased risk of developing infections, leading to discontinuation of treatment.

Objectives

The objective of the study is to identify the frequency and severity of lymphopenia and analyze risk factors for its development in our sample of patients with remitting recurrent multiple sclerosis (RRMS) treated with DMF. Another objective is to analyze whether the appearance of lymphopenia influences the evolution of the disease.

Methods

We carried out a retrospective, descriptive and analytical study of 50 RRMS patients treated with DMF between October 2014 and June 2020, followed for an average of 36.94 months.

Results

A total of 22 patients (44%) developed lymphopenia. Eleven patients developed grade 2 and 7 patients grade 3 lymphopenia. Eighty-two percent of patients developed lymphopenia in the first year. Only in 4 patients did lymphopenia resolve, 3 cases of grade II and 1 case of grade I lymphopenia.

Those patients who developed lymphopenia had a lower absolute lymphocyte count (ALC) before the start of DMF (p 0.013). Although with a trend towards statistical significance (OR 3.88, CI 0.87-17.3. p 0.068) an age at the start of DMF greater than 55 years was not correlated with an increased risk of lymphopenia. Seventy-six percent of the patients had received previous treatments for RRMS, including glatiramer acetate(22.5%), interferon (32.5%), teriflunomide (15.5%) and fingolimod (2.5%), without posing a risk of developing grade II-III lymphopenia.

In our population, the development of lymphopenia was not correlated with a greater probability of reaching NEDA3 at 2 years. Neither was it found to be associated with an increased risk of clinical or radiological activity or discontinuation due to ineffectiveness.

In our sample, lymphopenia was associated with a four times greater risk of developing infections (OR 4.1, CI 1.07-16.1. P 0.033), although all cases were mild. Six patients (12%) discontinued DMF due to sustained grade III lymphopenia. Three of them maintained an ALC of less than 800 at least 6 months after the end of DMF.

Conclusions

In our series, lymphopenia is a frequent adverse effect, it appears especially in the first year and in most cases it remains, even months after stopping DMF. Therefore, surveillance should be increased and control of ALC should be maintained given the increased risk of infection if lymphopenia develops, especially in those patients with lower ACL at baseline.

Background

The association between demyelinating diseases and the presence of anti-N-methyl-D-Aspartate receptor antibodies (anti-NMDAR-ab) has been analyzed in recent years. This infrequent coexistence has been seen above all with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein associated disorders (MOGAD). The overlap with multiple sclerosis (MS) has been poorly described. In most of the published cases, patients presented symptoms consistent with NMDAR encephalitis, before, after, or concomitantly with demyelinating disease.

Objectives

We present the case of a patient with newly diagnosed Relapsing Remitting Multiple Sclerosis (RRMS) and with detection of anti-NMDAR-ab, without symptoms suggestive of encephalitis.

Methods

27-year-old woman, with gender identity disorder who was admitted for distal paresthesias in her lower limbs and in her hands which had developed in the last week. The examination revealed hypoesthesia and moderate hypopalestesia in these areas, with hyperreflexia in her lower limbs, suspecting myelitis as a diagnostic possibility.

Results

We performed a lumbar puncture that showed mild pleocytosis with normal proteins, increased Ig G and the presence of oligoclonal bands Ig G in cerebrospinal fluid (CSF).

Brain and spinal cord magnetic resonance showed twelve brain lesions, as well as several lesions in the cervical and dorsal spinal cord with a typical demyelinating appearance of MS and some of them with gadolinium enhancing.

In an autoimmunity study, anti-NMDAR-ab were detected at high titers in CSF and serum, with negative anti-aquoporin 4 (AQP4) and anti-MOG Ig G antibodies (performed in two centers using cell-based assay).

Given the presence of anti-NMDAR-ab, it was decided to extend the study by conducting a screening test for occult neoplasia that was negative, as well as an electroencephalogram and a neuropsychological study that did not show data suggestive of anti-NMDAR-ab clinical expression.

In the presence of a typical clinical syndrome together with characteristic findings in the complementary tests of RRMS, we treated the sensitive spinal cord outbreak with megadoses of corticosteroids with full resolution. The review of the little published evidence shows cases similar to ours that months or years later can develop NMDAR encephalitis. Given this risk, we believed that the use of anti-CD20 therapy of proven efficacy in RRMS was justified, which in turn presents a mechanism of action similar to Rituximab, widely used in pathology secondary to anti-NMDAr-ab. Finally, after a few weeks of stability, Ocrelizumab treatment was started, with a good response.

Conclusions

The coexistence of MS and NMDAR encephalitis is an entity under study. In our case, the anti-NMDAR-ab is asymptomatic so far, but it forces us to dismiss neoplasia, to monitor symptoms in the following years, and it has also been decisive in the choice of the disease-modifying drug.

Background

Magnetic resonance imaging (MRI) is widely used for the diagnosis and follow-up of patients with multiple sclerosis (MS). It is considered the most reliable and accurate paraclinical tool to evaluate disease activity and progression due to the high sensitivity to detect demyelinating lesions. Coordination between Neurology and Neuroradiology departments is essential to ensure that radiological studies are effectively performed and interpreted. However, in clinical practice, this coordination can be improved to maximize MS management and care.

Objectives

To establish a set of organizational recommendations focused on the coordination between neurologists and neuroradiologists to improve MS management in clinical practice.

Methods

A panel of 17 experts, including neurologists and neuroradiologists, from eight Spanish academic hospitals participated in the study. The Consensus Recommendation Guideline was conducted in four phases: 1) definition of the scope and methodology of the study; 2) review of the literature on good practices or recommendations in the use of MRI in MS; 3) discussion of drafted recommendations to achieve a consensus between the authors; 4) formalization and validation of the contents in a set of recommendations.

Results

We provide nine recommendations to improve the coordination between Neurology and Neuroradiology departments, which can be summarized as follows: 1) standardize the MRI requests, reports and schedules, 2) create shared protocols for MRI studies, 3) establish multidisciplinary working committees and coordination sessions, and 4) generate formal communication channels to improve the coordination between professionals from both departments. These recommendations are based on the available scientific evidence, international good practice guidelines and the experience of the panel experts.

Conclusions

We propose a series of recommendations expected to serve as a functional guide to implement improvements in the coordination between neurologists and neuroradiologists that will ultimately lead to improve the diagnosis and follow-up of MS patients.

Background

The presence of antibodies against the oligodendrocyte myelin glycoprotein (antiMOG-ab) is related to demyelinating disease of the central nervous system that especially affects the optic nerves (ON) and spinal cord (SC).

Objectives

Isolated and recurrent involvement of the SC without involvement of the ON is infrequent. More infrequently, this involvement occurs in the form of non-longitudinally extensive transverse myelitis (NLEMT).

Methods

We present two patients with the presence of antiMOG-ab and two episodes of NLEMT without ON involvement during the course of the disease.

Results

The first case is a 43-year-old man, with a history of pars planitis in childhood, who was admitted in March 2019 with lower limbs (LL) sensory symptoms and urinary sphincter disturbance of two weeks of evolution. Spinal magnetic resonance imaging (MRI) revealed an enhancing cord lesion at T4 level. The patient showed a positive determination of antiMOG-ab in serum. After treatment with methylprednisolone (MP) megadose, the patient recovered without sequelae. Chronic immunosuppression was not started after this first episode. In June 2020, symptoms compatible with a new transverse myelitis (TM) began. Complementary tests showed a new T9-T10 gadolinium (GD) enhancing lesion in MRI, and maintained antiMOG-ab positivity. It was treated with MP megadose with symptons resolution. Currently, the patient is receiving prednisone at a dose of 1mg/ kg and is pending the initiation of Rituximab.

The second case is a 48-year-old man, with no history of interest, who was admitted in November 2009 for symptoms of sensory disturbance and weakness in LL. The MRI study showed the presence of a GD enhancing lesion at C3 level and no additional alterations were observed by complementary tests. AntiMOG-ab was not determined. The patient improved after treatment with MP megadoses. Interpreted as idiopathic TM it remained asymptomatic until December 2019, when it started a clinical picture compatible with a Brown-Sequard syndrome. The spinal MRI revealed a new lesion at C6 level. On this occasion, a positive determination of antiMOG-ab was obtained in serum. It was treated with MP megadoses with almost complete resolution of the symptoms. Currently on Rituximab treatment with good response after six months.

In both patients, the first determination of anti MOG-ab was obtained using ELISA techniques in our hospital laboratory. These results were confirmed in an external laboratory using cell-based assay techniques.
In both cases, optical coherence tomography and evoked potentials were performed, which did not show alterations of ON.

Conclusions

In patients with recurrent NLEMT and no involvement of ON, a determination of antiMOG-ab should be performed as part of their evaluation.

Background

Multiple Sclerosis (MS) is a chronic, inflammatory, autoimmune, neurodegenerative disease. Around 19% of treated patients with relapsing-remitting MS progress to Secondary Progressive MS (SPMS) 15 years after disease onset, representing the most severe stage of the disease. MS symptoms lead to a general disability, impacting the quality of life of patients and also being related with an important economic burden on the National Health System, the patients, their caregivers and the whole society.

Objectives

There are limited published data on the economic impact of SPMS. The main objective of the study was to estimate the economic impact of SPMS in Spain.

Methods

DISCOVER (CBAF312AES01) is an observational, non-interventional, cross-sectional, retrospective and multicenter study, including 297 SPMS patients ≥18 years treated and monitored according to routine clinical practice in Spain in 34 public hospitals. All data was collected in one single visit. Primary endpoint: total annual cost per patient, including direct healthcare and non-healthcare costs and indirect costs. Interim results from 99 patients are presented.

Results

62.6% females; mean (SD) age 53.1 (9.3) years; 40.4% with higher education; 86.9% living with a relative. Mean (SD) time since first MS diagnosis was 17.5 (8.9) years and since progression to SPMS 5.2 (4.3) years. At diagnosis, mean (SD) EDSS was 2.0 (1.1), being 5.0 (1.1) at the time of progression and 5.9 (0.8) at the study visit, 47.5% patients reaching EDSS>6. 12.8% of patients presented relapses between 12-24 months before the study. According to EQ-5D-5L, mean (SD) utility (<1) was 0.48 (0.27) for patients with Gd+ lesions and/or relapses 2 years before. According to EQ-5D-5L, mean (SD) utility (<1) for patients with cognitive impairment was 0.45 (0.29) vs 0.51 (0.21) for those without it. Mean (SD) utility for Spanish general population was 0.897 (0.21). EDSS score showed a significative effect (P=0.0074) on the economic burden of the disease, with total costs increasing from 14,546€ (EDSS 4-4.5) to 21,918€ (EDSS 5-5.5) and 26,832€ (EDSS=6). Costs related to patients with EDSS=6 from the societal, patient and healthcare system were 6,441€, 8,450€ and 11,941€, respectively.

Conclusions

Interim results of the DISCOVER study revealed a significant economic impact of MS progression, highlighting the importance of implementing therapeutic strategies specific to the SPMS patient within the early stages of progression.

Background

Patients with neuromyelitis optica spectrum disorders (NMOSD) experience a spectrum of symptoms negatively impacting on daily living and quality of life. The systematic assessment of patient perspectives has the capacity to provide crucial clinical information that could otherwise be lost when relying on clinical evaluation alone. However, the patient experience living with NMOSD is limited, in particular implementing standardized patient-reported outcomes (PROs).

Objectives

The primary objective of this study protocol is to assess the health-related quality of life and well-being of NMOSD patients.

Methods

A multicenter, non-interventional, cross-sectional study will be conducted with patients diagnosed with NMOSD (2015 Wingerchuk criteria) (PERSPECTIVES-NMO Study). Primary outcomes measures will be the 29-item Multiple Sclerosis Impact Scale and the Satisfaction with Life Scale. Demographic characteristics, clinical and imaging outcomes will be collected, including the number and type of attacks, antibody status, Expanded Disability Status Scale score, Nine-Hole Peg Test, Timed 25-Foot Walk, and Magnetic Resonance Imaging findings. Cognition will be evaluated using the Rao Brief Repeatable Neuropsychological Battery. Additional outcomes from the patient´s perspective (PROs) will be collected, including symptoms severity (SymptoMScreen questionnaire), fatigue (Fatigue Impact Scale for Daily Use), pain (MOS Pain Effects Scale), mood (Beck Depression Inventory-Fast Screen), perception of stigma (8-item Stigma Scale for Chronic Illness), and work-related difficulties (23-item Multiple Sclerosis Work Difficulties Questionnaire).

Results

Patient recruitment began in December 2019 with a planned total sample of 70 patients. The study is currently ongoing.

Conclusions

The study results are expected to provide meaningful insights into the clinical burden of disease. A better understanding of patient experiences may foster the development of patient-centered specific plans and more targeted rehabilitation in clinical practice.

Background

Patients with neuromyelitis optica spectrum disorders (NMOSD) experience a spectrum of symptoms negatively impacting on daily living and quality of life. The systematic assessment of patient perspectives has the capacity to provide crucial clinical information that could otherwise be lost when relying on clinical evaluation alone. However, the patient experience living with NMOSD is limited, in particular implementing standardized patient-reported outcomes (PROs).

Objectives

The primary objective of this study protocol is to assess the health-related quality of life and well-being of NMOSD patients.

Methods

A multicenter, non-interventional, cross-sectional study will be conducted with patients diagnosed with NMOSD (2015 Wingerchuk criteria) (PERSPECTIVES-NMO Study). Primary outcomes measures will be the 29-item Multiple Sclerosis Impact Scale and the Satisfaction with Life Scale. Demographic characteristics, clinical and imaging outcomes will be collected, including the number and type of attacks, antibody status, Expanded Disability Status Scale score, Nine-Hole Peg Test, Timed 25-Foot Walk, and Magnetic Resonance Imaging findings. Cognition will be evaluated using the Rao Brief Repeatable Neuropsychological Battery. Additional outcomes from the patient´s perspective (PROs) will be collected, including symptoms severity (SymptoMScreen questionnaire), fatigue (Fatigue Impact Scale for Daily Use), pain (MOS Pain Effects Scale), mood (Beck Depression Inventory-Fast Screen), perception of stigma (8-item Stigma Scale for Chronic Illness), and work-related difficulties (23-item Multiple Sclerosis Work Difficulties Questionnaire).

Results

Patient recruitment began in December 2019 with a planned total sample of 70 patients. The study is currently ongoing.

Conclusions

The study results are expected to provide meaningful insights into the clinical burden of disease. A better understanding of patient experiences may foster the development of patient-centered specific plans and more targeted rehabilitation in clinical practice.