Institute of Neuroscience and Physiology
Department of Clinical Neuroscience

Author Of 5 Presentations

Biomarkers and Bioinformatics Poster Presentation

P0080 - Exploring neurofilament light in CSF as a biomarker for multiple sclerosis in clinical practice (ID 586)

Speakers
Presentation Number
P0080
Presentation Topic
Biomarkers and Bioinformatics

Abstract

Background

Neurofilament light (NFL), a biomarker of axonal damage and disease activity in multiple sclerosis (MS), has been increasingly recognized for prognostic and therapeutic decisions.

Objectives

To assess the sensitivity and specificity of cerebrospinal fluid (CSF) NFL for disease activity and to evaluate its prognostic value in predicting disease severity and conversion from relapsing-remitting (RRMS) to secondary progressive MS (SPMS).

Methods

Patients with a confirmed diagnosis of RRMS (n=769) who had determined NFL in CSF as part of the diagnostic work-up or from assessments as part from regular clinical visits between 2001 and 2018 were retrospectively identified in the Swedish MS registry. Measurements over time of disease activity (clinical relapses and lesion formation on MRI) and disability (EDSS) were retrieved. We assessed NFL levels in relation to concomitant clinical and MRI activity and as outcome for treatment response.

Results

Patients with a concurrent clinical relapse had significantly higher NFL concentrations (median NFL no relapse 278 ng/L, relapsed 1122 ng/L, p<0.001) and a correlation with relapse severity was observed (p<0.001). Patients with gadolinium-enhancing lesions had higher median NFL levels (1414 ng/L) than those without (426 ng/L, p<0.001) and NFL levels correlated with the number of gadolinium enhancing lesions (p<0.001). CSF NFL showed sensitivity of 93.3% and specificity of 77.4% to disease activity (relapses and/or MRI activity). High NFL at diagnosis (n=414) was independently associated with worsening of disability and predicted progression to EDSS≥3 (n=128, p<0.001, HR 0.566 95% CI 0,413-0,711) and conversion to secondary progressive MS (n=39, p=0.0003, HR=0,380 95% CI 0,225-0,641). In a subset of patients (n=159), NFL was analysed at baseline and at follow-up (median time between LPs 23.7 months). Patients who switched from a first-line to a second-line therapy (n=65) exhibited significant reduction in NFL concentrations (p<0.001). However, patients who did not receive disease modifying therapy (DMT) (n=32), had first-line therapy (n=40), or switched to a third-line treatment (n=22) between baseline and follow-up did not show a significant decrease in their CSF NFL levels (p=0.975, p=0.658, and p=0.059 respectively).

Conclusions

Since 2001 CSF NFL has been part of the clinical assessment at Sahlgrenska University Hospital, Gothenburg. Thus, the results of this study are based on a real-life material and we can confirm the utility of NFL as a biomarker in MS. Our data underline NFL as a sensitive biomarker of disease activity, its usefulness for prediction of disability and clinical course and for monitoring DMT response. Serum/plasma NFL is most likely to show similar properties but probably at a lower precision.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0304 - Can the induction of thyroid autoimmune antibodies after alemtuzumab treatment predict secondary autoimmune thyroid disorder? (ID 663)

Speakers
Presentation Number
P0304
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab (ALZ) belongs to the immune reconstitution therapies for relapsing-remitting multiple sclerosis (RRMS). ALZ therapy is associated with an increased risk for secondary autoimmune diseases (SAD), in particular autoimmune thyroid disorders (AITD).

Objectives

To investigate if the occurrence of thyroid auto-antibodies (Ab), after initiating ALZ treatment, could predict the development of AITD.

Methods

All RRMS patients in Sweden initiating ALZ (n=124, 74 females) 2014-2019, were consecutively included in this prospective observational study. Plasma samples were obtained prior to ALZ and at 6, 12 and 24 months of follow-up for analyses of thyroglobulin Ab (TgAb), thyroperoxidase Ab (TPOAb) and thyrotropin receptor Ab (TRAb). Monthly serum samples for free thyroxin and thyroid stimulating hormone, as well as clinical symptoms were followed to detect AITD.

Results

At mean follow-up of 4.5 (SD 1.6) years 50 patients (40%) had developed AITD (43 Graves’ disease). Mean time from baseline to AITD was 2.1 (SD 1.6) years, in 62 % the development of thyroid Ab preceded AITD. At baseline 5% (n=6/114) patients had positive TRAb, 3% (n=3/115) positive TgAb, and 3% (n=3/115) positive TPOAb. Corresponding values at 6 months were 3% (n=2/78), 6% (n=5/85), 5% (n=4/86), at 12 months 14% (n=14/102), 15% (n=15/102), 18% (n=18/102), and at 24 months 22% (n=16/73), 19% (n=15/78), 23% (n=18/78). No treatment was given for AITD in 4% (n=2/50), 14% (n=7/50) had levothyroxine (L-T4) only, 36% (n=18/50) high dose anti-thyroid drug (ATD) with L-T4, 34% (n=17/50) thyroidectomy, 4% (n=2/50) ATD alone, 2% (n=1/50) radioactive iodine and for 6% (n=3/50) data were missing. Mean time from detection of auto-Ab to diagnosis of AITD was 4 (SD 11.3) months. At baseline 9 patients had thyroid Ab, but only those with TRAb (n=3) developed AITD. The OR for AITD was 1.51 given TRAb compared to those with no TRAb at baseline. At 24 months, 27 patients were positive for either of the thyroid Ab, 93% (25/27) of these developed AITD. In contrast, only, 30% (15/51) of those thyroid Ab negative developed AITD (p<0.0001 x2- test).

Conclusions

AITD was developed in 40% of ALZ treated patients, at 24 months 21% had AITD which was similar with that reported from the pivotal studies of ALZ. Thyroid Ab preceded AITD in 62 % of cases. In contrast, the risk of AITD was low in cases without thyroid Ab. Although, monitoring thyroid Ab may be useful identifying patients at high risk for AITD, this has not so far had any therapeutic incentives.

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Disease Modifying Therapies – Risk Management Poster Presentation

P0361 - Non-thyroid secondary autoimmune diseases after alemtuzumab treatment: real-world data from a nationwide prospective observational cohort in Sweden. (ID 664)

Speakers
Presentation Number
P0361
Presentation Topic
Disease Modifying Therapies – Risk Management

Abstract

Background

Alemtuzumab (ALZ) belongs to the immune reconstitution therapies for relapsing-remitting multiple sclerosis (RRMS). ALZ therapy is associated with an increased risk for secondary autoimmune diseases (SAD), in particular autoimmune thyroid disorders (AITD), but there are also an association to increased risk of immune mediated thrombocytopenic purpura (ITP) and other rare autoimmune disorders.

Objectives

To investigate the occurrence of SAD, other than AITD, and if auto-antibodies (Ab) could predict the development of non-thyroid SAD (NTSAD).

Methods

All RRMS patients in Sweden initiating ALZ (n=124, 74 females) 2014-2019, were consecutively included in this prospective observational study. Plasma samples were obtained prior to ALZ and at 6, 12 and 24 months of follow-up for analyses of glutamic acid decarboxylase Ab (GADAb), antinuclear Ab (ANA), smooth muscle Ab (SMA), antimitochondrial Ab (AMA) and anti-glomerular basement membrane Ab (GBMAb). Monthly blood and urine tests, as well as clinical symptoms, were followed to detect NTSAD.

Results

At mean follow-up of 4.5 (SD 1.6) years 8 patients (6.5%) had developed NTSAD; 5 ITP (4%), 2 neutropenia (2%), and 1 warm antibody haemolytic anaemia (1%). Mean time from baseline to respective NTSAD was 2.1 (SD 1.7) years, 0.6 (SD 0.7) years, and 5.5 years. At their diagnoses positive auto-Ab against platelets, neutrophils and erythrocytes, were present in 1, 0 and 1 ALZ treated patient respectively. No treatment was given for ITP in 3, 1 had intravenous immunoglobulin, romiplostim, corticosteroids, 1 had platelet transfusion, corticosteroids. 1 with neutropenia had granulocyte-colony stimulating factor. No treatment was given for the case with haemolytic anaemia. At baseline 1% (n=1/115) had positive GADAb, 12% (n=13/112) positive ANA, 4% (n=5/112) positive SMA, 0% (n=0/112) positive AMA and 3% (n=3/115) positive GBMAb. Besides these, the number of patients who at least once during the follow-up were positive for the auto-Ab that we regulatory checked for was as follows; 1% (n=1/124) GADAb, 10% (n=13/124) ANA, 3% (n=4/124) SMA, 0% (n=0/124) AMA and 0% (n=0/124) GBMAb, none of these developed any associated NTSAD.

Conclusions

In this real-world cohort study the occurrence of NTSAD, after ALZ treatment, was mainly hematologic, most frequent ITP (4%) and the majority required no treatment. Although the occurrence of auto-Ab was slightly more common after ALZ, compared to the general population, no corresponding NTSAD was found. This was in contrast to thyroid auto-Ab which often precede thyroid disease.

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Imaging Poster Presentation

P0575 - Exploring demyelination and brain atrophy in multiple sclerosis using quantitative magnetic resonance imaging (ID 680)

Speakers
Presentation Number
P0575
Presentation Topic
Imaging

Abstract

Background

Conventional Magnetic Resonance Imaging (MRI) has a high sensitivity for detecting inflammatory disease activity of the brain, but is time-consuming, only semi-quantitative and rely on subjective assessments. On the contrary, the technique called ‘synthetic MRI’ (SyMRI) uses a single pulse sequence, can create contrast-weighted images from quantitative maps based on relaxometry and simultaneously provides automatic brain volume and myelin measurements. All this information is delivered after a single 6-minute scan and software with post-processing time less than 1 minute. Measuring the change in brain volume and myelin content in vivo could provide new insights into the relationship between two main pathological processes in multiple sclerosis (MS), demyelination and neurodegeneration and the impact of disease modifying treatments (DMTs) on these processes.

Objectives

The aim was to assess brain volume and myelin content over time in patients with newly diagnosed MS and in healthy control persons.

Methods

We prospectively included 116 patients newly diagnosed with relapsing-remitting (RR) MS, and 51 healthy control subjects (HC). All patients initiated DMT and were dichotomized into those with disease activity (relapse and/or new or enlarging lesions on MRI) (n=74) and those without disease activity (n=42) at follow up. The MRI was performed at baseline in both groups and in patients at 6, 12, 24 and 36 months, and in HC only at 24 months. Brain parenchymal fraction (BPF) and myelin parenchymal fraction (MyPF) of the brain were calculated via SyMRI software.

Results

At baseline, there was no significant difference between HC and newly diagnosed MS in BPF (89% and 89.1%, respectively, p=0.97), but HC had significantly lower MyPF than patients (14.1% and 14.9%, respectively, p<0.001). At 36 months follow-up, the mean change of BPF and MyPF in patients was -0.9% (±1.6) p<0.001 and 0.3 % (±1.3) p=0.022, respectively. Patients without disease activity had significantly higher MyPF compared with patients with disease activity during follow-up time (15.7% and 14.9%, respectively, p=0.009). At 24 month follow-up, BPF and MyPF were unchanged in HC compared to baseline (p=0.94 and p=0.44, respectively).

Conclusions

SyMRI showed the development of significant brain atrophy in RRMS after 3 years of follow-up and signs of increased demyelination in patients with disease activity. However, patients had unexpectedly higher MyPF than controls at baseline and the MyPF increased in stable RRMS at follow-up. This might indicate increased remyelination. However, the sensitivity of SyMRI to quantify the myelin fraction of the brain deserves further validation.

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Observational Studies Poster Presentation

P0920 - The effect of alemtuzumab treatment in relapsing remitting multiple sclerosis: real-world data from a four-year prospective one center study. (ID 240)

Speakers
Presentation Number
P0920
Presentation Topic
Observational Studies

Abstract

Background

Background: Alemtuzumab (ALZ) belongs to the immune reconstitution therapies for relapsing-remitting multiple sclerosis (RRMS). ALZ is used as second or third line treatment in clinical practise, thus the real-world population treated with ALZ is markedly different from the populations in the pivotal trials of ALZ.

Objectives

Objectives: To assess basic characteristics and therapeutic effects on clinical and imaging parameters of disease activity for RRMS patients selected for ALZ.

Methods

Methods: RRMS patients were consecutively included at the MS Centre, Gothenburg. Patients were clinically assessed with Expanded Disability Status Scale (EDSS), occurrence of clinical relapses and with cerebral MRI at baseline, month 12, 24, 36 and 48.

Results

Resluts: 51 (31 females) RRMS patients, mean age and mean disease duration of 35.5 (±7.1) respectively 7.1 (±5.4) years were included. Prior to baseline 6 patients had first line treatment, 38 had second line and 7 were naïve. Reasons to switch to ALZ; break through disease activity despite disease modifying treatment (DMT) (n=23), side effects (n=3), positive JC virus antibody test during natalizumab (n=18), highly active disease from disease onset (n=7). All patients received the first course of ALZ, 50 the second, 14 a third, and 2 a fourth course. At baseline, month 12, 24, 36 and 48 median EDSS was 2 (0-7.5), 1.5 (0-7), 1.5 (0-7.5), 1.5 (0-7.5) and 1.5 (0-7), respectively. At 48 months 34 patients were relapse free, and the annual relapse rate was 0.12. Baseline MRI revealed high lesion load; T2 lesions >20 (n=35), T2 lesions 10-20 (n=12), T2 lesions 1-9 (n=4), 36 patients had no contrast enhancement. Upon follow-up at 12, 24 , 36 and 48 months, 39 patients, 42, 45 and 38 had no new or enlarged T2 lesions respectively, corresponding number with no contrast enhancement was 43, 45, 47, and 40. Mean brain parenchymal fraction at baseline was 0.862 (±0.037, n=43) and was unchanged at follow-up. 23 patients met No Evidence of Disease Activity (NEDA) at 48 months. 9 (18%) patients have switched from ALZ to another DMT (rituximab n=6, autologous hematopoietic stem cell transplantation n=3) due to disease activity.

Conclusions

Conclusions: This real-world population confirms that ALZ as second or third line treatment effectively reduced disease activity. Although most of our patients had previously failed on DMT the proportion of progression free survival (82%) and NEDA (45%) were of similar magnitude as those reported from the pivotal trials CARE-MS I&II.

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