Author Of 5 Presentations
P0027 - Are we ready for precision medicine in Multiple Sclerosis? A web-based survey across Europe (ID 1411)
Abstract
Background
We designed a web-based survey to assess the willingness and interest of European neurologists working with MS to implement precision medicine in their routine clinical practice. This study is a part of the EU-funded MULTIPLEMS grant.
Objectives
1) To assess how neurologists across European countries view the role of body-fluid biomarkers in clinical practice; 2) To survey clinical practices of diagnostic work up, therapy selection and monitoring, and frequency of data collection and clinical and paraclinical measurements.
Methods
The survey had three parts: a) demographics of respondents; b) opinion of the role of predictive, diagnostic, disease-activity biomarkers and treatment-response body-fluid biomarkers in clinical practice; c) survey of clinical practice and management of MS cases (including therapy choice and use of biomarkers) by evaluating 5 clinical cases with different characteristics (therapeutic management in drug naive patients and in patients displaying different forms of remaining disease activity, as well as stopping threapy in stable diasease since long).
Results
194 neurologists across 11 European countries responded to the survey, with a mean response rate of 45%. 57.7% were male and the mean age was 49.8 years. The importance of biomarkers in clinical practice was rated from 1 (low) to 7 (high), and it was generally high: 4.1 for predictive and disease-activity biomarkers, 5.2 for treatment-response and 5.7 for diagnostic biomarkers, with neurologists in Belgium, Denmark, Spain, Sweden and UK being the most positive. Determination of cerebrospinal fluid (CSF) oligoclonal bands was considered the most established biomarker for diagnosis (98.5% of neurologists), prediction (56.7%) and disease activity (36.5%), trailed by anti-aquaporin 4 (90.7%) and anti-myelin oligodendrocyte antibodies (85.1%) for diagnosis. Anti-JC (93.8%) and varicella virus (61.9%) and anti-drug (natalizumab (74.7%) and interferon-beta (68.6%)) were considered useful in context of therapy selection and monitoring by most neurologists, while neurofilament levels in CSF and serum and vitamin D levels were less established. Therapeutic management in the five case examples varied widely, likely as a result of differences in local and national guidelines.
Conclusions
European MS neurologists express a positive opinion on the role of body-fluid biomarkers to manage MS in clinical practice, however, these seem still to have had a limited impact on therapeutic management and selection, which also varied markedly across countries. This underscores the need for further research in this area.
P0164 - Smoking is associated with increased plasma neurofilament light levels in multiple sclerosis (ID 1834)
Abstract
Background
Elevated levels of plasma neurofilament light chain (pNfL) is associated with increased disease activity, physical disability and reduced treatment response in persons with multiple sclerosis (MS). However, the association between environmental exposures such as cigarette smoking and pNfL levels is not clear.
Objectives
To investigate the association between cigarette smoking, as one of the most prominent environmental factor associated with MS disease activity, and pNfL-levels in MS.
Methods
This is a retrospective population-based cohort study. Blood samples from incident MS cases were collected at time of diagnosis (from 2001). Concentrations of pNfL were determined using antibodies from UmanDiagnostics and the high-sensitive Single Molecule Array (SimoaTM) NF-light® Advantage kit. We assessed the impact of self-reported cigarette smoking habits at time of sampling on age-stratified pNfL levels above 80th, 95th, and 99th of non-MS controls' percentiles (>C80, >C95, and >C99).
Results
pNfL levels were measured in 2881 MS cases with smoking history of which 320 (11.1%) were current regular smokers and 828 (28.7%) were past regular smokers (median years since quitting 6; IQR 1 to 14). Current smoking was associated with significantly increased odds ratios (OR) of having pNfL-levels >C80, >C95 and >C99 with OR ranging from 1.27 (95% CI: 0.96-1.68) to 1.70 (95% CI: 1.24-2.33) comparing current smokers to never smokers and 1.44 (95% CI: 1.06-1.94) to 1.6 (95% CI: 1.12-2.27) comparing current smokers to past smokers. The OR of having pNfL-levels >C80, >C95 and >C99 in past smokers who quitted 6 to 10 years ago, compared to current smokers, ranged from 0.6 (95% CI: 0.39-0.92) to 0.55 (95% CI: 0.30-0.95), and from 0.62 (95% CI: 0.43-0.89) to 0.53 (95% CI: 0.31-0.87) in those with >10 years since quitting smoking. Although decreased, the ORs were not significant among those quitting smoking 1 to 5 years before sampling (P>0.05).
Conclusions
Current regular smoking is associated with significantly increased risk of displaying high pNfL levels in MS patients, which argue for a negative effect on disease activity. In contrast, there was a beneficial effect of quitting smoking that increased with time since stopping. Our findings support the rational for life style counselling in MS.
P0304 - Can the induction of thyroid autoimmune antibodies after alemtuzumab treatment predict secondary autoimmune thyroid disorder? (ID 663)
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.
P0361 - Non-thyroid secondary autoimmune diseases after alemtuzumab treatment: real-world data from a nationwide prospective observational cohort in Sweden. (ID 664)
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.
P0526 - Methylome and transcriptome analysis implicates NBPF locus in PPMS etiopathology (ID 880)
Abstract
Background
Multiple Sclerosis is characterized by autoimmune destruction of myelin and neurons in the CNS leading to a variety of neurological symptoms. Primary progressive multiple sclerosis (PPMS) is characterized by accumulation of clinical disability from the onset, without relapses or remissions. The mechanisms underpinning MS progression are still largely unknown and specific clinical translations are lacking.
Objectives
To identify DNA methylation and gene expression changes that associate with progressive MS states using genetic, epigenetic and network analysis approaches.
Methods
Our methylome analysis in blood showed a striking increase in methylation at the NBPF locus specifically in PPMS (n=279, p=5x10-6), which was validated in independent samples. We then discovered that genetic variants determine methylation levels at this locus (p-val. range 10-21-10-13) and that the strongest variant potentially associates with the risk of developing PPMS (nPPMS=482, ncontrols=11718, p<0.03, OR=1.2). The same variant associated with reduced expression of FMO5, PRKAB2 and CHD1L in blood (n=156, p-val. range 10-7-10-2).
Results
Notably, a large body of evidence strongly implicate the identified locus in nervous processes involved in brain size and neuropsychiatric disorders. Thus, we hypothesize that it harbors the gene(s) that predispose for progressive disability in PPMS. To functionally confirm the identified differentially methylated region (DMR) can potentially regulate gene expression in a DNA methylation-dependent manner, we have used an in-vitro epigenetic reporter system and our data showed that the DMR region has properties of a gene-regulatory region. Moreover, we investigated the putative relevance of the genes included in the NBPF locus in PPMS brain pathology by constructing an unbiased correlation network analysis using RNA-sequencing data from brain tissue samples of MS patients (nPPMS=5 and nSPMS=7) and controls (n=10). Strikingly, identified gene modules were found centered on genes from the NBPF locus in PPMS. Indeed, exploration of the biggest module, revealed CHD1L as a major central node within this network. Gene ontology analysis of each module underscored implication in nervous processes. Thus, this unbiased in-silico approach further supports the potential implication of genes of NBPF locus in nervous processes in PPMS patients.
Conclusions
Our DNA methylation studies along with the unbiased network analysis approach using the transcriptome data independently suggest that the locus on chromosome 1 predisposes for PPMS.