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Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland).Die Multiple Sklerose ist eine komplexe, autoimmun vermittelte Erkrankung des zentralen Nervensystems, charakterisiert durch inflammatorische Demyelinisierung sowie axonalen/neuronalen Schaden. Die Zulassung verschiedener verlaufsmodifizierender Therapien und unser verbessertes Verständnis der Krankheitsmechanismen und -entwicklung in den letzten Jahren haben die Prognose und den Verlauf der Erkrankung deutlich verändert. Diese Aktualisierung der Behandlungsempfehlung der Multiple Sklerose Therapie Konsensus Gruppe konzentriert sich auf die wichtigsten Empfehlungen für verlaufsmodifizierende Therapien der Multiplen Sklerose im Jahr 2021. Unsere Empfehlungen basieren auf aktuellen wissenschaftlichen Erkenntnissen und gelten für diejenigen Medikamente, die in weiten Teilen Europas, insbesondere in den deutschsprachigen Ländern (Deutschland, Österreich, Schweiz), zugelassen sind.

Introduction: Oral cladribine is a highly effective pulsed selective immune reconstitution therapy licensed for relapsing multiple sclerosis (RMS) since 2017. A full treatment course comprises two treatment cycles given 1 year apart, followed by two treatment-free years. The management of cladribine-treated patients beyond year 4 needs to be addressed as patients have now passed the initial 4 years since European Medical Agency approval. Areas covered: A panel of neurologists and a neuroradiologist experienced in MS treatment/monitoring evaluated clinical trial data and real-world evidence and proposed recommendations for the management of cladribine-treated patients beyond year 4. Expert opinion: Continuous monitoring of disease activity during the treatment-free period is important. Subsequent management depends on the presence or absence of inflammatory disease activity, determined in the absence of consistent guidelines via practice-driven neurological decision criteria. Persisting or newly occurring inflammatory disease activity is an indication for further treatment, i.e. either re-initiation of cladribine or switching to another highly effective disease-modifying therapy. The decision to retreat or switch should be based on clinical and radiological evaluation considering disease course, treatment history, and safety aspects. In the absence of disease activity, either retreatment can be offered, or the treatment-free period can be extended under structured monitoring.

Background and aims: To investigate effectiveness and safety of teriflunomide (14 mg once daily) in association with age and pre-treatment in unselected MS patients. Methods: Prespecified analysis of a non-interventional, prospective, real-world study in Germany. Results: A total of 558 (49.5%) patients were above 45 years old, and 593 patients (52.6%) had been pre-treated within 6 months prior to teriflunomide. Baseline Expanded Disability Status Scale (EDSS) was higher with older age, with lower number of relapses. Relapse rate decreased in all age groups, and in both treatment-naïve (0.82 ± 0.73 at baseline; 0.25 ± 0.55 under teriflunomide) and pre-treated (from 0.48 ± 0.76; 0.22 ± 0.50) patients after 12 months compared with the year before teriflunomide initiation. EDSS remained stable in patients of all age groups as well as in therapy-naïve and pre-treated patients over 24 months. The percentage of patients with adverse events (AEs) ranged between 29.2% (age group >25–35) and 38.9% (age group >55–65), with an increased discontinuation rate (most commonly due to diarrhoea, alopecia and nausea) in the higher age groups. AE rates were lower in pre-treated compared with treatment-naïve patients. Conclusion: Overall, patients of all age groups including older patients, and irrespective of pre-treatment, benefit from teriflunomide treatment in routine clinical practice. Registration: BfArM public study database number 2075.

Oral cladribine is a highly effective pulsed selective immune reconstitution therapy licensed for relapsing multiple sclerosis. A full treatment course comprises two treatment cycles given with 1 year of intermission. Further dosing is not routinely recommended in years 3 and 4.The long-term management of patients treated with oral cladribine has not been fully defined on the basis of clinical studies as of yet. The authors provide their expert opinion on this.Based on available evidence and experience from routine clinical use, the authors suggest a structured approach to the long-term management of patients treated with cladribine tablets according to their responder type, i. e. the degree and timing of disease activity, if any, after treatment initiation. Informed treatment decisions require structured patient monitoring by established clinical and imaging parameters. In patients with relevant disease activity in year 3 or 4 and beyond, the use of additional cycle(s) of oral cladribine might become an option. For patients requiring a treatment switch, the choice of therapies primarily includes moderately to highly effective MS drugs.

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland). in press, CA extern

Background: In relapsing–remitting multiple sclerosis (RRMS), ‘no evidence of disease activity’ (NEDA) is regarded as a key treatment goal. The increasing number of treatments allows for individualized treatment optimization in patients with suboptimal response to first-line disease-modifying therapies (DMTs). Therefore, monitoring of clinical and subclinical disease activity on DMTs has been recognized as an important component of long-term patient management. Methods: EPIDEM was a multicenter non-interventional retrospective study in a large cohort of RRMS patients receiving injectable DMTs for at least 2 years in outpatient centers throughout Germany. It documented measures and ratings of disease activity on DMTs to characterize the factors that made the treating neurologists consider to switch therapy towards potentially more effective or better-tolerated drugs. Results: The cohort included predominantly female patients with a mean age of 45 years and a mean disease duration of 9.6 years, who had been continuously treated with an injectable DMT for a median duration of 54 months. Overall, 34.0% of the patients had experienced ⩾1 relapse on any DMT in the previous 2 years; 21.0% exhibited magnetic resonance imaging (MRI) activity, and the Kurtzke Expanded Disability Status Scale (EDSS) score increased by at least 0.5 points in 20.1%. Overall, 50.3% of the patients with EDSS progression and 70.6% of the patients with relapses were assessed as clinically stable by the neurologists. A change of treatment was considered in a fraction of patients with disease activity: in 22.8% of those with relapse activity, in 37.8% of those with MRI activity and in 20.1% of those with EDSS progression. Conclusion: The results of EPIDEM underline the importance of standardized evaluation and documentation of ongoing disease activity and disability deterioration. Judged from the present data, the current paradigm of low tolerance for disease activity and recommendations for early treatment optimization have not been turned fully into action as yet. More widespread implementation of current guideline recommendations may allow patients to more benefit from the growing panel of effective treatment options.

Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance.

Relapsing–remitting multiple sclerosis (RRMS) requires efficient immunomodulatory treatment to reach “no evidence of disease activity” status at best. Alemtuzumab and fingolimod have proved to be efficient options in RRMS with active disease course. Yet, side effects and break-through disease may limit long-time treatment and necessitate switch of medication. Data on efficacy and safety of alemtuzumab following fingolimod treatment are limited, but useful for clinical practice. Clinical and MRI data of 50 RRMS patients with a history of therapy switch from fingolimod to alemtuzumab were retrospectively analyzed. Data were acquired from nine large German MS Centers from 2013 to 2016 and analyzed using descriptive statistics. On average, patients with disease duration of 12.9 years and median EDSS of 3.0 at baseline switched to alemtuzumab after 68 weeks of fingolimod treatment. Thereafter, patients on alemtuzumab were followed for a mean of 64 weeks. The annualized relapse rate decreased from 2.2 in the year prior to 0.34 in the following year after switching to alemtuzumab and EDSS stabilized. In a subgroup of patients (n = 23), MRI data point to a reduction in enhancing (4.47 vs. 0.26) and new/enlarging T2 lesions (5.8 vs. 0.27) after treatment adjustment. Side effects were generally as expected from published data for alemtuzumab (autoimmunity 2/50, severe infections 1/50). One patient suffered combined lethal necrotizing leukoencephalopathy and hemolytic anemia. Therapy switch was highly effective in reducing clinical and MRI surrogates of disease activity and was mainly well tolerated within one year of follow-up. Hence, alemtuzumab constitutes a promising therapy in RRMS with refractory disease activity despite fingolimod treatment. Further studies are warranted to confirm these beneficial findings and to reveal safety concerns in the longer-term follow-up.

Therapeutische und technische Innovationen der letzten Jahre haben die Versorgung von MS-Patienten erheblich verbessert. Fur eine optimale flachendeckende Versorgung ist allerdings die Etablierung intersektoraler Netzwerke erforderlich, die am sinnvollsten durch regionale Netzwerke getragen und ausgebaut werden kann.

Evoked potentials (EP) have a role in making the diagnosis of multiple sclerosis (MS) but their implication for predicting the future disease course in MS is under debate. EP data of 94 MS patients examined at first presentation, and after five and ten years were retrospectively analysed. Patients were divided into two groups in relation to the prior duration of disease at the time point of first examination: group 1 patients (n-44) were first examined within two years after disease onset, and group 2 patients (n-50) at later time points. As primary measures sum scores were calculated for abnormalities of single and combined EP (visual (VEP), somatosensory (SEP), magnetic motor evoked potentials (MEP)). In patients examined early after disease onset (group 1), a significant predictive value for abnormal EP was found with MEP and SEP sum scores at first presentation correlating significantly with Expanded Disability Status Scale (EDSS) values after five years, while the VEP sum score was not. The cumulative number of abnormal MEP, SEP and VEP results also indicated higher degrees of disability (EDSS≥ 3.5) after five years. Combined pathological SEP and MEP findings at first presentation best predicted clinical disability (EDSS≥ 3.5) after five years (odds ratio 11.0). EP data and EDSS at first presentation were not significantly linked suggesting that EP abnormalities at least in part represented clinically silent lesions not mirrored by EDSS. For patients in later disease phases (group 2), no significant associations between EP data at first presentation and EDSS at five and ten years were detected. Together with clinical findings and MR imaging, combined EP data may help to identify patients at high risk of long-term clinical deterioration and guide decisions as to immunomodulatory treatment.

We compared the gene expression patterns of fetal and adult porcine brains and identified a sequence tag that was more abundant in adult than in fetal brain. The RNA corresponding to the sequence tag has the highest expression level in adult cerebellum. Lower expression levels of the transcript were found in adult cerebrum, pituitary, and uterus, as well as in fetal brain, heart, intestine, kidney, and liver. The sequence tag was used to screen a cDNA library from adult porcine brain. Two independent clones of 2,273 nt and 1,701 nt were isolated. The shorter cDNA is a 5′-truncated form of the longer clone, and both clones have almost identical sequences with multiple start and stop codons in all three reading frames. Screening of two different human brain cDNA libraries with porcine cDNA probes resulted in four overlapping cDNA fragments, which were assembled to one contig of 2,336 nt in length. Like noncoding RNAs, the porcine and human sequences have no common conserved open reading frame and share stretches of high homology interrupted by stretches with almost no homology. The human and porcine RNAs were named UM 9(5)h and UM 9(5)p, respectively. They are part of larger transcripts, which are transcribed from single-copy genes, they have very similar tissue distributions, and their sequences are colinear with the respective genomic fragment.

Tumour necrosis factor-alpha ( TNF-alpha) has been proposed as one of the key mediators of inflammatory diseases of the CNS such as multiple sclerosis. It has been shown to induce the expression of adhesion molecules which is a prerequisite for the transmigration of immune cells through the blood-brain barrier. We therefore investigated the role of TNF-alpha in the expression and release of vascular cell adhesion molecule-1 (VCAM-1) in cultures of human cerebral endothelial cells (HCEC) in comparison with peripheral blood mononuclear cells (PBMC). A time- and dose-dependent expression of VCAM-1 and release of soluble VCAM-1 was detected in HCEC but not PBMC. TNF-alpha-induced release of soluble VCAM-1 was further increased by cotreatment with interferon-beta (IFN-beta), while IFN-beta alone did not affect VCAM-1 expression or the release of soluble VCAM-1. In addition, we observed that preincubation of PBMC with soluble VCAM-1 completely blocked their adhesion to HCEC. In conclusion, the proinflammatory effect of TNF-alpha on HCEC, which involves the induction of VCAM-1 expression and cellular adhesion, is followed by the consecutive effects of soluble VCAM-1 release in blocking adhesion and downregulating further cellular infiltration. Increasing soluble VCAM-1 release during active inflammation could be another mechanism by which IFN-beta treatment exerts protective effects in multiple sclerosis patients.

Several studies have reported a positive correlation between levels of soluble adhesion molecules in serum or cerebrospinal fluid and cranial MRI activity. We performed a cross-sectional study in 46 patients with newly diagnosed MS and determined levels of soluble intercellular adhesion molecule-1 (sICAM-1) as well as vascular cell adhesion molecule-1 (sVCAM-1) in correlation to the number and area of gadolinium enhancing lesions on cranial magnetic resonance images (MRI). The data revealed a significant positive correlation between sVCAM-1 serum levels and gadolinium enhancing lesions. In addition, CSF to serum ratios for sICAM-1 and sVCAM-1 correlated to MRI activity. In patients with a single enhancing lesion (SEL) there was a negative correlation between the QsCAM and the distance of the SEL to the ventricles. As these adhesion molecules are stable and markers of disease activity in MS, we further investigated sVCAM-1 serum levels during treatment with interferon beta-1b (Betaferon®). Significant increases in serum levels for sVCAM-1 in patients receiving Betaferon were associated with a favourable treatment response after 1 year in 17 out of 19 patients and correlated to decreased MRI activity, whereas stable or reduced sVCAM-1 levels occured more often in non-responders (five out of six patients). Therefore it can be hypothezised that soluble adhesion molecules are released from cerebral endothelial cells as an early immunoregulatory activity of the immune system to reduce cellular traffic across the blood brain barrier and this is further enhanced by IFN-beta treatment.

Inflammation has always been thought of as detrimental in the pathophysiology of multiple sclerosis (MS). However, emerging genetic data, magnetic-resonance-imaging studies, and immunopathological evidence challenge this simplistic view. The evidence leads to the conclusion that inflammation is tightly regulated, and that its net effect may be beneficial in MS, thus explaining some of the results from recent trials of anti-inflammatory agents. We argue that the use of anti-inflammatory drugs to treat MS may not be appropriate in all cases. Precise identification of the inflammatory pathways to be targeted in the different phases of the disease and the timing of such interventions are therefore crucial.