Predictors of relapse risk and treatment response in AQP4-IgG positive and seronegative NMOSD: A multicentre study.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) can be categorised into aquaporin-4 antibody (AQP4-IgG) NMOSD or seronegative NMOSD. While our knowledge of AQP4-IgG NMOSD has evolved significantly in the past decade, seronegative NMOSD remains less understood. This study aimed to evaluate the predictors of relapses and treatment responses in AQP4-IgG NMOSD and seronegative NMOSD. METHODS: This was a multicentre, international, retrospective cohort study using the MSBase registry. Recurrent relapse risk was assessed using an Andersen-Gill model and risk of first relapse was evaluated using a Cox proportional hazards model. Covariates that putatively influence relapse risk included demographic factors, clinical characteristics and immunosuppressive therapies; the latter was assessed as a time-varying covariate. RESULTS: A total of 398 patients (246 AQP4-IgG NMOSD and 152 seronegative NMOSD) were included. The AQP4-IgG NMOSD and seronegative NMOSD patients did not significantly differ by age at disease onset, ethnicity or annualised relapse rate. Both low-efficacy and high-efficacy immunosuppressive therapies were associated with significant reductions in recurrent relapse risk, with notably greater protection conferred by high-efficacy therapies in both AQP4-IgG NMOSD (HR 0.27, 95% CI 0.15 to 0.49, p<0.001) and seronegative NMOSD (HR 0.21, 95% CI 0.08 to 0.51, p<0.001). Longer disease duration (HR 0.97, 95% CI 0.95 to 0.99, p<0.001) and male sex (HR 0.52, 95% CI 0.34 to 0.84, p=0.007) were additional protective variables in reducing the recurrent relapse risk for the AQP4-IgG NMOSD group. CONCLUSION: Although further studies are needed to improve our understanding of seronegative NMOSD, our findings underscore the importance of aggressive treatment with high-efficacy immunotherapies in both NMOSD subtypes, regardless of serostatus.

Routine CSF parameters as predictors of disease course in multiple sclerosis: an MSBase cohort study.

BACKGROUND: It remains unclear whether routine cerebrospinal fluid (CSF) parameters can serve as predictors of multiple sclerosis (MS) disease course. METHODS: This large-scale cohort study included persons with MS with CSF data documented in the MSBase registry. CSF parameters to predict time to reach confirmed Expanded Disability Status Scale (EDSS) scores 4, 6 and 7 and annualised relapse rate in the first 2 years after diagnosis (ARR2) were assessed using (cox) regression analysis. RESULTS: In total, 11 245 participants were included of which 93.7% (n=10 533) were persons with relapsing-remitting MS (RRMS). In RRMS, the presence of CSF oligoclonal bands (OCBs) was associated with shorter time to disability milestones EDSS 4 (adjusted HR=1.272 (95% CI, 1.089 to 1.485), p=0.002), EDSS 6 (HR=1.314 (95% CI, 1.062 to 1.626), p=0.012) and EDSS 7 (HR=1.686 (95% CI, 1.111 to 2.558), p=0.014). On the other hand, the presence of CSF pleocytosis (≥5 cells/µL) increased time to moderate disability (EDSS 4) in RRMS (HR=0.774 (95% CI, 0.632 to 0.948), p=0.013). None of the CSF variables were associated with time to disability milestones in persons with primary progressive MS (PPMS). The presence of CSF pleocytosis increased ARR2 in RRMS (adjusted R2=0.036, p=0.015). CONCLUSIONS: In RRMS, the presence of CSF OCBs predicts shorter time to disability milestones, whereas CSF pleocytosis could be protective. This could however not be found in PPMS. CSF pleocytosis is associated with short-term inflammatory disease activity in RRMS. CSF analysis provides prognostic information which could aid in clinical and therapeutic decision-making.

Delay from treatment start to full effect of immunotherapies for multiple sclerosis.

In multiple sclerosis, treatment start or switch is prompted by evidence of disease activity. Whilst immunomodulatory therapies reduce disease activity, the time required to attain maximal effect is unclear. In this study we aimed to develop a method that allows identification of the time to manifest fully and clinically the effect of multiple sclerosis treatments ('therapeutic lag') on clinical disease activity represented by relapses and progression-of-disability events. Data from two multiple sclerosis registries, MSBase (multinational) and OFSEP (French), were used. Patients diagnosed with multiple sclerosis, minimum 1-year exposure to treatment, minimum 3-year pretreatment follow-up and yearly review were included in the analysis. For analysis of disability progression, all events in the subsequent 5-year period were included. Density curves, representing incidence of relapses and 6-month confirmed progression events, were separately constructed for each sufficiently represented therapy. Monte Carlo simulations were performed to identify the first local minimum of the first derivative after treatment start; this point represented the point of stabilization of treatment effect, after the maximum treatment effect was observed. The method was developed in a discovery cohort (MSBase), and externally validated in a separate, non-overlapping cohort (OFSEP). A merged MSBase-OFSEP cohort was used for all subsequent analyses. Annualized relapse rates were compared in the time before treatment start and after the stabilization of treatment effect following commencement of each therapy. We identified 11 180 eligible treatment epochs for analysis of relapses and 4088 treatment epochs for disability progression. External validation was performed in four therapies, with no significant difference in the bootstrapped mean differences in therapeutic lag duration between registries. The duration of therapeutic lag for relapses was calculated for 10 therapies and ranged between 12 and 30 weeks. The duration of therapeutic lag for disability progression was calculated for seven therapies and ranged between 30 and 70 weeks. Significant differences in the pre- versus post-treatment annualized relapse rate were present for all therapies apart from intramuscular interferon beta-1a. In conclusion we have developed, and externally validated, a method to objectively quantify the duration of therapeutic lag on relapses and disability progression in different therapies in patients more than 3 years from multiple sclerosis onset. Objectively defined periods of expected therapeutic lag allows insights into the evaluation of treatment response in randomized clinical trials and may guide clinical decision-making in patients who experience early on-treatment disease activity. This method will subsequently be applied in studies that evaluate the effect of patient and disease characteristics on therapeutic lag.

[Effective therapy in highly active pediatric multiple sclerosis]. / Magas aktivitású sclerosis multiplex hatásos kezelése gyermekkorban.

Multiple sclerosis (MS) is typically a disease of young adults. Childhood MS can be defined in patients under 18 years of age, although some authors set the limit un-der the age of 16 formerly known as "early-onset multiple sclerosis" or "juvenile multiple sclerosis", seen in 3-5% of all MS patients. Nowadays, owing to ever-evolving, better diagnostic tools and well-traced, strictly defined diagnostic criteria, childhood MS is showing an increasing incidence worldwide (0.05-2.85/100 000). MS is characterized by recurrent episodes of the central nervous system with demyelination separated in space and time. In childhood almost exclusively the relapsing-remitting (RR) type of MS occurs. Based on experience in adults, the goal in the pediatric population is also the early diagnosis, to initiate adequate DMT as soon as possible and to achieve symptom relief and good quality of life. Based on efficacy and safety studies in the adult population, inter-feron ß-1a and glatiramer acetate were first approved by the FDA and EMA for the treatment of childhood MS also. The increased relapse rate and rapid progression of childhood MS and unfavorable therapeutic response to nearly 45% of the first DMT necessitated the testing of more effective and second-line drugs in the population under 18 years of age (PARADIGMS, CONNECT). Although natalizumab was reported to be effective and well-tolerated in highly active RRMS in childhood, evidence based studies were not yet available when our patients' treatment started. In this article, we report on the successful treatment of three active RRMS patients with individually authorized off-label use of natalizumab.

Redefining the Multiple Sclerosis Severity Score (MSSS): The effect of sex and onset phenotype.

BACKGROUND: The Multiple Sclerosis Severity Score (MSSS) is a widely used measure of the disability progression rate. However, the global MSSS may not be the best basis for comparison between all patient groups. OBJECTIVE: We evaluated sex-specific and onset phenotype-specific MSSS matrices to determine if they were more effective than the global MSSS as a basis for comparison within these subsets. METHODS: Using a large international dataset of multiple sclerosis (MS) patient records and the original MSSS algorithm, we constructed global, sex-specific and onset phenotype-specific MSSS matrices. We compared matrices using permutation analysis. RESULTS: Our final dataset included 30,203 MS cases, with 28.9% males and 6.5% progressive-onset cases. Our global MSSS matrix did not differ from previously published data (p > 0.05). The progressive-onset-specific matrix differed significantly from the relapsing-onset-specific matrix (p < 0.001), with lower MSSS attributed to cases with the same Expanded Disability Status Score (EDSS) and disease duration. When evaluated with a simulation, using an onset-specific MSSS improved statistical power in mixed cohorts. There were no significant differences by sex. CONCLUSION: The differences in the disability accrual rate between progressive- and relapsing-onset MS have a significant effect on MSSS. An onset-specific MSSS should be used when comparing the rate of disability progression among progressive-onset cases and for mixed cohorts.

[Diagnosis of multiple sclerosis: A review of the 2017 revisions of the McDonald criteria]. / A sclerosis multiplex diagnosztikája: Összefoglaló a McDonald-kritériumok 2017-es felülvizsgálatáról.

The revolutionary progress of research in neuroimmu-nology has led to the introduction of disease modifying therapies in multiple sclerosis at the end of the last century. The International Panel on Diagnosis of Multiple Sclerosis originally proposed the 2001 McDonald criteria to facilitate the diagnosis of MS in patients with the first objective neurological symptom(s) suggesting demyelinating event, when magnetic resonance imaging is integrated with clinical and other paraclinical diagnostic methods. New terms have been introduced to substitute clinical information by MRI: dissemination in space - indicating a multifocal central demyelinating process and dissemination in time - indicating the development of new CNS lesions over time. The criteria for diagnosis of Multiple Sclerosis have continuously evolved, they were modified in 2005 and 2010 allowing for an earlier and more accurate diagnosis of MS over time, and they provided the most up-to-date guidance for clinicians and researchers. The last recommended revisions relied entirely on available evidence, and not on expert opinion thereby reducing the risk of the misdiagnosis. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical, clinically isolated syndrome. In this review, we provide an overview of the recent 2017 revisions to the criteria of dissemination in space and time with the importance of the presence of CSF-specific oligoclonal bands; keeping fully in mind that there is no better explanation for symptoms than diagnosis of MS. In the future, validation of the 2017 McDonald criteria will be needed in diverse populations. Further investigations are required on the value of new MRI approaches, on optic nerve involvement, on evoked potential and optical coherence tomography, in order to assess their possible contribution to diagnostic criteria.

[Is second-line immunomodulatory treatment effective in multiple sclerosis?] / Elonyös a másodvonalbeli immunmoduláns kezelés sclerosis multiplexben?

BACKGROUND AND PURPOSE: Natalizumab is the first evidence based monoclonal antibody, which was launched for treatment in relapsing remitting multiple sclerosis in Hungary in 2010. Standardized follow-up is required to use it. METHODS: Our aim was to evaluate the efficacy and to monitor the safety of natalizumab treatment by using an electronic database established for MS registry. Clinical activity was measured by annual relapse rates, functional status of patients measured by EDSS and MFSC. Radiological activity was evaluated by standard MRI protocol. Data, results of MS patients and side effects of natalizumab treatment were recorded in iMed software. RESULTS: 31 patients started the natalizumab treatment after 6.5±5.8 years from the onset of MS. The efficacy of treatment was evaluated after a mean of 67 (min: 14 max: 128) infusions in December 2016. The drop-out rate was low, due to the presence of neutralising antibodies in one case, pregnancy in two cases and development of malignant disease in one case which was not related to the natalizumab treatment. The treatment was well tolerated with excellent compliance without serious side effects. The annual relapse rate reduced from a mean of 1.7 to 0.03 (p<0.000001) in the first 12 months of treatment compared to the pretreatment 12 month activity, and it stayed at low level during the whole follow up. EDSS was stable or improved with an exception of two cases. In 23 subjects (77%) lack of new/enlarging T2 lesions and lack of gadolineum-enhancing lesions on MRI were observed. 18 patients (60%) had no evidence of disease activity (NEDA-3). PASAT test improved in most of the cases. CONCLUSION: The natalizumab therapy was very effective in all cases including those patients who had active disease under the previous immunomodulatory treatment.

[EEG-based cerebral networks in 14 neurological disorders]. / EEG-alapú agyi hálózatok 14 neurológiai betegségben.

Background - Brain networks have not been systematically investigated yet in most neurological disorders. Purpose - To investigate EEG functional connectivity (EEGfC) networks in 14 neurological disorders. Patients - Potentially eligible patients were collected from clinical and EEG databases. All the available clinical data and EEG records were critically revised. All the patients who suffered of a single neurological disorder (out of the 14) and had a good quality EEG recording entered the study. Confoundig factors as comorbidity and CNS-active drug effects were eliminated as far as possible. EEG analysis - Three minutes of resting-state, waking EEG activity were selected for analysis. Current source density (CSD) values were computed for 2394 cortical voxels by Low Resolution Electromagnetic Tomography (LORETA). Thereafter, Pearson correlation coefficients were computed between all pairs of 23 cortical regions of interest (ROI) in each hemisphere (LORETA Source Correlation, LSC software). Computation was carried out for conventional EEG broad bands and very narrow bands (1 Hz bandwidth) between 1 and 25 Hz as well. Correlation coefficients of each group were statistically compared to our normative EEG (LSC) database by two-talied t-tests. Bonferroni-corrected p<0.05 values were accepted as statistically significant, and were graphically displayed as topographical networks. Results and conclusion - Group-specific networks were demonstrated. However, non-specific networks, charasteristic for most groups, were detected as well. Common finding were: decreased connectivity in the alpha band and increased connectivity in the delta, theta bands and upper-beta band. Decreased alpha-band connectivity presumably reflected primary lesional effects and on the other hand, non-specific vulnerability of "rich club connections". Increased connectivity in the slow bands presumably indicated adaptive-compensatory activity of brain homeostasis.

Switch to natalizumab versus fingolimod in active relapsing-remitting multiple sclerosis.

OBJECTIVE: In patients suffering multiple sclerosis activity despite treatment with interferon ß or glatiramer acetate, clinicians often switch therapy to either natalizumab or fingolimod. However, no studies have directly compared the outcomes of switching to either of these agents. METHODS: Using MSBase, a large international, observational, prospectively acquired cohort study, we identified patients with relapsing-remitting multiple sclerosis experiencing relapses or disability progression within the 6 months immediately preceding switch to either natalizumab or fingolimod. Quasi-randomization with propensity score-based matching was used to select subpopulations with comparable baseline characteristics. Relapse and disability outcomes were compared in paired, pairwise-censored analyses. RESULTS: Of the 792 included patients, 578 patients were matched (natalizumab, n = 407; fingolimod, n = 171). Mean on-study follow-up was 12 months. The annualized relapse rates decreased from 1.5 to 0.2 on natalizumab and from 1.3 to 0.4 on fingolimod, with 50% relative postswitch difference in relapse hazard (p = 0.002). A 2.8 times higher rate of sustained disability regression was observed after the switch to natalizumab in comparison to fingolimod (p < 0.001). No difference in the rate of sustained disability progression events was observed between the groups. The change in overall disability burden (quantified as area under the disability-time curve) differed between natalizumab and fingolimod (-0.12 vs 0.04 per year, respectively, p < 0.001). INTERPRETATION: This study suggests that in active multiple sclerosis during treatment with injectable disease-modifying therapies, switching to natalizumab is more effective than switching to fingolimod in reducing relapse rate and short-term disability burden.

Change in autoantibody and cytokine responses during the evolution of neuromyelitis optica in patients with systemic lupus erythematosus: A preliminary study.

BACKGROUND: Neuromyelitis optica (NMO)-systemic lupus erythematosus (SLE) association is a rare condition characterized by multiple autoantibodies. OBJECTIVE: To examine if, during the evolution of NMO, anti-AQP4 responses are part of polyclonal B cell activation, and if T cell responses contribute. METHODS: In 19 samples of six patients who developed NMO during SLE, we examined the correlation of AQP4-IgG1 and IgM with (i) anti-MOG IgG and IgM, (ii) anti-nuclear, anti-nucleosome and anti-dsDNA IgG antibodies, (iii) cytokines and chemokines in the serum and (iv) longitudinal relation to NMO relapses/remission. RESULTS: AQP4-IgG1 was present 1-2-5 years before the first NMO relapse. During relapse, AQP4-IgG1, ANA, anti-dsDNA and anti-nucleosome antibodies were elevated. Anti-MOG IgG/IgM and AQP4-IgM antibodies were not detected. AQP4-IgG1 antibodies correlated with concentration of anti-nucleosome, IFN-γ,interferon-gamma-induced CCL10/IP-10 and CCL17/TARC (p<0.05, respectively). CCL17/TARC correlated with levels of anti-nucleosome and anti-dsDNA (p<0.05, respectively). Compared to healthy subjects, concentration of IFN-γ and CCL17/TARC was higher in NMO/SLE (p<0.05). CONCLUSIONS: AQP4-IgG1 antibodies are present in the sera years before the first NMO attack in patients with SLE; elevation of anti-AQP4 is part of a polyclonal B cell response during NMO relapses; in spite of multiple autoantibodies in the serum, MOG antibodies were not present; Th1 responses accompany autoantibody responses in NMO/SLE.

[ALEMTUZUMAB: BENEFITS AND CHALLENGES OF A NEW THERAPY IN MULTIPLE SCLEROSIS]. / ALEMTUZUMAB: EGY ÚJ TERÁPIA ELONYEI ÉS KIHÍVÁSAI SCLEROSIS MULTIPLEXBEN.

The widening spectrum of MS treatment is partially due to increasing knowledge about the pathogenesis of MS. The humanized monoclonal antibody against CD52, alemtuzumab has been approved in Europe for the treatment of MS, which results in long-term depletion of B and T cells due to complement- and antibody-mediated cytotoxicity. Based on phase 2 and 3 clinical trials, alemtuzumob decreases the risk of sustained neurological deficit and progression compared to high-dose subcutaneous interferon-ß1a in patients with active relapsing-remitting MS, either treatment-naïve or with breakthrough disease. We review advantages and benefits of the treatment, discuss safety concerns, and present a case to describe practical issues.

Eculizumab Treatment of Massive Hemolysis Occurring in a Rare Co-Existence of Paroxysmal Nocturnal Hemoglobinuria and Myasthenia Gravis.

The co-occurrence of myasthenia gravis (MG) and paroxysmal nocturnal hemoglobinuria (PNH) is rare; only one case has been published so far. We report a 63-year-old Caucasian female patient who was diagnosed with MG at the age of 43. Thymoma was also detected, and so it was surgically resected, which resulted in reasonable disease control for nearly 20 years. Slight hemolysis began to emerge, and then myasthenia symptoms progressed, so immunosuppressive therapy was started. Due to progressive disease and respiratory failure, the patient underwent plasmapheresis, and ventilatory support was stopped. Marked hemolysis was present, and diagnostic tests confirmed PNH with type III PNH cells. Her myasthenia symptoms aggravated, mechanical ventilation had to be started again, and due to the respiratory acidosis, massive hemolysis occurred. After two plasmapheresis sessions, the patient received eculizumab at 600 mg, resulting in prompt hemolysis control. After the second dose of the treatment, the patient was extubated. Still, due to their inability to cough, she developed another respiratory failure and pneumonia-sepsis, resulting in the patient's death. This case highlights the rare association between these two serious diseases and similar immune-mediated pathophysiology mechanisms involving the complement system.

Treatment of relapsing multiple sclerosis in Hungary - consensus recommendation from the Hungarian neuroimmunology society.

Multiple sclerosis (MS) may impact quality of life, careers and family plans of the affected individuals. The current treatments with disease modifying therapies aim to prevent people with MS (pwMS) from disability accumulation and progression. Different countries have different reimbursement policies resulting in inequalities in patient care among geographical regions. Access to anti-CD20 therapies for relapsing MS is restricted in Hungary because therapy of individual cases only is reimbursed. In the light of the latest research and national guidelines, 17 Hungarian MS experts agreed on 8 recommendations regarding relapsing pwMS using the Delphi round method. Strong agreement (> 80%) was achieved in all except one recommendation after three rounds, which generated a fourth Delphi round. The experts agreed on treatment initiation, switch, follow-up and discontinuation, as well as on special issues such as pregnancy, lactation, elderly population, and vaccination. Well-defined national consensus protocols may facilitate dialogue between policymakers and healthcare professionals and thus contribute to better patient care in the long run.

Elevated Blood Alcohol Concentration Is Associated with Improved Clinical Outcomes of Intravenous Thrombolysis Treatment in Acute Ischemic Stroke Patients-A Retrospective Study.

BACKGROUND: Intravenous thrombolysis (IVT) improves acute ischemic stroke (AIS) outcomes, but with limited success. In addition, ethanol potentiates the effect of r-tPA in ischemia models. METHODS: The effect of acute alcohol consumption on IVT outcomes was investigated in a retrospective cohort study. AIS patients with detectable blood alcohol concentration (BAC) during IVT were included (alcohol group; n = 60). For each case, 3 control subjects who underwent IVT but denied alcohol consumption were matched in terms of age, sex, affected brain area, and stroke severity. Outcomes were determined using the NIHSS at 7 days and the modified Rankin scale (mRS) at 90 days. RESULTS: Patients were younger and had a less severe stroke than in a standard stroke study. Favorable long-term outcomes (mRS 0-2) occurred significantly more frequently in the alcohol group compared to controls (90% vs. 63%, p < 0.001). However, the rates of hemorrhagic transformation were similar. Multiple logistic regression models identified elevated BAC as a significant protective factor against unfavorable short-term (OR: 0.091, 95% CI: 0.036-0.227, p < 0.001) and long-term outcomes (OR: 0.187, 95% CI: 0.066-0.535, p = 0.002). In patients with BAC > 0.2%, significantly lower NIHSS was observed at 3 and 7 days after IVT vs. in those with 0.01-0.2% ethanol levels. CONCLUSION: Elevated BAC is associated with improved outcomes in IVT-treated AIS without affecting safety.

Switching to natalizumab or fingolimod in multiple sclerosis: Comparative effectiveness and effect of pre-switch disease activity.

BACKGROUND: Patients with relapsing-remitting multiple sclerosis (RRMS) who experience relapses on a first-line therapy (interferon, glatiramer acetate, dimethyl fumarate, or teriflunomide; collectively, "BRACETD") often switch to another therapy, including natalizumab or fingolimod. Here we compare the effectiveness of switching from a first-line therapy to natalizumab or fingolimod after ≥1 relapse. METHODS: Data collected prospectively in the MSBase Registry, a global, longitudinal, observational registry, were extracted on February 6, 2018. Included patients were adults with RRMS with ≥1 relapse on BRACETD therapy in the year before switching to natalizumab or fingolimod. Included patients received natalizumab or fingolimod for ≥3 months after the switch. RESULTS: Following 1:1 propensity score matching, 1000 natalizumab patients were matched to 1000 fingolimod patients. Mean (standard deviation) follow-up time was 3.02 (2.06) years after switching to natalizumab and 2.58 (1.64) years after switching to fingolimod. Natalizumab recipients had significantly lower annualized relapse rate (relative risk=0.66; 95% confidence interval [CI], 0.59-0.74), lower risk of first relapse (hazard ratio [HR]=0.69; 95% CI, 0.60-0.80), and higher confirmed disability improvement (HR=1.27; 95% CI, 1.03-1.57) than fingolimod recipients. No difference in confirmed disability worsening was observed. CONCLUSIONS: Patients with RRMS switching from BRACETD demonstrated better outcomes with natalizumab than with fingolimod.

Comparative Effectiveness of Autologous Hematopoietic Stem Cell Transplant vs Fingolimod, Natalizumab, and Ocrelizumab in Highly Active Relapsing-Remitting Multiple Sclerosis.

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab. Main outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

The safety and efficacy of fingolimod: Real-world data from a long-term, non-interventional study on the treatment of RRMS patients spanning up to 5 years from Hungary.

BACKGROUND: Fingolimod was approved and reimbursed by the healthcare provider in Hungary for the treatment of highly active relapsing-remitting multiple sclerosis (RRMS) in 2012. The present study aimed to assess the effectiveness, safety profile, and persistence to fingolimod in a real-life setting in Hungary in RRMS patients who were either therapy naïve before enrollment or have changed to fingolimod from another disease-modifying therapy (DMT) for any reason. METHODS: This cross-sectional, observational study with prospective data collection was performed nationwide at 21 sites across Hungary. To avoid selection bias, sites were asked to document eligible patients in consecutive chronological order. Demographic, clinical, safety and efficacy data were analysed for up to 5 years from 570 consenting adult patients with RRMS who had received treatment with fingolimod for at least one year. RESULTS: 69.6% of patients remained free from relapses for the whole study duration; in the first year, 85.1% of patients did not experience a relapse, which rose to 94.6% seen in the 5th year. Compared to baseline at study end, 28.2% had higher, and 9.1% had lower, meanwhile, 62.7% of the patients had stable EDSS scores. Overall, the annualized relapse rate decreased from 0.804 observed at baseline to 0.185, 0.149, 0.122, 0.091, and 0.097 (77.0%, 82.1%, 85.2%, 89.7%, and 89.0% relative reduction, respectively) after 1, 2, 3, 4, and 5 years of treatment. The greatest reduction rate was seen in the group of therapy naïve patients. Treatment persistence on fingolimod after 60 months was 73.4%. CONCLUSION: In this nationwide Hungarian cohort, most patients under fingolimod treatment were free from relapses and disability progression. In addition, fingolimod has proven to be a well-tolerated DMT that has sustained its manageable safety profile, high efficacy, and positive benefit/risk ratio for up to 5 years in a real-life setting.

Do Hungarian multiple sclerosis care units fulfil international criteria?

A PATIENTS: Because of the past 3 decades' extensive research, several disease modifying therapies became available, thus a paradigm change is multiple sclerosis care was necessary. In 2018 a therapeutic guideline was created recommending that treatment of persons with multiple sclerosis should take place in specified care units where the entire spectrum of disease modifying therapies is available, patient monitoring is ensured, and therapy side effects are detected and treated promptly. In 2019 multiple sclerosis care unit criteria were developed, emphasizing personnel and instrumental requirements to provide most professional care. However, no survey was conducted assessing the real-world adaptation of these criteria. OBJECTIVE: To assess whether Hungarian care units fulfil international criteria. METHODS: A self-report questionnaire was assembled based on international guidelines and sent to Hungarian care units focusing on 3 main aspects: personnel and instrumental background, disease-modifying therapy use, number of people living with multiple sclerosis receiving care in care units. Data on number of persons with multiple sclerosis were compared to Hungarian prevalence estimates. Descriptive statistics were used to analyse data. RESULTS: Out of 27 respondent care units, 3 fulfilled minimum requirements and 7 fulfilled minimum and recommended requirements. The least prevalent neighbouring specialties were spasticity and pain specialist, and neuro-ophthalmologist and oto-neurologist. Only 15 centres used all available disease modifying therapies. A total number of 7213 people with multiple sclerosis received care in 27 respondent centres. Compared to prevalence estimates, 2500 persons with multiple sclerosis did not receive multiple sclerosis specific care in Hungary. CONCLUSION: Less than half of Hungarian care units provided sufficient care for people living with multiple sclerosis. Care units employing fewer neighbouring specialties, might have difficulties diagnosing and providing appropriate care for persons with multiple sclerosis, especially for people with progressive disease course, contributing to the reported low number of persons living with multiple sclerosis.

Ferritin and prolactin levels in multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a common demyelnating disorder of the central nervous system (CNS) and ethiopathogenesis has yet to be fully elucidated. The disease may present in several clinical forms that are closely associated with disease morbidity. In recent years various environmental and hormonal factors have been implicated in the pathogenesis of autoimmunity. OBJECTIVES: To evaluate ferritin and prolactin levels in MS patients and their correlation with clinical manifestations of the disease. METHODS: Serum samples from 150 multiple sclerosis patients were evaluated for demographic characteristics, clinical parameters as well as prolactin and ferritin levels utilizing the Liaison chemiluminescent immunoassays (DiaSorin, Italy). Sera from 100 matched healthy donors were used as controls. RESULTS: Hyperprolactinemia was documented in 10 of 150 MS patients (6.7%) and hyperferritinemia in 12 (8%), both of which were significantly more common in this group compared with healthy controls (P < 0.01 and P = 0.02 respectively). Among female MS patients, elevated prolactin levels were related to the secondary-progressive type of disease (P = 0.05), whereas hyperferritinemia was associated with male gender (P = 0.03) and with the relapsing-progressive type of the disease (P = 0.02). An inverse association was found between hyperferritinemia and the relapsing-remitting type of MS in male patients (P = 0.05) CONCLUSIONS: Our results suggest a plausible association between these biomarkers and certain clinical types and gender among MS patients. Further studies combining clinical data, CNS imaging and these markers are warranted.

[Current treatment of multiple sclerosis]. / A sclerosis multiplex kezelése napjainkban.

Multiple sclerosis (MS) is an autoimmune and degenerative disorder. In the past decades, the introduction of parenteral immunomodulatory therapies brought significant progress. These agents increase the number of relapses (shubs) by about 30%, and some of them has been shown to halter the accumulation of neurological symptoms and the development of disability. As first-line agents, interferon beta and glatiramer acetate (consisting of amino acids) can be used. Some new therapeutic strategies have been developed as a result of biotechnological development. The advantage of humanised monoclonal antibodies is that they affect the autoimmune inflammatory process more selectively. Among monoclonal antibodies, natalizumab, which binds to alpha-4-beta-1 integrin receptors and inhibits the migration of T-lymphocytes into the central nervous system, is available from February 2010 in Hungary, recommended as second-line treatment. The efficacy of natalizumab in decreasing relapse rate is > 60%. However, its use is associated with progressive multifocal leukoencephalopathy (PML) in one out of 1000 treated patient. Currently it is recommended as second-line treatment, if the patient has active disease despite immunomodulatory therapy. Among orally administered agents, a preparation containing fingolimod is expected to become available next year, and another pill, cladribin has been also found to be efficient in randomised, controlled phase III trials. Fingolimod acts on sphingosine 1-phosphate receptors-1 (S1P1). Cladribine is a purine nucleotide analogue, and its efficacy is based on long-term reduction of CD4+ and CD8+ lymphocytes. Further promising oral immunomodulatory agents are laquinimod and BG000012 (dimethylfumarate), which are currently being tested in phase III clinical trials in relapsing-remitting MS. The most efficient treatment should be chosen on the basis of the activity, aetiology and the posited pathomechanism of the disease. With the increasing number of therapeutic options, choosing the treatment that is optimal for the patient while also considering side effects might be challenging for both the patients and physicians.