[Monitoring of blood parameters under course-modified MS therapy : Substance-specific relevance and current recommendations for action]. / Monitoring von Blutparametern unter verlaufsmodifizierender MS-Therapie : Substanzspezifische Relevanz und aktuelle Handlungsempfehlungen.

With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.

Investigation of sex-specific effects of apolipoprotein E on severity of EAE and MS.

BACKGROUND: Despite pleiotropic immunomodulatory effects of apolipoprotein E (apoE) in vitro, its effects on the clinical course of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS) are still controversial. As sex hormones modify immunomodulatory apoE functions, they may explain contentious findings. This study aimed to investigate sex-specific effects of apoE on disease course of EAE and MS. METHODS: MOG(35-55) induced EAE in female and male apoE-deficient mice was assessed clinically and histopathologically. apoE expression was investigated by qPCR. The association of the MS severity score (MSSS) and APOE rs429358 and rs7412 was assessed across 3237 MS patients using linear regression analyses. RESULTS: EAE disease course was slightly attenuated in male apoE-deficient (apoE (-/-) ) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 2 [IQR 0.0-4.5]; wildtype = 4 [IQR 1.0-5.0]; n = 10 each group, p = 0.0002). In contrast, EAE was more severe in female apoE (-/-) mice compared to wildtype mice (cumulative median score: apoE (-/-) = 3 [IQR 2.0-4.5]; wildtype = 3 [IQR 0.0-4.0]; n = 10, p = 0.003). In wildtype animals, apoE expression during the chronic EAE phase was increased in both females and males (in comparison to naïve animals; p < 0.001). However, in MS, we did not observe a significant association between MSSS and rs429358 or rs7412, neither in the overall analyses nor upon stratification for sex. CONCLUSIONS: apoE exerts moderate sex-specific effects on EAE severity. However, the results in the apoE knock-out model are not comparable to effects of polymorphic variants in the human APOE gene, thus pinpointing the challenge of translating findings from the EAE model to the human disease.

[New therapeutic options in multiple sclerosis]. / Neue Therapieoptionen bei der Multiplen Sklerose.

Therapeutic options in the treatment of multiple sclerosis (MS) have broadened notably over the past years, especially for relapsing-remitting forms of MS. The revision of the diagnostic criteria simplified and accelerated MS diagnosis, definitions of disease courses were operationalized focussing on disease activity and progression as major determinants. The paradigm of an early treatment initiation is accepted and evidence-based. All these aspects have led to an increasing complexity of therapeutic decision making. Besides a benefit-risk-evaluation for each substance, individual patient-related factors have to be considered, e.g. life and family planning. This article reviews new and established disease-modifying drugs in the context of disease courses and stages and benefit-risk-considerations.

Management of disease-modifying treatments in neurological autoimmune diseases of the central nervous system.

The therapeutic armamentarium for autoimmune diseases of the central nervous system, specifically multiple sclerosis and neuromyelitis optica, is steadily increasing, with a large spectrum of immunomodulatory and immunosuppressive agents targeting different mechanisms of the immune system. However, increasingly efficacious treatment options also entail higher potential for severe adverse drug reactions. Especially in cases failing first-line treatment, thorough evaluation of the risk-benefit profile of treatment alternatives is necessary. This argues for the need of algorithms to identify patients more likely to benefit from a specific treatment. Moreover, paradigms to stratify the risk for severe adverse drug reactions need to be established. In addition to clinical/paraclinical measures, biomarkers may aid in individualized risk-benefit assessment. A recent example is the routine testing for anti-John Cunningham virus antibodies in natalizumab-treated multiple sclerosis patients to assess the risk for the development of progressive multi-focal leucoencephalopathy. Refined algorithms for individualized risk assessment may also facilitate early initiation of induction treatment schemes in patient groups with high disease activity rather than classical escalation concepts. In this review, we will discuss approaches for individiualized risk-benefit assessment both for newly introduced agents as well as medications with established side-effect profiles. In addition to clinical parameters, we will also focus on biomarkers that may assist in patient selection.

Efficacy and safety of ocrelizumab in patients with relapsing multiple sclerosis: Real-world experience of two Swiss multiple sclerosis centers.

BACKGROUND: Ocrelizumab (OCR) is a humanized monoclonal antibody directed against CD-20 positive lymphocytes, mainly B-lymphocytes. OCR is approved for treatment of primary progressive (PPMS) and relapsing multiple sclerosis (RMS). This study aims to provide real-world safety and efficacy data of people with RMS treated with OCR in two Swiss Multiple Sclerosis (MS) centers. METHODS: We have conducted a retrospective data analysis using the patient cohorts from the Cantonal Hospital Aarau and Bern University Hospital (RMS: n = 235). Statistical analyses were performed with Mann-Whitney U-Test, Chi-squared test and Spearman-Rho-Correlation. Adjustment for multiple testing was performed by Bonferroni procedure. RESULTS: After initiation of OCR, there was a decrease in disease activity in RMS patients. In our study, 152/190 (80.0 %) RMS patients fulfilled the criteria for NEDA-3 12 months and 88/104 (84.6 %) showed NEDA-3 24 months after OCR initiation. The most frequent adverse events (AEs) in our study were infections, taking place in 78/235 (33.2 %) RMS patients. COVID-19 was the most common infection, followed by urinary infections and other respiratory infections and infectious adverse events occurred significantly more frequent in patients with reduced IgG serum concentration. CONCLUSIONS: Our real-world study showed OCR being associated with low rates of any type of MS disease activity as indicated by NEDA-3. The adverse event profile is comparable to the known events especially infections and an association between infections and reduced IgG serum concentration was found.

Rapid differentiation of MOGAD and MS after a single optic neuritis.

BACKGROUND: Optic neuritis (ON) is a common manifestation of multiple sclerosis (MS) and myelin-oligodendrocyte-glycoprotein IgG-associated disease (MOGAD). This study evaluated the applicability of optical coherence tomography (OCT) for differentiating between both diseases in two independent cohorts. METHODS: One hundred sixty two patients from seven sites underwent standard OCT and high-contrast visual acuity (HCVA) testing at least 6 months after first ON. Of these, 100 patients (32 MOGAD, 68 MS) comprised the primary investigational cohort, while 62 patients (31 MOGAD, 31 MS) formed a validation cohort. A composite score distinguishing between MOGAD and MS was developed using multivariate logistic regression. RESULTS: Bilateral simultaneous ON occurred more frequently in MOGAD compared to MS (46.9 vs. 11.8%, p < 0.001). OCT revealed more peripapillary retinal nerve fiber layer (pRNFL) atrophy in all segments in MOGAD compared to predominantly temporal pRNFL atrophy in MS (p < 0.001). HCVA was better preserved in MS (p = 0.007). pRNFL thickness in all except for temporal segments was suitable for differentiating MOGAD and MS. Simultaneous bilateral ON and critical atrophy in nasal (< 58.5 µm) and temporal superior (< 105.5 µm) segments were included into the composite score as three independent predictors for MOGAD. The composite score distinguished MOGAD from MS with 75% sensitivity and 90% specificity in the investigational cohort, and 68% sensitivity and 87% specificity in the validation cohort. CONCLUSION: Following a single ON-episode, MOGAD exhibits more pronounced global pRNFL atrophy and lower visual acuity after ON compared to MS. The introduced OCT-based composite score enabled differentiation between the two entities across both cohorts.

Ocrelizumab-related neutropenia: Effects of age, sex and bodyweight using the FDA Adverse Event Reporting System (FAERS).

OBJECTIVE: Neutropenia is a rare complication of anti-CD20 treatment, such as Ocrelizumab (OCR) in Multiple Sclerosis (MS). Using FDA´s Adverse Event Reporting System (FAERS), a post-marketing, open access pharmacovigilance database, we aimed to identify risk factors of neutropenia in OCR-treated patients. METHODS: Data were retrieved from FAERS identifying OCR-treated patients with and without neutropenia. Only data with OCR as the single suspected product were considered. Multivariable logistic regression (MLR) analysis was run to study if MS disease course, age, sex and bodyweight were associated with the risk of neutropenia. RESULTS: Of 15,313 initial hits, 3177 complete datasets were included in the analysis. MLR demonstrated that MS disease course was not associated, whereas sex (female sex (reference male sex) 0.356, 95%CI 0.145-0.875, p = 0.0124), age (years, 0.909, 95%CI 0.875-0.944, p = 7.4105 × 10-7) and bodyweight (kilogram, 0.961, 95%CI 0.935-0.988, p = 0.005) were factors associated with OCR-related neutropenia (Nagelkerkes R2=0.17, n = 3177). No deaths were reported for identified neutropenia cases. CONCLUSION: Using FAERS, we identified male sex, younger age and lower bodyweight as factors associated with OCR-related neutropenia. With the limitations inherent to this open data source, our data need prospective validation, but elucidate potential factors for a personalized side effect profiling.

German guideline for diagnosis and treatment of multiple sclerosis - a survey focusing neurologists in daily practise.

We performed a web-based survey among German-speaking neurologists to evaluate the acceptance of the 2021 German guideline in the diagnosis and treatment of multiple sclerosis. Based on 327 replies in total, the current survey largely reproduced the findings of an earlier, smaller survey on the prefinal consultation version of the guideline and confirmed high acceptance rates. Half of the participants were practising neurologists. Neurologists from MS centers with more than 500 patients per year (n=26) were more critical of the guideline. They reiterated some of the criticisms of the previous feedback, and, in particular, felt that safety aspects are overemphasized in the guideline, thereby superseding early aggressive therapy.

Implementation study of the 2021 German guideline for diagnosis and treatment of multiple sclerosis.

BACKGROUND: In May 2021, a new guideline on the diagnosis and treatment of multiple sclerosis and related disorders was released in Germany. Since the success of a guideline depends on how it integrates into everyday clinical practice, the German Society for Neurology (DGN) has launched a multimethod implementation project. Here we report on the results based on the consultation version of the guideline. METHODS: We used qualitative and quantitative data analyses to capture the nature and extent of barriers and facilitating factors to the implementation. We centered on the guideline's chapter A on diagnosis, relapse therapy, and immunotherapy of multiple sclerosis. We performed nine online focus group discussions and a web-based survey and analyzed emails and letters with comments from stakeholders and independent parties that were sent spontaneously or by invitation. RESULTS: 94 neurologists answered the survey, and ≥70% agreed with the recommendations of the guideline on each major content topic. Barriers to implementation were detected in group discussions and written input. The most controversial issues of the guideline were "early treatment", "criteria for starting or switching therapy", "stepwise escalation versus early aggressive treatment", "classification of drugs into three categories of efficacy" and the scenarios on "treatment cessation". Some appreciated the highly structured recommendations, but others felt that the guideline restricts the free choice of therapy, or they were afraid of recourse claims. Some considered the guideline as too cautious regarding treatment initiation, possibly delaying necessary therapies. Others appreciated that conflicts of interests of the guideline's authoring group were minimized and thought that the new guideline is clearer, more extensive and practical. CONCLUSION: In contrast to the survey, feedback in the focus group discussions and from individuals was diverse and sometimes more critical. Based on the overall feedback rate of about 250 people in relation to the number of 6500 board-certified neurologists in Germany, the overall appreciation of the guideline can only be considered as an indicator and not proof of acceptance. Results of this analysis were incorporated into several adjustments to the final guideline of 2021. Since the guideline is to be updated regularly under the auspices of a "living guideline", active interaction with users will continue to matter and help to improve it.

Hypogammaglobulinemia: A contributing factor to multiple sclerosis fatigue?

OBJECTIVE: Fatigue is one of the most disabling and difficult to treat symptoms of autoimmune diseases and frequently presents in people with multiple sclerosis (PwMS). Hypogammaglobulinemia for immunoglobulin G (IgG) affects approximately 8-25% of PwMS. We performed a retrospective analysis to investigate the association of MS-fatigue and IgG hypogammaglobulinemia. METHODS: PwMS, treated at Eginition University Hospital Athens or at the University Hospital Bern, were included (n = 134 patients (Bern n = 99; Athens n = 35)). Mann Whitney U-test (MWT), ANOVA test, Chi2 test and multivariable linear regression models were run. RESULTS: 97/134 (72.4%) PwMS reported fatigue. In the multivariable linear regression analysis, IgG serum concentration (-1.6, 95%CI -2.7 - -0.5, p = 0.006), daytime sleepiness (0.8, 95%CI 0.2-1.4, p = 0.009), and a depressive mood (1.1, 95%CI 0.8-1.4, p < 0.001) were significantly associated with fatigue. The impact of IgG serum concentration (-2.9 95%CI -4.7 - -1.1, p = 0.002) remained significant also in the subcohort of PwMS without depressive symptoms or daytime sleepiness. CONCLUSIONS: We found an association between IgG hypogammaglobulinemia and fatigue in PwMS (Level of Evidence IV), which might be translated to other autoimmune diseases. It bears a potential therapeutic consequence considering IgG supplementation strategies, if our finding can be validated prospectively.

Characteristic retinal atrophy pattern allows differentiation between pediatric MOGAD and MS after a single optic neuritis episode.

BACKGROUND: Optic neuritis (ON) is the most prevalent manifestation of pediatric multiple sclerosis (MSped) and myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGADped) in children > 6 years. In this study, we investigated retinal atrophy patterns and diagnostic accuracy of optical coherence tomography (OCT) in differentiating between both diseases after the first ON episode. METHODS: Patients were retrospectively identified in eight tertial referral centers. OCT, VEP and high/low-contrast visual acuity (HCVA/LCVA) have been investigated > 6 months after the first ON. Prevalence of pathological OCT findings was identified based on data of 144 age-matched healthy controls. RESULTS: Thirteen MOGADped (10.7 ± 4.2 years, F:M 8:5, 21 ON eyes) and 21 MSped (14.3 ± 2.4 years, F:M 19:2, 24 ON eyes) patients were recruited. We observed a significantly more profound atrophy of both peripapillary and macular retinal nerve fiber layer in MOGADped compared to MSped (pRNFL global: 68.2 ± 16.9 vs. 89.4 ± 12.3 µm, p < 0.001; mRNFL: 0.12 ± 0.01 vs. 0.14 ± 0.01 mm3, p < 0.001). Neither other macular layers nor P100 latency differed. MOGADped developed global atrophy affecting all peripapillary segments, while MSped displayed predominantly temporal thinning. Nasal pRNFL allowed differentiation between both diseases with the highest diagnostic accuracy (AUC = 0.902, cutoff < 62.5 µm, 90.5% sensitivity and 70.8% specificity for MOGADped). OCT was also substantially more sensitive compared to VEP in identification of ON eyes in MOGAD (pathological findings in 90% vs. 14%, p = 0.016). CONCLUSION: First MOGAD-ON results in a more severe global peripapillary atrophy compared to predominantly temporal thinning in MS-ON. Nasal pRNFL allows differentiation between both diseases with the highest accuracy, supporting the additional diagnostic value of OCT in children with ON.

Natalizumab induced blood eosinophilia: A retrospective pharmacovigilance cohort study and review of the literature.

OBJECTIVE: To describe frequency of natalizumab related eosinophilia and clinical symptoms of eosinophilic disease in our monocentric cohort. METHODS: Comparison of clinical characteristics of 115 natalizumab treated and 116 untreated RRMS patients and review of literature. RESULTS: 38% of natalizumab treated patients had eosinophilia, which occurred significantly more frequently compared to untreated MS patients (3%, p-value<0.001). In symptomatic patients, mean eosinophil counts were significantly higher than in asymptomatic patients and symptoms developed within one year. DISCUSSION: Eosinophilia is a side effect of natalizumab and mostly asymptomatic. However, few patients develop within one year after start of natalizumab an eosinophilic disease as severe side effect.

Factors influencing patient satisfaction with the first diagnostic consultation in multiple sclerosis: a Swiss Multiple Sclerosis Registry (SMSR) study.

BACKGROUND: Patient satisfaction is predictive of adherence, malpractice litigation and doctor-switching. OBJECTIVE: To investigate which factors of the first diagnostic consultation (FDC) influence patient satisfaction and which topics persons with multiple sclerosis (PwMS) thought were missing. METHODS: Using retrospective patient-reported data of the Swiss Multiple Sclerosis Registry from PwMS with relapsing disease onset, we fitted ordered logistic regression models on satisfaction with FDC, with socio-demographic and FDC features as explanatory factors. RESULTS: 386 PwMS diagnosed after 1995 were included. Good satisfaction with the FDC was associated with a conversation more than 20 min [multivariable odds ratio, 95% confidence interval 3.9 (2.42; 6.27)], covering many topics [1.35 (1.19; 1.54) per additional topic], the presence of a significant others [1.74 (1.03; 2.94) ], and shared decision making [3.39 (1.74; 6.59)]. Not receiving a specific diagnosis was main driver for low satisfaction [0.29 (0.15; 0.55)]. Main missing topics concerned long-term consequences (reported by 6.7%), psychological aspects (6.2%) and how to obtain support and further information (5.2%). CONCLUSIONS: A conversation of more than 20 min covering many MS relevant topics, a clear communication of the diagnosis, the presence of a close relative or significant other, as well as shared decision making enhanced patient satisfaction with the FDC. ClinicalTrials.gov Identifier: NCT02980640.

Longitudinal analyses of anti-JCV antibody index for risk assessment of progressive multifocal leukoencephalopathy.

Risk assessment for natalizumab-associated progressive multifocal leukoencephalopathy (Nat-PML) comprises the anti-JC virus (JCV) antibody index (AI). The anti-JCV AI was longitudinally determined in a natalizumab-treated MS cohort (Nat-MS, n = 468) and samples of Nat-PML patients (n = 15). In Nat-MS, the median AI was 0.8 (25th to 75th percentile, 0.2-2.8) with an intra-individual coefficient of variation (CV) of 9.8% (4.8-17.6). Patients with an AI ≤ 0.9 exhibited higher CV. The AI was higher (3.4 (3.1-3.6)) in samples before Nat-PML diagnosis than in seropositive Nat-MS (2.4 (1.0-3.4), n = 298, p = 0.010). AIs ≥ 3.0 were associated with a 14.5-fold (95% CI 2.3-90.4) increased PML risk (p = 0.002). Groups with an AI below 1.5 exhibit higher variability or even serostatus fluctuation. AI dynamics require further investigation.

Identification of bacteria from a non-healing diabetic foot wound by 16 S rDNA sequencing.

Approximately 10-20% of diabetic foot wounds fail initial antibiotic treatment. It is generally believed that several bacterial species may be present in these types of wounds. Because some of these organisms cannot be easily cultured, proper identification is problematic and thus, appropriate treatment modalities cannot be applied. This report examined the bacterial flora present in a chronic diabetic foot wound that failed antibiotic treatment. A tissue sample was collected from the base of the wound and used for standard microbiological culturing. DNA from the sample was used to amplify bacterial 16 S rDNA gene sequences and a library of these sequences was made. The clones were placed into two major groups on the basis of their melting temperatures. Representatives of these groups were sequenced, and information was used to identify the bacteria present in the wound. The culture-based method identified a single anaerobic species, Bacteroides fragilis. The method employing rDNA sequencing identified B. fragilis as a dominant organism and Pseudomonas (Janthinobacterium) mephitica as a minor component. The results indicate that rDNA sequencing approach can be an important tool in the identification of bacteria from wounds.

A PCR assay for identification of Enterococcus faecium.

Enterococcus faecium has recently emerged as a serious nosocomial pathogen. The prevalence and severity of enterococcal infections, the mortality rate from such infections, and the antibiotic resistance of enterococci are often species dependent. Since conventional biochemical methods fail to differentiate E. faecium from certain newly described enterococcal species, a PCR-based assay was developed for the rapid identification of E. faecium.

Sensitive and specific method for rapid identification of Streptococcus pneumoniae using real-time fluorescence PCR.

Molecular surveillance of pathogens has shown the need for rapid and dependable methods for the identification of organisms of clinical and epidemiological importance. As the leading cause of community-acquired pneumonia, Streptococcus pneumoniae was used as a model organism to develop and refine a real-time fluorescence PCR assay and enhanced DNA purification method. Seventy clinical isolates of S. pneumoniae, verified by latex agglutination, were screened against 26 negative control clinical isolates employing a TaqMan assay on a thermocycler (LightCycler). The probe, constructed from the lytA gene, correctly detected all S. pneumoniae genomes without cross-reaction to negative controls. The speed and ease of this approach will make it adaptable to identification of many bacterial pathogens and provide potential for adaptation to direct detection from patient specimens.