Inter-alpha-trypsin inhibitor heavy chain H3 is a potential biomarker for disease activity in myasthenia gravis.

Myasthenia gravis is a chronic antibody-mediated autoimmune disease disrupting neuromuscular synaptic transmission. Informative biomarkers remain an unmet need to stratify patients with active disease requiring intensified monitoring and therapy; their identification is the primary objective of this study. We applied mass spectrometry-based proteomic serum profiling for biomarker discovery. We studied an exploration and a prospective validation cohort consisting of 114 and 140 anti-acetylcholine receptor antibody (AChR-Ab)-positive myasthenia gravis patients, respectively. For downstream analysis, we applied a machine learning approach. Protein expression levels were confirmed by ELISA and compared to other myasthenic cohorts, in addition to myositis and neuropathy patients. Anti-AChR-Ab levels were determined by a radio receptor assay. Immunohistochemistry and immunofluorescence of intercostal muscle biopsies were employed for validation in addition to interactome studies of inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3). Machine learning identified ITIH3 as potential serum biomarker reflective of disease activity. Serum levels correlated with disease activity scores in the exploration and validation cohort and were confirmed by ELISA. Lack of correlation between anti-AChR-Ab levels and clinical scores underlined the need for biomarkers. In a subgroup analysis, ITIH3 was indicative of treatment responses. Immunostaining of muscle specimens from these patients demonstrated ITIH3 localization at the neuromuscular endplates in myasthenia gravis but not in controls, thus providing a structural equivalent for our serological findings. Immunoprecipitation of ITIH3 and subsequent proteomics lead to identification of its interaction partners playing crucial roles in neuromuscular transmission. This study provides data on ITIH3 as a potential pathophysiological-relevant biomarker of disease activity in myasthenia gravis. Future studies are required to facilitate translation into clinical practice.

Pregnancy in myasthenia gravis: a retrospective analysis of maternal and neonatal outcome from a large tertiary care centre in Germany.

PURPOSE: Myasthenia gravis (MG) is a rare, potentially life-threatening autoimmune disease with fluctuating muscle weakness frequently affecting women of childbearing age. MG can affect maternal as well as neonatal outcome with risk of worsening of myasthenic symptoms in the mothers and risk of transient neonatal myasthenia gravis (TNMG) and arthrogryposis multiplex congenita (AMC) or foetal acetylcholine receptor antibody-associated disorders (FARAD) in the neonates. METHODS: Retrospective analysis of maternal and neonatal outcome in a cohort of pregnant MG patients treated at a tertiary care centre in Germany. RESULTS: Overall, 66 pregnancies were analysed. During 40 (63%) pregnancies, women experienced a worsening of myasthenic symptoms, of whom 10 patients (15.7%) needed acute therapy with IVIg or plasma exchange. There was no case of myasthenic crisis. Rate of caesarean section was comparable to the overall C-section rate at our centre (38% vs. 40%). However, there was a slightly higher rate for operative vaginal delivery (15% vs. 10%) as potential indicator for fatiguing striated musculature in MG patients during the expulsion stage. Rate of TNMG as well as AMC was 3% (two cases each). CONCLUSIONS: Maternal and neonatal outcome in our cohort was favourable with a low rate of myasthenic exacerbations requiring acute therapies and a low rate of TNMG and AMC/FARAD. Our data might help neurologists and obstetricians to advice MG patients with desire to have children.

Concordance between patient- and physician-reported Myasthenia Gravis Activities of Daily Living (MG-ADL) scores.

INTRODUCTION/AIMS: Myasthenia gravis (MG) is a neuromuscular disease characterized by abnormal skeletal muscle fatiguability. The MG Activities of Daily Living (MG-ADL) scale assesses eight symptoms and is often used as primary endpoint in MG clinical trials where it is completed by neurologists. However, in observational studies, patients frequently complete the MG-ADL scale independently of their neurologist. In this study we aimed to assess the concordance between self- and physician-reported MG-ADL scores. METHODS: An international observational study was conducted among adult patients with MG scheduled for a routine visit or who entered the hospital via emergency services. Consenting patients and physicians completed the MG-ADL. Concordance between assessments was calculated using Gwet's agreement coefficient (Gwet's AC) for the MG-ADL individual items and the intraclass correlation coefficient (ICC) for the MG-ADL total score. RESULTS: Data were collected from 137 patients (63% female; mean age, 57.7 years). Physicians assessed the patient's symptoms as slightly more severe (8.1 vs 7.5 MG-ADL total score, respectively), corresponding to a difference of 0.6 on a range from 0 to 24. The ICC for the MG-ADL total score between the patient and the physician assessment was 0.94 (95% confidence interval, 0.89 to 0.95), showing excellent concordance. Gwet's AC showed substantial to almost perfect agreement for all items, except eyelid droop, for which the agreement was moderate. DISCUSSION: Our results demonstrate that patients and neurologists have a concordant assessment of the patient's MG symptoms when using the MG-ADL scale. This evidence supports patient self-administration of the MG-ADL in clinical practice and research.

Complement activation profiles in anti-acetylcholine receptor positive myasthenia gravis.

BACKGROUND AND PURPOSE: Complement component 5 (C5) targeting therapies are clinically beneficial in patients with acetylcholine receptor antibody+ (AChR-Ab+ ) generalized myasthenia gravis (MG). That clearly implicates antibody-mediated complement activation in MG pathogenesis. Here, classical and alternative complement pathways were profiled in patients from different MG subgroups. METHODS: In a case-control study, concentrations of C3a, C5a and sC5b9 were simultaneously quantified, indicating general activation of the complement system, whether via the classical and lectin pathways (C4a) or the alternative pathway (factors Ba and Bb) in MG patients with AChR or muscle-specific kinase antibodies (MuSK-Abs) or seronegative MG compared to healthy donors. RESULTS: Treatment-naïve patients with AChR-Ab+ MG showed substantially increased plasma levels of cleaved complement components, indicating activation of the classical and alternative as well as the terminal complement pathways. These increases were still present in a validation cohort of AChR-Ab+ patients under standard immunosuppressive therapies; notably, they were not evident in patients with MuSK-Abs or seronegative MG. Neither clinical severity parameters (at the time of sampling or 1 year later) nor anti-AChR titres correlated significantly with activated complement levels. CONCLUSIONS: Markers indicative of complement activation are prominently increased in patients with AChR-Ab MG despite standard immunosuppressive therapies. Complement inhibition proximal to C5 cleavage should be explored for its potential therapeutic benefits in AChR-Ab+ MG.

[Myasthenia in adults, children, and adolescents: what's new?] / Myasthenie bei Erwachsenen, Kindern und Jugendlichen ­ was ist neu?

Therapy of myasthenia gravis (MG) is increasingly oriented to the patient's antibody status. In addition to symptomatic therapy, steroids, classic long-term immunosuppressive therapies and thymectomy are regularly used. In recent years, new therapeutic approaches have been developed that particularly benefit acetylcholine receptor (AChR) antibody (Abs) positive patients with highly active disease. While the C5 complement inhibitor eculizumab was reserved for treatment-refractory generalized courses of AChR-Abs positive MG, two new drugs, the neonatal Fc receptor inhibitor efgartigimod and the more advanced C5 complement inhibitor ravulizumab, have recently been approved as add-on therapy for AChR-Abs positive generalized MG (gMG). In highly active courses of MG with Abs against the muscle-specific receptor tyrosine kinase (MuSK), the use of rituximab should be considered early in the course of the disease. The efficacy of the new drugs in children and adolescents with juvenile MG (JMG) is currently being tested in clinical trials. The new guideline recommends the use of modern immunomodulators based on a step-by-step approach depending on disease activity. With the German Myasthenia Register (MyaReg), the changing therapeutic landscape and quality of life of patients with myasthenic syndromes can be assessed, thus providing real-world data on the care of MG patients. Despite treatment based on the previous guideline, many MG patients suffer considerable impairment to their quality of life. With the new immunomodulators, there is the possibility of early intensified immunotherapy, which, in contrast to long-term immunosuppressants, can lead to a rapid improvement in the course of the disease.

[Public health situation of CIDP patients in nine German centers-neuritis network Germany]. / Versorgungssituation von CIDP-Patienten in neun deutschen Zentren des Neuritis Netzes.

BACKGROUND: Diagnosis and treatment of patients with immune-mediated neuropathies is challenging due to the heterogeneity of the diseases. OBJECTIVES: To assess similarities and differences in the current care of patients with immune-mediated polyneuropathies in specialized centers in Germany within the German neuritis network "Neuritis Netz". MATERIAL AND METHODS: We conducted a cross-sectional survey of nine neurological departments in Germany that specialize in the care of patients with immune-mediated neuropathies. We assessed the diagnosis, the approach to diagnostic work-up and follow-up, typical symptoms at manifestation and progression of the disease, and treatment data. RESULTS: This report includes data from 1529 patients per year treated for immune-mediated neuropathies, of whom 1320 suffered from chronic inflammatory demyelinating polyneuropathy (CIDP). Diagnostic work-up almost always included nerve conduction studies, electromyography, and lumbar puncture in accordance with current guidelines. The use of ultrasound, biopsy, and MRI varied. The most important clinical parameter for therapy monitoring in all centers was motor function in the clinical follow-up examinations. A wide range of different immunosuppressants was used for maintenance therapy in about 15% of patients. CONCLUSIONS: These data provide important epidemiological insights into the care of patients with immune-mediated neuropathies in Germany. The further development of specific recommendations for treatment and follow-up examinations is necessary to ensure a uniform standard of patient care. This effort is greatly facilitated by a structured collaboration between expert centers such as Neuritis Netz.

Independent risk factors for myasthenic crisis and disease exacerbation in a retrospective cohort of myasthenia gravis patients.

BACKGROUND: Myasthenic crisis (MC) and disease exacerbation in myasthenia gravis (MG) are associated with significant lethality and continue to impose a high disease burden on affected patients. Therefore, we sought to determine potential predictors for MC and exacerbation as well as to identify factors affecting outcome. METHODS: We examined a retrospective, observational cohort study of patients diagnosed with MG between 2000 and 2021 with a mean follow-up of 62.6 months after diagnosis from eight tertiary hospitals in Germany. A multivariate Cox regression model with follow-up duration as the time variable was used to determine independent risk factors for MC and disease exacerbation. RESULTS: 815 patients diagnosed with MG according to national guidelines were included. Disease severity at diagnosis (quantitative MG score or Myasthenia Gravis Foundation of America class), the presence of thymoma and anti-muscle specific tyrosine kinase-antibodies were independent predictors of MC or disease exacerbation. Patients with minimal manifestation status 12 months after diagnosis had a lower risk of MC and disease exacerbation than those without. The timespan between diagnosis and the start of immunosuppressive therapy did not affect risk. Patients with a worse outcome of MC were older, had higher MGFA class before MC and at admission, and had lower vital capacity before and at admission. The number of comorbidities, requirement for intubation, prolonged mechanical ventilation, and MC triggered by infection were associated with worse outcome. No differences between outcomes were observed comparing treatments with IVIG (intravenous immunoglobulin) vs. plasma exchange vs. IVIG together with plasma exchange. CONCLUSIONS: MC and disease exacerbations inflict a substantial burden of disease on MG patients. Disease severity at diagnosis and antibody status predicted the occurrence of MC and disease exacerbation. Intensified monitoring with emphasis on the prevention of infectious complications could be of value to prevent uncontrolled disease in MG patients.

Eculizumab versus rituximab in generalised myasthenia gravis.

OBJECTIVE: Myasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction. However, evidence shaping treatment decisions, particularly for treatment-refractory cases, is sparse. Both rituximab and eculizumab may be considered as therapeutic options for refractory MG after insufficient symptom control by standard immunosuppressive therapies. METHODS: In this retrospective observational study, we included 57 rituximab-treated and 20 eculizumab-treated patients with MG to compare the efficacy of treatment agents in generalised, therapy-refractory anti-acetylcholine receptor antibody (anti-AChR-ab)-mediated MG with an observation period of 24 months. Change in the quantitative myasthenia gravis (QMG) score was defined as the primary outcome parameter. Differences between groups were determined in an optimal full propensity score matching model. RESULTS: Both groups were comparable in terms of clinical and demographic characteristics. Eculizumab was associated with a better outcome compared with rituximab, as measured by the change of the QMG score at 12 and 24 months of treatment. Minimal manifestation of disease was more frequently achieved in eculizumab-treated patients than rituximab-treated patients at 12 and 24 months after baseline. However, the risk of myasthenic crisis (MC) was not ameliorated in either group. INTERPRETATION: This retrospective, observational study provides the first real-world evidence supporting the use of eculizumab for the treatment of refractory, anti-AChR-ab positive MG. Nonetheless, the risk of MC remained high and prompts the need for intensified monitoring and further research effort aimed at this vulnerable patient cohort.

Anti-CD20 therapy for multiple sclerosis-associated uveitis: A case series.

BACKGROUND AND PURPOSE: Approximately 1% of patients with multiple sclerosis (MS) have uveitis, but data on the effects of immunotherapies for MS on MS-associated uveitis are scarce. The aim of this study was to investigate the ophthalmological outcomes in patients with MS-associated uveitis treated with anti-CD20 therapy. METHODS: A retrospective study of 12 eyes of six patients with MS-associated uveitis, refractory to previous immunotherapies, was conducted. Uveitis activity was assessed before initiation of anti-CD20 therapy and at regular follow-up visits. Primary outcome measures were: vitreous haze score; retinal vasculitis score, determined on fluorescein angiography images; macular edema, as quantified by central retinal thickness (CRT) on optical coherence tomography; and visual acuity (VA). Secondary outcomes included number of annualized uveitis or MS relapses, disease activity on cerebral magnetic resonance imaging (cMRI) and Expanded Disability Status Scale (EDSS) score. RESULTS: After a median (interquartile range [IQR]) treatment time of 28.5 (8-43) months, anti-CD20 therapy was associated with an improvement of vitreous haze score (p = 0.002), retinal vasculitis score (p = 0.001), CRT (p = 0.002), and VA (p = 0.007). The median (IQR) annualized uveitis relapse rate declined from 0.59 (0.56-0.94) before to 0 (0-0.49) after the start of anti-CD20 therapy. The median (IQR) annualized MS relapse rate declined from 0.62 (0.26-2.84) before to 0 (0-0) after the start of anti-CD20 therapy. After initiation of anti-CD20 therapy, there was no disease activity on cMRI, and EDSS score improved (n = 2) or remained stable (n = 4). No severe adverse events were observed. CONCLUSION: These findings suggest that anti-CD20 therapy may be a valuable treatment option for MS-associated uveitis.

Myasthenia gravis - a retrospective analysis of e-mail inquiries made to a patient organisation and specialized center to uncover unmet needs from patients and caregivers.

BACKGROUND AND AIMS: Myasthenia Gravis requires expert treatment from specialized neurologists. In Germany, this treatment is mainly provided by 18 Integrated Myasthenia Centers (iMZ) accredited by the German Myasthenia Gravis Association (DMG). The DMG is a large and well-organized patient organisation that is regarded as a trusted source for disease-specific information. The aim of this study was to analyse the type of requests that each of these institutions receives in order to identify any potential unmet needs regarding the availability of advice for patients and caregivers. This data can then be used in further research to tailor modern digital communication tools to the specific needs of MG patients. METHODS: Counselling requests sent via e-mail to both institutions were extracted for defined examination periods and divided into a period 'before COVID-19 pandemic' (01.07.2019-31.12.2019) and 'during COVID-19 pandemic' (01.07.2020-31.12.2020). Requests were then analysed using four main categories: medical requests, organisational issues, COVID-19 and social legislation inquiries. RESULTS: One thousand seven hundred eleven requests for advice were addressed to DMG and iMZ Charité. Most inquiries directed to the DMG (47%; n = 750) were related to medical issues, most frequently to side effects of medications (n = 325; 20%) and questions about treatment (n = 263; 16%), followed by inquiries regarding organisational issues (26%; n = 412). About half of the inquiries (n = 69; 58%) to the iMZ Charité were related to medical issues and almost one in three inquiries concerned organisational issues (n = 37; 30%). About one in ten inquiries concerned socio-legal matters (iMZ: n = 7; 6% and DMG: n = 177; 11%). During the pandemic, COVID-19 related issues accounted for 8% (n = 6) of inquiries at iMZ, and 16% (n = 253) at DMG. CONCLUSIONS: MG sufferers have a high demand for timely advice. In the current setting, they address their requests to both iMZs and the DMG via e-mail. Our findings confirm that the DMG is highly trusted by patients and caregivers and is used to obtain second opinions. A relevant proportion of requests to the iMZ could be answered more effectively through standardized responses or improved process management. The implementation of modern digital solutions, including telemedicine, for communication between patient and specialist should be evaluated in further research.

Burden of disease in Lambert-Eaton myasthenic syndrome: taking the patient's perspective.

BACKGROUND: Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune-mediated neuromuscular disorder leading to muscle weakness, autonomic dysregulation and hyporeflexia. Psychosocial well-being is affected. Previously, we assessed burden of disease for Myasthenia gravis (MG). Here, we aim to elucidate burden of disease by comparing health-related quality of life (HRQoL) of patients with LEMS to the general population (genP) as well as MG patients. METHODS: A questionnaire-based survey included sociodemographic and clinical data along with standardized questionnaires, e.g. the Short Form Health (SF-36). HRQoL was evaluated through matched-pairs analyses. Participants from a general health survey served as control group. RESULTS: 46 LEMS patients matched by age and gender were compared to 92 controls from the genP and a matched cohort of 92 MG patients. LEMS participants showed lower levels of physical functioning (SF-36 mean 34.2 SD 28.6) compared to genP (mean 78.6 SD 21.1) and MG patients (mean 61.3 SD 31.8). LEMS patients showed lower mental health sub-scores compared to genP (SF-36 mean 62.7 SD 20.2, vs. 75.7 SD 15.1) and MG patients (SF-36 mean 62.7 SD 20.2, vs. 66.0 SD 18.). Depression, anxiety and fatigue were prevalent. Female gender, low income, lower activities of daily living, symptoms of depression, anxiety and fatigue were associated with a lower HRQoL in LEMS. DISCUSSION: HRQoL is lower in patients with LEMS compared to genP and MG in a matched pair-analysis. The burden of LEMS includes economic and social aspects as well as emotional well-being. TRIAL REGISTRATION INFORMATION: drks.de: DRKS00024527, submitted: February 02, 2021, https://drks.de/search/en/trial/DRKS00024527 .

Identifying patients at risk for myasthenic crisis with hemogram and inflammation-related laboratory parameters - a pilot study.

Background: Myasthenia gravis (MG) is a rare autoimmune disease characterized by fatigable weakness of the voluntary muscles and can exacerbate to life-threatening myasthenic crisis (MC), requiring intensive care treatment. Routine laboratory parameters are a cost-effective and widely available method for estimating the clinical outcomes of several diseases, but so far, such parameters have not been established to detect disease progression in MG. Methods: We conducted a retrospective analysis of selected laboratory parameters related to inflammation and hemogram for MG patients with MC compared to MG patients without MC. To identify potential risk factors for MC, we applied time-varying Cox regression for time to MC and, as a sensitivity analysis, generalized estimating equations logistic regression for the occurrence of MC at the next patient visit. Results: 15 of the 58 examined MG patients suffered at least one MC. There was no notable difference in the occurrence of MC by antibody status or sex. Both regression models showed that higher counts of basophils (per 0.01 unit increase: HR = 1.32, 95% CI = 1.02-1.70), neutrophils (per 1 unit increase: HR = 1.40, 95% CI = 1.14-1.72), potentially leukocytes (per 1 unit increase: HR = 1.15, 95% CI = 0.99-1.34), and platelets (per 100 units increase: HR = 1.54, 95% CI = 0.99-2.38) may indicate increased risk for a myasthenic crisis. Conclusion: This pilot study provides proof of the concept that increased counts of basophils, neutrophils, leukocytes, and platelets may be associated with a higher risk of developing MC in patients with MG.

Functional Signature of LRP4 Antibodies in Myasthenia Gravis.

BACKGROUND AND OBJECTIVES: Antibodies (Abs) specific for the low-density lipoprotein receptor-related protein 4 (LRP4) occur in up to 5% of patients with myasthenia gravis (MG). The objective of this study was to profile LRP4-Ab effector actions. METHODS: We evaluated the efficacy of LRP4-specific compared with AChR-specific IgG to induce Ab-dependent cellular phagocytosis (ADCP), Ab-dependent cellular cytotoxicity (ADCC), and Ab-dependent complement deposition (ADCD). Functional features were additionally assessed in an independent AChR-Ab+ MG cohort. Levels of circulating activated complement proteins and frequency of Fc glycovariants were quantified and compared with demographically matched 19 healthy controls. RESULTS: Effector actions that required binding of Fc domains to cellular FcRs such as ADCC and ADCP were detectable for both LRP4-specific and AChR-specific Abs. In contrast to AChR-Abs, LRP4-binding Abs showed poor efficacy in inducing complement deposition. Levels of circulating activated complement proteins were not substantially increased in LRP4-Ab-positive MG. Frequency of IgG glycovariants carrying 2 sialic acid residues, indicative for anti-inflammatory IgG activity, was decreased in patients with LRP4-Ab-positive MG. DISCUSSION: LRP4-Abs are more effective in inducing cellular FcR-mediated effector mechanisms than Ab-dependent complement activation. Their functional signature is different from AChR-specific Abs.

Identification of disease phenotypes in acetylcholine receptor-antibody myasthenia gravis using proteomics-based consensus clustering.

BACKGROUND: The clinical heterogeneity of myasthenia gravis (MG), an autoimmune disease defined by antibodies (Ab) directed against the postsynaptic membrane, constitutes a challenge for patient stratification and treatment decision making. Novel strategies are needed to classify patients based on their biological phenotypes aiming to improve patient selection and treatment outcomes. METHODS: For this purpose, we assessed the serum proteome of a cohort of 140 patients with anti-acetylcholine receptor-Ab-positive MG and utilised consensus clustering as an unsupervised tool to assign patients to biological profiles. For in-depth analysis, we used immunogenomic sequencing to study the B cell repertoire of a subgroup of patients and an in vitro assay using primary human muscle cells to interrogate serum-induced complement formation. FINDINGS: This strategy identified four distinct patient phenotypes based on their proteomic patterns in their serum. Notably, one patient phenotype, here named PS3, was characterised by high disease severity and complement activation as defining features. Assessing a subgroup of patients, hyperexpanded antibody clones were present in the B cell repertoire of the PS3 group and effectively activated complement as compared to other patients. In line with their disease phenotype, PS3 patients were more likely to benefit from complement-inhibiting therapies. These findings were validated in a prospective cohort of 18 patients using a cell-based assay. INTERPRETATION: Collectively, this study suggests proteomics-based clustering as a gateway to assign patients to a biological signature likely to benefit from complement inhibition and provides a stratification strategy for clinical practice. FUNDING: CN and CBS were supported by the Forschungskommission of the Medical Faculty of the Heinrich Heine University Düsseldorf. CN was supported by the Else Kröner-Fresenius-Stiftung (EKEA.38). CBS was supported by the Deutsche Forschungsgemeinschaft (DFG-German Research Foundation) with a Walter Benjamin fellowship (project 539363086). The project was supported by the Ministry of Culture and Science of North Rhine-Westphalia (MODS, "Profilbildung 2020" [grant no. PROFILNRW-2020-107-A]).

Preventing long-term disability in CIDP: the role of timely diagnosis and treatment monitoring in a multicenter CIDP cohort.

BACKGROUND: Chronic inflammatory demyelinating polyneuropathy (CIDP) is an inflammatory disease affecting the peripheral nerves and the most frequent autoimmune polyneuropathy. Given the lack of established biomarkers or risk factors for the development of CIDP and patients' treatment response, this research effort seeks to identify potential clinical factors that may influence disease progression and overall treatment efficacy. METHODS: In this multicenter, retrospective analysis, we have screened 197 CIDP patients who presented to the University Hospitals in Düsseldorf, Berlin, Cologne, Essen, Magdeburg and Munich between 2018 and 2022. We utilized the respective hospital information system and examined baseline data with clinical examination, medical letters, laboratory results, antibody status, nerve conduction studies, imaging and biopsy findings. Aside from clinical baseline data, we analyzed treatment outcomes using the Standard of Care (SOC) definition, as well as a comparison of an early (within the first 12 months after manifestation) versus late (more than 12 months after manifestation) onset of therapy. RESULTS: In terms of treatment, most patients received intravenous immunoglobulin (56%) or prednisolone (39%) as their first therapy. Patients who started their initial treatment later experienced a worsening disease course, as reflected by a significant deterioration in their Inflammatory Neuropathy Cause and Treatment (INCAT) leg disability score. SOC-refractory patients had worse clinical outcomes than SOC-responders. Associated factors for SOC-refractory status included the presence of fatigue as a symptom and alcohol dependence. CONCLUSION: Timely diagnosis, prompt initiation of treatment and careful monitoring of treatment response are essential for the prevention of long-term disability in CIDP and suggest a "hit hard and early" treatment paradigm.

Autoantibody detection by a live cell-based assay in conventionally antibody-tested triple seronegative Myasthenia gravis.

Autoantibody testing is the mainstay in confirming the diagnosis of autoimmune myasthenia gravis (MG). However, in approximately 15% of patients, antibody testing in clinical routine remains negative (seronegative MG). This study aimed at assessing the prevalence of "clustered" AChR- and MuSK- and LRP4- autoantibodies using a live cell-based assay in a large German cohort of seronegative myasthenia gravis (SNMG) patients. A total of 67 SNMG patients were included. Clustered AChR-ab were identified in 4.5% (n = 3) of patients. Two out of the three patients showed binding to the adult AchR as well as the fetal AchR. None of the patients was positive for MuSK- or LRP4-autoantibodies. There were no differences in clinical characteristics between the patients with and without clustered AChR-ab detection. Comparison of clinical data of our cohort with clinical data from the nationwide Myasthenia gravis registry showed broad similarities between seronegative MG patients of both cohorts.

The burden of myasthenia gravis - highlighting the impact on family planning and the role of social support.

Background: Myasthenia gravis (MG) is a rare autoimmune disease and chronic condition that necessitates specialized care. Patients experience a significant burden of disease affecting various aspects of their lives. The aim of this study was to investigate the impact of MG on family planning, challenges associated with pregnancy, childcare responsibilities and the extent to which MG patients perceive and utilize social support. Methods: This analysis used data from our main data of a large cross-sectional study built on a questionnaire-based survey encompassing 1,660 MG patients and members of the German Myasthenia Association (Deutsche Myasthenie Gesellschaft), and focused on sociodemographic, clinical and family planning relevant data points. Results: Decisions regarding family planning were significantly impacted for individuals with MG when MG symptoms started either before or during their family planning (men: n = 19 and 29.7%; women: n = 156 and 58.4%). In this subgroup a substantial proportion opted against parenthood due to MG (men: n = 8 and 50.0%; women: n = 54 and 38.0% and/or another n = 12 and 8.4% of female participants encountered partner-related refusals). In the subgroup of female SP with MG starting before or during family planning who have reported ever been pregnant the self-reported miscarriage rate was 29.0% (n = 51). MG patients with medium incomes or moderate disease severity reported lower levels of perceived social support. 42.7% (n = 606) of participants needed assistance in negotiations with health insurers and 28.0% (n = 459) needed support for transportation to medical appointments. Conclusion: This study shows a significant impact of MG on family planning decisions, affecting both women and men, and often resulting in life-altering decisions such as voluntary childlessness due to MG. The significance of social support becomes evident as a vital factor, especially when navigating through the healthcare system. Tailored healthcare approaches, organized guidance and comprehensive support is needed to enable informed decision-making and offer assistance for MG patients. Clinical trial registration: https://clinicaltrials.gov/study/NCT03979521, Registered 7 June 2019 (retrospectively registered).

Eculizumab treatment alters the proteometabolome beyond the inhibition of complement.

Therapeutic strategies targeting complement have revolutionized the treatment of myasthenia gravis (MG). However, a deeper understanding of complement modulation in the human system is required to improve treatment responses and identify off-target effects shaping long-term outcomes. For this reason, we studied a cohort of patients with MG treated with either eculizumab or azathioprine as well as treatment-naive patients using a combined proteomics and metabolomics approach. This strategy validated known effects of eculizumab on the terminal complement cascade. Beyond that, eculizumab modulated the serum proteometabolome as distinct pathways were altered in eculizumab-treated patients, including the oxidative stress response, mitogen-activated protein kinase signaling, and lipid metabolism with particular emphasis on arachidonic acid signaling. We detected reduced levels of arachidonate 5-lipoxygenase (ALOX5) and leukotriene A4 in eculizumab-treated patients. Mechanistically, ligation of the C5a receptor (C5aR) is needed for ALOX5 metabolism and generation of downstream leukotrienes. As eculizumab prevents cleavage of C5 into C5a, decreased engagement of C5aR may inhibit ALOX5-mediated synthesis of pro-inflammatory leukotrienes. These findings indicate distinct off-target effects induced by eculizumab, illuminating potential mechanisms of action that may be harnessed to improve treatment outcomes.

Comparative analysis of albumin quotient and total CSF protein in immune-mediated neuropathies: a multicenter study on diagnostic implications.

Introduction: Blood-cerebrospinal fluid (CSF) barrier dysfunction is pivotal for diagnosing immune-mediated neuropathies, especially in spinal nerve root inflammation. Typically, either total CSF protein or the CSF to serum albumin ratio (QAlb) is measured. Total CSF protein measurements have limitations, notably its fixed reference value regardless of age, in contrast to the age-dependent reference for QAlb. Our goal was to evaluate both markers in patients with immune-mediated neuropathies. Methods: In our multicenter research, we collected retrospective CSF data from patients suffering from immune-mediated neuropathies across four German research centers. These parameters were analyzed in relation to their clinical characteristics. Results: Out of 419 samples, 36 (8.6%) displayed a notable variation between total CSF protein and QAlb values. A detailed analysis revealed that patients displaying elevated QAlb but normal total CSF protein levels were significantly younger at disease onset (p = 0.01), at the time of diagnosis (p = 0.005), and when undergoing lumbar puncture (p = 0.001) compared to patients with elevated CSF protein and normal QAlb levels. These effects were especially evident for the subgroup of samples derived by female patients. Discussion: Our work confirms the crucial role of QAlb in diagnosing immune-mediated neuropathies and particularly its efficacy as a marker for evaluating the blood-CSF barrier in patients with an earlier disease onset. Considering the significance of the albumin quotient, its assessment is especially advisable in younger patients of female sex to avoid missing a potential barrier dysfunction that might be falsely negative when using total protein.

Risk and course of COVID-19 in immunosuppressed patients with myasthenia gravis.

BACKGROUND: Patients with myasthenia gravis (MG) are potentially prone for a severe COVID-19 course, but there are limited real-world data available on the risk associated with COVID-19 for patients with MG. Here, we investigate whether current immunosuppressive therapy (IST) influences the risk of SARS-CoV-2 infection and COVID-19 severity. METHODS: Data from the German myasthenia gravis registry were analyzed from May 2020 until June 2021 and included patient demographics, MG disease duration, comorbidities, current IST use, COVID-19 characteristics, and outcomes. Propensity score matching was employed to match MG patients with IST to those without, and multivariable binary logistic regression models were used to determine associations between IST with (1) symptomatic SARS-CoV-2 infection and (2) severe COVID-19 course, as measured by hospitalization or death. RESULTS: Of 1379 patients with MG, 95 (7%) patients (mean age 58 (standard deviation [SD] 18) presented with COVID-19, of which 76 (80%) received IST at time of infection. 32 patients (34%) were hospitalized due to COVID-19; a total of 11 patients (12%) died. IST was a risk factor for hospitalization or death in the group of COVID-19-affected MG patients (odds ratio [OR] 3.04, 95% confidence interval [CI] = 1.02-9.06, p = 0.046), but current IST was not associated with a higher risk for SARS-CoV-2 infection itself. DISCUSSION: In this national MG cohort study, current IST use was a risk factor for a severe disease course of COVID-19 but not for SARS-CoV-2 infection itself. These data support the consequent implementation of effective strategies to prevent COVID-19 in this high-risk group. TRIAL REGISTRATION INFORMATION: German clinical trial registry ( https://www.drks.de ), DRKS00024099, first patient enrolled: February 4th, 2019.