Real-world evidence on siponimod treatment in patients with secondary progressive multiple sclerosis.

BACKGROUND: Therapeutic options targeting inflammation in multiple sclerosis (MS) have evolved rapidly for relapsing-remitting MS, whereas few therapies are available for progressive forms of MS, in particular secondary progressive MS (SPMS). The approval of siponimod for SPMS has allowed for optimism in the otherwise discouraging therapeutic landscape. METHODS: We conducted a retrospective, multicenter, non-interventional study analyzing the efficacy and safety of siponimod under real-world conditions in 227 SPMS patients. According to the retrospective study framework, data was acquired at prespecified time points. Clinical readouts were assessed every three months. Disease progression was determined as increase in expanded disability status scale (EDSS), radiological progression, or the occurrence of new relapses under treatment. For safety analyses, adverse events (AE) and reasons for discontinuation were documented. The collected data points were analyzed at baseline and after 6, 12 and 18 months. However, data were predominately collected at the 6- and 12-month time points as many patients were lost to follow-up. In a group consisting of 41 patients, a more detailed investigation regarding disease progression was conducted, including data from measurement of cognitive and motoric functions. RESULTS: Under siponimod therapy, 64.8% of patients experienced sustained clinical disease stability at 12 months. Out of the stable patients 21.4% of patients improved. Of the remaining patients, 31.5% experienced EDSS progression, 3.7% worsened without meeting the threshold for progression. Relapses occurred in 7.4%. Radiological disease activity was detected in 24.1% of patients after six months of treatment and in 29.6% of patients at 12 months follow-up. The in-depth cohort consisting of 41 patients demonstrated no substantial changes in cognitive abilities measured by Paced Auditory Serial Addition Test and Symbol Digit Modalities Test or motoric functions measured with Timed 25-Foot Walk, 100-m timed test, and 9-Hole Peg Test throughout the 12-month study period. Radiological assessment showed a stable volume of white and grey matter, as well as a stable lesion count at 12 months follow-up. AE were observed in nearly half of the included patients, with lymphopenia being the most common. Due to disease progression or AE, 31.2% of patients discontinued therapy. CONCLUSION: Treatment with siponimod had an overall stabilizing effect regarding clinical and radiological outcome measures. However, there is a need for more intensive treatment management and monitoring to identify disease progression and AE.

Communication, Coordination, and Security for People with Multiple Sclerosis (COCOS-MS): a randomised phase II clinical trial protocol.

INTRODUCTION: Patients with multiple sclerosis (MS) have complex needs that range from organising one's everyday life to measures of disease-specific therapy monitoring to palliative care. Patients with MS are likely to depend on multiple healthcare providers and various authorities, which are often difficult to coordinate. Thus, they will probably benefit from comprehensive cross-sectoral coordination of services provided by care and case management (CCM). Though studies have shown that case management improves quality of life (QoL), functional status and reduces service use, such benefits have not yet been investigated in severely affected patients with MS. In this explorative phase ll clinical trial, we evaluated a CCM with long-term, cross-sectoral and outreaching services and, in addition, considered the unit of care (patients and caregivers). METHODS AND ANALYSIS: Eighty patients with MS and their caregivers will be randomly assigned to either the control (standard care) or the intervention group (standard care plus CCM (for 12 months)). Regular data assessments will be done at baseline and then at 3-month intervals. As primary outcome, we will evaluate patients' QoL. Secondary outcomes are patients' treatment-related risk perception, palliative care needs, anxiety/depression, use of healthcare services, caregivers' burden and QoL, meeting patients' and caregivers' needs, and evaluating the CCM intervention. We will also evaluate CCM through individual interviews and focus groups. The sample size calculation is based on a standardised effect of 0.5, and one baseline and four follow-up assessments (with correlation 0.5). Linear mixed models for repeated measures will be applied to analyse changes in quantitative outcomes over time. Multiple imputation approaches are taken to assess the robustness of the results. The explorative approach (phase ll clinical trial) with embedded qualitative research will allow for the development of a final design for a confirmative phase lll trial. ETHICS AND DISSEMINATION: The trial will be conducted under the Declaration of Helsinki and has been approved by the Ethics Commission of Cologne University's Faculty of Medicine. Trial results will be published in an open-access scientific journal and presented at conferences. TRIAL REGISTRATION NUMBER: German Register for Clinical Studies (DRKS) (DRKS00022771).

Aß-related Angiitis (ABRA)-A Rare Paraneoplastic Cause of Cerebral Vasculitis in a Young Patient: A Pathway From Unspecific Neurological Symptoms to Final Diagnosis.

INTRODUCTION: Aß-related angiitis (ABRA) is a very rare disease entity with combined features of cerebral amyloid angiopathy and primary angiitis of the CNS. However, the pathogenesis has not been conclusively described yet. Interestingly though, a possible paraneoplastic origin has been reported in the past. ABRA leads to severe encephalopathy with a broad spectrum of unspecific neurological symptoms and usually occurs in older patients. Because of the response to immunological treatment, it is important to confirm the diagnosis as fast as possible. Unfortunately, the pathway to a definite diagnosis is often complicated and prolonged. CASE REPORT: Here, we describe a 48-year-old-female patient presenting headache, behavioral changes as well as subacute fatigue and epileptic seizures in the recent past. The initial neuroradiological examination demonstrated extended lesions in the left hemisphere compatible with an inflammatory or neoplastic disease. After extensive investigations, initially without a definite result, we finally validated the diagnosis of ABRA by brain biopsy. Shortly afterwards a routine check-up revealed an invasive mammary carcinoma. Owing to a mandatory mastectomy and chemotherapy, an immunosuppressive therapy was not implemented. CONCLUSIONS: The reported case demonstrates our diagnostic approach and the clinical difficulties in validating a rare cause of encephalopathy in a young patient with nonspecific clinical and neuroradiological findings. Because of the possibility of an effective treatment, it is important to consider ABRA in the differential diagnosis especially when blood tests, analysis of cerebrospinal fluid, and angiography show normal results. Since a paraneoplastic genesis is presumed, a search for an underlying tumor disease should be considered.

The BETACONNECT™ system: MS therapy goes digital.

Adherence to long-term treatment in chronic diseases such as multiple sclerosis is challenging. Many disease-modifying drugs (DMDs) for MS need to be injected. Injection devices may improve satisfaction with the injection procedure and boost adherence. Meeting patients' needs in handling and design of autoinjectors and other supporting elements may be key to successful therapy. The BETACONNECT™ system is a platform-based approach in DMD therapy. It combines autoinjector technology with digital tools to support patient self-management and facilitate communication between patients and healthcare providers. Here, we describe the components of the BETACONNECT system and review data on patients' satisfaction with the BETACONNECT autoinjector and how it compares to other devices. Additionally, we present first data on patients' satisfaction with the myBETAapp™.

Hashimoto encephalopathy: rare cause of stroke in young patient.

INTRODUCTION: Hashimoto encephalopathy is a very rare autoimmune disease of unknown etiology. The spectrum of clinical manifestations is wide, and there is no characteristic presentation. Because of the good response to corticosteroid treatment, it is important to confirm the diagnosis as fast as possible. CASE REPORT: We report an 18-year-old man stroke patient with fever, headache, and neuropsychological symptoms. He presented with clinical, neuroradiologic, and cerebrospinal fluid-findings of cerebral small vessel vasculitis. After extensive investigations and exclusion of other causes of stroke, vasculitis, and collagenosis, we validated the diagnosis of Hashimoto encephalopathy. Treatment with corticosteroids leads to a prompt remission of disease and a good recovery of the patient. CONCLUSIONS: The reported case demonstrates the clinical difficulties in validating a rare cause of stroke in a young patient. Because of the highly effective treatment it is important to consider HE in the differential diagnosis in patients with nonspecific clinical symptoms and MRI findings even when laboratory tests, angiography, and MR-angiography are normal.

A novel role of interleukin-1-converting enzyme in cytokine-mediated inducible nitric oxide synthase gene expression: Implications for neuroinflammatory diseases.

Inducible nitric oxide synthase (iNOS)-derived NO plays an important role in several neurological disorders. Understanding of mechanisms involved in the regulation of iNOS induction is of particular interest. Here, we investigated mechanisms of iNOS induction in rat astrocytes (AC) and in brain endothelial cells (BEC). We find that activation of AC or BEC with pro-inflammatory cytokines reveals a different cell-specific activation pattern for iNOS expression. Despite these differences, in both cell types iNOS expression and activity exclusively depends on the endogenous availability of bioactive IL-1beta as inhibition of ICE activity significantly decreases iNOS promoter activity, iNOS expression and enzyme activity. In summary, we here provide evidence that ICE represents a target for modulating iNOS expression and high-output NO formation in AC and BEC, to our knowledge the first report of a role of ICE in iNOS expression and the advantage of ICE inhibition in attenuating NO mediated inflammation and pathology.

Revisiting an old antimicrobial drug: amphotericin B induces interleukin-1-converting enzyme as the main factor for inducible nitric-oxide synthase expression in activated endothelia.

We have investigated the impact of the widely used antifungal agent Amphotericin B (AmB) on cytokine activated aortic endothelial cells (AEC) and their inflammatory response as monitored by cytokine and inducible nitric-oxide synthase (iNOS) expression as well as high-output nitric oxide synthesis. Because both blood-borne infections and systemically administered drugs will first encounter vessel lining endothelial cells, this cell type represents an important participant in innate immune reactions against xenobiotics. Culturing cytokine-activated AEC in the presence of 1.25 microg/ml AmB, a concentration equivalent to serum levels during patient treatment, we find increases in iNOS promoter activity up to 120%, in iNOS mRNA or protein expressions by factors of up to 3.5 +/- 1.1, and in iNOS activity of up to 180% compared with cells with cytokines only. In parallel, a strong increase in endothelial interleukin (IL)-1beta-converting enzyme (ICE) and IL-1beta expression and activity was observed. Specific inhibition of ICE activity or IL-1beta functionality significantly reduces expression and activity of the iNOS to control values. Because ICE activity is essential for the endogenous synthesis of active IL-1beta, ICE overexpression represents the key signal in the AmB-induced and IL-1beta-mediated effects on iNOS activity. In summary, in endothelial cells, AmB strongly augments cytokine-induced iNOS expression and activity by increasing the expression and activity of the ICE. This adjuvant activity for augmented endogenous cytokine processing adds to the efficacy of the antimycotic activity of AmB. Furthermore, our data underline the relevance of the endothelial iNOS as a potent effector of the innate immune system.