Real-world therapy management of patients with multiple sclerosis receiving cladribine tablets beyond year 4 - Results from a German cladribine cohort.

BACKGROUND: The current approval of oral cladribine covers four years, with two treatment courses in the first two years, followed by two treatment-free years. For decision-making in year 5, experts recommend three scenarios: Extending the treatment-free period, retreatment with cladribine, or therapy switch. OBJECTIVE: To assess the implementation of the three year-5-scenarios in clinical practice in a large multicentric real-world cohort in Germany. METHODS: Data from adult patients diagnosed with highly active RMS (first dose between 8/2017 and 8/2018) were included. The primary outcome was the percentages of patients who remained treatment-free in year 5, were retreated with cladribine, or switched to another therapy. RESULTS: In total, 187 patients (75 % female, mean age 38.6 years, median EDSS 2.5, 21 % DMT-naive) were evaluated. Overall, 27 (14 %) switched treatment within year 1-4, 36 (19 %) continued therapy with cladribine tablets in year 5, and 8 (4 %) switched therapy in year 5. All other patients (n = 118, 63 %) continued to be monitored without therapy in year 5. CONCLUSION: The recommended three treatment scenarios in year 5 appear to be feasible in clinical practice. Treatment-free structured monitoring is the most frequently applied strategy, highly likely due to the prospect of continuing low disease activity under cladribine treatment.

REBISTART: Adherence of Patients with Multiple Sclerosis to Treatment with Subcutaneous Interferon Beta in the Context of a Patient Support Program.

INTRODUCTION: Treatment adherence is a critical success factor in the disease-modifying therapy (DMT) of multiple sclerosis (MS). The REBISTART study prospectively evaluated adherence in patients using components of a patient support program (PSP). METHODS: The 12-month non-interventional multicenter study examined the real-world adherence to subcutaneously (sc) injected interferon beta-1a (Rebif®). Patient-assessed adherence was measured by a visual analog scale (VAS) and the Morisky Medication Adherence Scale (MMAS). Objective adherence data were obtained by readouts from the RebiSmart® injection device. RESULTS: Of 333 patients, 70.9% used the nursing service as the core component of the PSP. Self-assessed VAS-based adherence was stable over time at 94.0-96.3%. Similarly, MMAS score (maximum 4) was 3.8-3.9 at all visits, also reflecting high self-assessed adherence. In 269 patients using the RebiSmart® injection device, mean readout-based objective adherence was similarly high (93.0-98.4% throughout visits). At last available visit, VAS-based adherence was independent of participation in the PSP nursing service (93.1% with participation versus 91.7% without it). Adherence was also independent of injection method or disease-related measures, including fatigue, depression, cognition, and quality of life. The most frequent reason for the premature discontinuations (38.7% of patients) was "change of treatment" (10.0%). DISCUSSION: We suggest that subgroups that may specifically benefit from PSP include patients who live alone, use multiple comedications, and are affected by cognitive impairment, depression, and/or fatigue. Further studies should investigate the potential usefulness of PSPs in these populations. CONCLUSIONS: Very high adherence rates independent of the PSP nursing service over 1 year of treatment indicate that IFN beta-1a sc is an easy-to-use and well-tolerated disease-modifying drug. TRIAL REGISTRATION NUMBER: Vfa.de: No. 892. https://www.vfa.de/de/arzneimittel-forschung/datenbanken-zu-arzneimitteln/nisdb/nis-details/_892 .

Humoral immune response and lymphocyte levels after complete vaccination against COVID-19 in a cohort of multiple sclerosis patients treated with cladribine tablets.

BACKGROUND: Patients with multiple sclerosis (MS) receiving immunomodulatory drugs were excluded from clinical trials on COVID-19 vaccines. Therefore, data regarding the efficacy of COVID-19 vaccines to induce humoral immunity in MS patients treated with B- and T-cell depleting agents is urgently warranted. Cladribine tablets are a high-efficacy disease-modifying treatment that exerts its therapeutic effect via sustained but transient lymphocyte depletion. AIM: We report humoral responses in a German cohort of MS patients treated with cladribine tablets. METHODS: This retrospective analysis included patients ≥18 years who were treated with cladribine tablets for relapsing MS in the first or second year and were fully vaccinated against COVID-19. Two weeks after the second vaccination at the earliest, blood samples were obtained for the assessment of anti-SARS-CoV-2 IgG antibodies, lymphocyte counts, B-cells, CD4+ T-cells, and CD8+ T-cells. Anti-SARS-CoV-2 IgG antibodies were quantified with the LIAISON® SARS-CoV-2 TrimericS IgG assay. Positivity was defined at a cutoff value of 33.8 BAU/mL. RESULTS: In total, 38 patients (73.7% female, aged 23-66 years) were included in the analysis. Ten patients (26.3%) were treatment-naïve before initiating treatment with cladribine tablets. Most patients (84.2%) received mRNA vaccines. The time between the last dose of cladribine tablets and vaccination ranged between 2 and 96 weeks. Six patients (15.8%) were vaccinated within 4 weeks of their last cladribine dose. All patients achieved positive anti-SARS-CoV-2 IgG antibody levels. Humoral immune response was independent of age, time of vaccination in relation to the last cladribine dose, lymphocyte counts as well as B- and T-cell counts. CONCLUSIONS: Treatment with cladribine tablets did not impair humoral response to COVID-19 vaccination. Time since last cladribine dose, age, prior therapy, lymphocyte count as well as B- and T-cell counts had no effect on seropositivity of anti-SARS-CoV-2 IgG antibodies.

Oral pulsed therapy of relapsing multiple sclerosis with cladribine tablets - expert opinion on issues in clinical practice.

BACKGROUND: Oral cladribine is the first oral pulsed therapy licensed for relapsing multiple sclerosis (RMS). Three years after the introduction into the European market, we evaluated practical aspects in the use of cladribine tablets, incorporating the experience gained in routine clinical practice and real-world studies. METHODS: Based on a structured review process, a panel of nine neurologists experienced in MS therapy discussed salient statements regarding the use of cladribine tables. For each statement the level of evidence was determined according to the levels of evidence recommended by the Centre for Evidence-Based Medicine, Oxford. The strength of each expert statement was then evaluated by means of a linear scale from 1 (very strong rejection) to 9 (very strong approval). Votes were collected by a formalized blinded process. Consent was considered to be reached if at least 75% of the experts agreed on a particular statement (i.e. voted for 7-9 points on the linear scale). RESULTS: . Statements include efficacy in early RMS, risk of side effects and infections, vaccination, pregnancy, and monitoring requirements. CONCLUSION: The consented recommendations summarize the practical experience inthe use of cladribine tablets in a real-world setting. These may provide guidance for unanswered questions arising with the introduction of new treatments such as cladribine tablets.

Validation of a new neurological score (FOUR Score) in the assessment of neurosurgical patients with severely impaired consciousness.

BACKGROUND: The Glasgow coma scale (GCS) was introduced as a scoring system for patients with impaired consciousness after traumatic brain injury (TBI). Since, it has become the worldwide standard in TBI assessment. The GCS has repeatedly been criticized for its several failures to reflect verbal reaction in intubated patients, and to test brain stem reflexes. Recently, the full outline of unresponsiveness (FOUR) score was introduced, which is composed of four clinically distinct categories of evaluation: eye reaction, motor function, brainstem reflexes and respiratory pattern. This study aims to validate the FOUR score in neurosurgical patients. METHODS: FOUR score and GCS were assessed in a consecutive series of neurosurgical patients with severely impaired consciousness (GCS < 9). Their correlation with the 30-day Glasgow outcome score (GOS) was compared. Patients admitted for TBI, spontaneous intracranial hemorrhage (intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, cerebellar hemorrhage), or malignant middle cerebral artery infarction were included. RESULTS: We assessed a total of 101 patients (mean age = 64y, SD = 36.1y). The area under the curve (AUC) for mortality was 0.768 (P = 0.0001) for the FOUR Score, and 0.699 (P = 0.001) for the GCS. For poor outcome (GOS = 2-3) the FOUR score AUC was 0.683 (P = 0.018), the GCS AUC was 0.682 (P = 0.019). The FOUR score value for favorable outcome (GOS = 4-5) was 0.748 (P = 0.001), the corresponding GCS value was 0.704 (P = 0.002). CONCLUSIONS: The FOUR score was more robust than the GCS in predicting mortality after 30 days in neurosurgical patients with severely impaired consciousness. There was no relevant difference in predicting poor and good outcome.

Health-related quality of life in ALS, myasthenia gravis and facioscapulohumeral muscular dystrophy.

Neuromuscular disorders are rare diseases with a chronic and debilitating course. Unfortunately, data on the health-related quality of life (HRQoL) in neuromuscular diseases are limited. The objective of this multicentre cross-sectional study was to compare the HRQoL in patients with amyotrophic lateral sclerosis (ALS), facioscapulohumeral muscular dystrophy (FSHD) and myasthenia gravis (MG) and to identify the determinants of the HRQoL in these diseases. We recruited 91 consecutive outpatients with ALS (n = 37), FSHD (n = 17) or MG (n = 37) in seven specialized German health centres. The HRQoL was determined using the 36-Item Short Form Health Survey (SF-36) and the EuroQol (EQ-5D). Independent predictors of the HRQoL were identified using multiple regression analysis. The HRQoL in all domains of the SF-36, except for bodily pain, was significantly reduced. The domains related to physical health (physical functioning, physical role) were most affected. The EQ-5D-index score was most reduced in ALS (0.54) and least reduced in MG (0.89). Independent predictors of a reduced HRQoL were disease severity and depression in ALS, and disease severity, depression, older age and increased body-mass index in MG. The patterns of HRQoL-impairment in neuromuscular disorders share some common features, such as a more pronounced reduction in the HRQoL related to physical health, but there are a number of disease-specific features that should be considered in outcomes of clinical trials and treatment guidelines. In addition to the treatment of motor symptoms, greater attention should be paid to the treatment of depression, which was found to be among the independent predictors of the HRQoL in ALS and MG.

Socioeconomic burden of amyotrophic lateral sclerosis, myasthenia gravis and facioscapulohumeral muscular dystrophy.

Neuromuscular disorders (NMD) are chronic devastating diseases. The aim of this multicenter cross-sectional study was to evaluate the socioeconomic impact of three NMDs in Germany. Patients (n = 107) with amyotrophic lateral sclerosis (ALS), myasthenia gravis (MG) or facioscapulohumeral muscular dystrophy (FSHD) were recruited consecutively in seven centers in Germany. The health-economic data were collected using a "bottom-up" approach consisting of comprehensive questionnaires and patient diaries. Costs were evaluated from the societal perspective in 2009 Euros (EUR). Total annual costs from the societal perspective were EUR 36,380 (95% CI 27,090-47,970) per patient in ALS, EUR 26,240 (95% CI 17,770-37,940) in FSHD and EUR 14,950 (95% CI 10,470-21,730) in MG. The main components of costs were the expenditures of health insurance and the loss of productivity of patients and their caregivers. The following independent cost-driving factors were identified: disease severity, assistance in activities of daily living (ADL), dementia and younger age in ALS, disease severity in FSHD and assistance in ADL, disease severity and assistance in ADL in MG. The socioeconomic burden of NMDs in Germany is considerable. Further studies evaluating both the health-economic and clinical effects of NMD treatment as well as disease management programs and benchmarking activities are necessary.

In vivo voxel-based relaxometry in amyotrophic lateral sclerosis.

We applied voxel-based relaxometry (VBR) in 12 ALS patients and 12 matched healthy controls and compared the results with those of voxel-based morphometry (VBM). VBR revealed a reduced relaxation rate in the right precentral gyrus and ventral pons. Individual region of interest (ROI)-based analysis of R2 maps confirmed our VBR results. VBM depicted a reduction of white matter in the paracentral lobules and in the right middle cerebellar peduncle. Our data suggests that VBR and ROI analysis of R2 maps may have a higher sensitivity in detecting local tissue atrophy in the motor cortex and along the corticospinal tract than VBM. Larger prospective studies are necessary to evaluate the usefulness and relevance of VBR and ROI-based analysis of R2 maps in clinical practice.

Homocysteine and carotid intima-media thickness in a german population: lack of clinical relevance.

BACKGROUND AND PURPOSE: Common carotid artery intima-media thickness (CCA IMT) is a predictor of stroke. This study aimed to analyze whether homocysteine (Hcys) metabolism influences CCA IMT. METHODS: We analyzed the association of personal, clinical, and biochemical data (multivariate analysis) and of 9 polymorphisms involved in Hcys metabolism (ANOVA) with CCA IMT in 714 individuals of 187 families. RESULTS: CCA IMT was significantly predicted by age, sex, creatinine levels, lipoprotein(a) levels, pack-years of smoking, the presence of hypertension, and the presence of diabetes mellitus but not by Hcys levels. Homozygosity for the T allele of the polymorphism methylenetetrahydrofolate reductase c.677C>T was significantly associated with higher Hcys levels but not with a higher CCA IMT. CONCLUSIONS: These data do not support the thesis that elevated Hcys levels are causally involved in cerebrovascular disease.

Heritability of carotid artery atherosclerotic lesions: an ultrasound study in 154 families.

BACKGROUND AND PURPOSE: Ultrasound examination of the carotid arteries yields several quantitative measures that may serve as intermediate phenotypes in genetic studies. This study was undertaken to compare the heritabilities of 3 ultrasound measures: intima-media thickness (IMT), plaque score, and maximal stenosis. METHODS: We studied 565 individuals from 154 families ascertained by an affected parent with carotid artery atherosclerosis. IMT, plaque score, and maximal stenosis of the carotid arteries were examined by B-mode ultrasound and analyzed quantitatively. Heritability estimates were obtained by variance component analysis as implemented in the program SOLAR (sequential oligogenic linkage analysis routines). Covariates were age, sex, weight, height, body mass index (BMI), arterial hypertension, diabetes mellitus, amount of nicotine consumed, and plasma levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol, LDL/HDL ratio, lipoprotein(a) [Lp(a)], triglycerides, factor VIII, factor XIII, fibrinogen, and von Willebrand factor (vWF). RESULTS: After accounting for the covariables age, sex, hypertension, diabetes mellitus, and Lp(a), heritability of IMT was estimated as h2=0.61+/-0.17 (P=0.001). Variation of plaque score was influenced by age, sex, hypertension, diabetes mellitus, hypercholesterolemia, amount of nicotine consumed, factor VIII, and vWF. When these were considered, no significant heritability could be detected. Heritability of stenosis was estimated as h2=0.47+/-0.07 (P=0.006), with age, sex, BMI, hypertension, diabetes mellitus, amount of nicotine consumed, and LDL/HDL ratio as covariates. CONCLUSIONS: Among the 3 ultrasound measures studied, IMT had the highest heritability. IMT was strongly influenced by genetic determinants other than those influencing known risk factors. This makes IMT a promising candidate for use as an intermediate phenotype in genetic studies aiming to identify novel genes for atherosclerosis.

On the early diagnosis of IVIg-responsive chronic multifocal acquired motor axonopathy.

Multifocal acquired motor axonopathy (MAMA) is a treatable, immune mediated motor neuropathy with purely axonal electrophysiological features. Distinction from degenerative neuronopathies such as progressive muscular atrophy (PMA) or early motor neuron disease (MND) can be difficult because of the similar clinical and electrophysiological findings. Here, we report the clinical, electrophysiological and laboratory findings in 6 patients with MAMA. Electrophysiological testing showed purely axonal findings with evidence of pathological spontaneous activity and chronic neurogenic changes. Of particular note, pathological spontaneous activity in paraspinal myotoms was not detectable in any of the patients even though it had been documented in peripheral muscles of the corresponding myotome(s). Elevated serum ganglioside antibody levels,most frequently anti-GD1a antibodies, were present in all 6 patients. IV Ig treatment led to clinical improvement in all but one patient, who showed an allergic response when exposed to IVIg. Our findings indicate that paraspinal EMG and anti-GD1a antibodies can facilitate the early identification of treatable, IVIg responsive, patients with MAMA.

Cranial magnetic resonance imaging in genetically proven myotonic dystrophy type 1 and 2.

Cranial magnetic resonance imaging (MRI) in 19 German patients with genetically proven myotonic dystrophy Type 1 (DM1, n = 10) or Type 2 (DM2, n = 9) showed pathological findings consisting of white matter lesions (WML) and/or brain atrophy in 9/10 DM1 and 8/9 DM2 patients. Anterior temporal WML (ATWML) were exclusively seen in DM1 patients. Our findings indicate a high frequency of central nervous system (CNS) involvement in both disorders. However, temporopolar pathology, previously associated with intellectual dysfunction, seems to be restricted to DM1.