Disease-modifying Treatment For Patients Research Articles

Efficacy of long-term albumin therapy in the treatment of decompensated cirrhosis

Efficacy of long-term albumin therapy in the treatment of decompensated cirrhosis

Advocacy of Precision Allergy Molecular Diagnosis in Decision Making for the Eligibility of Customized Allergen Immunotherapy.

Allergen immunotherapy (AIT) with aeroallergens is the only disease-modifying treatment for patients with different allergic conditions. Despite the effectiveness of AIT having been proven in both randomized controlled trials and real-world studies, it remains underused in less than 10% of subjects with allergic rhinitis (AR) and/or asthma (A). We aimed to determine the current eligibility for house dust mite (HDM) AIT by means of a precision allergy molecular diagnosis (PAMD@) model in a selected cohort of youngsters with different allergic phenotypes according to the available evidence. A complex response to both HDM and storage mite allergens was depicted regardless of the subjects' basal atopic condition. No solely specific IgE-binding responses to Der p 1, Der p 2, and/or Der p 23 were found in the studied cohort. Despite the patients with A and atopic dermatitis showing significantly higher serum titers to six mite allergens than subjects with AR, no specific molecular profile was regarded as disease specific. Given the increasing complexity of specific IgE responses to the local prevailing aeroallergens, the identification and presence of such molecules are needed in commercially available AIT in the era of precision medicine.

[Translated Article] Disease-modifying treatments for patients with multiple sclerosis in Spain

Multiple sclerosis is a chronic demyelinating disease of the central nervous system and long-term disabling. Different disease-modifying treatments are available. These patients, despite being generally young, have high comorbidity and risk of polymedication due to their complex symptomatology and disability. Objective primaryTo determine the type of disease-modifying treatment in patients seen in Spanish hospital pharmacy departments. Secondary objectives: to determine concomitant treatments, determine the prevalence of polypharmacy, identify the prevalence of interactions and analyze pharmacotherapeutic complexity. MethodObservational, cross-sectional, multicentre study. All patients with a diagnosis of multiple sclerosis and active disease-modifying treatment who were seen in outpatient clinics or day hospitals during the second week of February 2021 were included. Modifying treatment, comorbidities and concomitant treatments were collected to determine multimorbidity pattern, polypharmacy, pharmacotherapeutic complexity (Medication Regimen Complexity Index) and drug–drug interactions. Results1407 patients from 57 centres in 15 autonomous communities were included. The most frequent form of disease presentation was the relapsing remitting form (89.3%). The most prescribed disease-modifying treatment was dimethyl fumarate (19.1%), followed by teriflunomide (14.0%). Of the parenteral disease-modifying treatments, the two most prescribed were glatiramer acetate and natalizumab with 11.1% and 10.8%. 24.7% of the patients had 1 comorbidity and 39.8% had at least 2 comorbidities. 13.3% belonged to at least one of the defined patterns of multimorbidity and 16.5% belonged to 2 or more patterns. The concomitant treatments prescribed were psychotropic drugs (35.5%); antiepileptic drugs (13.9%) and antihypertensive drugs and drugs for cardiovascular pathologies (12.4%). The presence of polypharmacy was 32.7% and extreme polypharmacy 8.1%. The prevalence of interactions was 14.8%. Median pharmacotherapeutic complexity was 8.0 (IQR: 3.3–15.0). ConclusionsWe have described the disease-modifying treatment of patients with multiple sclerosis seen in Spanish pharmacy services and characterized concomitant treatments, the prevalence of polypharmacy, interactions, and their complexity.

Tratamientos modificadores de la enfermedad en pacientes con esclerosis múltiple en España

Multiple sclerosis is a chronic demyelinating disease of the central nervous system and long-term disabling. Different disease-modifying treatments are available. These patients, despite being generally young, have high comorbidity and risk of polymedication due to their complex symptomatology and disability. Objective primaryTo determine the type of disease-modifying treatment in patients seen in Spanish hospital pharmacy departments. Secondary objectivesTo determine concomitant treatments, determine the prevalence of polypharmacy, identify the prevalence of interactions and analyse pharmacotherapeutic complexity. MethodObservational, cross-sectional, multicentre study. All patients with a diagnosis of multiple sclerosis and active disease-modifying treatment who were seen in outpatient clinics or day hospitals during the second week of February 2021 were included. Modifying treatment, comorbidities and concomitant treatments were collected to determine multimorbidity pattern, polypharmacy, pharmacotherapeutic complexity (Medication Regimen Complexity Index) and drug-drug interactions. Results1,407 patients from 57 centres in 15 autonomous communities were included. The most frequent form of disease presentation was the relapsing remitting form (89.3%). The most prescribed disease-modifying treatment was dimethyl fumarate (19.1%), followed by teriflunomide (14.0%). Of the parenteral disease-modifying treatments, the two most prescribed were glatiramer acetate and natalizumab with 11.1% and 10.8%. 24.7% of the patients had one comorbidity and 39.8% had at least 2 comorbidities. 13.3% belonged to at least one of the defined patterns of multimorbidity and 16.5% belonged to 2 or more patterns. The concomitant treatments prescribed were psychotropic drugs (35.5%); antiepileptic drugs (13.9%) and antihypertensive drugs and drugs for cardiovascular pathologies (12.4%). The presence of polypharmacy was 32.7% and extreme polypharmacy 8.1%. The prevalence of interactions was 14.8%. Median pharmacotherapeutic complexity was 8.0 (IQR: 3.3 -- 15.0). ConclusionsWe have described the disease-modifying treatment of patients with multiple sclerosis seen in Spanish pharmacy services and characterised concomitant treatments, the prevalence of polypharmacy, interactions, and their complexity.

Progranulin upregulation by antisense oligonucleotides targeting regRNAs for treatment of FTD‐GRN

AbstractBackgroundHeterozygous mutations in progranulin (GRN) gene leading to progranulin protein (PGRN) haploinsufficieny are the major genetic cause of GRN‐related frontotemporal dementia (FTD‐GRN)1, 2 and 3. Decreased levels of PGRN disrupt lysosome homeostasis, cause aberrant microglia activation and neuronal cell death resulting in progressive behavioral changes, language deficits and memory impairment4. We hypothesize that upregulation of PGRN in both neuronal cells and microglia would be effective for treating FTD‐GRN patients.MethodRegulatory RNAs (regRNAs) are a class of noncoding RNAs that modulate gene transcription. We have developed an RNA Actuating Platform (RAPTM) that identified regRNAs and enables tunable upregulation of genes by specific targeting of regRNAs with antisense oligonucleotides (ASOs).ResultOur platform identified shared GRN regRNAs in human iPSC‐derived neuron and microglia like cells (iMGLs). ASOs targeting shared regRNAs were screened in a human neuroblastoma cell line to identify lead ASOs that upregulate GRN at least 2‐fold. We showed that the lead ASOs upregulate GRN in both human iPSC‐derived neurons and iMGL cells. Moreover, this level of GRN upregulation was sufficient to rescue staurosporine‐induced toxicity in FTD‐GRN patient iPSC‐derived neurons.Furthermore, we identified mouse Grn regRNA‐targeting ASOs that upregulate Grn transcription 2.5‐fold in mouse neuroblastoma cell lines and primary neurons. We tested these ASOs for efficacy in an FTD‐GRN mouse model (Grn+/tm1.1Far )5 by intracerebroventricular injection. Grn upregulation is observed across disease‐relevant brain regions, including cortex in the Grn haploinsufficient mice.ConclusionHere, we describe the development of oligonucleotide drug candidates that target regRNAs to upregulate GRN expression as a therapeutic approach for FTD‐GRN. We believe that our strategy will restore secreted and lysosomal PGRN levels in both microglia and neurons thereby decreasing neuroinflammation and neurotoxicity. We are developing these oligonucleotides as a disease modifying treatment for patients with FTD‐GRN.

Evaluation of Simvastatin as a Disease-Modifying Treatment for Patients With Parkinson Disease

Current treatments manage symptoms of Parkinson disease (PD), but no known treatment slows disease progression. Preclinical and epidemiological studies support the potential use of statins as disease-modifying therapy. To determine whether simvastatin has potential as a disease-modifying treatment for patients with moderate PD. This randomized clinical trial, a double-blind, parallel-group, placebo-controlled futility trial, was conducted between March 2016 and May 2020 within 23 National Health Service Trusts in England. Participants aged 40 to 90 years with a diagnosis of idiopathic PD, with a modified Hoehn and Yahr stage of 3.0 or less while taking medication, and taking dopaminergic medication with wearing-off phenomenon were included. Data were analyzed from May 2020 to September 2020, with additional analysis in February 2021. Participants were allocated 1:1 to simvastatin or matched placebo via a computer-generated random sequence, stratified by site and Hoehn and Yahr stage. In the simvastatin arm, participants entered a 1-month phase of simvastatin, 40 mg daily, followed by 23 months of simvastatin, 80 mg daily, before a 2-month washout period. The prespecified primary outcome was 24-month change in Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) part III score measured while not taking medication (high scores indicate worse outcome). The primary futility analysis included participants who commenced the 80-mg phase and had valid primary outcome data. The safety analysis included all participants who commenced trial treatment and is reported by dose at time of event. Of 332 patients assessed for eligibility, 32 declined and 65 were ineligible. Of 235 recruited participants, 97 (41%) were female, 233 (99%) were White, and the mean (SD) age was 65.4 (9.4) years. A total of 216 patients progressed to the 80-mg dose. Primary outcome analysis (n = 178) indicated the simvastatin group had an additional deterioration in MDS-UPDRS III score while not taking medication at 24 months compared with the placebo group (1.52 points; 2-sided 80% CI, -0.77 to 3.80; 1-sided futility test P = .006). A total of 37 serious adverse events (AEs), including 3 deaths, and 171 AEs were reported for participants receiving 0-mg simvastatin; 37 serious AEs and 150 AEs were reported for participants taking 40 mg or 80 mg of simvastatin. Four participants withdrew from the trial because of an AE. In this randomized clinical trial, simvastatin was futile as a disease-modifying therapy in patients with PD of moderate severity, providing no evidence to support proceeding to a phase 3 trial. ISRCTN Identifier: 16108482.

Discontinuation of second- versus first-line disease-modifying treatment in middle-aged patients with multiple sclerosis.

There has been scant research on the consequences of discontinuing second-line disease-modifying treatment (DMT) in middle-aged patients with multiple sclerosis (MS). The objective was therefore to examine the occurrence of focal inflammatory activity after the discontinuation of second versus first-line DMT in patients over 45years. Patients who had been treated for at least 6months with second (natalizumab, fingolimod, anti CD20) or first-line DMT and who stopped their DMT were retrospectively included. Kaplan-Meier survival curves were used to study the occurrence of relapse and MRI activity according to the type of DMT stopped. Proportional hazard Cox models were calculated to identify factors associated with focal inflammatory activity. The annualized relapse rate was calculated under treatment and for every 3months after DMT discontinuation. We included 232 patients (median age: 52.8years), 49 of whom stopped second-line DMT. The probability of having a relapse within the year following discontinuation was 6% for first-line DMT, 9% for fingolimod and 43% for natalizumab. In multivariate analysis, the probability of relapse after DMT discontinuation was significantly increased with natalizumab compared to first-line DMT (HR = 3.24; 95% CI [1.52; 6.90]). A peak of relapse was observed at 0-3months after stopping natalizumab or fingolimod. Our study suggests that the risk of inflammatory activity is greater after discontinuation of natalizumab compared to other DMT even in middle-aged patients. As for younger patients, natalizumab discontinuation should only be considered if there is an adequate substitution of a different therapy. .

Autologous stem cell transplantation improves cardiopulmonary exercise testing outcomes in systemic sclerosis patients.

Autologous haematopoietic stem cell transplantation (AHSCT) is a disease-modifying treatment for patients with severe SSc. Here, we aimed at assessing cardiopulmonary function outcomes of SSc patients after AHSCT. Twenty-seven SSc adult patients treated with AHSCT were included in this retrospective study. Most had the diffuse cutaneous subset (93%) and pulmonary involvement (85%). Before and 12 months after AHSCT, patients underwent cardiopulmonary exercise testing, transthoracic echocardiography, pulmonary function test with diffusing capacity for carbon monoxide (DLCO), 6-min walk test (6MWT) and quality of life evaluations. After AHSCT, the peak VO2 increased from 954 to 1029 ml/min (P = 0.02), the percentage of predicted peak VO2 increased from 48.9 to 53.5 m (P = 0.01), and the distance measured by the 6MWT increased from 445 to 502 m (P = 0.01), compared with baseline. Improvements in peak VO2 correlated positively with improvements in 6MWT distance, and negatively with a decrease in resting heart rate. At baseline, patients with DLCO >70% had higher peak VO2 values than those with DLCO <70% (P = 0.04), but after AHSCT all patients showed improved VO2 values, regardless of baseline DLCO levels. Increases in VO2 levels after AHSCT positively correlated with increases in the physical component scores of the Short Form-36 quality of life questionnaire (r = 0.70; P = 0.0003). AHSCT improves the aerobic capacity of SSc patients probably reflecting combined increments in lungs, skeletal muscle and cardiac function.

Highly active disease and access to disease-modifying treatments in patients with relapsing-remitting multiple sclerosis in Poland.

In Poland, access to second-line disease-modifying treatments (DMTs) for relapsing-remitting multiple sclerosis is limited by reimbursement criteria that require evidence of more aggressive disease compared to the approved indications. In a retrospective study carried out in DMT clinics across Poland, we asked neurologists to provide patient data on relapses and neuroimaging disease activity. Included were only patients with active disease, defined as one or more relapse and at least one new lesion between starting DMT and the last visit. For patients who had not received DMT, active disease was defined as at least one gadolinium-positive lesion or two or more new T2 lesions and two or more relapses within 12 months. We analysed the proportions of patients eligible for second-line DMTs based on the current reimbursement criteria and based on the broader criteria, which were in line with the approved indications. In total, 48 neurologists provided data for 641 patients (women 64%; mean age 38 years). Of the 641 patients, 610 (95%) received DMTs: 532 first-line and 78 second-line. Of the 532 patients on first-line DMTs, 40 (7.5%) were eligible for second-line treatment based on the current reimbursement criteria, and an additional 126 (23.6%) would be eligible for second-line treatment based on the broader criteria. Of the 31 patients who did not receive any DMTs, one patient was eligible for second-line treatment, and another two patients would be eligible for second-line treatment based on the broader criteria. Moreover, 13 previously treated patients would be eligible for second-line DMTs based on the broader criteria. When extrapolated to the whole of Poland, our study shows that an additional 1,581 patients would be eligible for second-line DMTs if the current reimbursement criteria were to be replaced by broader criteria complying with the approved indications. An urgent change is required in the reimbursement criteria in order to expand access to second-line DMTs for patients with relapsing-remitting MS in Poland.

The Effect of Angiotensin II Receptor Blockers in Patients with Hypertrophic Cardiomyopathy: An Updated Systematic Review and Meta-analysis of Randomized Controlled Trials

Background: Angiotensin receptor blocker (ARB) therapy has been evaluated to slow down the disease progression in patients with hypertrophic cardiomyopathy (HCM), but there is scarce evidence available to date. Therefore, our meta-analysis aimed to explore the efficacy of ARB therapy as a potential disease-modifying treatment in patients with HCM. Methods: A literature search was performed using PubMed, Scopus, Web of Science, Embase, Cochrane library, and Clinicaltrials.gov databases from inception to December 13th, 2021. We included only randomized controlled trials (RCTs). The quality of included studies was assessed by the Cochrane Collaboration’s tool. Primary outcomes included the reduction in left ventricular mass and improvement in other echocardiographic features of myocardial dysfunction. The secondary outcome was a net reduction in systolic blood pressure. Meta-analysis was performed using pooled standardized mean difference (SMD) and corresponding 95% confidence interval (CI). Results: A total of 1286 articles were screened. Seven RCTs met the inclusion criteria representing a total of 397 patients with HCM (195 patients were in the ARB group). ARB treatment was associated with significant reduction in left ventricular mass (SMD: –0.77; 95% CI: –1.40, –0.03; p = 0.04). ARB therapy was also associated with a significant reduction in systolic blood pressure (SMD: –0.33; 95% CI: –0.61, –0.05: p = 0.02). Conclusions: ARB therapy is associated with a marked reduction in left ventricular mass and systolic blood pressure in patients with hypertrophic cardiomyopathy. We recommend further studies with a larger patient population size to confirm the findings of our meta-analysis. Clinical Trial Registration: OSF Registries, DOI: 10.17605/OSF.IO/DAS7C.

Neurological update: treatment escalation in multiple sclerosis patients refractory to fingolimod\u2014potentials and risks of subsequent highly active agents

A critical issue in the management of relapsing MS (RMS) is the discontinuation of disease-modifying treatments (DMT) due to lack of efficacy, intolerability or impending risks. With new therapeutic agents introduced into the treatment of RMS, immediate- and long-term consequences of sequential drug use, as well as the effect of the sequence in which the drugs are given, are unclear but may affect efficacy, adverse events, and long-term immunocompetence. In the absence of clinical studies specifically addressing these concerns, observations from clinical practice are of particular value in guiding current management algorithms. Prompted by a study published by Ferraro et al. in this journal, we set out to provide an overview of the published real-world evidence on the effectiveness and safety of switching from fingolimod to another DMT in patients with active RMS. Seventeen publications reporting relevant information were identified. The literature suggests that immune cell depletion induced by alemtuzumab or ocrelizumab is associated with an increased risk of relapse and worsening disability in patients switching from fingolimod compared to patients switching from other therapeutic agents. However, the evidence reported for natalizumab and cladribine is inconclusive. While shortening of the washout period may limit early disease reactivation after fingolimod discontinuation, there is no strong evidence that the duration of the washout period or the absolute lymphocyte count at baseline are predictors of attenuated long-term efficacy. Further real-world studies are required to better understand outcomes among patients who are under-represented in controlled trials.

Optimization of the method for diagnostics of cardial autonomic neuropathy in diabetes mellitus 2 types

Introduction. Early diagnosis of cardiac autonomic neuropathy is the basis for the risk of heart disease and premature death in patients with type 2 diabetes mellitus (type 2 diabetes). All patients with type 2 diabetes and prediabetes should undergo annual screening, including history taking and neurophysiologic evaluation, for early diabetic autonomic neuropathy. This article describes a modern diagnostic technique based on changes in heart rate variability, which allows early detection of damage to the parasympathetic nervous system and timely prescribing disease-modifying treatment in patients with type 2 diabetes.Materials and methods. The study included 50 patients with type 2 diabetes (cf. Age 56.5 ± 13.5 years) and 30 healthy subjects (cf. Age 58 ± 10 years), matched by sex and age. according to the NSC questionnaire, the severity of neurological deficit - according to the NIS-LL scale, neuropathic pain syndrome - according to the TSS scale.Results. In the study group of patients with type 2 diabetes, severe CAN was detected in 13.3%, moderate CAN in 40% of patients, in 46.6% of patients, CAN was not detected. In the group of healthy volunteers, disorders of the autonomic nervous system of moderate were detected in 3.3%, in the remaining 96.7% of autonomic disorders were not accepted.Conclusion. The results of pulse oximetric tests with deep breathing are comparable to the results of the QAT device Case-4 (p &lt; 0.001). The method of pulse oximetric diagnostics is more practical to use in comparison with the hardware QAT.

How to switch disease-modifying treatments in multiple sclerosis: Guidelines from the French Multiple Sclerosis Society (SFSEP)

BackgroundToday, there are no recommendations on switching disease-modifying treatments (DMTs) in multiple sclerosis (MS). ObjectivesTo establish guidelines on switching DMTs MS. MethodsA Steering Committee composed of seven MS experts from the French Group for Recommendations in Multiple Sclerosis (France4MS) defined 15 proposals. These proposals were then submitted to a Rating Group, composed of 48 French MS experts, for evaluation. The proposals were classified as ‘appropriate’, ‘inappropriate’ or ‘uncertain’. ResultsSwitching from a first-line therapy to another first-line therapy or a second-line therapy could be done without a washout period. Switching from a second-line therapy to a first-line therapy could be done without a washout period with fingolimod or natalizumab, after 3 months with ocrelizumab or mitoxantrone, and, if disease activity occurs with alemtuzumab or cladribine. The switch from a second-line therapy to another second-line therapy could be done after a washout period of 1 month with fingolimod or natalizumab, after 3 months with ocrelizumab, after 6 months with mitoxantrone, and, if disease activity occurs, with alemtuzumab or cladribine. ConclusionThis expert consensus approach provides physicians with some guidelines on optimizing the benefit/risk ratio when switching DMTs in patients with MS.

Transcriptomic Profiling of the Liver Sinusoidal Endothelium during Cirrhosis Reveals Stage-Specific Secretory Signature.

Simple SummaryWe define the transcriptome and secretome of primary LSECs during the progression of cirrhosis, revealing specific molecular signatures, novel biomarkers and therapeutic targets for new disease-modifying treatments for patients with advanced chronic liver disease.The poor prognosis of chronic liver disease (CLD) generates the need to investigate the evolving mechanisms of disease progression, thus disclosing therapeutic targets before development of clinical complications. Considering the central role of liver sinusoidal endothelial cells (LSECs) in pre-neoplastic advanced CLD, the present study aimed at investigating the progression of CLD from an endothelial holistic perspective. RNAseq defined the transcriptome of primary LSECs isolated from three pre-clinical models of advanced CLD, during the progression of the disease, and from fresh human cirrhotic tissue. At each stage of the disease, the effects of LSECs secretome on neighboring cells and proteomic analysis of LSECs-derived extracellular vesicles (EVs) were also determined. CLD was associated with deep common modifications in the transcriptome of LSECs in the pre-clinical models. Pathway enrichment analysis showed predominance of genes related with pro-oncogenic, cellular communication processes, and EVs biogenesis during CLD progression. Crosstalk experiments revealed endothelial EVs as potent angiocrine effectors. The proteome of LSECs EVs showed stage-specific signatures, including over-expression of tropomyosin-1. Proof-of-principle experiments treating cirrhotic HSCs with recombinant tropomyosin-1 suggested de-activating effects. Our data provide the basis for discovering novel biomarkers and therapeutic targets for new disease-modifying treatments for patients with advanced CLD.

Adherence to disease-modifying treatments in patients with multiple sclerosis in Spain.

PurposeAdherence to disease-modifying treatments is essential in order to maximize the beneficial effects of treatment for multiple sclerosis (MS). There are numerous treatments that have been approved. Treatment selection is essential in patient adherence. In addition, patient preference plays an increasingly significant role in treatment decision-making. This study aims to evaluate the degree of adherence, along with other variables that may influence this adherence, in Spain.MethodsA cross-sectional study was conducted with 157 MS patients with disease-modifying treatments. Adherence was assessed using the Morisky Green scale, and other related factors were measured using a questionnaire that addressed demographics, disease characteristics, global perception of pathology, impact of medication on patient’s life, and treatment decision-making.ResultsThe adherence rate was 71% and was associated with the following variables: older age, more treatments received, time to diagnosis 5–10 years, absence of exacerbations, better cognitive status, being married/in a union, clear information about the disease, and higher treatment satisfaction. The main cause for non-compliance was forgetfulness (27%).ConclusionThe adherence rate is acceptable. It is widely known that treatment satisfaction is related to adherence. In our study, patients’ level of satisfaction was higher with oral treatments. However, oral administration showed a greater lack of adherence. The main cause of lack of adherence was forgetfulness. In relation to other variables, cognitive status and family support showed a correlation with treatment adherence.

Emerging Magnetic Resonance Imaging Techniques and Analysis Methods in Amyotrophic Lateral Sclerosis.

Objective markers of disease sensitive to the clinical activity, symptomatic progression, and underlying substrates of neurodegeneration are highly coveted in amyotrophic lateral sclerosis in order to more eloquently stratify the highly heterogeneous phenotype and facilitate the discovery of effective disease modifying treatments for patients. Magnetic resonance imaging (MRI) is a promising, non-invasive biomarker candidate whose acquisition techniques and analysis methods are undergoing constant evolution in the pursuit of parameters which more closely represent biologically-applicable tissue changes. Neurite Orientation Dispersion and Density Imaging (NODDI; a form of diffusion imaging), and quantitative Magnetization Transfer Imaging (qMTi) are two such emerging modalities which have each broadened the understanding of other neurological disorders and have the potential to provide new insights into structural alterations initiated by the disease process in ALS. Furthermore, novel neuroimaging data analysis approaches such as Event-Based Modeling (EBM) may be able to circumvent the requirement for longitudinal scanning as a means to comprehend the dynamic stages of neurodegeneration in vivo. Combining these and other innovative imaging protocols with more sophisticated techniques to analyse ever-increasing datasets holds the exciting prospect of transforming understanding of the biological processes and temporal evolution of the ALS syndrome, and can only benefit from multicentre collaboration across the entire ALS research community.

Does evidence support the use of cat allergen immunotherapy?

Cat allergy can manifest as allergic rhinitis, conjunctivitis and/or asthma. With widespread cat ownership and exposure, cat allergy has emerged as a major cause of morbidity. Cat allergen immunotherapy is a potential disease modifying treatment for patients with cat allergy. We examine evidence on the effectiveness, cost-effectiveness and safety of cat allergen immunotherapy and consider the clinical contexts in which it should be prescribed. The European Association of Allergy and Clinical Immunology systematic reviews on allergic rhinitis and asthma along with the accompanying guidelines on allergic rhinitis were used as primary sources of evidence. Subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT) are most common routes of administration for allergen immunotherapy (AIT). A limited number of high-quality studies related to cat dander have shown mixed results in improvements in ocular and nasal symptoms, asthma symptoms, peak expiratory flow rate and medication use scores with subcutaneous immunotherapy. Two studies examining cat dander and cat-related allergy response with sublingual immunotherapy have shown mixed results in terms of symptomatic response. One randomized trial examining intralymphatic immunotherapy has shown a positive symptom response and a favourable safety profile. Although studies have reported mixed results regarding safety of SCIT, adverse events have been reported more commonly with SCIT than SLIT. There is a limited body of high-quality evidence on the effectiveness and safety of cat AIT and no high-quality data on its cost-effectiveness. The available evidence on effectiveness is mixed based on studying a limited array of immunological, physiological and patient-reported outcome measures. Based on this evidence and extrapolating on the wider evidence base in AIT, it is likely that some patients may benefit from this modality of treatment, particularly those with moderate-to-severe disease who are inadequately controlled on allergen avoidance measures and pharmacotherapy and those who are monosensitized to Felix Domesticus 1. Further evidence is, however, required from larger trials before more definitive advice can be offered.

Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomised trial

Evidence is scarce on the efficacy of long-term human albumin (HA) administration in patients with decompensated cirrhosis. The human Albumin for the treatmeNt of aScites in patients With hEpatic ciRrhosis (ANSWER) study was designed to clarify this issue. We did an investigator-initiated multicentre randomised, parallel, open-label, pragmatic trial in 33 academic and non-academic Italian hospitals. We randomly assigned patients with cirrhosis and uncomplicated ascites who were treated with anti-aldosteronic drugs (≥200 mg/day) and furosemide (≥25 mg/day) to receive either standard medical treatment (SMT) or SMT plus HA (40 g twice weekly for 2 weeks, and then 40 g weekly) for up to 18 months. The primary endpoint was 18-month mortality, evaluated as difference of events and analysis of survival time in patients included in the modified intention-to-treat and per-protocol populations. This study is registered with EudraCT, number 2008-000625-19, and ClinicalTrials.gov, number NCT01288794. From April 2, 2011, to May 27, 2015, 440 patients were randomly assigned and 431 were included in the modified intention-to-treat analysis. 38 of 218 patients died in the SMT plus HA group and 46 of 213 in the SMT group. Overall 18-month survival was significantly higher in the SMT plus HA than in the SMT group (Kaplan-Meier estimates 77% vs 66%; p=0·028), resulting in a 38% reduction in the mortality hazard ratio (0·62 [95% CI 0·40-0·95]). 46 (22%) patients in the SMT group and 49 (22%) in the SMT plus HA group had grade 3-4 non-liver related adverse events. In this trial, long-term HA administration prolongs overall survival and might act as a disease modifying treatment in patients with decompensated cirrhosis. Italian Medicine Agency.

Survey of diagnostic and treatment practices for multiple sclerosis (MS) in Europe. Part 2: Progressive MS, paediatric MS, pregnancy and general management.

The European Charcot Foundation supported the development of a set of surveys to understand current practice patterns for the diagnosis and management of multiple sclerosis (MS) in Europe. Part 2 of the report summarizes survey results related to secondary progressive MS (SPMS), primary progressive MS (PPMS), pregnancy, paediatric MS and overall patient management. A steering committee of MS neurologists developed case- and practice-based questions for two sequential surveys distributed to MS neurologists throughout Europe. Respondents generally favoured changing rather than stopping disease-modifying treatment (DMT) in patients transitioning from relapsing-remitting MS to SPMS, particularly with active disease. Respondents would not initiate DMT in patients with typical PPMS symptoms, although the presence of ≥1 spinal cord or brain gadolinium-enhancing lesion might affect that decision. For patients considering pregnancy, respondents were equally divided on whether to stop treatment before or after conception. Respondents strongly favoured starting DMT in paediatric MS with active disease; recommended treatments included interferon, glatiramer acetate and, in John Cunningham virus negative patients, natalizumab. Additional results regarding practice-based questions and management are summarized. Results of part 2 of the survey of diagnostic and treatment practices for MS in Europe largely mirror results for part 1, with neurologists in general agreement about the treatment and management of SPMS, PPMS, pregnancy and paediatric MS as well as the general management of MS. However, there are also many areas of disagreement, indicating the need for evidence-based recommendations and/or guidelines.

Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis

Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking. To assess the effectiveness and drug discontinuation rates of rituximab among patients with newly diagnosed RRMS compared with injectable DMTs, dimethyl fumarate, fingolimod, or natalizumab. This retrospective cohort study used prospectively collected data to examine specialized care of 2 Swedish county-based community samples of patients with RRMS. Patients with RRMS who received diagnoses from January 1, 2012, to October 31, 2015, who resided in Stockholm or Västerbotten Counties were identified from a Swedish multiple sclerosis registry. All reasons for drug discontinuation of initial treatment choice (main outcome) and specific reasons for switching (secondary outcomes) were analyzed with multivariable Cox regression, including propensity scores. Among 494 patients (median [interquartile range] age, 34.4 [27.4-43.4] years; 158 men [32.0%]), 215 received an injectable DMT (43.5%); 86 (17.4%), dimethyl fumarate; 17 (3.4%), fingolimod; 50 (10.1%), natalizumab; 120 (24.3%), rituximab; and 6 (1.2%), other DMT. Regional preferences were pronounced, with 42 of 52 (81%) and 78 of 442 (18%) receiving rituximab in Västerbotten and Stockholm, respectively. The annual discontinuation rate for rituximab, injectable DMTs, dimethyl fumarate, fingolimod, and natalizumab were 0.03, 0.53, 0.32, 0.38, and 0.29, respectively. Continued disease activity was the main reason for discontinuation of injectable DMTs, dimethyl fumarate, and fingolimod; positive John Cunningham virus serology results were the main reason for discontinuation of natalizumab. Rate of clinical relapses and/or neuroradiologic disease activity were significantly lower for rituximab compared with injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates also compared with natalizumab and fingolimod. The annual discontinuation rate of initial treatment choice was significantly lower in Västerbotten compared with Stockholm (0.09 and 0.37, respectively). Rituximab was superior to all other DMT in terms of drug discontinuation and displayed better clinical efficacy compared with injectable DMTs and dimethyl fumarate with borderline significance compared with natalizumab and fingolimod. The county where rituximab constituted the main initial treatment choice displayed better outcomes in most measured variables. Collectively, our findings suggest that rituximab performs better than other commonly used DMTs in patients with newly diagnosed RRMS.