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1.
Mult Scler Relat Disord ; 35: 19-25, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31279232

RESUMO

There is increasing evidence that agents that target peripheral B cells and in some instances plasma cells can exhibit marked effects on relapsing multiple sclerosis. In addition, B cells, including plasma cells, within the central nervous system compartment are likely to play an important role in disease progression in both relapsing and progressive MS. However, current B cell-targeting antibodies may not inhibit these, because of poor penetration into the central nervous system and often oligoclonal bands of immunoglobulin persist within the cerebrospinal fluid despite immunotherapy. Through targeting B cells and plasma cells in the CNS, it may be possible to obtain additional benefit above simple peripheral depletion of B cells. As such there are a number of inhibitors of B cell function and B cell depleting agents that have been developed for myeloma and B cell leukaemia and lymphoma, which could potentially be used off-label or as an experimental treatment for advanced (progressive) MS.

2.
Br J Radiol ; 92(1101): 20180926, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30994035

RESUMO

Multiple sclerosis is a chronic inflammatory demyelinating and degenerative disease of the central nervous system. It is the most common non-traumatic cause of chronic disability in young adults. An early and accurate diagnosis, and effective disease modifying treatment are key elements of optimum care for people with MS (pwMS). MRI has become a critical tool to confirm the presence of dissemination in space and time of lesions characteristic of inflammatory demyelination, a cornerstone of MS diagnosis, over and above exclusion of numerous differential diagnoses. In the modern era of early and highly effective DMT, follow-up of pwMS also relies heavily on MRI, to both confirm efficacy and for pharmacovigilance. Since criteria for MS rely heavily on MRI, an agreed standardized acquisition and reporting protocol enabling efficient and equitable application across the UK is desirable. Following a recent meeting of MS experts in London (UK), we make recommendations for a standardized UK MRI protocol that captures the diagnostic phase as well as monitoring for safety and treatment efficacy once the diagnosis is established. Our views take into account issues arising from the (repeated) use of contrast agents as well as the advent of (semi-) automated tools to further optimize disease monitoring in pwMS.


Assuntos
Encéfalo/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Encéfalo/patologia , Diagnóstico Diferencial , Humanos , Esclerose Múltipla/patologia , Reino Unido
3.
Mult Scler Relat Disord ; 30: 176-186, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30785074

RESUMO

Oral cladribine is a novel treatment for relapsing multiple sclerosis (MS). This appears to be a semi-selective immune-reconstitution therapy that induces long-term therapy from short treatment cycles. It has a relatively good safety profile that currently does not require extensive monitoring associated with some continuous immunosuppressive and relatively non-selective immune reconstitution therapies. The efficacy and safety of cladribine relates to its particular physicochemical properties, the function of the lymphocyte subsets that are selectively targeted by the drug and the repopulation kinetics of these subsets. As such, there is marked and long-term depletion of memory B cell subsets, which probably relates to the therapeutic efficacy. This is also coupled with a more limited, but likewise long-term, depletion of CD4 T subsets. There is limited depletion of cells of the innate immune system and modest effects on CD8 and probably plasma cells, which provide immediate and durable protection from infection. Targeting of CD4 T regulatory cells, CD8 T suppressor cells and regulatory B cell subsets appears more limited as these populations recover rapidly and so repopulating pathogenic cells re-emerge into a regulatory environment. This appears to lead to re-establishment of immune-tolerance that produces long-term control of MS. Although this hypothesis contains a number of unknown details, it is based on knowledge about the biology of cladribine, basic immunology and the effects of other high-efficacy B and T cell depleting agents that exhibit stereotyped repopulation behaviours. These concepts are relatively simple to interrogate, and can be modified as new knowledge about the durability of disease control and safety with cladribine emerges.


Assuntos
Cladribina/farmacologia , Imunossupressores/farmacologia , Linfócitos/efeitos dos fármacos , Animais , Antígenos CD/metabolismo , Apoptose/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Cladribina/metabolismo , Cladribina/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Linfócitos/classificação , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico
4.
Lancet Neurol ; 18(2): 198-210, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30663609

RESUMO

Pathological evaluation is the gold standard for identifying processes related to multiple sclerosis that explain disease manifestations, and for guiding the development of new treatments. However, there are limitations to the techniques used, including the small number of donors available, samples often representing uncommon cases, and impossibility of follow-up. Correlative studies have demonstrated that MRI is sensitive to the different pathological substrates of multiple sclerosis (inflammation, demyelination, and neuro-axonal loss). The role of MRI in evaluating other pathological processes, such as leptomeningeal involvement, central vein and rim of lesions, microstructural abnormalities, iron accumulation, and recovery mechanisms, has been investigated. Although techniques used for quantifying pathological processes in different regions of the CNS have advanced diagnosis and monitoring of disease course and treatment of multiple sclerosis, new perspectives and questions have emerged, including how different pathological processes interact over the disease course and when remyelination might occur. Addressing these questions will require longitudinal studies using MRI in large cohorts of patients with different phenotypes.

5.
Mult Scler Relat Disord ; 27: 370-377, 2018 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-30476873

RESUMO

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system that mainly affects young adults. While there is no cure for MS, disease modifying treatments (DMTs) reduce the relapse rate and partial accrual of disability. More effective DMTs may have higher risks including life-threatening infections or secondary autoimmunity. The complexity and novelty of available treatments cause challenges for clinicians when prescribing treatments and for people with MS (PwMS) when deciding what trade-offs they are willing and ready to make. OBJECTIVE: To explore the experience of people with relapsing remitting MS (PwRRMS) and their perspectives in choosing treatments. METHODS: Critical interpretive synthesis was employed to review and synthesis the published literature. Eighty-three publications were selected in a multi-step systematic process. RESULTS: Findings are presented in four interrelated areas: the influence of the clinical evidence-base in decision making; the meaning of DMT efficacy for PwRRMS; the influence of models of decision-making and information acquisition practices in PwRRMS; and the importance of psychosocial dimensions in DMT decision making. Synthesis of the findings revealed that alongside medical and individual reasoning, contextual circumstances play an important role in making treatment decisions. CONCLUSION: This review identifies and explains the importance of diverse contextual circumstances (clinical, social, psychological) that are important for PwRRMS when making treatment decisions. The findings demonstrate the importance of eliciting, understanding and addressing such contextual factors.

6.
Mult Scler Relat Disord ; 27: 247-253, 2018 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-30419510

RESUMO

BACKGROUND: Whilst there is a broad selection of drugs licensed as disease modifying treatments (DMTs) for people with relapsing multiple sclerosis (pwRMS), access to DMTs remains restricted, particularly for people with progressive MS (pwPMS). Cladribine has shown efficacy at all stages of MS. Following withdrawal from the market of oral cladribine in 2011, partly due to issues associated with lymphopenia, and following a thorough risk assessment, we started using subcutaneously injected cladribine (Litak®) to treat both pwRMS and pwPMS. Here, we report on the real life safety and tolerability of this treatment option. METHODS: Cladribine was offered to (i) pwRMS as a choice despite fulfilling NHS England (NHSE) criteria for licensed DMTs, and (ii) pwRMS and pwPMS not eligible for NHSE approved DMTs. To avoid lymphocyte depletion lower than 0.5 × 109/l (WHO grade 2) cladribine was administered using a personalised dosing scheme (30-40 mg in week 1; and another 0-30 mg in week 5 pending total lymphocyte count at week 4). Anti-viral prophylaxis was given from day 1 for 60 days. Patients approaching week 48 were given a second treatment cycle. Data collection included side effects, relapses, change in disability and MRI indices. RESULTS: Seventy-one pwMS (40 female, 31 male; 36 RMS, 35 PMS,) received at least one treatment cycle. Mean age for starting cladribine was 44 years (range 22-72 years), median EDSS was 5 (range 1-8.5). Maximum follow-up was 28 months. 35/71 pwMS were followed up for at least 20 weeks. These patients had a median EDSS of 5.0 (range 1.0-7.5) at baseline and 5.5 (range 1.0-8.0) after a mean follow-up of 11 months (range 5-28). Cladribine was well tolerated with very few treatment-related adverse events observed. Personalised dosing led to grade 1-2 lymphopenia in 50% of cases. A single patient developed transient grade 3 lymphopenia. No cases of varicella or other infections were observed. Four/17 people with relapsing MS, experienced a total of six relapses during a mean follow-up of 13 months (range 5-28 months). In people with PMS (n = 18) median EDSS was 5.5 (2.0-7.5) at baseline and 6.0 (2.5-7.5) after a median of 10 months (range 5-18). In pwPMS MRI showed that 25% had active scans at baseline, and 0% at follow-up. CONCLUSION: Personalised dosing of cladribine avoided severe lymphopenia in all but one patients and was very well tolerated across a large spectrum of disease severity. Our data suggests cladribine may offer benefit people with relapsing and progressive MS alike. The personalised protocol used appears safe, however warrants controlled studies to more definitively assess efficacy and safety, particularly in groups of pwMS who are not eligible for licensed DMT including oral cladribine (Mavenclad®).

7.
Brain Pathol ; 28(5): 765-772, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30375114

RESUMO

In people with multiple sclerosis (MS), the spinal cord is the structure most commonly affected by clinically detectable pathology at presentation, and a key part of the central nervous system involved in chronic disease deterioration. Indices, such as the spinal cord cross-sectional area at the level C2 have been developed as tools to predict future disability, and-by inference-axonal loss. However, this and other histo-pathological correlates of spinal cord magnetic resonance imaging (MRI) changes in MS remain incompletely understood. In recent years, there has been a surge of interest in developing quantitative MRI tools to measure specific tissue features, including axonal density, myelin content, neurite density, and orientation, among others, with an emphasis on the spinal cord. Quantitative MRI techniques including T1 and T2 , magnetization transfer and a number of diffusion-derived indices have all been applied to MS spinal cord. Particularly diffusion-based MRI techniques combined with microscopic resolution achievable using high magnetic field scanners enable a new level of anatomical detail and quantification of indices that are clinically meaningful.

9.
Brain ; 141(10): 2834-2847, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30212896

RESUMO

Although many suspected autoimmune diseases are thought to be T cell-mediated, the response to therapy indicates that depletion of B cells consistently inhibits disease activity. In multiple sclerosis, it appears that disease suppression is associated with the long-term reduction of memory B cells, which serves as a biomarker for disease activity in many other CD20+ B cell depletion-sensitive, autoimmune diseases. Following B cell depletion, the rapid repopulation by transitional (immature) and naïve (mature) B cells from the bone marrow masks the marked depletion and slow repopulation of lymphoid tissue-derived, memory B cells. This can provide long-term protection from a short treatment cycle. It seems that memory B cells, possibly via T cell stimulation, drive relapsing disease. However, their sequestration in ectopic follicles and the chronic activity of B cells and plasma cells in the central nervous system may drive progressive neurodegeneration directly via antigen-specific mechanisms or indirectly via glial-dependent mechanisms. While unproven, Epstein-Barr virus may be an aetiological trigger of multiple sclerosis. This infects mature B cells, drives the production of memory B cells and possibly provides co-stimulatory signals promoting T cell-independent activation that breaks immune tolerance to generate autoreactivity. Thus, a memory B cell centric mechanism can integrate: potential aetiology, genetics, pathology and response to therapy in multiple sclerosis and other autoimmune conditions with ectopic B cell activation that are responsive to memory B cell-depleting strategies.

10.
Mult Scler ; 24(13): 1657-1664, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30231004

RESUMO

e-Health (or digital healthcare) is becoming increasingly relevant in multiple sclerosis (MS) clinical management. We aim to review and discuss current status and future perspective of e-health in people with multiple sclerosis (pwMS). The first part of this review describes how information on MS can be conveyed through the Web and digital media. The second part illustrates recent advances in digital technology that can improve clinical management and in motor and cognitive rehabilitation of pwMS. Finally, this review advocates future development of the "digital case manager" as a new figure to coordinate clinical management and care of pwMS. The digital revolution is changing the medical approach to MS in terms of information conveying and sharing, rehabilitation, and healthcare management.

11.
Mult Scler J Exp Transl Clin ; 4(2): 2055217318783767, 2018 Apr-Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30090639

RESUMO

Background: A considerable number of people with multiple sclerosis (pwMS) live in low- and middle-income countries (LMIC), where lack of resource adversely affects access to effective disease-modifying treatment. Objective: The objective of this commentary is to propose a useful cost-effective disease-modifying treatment option for pwMS in LMIC with potential high efficacy and high convenience to the pwMS and treating physician.Viewpoint: We propose using generic 2-chloro-2'-deoxyadenosine (cladribine), a small molecule licensed for treatment of people with hairy cell leukaemia, as a solution of this significant equity imbalance. Cladribine has been shown in phase II and III trials to be a highly effective disease-modifying treatment for pwMS, and its adverse effect profile is comparable with any DMT currently licensed in high-income economies where an oral preparation has recently been licensed by the European Medicines Agency. Conclusion: Our viewpoint takes into account experience we have gathered over the past three years in the use of generic cladribine to treat pwMS. Whilst here we focus on MS, there is significant potential for use of cladribine in other conditions that could benefit from its mechanism of action.

12.
Mult Scler Relat Disord ; 24: 123-128, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29990894

RESUMO

BACKGROUND: Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS. OBJECTIVES: To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS. METHODS: This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments. RESULTS: All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1ß, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir. CONCLUSIONS: Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.


Assuntos
Inibidores de Integrase de HIV/uso terapêutico , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Raltegravir Potássico/uso terapêutico , Adulto , Meios de Contraste , Progressão da Doença , Feminino , Gadolínio , Humanos , Imagem por Ressonância Magnética , Masculino , Esclerose Múltipla Recidivante-Remitente/virologia , Falha de Tratamento
13.
J Neurol Neurosurg Psychiatry ; 89(12): 1266-1271, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29991490

RESUMO

OBJECTIVES: The aims of this manuscript were to review the evidence for the efficacy and safety of cladribine in multiple sclerosis (MS) and to review the molecular and cellular mechanisms by which cladribine acts as a disease-modifying therapy in MS. METHODS: This is a narrative review of the available clinical and preclinical data on the use of cladribine in MS. RESULTS: Clinical trial data argue strongly that cladribine is a safe and effective therapy for relapsing MS and that it may also be beneficial in progressive MS. The pharmacology of cladribine explains how it is selectively toxic towards lymphocytes. Immunophenotyping studies show that cladribine depletes lymphocyte populations in vivo with a predilection for B cells. In vitro studies demonstrate that cladribine also exerts immunomodulatory influences over innate and adaptive immunity. CONCLUSIONS: Cladribine is a safe and effective form of induction therapy for relapsing MS. Its mechanism of benefit is not fully understood but the most striking action is selective, long-lasting, depletion of B lymphocytes with a particular predilection for memory B cells. The in vivo relevance of its other immunomodulatory actions is unknown. The hypothesis that cladribine's action of benefit is to deplete memory B cells is important: if correct, it implies that selective targeting of this cell population and sparing of other lymphocytes could modify disease activity without predisposing to immunosuppression-related complications.

14.
JAMA Neurol ; 75(7): 781-782, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29800951
15.
BMJ Case Rep ; 20182018 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-29794010

RESUMO

Rhomboencephalitis, at least in its acute phase, is often a severely disabling syndrome, and can be life threatening. A range of underlying conditions can lead to this clinical syndrome. Rapid diagnosis to initiate treatment early is key to a beneficial outcome. We report the case of a 22 year old Afro-Caribbean woman, who presented with a two -week history of walking difficulties, upper limb incoordination and slurred speech. Her brainstem function deteriorated at pace, and she developed hypersomnia. A broad diagnostic approach led to prophylactic treatment for the most common infectious causes. This did not improve her symptoms. Non-infectious inflammatory causes were therefore considered and plasma exchange treatment was initiated leading to marked improvement within days. Screening for autoimmune conditions confirmed aquaporin-4 positive neuromyelitis optica spectrum disorder (NMOSD) as the underlying cause. Immunotherapy with rituximab was started. So far, no relapse has been observed. While the definition of NMOSD continues to be refined, aquaporin-4 testing should be considered early in patients presenting with rhomboencephalitis who do not respond to antibiotic and antiviral treatment. Vigilance and early intervention are key to limit morbidity and mortality from NMOSD.


Assuntos
Tronco Encefálico/diagnóstico por imagem , Neuromielite Óptica/diagnóstico , Ataxia/etiologia , Diagnóstico Diferencial , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/uso terapêutico , Infusões Intravenosas , Imagem por Ressonância Magnética , Neuromielite Óptica/complicações , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/tratamento farmacológico , Troca Plasmática , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Adulto Jovem
17.
J Neurol ; 265(5): 1199-1209, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29550884

RESUMO

BACKGROUND: The mechanism of action of oral cladribine, recently licensed for relapsing multiple sclerosis, is unknown. OBJECTIVE: To determine whether cladribine depletes memory B cells consistent with our recent hypothesis that effective, disease-modifying treatments act by physical/functional depletion of memory B cells. METHODS: A cross-sectional study examined 40 people with multiple sclerosis at the end of the first cycle of alemtuzumab or injectable cladribine. The relative proportions and absolute numbers of peripheral blood B lymphocyte subsets were measured using flow cytometry. Cell-subtype expression of genes involved in cladribine metabolism was examined from data in public repositories. RESULTS: Cladribine markedly depleted class-switched and unswitched memory B cells to levels comparable with alemtuzumab, but without the associated initial lymphopenia. CD3+ T cell depletion was modest. The mRNA expression of metabolism genes varied between lymphocyte subsets. A high ratio of deoxycytidine kinase to group I cytosolic 5' nucleotidase expression was present in B cells and was particularly high in mature, memory and notably germinal centre B cells, but not plasma cells. CONCLUSIONS: Selective B cell cytotoxicity coupled with slow repopulation kinetics results in long-term, memory B cell depletion by cladribine. These may offer a new target, possibly with potential biomarker activity, for future drug development.


Assuntos
Subpopulações de Linfócitos B/efeitos dos fármacos , Cladribina/efeitos adversos , Fatores Imunológicos/efeitos adversos , Esclerose Múltipla/sangue , Esclerose Múltipla/tratamento farmacológico , Administração Oral , Adulto , Alemtuzumab/efeitos adversos , Alemtuzumab/uso terapêutico , Apoptose/efeitos dos fármacos , Subpopulações de Linfócitos B/metabolismo , Cladribina/uso terapêutico , Estudos Transversais , Desoxicitidina Quinase/metabolismo , Relação Dose-Resposta a Droga , Feminino , Humanos , Fatores Imunológicos/uso terapêutico , Linfonodos/efeitos dos fármacos , Linfonodos/metabolismo , Linfonodos/patologia , Linfopenia/sangue , Linfopenia/etiologia , Masculino , Esclerose Múltipla/patologia , RNA Mensageiro/metabolismo , Resultado do Tratamento
18.
J Neurol ; 265(5): 1089-1095, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29502317

RESUMO

BACKGROUND: Whilst the dangers of 'legal highs' have been widely publicised in the media, very few cases of the neurological syndrome associated with the inhalation of nitrous oxide (N2O) have been reported. Here we set out to raise awareness of subacute degeneration of the spinal cord arising from recreational N2O use so that formal surveillance programs and public health interventions can be designed. METHODS: Case series documenting the clinical and investigational features of ten consecutive cases of subacute degeneration of the spinal cord presenting to a hospital with a tertiary neurosciences service in East London. RESULTS: Sensory disturbance in the lower (± upper) limbs was the commonest presenting feature, along with gait abnormalities and sensory ataxia. MRI imaging of the spine showed the characteristic features of dorsal column hyperintensity on T2 weighted sequences. Serum B12 levels may be normal because subacute degeneration of the spinal cord in this situation is triggered by functional rather than absolute B12 deficiency. DISCUSSION: A high index of suspicion is required to prompt appropriate investigation, make the diagnosis and commence treatment early. This is the largest reported series of patients with subacute degeneration of the spinal cord induced by recreational use of N2O. However, the number of patients admitted to hospital likely represents the 'tip of the iceberg', with many less severe presentations remaining undetected. After raising awareness, attention should focus on measuring the extent of the problem, the groups affected, and devising ways to prevent potentially long-term neurological damage.


Assuntos
Doenças Neurodegenerativas/induzido quimicamente , Óxido Nitroso/toxicidade , Doenças da Medula Espinal/induzido quimicamente , Transtornos Relacionados ao Uso de Substâncias/etiologia , Adolescente , Adulto , Ataxia/induzido quimicamente , Ataxia/diagnóstico por imagem , Ataxia/fisiopatologia , Ataxia/terapia , Diagnóstico Diferencial , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/terapia , Estudos Retrospectivos , Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/diagnóstico por imagem , Doenças da Medula Espinal/fisiopatologia , Doenças da Medula Espinal/terapia , Transtornos Relacionados ao Uso de Substâncias/diagnóstico por imagem , Transtornos Relacionados ao Uso de Substâncias/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/terapia , Vitamina B 12/sangue , Adulto Jovem
19.
Patient ; 11(4): 391-402, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29313265

RESUMO

BACKGROUND: Multiple sclerosis (MS) is a chronic disabling, inflammatory, and degenerative disease of the central nervous system that, in most cases, requires long-term disease-modifying treatment (DMT). The drugs used vary in efficacy and adverse effect profiles. Several studies have used attribute-based stated-preference methods, primarily to investigate patient preferences for initiating or escalating DMT. OBJECTIVES: To conduct a systematic review of attribute-based stated-preference studies in people with MS to identify common methods employed and to assess study quality, with reference to the specific challenges of this disease area. METHODS: We conducted a systematic search for studies related to attribute-based stated-preference and MS in multiple databases, including Cochrane and MEDLINE. Studies were included if they were published in a peer-reviewed journal, were on the topic of MS, and used a survey methodology that measured stated preferences for attributes of a whole. Analysis was conducted using narrative synthesis and summary statistics. Study quality was judged against the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) conjoint analysis checklist. RESULTS: We identified 16 relevant articles reporting 17 separate studies, all but one focusing on DMTs. Most studies were discrete-choice experiments. Study quality was generally high, but we recommend the following: (1) that consideration of sample sizes be improved, (2) that survey design choices be justified and documented, (3) that qualitative approaches for attribute and level selection be incorporated to better involve patients, and (4) that reporting of experimental practice be improved. The effects of DMTs on reproduction and the impact of how risk and uncertainty are presented were identified as neglected research topics. The ISPOR conjoint analysis checklist was found to be unsuitable for the assessment of study quality. CONCLUSION: Attribute-based stated preference is a useful method with which to examine the preferences of people with MS in their choice of DMT. However, further research embracing the methodological recommendations identified, particularly greater use of qualitative methods in attribute development, is needed.

20.
Immunology ; 154(2): 253-260, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29247512

RESUMO

Alemtuzumab is a lymphocyte-depleting antibody and one of the most effective treatments for relapsing multiple sclerosis. However, it also causes loss of immune-tolerance leading to secondary autoimmunity and marked anti-drug antibody responses. Although these anti-drug responses have been reported to be of no significance, we hypothesized that they will affect the depleting capacity and treatment response in some individuals. This was found following analysis of the regulatory submission of the pivotal phase III trials, which was obtained from the European Medicines Agency. At the population level there was lack of influence of 'ever-positive' alemtuzumab-specific antibody responses on lymphocyte depletion, clinical efficacy and adverse effects during the 2-year trial. This was not surprising as no one before the first infusion, and only 0·6% of people before the second-infusion, had pre-infusion, neutralizing antibodies (NAbs). However, at the individual level, NAbs led to poor lymphocyte depletion. Importantly, it was evident that 31% of people had NAbs and 75% had binding antibodies at the end of treatment-cycle 2, which suggests that problems may occur in people requiring additional alemtuzumab cycles. In addition, we also identified individuals, following 'post-marketing' alemtuzumab use, whose lymphocyte level was never effectively depleted after the first infusion cycle. Hence, although alemtuzumab depletes lymphocytes in most individuals, some people fail to deplete/deplete poorly, probably due to biological-response variation and NAbs, and this may lead to treatment failure. Monitoring depletion following infusion and assessment of the neutralizing response before re-infusion may help inform the decision to retreat or switch therapy to limit treatment failure.

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