RESUMO
With the approval of various substances for the immunotherapy of multiple sclerosis (MS), treatment possibilities have improved significantly over the last few years. Indeed, the choice of individually tailored preparations and treatment monitoring for the treating doctor is becoming increasingly more complex. This is particularly applicable for monitoring for a treatment-induced compromise of the immune system. The following article by members of the German Multiple Sclerosis Skills Network (KKNMS) and the task force "Provision Structures and Therapeutics" summarizes the practical recommendations for approved immunotherapy for mild to moderate and for (highly) active courses of MS. The focus is on elucidating the substance-specific relevance of particular laboratory parameters with regard to the mechanism of action and the side effects profile. To enable appropriate action to be taken in clinical practice, any blood work changes that can be expected, in addition to any undesirable laboratory findings and their causes and relevance, should be elucidated.
Assuntos
Imunoterapia/efeitos adversos , Imunoterapia/métodos , Monitorização Imunológica/métodos , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Humanos , Imunocompetência/efeitos dos fármacos , Imunocompetência/imunologia , Esclerose Múltipla/classificaçãoRESUMO
The individual risk of contracting multiple sclerosis (MS) is determined by genetic predisposition as well as environmental factors. In monozygotic twins the concordance rate for MS is approximately 30 % indicating that environmental factors are even more important than genetic factors. Observations in a T-cell receptor-transgenic, spontaneous mouse model strongly point to an important contribution of the individual gut microbiome (microbiota). Mice maintained in a germ-free environment are completely protected from experimental autoimmune encephalomyelitis (EAE) in this model, whereas mice that are kept under normal conditions spontaneously develop a relapsing-remitting central nervous system (CNS) disease which is astoundingly similar to human MS. It appears that the autoimmune reaction against CNS tissue is "remotely controlled" by the gut microbiota. This may be explained by the facts that the microbiota influences the gut-associated lymphoid tissue (GALT) and, vice versa, the GALT regulates systemic immunity. The precise role of the microbiota in MS remains to be clarified. New methods of DNA sequencing and bioinformatics allow the analysis of very complex bacterial metagenomes. If individual microbial risk profiles can be identified this would provide completely new perspectives for the prophylaxis and therapy of MS.
Assuntos
Microbioma Gastrointestinal/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/microbiologia , Modelos Imunológicos , Esclerose Múltipla/imunologia , Esclerose Múltipla/microbiologia , Microbioma Gastrointestinal/genética , Humanos , Imunidade Inata/imunologia , Metagenoma/genética , Esclerose Múltipla/genéticaRESUMO
In recent years the approval of new substances has led to a substantial increase in the number of course-modifying immunotherapies available for multiple sclerosis. Therapy conversion therefore represents an increasing challenge. The treatment options sometimes show complex adverse effect profiles and necessitate a long-term and comprehensive monitoring. This article presents an overview of therapy conversion of immunotherapies for multiple sclerosis in accordance with the recommendations of the Disease-Related Competence Network for Multiple Sclerosis and the German Multiple Sclerosis Society as well as the guidelines on diagnostics and therapy for multiple sclerosis of the German Society of Neurology and the latest research results. At the present point in time it should be noted that no studies have been carried out for most of the approaches for therapy conversion given here; however, the recommendations are based on theoretical considerations and therefore correspond to recommendations at the level of expert consensus, which is currently essential for the clinical daily routine.
Assuntos
Alergia e Imunologia/normas , Imunossupressores/administração & dosagem , Imunoterapia/normas , Esclerose Múltipla/tratamento farmacológico , Neurologia/normas , Guias de Prática Clínica como Assunto , Relação Dose-Resposta a Droga , Esquema de Medicação , Alemanha , Humanos , Imunossupressores/normas , Esclerose Múltipla/imunologiaRESUMO
Multiple sclerosis (MS) is an inflammatory, presumably autoimmune disease affecting the central nervous system. Early stages of the disease are characterized by conspicuous inflammation of the white and grey matter. During later stages, presumably secondary neurodegeneration leads to physical disability progression. Over the last decade increasingly effective therapeutic options have been approved. Currently 11 immunomodulatory or immunosuppressive therapies targeting relapse rate, disease progression and paraclinical disease activity are available, mostly for relapsing forms of MS. However, the ideal of "precision medicine" is still in the distant future since biomarkers for individualized treatment are lacking. For implementation of risk-management plans to minimize the risk of severe side effects, interdisciplinary collaboration between neurologists and internists is essential. In this review article we summarize practical aspects of the implemented risk-management plans, and discuss possible side effects and special caveats of the three new immunotherapies teriflunomide, dimethyl fumarate, and alemtuzumab. This article is based on, among others, the recently updated guidelines of the German Society of Neurology. Particular attention is given to the risks of new therapies, monitoring, and on special aspects needing attention when changing treatments. Teriflunomide, dimethyl fumarate, and alemtuzumab expand treatment options for relapsing-remitting MS. Treatment selection should take into consideration the safety profile of the substance, previous and concomitant diseases, and other individual factors. This requires in-depth consultation and individual assessment of current disease activity, the potential efficacy of the therapy, and the possible risks and side effects.
Assuntos
Fatores Imunológicos/uso terapêutico , Imunossupressores/uso terapêutico , Esclerose Múltipla/imunologia , Esclerose Múltipla/terapia , Humanos , Resultado do TratamentoRESUMO
We observed two cases of progressive multifocal leukoencephalopathy (PML) that occurred in the same "infusion group". The group consisted of four patients with relapsing-remitting multiple sclerosis (RRMS) who had been treated with natalizumab (NAT) in the same medical practice for more than four years at the same times and in the same room, raising concerns about viral transmission between members of the infusion group. DNA amplification and sequence comparison of the non-coding control region (NCCR) of JC virus (JCV) present in cerebrospinal fluid (CSF) samples from PML patients #1 and #2 revealed that the amplified JCV sequences differed from the JCV archetype. The NCRR of the viral DNA was unique to each patient, arguing against the possibility of viral transmission between patients. Statistical considerations predict that similar co-occurrences of PML are likely to happen in the future.
Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Leucoencefalopatia Multifocal Progressiva/complicações , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Feminino , Humanos , Vírus JC/genética , Leucoencefalopatia Multifocal Progressiva/transmissão , Leucoencefalopatia Multifocal Progressiva/virologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/virologia , Natalizumab , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
BACKGROUND: Familial Mediterranean fever (FMF) is an inherited autoinflammatory disease caused by mutations in the MEFV gene and characterized by recurrent febrile polyserositis. A possible association of FMF and multiple sclerosis (MS) has been suggested in cohorts from Turkey and Israel. OBJECTIVE: The objective of this study was to investigate the prevalence of MEFV mutations in subjects with MS and in controls in Germany. METHODS: One-hundred and fifty seven MS patients with at least one symptom or without symptoms suggestive of FMF from our outpatient clinic were investigated for mutations in exons 2, 3, and 10 of the MEFV gene (group 1). 260 independent MS patients (group 2) and 400 unrelated Caucasian controls (group 3) were screened selectively for the low-penetrance pyrin mutations E148Q and K695R RESULTS: In group 1, 19 MS patients (12.1%) tested positive for a mutation in the MEFV gene, mainly the E148Q (n=7) substitution. Fifteen of the 19 mutation-positive individuals reported at least one symptom suggestive of FMF. In three cases, we could identify additional family members with MS. In these pedigrees, the E148Q exchange co-segregated with MS (p=0.026). Frequencies of the pyrin E148Q and K695R mutations were not statistically different between MS group 2 and controls but they occurred with a surprisingly high frequency in the German population. CONCLUSION: The MEFV gene appears to be another immunologically relevant gene locus which contributes to MS susceptibility. In particular, the pyrin E148Q mutation, which co-segregated with disease in three MS families, is a promising candidate risk factor for MS that should be further explored in larger studies.
Assuntos
Proteínas do Citoesqueleto/genética , Febre Familiar do Mediterrâneo/genética , Esclerose Múltipla Crônica Progressiva/genética , Esclerose Múltipla Recidivante-Remitente/genética , Mutação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Pré-Escolar , Análise Mutacional de DNA , Avaliação da Deficiência , Éxons , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/imunologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Alemanha , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/imunologia , Esclerose Múltipla Recidivante-Remitente/diagnóstico , Esclerose Múltipla Recidivante-Remitente/imunologia , Fenótipo , Estudos Prospectivos , Pirina , Medição de Risco , Fatores de Risco , Adulto JovemRESUMO
We report a 55-year-old male patient with secondary progressive multiple sclerosis who developed an acute febrile syndrome with fever, neutrophilia and tender erythematous plaques and papules on his upper extremities after his fifth mitoxantrone infusion. Infectious, haematological and rheumatological diseases were ruled out, but skin biopsy showed neutrophilic infiltrations in the dermis consistent with Sweet's syndrome. Treatment with oral corticosteroids led to prompt improvement of systemic and cutaneous symptoms. To our knowledge, this is the first report of a patient with Sweet's syndrome after mitoxantrone therapy. Clinicians should be aware of Sweet's syndrome in patients with otherwise unexplained acute febrile illness and erythematous skin rash in association with mitoxantrone therapy. Skin biopsy helped to exclude other diseases and confirmed Sweet's syndrome.
Assuntos
Mitoxantrona/efeitos adversos , Esclerose Múltipla/tratamento farmacológico , Síndrome de Sweet/induzido quimicamente , Glucocorticoides/uso terapêutico , Humanos , Masculino , Metilprednisolona/uso terapêutico , Pessoa de Meia-Idade , Mitoxantrona/uso terapêutico , Síndrome de Sweet/tratamento farmacológico , Resultado do TratamentoRESUMO
In this article the recent clinical data on novel therapy of relapsing multiple sclerosis with oral fingolimod (FTY720), lead substance of the recently described class of sphingosine-1-phosphate (S1P) receptor modulators are reviewed. Results of the two phase III studies (FREEDOMS; TRANSFORMS) corroborating previous phase II trial observations suggest that fingolimod has a strong anti-inflammatory effect in relapsing multiple sclerosis (MS), most probably by suppression of lymphocyte re-circulation from lymph nodes to inflammatory tissues (lymphocyte egress). Patients treated with fingolimod show a robust reduction of relapse frequency, compared to placebo (FREEDOMS) or an active comparator (interferon-ß1a) (TRANSFORMS) and they show less inflammatory lesions on brain MR imaging. Furthermore, data from experimental research indicate that fingolimod may equally promote neural repair in vivo as well. Thus, the proposed immunological and neurobiological profile of fingolimod as well as the data from the recent clinical trials will be discussed in the context of the expected safety profile.
Assuntos
Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Propilenoglicóis/administração & dosagem , Receptores de Lisoesfingolipídeo/antagonistas & inibidores , Esfingosina/análogos & derivados , Administração Oral , Cloridrato de Fingolimode , Humanos , Imunossupressores/administração & dosagem , Prevalência , Medição de Risco , Fatores de Risco , Esfingosina/administração & dosagem , Resultado do TratamentoRESUMO
Natalizumab (Tysabri®) is the first monoclonal antibody approved for the treatment of relapsing forms of multiple sclerosis (MS) but while treatment is highly efficient, it carries the risk of progressive multifocal leukoencephalopathy (PML). Based on reports of confirmed cases of PML, the risk of PML might increase beyond 24 months of treatment. Thus, attempts to stratify patients treated with natalizumab into those carrying higher or lower risk for developing PML are currently being undertaken. Among these strategies JC virus serology might potentially be the first tool available. As a large variety of methods have been published resulting in controversial results for JC virus seroprevalence, standardized testing will be mandatory when applying this method in clinical practice. In addition, risk management strategies for the seropositive majority of patients need to be redefined and optimized further.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/prevenção & controle , Esclerose Múltipla/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Humanos , Leucoencefalopatia Multifocal Progressiva/diagnóstico , Esclerose Múltipla/complicações , Natalizumab , Medição de Risco , Fatores de Risco , Resultado do TratamentoRESUMO
Polymyositis mediated by gamma/delta T cells is a unique disease in which autoaggressive T lymphocytes surround, invade, and destroy muscle fibers. Histochemically, the vast majority of muscle-infiltrating T cells in a patient with polymyositis were reactive with a pan-gamma/delta T cell receptor (TCR)-specific monoclonal antibody (TCR-delta 1+), but unlike > 90% of peripheral blood gamma/delta T cells, these lymphocytes did not react with V delta 1- or V gamma 9-specific antibodies (A13- and Ti gamma A-, respectively). Differential reactivity with two different V delta 2-specific monoclonal antibodies (BB3-/TiV-delta 2+) indicated that the infiltrating T cells express a V delta 2-containing TCR with unusual additional structural features. Using conventional and anchored polymerase chain reaction for the analysis of TCR transcripts, we found a striking predominance of one unusual V delta 2-J delta 3 recombination and one V gamma 3-J gamma 1 recombination. Both the unusual phenotype (TCR-delta 1+/A13-/Ti gamma A-/BB3-/TiV-delta 2+) and the dominance of distinct TCR transcripts are compatible with the assumption that one T cell clone, which expresses a V gamma 3-J gamma 1-C gamma 2/V delta 2-J delta 3-C delta disulfide-linked TCR, dominates among the infiltrating T cells of the polymyositis muscle specimen analyzed.
Assuntos
Músculos/imunologia , Polimiosite/imunologia , Receptores de Antígenos de Linfócitos T gama-delta/genética , Linfócitos T Citotóxicos/imunologia , Sequência de Bases , Fluoresceína-5-Isotiocianato , Humanos , Microscopia de Fluorescência , Dados de Sequência Molecular , Oligodesoxirribonucleotídeos , Oligonucleotídeos Antissenso , Reação em Cadeia da Polimerase/métodos , Polimiosite/genética , Polimiosite/patologiaRESUMO
In polymyositis (PM), CD8+ T cell receptor (TCR) alpha/beta + cells invade and destroy major histocompatibility complex class I-positive muscle fibers. We combined polymerase chain reaction (PCR) and double-fluorescence immunocytochemistry to analyze the T cell receptor (TCR) repertoire expressed in muscle of PM patients. In patient 1, inverse PCR revealed a preferential usage of TCR V alpha 33.1, V beta 13.1, and V beta 5.1. Six of six TCR V alpha 33.1+ clones and five of seven V beta 13.1+ clones had identical nucleotide sequences. In contrast, the V beta 5.1+ TCRs were more heterogeneous. Similar results were obtained with an independent PCR method using primers specific for TCR V alpha 33, V beta 13, or V beta 5. No TCR sequences could be amplified from noninflammatory control muscle. Furthermore, none of the TCR sequences found in PM muscle could be detected in blood from the same patient or from a normal control subject. Immunohistochemistry confirmed that V beta 5.1 and V beta 13.1 were overrepresented in the muscle lesions of this patient. 32% of all CD8+ T cells were V beta 13.1+, and 16% were V beta 5.1+. However, approximately 60% of the CD8+ T cells that invaded muscle fibers were V beta 13.1+, whereas 10% were V beta 5.1+. In patient 2, 50% of the T cells were V beta 5.1+, and as in patient 1, these T cells were mainly located in interstitial areas. In patient 3, > 75% of the autoinvasive T cells stained with an anti-V beta 3 mAb. Sequence analysis of 15 PCR clones amplified with a V beta 3-specific primer showed that 9 (60%) sequences were identical. The results suggest that (a) a strikingly limited TCR repertoire is expressed in PM muscle; (b) there is a dissociation between the TCR usage of autoinvasive and interstitial T cells; and (c) the autoinvasive T cells are clonally expanded.
Assuntos
Linfócitos T CD8-Positivos/fisiologia , Polimiosite/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/análise , Sequência de Aminoácidos , Sequência de Bases , Agregação Celular , Humanos , Dados de Sequência Molecular , Músculos/imunologia , Reação em Cadeia da PolimeraseRESUMO
Clonal composition and T cell receptor (TCR) repertoire of CD4(+) and CD8(+) T cells infiltrating actively demyelinating multiple sclerosis (MS) lesions were determined with unprecedented resolution at the level of single cells. Individual CD4(+) or CD8(+) T cells were isolated from frozen sections of lesional tissue by micromanipulation and subjected to single target amplification of TCR-beta gene rearrangements. This strategy allows the assignment of a TCR variable region (V region) sequence to the particular T cell from which it was amplified. Sequence analysis revealed that in both cases investigated, the majority of CD8(+) T cells belonged to few clones. One of these clones accounted for 35% of CD8(+) T cells in case 1. V region sequence comparison revealed signs of selection for common peptide specificities for some of the CD8(+) T cells in case 1. In both cases, the CD4(+) T cell population was more heterogeneous. Most CD4(+) and CD8(+) clones were represented in perivascular infiltrates as well as among parenchymal T cells. In case 2, two of the CD8(+) clones identified in brain tissue were also detected in peripheral blood. Investigation of the antigenic specificities of expanded clones may help to elucidate their functional properties.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Esclerose Múltipla/imunologia , Adulto , Encéfalo/imunologia , Encéfalo/patologia , Linfócitos T CD4-Positivos/citologia , Linfócitos T CD8-Positivos/citologia , Células Clonais , Feminino , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/patologia , Reação em Cadeia da Polimerase/métodos , Receptores de Antígenos de Linfócitos T alfa-beta/genéticaRESUMO
Brain-derived neurotrophic factor (BDNF) has potent effects on neuronal survival and plasticity during development and after injury. In the nervous system, neurons are considered the major cellular source of BDNF. We demonstrate here that in addition, activated human T cells, B cells, and monocytes secrete bioactive BDNF in vitro. Notably, in T helper (Th)1- and Th2-type CD4(+) T cell lines specific for myelin autoantigens such as myelin basic protein or myelin oligodendrocyte glycoprotein, BDNF production is increased upon antigen stimulation. The BDNF secreted by immune cells is bioactive, as it supports neuronal survival in vitro. Using anti-BDNF monoclonal antibody and polyclonal antiserum, BDNF immunoreactivity is demonstrable in inflammatory infiltrates in the brain of patients with acute disseminated encephalitis and multiple sclerosis. The results raise the possibility that in the nervous system, inflammatory infiltrates have a neuroprotective effect, which may limit the success of nonselective immunotherapies.
Assuntos
Linfócitos B/imunologia , Encefalopatias/imunologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Monócitos/imunologia , Linfócitos T/imunologia , Autoantígenos/imunologia , Fator Neurotrófico Derivado do Encéfalo/genética , Encefalite/imunologia , Glicoproteínas/imunologia , Humanos , Inflamação/imunologia , Ativação Linfocitária , Esclerose Múltipla/imunologia , Proteína Básica da Mielina/imunologia , Doenças Neurodegenerativas/imunologia , Oligodendroglia/imunologia , RNA Mensageiro/isolamento & purificação , Transcrição GênicaRESUMO
We report a 16-year-old female patient with a severe course of multiple sclerosis and concomitant symptoms suggestive of a hereditary autoinflammatory disease. Genetic analyses revealed that she inherited a TNFRSF1A R92Q mutation from her mother and a pyrin E230K mutation from her father. To our knowledge, this is the first report of a patient with severe childhood multiple sclerosis and mutations in two genes which predispose to hereditary autoinflammatory disorders. We speculate that these mutations contribute to early multiple sclerosis manifestation and enhance the inflammatory damage inflicted by the autoimmune response.
Assuntos
Proteínas do Citoesqueleto/genética , Esclerose Múltipla/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Adolescente , Feminino , Humanos , Masculino , Mutação , Linhagem , PirinaRESUMO
Currently, the hypothesis that altered venous hemodynamics might play a causative role in the pathogenesis of multiple sclerosis (MS) is being controversially discussed. This new "venous hypothesis" postulates that obstructions of the cervical venous system cause an increased pressure of the intracranial venous system and that in turn intracranial congestion disintegrates the blood-brain barrier initiating the inflammatory process in MS.The "venous hypothesis" is analyzed and evaluated with regard to the following aspects: first concerning the validity of published data, second with regard to the plausibility in view of the currently approved pathogenetic model of MS, and third with regard to the compatibility with preliminary neurosonological findings in a small but unselected cohort of patients at our department.The authors conclude that the "chronic cerebrospinal venous insufficiency (CCSVI)" cannot represent the exclusive pathogenetic factor in the pathogenesis of MS. In our cohort, only 20% of the patients fulfilled the required neurosonological features of CCSVI. So far, the pathogenetic relevance of these findings remains speculative. Thus, based on the current scientific position we cannot justify invasive "therapeutic" approaches, especially if they are performed outside of clinical trials.
Assuntos
Encéfalo/irrigação sanguínea , Esclerose Múltipla/etiologia , Medula Espinal/irrigação sanguínea , Insuficiência Venosa/complicações , Adulto , Idoso , Barreira Hematoencefálica/fisiologia , Veias Cerebrais/diagnóstico por imagem , Veias Cerebrais/fisiopatologia , Doença Crônica , Estudos de Coortes , Constrição Patológica/complicações , Constrição Patológica/diagnóstico por imagem , Constrição Patológica/fisiopatologia , Feminino , Hemodinâmica/fisiologia , Humanos , Veias Jugulares/diagnóstico por imagem , Veias Jugulares/fisiopatologia , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/fisiopatologia , Fatores de Risco , Ultrassonografia Doppler Transcraniana , Insuficiência Venosa/diagnóstico por imagem , Insuficiência Venosa/fisiopatologiaRESUMO
Immune cells infiltrate the CNS in many neurological diseases with a primary or secondary inflammatory component. In the CNS, immune cells employ shared mediators to promote crosstalk with neuronal cells. The net effect of this neuro-immune crosstalk critically depends on the context of the interaction. It has long been established that inflammatory reactions in the CNS can cause or augment tissue injury in many experimental paradigms. However emerging evidence suggests that in other paradigms inflammatory cells can contribute to neuroprotection and repair. This dual role of CNS inflammation is also reflected on the molecular level as it is becoming increasingly clear that immune cells can release both neurodestructive and neuroprotective molecules in CNS lesions. It is thus the balance between destructive and protective factors that ultimately determines the net result of the neuro-immune interaction.
Assuntos
Doenças do Sistema Nervoso Central/imunologia , Quimiotaxia de Leucócito/imunologia , Encefalite/imunologia , Sistema Imunitário/imunologia , Neuroimunomodulação/imunologia , Animais , Doenças do Sistema Nervoso Central/fisiopatologia , Quimiocinas/metabolismo , Citocinas/metabolismo , Encefalite/fisiopatologia , Humanos , Sistema Imunitário/fisiopatologia , Degeneração Neural/imunologia , Degeneração Neural/fisiopatologia , Fatores de Crescimento Neural/metabolismo , Transdução de Sinais/imunologiaRESUMO
B cells are increasingly recognized as major players in multiple sclerosis pathogenesis. The BAFF/APRIL system is crucial for B cell homoeostasis and may drive B cell-dependent autoimmunity. We asked whether this system is affected by Interferon (IFN)-beta therapy. We analysed transcription of the ligands (BAFF, APRIL, TWE-PRIL) and the corresponding receptors (BAFF-R, TACI and BCMA) by TaqMan-PCR ex vivo in whole blood and in immune cell subsets purified from IFN-beta-treated multiple sclerosis patients. Serum BAFF concentrations were determined by ELISA. This cross-sectional study involved 107 donors. IFN-beta therapy strongly induced BAFF transcription proportionally to the IFN-beta biomarker MxA in monocytes and granulocytes in vivo. BAFF serum concentrations were elevated in IFN-beta-treated multiple sclerosis patients to a similar level as observed in SLE patients. In cultured PBMC, neutrophils, fibroblasts and astrocytes, BAFF was induced by IFN-beta concentrations similar to those reached in vivo in treated multiple sclerosis patients. BAFF turned out to be the main regulated element of the BAFF/APRIL system. In untreated multiple sclerosis patients, there was no BAFF increase as compared to healthy controls. Our study reveals a complex situation. We show that IFN-beta therapy induces a potent B cell survival factor, BAFF. However, B cell depletion would be desirable at least in some multiple sclerosis patients. The systemic induction of BAFF by IFN-beta therapy may facilitate the production of various autoantibodies and of IFN-neutralizing antibodies. Individual MS/NMO patients who have major B cell involvement may benefit less than others from IFN-beta therapy, thus explaining interindividual differences of the therapeutic response.
Assuntos
Fator Ativador de Células B/metabolismo , Linfócitos B/efeitos dos fármacos , Imunoterapia/métodos , Interferon beta/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Adulto , Autoimunidade , Fator Ativador de Células B/sangue , Receptor do Fator Ativador de Células B/metabolismo , Linfócitos B/imunologia , Estudos de Casos e Controles , Células Cultivadas , Estudos Transversais , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Interferon beta/análise , Masculino , Esclerose Múltipla/imunologia , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismoRESUMO
As new cases arise of progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS) treated with the monoclonal antibody natalizumab, a critical discussion about risks and advantages of this specific kind of immunotherapy appears necessary. Practical consequences and treatment options are addressed based on current concepts of PML's pathogenesis in patients treated with natalizumab. Critical patient selection based on risk:benefit considerations, limited therapy regimens, early diagnosis of PML by clinical and paraclinical criteria, and therapeutic perspectives for treating PML are discussed. The risk of PML in patients with MS needs to be continually monitored and should be reduced with all means available to ensure optimal outcome.
Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Leucoencefalopatia Multifocal Progressiva/induzido quimicamente , Leucoencefalopatia Multifocal Progressiva/complicações , Leucoencefalopatia Multifocal Progressiva/prevenção & controle , Anticorpos Monoclonais Humanizados , Humanos , NatalizumabRESUMO
This review updates and extends earlier Consensus Reports related to current basic and escalating immunomodulatory treatments in multiple sclerosis (MS). The recent literature has been extracted for new evidence from randomized controlled trials, open treatment studies and reported expert opinion, both in original articles and reviews, and evaluates indications and safety issues based on published data. After data extraction from published full length publications and critically weighing the evidence and potential impact of the data, the review has been drafted and circulated within the National MS Societies and the European MS Platform to reach consensus within a very large group of European experts, combining evidence-based criteria and expert opinion where evidence is still incomplete. The review also outlines a few areas of controversy and delineates the need for future research.