Classical immunomodulatory therapy in multiple sclerosis: how it acts, how it works

Abstract

Interferon beta (IFNβ) and glatiramer acetate (GA) were the first immunomodulators approved to the treatment of relapsing-remitting multiple sclerosis (MS) and clinically isolated syndromes. Despite the enlargement of the therapeutic armamentarium, IFNβ and GA remain the most widely drugs and the therapeutic mainstay of MS. Objective: To review the mechanisms of action of IFNβ and GA and main clinical results in MS. Results: IFNβ modulates T and B-cell activity and has effects on the blood-brain barrier. The well proved mechanism of GA is an immune deviation by inducing expression of anti-inflammatory cytokines. Some authors favor the neuroprotective role of both molecules. Clinical trials showed a 30% reduction on the annualized relapse rate and of T2 lesions on magnetic resonance. Conclusion: Although the precise mechanisms how IFNβ and GA achieve their therapeutics effects remain unclear, these drugs have recognized beneficial effects and possess good safety and tolerability profiles. The large clinical experience in treating MS patients with these drugs along almost two decades deserves to be emphasized, at a time where the appearance of drugs with more selective mechanisms of action, but potentially less safer, pave the way to a better selection of the most appropriate individualized treatment. Key words: multiple sclerosis, interferon beta, glatiramer acetate, immunomodulatory therapy.Terapêutica imunomoduladora clássica na esclerose múltipla: como atua, como funciona RESUMO O interferão beta (IFNβ) e o acetato de glatirâmero (GA) foram os primeiros imunomoduladores aprovados para o tratamento da esclerose múltipla (EM) surtoremissão e doentes com síndromes clinicamente isoladas. Apesar do alargamento do armamentário terapêutico, o IFNβ e o GA continuam a ser os medicamentos mais usados na EM. Objetivo: Rever os mecanismos de acção do IFNβ e do GA e os principais resultados na clínica. Resultados: O IFNβ modula a actividade das células T e B e tem efeitos sobre a barreira hemato-encefálica. O mecanismo melhor comprovado do GA é o desvio imune através da indução da expressão de citocinas. Alguns autores favorecem ainda um papel neuroprotetor para ambos. Os ensaios clínicos mostraram diminuição da taxa anualizada de surtos de 30% e das lesões em T2 na ressonância magnética. Conclusão: Embora os mecanismos pelos quais o IFNβ e o GA atingem os seus efeitos terapêuticos continuem a ser pouco claros, estes fármacos possuem efeitos benéficos reconhecidos e bons perfis de segurança e tolerabilidade. A grande experiência clínica no tratamento da EM com estes fármacos ao longo de quase duas décadas merece ser destacada, numa altura em que o aparecimento de novos fármacos com mecanismos de acção mais seletivos, mas potencialmente menos seguros, possibilitarão melhor seleção e individualização do tratamento. Palavras-chave: esclerose múltipla, interferão beta, acetato de glatirâmero, terapêutica imunomoduladora.

Physiopathology of symptoms and signs in multiple sclerosis

“…It is undeniable that the discovery of DMD represents a remarkable step forward in the control of the disease, is a non-stop research field and brings hope to the possibility of cure. Even so, the positive effects of first-line DMD are considered to be rather modest, since the drugs act in the inflammatory, but not in the neurodegenerative mechanisms of the disease, hence the impact in the long term disability is small, whereas the better efficacy of second-line drugs must be weighed against a poorer safety profile 1 . Therefore, in the clinical setting, the people afflicted with MS must be subjected to a comprehensive and individualized therapeutically intervention, able to control the symptoms and signs of the disease, thus ameliorating their well-being.…”

“…The clinical recovery may be total or partial and remissions are expected to be longer in patients treated with DMD 1 . Various mechanisms underpin the recovery of functions, acting in different aspects and levels of myelin and axonal impairment (Table 2); however, the CNS repair has a dual face, so that some patients experience neurological symptoms related to defects in axonal conduction.…”

Critical Appraisal of Effectiveness of Oral Fingolimod on Relapsing Multiple Sclerosis

“…Symptomatic treatments include glucocorticoid therapy, benzodiazepines, muscle relaxers, anticonvulsants, antidepressants, and medications used to treat bladder and bowel dysfunction (Antezana, 2014). Currently, no curative medication therapies are available in the treatment of MS (Mendes and Sá, 2011). DMTs provide symptomatic relief and reduced MS progression.…”

The Peripheral Network between Oxidative Stress and Inflammation in Multiple Sclerosis

“…We stratified the studied population in patients under treatment (MSTP, n= 23) or not (MsnoTP, n=31) because of the known influences of IFN-~, Glatimer Acetate and Azathioprine on immune system phenotypes (13,23,24). Age, gender ratio, disease duration and EDSS were equally distributed in HC, MSTP and MSnoTP (Table I).…”