Relapse Therapy in Multiple Sclerosis – The Role of Plasma Exchange

Relapse Therapy in Multiple Sclerosis – The Role of Plasma Exchange

Gold Ralf , Linker Ralf A, Schröder Alexandra K
Published: European Neurological Review - Volume 4 - Issue I
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Glucocorticosteroid Therapy of Acute Multiple Sclerosis Relapses
On an empirical basis, glucocorticosteroids (GS) form the basis of relapse therapy in multiple sclerosis (MS). Soon after the discovery of naturally occurring GS in the adrenal gland in 1938, synthesis of steroid hormones was achieved in 1947, thus opening the way for the development of new and more potent GS compounds, and also therapy of human autoimmune disorders with GS.1 However, until the 1970s treatment with adreno- corticotropic hormone (ACTH) as a pituitary regulator, which leads to the release of endogenous gluco- and mineralocorticosteroid hormones, was still widely used instead of GS. Today, ACTH has been abandoned as a treatment of autoimmune diseases in clinical neuroimmunology.

Over the last seven decades, since the discovery of GS, a variety of genomic effector mechanisms have been described that are mediated by glucocorticoid receptors (GRs) acting as a transcription factor. In T cells, GS exert a distinct mode of action, ultimately resulting in T-cell apoptosis. This was shown in peripheral blood mononuclear cells from MS patients treated with GS during relapse.2 Studies in experimental autoimmune encephalomyelitis (EAE) – an animal model mimicking many aspects of MS – revealed a dose–response curve for induction of T-cell apoptosis, with methylprednisolone doses up to 50mg/kg being most efficient.3 In addition, recent data in GR knockout mice clearly underscore the importance of genomic mechanisms of action for EAE treatment.4 In humans, short-term application of such high doses is well tolerated, as revealed in patients receiving high-dose GS (30mg/kg bodyweight [BW]) for treatment of spinal cord injury.5

The efficacy of intravenous (IV) high-dose GS in acute deterioration of MS was first described by Dowling et al.,6 followed by a number of uncontrolled trials pointing at rapid clinical improvement. In the first randomised, controlled study, by Milligan and Compston,7 50 patients received either 500mg of IV methylprednisolone or placebo over five days. The trial included patients with acute relapses and also with deterioration of progressive MS symptoms. In relapse treatment, IV GS were associated with faster remission, while chronic progressive patients displayed a benefit in motor function that lasted for the first four weeks only. The tolerability of such short-term, high-dose GS pulses in a routine clinical setting is good, while some transient mild disturbance of memory functions may occur.8

The data on efficacy of GS were corroborated by a further class I study by Beck and colleagues in optic neuritis (ON).9,10 In this study, patients received 1,000mg of IV methylprednisolone for three days, followed by oral tapering at 1mg/kg BW for 11 days. Compared with oral treatment with 1mg/kg prednisone or placebo, this high-dose GS pulse resulted in a faster improvement of visual acuity. The effect disappeared after six months, yet a positive impact on the visual fields as well as contrast and colour vision persisted over time. The three groups were followed up for relapses during the study over the full disease course.10,11 Surprisingly, GS pulses reduced subsequent relapses after ON: 14.7% of oral GS recipients, but only 7.5% of patients treated with high-dose GS, fulfilled the criteria for definite relapsing–remitting MS within two years. Thus, this study may be regarded as the first follow-up of patients with a first demyelinating event, which today is referred to as clinically isolated syndrome (CIS). As no other long-term immunotherapy was established at that time, the further follow-ups of this cohort over a longer time period instead reflect the natural variability of MS and therefore are not discussed here.

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