The Prevention of Post-Partum Relapses with Progestin and Estradiol in Multiple Sclerosis (POPART'MUS) trial: Rationale, objectives and state of advancement

Abstract

Multiple sclerosis (MS) affects 1 in 1000 people in western countries, mainly women in their childbearing years. It is an autoimmune disease of the central nervous system, which results in a chronic focal inflammatory response with subsequent demyelination and axonal loss. It usually begins with acute episodes of neurological dysfunction, the relapses, followed by periods of partial or complete remission. This relapsing–remitting phase is usually followed by a steady, continuous and irreversible worsening of the neurological dysfunction, which characterizes the progressive phase of the disease.

Recent prospective studies reported a significant decline by two-third in the rate of relapses during the third trimester of pregnancy and a significant increase by two-third during the first three months post-partum by comparison to the relapse rate observed during the year prior to the pregnancy. These dramatic changes in the relapse rate occur at a time when impregnation of many substances, among which sexual steroids, is at its highest, before a dramatic decline to the pre-pregnancy levels, immediately following delivery.

It may be hypothesized that sexual steroids could exert beneficial effects through a modulation of the immune state with a lowering of the pro-inflammatory lymphocyte responses of the Th1 type and an enhancement of anti-inflammatory responses of the Th2 type. They may also play a direct role in remyelination of central nervous system lesions, as they do in the peripheral nervous system, where progesterone increases the extent of myelin sheath formation after a cryolesion of the male mouse sciatic nerve.

The POPART'MUS study is a European, multicentre, randomized, placebo-controlled and double-blind clinical trial, which aims to prevent MS relapses related to the post-partum condition, by administrating high doses of progestin, in combination with endometrial protective doses of estradiol. Treatment is given immediately after delivery and continuously during the first three months post-partum. At present, 126 patients have been enrolled and 107 patients have completed the protocol. Assuming the results of the trial to be positive, this new treatment could be considered in the relapsing–remitting phase of the disease in women afar from pregnancy and post-partum. The trial is registered under the reference NTC00127075.

Introduction

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, which results in a chronic inflammatory response with subsequent demyelination and axonal loss. It has been considered to be mediated by CD4⁺ type 1 T helper (Th1) lymphocytes, which are responsible for the secretion of pro-inflammatory cytokines (IFNγ, IL2, TNFα), whereas anti-inflammatory Th2 responses (IL4,5,10,13 secretions) are down-regulated. In cell-mediated autoimmune diseases like MS, the Th1/Th2 cytokine balance is considered to shift towards Th1 and away from Th2.

There is evidence from various studies that pregnancy might influence the course of autoimmune diseases, particularly MS. It has been clearly shown that the rate of relapses is reduced during the last three months of pregnancy [1], [2], [3], [4], while the relapse rate is increased in the post-partum period [4], [5], [6], [7], [8], [9], [10]. Among the 227 pregnancies studied prospectively in the European PRIMS study, the mean relapse rate was 0.7 per woman per year in the year before pregnancy; it was 0.2 during the third trimester of pregnancy and 1.2 during the first three months post-partum.

From an immunological point of view, pregnancy seems to be associated with a shift away from cell-mediated immunity towards increased humoral immunity: pregnancy could modify the balance between Th1 and Th2 responses by inhibiting the Th1 response, particularly the production of INFγ and enhancing the production of Th2 anti-inflammatory cytokines [11]. Conversely, the post-partum period with its hormonal changes and its increased risk of MS relapses is associated with a shift towards Th1 and away from Th2 responses. Currently approved disease-modifying agents (DMAs), if administered just after delivery, are unlikely to prevent post-partum relapses because of their delay of action.

Sexual hormones, especially progesterone, may have an effect on the immune system by inducing a shift in the Th1/Th2 balance towards Th2 anti-inflammatory responses [12], [13], [14], [15]. They could therefore provide a new tool in preventing MS relapses in women. Their effect on remyelination could also be beneficial in this respect [16], [17], [18], [19].

We hypothesized that a progesterone derivative, administered just after delivery, could prevent the post-partum relapses. Assuming the results of the trial to be positive, this new treatment could be considered in the relapsing–remitting phase of the disease in women afar from pregnancy and post-partum. Our objective is to compare MS clinical activity, in terms of relapses during the post-partum period, in women treated immediately after delivery and for 3 months with progestin and estradiol, by comparison to placebo-treated women. Progestin is given at high doses leading to a plasma concentration which is fairly similar to that reached during pregnancy. It is combined with low doses of estradiol in order to avoid uterine endometrial atrophy caused by the progestin when given in monotherapy. This treatment has anti-conceptional properties.