Background

Coagulation components have a pivotal role to show not only as members of hemostasis system but either as regulators of innate immune response in neuroinflammatory diseases such as Multiple Sclerosis (MS). In fact, thrombin and fibrin(ogen) deposition in vasculature of the central nervous system (CNS) in MS animal models has been shown to modulate the microglia motility upon pre-demyelinated areas, to trigger and sustain inflammatory responses into perivascular lesions and, inevitably, to contribute in the axonal damage and neurodegenerative phenotype. Intriguingly, our early work has reported the presence of IgG antibodies (Abs) against coagulation components in patients with MS, albeit their role in MS pathogenesis is unknown.

Objectives

To characterize the impact of MS-derived IgG Abs against a panel of seven coagulant antigens (VIIa, thrombin, prothrombin, Xa, XII, protein C, plasmin) upon the activation of human astrocytes.

Methods

Purification of IgG Abs from 15 MS patients, who were positive for the presence of IgG against coagulation components and from 15 age and gender matched healthy donors was carried out. A human cell line of astrocytes was then treated with 100μg/ml of purified IgG for 4h and the extracted cell lysates were first quantified and then analyzed by immunoblot for the expression of the protease activator receptor -1 (PAR-1), a thrombin-activated receptor.

Results

Increased levels of PAR-1 expression were observed in astrocytes treated with IgG from MS patients who were positive for the presence of anti-thrombin and anti-plasmin IgG Abs, while not important effect was observed with IgG against other coagulant antigens of interest or with IgG derived from controls.

Conclusions

As the non-coagulation functions of thrombin are mediated by PAR-1, it is necessary to enlighten on the intracellular mechanisms that trigger the activation of PAR-1. Here, we have revealed that selective IgG Abs from MS patients can elicit the PAR-1 expression and thus may be involved in pro-inflammatory pathways that are mediated by thrombin. These findings point toward the importance of these molecules as potential biomarkers for the prognosis and/or diagnosis of MS and may prove valuable in further studies for the establishment of novel therapeutic strategies in MS.

Background

Teriflunomide is a disease-modifying immunomodulatory drug with anti-inflammatory properties that selectively and reversibly inhibits the mitochondrial enzyme dihydro-orotate dehydrogenase, with consequent inhibition of de novo pyrimidine synthesis and reduced lymphocyte proliferation. Oral teriflunomide is approved by EMA for the treatment of adult patients with Relapsing-Remitting Multiple Sclerosis (RRMS).

Objectives

The purpose of our review was to assess for the first time the real-life efficacy, safety, and retention of Teriflunomide (TER) in Cypriot patients with RRMS, and to compare our results with those of other studies performed in similar populations.

Methods

Twenty-four adult patients were assessed retrospectively one year after the initiation of TER. Four patients (17%) received TER as the first Disease-Modifying Treatment (DMT), whereas twenty patients (83%) were converted to TER from other DMTs.

Results

At TER initiation, patients were of a mean age of 44 years (range: 21-63) and had a mean MS duration of 14 years (range: 0.5-30).

In treatment-naïve patients, mean Annual Relapse Rate (ARR) during the year before TER treatment was 0.5 (range: 0-1) and mean EDSS progression 0.5 (range: 0-1.5). Twelve months after TER, mean ARR remained stable (p=0.423) whereas EDSS progression was reduced by 25% (p=0.057).

In DMT-converted patients, mean Annual Relapse Rate (ARR) during the year before TER treatment was 0.4 (range: 0-3) and mean EDSS progression 0.3 (range: 0-1.5). Twelve months after TER, both mean ARR and EDSS progression remained stable (p= 0.111 and p= 0.241 respectively).

TER retention rate was 79%. Five patients (21 %) discontinued TER: Three due to disease progression, one due to extreme neck pain and one due to lactose intolerance.

Most frequent ADRs were infections (26% of patients), increased ALT (21% of patients) and gastrointestinal discomfort (21% of patients).

Conclusions

Teriflunomide proved to be equally effective to previously used DMTs in our DMT-converted patients, whereas it significantly reduced disease progression in our treatment-naïve patients. ADRs were mostly mild and transient leading to high retention to therapy.

Our results are in line with those of other studies demonstrating the efficacy, safety, and retention of Teriflunomide in similar populations.