Methotrexate alone and methotrexate combined with etanercept in treatment of rheumatoid arthritis

Abstract

After the breakthrough in the treatment of rheumatoid arthritis and numerous related disorders with biological therapies targeting TNFa at the Kennedy Institute in London Millions of patients have tremendously benefitted. However, we cannot cure these diseases yet and have to search for additional therapeutic targets. Since it was shown that synovial fibroblasts (SF) are not only effector cells responding to inflammatory stimuli, but appear endogenously activated and potentially involved into spreading the disease [1], we searched for the epigenetic modifications leading to the activated phenotype of these cells. Epigenetics in its scientific definition "is the study of all heritable and potentially reversible changes in genome function that do not alter the nucleotide sequence within the DNA", but might be considered in simpler terms as the regulation of gene expression. Epigenetic modifications include: Acetylation, Methylation, Phosphorylation, Sumoylation, miRs or microRNAs. Our laboratory is studying these processes and we have found that RASF reside in a hyperacetylated synovial tissue and appear hypomethylated [2]. Hypomethylation leads to the activated phenotype of RASF which is characterized by the production of matrix-degrading enzymes and of potent chemokines induced by Toll-like receptor signalling. Current strategies are designed to methylate these cells to deactivate and "normalise" them again. miRs are about 20 nucleotide long smallRNAs acting to destroy specific mRNA. In the race to identify specific miRs as novel targets we have identified for example, that interleukin-6 modulates the expression of the Bone Morphogenic Protein Receptor Type II through a novel STAT3microRNA cluster 17/92 pathway, which helps to explain the loss of the BMPR2 in the vascular cells in pulmonary hypertension [3]. Moreover, miR-203 is regulating the production of IL-6 [4]. Most interestingly, epigenetic therapy is also on the horizon [5]. References 1. Lefèvre S, et al: Synovial fibroblasts spread rheumatoid arthritis to unaffected joints.

Gërmia – from a regional park to the protected landscape

“…Its geodiversity and biodiversity richness have been reported by several authors: for geology (Milovanovic & Ciric, 1968); pedology (Pavičević et al, 1974); flora (Krasniqi, 1972(Krasniqi, , 1987Krivoshej, 1989;Amidžić, 1988;Mustafa, 1998;1999;Mustafa et al, 2008;Rexhepi, 1994Rexhepi, , 2000Veselaj, 2000;Veselaj et al, 2006.) and fauna (Mustafa & Hoxha, 2002;Jakšić, 2003). It is considered one of the richest areas in terms of biodiversity in Kosovo after Sharri and Bjeshkët e Nemuna National Parks.…”

Myths in Kosovar Textbooks: History in the Service of Identity Construction

“…An image showing the monumentofScanderbeg in Prishtina is stamped on the first page of the fifth grade history textbook; the introduction to Scanderbeg asserts:' The noble family of Kastriot was from Has'. 70 It is telling that from an umber of theories concerning Scanderbeg's origin, these authors choose the theorythat he came from avillage near modernKosovo. It is unclear whether this represents an attempt to establish ac onnection between the students of Kosovo and Scanderbeg,oradisguised desire to 'usurp' him.…”