Publications

Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a Phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1)

J Am Acad Dermatol 2015;73:37-49. doi: 10.1016/j.jaad.2015.03.049

Papp K,

Reich K,

Leonardi CL,

Kircik L,

Chimenti S,

Langley RG,

Hu C,

Stevens RM,

Day RM,

Gordon KB,

Korman NJ,

Griffiths CE

Here, investigators reported that efficacy measures for skin and scalp were significantly greater for apremilast than for placebo in patients with PsO at baseline. Previously, clinical study data has highlighted that the use of apremilast leads to a reduction in the expression within the epidermis of numerous inflammatory cytokines relevant to PsO. As a result, ESTEEM 1 evaluated the efficacy/safety of apremilast at 30 mg BID for moderate to severe PsO.

Keywords:

• Apremilast,
• Efficacy,
• Safety,
• Phase 3

Tofacitinib STAT aktivasyonunun inhibisyonu ve negatif geri besleme inhibisyonunun indüksiyonu ile psöriatik artritteki sinoviyal inflamasyonu düzenler

Annals of the Rheumatic Diseases. 2015 Sep 9. doi:10.1136/annrheumdis-2014-207201

W Gao,

T McGarry,

C Orr,

J McCormick,

D J Veale,

U Fearon

Psoriatic arthritis (PsA) is a chronic inflammatory arthritis associated with psoriasis (Ps) and characterised by synovitis and progressive destruction of articular cartilage and bone. Recently developed agents for PsA target IL12p40, IL-6 and IL-17, several of which signal through the JAK family of receptor-associated tyrosine kinases. Tofacitinib is a drug of the JAK inhibitor class and is currently approved for the treatment of RA in 27 countries. This study evaluated the effect of tofacitini...

Keywords:

• JAK,
• Tofacitinib,
• Basic Science,
• Review

Aktif Romatoid Artrit Hastalarında Tofacitinib Monoterapisinin Etkinlik ve Güvenliliği: 12 haftalık, Randomize, Faz 2 çalışma

Modern Rheumatology. 2015 Jul;25(4):514-21. doi: 10.3109/14397595.2014.995875.

Tanaka Y,

Takeuchi T,

Yamanaka H,

Nakamura H,

Toyoizumi S,

Zwillich S.

The oral Janus kinase (JAK) inhibitor, Tofacitinib, preferentially inhibits signalling by heterodimeric receptors associated with JAK3 and/or JAK1, blocking signalling for several cytokines. The purpose of this study was to evaluate the efficacy of tofacitinib monotherapy versus placebo in Japanese patients with inadequate response to disease-modifying anti-rheumatic drugs (DMARDs). Data on response rates – ACR20/50/70, DAS28-4(ESR), and HAQ-DI – laboratory parameters and adverse events were col...

Keywords:

• JAK,
• Tofacitinib,
• Phase 2

Kronik plak psöriasis tedavisinde bir oral Januz kinaz inhibitorü, Tofacitinib: İki randomize, plasebo kontrollü, faz 3 çalışma

British Journal of Dermatology. 7 July 2015 DOI: 10.1111/bjd.14018. [Epub ahead of print]

Papp KA,

Menter MA,

Abe M,

Elewski B,

Feldman SR,

Gottlieb AB,

Langley R,

Luger T,

Thaci D,

Buonanno M,

Gupta P,

Proulx J,

Lan S,

Wolk R; OPT Pivotal 1 and OPT Pivotal 2 Investigators.

The management of moderate to severe chronic plaque psoriasis has benefited from the introduction of biological therapies, but unmet needs still remain, especially for oral therapies. Tofacitinib is an orally active agent that blocks signalling of key cytokines implicated in the immune response and inflammatory pathways of psoriasis. The Phase III studies presented in this paper analysed efficacy and safety endpoints.Both studies demonstrated that tofacitinib in both 5 mg and 10 mg twice daily d...

Keywords:

• JAK,
• Tofacitinib,
• Phase 3

TNF-α ve IL-6 ‘nın  inflamatuar artritli eklemlerde Dkk-1 regülasyonu farklıdır

Arthritis Rheumatol. 2015 May 4. doi: 10.1002/art.39183. [Epub ahead of print]

Yeremenko N,

Zwerina K,

Rigter G,

Pots D,

Fonseca J,

Zwerina J,

Schett G,

Baeten D.

Different inflammatory joint diseases have distinct patterns of bone damage, but the molecular pathways determining each one remains poorly defined. This study investigates the wingless (Wnt)-signalling pathway, by analysing the expression of Dkk-1 (an inhibitor of the Wnt pathway) and its regulation by the pro-inflammatory cytokines TNF-α and IL-6 in SpA versus RA inflamed peripheral joints.Findings from the study show an inverse correlation of Dkk-1 with IL-6 in vivo and a differential regulat...

Keywords:

• IL-6,
• Basic Science,
• MOA,
• Review

Süper güçlendiriciler(enhancer) T hücrelerinde hastalıkla-ilişkili düzenleyici devreleri tarif eder

Nature. 2015 Feb 16. doi: 10.1038/nature14154. [Epub ahead of print]

Vahedi G,

Kanno Y,

Furumoto Y,

Jiang K,

Parker SC,

Erdos MR,

Davis SR,

Roychoudhuri R,

Restifo NP,

Gadina M,

Tang Z,

Ruan Y,

Collins FS,

Sartorelli V,

O'Shea JJ.

Transcription machinery (proteins responsible for activating or ‘switching off’ genes) is not distributed in the genome in a symmetrical (or even) manner. Some parts of the genome, so called super-enhancers (SEs), accumulate an exceptionally high level of proteins relevant to the regulation of transcription (i.e. the machinery is concentrated in particular parts of the genome). In this paper, the investigators asked about the locale of these regions in the genome of T cells. Then they addressed...

Keywords:

• Preclinical,
• MOA

JAK-STAT yolunun romatoid artritteki aktivitesi: STAT3’ün konstitütif aktivasyonu interlökin 6 seviyeleri ile ilişkilidir.

Rheumatology (Oxford). 2014 Nov 17. pii: keu430. [Epub ahead of print]

Isomäki P,

Junttila I,

Vidqvist KL,

Korpela M,

Silvennoinen O.

Non-response, parenteral administration and cost to produce are all aspects associated with the currently available anti-cytokine agents for RA. These related factors mean that alternative drugs are now being developed. Recent developments in therapeutic drugs to treat RA have focused on Janus kinases (JAKs) and signal transducer and activator of transcription (STATs) transcription pathways. Several cytokines that regulate immune responses in RA, such as IFN-g, IL-6 and IL-10, activate JAK-STAT ...

Keywords:

• Preclinical,
• MOA

Romatoid artritte tedavi için terapötik fırsat olarak TNFα ve IL-17’nin kombine inhibisyonu: Yeni bir bispesifik antikorun geliştirilmesi ve nitelendirilmesi.

Arthritis Rheumatol. 2015;67(1):51–62

Fischer JA,

Hueber AJ,

Wilson S,

Galm M,

Baum W,

Kitson C,

Auer J,

Lorenz S,

Moelleken J,

Bader M,

Tissot AC,

Tan SL,

Seeber S,

Schett G

Single cytokine inhibition, e.g. TNFα or IL-6, has fundamentally improved the therapeutic armamentarium for the treatment of RA; yet clinically meaningful responses are achieved in only about half of RA patients treated. In addition, it is now well established that the pathogenesis of RA involves multiple mechanisms of cell activation and cell recruitment. These two factors have led to the emergence of the concept of dual specificity, sparking interest in the biologic arena, with a focus o...

Keywords:

• IL-17,
• TNF

Protein kinaz TYK2'nin psödokinaz–kinaz alanlarının yapısı Janus kinaz (JAK) otoinhibisyonu için bir mekanizma ortaya çıkarmaktadır

Proc Natl Acad Sci U S A. 2014 May 19. pii: 201401180. [Epub ahead of print]

Lupardus PJ,

Ultsch M,

Wallweber H et al

The JAK family of kinases (JAK1, JAK2, JAK3 and TYK2) are receptor-associated tyrosine kinases that act downstream of many cytokines and interferons. Recent studies have provided structural information about the kinase and pseudokinase domains of JAKs however the molecular mechanism by which JAK activity is regulated by the pseudokinase domain is poorly understood. This study builds on a recent finding that the N terminus of the JAK1 pseudokinase group may act as a switch for kinase activation b...

Keywords:

• TYK2,
• JAK,
• Preclinical,
• MOA

Osteoartrit benzeri durumlarda TAK1 ve/veya JAK inhibisyonu insan mezenkimal kök hücrelerinin bozulmuş kıkırdak farklılaşmasını düzeltebilir

Tissue Engineering Part A doi:10/1089/ten.TEA.2013.0553

Van Beuningen HM,

de Vries-van Melle ML,

Vitters El et al.

As it is nonvascularized and noninnervated, articular cartilage has a limited capacity to repair which presents a major clinical problem. In order to circumvent this inability to repair, stem cells can be placed into the joint or stimulated within the bone marrow. However, as the cartilage requiring repair is often in diseased joints, the factors involved in the disease state are potentially non-beneficial to the chondrogenesis of mesenchymal stem cells. In this study van Beuningen et al. invest...

Keywords:

• JAK,
• Preclinical,
• MOA