European perspective on the management of rheumatoid arthritis: clinical utility of tofacitinib

Abstract

Xeljanz® (tofacitinib) is an oral small-molecule inhibitor that reversibly inhibits Janus-activated kinase (JAK)-dependent cytokine signaling, thus reducing inflammation. As a result of these mechanisms, effects on the immune system such as a moderate decrease in the total lymphocyte count, a dose-dependent decrease in natural killer (NK) cell count, and an increase in B-cell count have been observed. Therefore, tofacitinib provides an innovative approach to modulating the immune and inflammatory responses in patients with rheumatoid arthritis (RA), which is especially important in individuals who do not respond to tumor necrosis factor inhibitors or show a loss of response over time. The aim of this article was to review studies on the pharmacology, mode of action, pharmacokinetics, efficacy, and safety of tofacitinib in patients with RA. Tofacitinib has been shown to reduce symptoms of RA and improve the quality of life in the analyzed groups of patients. Moreover, it showed high efficacy and an acceptable safety profile in Phase III randomized clinical trials on RA and was the first JAK inhibitor approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in the RA therapy, thus providing a useful alternative treatment strategy. Randomized controlled studies revealed a significant benefit over placebo in efficacy outcomes (American College of Rheumatology [ACR] 20 and ACR50 response rates); accordingly, clinically meaningful improvements in patient-related outcomes compared with placebo have been reported. The safety profile seems acceptable, although some severe adverse effects have been observed, including serious infections, opportunistic infections (including tuberculosis and herpes zoster), malignancies, and cardiovascular events, which require strict monitoring irrespective of the duration of tofacitinib administration. As an oral drug, tofacitinib offers an alternative to subcutaneous or intravenous biologic drugs and should be recognized as a more convenient way of drug administration.

Aliskiren, tadalafil, and cinnamaldehyde alleviate joint destruction biomarkers; MMP-3 and RANKL; in complete Freund's adjuvant arthritis model: Downregulation of IL-6/JAK2/STAT3 signaling pathway

“…Afterward, STAT protein is activated, where p-STAT dimers are formed and then translocated to the nucleus to stimulate the transcription of certain genes ( Malemud, 2018 ). The importance of JAK/STAT signaling in the propagation of RA led to the development of new drugs targeting this pathway, such as tofacitinib (JAK3 inhibitor) which was the first JAK inhibitor approved by Food and Drug Administration (FDA) and European Medicines Agency (EMA) for treatment of RA ( Kaur et al, 2014 , Kawalec et al, 2018 ).…”

Tofacitinib Induced Psoriasiform Lesion in a Patient With Rheumatoid Arthritis

“…Tofacitinib is a small- molecule, inhibiting JAK1 and JAK3 and, to a lesser extent, JAK2. [ 4 ] In psoriasis pathogenesis, many of the cytokines take role through the JAK-signal transducers and activators of transcription (STAT) signaling pathway like the expression of interleukin (IL)-23 and IL-23 dependent releasing of IL-17, differentiation of T helper type 1 (Th1) cells. In RA pathogenesis, production of IL-17 and interferon-gamma (IFN-γ) and proliferation of CD4 T cells (presumably Th1 and Th17) is dependent to JAK-STAT signaling pathway.…”

Safety differentiation: emerging competitive edge in drug development

“…The subcutaneously administered IL-6 antibody, sarilumab, developed by Sanofi/Regeneron and approved for RA in 2017, may offer advantages to the SoC although some side effects of immunosuppression have been shown [32]. The oral small molecule JAK-3 inhibitor, tofacitinib, developed for RA by Pfizer and approved in 2012, also shows immunosuppressive effects [33]. However, it has a significant advantage in the clinical management of RA as the immune-system recovers more rapidly after stopping the treatment as compared to the intravenously or subcutaneously administered biologic, anti-TNF-alpha.…”