Clinical utility of the oral JAK inhibitor tofacitinib in the treatment of rheumatoid arthritis

Abstract

Immune/inflammatory cells act in rheumatoid arthritis (RA)-affected patients by synthesizing several inflammatory mediators, including cytokines that initiate intracellular signaling. Recently, small molecule inhibitors of transduction and transcription signals that influence the intracellular pathways (such as the Janus kinase [JAK] family of tyrosine kinases) have been tested for RA treatment. Four members of the JAK family are known: JAK1, JAK2, JAK3, and TyK2. JAK1/JAK3 constitutively binds to the cytoplasmic portion of the cytokine receptor - the common gamma chain - that represents a common subunit of several cytokines involved in T-cell and natural killer cell development, as well as in B-cell activation. Tofacitinib is an oral JAK inhibitor that is now available and effective in RA treatment, as shown in multiple Phase II and Phase III clinical trials. However, long-term safety data and comparisons with other disease-modifying antirheumatic drugs and small molecule inhibitors are necessary to better determine the role of tofacitinib in RA.

Keywords: Janus kinase inhibitors; intracellular signaling; kinases; rheumatoid arthritis; small molecules inhibitors; tofacitinib.

Figure 1

Intracellular signaling pathways. Notes: Intracellular pathways offer many options for the inhibition of cytokine signaling. JAK/STAT pathways are one of several intracellular hubs in the inflammatory cytokine network. There are several kinase cascades operating for the intracellular signaling; these include: JAK, MAP, Syk, NF-κB, STAT, TyK2, ERK, MAP3KS that phosphorylates and activates a MKK (for example, ERK), JNK, C-Jun, ATF2, Elk-1, C-Myc, NIK, IKK, and IκBα. Abbreviations: JAK, C-Jun N-terminal kinase; TyK2, tyrosine kinase 2; MAP3KS, mitogen-activated protein kinase kinase kinase; Syk, spleen tyrosine kinase; STAT, signal transducers and activators of transcription; MeK 1/2, dual-specificity kinase MAP kinase kinase; ERK, extracellular signal-regulated kinases; NIC, nuclear factor-kappa B inducing kinase; MKK, mitogen-activated protein kinase kinase; IKK, inhibitor kappa B kinase; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; IkBα, subunits of IKK; ATF2, activating transcription factor 2; MAPKA, mitogen-activated protein kinase A; PK2, protein kinase 2; C-Jun, transcription factor C-Jun; Elk-1, Ets-like protein 1 transcription factor; C-Myc, cellular oncogene; NIK, nuclear factor kappa B inducer kinase.

Figure 2

The JAK–STAT intracellular signaling pathway. Notes: JAK is involved in the intracellular signal transduction pathways via STATs. JAK3 binds to the gamma chain, which is a common receptor subunit for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. The JAK inhibitor, tofacitinib, mainly inhibiting JAK3 and JAK1, blocks the synthesis of proinflammatory cytokines (IFN-gamma, IL-6 and, to a lesser extent, IL-12 and IL-23). Abbreviations: IL, interleukin; JAK, Janus kinase; STAT, signal transducers and activators of transcription; TNF, tumor necrosis factor; IFN, interferon.