review
JAK inhibitors in the treatment
of rheumatoid arthritis
Progress in treating rheumatoid arthritis has been achieved with Janus kinase inhibitors, orally
available disease-modifying anti-rheumatic drugs targeting the intracellular kinase JAK and
having similar efficacies to biologics
Manuel Pombo-Suarez
MD
Rheumatology
Department, Complejo
Hospitalario Universitario
de Santiago de
Compostela. Spain
Juan Gomez-Reino MD
Fundación Ramón
Domínguez Complejo
Hospitalario Universitario
de Santiago de
Compostela, Spain
Rheumatoid arthritis (RA) is a systemic
autoimmune disease characterised by
inflammation, synovitis and progressive destruction
of the articular cartilage and underlying bone, along
with various extra-articular manifestations.
Cytokines act as soluble mediators responsible for
the inflammatory process, activating endothelial
cells and attracting immune cells to accumulate
within the synovial compartment. 1
The basis of RA treatment is the use of disease-
modifying anti-rheumatic drugs (DMARDs). There
are two major classes of DMARDs: synthetic
(sDMARDs) and biological (bDMARDs). Furthermore,
sDMARDs are divided into conventional synthetic
(csDMARDs) and targeted synthetic (tsDMARDs). 2
This classification is based on the development
process. The use of csDMARDs has evolved empirically,
as their modes of action are largely unknown. By
contrast, tsDMARDs have been developed to target
specific molecules that are known to play a role in
RA pathogenesis. This is the case of the subjects of
this review, being designed to inhibit molecules of
the Janus kinase (JAK) transduction pathway.
The JAK inhibitors are a recent class of drugs
for the treatment of RA. Unlike previous therapies
that were based on blocking different cytokines
outside the cell, JAK inhibitors act by disrupting
signalling pathways within the cell. In recent years,
intracellular signalling proteins, as kinases, have
emerged as potential targets for regulating the
immune system in arthritis. JAKs are intracellular
transducers of signals from many extracellular
cytokines. There are four types of JAKs: JAK1; JAK2;
JAK3; and non-receptor tyrosine protein kinase,
TYK2. Distinct cytokine receptors are paired with
different JAKs, which are activated upon cytokine
binding. This triggers the regulation of gene
expression through activation of various signalling
molecules. 3 Suppressing the cytokine effect through
JAK inhibition seems a feasible approach to treat RA.
Each JAK inhibitor has specific affinities to different
JAKs; therefore distinctive cytokines and other
soluble factors are blocked and particular effects
are expected.
Treatment recommendations
Present recommendations for the treatment of
RA suggest that therapy should be initiated with
a csDMARD, methotrexate (MTX) being the most
commonly used. Until the advent of tsDMARDs,
bDMARDs were the single available option in
patients who failed to respond to csDMARDs. The
arrival of bDMARDs meant a dramatic step forward
in the treatment of RA and made it possible to
increase the level of demand, supporting a ‘treat to
target’ strategy aimed at lowering disease activity
hospitalpharmacyeurope.com | 2018 | Issue 00 | 37