rheumatology and
musculoskeletal
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,
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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 or remission. However,
up to one third of patients do not adequately
respond to bDMARDs and more lose response
over time or experience adverse events. 5 Thus
there is a demand for new therapies to fill the gap
and that is where tsDMARDs, specifically JAK
inhibitors, come into play. Presently, tsDMARDs
are recommended for the treatment of patients
who failed with csDMARD added to the csDMARD
in a similar way than bDMARDs. 4 Interestingly,
if the use of csDMARD as comedication is
contraindicated, tsDMARDs are preferred over
all bDMARDs, because JAK inhibitors have shown
better efficacy on monotherapy compared with
MTX. 6,7
JAK inhibitors
A large number of clinical trials have already
demonstrated the efficacy of different JAK
inhibitors; To date, tofacitinib and baricitinib
have been approved by the European Medicines
Agency (EMA) and by the Food and Drug
Administration (FDA). Tofacitinib has been
marketed in a number of countries, including the
USA, in the last five years. Many JAK inhibitors
with different specificities are being developed,
and a number of these are expected to be
launched in the coming years.
JAK1/3 inhibitors
Tofacitinib is a selective inhibitor with a high
affinity for JAK1 and 3 and for JAK2, to a lesser
extent. Phase III trials have shown efficacy for
tofacitinib in RA patients who have failed
DMARDs, both as monotherapy 6 and in
combination with MTX. 8 A study has
demonstrated that tofacitinib plus MTX was
non-inferior to adalimumab plus MTX, and that
tofacitinib monotherapy was not non-inferior
relative to the two combination groups. 9
Tofacitinib also demonstrated higher rates of
response when compared with placebo in patients
with insufficient response to bDMARDs. 10
Tofacitinib was the first JAK inhibitor to reach
the market, being approved in the USA and 44
other countries in 2012. It took longer to obtain
approval from the EMA, and this was granted in