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
March 2017. The reasons behind this delay were
unresolved safety concerns (mainly infections) and
doubts about reduction of structural progression.
Pooled data from studies of tofacitinib in patients
with RA showed that the overall risk of infection
(including serious infection) and mortality rates in
RA patients treated with tofacitinib were similar to
those observed in RA patients treated with biologic
agents. 11 Regarding joint damage, a subsequent trial
showed that tofacitinib monotherapy was superior
to MTX in preventing radiological progression. 12 The
overall rates and types of malignancies observed in
the tofacitinib clinical programme remained stable
over time with increasing tofacitinib exposure and
were in line with what is expected in patients with
moderate to severe RA. 13
The EMA approved tofacitinib at a dose of 5mg
twice daily, being indicated in combination with
MTX for the treatment of moderate to severe active
RA in adult patients who have had an inadequate
response to MTX. It also can be used as monotherapy
in cases of intolerance to MTX or when continued
treatment with MTX is inappropriate.
JAK1/2 inhibitors
Baricitinib is a JAK1/2 inhibitor with moderate
activity on TYK2 and no influence on JAK3. Phase
III studies demonstrated that baricitinib alone or in
combination with MTX had superior efficacy to MTX
monotherapy as initial treatment for patients with
active RA. 7 In patients with inadequate response to
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MTX, baricitinib was superior when compared with
placebo and adalimumab. 14 It also demonstrated
clinical improvement and inhibition of progression
of radiographic joint damage in patients who failed
to respond to csDMARDs 15 and clinical improvement
in patients with inadequate response to bDMARDs. 16
Baricitinib was approved by the EMA in March
2017 at a dose of 4 or 2mg once daily. It is indicated
for the treatment of moderate to severe active
rheumatoid arthritis in adult patients who have
responded inadequately to, or who are intolerant
to, one or more DMARDs. It can be used as
monotherapy or in combination with MTX.
Baricitinib approval was initially rejected by the
FDA, on the basis that additional clinical data were
needed to determine the most appropriate doses
and to further characterise safety concerns across
treatment arms. A major reason behind this decision
was the presence of thromboembolic events in
five patients receiving baricitinib in clinical trials.
It just has been approved by the FDA at a dose of
2mg once daily in adult patients with moderately-
to-severely active RA who have had an inadequate
response to one or more tumor necrosis factor (TNF)
inhibitor therapies. It may be used as monotherapy
or in combination with MTX or other csDMARDs.
Baricitinib was approved with a Boxed Warning
for the risk of serious infections, malignancies and
thrombosis. As part of the approval, the sponsor has
agreed to conduct a randomised controlled clinical
trial to evaluate the long-term safety of baricitinib in
patients with RA.
JAK1 inhibitors
Filgotinib is a selective inhibitor of JAK1 over JAK2,
JAK3 and TYK2. The rationale for the development
of more selective inhibitors such as filgotinib is
that less selective JAK inhibitors lead to pan-JAK
inhibition that might generate dose-limiting side
effects.
Published results of Phase II studies in patients
with insufficient response to MTX showed that
filgotinib was superior to placebo with an acceptable
safety profile. 17,18 It has also shown efficacy as
monotherapy. 19
Upadacitinib is another selective inhibitor of
JAK1. It has also demonstrated efficacy in Phase II
trials, with a favorable safety and tolerability profile
in patients with inadequate response to MTX and to
bDMARDs. 20,21 Phase III clinical trials are currently
ongoing.
JAK3 inhibitors
Decernotinib selectively inhibits JAK3 over the other
JAKs. Taking this into account it would be expected
that some of the side effects seen with less specific
JAK inhibitors might be avoided. Decernotinib has
shown superiority compared with placebo in a Phase
II study. 22 Development is currently on hold.
Peficitinib inhibits all of the JAKs, having
a moderate selectivity for JAK3. Its milder effect
on JAK2 suggests that effects on red blood cells
and platelets caused by JAK2 inhibition might
be less intense. Results from Phase II trials have
demonstrated an acceptable response in patients
with inadequate response to csDMARDs. 23,24 Phase III
trials are underway.
Safety profile
Information from clinical trials is creating
a characteristic safety profile for this new class
of molecules. What is difficult to answer at this
moment is whether the different selectivities of
each JAK inhibitor will establish distinctions