Unlike previous
therapies that
were based on
blocking different
cytokines outside
the cell, JAK
inhibitors act by
disrupting
signalling
pathways within
the cell
between them. To date, it seems that there is a large
overlap between JAK inhibitors despite their various
specifities. Infections and changes in laboratory
parameters seem to be common issues with JAK
inhibitors. 25
Most of the safety information for this class of
drugs comes from the tofacitinib development
programme and post-marketing experience. Some
of the changes in laboratory parameters resemble
those seen with the bDMARD, tocilizumab,
reflecting the inhibition of IL-6. Changes seen with
tofacitinib include a decrease in lymphocytes,
neutrophils, natural killer cells and platelets,
increased levels of transaminases and lipids, and
a small increase in serum creatinine. During the
development process, only a small percentage of
patients developed serious adverse events related
to these; further work in necessary to completely
understand the consequences of these changes. 25
Baricitinib showed similar laboratory changes but
differences were detected in relation to lymphocyte
and platelet counts, which mostly remained
unchanged, and levels of haemoglobin, which were
reduced. Special concern regarding thrombotic
risk is raised. Further information is needed to
clarify this issue. Data for other JAK inhibitors
are preliminary but it seems that differences in
laboratory parameters observed between JAK
inhibitors are difficult to explain looking at only
their different effect on JAKs. It has to be
considered that information of these newer
molecules comes from phase II studies where
different doses are used, losing JAK inhibitors’
specificity at higher doses.
There are limited data on the malignancy
risk associated with the use of JAK inhibitors.
Information comes from tofacitinib and baricitinib
long-term extension studies and the risk of
cancer seems to be similar to that observed with
bDMARDs. 13,26 There are no long-term data for other
JAK inhibitors. Even though preliminary data are
encouraging, many more years of exposure are
needed to profile the malignancy risk of this class
of drugs.
Serious infection rates with tofacitinib and
baricitinib are similar to those observed with
bDMARDs. 11,26 Particular reference to varicella zoster
virus has to be made. There is an increase in the risk
of herpes zoster in patients receiving JAK inhibitors
that seems to be a class effect because it is described
with most of them. 25 Treatment with tofacitinib
showed an increase of the risk in clinical trials 27 that
was confirmed with real-world data. 28 Most of the
cases were localised infections, no visceral disease
or deaths were reported and the concomitant use of
steroids or methotrexate considerably influenced the
risk. 29 Patients receiving tofacitinib as monotherapy
had a significant reduced risk of herpes zoster.
Studies with baricitinib and other JAK inhibitors,
even though less consistent because of reduced years
of exposure, show similar results. There is a live
vaccine to prevent herpes zoster but attenuated live
vaccines are contraindicated in patients receiving
JAK inhibitors. The exact interval that is required
between vaccination and the start of JAK inhibitor
treatment needs to be determined.
To date, the safety profile of JAK inhibitors
seems to be similar to that of bDMARDs, with the
exception of herpes zoster. 25 Apart from tofacitinib
and, to a lesser extent, baricitinib, safety data on
JAK inhibitors are limited and further studies are
needed but it seems that the safety profiles of JAK
inhibitors will be difficult to predict on the basis of
their selectivity.
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