Therapeutics

Current and future status of JAK inhibitors

Donal P McLornan, Janet E Pope, Jason Gotlib, Claire N Harrison

An enhanced understanding of the importance of Janus kinase (JAK) and signal transducer and activator of Lancet 2021; 398: 803–16
transcription (STAT) signalling in multiple disease states has led to an increasing applicability of therapeutic Department of Haematology,
intervention with JAK inhibitors. These agents have revolutionised treatments for a heterogeneous group of disorders, Guy’s and St Thomas’ NHS
Foundation Trust, London, UK
such as myeloproliferative neoplasms, rheumatoid arthritis, inflammatory bowel disease, and multiple immune-driven
(D P McLornan PhD,
dermatological diseases, exemplifying rapid bench-to-bedside translation. In this Therapeutics paper, we summarise Prof C N Harrison DM);
the currently available data concerning the successes and safety of an array of JAK inhibitors and hypothesise on how Department of Rheumatology,
these fields could develop. University of Western Ontario,
London, ON, Canada
(Prof J E Pope MD); Division of
Introduction transduction (figure). Activation and transphosphorylation Hematology, Stanford
Janus kinases (JAKs) are multidomain non-receptor of JAKs induces signal trans­ ducer and activator of University School of Medicine,
tyrosine kinases that have pivotal roles in cellular signal transcription (STAT) recruit­ment, dimerisation, nuclear Stanford Cancer Institute,
Stanford, CA, USA
transduction. The targeting of JAK-associated pathways translocation, and resultant transcriptional responses.2,5 (Prof J Gotlib MD)
through the use of JAK inhibitors has rapidly entered the JAK signalling is tightly regulated at multiple levels, cross
Correspondence to:
clinical arena for a wide array of disease states, including talk with many other intracellular pathways is evident, and Prof Claire Harrison, Department
myeloproliferative neoplasms, rheumatoid arthritis and full elucidation of these complex networks is ongoing. of Haematology, Guy’s and
other immune-mediated arthropathies, numerous inflam­ This evolutionary conserved pathway can be deregulated St Thomas’ NHS Foundation
Trust, London SE1 9RT, UK
matory dermatological disorders, and inflammatory bowel in many disease states, most frequently through acquired
claire.harrison@gstt.nhs.uk
disease, exemplifying rapid bench-to-bedside translation activating mutations or gene amplification.
and modifying many classic treatment algorithms. JAK–STAT signalling has a pivotal role in a pleotropic
Clinicians need to be up to date with this rapidly changing range of systems, including the orchestration and
field, given the unique opportunities afforded by JAK functional capability of immune responses, in particular
inhibitors in the modulation of signalling and pathogenetic T-cell polarisation, control of haematopoiesis and
immune responses in many disease areas. Furthermore,
an understanding is required of the potential safety
concerns and limitations of JAK inhibitors, which had Extracellular
EPO
halted many initially promising clinical trials. In this IL-6
Therapeutics paper, we provide an expert, up-to-date
gp130
Epo receptor IL-6
overview of JAK inhibitors and discuss how this complex receptor
therapeutic field might develop. We highlight the use
of JAK inhibitors in clinical scenarios, including
haematology-oncology, rheumatology, dermatology, and
gastro­enterology, as they are the most established in these
P
scenarios and have revolutionised many traditional PI3K JAK2 JAK2 RAS JAK2
TYK2
P
treatment pathways. Other potential applications in a P P P
P JAK1
disparate group of disorders are being developed and we P RAF P
AKT
await evaluation with interest. P P P
STAT5 dimerisation P STAT3 dimerisation
P P
P MEK P
JAK–STAT signalling in health and disease MTOR
P
P
In humans, the JAK family comprises JAK1, JAK2, JAK3, Nuclear P
ERK
and TYK2.1–4 Irrespective of type, all cytokine receptors are translocation
P
associated with one or more of the JAKs to facilitate signal
P
Nucleus
P Transcriptional
Search strategy and selection criteria activation or inhibition
P
We identified references for this Therapeutics paper by
searching MEDLINE, PubMed, and references from relevant Figure: Simplified overview of JAK–STAT signalling via EPO receptor and IL-6 receptor activation
articles using relevant search terms, such as “Jak inhibitor”, Cytokine receptors do not have intrinsic kinase or phosphatase activity. For ligands such as EPO, the receptor
“myeloproliferative”, and “rheumatoid arthritis”, and subunits are bound as homodimers, whereas, for interleukins and interferons, the receptor subunits are
searching between Jan 1, 1995, and Dec 31, 2020. Only heterodimers. JAK family members are essential to transduce cytokine-mediated signals via the JAK–STAT pathway.
After receptor–ligand binding, STATs dimerise and can translocate to the nucleus to influence transcriptional
articles published in English were included. Abstracts and activation. Prosurvival pathways, such as the PI3K–AKT and RAS–RAF–EFL pathways, can be upregulated.
reports from meetings were included only when we deemed EFL=elongation factor-like GTPase. ERK=extracellular signal-regulated kinase. JAK=Janus kinase. MEK=mitogen-
them of pivotal importance to the readership. activated protein kinase. P=phosphorylation. PI3K=phosphoinositide 3-kinase. RAF=Raf family kinases.
RAS=Ras family GTPases. STAT=signal transducer and activator of transcription.

www.thelancet.com Vol 398 August 28, 2021 803

 Therapeutics
Panel 1: Drug selectivity profiles
Drug (suggested selectivity against Janus kinase [JAK]
family members)
• Ruxolitinib (JAK1 and JAK2 >JAK3 >TYK2)
• Baricitinib (JAK1 and JAK2, and moderate activity against
TYK2)
• Tofacitinib (JAK3 >JAK2 >JAK1)
• Fedratinib (JAK2)
• Momelotinib (JAK1 and JAK2)
• Pacritinib (JAK2 >JAK1 and JAK3)
• Fligotinib (JAK1 >JAK2 >JAK3 and TYK2)
• Upadacitinib (JAK1 >JAK2 and JAK3)
• Itacitinib (JAK1)
• Decernotinib (JAK3)
• Peficitinib (all JAK proteins)
• Deucravacitinib (BMS-986165; TYK2)
• Abrocitinib (JAK1)
• NDI-031301 (TYK2)
• Ritlecitinib (PF-06651600; JAK3)
inflam­mation, adipogenesis, and growth.6–8 The essential
role of JAKs in cytokine signalling is pivotal to under­
standing how many cytokine-dependent inflammatory,
auto­immune, and neoplastic disorders associated with
deregulated activity can be manipulated and targeted
through therapeutic JAK inhibition.
Within haematology, the largest area of clinical expan­
sion for JAK inhibitors has been in the myeloproliferative
neoplasm field. The JAK2 Val617Phe mutation, leading
to constitutive activation, is located in the JH2 domain
and is found in approximately 60% of individuals with
myelofibrosis, 50–60% with essential thrombocythaemia,
and 97–98% with polycythaemia vera.9–12 Furthermore,
irrespective of JAK2 mutational status, many
myeloproliferative neoplasm disorders are characterised
by upregulated JAK–STAT signalling via mutations in
additional canonical genes, such as CALR.13 There has
been rapid clinical development of JAK inhibitors and,
in 2011, ruxolitinib (a JAK1 and JAK2 inhibitor) was the
first JAK inhibitor to be approved for use in myelofibrosis
by the US Food and Drug Administration (FDA) and
European Medicines Agency (EMA).
Deregulated JAK–STAT signalling contributes to
autoimmune and chronic inflammatory phenotypes,
often in a disease-independent way, and JAK-dependent
cytokines (eg, IL-6) are often pivotal pathological drivers,
thus explaining the rationale of JAK inhibitors in these
disorders.14 Both first and later generation JAK in­
hibitors have been explored across a disparate group of
disorders, including atopic dermatitis and alopecia
areata, immune-mediated arthropathies, inflammatory
bowel disease, and interferonopathies, as we will
discuss in this Therapeutics paper. Despite many
overlapping pathogenetic autoimmune mechanisms,
specific drug therapeutic efficacy can vary markedly.
804 www.thelancet.com Vol 398 August 28, 2021
In the oncology field, many solid tumours have
aberrant JAK signalling as part of a prosurvival
phenotype and to facilitate tumour migration.15 In depth
review is outside the remit of this article, but clinically
relevant examples of JAK in oncology include JAK2
locus amplification in gastric adenocarcinoma and
amplification or enhanced nuclear translocation of
STAT5 in prostate cancer, offering the prospect of benefit
of JAK inhibitors.15–18
With regard to targeting JAK family members other
than JAK2, TYK2 is an essential regulator of both the
IL-12 and T-helper (Th)1 and IL-23 and Th17 axes and
the type I interferon pathways.15,19 Thus, specifically
targeting TYK2 could be beneficial across a range of
immune-mediated and neoplastic disorders but,
historically, TYK2 inhibitor development has been
challenging. TYK2 expression and dependency is
prevalent in anaplastic large-cell lymphoma, and TYK2
inhibition induces apoptosis in anaplastic large-cell
lymphoma models.20 The most advanced TYK2 inhibitor
in clinical use is the oral agent, deucravacitinib (Bristol
Myers Squibb, New York, NY, USA), discussed later in
detail.21 Finally, JAK3 activation has additionally been
found in a wide array of B-cell lymphoid malig­nancies,
highlighting several areas for potential future therapeutic
exploitation.22
Overview of JAK inhibitors: current and future
perspectives
Currently licensed JAK inhibitors include tofacitinib
(Pfizer, New York, NY, USA), ruxolitinib (Novartis, Basel,
Switzerland), fedratinib (Celgene, Summit, NJ, USA),
upadacitinib (AbbVie, North Chicago, IL, USA), peficitinib
(Astellas Pharma, Tokyo, Japan), and baricitinib (Eli Lilly,
Indianapolis, IN, USA; panel 1). Clinically relevant
selected agents are highlighted in panel 1 and table and
are discussed in detail in relevant disease areas.
Achievement of JAK isoform specificity is difficult due
to structural homology between family members.
Additionally, even if specificity is attempted, given the
wide and complex roles of JAKs and the interdepend­
ency of many cytokine receptors, resultant effects can be
pleotropic.35 More novel JAK inhibitor compounds are in
advanced development, such as ritlecitinib (previously
known as PF-06651600; Pfizer), which acts as a potent
inhibitor of JAK3 and tyrosine-protein kinase Tec (TEC)
family kinase members (ie, BTK, BMX, ITK, RLK, and
TEC) and can inhibit the functional capacity of both
CD8+ T cells and natural killer cells. The dual action of
ritlecitinib might have an important role in therapeutic
intervention for a plethora of inflammatory diseases.36
There is still much to learn about improving target
specificity in JAK–STAT signalling and how this might
translate into clinical efficacy and the potential mitigation
of observed side-effects. Long-term safety data of many of
these agents are emerging but still require robust
follow-up.
 Therapeutics

Phase Agent Study population Main findings Safety and tolerability

Myelofibrosis
COMFORT-123 3 Ruxolitinib vs 309 patients with intermediate-2 59% of patients given ruxolitinib had ≥35% SVR at any Most common grade 3–4 adverse events
placebo or high-risk myelofibrosis point during the trial and impressive symptom responses; were anaemia and thrombocytopenia
evident survival advantage vs placebo
COMFORT-224 3 Ruxolitinib vs 219 patients with intermediate-2 53·4% in the ruxolitinib group had ≥35% SVR at any point; Most common grade 3–4 adverse events
BAT or high-risk myelofibrosis probability of ongoing spleen response at 5 years was 0·48; were anaemia and thrombocytopenia;
intention-to-treat analysis showed ruxolitinib associated increased risk of non-melanoma skin
with improved overall survival cancer
JUMP25 3b (expanded Ruxolitinib 1144 patients with intermediate-2 56·9% of patients had ≥50% reduction in palpable spleen Most common adverse event was drug
access) or high-risk myelofibrosis, as well length at week 24 and 62·3% at week 48; 44% to 46% and related cytopenia; herpes zoster (3·6%) and
as an analysis of 163 patients with 46% to 52% of patients had objective symptom responses influenza (3·0%) were the most common
intermediate-1 myelofibrosis viral infections
ROBUST26 2 (open label) Ruxolitinib 48 patients with intermediate-1, Treatment success was ≥50% reduction in spleen length or Most common adverse event was drug
intermediate-2, and high-risk ≥50% decrease in myelofibrosis symptoms at 48 weeks, related cytopenia, similar to other studies;
myelofibrosis and 50% of all patients and 57% of patients with one case of progressive multifocal
intermediate-1 risk had treatment success leukoencephalopathy was reported
SIMPLIFY-127 3 Momelotinib 432 patients with intermediate-2 First-line momelotinib was statistically non-inferior to Common side effects included cytopenia
vs ruxolitinib in or high-risk disease or symptomatic ruxolitinib on spleen response rates (p=0·011) but was and treatment emergent peripheral
patients with intermediate-1 myelofibrosis inferior with regard to symptom response; transfusion rates neuropathy
JAK inhibitor- and independence were better in the momelotinib group
naive disease
SIMPLIFY-228 3 Momelotinib 104 patients in the momelotinib In patients who had been given ruxolitinib, momelotinib Common side effects included cytopenia
vs BAT group and 52 in the BAT group was not superior to BAT for SVR and treatment emergent peripheral
(46 given ruxolitinib) neuropathy
PERSIST-129 3 Pacritinib vs 220 patients with intermediate-1 Primary endpoint of SVR of ≥35% was found in 42 (19%) of Common grade 3–4 adverse events were
BAT risk or above in the pacritinib group 220 patients in the pacritinib group vs five (5%) of anaemia (17%), thrombocytopenia (12%),
and 107 in the BAT group 107 patients in the BAT group (p=0·0003) and diarrhoea (5%); serious adverse events
were cardiac failure (2%); 12% of patients
died due to adverse events in the pacritinib
group and 13% of patients in the BAT
group
PERSIST-230 3 Pacritinib vs 311 patients with intermediate-1 Pacritinib (groups combined) was significantly more effective Most common grade 3–4 adverse events
BAT risk or above with a platelet count than BAT for ≥35% SVR rates and had ≥50% reduction were anaemia, thrombocytopenia, and
(two-dose of 100 × 10⁹ cells per L or less (not significant) in total symptom score; pacritinib twice daily gastrointestinal adverse events (diarrhoea
strata vs BAT) led to significant improvements in both endpoints vs BAT; and vomiting)
more patients given pacritinib had reduced red blood cell
transfusion dependence at week 24
JAKARTA31 3 Fedratinib 289 patients with intermediate-2 SVR (≥35%) was reached by 36% of patients given Gastrointestinal symptoms, anaemia,
(two-dose or high-risk disease fedratinib 400 mg and 40% of patients given fedratinib and increased concentrations of liver
strata vs 500 mg vs 1% in the placebo group (p<0·001); there was a aminotransferase; encephalopathy was
placebo) 50% reduction in total symptom score at week 24, 36% in reported in four women receiving
the fedratinib 400 mg group, 34% for the fedratinib fedratinib 500 mg; Wernicke’s
500 mg group, and 7% in the placebo group (p<0·001) encephalopathy was diagnosed in
three patients and suspected in one patient
in the treatment cohort
JAKARTA232 2 Fedratinib 97 patients with intermediate-1 31% of patients had at least ≥35% SVR by the end of the Grade 3–4 adverse events were anaemia
risk or above who were previously sixth cycle; 27% had ≥50% symptom response rate and thrombocytopenia; the trial was
treated with ruxolitinib temporarily halted due to perceived risks of
Wernicke’s encephalopathy
Polycythaemia vera
RESPONSE33 3 Ruxolitinib vs 212 patients requiring phlebotomy Primary endpoint of patients who reached both Grade 1–2 adverse events were fatigue,
BAT or who were resistant or intolerant haematocrit control (<45% without phlebotomy) and headache, and diarrhoea; herpes zoster
to hydroxycarbamide with SVR >35% at week 32 was reached by 21% of the ruxolitinib infection was more common in the
splenomegaly group vs 0·9% in the BAT group; there were fewer ruxolitinib group than in the placebo
thrombotic events for patients given ruxolitinib group; increased risk of non-melanoma
skin cancer
RESPONSE-234 3b Ruxolitinib vs 149 patients requiring phlebotomy 62% of patients in the ruxolitinib group vs 19% in the BAT Grade 3–4 adverse events were
BAT or were resistant or intolerant to group had the primary endpoint of haematocrit control hypertension and angina; two patients died
hydroxycarbamide (<45% without phlebotomy) at week 32 in the BAT group
BAT=best alternative therapy. JAK=Janus kinase. SVR=splenic volume reduction.

Table: Overview of key clinical trials of JAK inhibitors for myeloproliferative neoplasms

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 Therapeutics
Clinical relevance
Haematological disorders
There have been many trials, both completed and ongoing
or planned, exploring the use of JAK inhibitors in
myeloproliferative neoplasms (table). Availability of these
new oral JAK inhibitors revolutionised the field and
we highlight four JAK inhibitors that have made
the most impact (ruxolitinib, fedratinib, momelotinib, and
pacritinib). Historically, sparse therapeutic options were
available for myelofibrosis, a disorder characterised by an
average life expectancy of 5 years, constitutional symp­
toms, progressive splenomegaly, and variable cytopenias.
Two large phase 3 trials (COMFORT-I and COMFORT-II)
supported the efficacy of ruxolitinib, leading to rapid
drug approval.23,24 In COMFORT-1, 309 patients with
intermediate-2 or high-risk myelofibrosis (according to the
International Prognostic Scoring System criteria) were
randomly assigned to a placebo group or ruxolitinib group.
For the ruxolitinib group, 65 (42%) of 155 had a 35% or
greater splenic volume reduction at 24 weeks after initial
dose, and myelofibrosis symptom responses were
impressive alongside improve­ments in quality of life. The
median duration of spleen response was 168 weeks on
ruxolitinib and there was a significant overall survival
advantage versus placebo (hazard ratio 0·69; p=0·025).
Similar results were seen in COMFORT-II, comparing
ruxolitinib with the best available therapy. Probability of
ongoing spleen response 5 years after first dose was 48%,
highlighting long-term efficacy, and there was a survival
advantage favouring ruxolitinib.37 Rapid introduction into
clinical use has seen many thousands of patients with
myelofibrosis globally benefiting from ruxolitinib. Other
key trials of ruxolitinib in myelofibrosis and their main
findings, including side-effects and adverse events, are
highlighted in the table.
With regard to polycythaemia vera, the phase 3
RESPONSE trial compared ruxolitinib with the best
available therapy in patients with polycythaemia vera who
required phlebotomy or were intolerant or resistant to the
cytoreductive agent, hydroxycarbamide.33 The primary
endpoint of the proportion of patients with haematocrit
control (<45% without phlebotomy) and splenic volume
reduction of 35% or more at week 32 favoured
ruxolitinib (21%) versus best available therapy (0·9%).
The RESPONSE-2 study supported the superiority of
ruxolitinib to the best available therapy in patients with
inadequately controlled polycythaemia vera without
splenomegaly.34 Ruxolitinib gained approval as a second-
line therapy in polycythaemia vera, a potentially important
step in reducing long-term thrombotic complications in
patients.
Fedratinib is a potent JAK2 inhibitor (with anti-FLT3
properties) investigated in myelofibrosis that has shown
superiority to placebo at 400 mg and 500 mg doses in
the phase 3 trial, JAKARTA.31 Updated results from
JAKARTA2, a phase 2 study investigating efficacy of
400 mg of fedratinib in 97 patients with myelofibrosis who
806 www.thelancet.com Vol 398 August 28, 2021
had been given ruxolitinib, showed that 30 (31%) of
97 patients had a 35% or better splenic volume reduction
by the end of the sixth cycle and 26 (27%) of 97 had a
50% or better symptom response rate.32 However, in 2013,
fedratinib was temporarily placed on hold due to concerns
of increased susceptibility to Wernicke’s encephalopathy,
which were subsequently revised. Fedratinib re-entered
the clinical arena after development by Celgene in
two large phase 3 studies (FREEDOM-1 and FREEDOM-2)
for patients with myelofibrosis who have previously been
given ruxolitinib. On Aug 16, 2019, the FDA approved
fedratinib for first-line and second-line therapy for
myelofibrosis.38 However, a black box warning remains for
serious and possibly fatal encephalopathy. Unaddressed
issues for use in patients with myelofibrosis are whether
active thiamine monitoring is required for patients
receiving fedratinib and also how to safely transition from
ruxolitinib to fedratinib (or vice versa). Consideration
needs to be given to tapering dose, monitoring for with­
drawal, and use of steroids or short-term reintroduction
of ruxolitinib or fedratinib.
Anaemia is common in myelofibrosis and is an unmet
clinical need.39 Momelotinib, a potent JAK1 and JAK2
inhibitor (Sierra Oncology, Vancouver, BC, Canada,
previously Gilead Sciences, Foster City, CA, USA) was
evaluated in two phase 3 trials for myelofibrosis
(SIMPLIFY-1 and SIMPLIFY-2) with heterogeneous
results with regard to splenic volume reduction and
symptom responses.27,28 These studies had several key
anaemia endpoints, including transfusion rates, which
mostly favoured momelotinib in both the first-line and
second-line setting. The particular benefit of momelotinib
is that it can improve anaemia alongside reductions
in symptoms and splenomegaly. Mechanistically,
momelotinib inhibits both JAK–STAT and the iron
sensing bone morphogenic protein–activin receptor type-1
(BMP–ACTR1) pathways, reducing hepcidin expression
and improving functional iron availability, which
could induce erythroid responses. The development focus
is now on patients with second-line anaemia and
transfusion-dependent myelofibrosis in the international
phase 3 MOMENTUM study (NCT04173494).
Pacritinib is an oral multi-kinase inhibitor with spe­
cificity for JAK2, FLT3, IRAK1, and CSF1R. The focus of
pacritinib development has been for patients with
myelofibrosis and thrombocytopenia. Two large phase 3
trials investigated effi­cacy in myelofibrosis (PERSIST-1
and PERSIST-2).29,30 However, both phase 3 trials were
placed on full clinical hold by the FDA in 2016 due to
concerns about deaths in the group given pacritinib and
initial concerns about excess cardiac or haemorrhagic
events in PERSIST-1. This hold was subsequently removed
in 2017; the dose finding PAC203 phase 2 study (with
patients who were previously given ruxolitinib) showed
greatest efficacy at 200 mg twice daily,40 and the phase 3
trial, PACIFICA, will compare pacritinib with the best
available therapy in patients with myelofibrosis with

platelet counts less than 50 × 10⁹ cells per L (NCT03165734).
Practically, if approved, pacritinib is a very attractive agent
for patients with thrombocytopenic myelofibrosis, in
which many other agents might be avoided altogether, or
if a reduced dose is needed therefore limiting efficacy.
It must be stressed that JAK inhibitors can have
limitations within the myeloproliferative neoplasm
therapeutic arena, including inadequate dose density,
absence of true disease modification, and, ultimately, loss
of response. Many agents are being investigated along­
side ruxolitinib in myelofibrosis, including azacytidine
in advanced phase disease, recombinant interferons,
erythropoiesis maturation agents (eg, luspatercept),
bromodomain inhibitors, and histone deacetylase in­
hibitors, showing the potential of dual therapy, incor­
porating JAK inhibitors, to maximise responses.39
Graft-versus-host disease
Graft-versus-host disease (GVHD) represents one of
the most substantial challenges after allogeneic
haematopoietic stem-cell transplantation. Pathogenetic
mechanisms are multifactorial but reliant, at least partly,
on proinflammatory JAK–STAT signalling, not only in
alloreactive effector T cells but also in dendritic cells and
B cells.41 First-line therapy, often systemic steroids, is
effective only in inducing complete responses in a
small proportion of cases and subse­quent strategies are
heterogeneous. Historically, steroid-refractory acute
GVHD carries high mortality rates and is still an unmet
clinical need. Regarding JAK inhibitors, Spoerl and
colleagues42 showed in preclinical models that ruxolitinib
reduced effector T-cell pro­ liferation, suppressed pro­
inflammatory cytokines and CD4+ cell differentiation
into IFN-γ and IL17A-producing cells, and increased the
number of FoxP3-positive regulatory T cells. After initial
clinical proof of concept, a large retrospective multi­
national study evaluated the efficacy of ruxolitinib in
95 patients with steroid-refractory GVHD who had been
frequently heavily pretreated.43 Excellent overall response
rates, not pre­viously observed, were shown in 44 (82%)
of 54 patients with steroid-refractory acute GVHD
(including 25 [46%] of 54 complete responses) and
35 (85%) of 41 patients with chronic GVHD. The
6-month overall survival rates were 79% for patients with
acute GVHD and 97·4% for patients with chronic
GVHD. Cytopenias and cytomegalovirus reactivations
were noted in some patients. The FDA granted approval
for the use of ruxolitinib in steroid-refractory acute
GVHD in patients who are 12 years and older, and, more
recently, both the REACH-2 and REACH-3 phase 3 trials
have shown efficacy (evaluating ruxolitinib in steroid-
refractory acute GVHD and chronic GVHD).44–46
Rheumatological disorders
Rheumatoid arthritis
Contemporary treatment of rheumatoid arthritis has
evolved rapidly, with many clinicians considering JAK
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Therapeutics
inhibitors for rheumatoid arthritis that is refractory to
conventional synthetic disease modifying anti-rheumatic
drugs (DMARDs) or biologics. As clinical knowledge
accumulates, with the focus on early therapeutic inter­
vention and treat-to-target strategies, it is unknown
whether JAK inhibitors will become front-line treatments,
although side-effects and the paucity of long-term data
should be considered.
Many JAK inhibitors have been used in randomised
trials for rheumatoid arthritis (eg, tofacitinib, baricitinib,
upadacitinib, filgotinib, peficitinib, and decernotinib).47,48
Tofacitinib and baricitinib are approved in multiple
countries, and in 2019, upadacitinib, a JAK1 inhibitor,
was approved for rheu­matoid arthritis in the USA and
peficitinib was approved in Japan.49 Overall, there are
benefits of JAK inhibitors that might be considered a
class effect (eg, rapid onset of action in rheumatoid
arthritis with clinical benefit) and there are also important
side-effects within the class (eg, cytopenias, particularly
lymphopenia; increased risk of infection, including
reactivation of herpes zoster; hypercholesterolaemia;
and, for some JAK inhibitors, increased thromboembolic
events, which will be discussed later; panel 2).47,48 For
rheumatoid arthritis, an important class effect appears to
be clinical efficacy as monotherapy alongside efficacy
in combination with conventional synthetic DMARD
(reviewed by Westhovens).50 These agents are contra­
indicated in pregnancy and breastfeeding and no
evidence exists for safe use in children.
Clinical trial programmes of rheumatoid arthritis for
JAK inhibitors have followed a similar sequenced trial
design. JAK inhibitors show efficacy in patients with
active rheumatoid arthritis that does not inadequately
respond to methotrexate compared with placebo or
a standard-of-care drug (eg, the biologic DMARD,
adalimumab [a TNF inhibitor]). Often, JAK inhibitors
are combined with background methotrexate or, less
frequently, with other DMARDs. Some trials evaluated
monotherapy (ie, JAK inhibitors with no background
DMARDs), as discussed previously, and additional
studies have been done in patients previously untreated
with methotrexate.47,48 Outcome measures vary but often
consist of standardised responses—eg, the American
College of Rheumatology (ACR) criteria measures
improvement by 20%, 50%, and 70% in cumulative
response scores.51 Frequently, trials report on improve­
ment in the disease activity score (ie, DAS28).52 Both
the ACR criteria and DAS28 are composite scores
studying changes in tender and swollen joint counts,
patient global assessment, and inflammatory markers.
Frequently, the proportion of patients with low disease
activity or who have had remission is also reported. Low
disease activity or remission outcomes are difficult to
reach. Results with JAK inhibitors are similar to other
advanced therapies and, when compared head to
head, they are sometimes numerically and statistically
better than the biologic DMARD, adalimu­mab.47,48 In
 Therapeutics
Panel 2: Potential side-effects and general monitoring for Janus kinase inhibitors in rheumatological diseases*
Cytopenias
• Monitor white blood cell count with differential,
haemoglobin, and platelet count; for tofacitinib, baseline
and periodic measures every 3 months
• Repeat measurements if absolute lymphocyte count is less
than 500 cells per mm³, and, if this count is persistent and
from treatment, look for the cause and consider stopping,
holding, or decreasing Janus kinase (JAK) inhibitor use
• Interrupt treatment if absolute neutrophil count is
500–1000 cells per mm³, or repeat or reduce dose, and if
persistently less than 500 cells per mm³ consider stopping
medication (if because of JAK inhibitor treatment)
• If haemoglobin concentration is less than 8 g/L, or if there
is a decrease of 2 g/L or more, interrupt treatment and
look for the cause
• Thrombocytosis can occur rarely, should be monitored
and, in general, it is not thought to be associated with
thromboembolic risk in patients taking baricitinib;
consideration of haematology review and alternative
causes might be required if thrombocytosis substantial
and persistent
Transaminitis
• Baseline and periodic liver enzyme monitoring, such as for
alanine aminotransferase concentration
• Investigate or repeat monitoring if a patient’s liver
enzyme concentrations are three to five times the upper
limit of healthy range
• For patients given tofacitinib, monitoring every 3 months is
required
Hyperlipidaemia
• Assess cholesterol profile after drug continuation (eg, 2 or
3 months after first dose) and, depending on the results,
treat or follow up according to the relevant lipid guidelines
Increased risk of infection
Prevention
• If appropriate, vaccinate for herpes zoster virus (eg, if the
patient is older than 50 years) to prevent reactivation;
all vaccinations should be updated (preferably before
starting treatment, but, in our opinion, JAK inhibitor use
could be paused after a risk assessment for a short period of
time, such as 2 weeks, if giving a live vaccine)
• Administer influenza vaccine and pneumococcal vaccine
according to country guidelines
• Test for tuberculosis with country standard; if latent, treat
Mycobacterium tuberculosis infection; and, if positive, consider
tuberculosis treatment concomitantly with JAK inhibitors as
per country guidelines for tuberculosis treatment
Active viraemia
• Do not administer JAK inhibitors in patients with active
hepatitis B or HIV infection
• If patient has active hepatitis C viral replication refer them
for curative therapy
808 www.thelancet.com Vol 398 August 28, 2021
Renal impairment and serious liver disease
• Read product monograph for possible dose adjustments or
relative contraindications
• Some JAK inhibitors need dose reduction in patients with
moderate renal impairment (eg, baricitinib)
• Safety in patients with severe renal impairment or
end-stage renal disease is unknown and JAK inhibitor use is
not recommended in patients with rheumatic disease in
these situations
Thromboembolism
Venous thromboembolic disease
• JAK inhibitors that are not used for haematology-oncology
have a warning for venous thromboembolic disease risk;
a higher rate of venous thromboembolism was found in a
long-term study of tofacitinib in patients with rheumatoid
arthritis who were older than 50 years, with at least
one cardiovascular disease risk factor and taking tofacitinib
10 mg twice daily
• For tofacitinib, the recommended dose in most countries is
5 mg twice a day or 11 mg (for prolonged release) once a day
• A greater frequency of venous thromboembolism was
shown with baricitinib 4 mg daily than with placebo or 2 mg
daily, and only in the randomised controlled trials and not in
the long-term extension studies
• Other JAK inhibitors have not shown an increased risk of
venous thromboembolic disease, but this risk might be a
class effect
• Increased cardiovascular events do not yet appear to be a
risk of JAK inhibitors
Malignancy
• In general, we do not recommend use of JAK inhibitors for
rheumatic diseases during chemotherapy or active non-skin
malignancy
• Surveillance is required for patients with non-melanoma
skin cancers
• For other diseases refer to product monograph
Drug interactions
• Some JAK inhibitors used in rheumatology have drug
interactions; usually, with drugs that are not commonly used
• Ketoconazole increases tofacitinib maximal plasma
concentrations through inhibition of cytochrome P450 3A4
and cytochrome P450 2C19
• Other interactions with tofacitinib include fluconazole
• Rifampin might increase tofacitinib metabolism
• Baricitinib does not appear to have clinically relevant drug
interactions
• Use of JAK inhibitors with other potent immunosuppressives
is not recommended due to immunosuppression
(immunosuppressants such as tacrolimus and ciclosporin,
and biologics used in the rheumatology field)
*For each JAK inhibitor used, we suggest clinician review of monitoring recommendations.

rheumatoid arthritis treatment, additional evaluation is
needed to address topics such as: the optimal sequencing
of advanced therapies after non-responsiveness to
methotrexate; whether there is a benefit in switching to
alternative JAK inhibitors after a patient has not
responded or is intolerant; and how to prevent
attenuated efficacy of JAK inhibitors. Regarding efficacy
and adverse events, dose response rates of each JAK
inhibitor are being clarified and long-term data are
being accumulated. For example, the DARWIN 1 (using
filgotinib in combination with methotrexate) and
DARWIN 2 (using filgotinib monotherapy) trials
showed that patients who were given filgotinib had
dose-dependent responses accompanied by dose-
dependent leukopenia and thrombocytopenia and early
increases in high-density and low-density lipoproteins
that then stabilised.53,54 DARWIN 1 and DARWIN 2 also
reported increases in haemoglobin concentrations in
patients given filgotinib. For upadacitinib, results of
two trials (BALANCE-1 and BALANCE-2) showed dose-
dependent clinical responses and higher rates of adverse
events at higher doses.55,56
The advantages of JAK inhibitors in rheumatoid
arthritis include oral delivery (other options are
subcutaneous or intravenous), an equal or superior
benefit compared with TNF inhibitors, and the
possibility of better retention than TNF inhibitors,
which are subject to drug induced antibodies that
attenuate benefit. Better durability with JAK inhibitors
in rheumatoid arthritis in patients who inade­quately
respond to biologic DMARDs when switching therapies
is of key clinical relevance; TNF inhibitors showed
shortest treatment duration and JAK inhibitors, both as
monotherapy or combination, had the longest treatment
persistence.57 For example, results from the ORAL
Sequel long-term extension study, which evaluated open
label tofacitinib 5 mg and 10 mg twice daily (for up to
9·5 years) in patients with rheumatoid arthritis who had
been enrolled in phase 1, phase 2, or phase 3 index
studies, showed a consistent safety profile and sustained
efficacy.58 Cumulatively, 52% of patients discontinued
tofacitinib, of whom, 24% discontinued due to adverse
events and 4% due to tofacitinib having little of efficacy.
Another area of interest is withdrawing methotrexate
for patients with rheumatoid arthritis who are inad­
equate responders. Two randomised controlled trials
have been done with tofacitinib; switching to tofactinib
from methotrexate is in fact not as efficacious as actually
adding tofacitinib to methotrexate.59,60 The other strategy
of adding tofacitinib to methotrexate and only randomly
assigning patients with a very low disease state to stop or
continue methotrexate showed that the two strategies
were equal.59,60 Additionally, it is important to note that
not all JAK inhibitors for rheumatoid arthritis continue
development after late phase trials—eg, decernotinib
(Vertex Pharmaceuticals, Boston, MA, USA), a selective
JAK3 inhibitor, was investigated both as monotherapy
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Therapeutics
and alongside methotrexate, and despite early signs of
efficacy, there were negative safety signals (eg, infections)
and increased aminotransferase con­centrations in some
patients, and development was discontinued.61,62
Spondyloarthropathies
Regarding spondyloarthritis (considering both psoriatic
arthritis and ankylosing spondylitis), JAK inhibitors
might address multiple disease manifestations.
Tofacitinib has received approval for 5 mg orally twice a
day for the treatment of psoriatic arthritis in many
countries (reviewed in Virtanen and colleagues47). Data
have shown the positive benefits of TNF inhibitor
exposure with respect to improvement in composite
scores (ie, ACR criteria responses) and skin improve­
ment. Efficacy was shown in patients who were previously
given conventional synthetic DMARD treatment (in
whom the majority were given methotrexate as back­
ground treatment). Results showed an improvement in
composite scores, compared with patients given the
placebo, and were numerically very similar (ie, not non-
inferior) to patients given adalimumab (the usual
standard of care).47 With respect to joint involvement,
there was no obvious advantage in exceeding the 5 mg
orally twice a day dose. The EQUATOR trial investigated
the efficacy of filgotinib, a more JAK1 specific inhibitor
than other JAK inhibitors, versus placebo in moderate-to-
severe psoriatic arthritis after intolerance or inadequate
response to at least one conventional synthetic DMARD,
with clinically relevant responses at 16 weeks after first
dose favouring filgotinib (80% vs 33%).63 Upadacitinib is
being investigated for psoriatic arthritis in the phase 3
SELECT-PsA 1 and SELECT-PsA 2 trials.64,65 For
SELECT-PsA 1, 1702 patients with psoriatic arthritis who
did not respond, or were intolerant, to at least one
non-biologic DMARD were randomly assigned to 15 mg
or 30 mg upadacitinib daily, placebo, or adalimumab (the
active comparator). ACR criteria improvement by 20%
(ACR20) response rates at 12 weeks were 79% for
updacitinib 30 mg, 71% for updacitinib 15 mg, 65% for
adalimumab, and 36% for placebo.64 Moreover, a
substantial proportion of patients given upadacitinib
had improvements in enthesitis and dactylitis. The
SELECT-PsA 2 trial also showed that updacitinib had
better efficacy than the placebo.65 Regarding ankylosing
spondylitis, the TORTUGA trial showed efficacy of
filgotinib versus placebo (with an early efficacy and
predictable safety and tolerability), and the SELECT-AXIS 1
trial supported efficacy of upadacitinib versus placebo in
patients with biologic-naive ankylosing spondylitis.66,67
Determination of long-term efficacy and safety will be
important.
Systemic lupus erythematosus
The heterogeneous pathogenesis and clinical phenotype
of systemic lupus erythematosus is often therapeutically
challenging, necessitating novel approaches. Tofacitinib
 Therapeutics
has been investigated in a phase 1b trial for mild-to-
moderate lupus based on STAT4 risk alleles, in which the
presence of rs7574865A→T in individuals with lupus is
associated with enhanced T-cell responses to IL-12 and
IFN-γ. These enhanced T-cell responses make JAK
inhibitors an attractive therapeutic option.68 In a double
blind, phase 2 study, baricitinib 2 mg or 4 mg was
evaluated against placebo in a 1:1:1 design of 314 adult
patients with systemic lupus erythematosus and active
skin or joint disease.69 The primary endpoint was assessed
by improvements in the Systemic Lupus Erythematosus
Disease Activity Index-2000. A once daily baricitinib 4 mg
dose improved symp­toms and signs of systemic lupus
erythematosus in patients with poorly controlled disease
(74 [67%] of 104 responded at 24 weeks vs 53% in the
placebo group for skin or arthritis), whereas there was no
statistically significant improve­ment in the 2 mg dose.
Serious adverse events were seen in 9·6% of patients in
the baricitinib 4 mg group versus 4·8% in the placebo
group. As raised by Yuan and colleagues70 in response to
the study, the 4 mg dosing strategy of baricitinib was not
approved by the FDA for rheumatoid arthritis due to
safety concerns of potential infectious and thrombotic
complications, hence additional follow-up and more
knowledge are required for this dosing regimen.
Two dosing strata are being explored in the phase 3 trial,
BRAVE II, with an ongoing long-term follow-up study
from the earlier trials (SLE-BRAVE-X; NCT03843125).
Dermatological disorders
A large volume of evidence highlights the efficacy of
JAK inhibitors in multiple skin disorders. Early focus
was predominantly addressing psoriasis management,
but focus now extends to many other disease states,
including alopecia areata, vitiligo, and atopic dermatitis,
and includes systemic and topical use.
Regarding moderate-to-severe psoriasis, Papp and
colleagues71 initially evaluated the role of tofacitinib in
two large phase 3 trials (OPT Pivotal 1 [n=901] and OPT
Pivotal 2 [n=960]) showing efficacy of tofacitinib (5 mg or
10 mg twice daily) over placebo. In the OPT Pivotal 2
phase 3 trial, the 10 mg twice daily tofacitinib regimen
was found to be non-inferior to etanercept with similar
serious adverse event rates during 12 weeks of treatment,
and no new safety signals emerged.72 Despite these
findings, the FDA declined approval for use of tofacitinib
in psoriasis in 2015 on the basis of the extent of the
safety data and clinical findings, and hence additional
development for this indication was halted.
Deucravacitinib (Bristol Myers Squibb) was evaluated
in an initial phase 2 trial in patients with moderate-to-
severe plaque psoriasis.21 Doses of 3 mg daily and higher
resulted in greater clearing of psoriasis than did placebo
during 12 weeks, with a favourable risk–benefit ratio.
For example, week 12 Psoriasis Activity Severity Index
scores between 67% and 75% were observed with doses
greater than 6 mg daily, similar to those seen with
810 www.thelancet.com Vol 398 August 28, 2021
adalimumab and with the benefit of oral administration.
Moreover, therapy did not appear to induce substantial
haematological or liver enzyme abnormalities or raised
lipid concentrations. The most common adverse events
were nasopharyngitis, gastro­ intestinal upset, and
headaches. The phase 2 efficacy of deucravacitinib led
to subsequent evaluation in two large phase 3 trials,
POETYK-PSO-1 and POETYK-PSO-2 (NCT03611751), in
which deucravacitinib was compared with placebo and
apremilast (a selective PDE4 inhibitor). For POETYK-
PSO-1, results have shown that both primary endpoints
were met versus placebo by week 16 (Psoriasis Activity
Severity Index 75% and a static Physician’s Global
Assessment score of clear or almost clear), in addition
to the secondary endpoint of superiority to apremilast.21,73
Safety data were similar to previous trials. Full results
from POETYK PSO-2 are expected in late 2021.
In alopecia areata, in which hair follicle destruction
is driven by CD8+ and NKG2+ T cells, multiple JAK
inhibitors have shown promising efficacy.74,75 Tofacitinib
5 mg twice daily for 3 months showed efficacy in a single
group trial in patients with severe disease, but responses
did not have durability after discontinuation.76 An open
label study of oral ruxolitinib, 20 mg twice daily for
3–6 months, showed that nine of 12 patients with alopecia
areata had robust responses, with average hair growth of
90% by end of treatment.77 BRAVE-AA1 (NCT03570749)
was an adaptive phase 2/3 trial investigating baricitinib
1 mg, 2 mg, or 4 mg daily in patients with severe or very
severe alopecia areata. Breakthrough therapy status was
granted for baricitinib in patients with alopecia areata in
March, 2020.78 Reports from the phase 2 component of
BRAVE-AA1 showed efficacy for both the 2 mg and 4 mg
doses compared with placebo, leading to clinically
significant improvements and no new safety concerns or
serious adverse events.78 The phase 3 BRAVE-AA1 and
BRAVE-AA2 (NCT03899259) will additionally evaluate
the efficacy and safety of the 2 mg and 4 mg doses.
Ritlecitinib (Pfizer) also had breakthrough therapy
designation; data from the phase 2 trial in alopecia areata
showed that patients given ritlecitinib significantly
improved compared with those taking placebo as early as
6 weeks into treatment and met its primary endpoint in
improving hair growth by week 24, as did brepocitinib.79
Additionally, CTP-543 (a JAK1 and JAK2 inhibitor,
Concert Pharmaceuticals, Lexington, MA, USA) is being
explored in a phase 3 alopecia areata trial—THRIVE-AA1
(NCT04518995). Top-line data for THRIVE-AA1 is
expected to be reported in 2022.
A major focus has been exploring applicability of
JAK inhibitors for atopic dermatitis. Abrocitinib
(PF-04965842; Pfizer), which gained FDA breakthrough
therapy desig­ nation for moderate-to-severe atopic
dermatitis in 2018, has shown positive results compared
with placebo.80 In the JADE mono-1 trial,80 387 patients
were randomly assigned to abrocitinib (200 mg or 100 mg
daily) or placebo for 12 weeks. Coprimary endpoints

assessed the proportion of patients who had an
Investigator Global Assessment response score of 0
(clear) or 1 (almost clear) with a two-grade or better
improvement from baseline, and proportion achieving
75% or better improvement in Eczema Area and Severity
Index score (EASI-75). 62 (40%) of 156 patients in the
abrocitinib 100 mg dosing strata and 96 (63%) of 153 in
the 200 mg dosing strata had an EASI-75 response
compared with nine (12%) of 76 in the placebo group
(p<0·0001). Abrocitinib was well tolerated with no
treatment related deaths. In the JADE mono-2 trial, both
dosing strata of abrocitinib showed efficacy in patients
with atopic dermatitis and, in general, both doses were
well tolerated.81 The balance of efficacy or safety against
the current standard of care (dupilumab) requires
additional evaluation considering the slight drop in
platelet count seen in some patients and consideration
given to the risk of infection. Both baricitinib and
upadacitinib have been investigated for use in atopic
dermatitis, with the EMA granting an extension of
indication for baracitinib for moderate-to-severe atopic
dermatitis in September, 2020.82,83 Topical ruxolitinib has
also showed efficacy.84
Given the dependency of vitiligo progression on IFN-γ
signalling, JAK inhibitors have also been investigated in
this setting. Results from a multicentre, double blind,
phase 2 study comparing topical ruxolitinib with a control,
showed good tolerability of ruxolitinib topical cream,
which was associated with substantial repigmentation of
vitiligo lesions, suggesting another area in which these
agents could be used.85
Inflammatory bowel disease
Disease-associated proinflammatory cytokines signal,
either directly or indirectly, through the JAK–STAT
pathway hence providing rationale for exploring JAK
inhibitors in the inflammatory bowel disease setting. In
ulcerative colitis, a breakdown of mucosal integrity exists
with luminal microflora stimulating an uninhibited
proinflammatory response. Innate lymphoid cells, Th9,
and IL-13-producing natural killer cells all contribute
to epithelial damage and chronic inflam­ mation.86 In
Crohn’s disease, the pathogenesis is also multifactorial,
with polarised Th1 responses under the control of IL-12,
signalling via JAK2-TYK2, and IL-27, signalling via
JAK1, JAK2, and TYK2, among others.87 Genome wide
association studies have shown a significant association
between Crohn’s disease and the IL23R gene, high­
lighting the proinflammatory role of IL-23 and the Th17
cell pathway.88
Despite the recognised efficacy of biological agents
such as the TNF inhibitors, anti-integrins, and anti-IL-12
and IL-23 monoclonal antibodies, approximately more
than 50% of patients with moderate-to-severe ulcerative
colitis do not have sustained remissions.89,90 Efficacy of
oral tofacitinib in ulcerative colitis was reported after
three large, placebo-controlled phase 3 trials—two trials
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Therapeutics
that investigated tofacitinib as induction therapy
(OCTAVE Induction-1 and OCTAVE Induction-2) in
patients who had non-successful responses to
conventional or anti-TNF agents and one trial as
maintenance (Octave Sustain).91 Remission was defined
by the Mayo score 2 or less and physician global
assessment. For both induction studies, tofacitinib had
significantly better 8-week remission rates (18·5% in the
tofacitinib group vs 8·2% in the placebo group in
OCTAVE Induction-1, and 16·6% in the tofacitinib
group vs 3·6% in the placebo group in OCTAVE
Induction-2) and remission rates were improved in both
tofacitinib dosing groups of OCTAVE Sustain, as were
glucocorticoid-free 52-week remission rates. Responses
to tofacitinib often happened quickly and, when com­
pared with placebo, there were increases in LDL and
HDL concentration, which plateaued after 4 weeks, and
increased infectious complications, including herpes
zoster reactivation. Toxicity with tofacitinib in inflam­
matory bowel disease appears to be dose dependent.
Tofacitinib was associated with more cases, albeit a small
number, of non-melanoma skin cancers than the
placebo. An open extension study, OCTAVE Open
(NCT01470612), will provide important long-term efficacy
and safety data. Tofacitinib appears to be a highly active
agent in ulcerative colitis and is currently being
positioned in the treatment pathway after FDA approval.
Guidelines from the American College of Gastro­
enterology placed tofacitinib either as first-line therapy
for moderate-to-severely active ulcerative colitis or as
second-line therapy after TNF inhibitors.92 Outside of
clinical trials, Weisshoff and colleagues93 reported real-
world data of tofacitinib in 58 patients with moderate-to-
severe inflammatory bowel disease and resistance to
TNF inhibitors; they described meaningful clinical
responses in 40 (69%) of 58 patients at 8 weeks
and steroid-free clinical remission in 7 (27%) of 26 at
12 months after starting treatment.93 However, the FDA
and EMA have placed warnings concerning tofacitinib
10 mg twice daily in patients with ulcerative colitis due to
the risk of thromboembolic events, as discussed later.
For Crohn’s disease, two phase 2b studies investigated
tofacitinib induction and maintenance in moderate-to-
severe Crohn’s disease, yet in contrast to ulcerative
colitis, although minor treatment effects were noted,
efficacy endpoints were not significantly different
from placebo.94 This result might reflect the dif­
ferential immune-mediated pathogenesis compared
with ulcerative colitis, JAK inhibitors specificity in
Crohn’s disease, or trial design and patient inclusion;
therefore, JAK inhibitors therapy in Crohn’s disease
require additional exploration.
Regarding other JAK inhibitors, the FITZROY study
investigated filgotinib in moderate-to-severe Crohn’s
disease and showed better clinical efficacy than the placebo
and acceptable safety in patients who had TNF inhibitor-
treated and treatment-naive disease.95 Upadacitinib has
 Therapeutics
been investigated in phase 2 trials for both moderate-to-
severe ulcerative colitis and Crohn’s disease. For moderate-
to-severe ulcerative colitis, the phase 2b trial showed better
remission induction efficacy than the placebo at 8 weeks.96
For moderate-to-severe Crohn’s disease (CELEST trial),
upadacitinib was superior to the placebo in inducing
endoscopic improvements in patients, most of whom
were refractory to biologics.97 Upadacitinib efficacy is now
being assessed in the phase 3 trial setting—eg, an
ulcerative colitis trial, named U-Accomplish, comparing
upadacitinib to placebo as assessed by the adapted
Mayo score; and a Crohn’s disease trial delineating the
efficacy and safety in patients with moderate-to-severe
disease who are non-responsive or intolerant to biologic
therapies.98 Additional JAK inhibitors undergoing
assessment in the setting of inflammatory bowel disease
include peficitinib, ritlecitinib, brepocitinib, and TD-1473,
a novel pan-JAK inhibitor that has marked gastro­
intestinal specificity.99,100 Efficacy and longer-term data are
awaited, particularly as some cytokines that promote
bowel mucosal integrity also rely on JAKs for signalling,
and the exact use of these JAK inhibitors in the therapeutic
setting requires clarification.
Overview of safety concerns
We have discussed specific side-effects of JAK inhibitors
and have highlighted them in the table (with a
haematology focus) and panel 2 (rheumatology focus).
Frequently, side-effects of JAK inhibitors are mild-to-
moderate, predictable, and easy to manage, yet dose
modifications might be mandatory in some patients and
patients need close monitoring. Moreover, clinicians
should be vigilant for serious and sometimes life-
threatening complications. Complications include
rebound phenomena, which is rare and can cause a
severe cytokine storm and systemic inflam­ matory
response in patients, in particular in patients given
ruxolitinib.101 On-target effects of agents such as
ruxolitinib include expected cytopenias (predominantly
JAK2 related) and, due to immunosuppressive proper­
ties, JAK inhibitors have a heterogeneous risk of
infectious complications.7,23,24,31,58,102 Depending on the
agent, these infectious complications can include upper
respiratory and urinary tract infections and, in general,
herpes zoster reactivation, which could be considered
a class effect. Atypical infections, such as Mycobacterium
tuberculosis reactivation and John Cunningham virus-
mediated neurological disease, have been described with
ruxolitinib (reviewed by McLornan and colleagues).7
Monitoring of renal and liver function is needed and
hyperlipidaemia could be considered a potential class
effect of JAK inhibitors, with marked phenotypic
variability, requiring lipid monitoring. As discussed,
fedratinib has a black box warning for encephalopathy
risk, after earlier cases of Wernicke’s encephalopathy,
and momelotinib is associated with low level (usually
≤2 grade) sensory neuropathy.27,28,31,32,38
812 www.thelancet.com Vol 398 August 28, 2021
As discussed, the FDA approved the baracitinib 2 mg
dose but not the 4 mg dose due to thromboembolic risk.
For tofacitinib, a boxed warning was added in 2019 by the
FDA for an increased risk of thromboembolism and
death with the 10 mg twice daily dose in patients with
rheumatoid arthritis or ulcerative colitis, which was
added after increases in these events in individuals
older than 50 years who had at least one cardiovascular
risk factor. Direct thrombotic risk comparison between
specific JAK inhibitors has been attempted but results
are controversial.103 Although rare, gastrointestinal
perfora­tion has been described for a few patients with
rheu­matoid arthritis (some of whom had other risk
factors) given either tofacitinib or baracitinib.104
Future developments and combinatorial
approaches
It is clear that JAK inhibitors have revolutionised our
therapeutic armamentarium across a pleiotropic range of
immune-mediated and inflammatory disorders, and
across clonal myeloid disorders, such as myeloproliferative
neoplasm. As a class of agents, many patients are likely to
benefit from JAK inhibitors in the coming years; however,
increased clinical experience is required to establish the
risk–benefit ratio for each agent in specific clinical
indications. Vigilance in the clinical community is required
concerning the common and rare side-effects of these
drugs, which include atypical infectious complications,
withdrawal syndrome, poten­ tial cytopenias and liver
dysfunction, disturbed lipid metabolism, and risk of
thrombosis with some agents (depending on underlying
clinical condition), additional understanding of potential
risk of B-cell lymphoma,105 coupled with a need for
enhanced skin surveillance for non-melanoma skin
cancers. Long-term efficacy data and postmarketing
surveillance is required for all current JAK inhibitors.
Increasingly, combinatorial therapies with JAK inhibitors
are being explored, aiming to maximise treatment
responses after recognition that deregulated JAK–STAT
signalling is not the only pathogenetic mechanism in
disorders such as myelo­fibrosis and rheumatoid arthritis.
Drugs can be given simultaneously or sequenced—eg, a
trial of the histone deacetylase inhibitor, pracinostat, and
ruxolitinib in patients with myelofibrosis in which patients
were given 3 months of ruxolitinib and then pracrinostat.
Novel combinatorial approaches in myelofibrosis with JAK
inhibitors include targeting the neuro–haematopoietic axis
and targeted inhibition of nuclear–cytoplasmic transport
(leading to accumulation of p53).106,107 From a practical
stance, the future could bring access to generic JAK
inhibitors within rheumatoid arthritis and myelopro­
liferative neoplasms disease areas and rapidly change the
therapeutic landscape.
As the exciting field of JAK inhibitors progresses,
clinicians need to understand mechanisms of resistance
or loss of response to JAK inhibitors, with particular
relevance to myeloproliferative neoplasm, and how best

these can be attenuated. It is well established that
myeloproliferative neoplasm cells can become persistent
to type I JAK inhibitors (which stabilise the active kinase
conformation) and, in vitro, reversal is possible by use of
a type II inhibitor (which bind to JAK2 in the inactive
conformation), such as CHZ868; although, cell line
research has also shown that the Leu884Pro mutation of
JAK2 can confer resistance to type II inhibitors by
weakening the interaction between inhibitor and
target.108–110 Whether reversal of so-called persistence can
be clinically achieved with other similar agents is an
unknown. There are case reports of disease responsiveness
in myelofibrosis being reset after withdrawal and
introduction of ruxolitinib.111 Finally, concerning resis­
tance, unlike BCR–ABL tyrosine kinase inhibitors, there
have been no reports of acquired point mutations
conferring resistance to clinically used JAK inhibitors.
It is not known whether JAK inhibitors should be
used earlier in the disease process (eg, in myelofibrosis
and rheumatoid arthritis) and whether JAK inhibitors
should be introduced in front-line settings for
conventionally low-risk or less advanced disease in
an attempt to delay disease progression. Any such
interventions need to be investigated in clinical trials to
gain maximum knowledge and an understanding of the
risk–benefit ratio.
The medical community will see these agents being
increasingly used to treat autoinflammatory condi­
tions—eg, JAK inhibitors are being assessed for use in
rare autoinflammatory interferonopathies, such as
STING-associated vasculopathy with onset in infancy
syndrome and chronic atypical neutrophilic dermatoses
with lipodys­ trophy and elevated temperature syn­
drome.112 These interferonopathies possess a prominent
type I IFN gene signature and, typically, do not respond
to IL-1 and TNF blockade. Sanchez and colleagues113
reported on the use of baricitinib in 18 patients
with chronic atypical neutrophilic dermatoses with
lipodystrophy and elevated temperature syndrome,
STING-associated vasculopathy with onset in infancy
syndrome, Aicardi-Goutières syndrome, or undefined
interferonopathy. Baracitinib treatment was associated
with heterogeneous improve­ ments in interferon and
inflammatory biomarker measure­ ments and with
clinical manifestations in some patients. Long-term
safety data are awaited. It is the broad anti-inflammatory
actions of JAK inhibitors that have led to these agents
being evaluated in the management of SARS-CoV-2
with heterogeneous results.113
Ultimately, potential disease-associated immune
signatures might aid clinicians to select which patients
across disease groups who will benefit most from a
particular JAK inhibitor, being of best clinical use in
disease areas such as rheumatoid arthritis and mye­
loproliferative neoplasm, in which there are multiple
licensed products and more on the horizon. Personalised
stratification to appropriate JAK inhibitors therapy will
www.thelancet.com Vol 398 August 28, 2021 813
Therapeutics
surely be an attractive goal across the entire range of
disorders we have discussed.
Contributors
The first draft was written by DPM, JEP, and CNH. JG wrote sections
and made additional edits to the manuscript. All authors did the
literature search, interpreted data and evidence for this review article,
and approved the final manuscript.
Declaration of interests
DPM reports speaker and advisory board fees from JAZZ
pharmaceuticals and Novartis. JEP reports speaker and advisory board
fees from Pfizer, Lily, AbbVie, and Gilead Pharmaceuticals. JG reports
funding for clinical trial conduct, advisory boards, and travel
reimbursement from Incyte; funding for clinical trial conduct, advisory
board funding, and travel reimbursement from Celgene; funding for
clinical trial conduct from CTI Biopharma; and funding for clinical trial
conduct and advisory boards from Gilead. CNH reports speaker and
advisory board fees from Novarti, Gilead, CTI Biopharma, and Celgene;
speaker fees from JANNSEN; advisory board fees from AOP Pharma,
Roche Pharmaceuticals, and Sierra Oncology.
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