Drug Profile

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Tofacitinib for the treatment

of rheumatoid arthritis
Expert Rev. Clin. Immunol. 8(4), 319331 (2012)

Cristiano AF Zerbini*
andAndrea Barranjard
Vannucci Lomonte
Centro Paulista de Investigao Clinica
& Department of Rheumatology,
Hospital Helipolis, So Paulo, Brazil
*Author for correspondence:
Tel.: +55 11 35146022
Fax: +55 11 35146024
criszerb@uol.com.br

Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects approximately 1% of

the worldwide population. It primarily targets the synovial membrane of joints, leading to a
synovial proliferation, joint cartilage lesion and erosions in the adjacent bone tissue. The disease
is usually progressive and if the inflammatory process is not adequately suppressed, joint
deformity takes place, leading to a significant functional disability and work incapacity. Over
the last decade, biological therapy was established as a major step towards disease control in
those patients who experienced failure after treatment with disease-modifying antirheumatic
drugs. Despite the growing number of biological agents with different immunological targets,
a significant number of patients do not receive appropriate disease control, or have the use of
these agents limited because of adverse events. As such, the search for new molecules with a
higher efficacy and better safety profile is ongoing. This article focuses on a new drug, tofacitinib,
which is a synthetic disease-modifying antirheumatic drug for treatment of RA. Preclinical studies
in arthritis and transplantation animal models are reviewed as a background for the possible
use of tofacitinib treatment in humans. Four PhaseII (one A and three B dose-ranging) trials
lasting from 6 to 24 weeks in RA patients showed significant American College of Rheumatology
20 improvements as early as week 2 and sustained at week 24 in two studies. Tofacitinib PhaseIII
studies in RA are included in a clinical program called ORAL Trials. Long-term follow-up from
ongoing studies will contribute to a more accurate tofacitinib efficacy and safety profile. Trials
in other illness such as psoriasis, psoriatic arthritis, renal transplant rejection prevention,
inflammatory bowel diseases and dry eye are underway.
Keywords : JAK inhibition janus kinase inhibition mechanism of action rheumatoid arthritis tofacitinib
treatment

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a common systemic

autoimmune disease characterized by a chronic
and progressive inflammatory polyarthritis [1] .
Affected patients often experience inflammatory
signs of small joints of the hands and feet but
many other joints may be involved such as
temporomandibular joints, wrists, elbows,
shoulders, hips, knees and ankles. Although a
monoarticular involvement may occur initially,
the articular signs of inflammation usually
become symmetrical. Many patients complain
of joint stiffness early in the morning that may
last for more than one hour. The duration of this
sensation is in direct proportion with the degree
of the articular inflammation.
Immune response

Th1 cell activation by a still unknown antigen

is the first event in the beginning of the RA
development process. The inflamed synovium
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10.1586/ECI.12.19

contains a great amount of T cells. These

cells, mostly CD4 + with memory phenotype,
constitute about 50% of the cell population in
the RA synovial membrane. B lymphocytes and
plasma cells comprise only 5% of the synovial
cell population but their activation by CD4 +
Tcells help them to increase the production of
synovial antibodies. The concept of RA as a Th1
disease became weaker after the finding that Th1
cytokines including IFN-g, although detected in
the RA synovial tissue, are in far lower levels
than the inflammatory cytokines TNF-a, IL-6
and IL-1 [2] . After the identification of the Th17
pathway the proinflammatory role of T cells in
RA became better understood. Th17 lineage is
distinct from Th1 and Th2 lineages of T effector
cells [3] . Th17 and its signature cytokine IL-17
may play a central role in the pathogenesis
of R A. IL-6 and TGF-b induce the Th17
differentiation whereas IL-23, a member of the
IL-12 family, promotes its survival, expansion

2012 Expert Reviews Ltd

ISSN 1744-666X

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Zerbini & Lomonte

and pathogenicity[4] . IL-17 acts on many cells found in the

inflamed synovium and also induces a wide variety of effector
molecules. Fibroblasts, monocytes, macrophages, chondrocytes
and osteoclasts are stimulated by IL-17. Proinflammatory
cytokines such as IL-1, IL-6 and TNF-a, prostaglandin E 2 ,
matrix metalloproteinases, and COX-2 have their production
upregulated by IL-17. It also upregulates the receptor activator
for nuclear factor k B ligand (RANKL) production on osteoblasts
and chondrocytes. RANKL promotes the differentiation and
activation of osteoclasts with consequent development of bone
erosions and osteoporosis [5] . IFN-g has inhibitory effects on Th17
cells and this has been linked to a protective effect on joints [6] .
Another lineage of Tcells may play a role in the development
of RA. Treg cells are a population of CD4 + CD25 + T cells that
suppress CD4 and CD8 T-cell responses through cellcell
contact [7] . These cells may be functionally abnormal in the
peripheral blood of patients with active RA [8] . The impairment
of Treg cell function may be induced by TNF-a and reversed by
anti-TNF treatments explaining, at least in part, the efficacy of
this therapy.
Many changes take place in the RA synovial membrane after
the beginning of the inflammatory process. Normal synovial
membrane is composed of one to three cell layers without a
definite underlying basement membrane and a synovial sublining

within the joint capsule. After the initiation of the inflammatory

process (synovitis) hyperplasia of the synovial lining takes place.
This is caused by tissue edema after vessel proliferation and new
vessel formation. Angiogenesis, the generation of new blood
vessels, is one of the early pathologic responses in the synovitis.
Angiogenesis is induced by the transcription factor HIF-1 and
some angiogenic factors produced by synovial cells: HBGF,
macrophage angiogenic factor, VEGF, prostaglandin E1 and E2,
IL-8, CXC chemokines and others [9] . Angiogenesis is critical
for the development of synovitis. The growth of new blood
vessels and the generation of adhesion molecules (i.e., integrins,
E selectin and vascular cell adhesion molecule 1) facilitate the
migration of cells to the synovial membrane. The synovial
lesion starts with the initial transudation of fluid (edema)
after neovascularization followed by a local accumulation of
cells (lymphocytes, macrophages and mast cells). These cells
can produce many cytokines and their autocrine and paracrine
communication results in a proliferative response of the affected
sinovium. The inflammatory process begins to be more organized
and synovial lining hyperplasia becomes more intense, extending
itself to a depth of more than ten cell layers. The synovial cells
(synoviocytes) are divided into two types: macrophage-like cells
(type A) and fibroblast-like cells (typeB). Resident synovial cells,
under the action of multiple cytokines, change phenotype and
may be transformed into very active and
destructive cells. Cadherin-11, a synovial
Vascular bed
integral membrane protein, mediates the
ACPA
IL-2 +
fibroblast-like synoviocyte invasion of
B cell
synovial tissue [10] . These transformed cells
RF
produce very active enzymes, the matrix
metalloproteinases (MMP-1, MMP-3 and
Macrophage
IL-18
+
MMP-13) responsible for the destructive
IL-15
IL-12
GM-CSF +
T cell IL-2 +
process of cartilage. The invading
M-CSF
inflammatory process containing many
TNF-
cytokines and cells is called pannus.
Chemokines
- IL-4 IL-17 +
Of special interest are the interactions
IL-10 IFN-
of cytokines in the R A synovium [11] .
IL-1
+ IL-18
Briefly, TNF-a, IL-1, IL-6, IL-18, VEGF
- IL-10
TNF-
and chemokines cause the recruitment
Prostaglandins
IL-6
of inflammatory cells. IFN-a, IFN-b,
FLS
IL-8 +
Pannus
IL-6
TNF-a and IL-15 facilitate, by different
GM-CSF
OPG RANKL formation
mechanisms, the retention of cells in the
IL-1
M-CSF
MMPs
synovium. IL-23, IL-12, IL-27, IL-15, IL-18
+ M-CSF
+
TNF-
and chemokines organize and activate T
Osteoclast
cells. TNF-a, IL-17 and TGF-b mediate
the proliferative and destructive part of the
inflammatory process (Figure1) .
The knowledge of RA pathogenesis is
critical for the understanding of how old
Bone Cartilage
Expert Rev. Clin. Immunol. Future Science Group (2012)
and new therapeutic interventions can
avoid joint damage and prevent morbidity
Figure1. Cytokine network in the rheumatoid arthritis sinovium.
and even mortality. Disease modifying
ACPA: Anticitrullinated protein antibody; FLS: Fibroblast-like sinoviocyte;
antirheumatic drugs (DMARDs) are the
GM-CSF:Granulocytemacrophage colony-stimulating factor; M-CSF:Macrophage
colony-stimulating factor; MMP: Matrix metalloproteinase; OPG: Osteoprotegerin;
cornerstone in the treatment of RA. These
RANKL: Receptor activator for NF-kB ligand; RF: Rheumatoid factor.
drugs can change the natural history of RA

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Expert Rev. Clin. Immunol. 8(4), (2012)

Tofacitinib for the treatment of rheumatoid arthritis

Drug Profile

Table1. Biologics approved for the treatment of rheumatoid arthritis.

Generic name (trade name)

Properties

Abatacept (Orencia )

Fusion protein of the extracellular domain of human CTLA4 linked to a fragment of the FC segment
of human IgG1 specific for CD80/86

Adalimumab (Humira)

Human mAb specific for TNF

Anakinra (Kineret)

Recombinant human IL-1 receptor antagonist

Certolizumab pegol (Cimzia )

PEGylated humanized antibody F(ab) fragment specific for human TNF

Etanercept (Enbrel )

Fusion protein of extracellular domain of the human p75 TNF-a receptor linked to the FC portion of
human IgG1

Golimumab (Simponi)

Human mAb specific for TNF

Infliximab (Remicade )

Chimeric mAb specific for TNF

Rituximab (Rituxan /MabThera )

Chimeric mAb specific for CD20 antigen

Tocilizumab (RoActemra /Actemra ) Humanized mAb specific for the IL-6 receptor

mAb: Monoclonal antibody.

Data taken from [54].

by reducing the structural joint damage seen in the radiographic

exams and preserving joint integrity and function. Methotrexate
(MTX) is the most used DMARD in clinical practice and
can be prescribed initially as monotherapy or in combination
with other drugs. In the last 10years significant progress has
been made in the treatment of R A after the introduction of
the biological DMARDs in the clinical routine (Table1) . These
new drugs, used alone or in combination with MTX, provide
better and faster results in the resolution of the inflammatory
process. The American College of Rheumatology (ACR) and
the European League Against Rheumatism have published
recommendations for the management of R A including
biological DMARDs. These recommendations can be found
at [101,102] . Some studies showed patients reaching ACR70 and
even remission evaluated by Disease Activity Score in 28 joints
(DAS28) [1215] . Unfortunately, there are RA patients that are
not responsive to the available therapeutic agents and some
patients cannot use them after developing side effects. In the
search for new biological treatments efforts have been made to
find more selective immunosuppressive therapies such as those
targeting the cytokine signaling pathways. One of these targets
is the JAK pathway.
The JAK pathway

JAKs play an important role as gate keepers in the signal

transduction pathway of many cytokines involved in the acquired
and innate immunity [16,17] . This family of tyrosine kinases is
composed of four intracellular nonreceptor enzymes (JAK1,
JAK2, JAK3 and Tyk2) and was named after the Roman god
of gates and doors (Janus). JAK3 is predominantly expressed
at high levels in hematopoietic tissues, being found in myeloid
cells, thymocytes, natural killer (NK) cells, and activated B and
T lymphocytes. It is not expressed in resting T cells [18] . JAK3
binds to only one cytokine receptor, the common g chain or
gc (Figure2) . This chain is shared by many cytokine receptors,
including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 [19] . JAK1 is
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largely expressed (lymphoid cells, nervous system) and binds

to the b-subunit of these cytokine receptors. After the binding
of a cytokine to its membrane receptor, JAK1 and JAK3 come
into close proximity and become bound to the cytoplasmic tail
of the assembled receptor. These enzymes then undergo autotransphosphorylation. This leads to the binding and activation of
the monomeric signal transducers and activators of transcription
(STAT) proteins, which bind to the cognate cytokine receptors
via conserved Src homology 2 domains [20] . Receptor-bound
STATs become phosphorylated at their C-terminus and undergo
dimerization (homo- and hetero-dimerization), which allows
them to be translocated to the nucleus where they bind to gene
promoter regions to regulate the transcription of a wide variety
of targeted genes. This activation of gene transcription is critical
for the lymphocyte development and the immune response.
JAK3 germline inactivating mutations have been described in
the autosomal recessive severe-combined immunodeficiency
disease, an inherited immunodeficiency characterized by a
profound defect in mature T and NK cells [21] . In this disease
patients develop life-threatening infections early in life
and are treated by hematopoietic stem cell transplantation.
Mutations in JAK3 or gc receptors lead to virtually identical
immunodeficiency phenotypes showing that JAK3 requires the
structure of gc to become activated. JAK3-deficient mice have a
similar phenotype displaying absence of lymph nodes, deficiency
in the development of thymic progenitor cells and low number
of circulating T and NK cells [22] . The critical role played
by the JAK family of enzymes in immune cell development
and function makes these molecules an attractive target for
modulation of immune function as a strategy for treating
autoimmune diseases. Some new protein kinase inhibitors are
already in development (Table2) .
With the intention to re-assess the role of more efficient
treatments of RA, a disease still incurable and with a small
chance of remission, this paper provides an overview of recent
information on tofacitinib, a highly potent oral DMARD.
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Zerbini & Lomonte

selectivity within the human kinome (set of

protein kinases in the genome). Tofacitinib
showed nanomolar inhibitory potency
against all JAK family kinases in enzyme
studies and functional specificity for JAK1
Cytokine receptor

and JAK1/3 over JAK2 in cell assays. In

enzyme studies its inhibitory activity,
measured by its concentration providing
50% enzymatic inhibition (IC50), showed
IC50 = 3.2 nM for JAK1, IC50 = 4.1 nM for
JAK2, IC50 = 1.6 nM for JAK3 and IC50
Cellular

JAK3SCID
JAK1
JAK3
= 34.0 nM for Tyk2, with approximately
membrane
1000-fold selectivity for JAK3 compared
with 82 other kinases for which IC50 has
been determined [25] . In a cellular setting,
a series of assays were performed with
P
combinations of JAK enzymes to evaluate
STAT
the potency of tofacitinib. The inhibitory
effect of tofacitinib was much more
potent against JAK1/3-dependent activity
than with other JAKs. In the two assays
mediated by JAK3 and JAK1, the IL-2Nuclear
membrane
dependent T-cell proliferation showed an
IC50 of ~11 nM and the mixed lymphocyte
showed IC50=87nM. A granulocyte
macrophage-colony stimulating factor
Transcription
(GM-CSF)-proliferation assay driven by
JAK2 resulted in an IC50 of ~324nM in a
Hu03 cell based assay, which suggests that
inhibition of JAK2 could only be seen at
higher concentrations invivo. The activity
Figure2. Cytokine signaling through the JAK1/JAK3/STAT pathway.

of tofacitinib has also been determined in

JAK3 and g mutations leading to virtually identical phenotypes of SCID (autosomal
recessive SCID).
human whole blood assays monitoring
X-SCID: X-linked severe-combined immunodeficiency disease.
STAT phosphorylation [26] . Tofacitinib
Reproduced with permission from [55] .
inhibited JAK1/3-dependent signaling of
the gc chain cytokines with an IC50 between
Tofacitinib (CP-690,550)
25 and 60. JAK2-driven STAT phosphorylation stimulated by
Tofacitinib (CP-690,550) or ((3R,4R)-4-methyl-3-(methyl- GM-CSF was inhibited only at higher concentrations (1377
1H-pyrrolo[2,3-d]pyrimidin-4-ylamino) -b-oxo-1-piper- nM). IFN-g protein production from the blood following either
idinepropanenitrile, 2-hydroxy-1,2,3-propanetricarboxylate), IL-2 (JAK1/3) or IL-12 (JAK2/TYK2) stimulation showed only
previously named tasocitinib (Figure3) , is a potent inhibitor of moderate selectivity. These cellular setting data support tofacitinib
the JAK family of tyrosine kinases[23,24] with a high degree of as a potent inhibitor of JAK3- and JAK1-dependent signaling
IL-2, IL-4, IL-7, IL-9, IL-15, IL-21

X-SCID

Table2. Protein kinase inhibitors in clinical development.

Compound

Target(s)

Selected indications (Phase)

INCB-28050

JAK1/2

Rheumatoid arthritis (PhaseII)

Tofacitinib/CP-690550

JAK1/3

Rheumatoid arthritis (PhaseIII), psoriasis (PhaseIII), inflammatory bowel disease (PhaseII)

VX-509

JAK3

Rheumatoid arthritis (PhaseII)

VX-702

p38 MAPK

Rheumatoid arthritis (PhaseII)

BMS-582949

p38 MAPK

Rheumatoid arthritis, atherosclerosis (PhaseII), psoriasis (PhaseIII)

Fostamatinib disodioum/R-788

SYK

Rheumatoid arthritis, B-cell lymphoma, immune thrombocytopenic purpura, peripheral

T-cell lymphoma, solid tumors (PhaseII)

Data taken from [54].

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Expert Rev. Clin. Immunol. 8(4), (2012)

Tofacitinib for the treatment of rheumatoid arthritis

with moderate functional selectivity over JAK2/Tyk2-and

JAK2-driven activation of the pathway.
The stereochemistry of tofacitinib and a model of spatial
binding to JAK3 were elegantly analyzed [27] . The chirality
(property of a molecule that lacks an internal plane of symmetry
and thus does not have a superimposable mirror image) of
tofacitinib defined its ability to bind to JAK3 and block JAK3
dependent STAT5 phosphorylation. This conclusion was
obtained after a combination of molecular modeling, target
profiling and cell-based analysis.
Pharmacokinetics & metabolism

The pharmacokinetics of tofacitinib has been analysed across RA

patients, patients with Crohns disease, patients with ulcerative
colitis, denovo and stable renal transplant patients, renally
impaired subjects, hepatically impaired subjects, patients with
psoriasis and healthy volunteers. Single oral doses ranging from
0.1 to 100mg, two-times a day (b.i.d.) oral doses ranging from
1 to 50mg and once a day (q.d.) oral doses ranging from 20 to
60mg were evaluated in these subjects for a period ranging from
2 weeks to 3years. Tofacitinib is rapidly absorbed and eliminated
with a time to peak concentration (Tmax) of approximately 0.5h
and a half-life of approximately 3h. The protein binding of
tofacitinib is approximately 40%, raising the possibility of a low
drug interaction due to drug displacement.
The clearance of tofacitinib, calculated in healthy volunteers
after intravenous administration is approximately 24.7 l/h.
The clearance of tofacitinib appears to be 70% by hepatic
metabolism and 30% by renal excretion of the unchanged drug.
The metabolism of tofacitinib is mainly mediated by CYP3A4
with a small part mediated by CYP2C19 [28] . Inhibitors or
inducers of CYP3A4 may interact with tofacitinib [29,30] . The
coadministration of tofacitinib and MTX had no effect on
tofacitinib pharmacokinetics. During this coadministration,
small variations observed in the extent of absortion (area
under the plasma concentrationtime curve; AUC) and peak
concentrations (Cmax) of MTX were considered not clinically
significant. Coadministration of tofacitinib with fluconazole,
a moderate inhibitor of CYP3A4 and a strong inhibitor of
CYP2C19, increased the AUC and Cmax of tofacitinib by 79
and 27%, respectively. The coadministration of cyclosporine,
a moderate inhibitor of CYP3A4, increased the AUC of
tofacitinib by 73% and decreased the Cmax by 17%. In patients
with renal impairment the mean AUC (0-) was 137% in mild
renally impaired subjects reaching 143 and 223% for those with
moderate and severe renal impairment, respectively [31] .
Animal models

Tofacitinib showed its efficacy in two arthritis animal models:

murine collagen-induced arthritis and rat adjuvant-induced
arthritis (AIA). Animal arthritis was induced by standard
protocols and tofacitinib was delivered by osmotic pump
infusion at doses 0 (control), 1.5, 5 and 15mg/kg/day [32] .
In the murine model, when efficacy was scored based on the
severity of paw swelling, the effective median dose (ED50) was
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Drug Profile

CN
O

N
N

N
H

Figure3. Tofacitinib.

approximately 1.5mg/kg/day, or an average serum concentration

(Cave) of 6ng/ml. At the end of the study, after animals were
euthanized, inflammation score based on histological findings
showed the ED50 to be equivalent to a dose of 6.5mg/kg or
Cave of 38ng/ml. Histological evaluation also showed a dosedependent reduction in the inflammatory process and cartilage
destruction after tofacitinib treatment. Doses of 5 and 15mg/
kg/day produced an almost entire suppression of clinical scores
and the 15mg/kg/day dose was associated with a significant
reduction in the levels of IL-6. In the AIA model Meyer etal.
evaluated the potency of tofacitinib administered orally on paw
edema (arthritis), plasma cytokines, neutrophil counts and
bone marrow differentials [26] . In this model, an adjuvant of
Mycobacterium butyricum was injected subcutaneously at the
base of the rat tail on day 0. The induced paw arthritis was
fully developed on day 13 post-immunization and peaked
on day 21. Plasma neutrophils and cytokines IL-17 and IL-6
significantly increased with disease progression. Neutrophil
counts and IL-17 peaked on day 14 and declined on day 21 but
IL-6 peaked also on day14 but remained elevated through day
21. In this experiment, tofacitinib or vehicle control was given
orally to rats twice daily from day 14 to day21. Tofacitinib
at 10mg/kg showed good efficacy at reducing paw volume to
normal by day 21. The relation between paw volume response
and tofacitinib exposure represented an ED50 of 0.55mg/kg. In
the same study this ED50 exposure was compared with the invitro
rat whole blood JAK1/2, and JAK1/3 IC50 values showing that
this value of exposure was sufficient to inhibit JAK1 and JAK3
but not JAK2. Disease-elevated neutrophil count decreased to
normal range in AIA rats treated with the 10mg/kg tofacitinib
dose. Levels of IL-17 and IL-6 also decreased dose-dependently
showing approximately 80% inhibition in comparison with
control levels. Tofacitinib at 10mg/kg also inhibited the AIAinduced increase in maturing myeloid cells harvested from rat
femur bone marrow by 50%. Neutrophilia observed in the AIA
rats was mainly related to the inflammatory process but also, at
least in part, to the increase in granulopoiesis. The small dose of
tofacitinib used in this experiment and the doses currently being
administered in PhaseIII clinical trials in RA (5 to 10mg b.i.d.)
are associated with a JAK2 IC50, which is much less significant
than the JAK1/JAK3 IC50 [33] . Taking this into account, the
observed decrease in plasma neutrophils was probably related
to attenuation of the inflammatory process and not due to the
suppression of granulopoiesis associated with inhibition of JAK2.
Neither neutropenia nor myelosuppression were observed in the
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AIA rats. This study demonstrated a good relationship between

pharmacologic parameters of JAK1/JAK3 inhibition and efficacy
of tofacitinib in the treatment of inflammation in the AIA rat
model. Signs of arthritis (paw edema), levels of inflammatory
cytokines and neutrophilia correlate very well with disease
severity and all of them were reduced after tofacitinib treatment.
Ghoreschi etal. analyzed the effects of tofacitinib on adaptive
and innate immune responses in a model of cytokine stimulation
of mouse and human T cells invitro and also the drug effect
on Th differentiation of naive murine CD4 + Tcells [33] . Their
study showed that tofacitinib inhibited IL-4 (cytokine that
signals through JAK3/JAK1) dependent Th2 cell differentiation
and also generation of inflammatory Th17 cells in response to
IL-23, IL-6 and IL-1b. Interestingly, tofacitinib, by suppressing
STAT5, may stimulate the expression of a less pathogenic IL-17
produced when Th17 cells are generated with TGF-b and
IL-6 rather than the more pathogenic cytokine when Th17 is
generated in the absence of TGF-b. This study also suggests that
tofacitinib prevented Th1 differentiation by a mechanism other
than JAK3 inhibition. Tofacitinib inhibited Th1 differentiation
by inhibiting STAT1 activation and suppressing the expression
of the Th1-associated transcription factor T-bet. To examine
the possible effect of tofacitinib in the innate immune response
the authors observed the drug action on the model of acute
response to lipopolysaccharides. This inflammatory response is
highly dependent upon IFN-g and STAT1. After a single dose of
tofacitinib, production of STAT1, TNF and IL-6 were suppressed
confirming the blockade of innate immune response. The data
obtained in this study show that the immunosuppressive effects
of tofacitinib appear to be associated with interference in the
innate and adaptive types of immune responses.
Tofacitinib treatment effects on subsets of circulating
lymphocytes were assessed in rodent and monkey experiments
[34,35] . Based on baseline NK cell numbers, tofacitinib was
administered in a single-day dose to 20 cynomologous
macaques divided into groups of five animals. Each group was
randomized to one of following tofacitinib treatments: vehicle,
10, 50 or 200mg/kg/day. Fluorescence-activated cell sorting
and pharmacokinetics analysis were performed at different times
after the first dose. There were no significant compound-related
reductions on NK cells for up to 2weeks after the single-day
dosing and also no changes in other T or B lymphocytes.
The immunosuppressive effects of tofacitinib were also
evaluated in murine and primate models of transplantation
either alone or in combination with other drugs. Tofacitinib
invivo efficacy was tested in two rodent models: vascularized
and nonvascularized allogeneic cardiac transplantation models
[36,37] . In both models tofacitinib monotherapy was effective in
prolonging cardiac transplants in a concentration-dependent way.
The combination of tofacitinib with cyclosporine or rapamycin
in mouse models of transplantation was also assessed. These
experiments showed improvement of cardiac graft survival during
tofacitinib therapy, either alone or in combination with other
immunosuppressants. Improvement was measured by increase
in transplant mean survival time and also by observation of a
324

lower infiltration of inflammatory cells in the transplanted organ.

Tofacitinib was evaluated as monoterapy or in combination with
mycophenolate mofetil (MMF) in a model of life-sustaining renal
transplantation in cynomologus monkeys [38,39] . Tofacitinib and
MMF were given b.i.d. by oral gavages. All animals were observed
for 90days and then euthanized or euthanized sooner if a renal
allograft failure was observed. Results showed that survival and
terminal histological findings seen in combination therapy or
tofacitinib monotherapy were comparable and both were superior
to placebo or MMF alone.
Clinical studies

Tofacitinib clinical trials are listed at [103] .

Efficacy
PhaseIIa monotherapy study

The proof of concept monotherapy study was a randomized,

double-blind, placebo-controlled, multicenter study designed to
compare three doses of tofacitinib administered orally b.i.d. in
comparison to placebo in the treatment of signs and symptoms of
patients with active RA [40] . This study included 264RA patients
who experienced failure with MTX or a TNF-a inhibitor, who
were randomized to receive tofacitinib 5, 15 or 30mg b.i.d. or
placebo for 6weeks in a 1:1:1:1 ratio. Efficacy was evaluated at
weeks 1, 2, 4, 6 (treatment end) and 8. The ACR20 response
rates at week 6 were 70.5, 81.2, 76.8 and 29.2%, respectively
(with p<0.001 for all treatment groups compared with placebo).
Improvements in disease activity were observed as early as
week 1 of treatment for all tofacitinib groups in comparison to
placebo. Increased ACR50 and ACR70 response rates, relative
to placebo, were seen at all time points, with a statistically
significant difference versus placebo in all tofacitinib groups by
week 4. All components of ACR response criteria improved in
tofacitinib groups by week6 compared with placebo. A difference
in response was seen between the 5mg b.i.d. dosage and the two
higher dosages, but no clear difference was observed between
the 15- and 30-mg b.i.d. dosages in any of the individual ACR
component scores. DAS28 was an exploratory end point in this
study and it was calculated with C-reactive protein (CRP) levels
(DAS28-3[CRP]). Decreases in DAS28-3(CRP) were dosedependent in the tofacitinib groups, and the percentages of
patients with a moderate or good response to treatment according
to the European League Against Rheumatism criteria were
numerically superior in the higher dosages groups in comparison
to the 5mg b.i.d. group.
At week 6, significantly more patients receiving tofacitinib
than placebo experienced a 50% improvement in pain according
to Visual Analogue Scale scores (44, 66, 78 and 14% for 5, 15
and 30mg b.i.d. tofacitinib and placebo groups, respectively).
A statistically significant difference was found between all
tofacitinib groups and placebo at week6 regarding the Health
Assessment Questionnaire Disability Index (HAQ-DI) and the
Short Form36 Health Survey physical component. These data
demonstrated tofacitinib efficacy in improving pain, function and
health status in patients with RA [41] .
Expert Rev. Clin. Immunol. 8(4), (2012)

Tofacitinib for the treatment of rheumatoid arthritis

PhaseIIb dose-ranging combination study

Five hundred and seven RA patients who had an inadequate

response to MTX were randomized to receive tofacitinib 1, 3,
5, 10 or 15mg b.i.d., 20mg q.d. or placebo for 24 weeks, with
background MTX in this double-blind, multicenter study[42] .
After week 12, subjects in the placebo group as well as those in the
1mg b.i.d., 3mg b.i.d. and 20mg q.d. groups could be reassigned
to the 5mg b.i.d. group if a reduction of at least 20% in swollen
and painful/tender joint counts was not achieved. Tofacitinib
doses equal to or greater than 3mg b.i.d. had significantly higher
ACR20 response rates at week 12than placebo group (52.9% for
tofacitinib 3mg b.i.d., 50.7% for 5mg b.i.d., 58.1% for 10mg
b.i.d., 56.0% for 15mg b.i.d., 53.8% for 20mg q.d. and 33.3% for
placebo group, with p0.05 for all tofacitinib groups). ACR20
response rates and secondary end points of the study, including
ACR50, ACR70, and DAS28-3(CRP) remission were sustained
at week 24 for doses 5mg b.i.d. and higher. In conclusion, the
addition of tofacitinib equal to or greater than 5mg b.i.d. to
MTX therapy in this population showed sustained efficacy over
24 weeks, with the highest ACR20 response rates in the 10mg
b.i.d. group and the highest ACR50 and 70 response rates in the
15mg b.i.d. tofacitinib group.

Drug Profile

to be seen in the 5-, 10- and 15-mg groups for ACR20 response
rates and secondary end points of the study, including ACR50,
ACR70 and DAS28-4(erytrocyte sedimentation rate [ESR]). The
highest ACR50 and ACR70 response rates at week 24 were seen
for tofacitinib 10mg b.i.d. and 15mg b.i.d.
PhaseIIb dose-ranging combination study in Japan

The Japanese combination study included one hundred and 40RA

patients with inadequate response to background MTX[44] . The
subjects were randomized to receive tofacitinib 1, 3, 5 and 10mg
b.i.d. or placebo in combination with MTX for 12 weeks. ACR20
response rates at week 12 were 64.3, 77.8, 96.3 and 80.8%,
respectively, compared with 14.3% for placebo (p<0.0001
for all tofacitinib groups). At week 2 all tofacitinib groups had
a significantly greater ACR20 response than placebo. Dosedependent increases in both DAS remission rates and low DAS rates
were observed for treatment groups, regardless of DAS28-3(CRP)
score at baseline. In patients with high disease activity at baseline,
the tofacitinib 10mg b.i.d. group had the greatest percentage of
DAS remission (45.5%, p<0.01) and low DAS at week 12 (72.7%,
p<0.0001). Table3 summarizes PhaseII tofacitinib studies.
PhaseIII monotherapy study

PhaseIIb dose-ranging monotherapy study

In this 24-week double-blind, dose-ranging monotherapy study,

384 RA patients with an inadequate response to a DMARD were
randomized to placebo; tofacitinib 1, 3, 5, 10 or 15mg orally
b.i.d.; or adalimumab 40mg subcutaneously every 2weeks [43] .
Patients randomized to tofacitinib 1 or 3mg or placebo who did
not achieve a reduction of at least 20% from baseline in swollen
and tender/painful joint counts at week 12 were blindly reassigned
to tofacitinib 5mg b.i.d. All patients receiving adalimumab were
reassigned to tofacitinib 5mg b.i.d. at week 12. The primary end
point was the ACR20 response rate at week 12. The safety of
reassignment from adalimumab to tofacitinib was evaluated. As
reported for the combination study, ACR20 response rates were
significantly higher for all tofacitinib doses equal to or greater
than 3mg b.i.d. at week 12 in comparison to placebo: 39.2%
for 3mg (p<0.05), 59.2% for 5mg (p<0.0001), 70.5% for
10mg (p<0.0001) and 71.9% for 15mg (p<0.0001). ACR20
response rates at week 12 were 35.9% for adalimumab (p=0.105
vs placebo) and 22.0% for placebo. At week 24, efficacy continued

This randomized, double-blind, placebo-controlled, 6month

study evaluated two doses of tofacitinib monotherapy in
610patients with active RA who had failed at least one DMARD
therapy [45] . Patients were randomized to one of the following
sequences: tofacitinib 5mg b.i.d.; tofacitinib 10mg b.i.d.; placebo
followed by tofacitinib 5mg b.i.d. after 3months and; placebo
followed by tofacitinib 10mg b.i.d. after 3months. The advance of
placebo to tofacitinib groups after 3months was done in a blinded
fashion. The month 3 ACR20 response rates for tofacitinib 5 and
10mg b.i.d. were 59.8 and 65.7% respectively in comparison to
26.7% for the placebo group (p< 0.0001). As early as week 2,
significant ACR20 response rates versus placebo were seen for
tofacitinib 5 and 10mg b.i.d. (p< 0.0001), as well as significant
ACR50 response rates for tofacitinib 10mg b.i.d. (p<0.05) and
significant ACR70 response rates for tofacitinib 5mg (p<0.05)
and 10mg b.i.d. (p<0.001). By month 6, similar changes from
baseline were observed for those patients who advanced from
placebo to tofacitinib groups in comparison to the respective
dosing groups at month 3.

Table3. PhaseII trials of tofacitinib for rheumatoid arthritis treatment.

Study

ClinicalTrials.gov
identifier

Doses (mg)

Patients (n) Duration of

Ref.
treatment (weeks)

PhaseIIa monotherapy

NCT00147498

5, 15, 30 b.i.d. and placebo

264

PhaseIIb dose-ranging combination

NCT00413660

[40]

1, 3, 5, 10, 15 b.i.d., 20 q.d. and 507

placebo

24

[42]

PhaseIIb dose-ranging monotherapy NCT00550446

1, 3, 5, 10, 15 b.i.d., adalimumab 384

40.q2wk, and placebo

24

[43]

PhaseIIb dose-ranging combination

(Japan)

1, 3, 5, 10 b.i.d. and placebo

12

[44]

NCT00603512

140

40.q2wk: 40 mg every 2 weeks; b.i.d.: Two-times a day; q.d.: Once a day.

www.expert-reviews.com

325

Drug Profile

Zerbini & Lomonte

PhaseIII combined therapy study in MTX inadequate responders

This is an ongoing 2-year study to examine structural progression

with tofacitinib in RA patients with inadequate response to MTX.
Only partial results from a 1-year interim analysis are available at
present[46] . In this double-blind study 797patients were randomized
to one of four groups: tofacitinib 5mg b.i.d., tofacitinib 10mg b.i.d,
placebo advanced to tofacitinib 5mg b.i.d., or placebo advanced
to tofacitinib 10mg b.i.d. After 3months, patients who had not
achieved at least 20% improvement in joint counts advanced to
tofacitinib 5 or 10mg b.i.d., while the remaining patients on
placebo advanced to tofacitinib 5mg or 10mg b.i.d. at month 6.
x-rays were analyzed and modified total Sharp-Score with linear
extrapolation was used. ACR20 response rates at month 6 were 51.5
and 61.8% for tofacitinib 5mg and 10mg, respectively, and 25.3%
for placebo (p < 0.0001). Tofacitinib 10mg b.i.d. significantly
reduced radiographic progression of joint damage in comparison
to placebo (mean changes in mTSS were 0.06 for tofacitinib versus
0.47 for placebo, p<0.05) and produced significant improvements
in DAS28-4(ESR) <2.6 at month 6 (p<0.0001) and in mean
changes in HAQ-DI at month 3 (p<0.0001). On the other hand,
tofacitinib 5mg b.i.d. was not statistically different from placebo
regarding structural progression. Due to step-down statistical
analysis, the significance for HAQ-DI and DAS28-4(ESR) for
tofacitinib 5mg b.i.d. was not declared.
PhaseIII combined therapy study in anti-TNF inadequate
responders

In this 6month, double-blind, placebo-controlled study, 399 RA

patients with inadequate response to one or more TNF inhibitors
were included [47] . Patients remained on background treatment
with MTX and were randomized to tofacitinib 5mg b.i.d.,
10mg b.i.d. or placebo. At month 3, placebo patients advanced to

tofacitinib 5mg b.i.d. or 10mg b.i.d. according to randomization.

ACR20 response rates, at month 3, for tofacitinib 5 and 10mg
b.i.d. were 41.7% (p<0.05) and 48.1% (p<0.001), respectively,
versus 24.4% for placebo. At the same month, ACR50 response
rates were 26.5, 27.8 (both p<0.0001) and 8.4%, while ACR70
response rates were 13.6 (p < 0.0001), 10.5 (p < 0.0001) and 1.5%
for tofacitinib 5mg b.i.d., tofacitnib 10mg b.i.d. and placebo,
respectively. At month 3, a significant improvement in HAQ-DI
and DAS28-4(ESR) was observed for both tofacitinib groups
in comparison to placebo. At month 6, ACR response rates, as
well as HAQ-DI and DAS28-4(ESR), continued to improve
in the tofacitinib arms. The proportion of patients in remission
(DAS28-4[ESR] 2.6) was significantly higher for tofacitinib
5mg and 10mg b.i.d. in comparison to placebo at month 3, and
this proportion increased at month 6.
PhaseIII studies of tofacitinib in RA are included in a clinical
program called ORAL Trials. Other PhaseIII studies than those
listed above are ongoing and listed in Table4, which shows ORAL
Trials characteristics.
Ongoing long-term open-label study

Patients who had concluded their participation in a PhaseII or

PhaseIII qualifying index study of tofacitinib were invited to
enroll in a long-term open-label study. Patients received tofacitinib
5 or 10mg b.i.d. An interim analysis of 1070patients treated
for a total duration of 1295.7patient-years revealed sustained
improvement in disease activity: mean baseline DAS28-4(ESR)
was 6.41, while at month 12 DAS28-4(ESR) was 3.70 and at
month 24 it was 3.55 [48] . ACR20, 50 and 70 response rates
were maintained at month 24 evaluation. Mean HAQ-DI scores
were improved compared with baseline and remained consistent
over time for all patients. ACR20 response rates were similar

Table4. Pivotal PhaseIII studies of tofacitinib in rheumatoid arthritis.

Study

ClinicalTrials.gov RA population
identifier

Tofacitinib
regimen

ORAL
Solo

NCT00814307

Traditional or
Monotherapy
biologic DMARD-IR

Placebo control 6

Signs, symptoms, physical

function and safety

[45]

ORAL
Scan

NCT00847613

MTX-IR

Placebo control 24

Signs, symptoms, physical

function, radiographic
progression and safety

[46]

ORAL
Sync

NCT00856544

Traditional or
Combined therapy Placebo control 12
biologic DMARD-IR (background
traditional DMARD)

Signs, symptoms, physical

function and safety

[103]

ORAL
NCT00853385
Standard

MTX-IR

Combined therapy
(MTX)

Placebo control 12
Adalimumab

Signs, symptoms, physical

function and safety

[103]

ORAL
Step

NCT00960440

Anti-TNF-IR

Combined therapy
(MTX)

Placebo control 6

Signs, symptoms, physical

function and safety

[47]

ORAL
Start

NCT01039688

MTX-naive

Monotherapy

MTX control

Signs, symptoms, physical

function, radiographic
progression and safety

[103]

Combined therapy
(MTX)

Comparator

Duration
(months)

24

End points

Ref.

DMARD: Disease-modifying antirheumatic drug; IR: Inadequate responder; MTX: Methotrexate; RA: Rheumatoid arthritis.
Data taken from [103].

326

Expert Rev. Clin. Immunol. 8(4), (2012)

Tofacitinib for the treatment of rheumatoid arthritis

in patients receiving tofacitinib monotherapy compared with

patients on background MTX therapy [49] .
Safety

In the PhaseIIa monotherapy study, the 30mg b.i.d. tofacitinib

group experienced a higher incidence of leukopenia, neutropenia,
anemia, lymphopenia and thrombocytopenia than the other
treatment groups. An increase in infections was observed with
higher tofacitinib dosages (26, 25, 30 and 30% for placebo, 5, 15
and 30mg b.i.d. tofacitinib groups, respectively), but the majority
were mild or moderate in severity and responded promptly to
therapy. A dose response increase in the level of total cholesterol,
low-density lipoprotein and high-density lipoprotein, and a decrease
in the neutrophil count and hemoglobin were seen. There were
increases in the blood EpsteinBarr virus DNA levels in all groups,
including placebo (median increases of seven copies per 500mg
of DNA). The increases were largest in the 30mg b.i.d. tofacitinib
group. Three patients experienced serious adverse events considered
related to the study drug (infectious gastroenteritis and severe
leukopenia in patients receiving tofacitinib, and Staphylococcus
aureus pneumonia in a patient receiving placebo) [40] .
In the dose-ranging combination study, the most common
adverse events in the tofacitinib groups were urinary tract
infection, diarrhea, nasopharyngitis, arthralgia and headache [42] .
An increased incidence of infection in the tofacitinib groups was
observed in comparison with placebo, but with no dose effect. Five
serious infections with tofacitinib were observed during the study
(three pneumonia, one respiratory tract infection and one urinary
tract infection). There was one death in the tofacitinib 3mg b.i.d.
group, due to pneumonia followed by respiratory and cardiac failure.
Some increases in liver enzymes were seen, as well as increases in
cholesterol and a small increase in serum creatinine. Decreases in
hemoglobin and neutrophils were observed in the tofacitinib groups.
The 15mg b.i.d. group reported the highest percentage of subjects
who discontinued treatment due to an adverse event.
The most common treatment-emergent adverse events in
the tofacitinib arms in the dose-ranging monotherapy study
were urinary tract infection, upper respiratory tract infection,
nasopharyngitis, nausea, dizziness, diarrhea, headache and
bronchitis [43] . Five patients experienced serious infections
including pneumonia (n=2, tofacitinib), pneumococcal sepsis
(n=1, tofacitinib), acute pyelonephritis (n=1, after reassignment
from adalimumab to tofacitinib at week 12), and joint infection
(n=1, placebo). The tofacitinib 15mg b.i.d. group had the highest
frequency of serious adverse events and severe adverse events; one
death due to cerebrovascular accident was reported in this dose
group. Dose-dependent increases in serum lipids and decreases in
neutrophils levels were observed in the tofacitinib groups. Increased
levels of serum creatinine and changes in hemoglobin were seen
in all treatment groups. Elevations of liver enzymes were few
and similar in all study groups. The switch from adalimumab to
tofacitinib was, in general, well-tolerated.
In the Japanese combination study, the most commonly
reported adverse events were nasopharyngitis, increased alanine
transaminase, and increased aspartate transaminase [44] . The
www.expert-reviews.com

Drug Profile

proportion of patients reporting infections over 12 weeks was 10.7,

29.6, 11.1 and 42.3% in tofacitinib 1-, 3-, 5- and 10-mg groups,
respectively, compared with 21.4% for placebo. The most common
infections were nasopharyngitis (8.3%), gastroenteritis (2.8%)
and pharyngitis (1.9%). A significant dose-dependent decrease in
mean neutrophil counts was observed for all tofacitinib groups in
comparison to placebo at week 12, but it did not result in therapy
discontinuation. Small changes in mean hemoglobin levels and
increases in serum creatinine and serum lipids were observed in the
tofacitinib groups. Serious infections and death were not reported.
In the PhaseIII monotherapy study, changes in neutrophils,
hemoglobin, serum creatinine, alanine transaminase, aspartate
transaminase, and cholesterol occurred [45] . Twenty-five patients
(4.1%) experienced serious adverse events. One death due to
cardiac arrest and hyperkalemia in a patient who experienced
diarrhea occurred in the tofacitinib 10mg b.i.d. group. No new
potential safety signals were detected.
In a PhaseIII combined therapy study in MTX inadequate
responders, the most frequent adverse events were infections and
infestations [46] . There were seven opportunistic infections, of
which three were serious. Four deaths were reported in tofacitnib
5mg b.i.d. group while tofacitinib 10mg b.i.d. and placebo groups
had one death each reported. Laboratory abnormalities were
similar to those reported in other tofacitinib studies.
In a PhaseIII combined therapy study in anti-TNF inadequate
responders, serious infections were reported in two patients in
each tofacitinib arm, and one patient in the placebo arm [47] . No
opportunistic infections were seen. One death due to pulmonary
embolism was reported in the placebo advanced to tofacitinib
10mg b.i.d. arm in a patient with known risk factors. Nonserious
adverse events and laboratory abnormalities were consistent with
previously reported studies.
In the long-term open-label study, most frequently reported
adverse events were infections and infestations (18.4%),
gastrointestinal disorders (10.2%) and laboratory abnormalities
(7.4%) [48] . The most frequently reported serious adverse events
were infections (2.62 per 100patient-years experience). No
significant difference in the safety profile was observed regarding
the use or not of concomitant MTX [49] . The most common
treatment-related adverse events in patients using MTX were
urinary tract infection (4.7%), bronchitis (4.0%) and sinusitis
(3.6%), while in non-MTX patients they were upper respiratory
tract infection (2.5%), bronchitis (2.3%) and herpes zoster (2.2%).
Liver laboratory test abnormalities were mild to moderate and more
frequent in the MTX combined group (mild in 3.6% and moderate
in 2.6% in the MTX group).
In summary, according to integrated safety data, most common
adverse events observed with tofacitinb are infections, including
nasopharingitis, upper respiratory tract infection, urinary tract
infection, bronchitis, herpes zoster and influenza. Following
infections, gastrointestinal disorders are the most common adverse
events [50,51] .
In long-term extension studies up to 36months, the incidence
rate of serious adverse events was 11.34 per 100patientsyears (95%CI: 10.2012.62), while the incidence rates of
327

Drug Profile

Zerbini & Lomonte

serious infections was 3.01 per 100patients-years (95%CI:

2.453.68)[50] .
Most frequent laboratory abnormalities observed with
tofacitinib are increase of creatinine and liver enzymes levels and
decrease of hemoglobin and neutrophils [50] .
Conclusion

RA is a common inflammatory disease. After the initial diagnosis,

treatment must be initiated as soon as possible; otherwise patients
will suffer from chronic joint pain, further functional disability
and excess mortality. RA is a heterogeneous disease and response
to treatment is not predictable for many patients. Recently,
translational research studies have led to new therapeutic targets but
RA treatment is not satisfactory for more than a third of patients. If
MTX alone or in combination with other synthetic DMARDs does
not control the disease, a biologic DMARD that targets TNF is
usually added to the therapeutic regimen. Other biologic agents may
be used such as those targeting IL-1 receptor, IL-6 receptor, CD20
B-cell antigen and T-cell activation surface antigens CD80 and
CD86. These biologic drugs require intravenous or subcutaneous
administration, are very expensive and are not always effective.
Tofacitinib, a new oral, potent and selective DMARD targeting
the intracellular JAK pathway, showed good results in PhaseII and
open label studies as a therapeutic option for RA patients. Based on
these studies doses of 5 and 10mg were selected for the PhaseIII
programme named ORAL Trials. These PhaseIII trials include
evaluations of signs, symptoms, physical function, radiographic
progression and safety of this investigational drug when used
as monotherapy or combined with MTX or other DMARDs.
Different RA patient populations will receive tofacitinib treatment
including MTX-naive patients and inadequate responders to
MTX, other DMARDs and also to anti-TNF agents. Patients that
completed the PhaseII trials and those completing the PhaseIII
programme will continue to be evaluated in open-label ongoing
extension studies that will help to determine the long-term efficacy,
tolerability and safety of tofacitinib treatment in RA patients.
Expert commentary

The way rheumatologists see the treatment of RA has considerably

changed in the past 12years. There is a worldwide consensus that
RA treatment must start very early and be effective in suppressing
synovitis without inducing undesirable adverse side effects. The
ultimate goal of an early and aggressive treatment of RA is to reach
complete remission in order to have the greatest impact in preventing
damage and further disability. Biologic DMARDs contributed
very much to this new notion. In PhaseII open-label studies,
tofacitinib results in RA seemed to be noninferior to biological
therapies. Tofacitinib successfully suppressed disease activity and
was well tolerated in the initial clinical trials. This small-molecule
JAK inhibitor downregulates six inflammatory cytokines and seems
more attractive as an inhibitor of the synovitis than the anti-TNF
or anti-IL-6 compounds which are more specifically targeted.
Tofacitinib, administrated as monotherapy or on background MTX
therapy, showed good safety and efficacy data in four randomized
PhaseII trials. One of these studies also showed efficacy of a single
328

daily dosing (20mg) of tofacitinib suggesting future trials with this

unique administration. The results of the PhaseIII monotherapy
trial demonstrated, as early as week2, significant ACR20 response
rates for tofacitinib 5 and 10mg b.i.d., as well as significant ACR50
response rates for tofacitinib 10mg b.i.d. and ACR70 response rates
for tofacitinib 5 and 10mg b.i.d. These results are in the same range
as biologic therapies particularly the anti-TNF therapies. In the
open-label extension trial efficacy was sustained for 24months with
a DAS change from 6.4 at open-label baseline to 3.55 at 24months.
Being an oral drug, tofacitinib will be easier to administer and will
probably have a better compliance than the injectable biologics.
ORAL ongoing studies will give us a clue on how tofacitinib will be
included in a new RA treatment strategy. Those trials will provide
more information about tofacitinib administration as monotherapy
compared with its administration on background MTX. There are
also current clinical studies in other indications including psoriasis,
psoriatic arthritis, inflammatory bowel disease and prevention of
transplant rejection.
The successful results obtained in the preclinical and clinical
tofacitinib trials showed that inhibition of the JAK family of enzymes
is an effective means for modulation of the immune function as a
strategy for treating RA and other autoimmune diseases.
Five-year view

Biochemistry and molecular biology made a huge contribution to

our understanding of the pathogenic mechanisms involved in RA.
The discovery and characterization of anticitrullinated protein
antibodies, the development of biologic drugs and the evolving
concept that RA must be treated aggressively in its early stages
enormously changed the way rheumatologists see the disease today.
Pathways involved in the chronic phase of this disease are much
clearer than 10years ago but there are still many questions regarding
the initiating cellular and molecular events leading to the synovitis.
New studies are underway to better analyze the initiation of
autoimmunity in RA. Those include: T-cell tolerance breakdown
early in disease; T-cell cross-reaction activated by foreign antigens
with self-antigens (molecular mimicry) and; T-cell reaction to
articular neo-epitopes. Studies have shown that IgM rheumatoid
factor and anticitrullinated protein antibodies can be detected
in the serum of RA patients many years before the initiation of
clinical disease. Recently, one study showed that the synovium is not
abnormal during this preclinical stage suggesting that autoimmunity
precedes the development of synovitis in individuals at risk for
RA development [52] . These new data and the identification of
individuals susceptible to the development of autoimmunity
through the presence of specific MHC or other genetic factors will
make clinicians do a better diagnosis and a long-term prognosis even
before the first signs of an inflammatory arthritis.
The concept of making a good assessment of prognosis and
perform a quick therapeutic action for an individual RA patient
today represents a critical challenge to the rheumatologist. New
approaches to the initial clinical investigation are being developed
to more accurately define the prognosis of an early inflammatory
arthritis. A recent publication established ten recommendations
on how to investigate and follow-up in undifferentiated peripheral
Expert Rev. Clin. Immunol. 8(4), (2012)

Tofacitinib for the treatment of rheumatoid arthritis

inflammatory arthritis. The 3E Initiative (Evidence, Expertise,

Exchange) made a multinational effort to formulate practical
recommendations for the everyday practice [53] . These will help
clinicians to discriminate between a benign course of the disease
and a more severe illness associated with joint destruction and extraarticular features. The recent 2010 ACR/EULAR classification
criteria for RA, has been also developed with this purpose [22] . In the
future rheumatologists will see the results of its universal application.
Another developing medical field to play an important role in
the future of rheumatology is the relation between treatment and
individual genetic variations. Efforts in this direction has been made
by studies in two areas of medical research: pharmacogenomics, the
application of genomics to production of better drug design and
better drug selection based on individual patients genetic profiles,
and its branch pharmacogenetics, the relation between individual
genetic variations and his/her response to drug therapy. These new
fields of investigation will help the rational individualization of
therapy using a genetic approach in the next few years.
Inhibitors of signal transduction of the intracellular pathways
of inflammation are now in development. We have reviewed the

Drug Profile

first of these new drugs. Tofacitinib, a potent, orally active JAK

inhibitor, showed rapid, statistically significant and clinically
meaningful reductions in signs and symptoms of RA in patients
in PhaseII and III trials. Tolerance was acceptable with mild
to moderate side effects. In the initial trials tofacitinib showed
comparable results to anti-TNF therapy with the advantage of
being an oral drug and probably less expensive than the biologics.
Studies currently underway will show us how this new class of
drugs will fit in the treatment of RA and other rheumatic diseases.
Financial & competing interests disclosure

CAF Zerbini has received grants for Reseach from Merck, Pfizer, Amgen,
Lilly, Novartis, Sanofi-Aventis, Servier, GSK and Roche, has presented at
medical conferences for Pfizer, Merck, Sanofi-Aventis and Servier and is on
the board committees for Sanofi-Aventis, Pfizer and Merck. The authors
have no other relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript apart from those
disclosed.
No writing assistance was utilized in the production of this manuscript.

Key issues
JAKs are a family of tyrosine kinases composed of four membrane-associated intracellular nonreceptor enzymes (JAK1, JAK2, JAK3
andTyk2).
JAK3 is predominantly expressed at high levels in hematopoietic tissues, being found in myeloid cells, thymocytes, natural killer cells and
activated B and T lymphocytes. JAK3 binds to only one cytokine receptor, the common g chain or gc. This chain is shared by many
inflammatory cytokine receptors, including IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.
Tofacitinib is an oral selective and potent inhibitor of JAK1 and 3 capable of interfering with signaling through cytokine receptors of all the
cytokines listed above.
Tofacitinib is rapidly absorbed and eliminated with a time to peak concentration of approximately 0.5h and a half-life of approximately 3h.
The protein binding of tofacitinib is approximately 40%, raising the possibility of a low drug interaction due to drug displacement.
There is no need for dosage adjustment with coadministration of tofacitinib and methotrexate. Tofacitinib dosage adjustments or food
restrictions are not warranted during chronic treatment.
Tofacitinib administration showed significant anti-inflammatory effects in two rodent models of arthritis and animal models of
transplantation.
In a proof-of-concept monotherapy study, improvements in disease activity were observed as early as 1 week after treatment for all
tofacitinib groups (5, 15 and 30mg two-times a day) in comparison to placebo. Increased American College of Rheumatology (ACR)50 and
ACR70 response rates relative to placebo were seen at all time points by week 4.
Three Phase IIb dose-ranging trials lasting from 6 to 24 weeks in RA patients showed significant ACR20 improvements as early as week2
and sustained at week 24 in two studies. These studies led to the identification of the two-times a day doses now used in the PhaseIII trials.
A PhaseIII 6month monotherapy study evaluated two doses of tofacitinib in 610 RA patients. The month 3 ACR20 response rates for
tofacitinib 5 and 10mg two-times a day were significantly better than the placebo group responses.
PhaseIII studies in RA are included in a large clinical program called ORAL Trials. Additional results will be available soon.
Dose-related increases in the number of adverse events were observed in the clinical trials. Common adverse events included headache,
nausea, upper respiratory infections, urinary tract infections, anemia, leukopenia, neutropenia and hypercholesterolemia.
Results from the RA studies show that there is potential for trials in other illnesses like psoriasis, inflammatory bowel diseases and organ
transplantation.
rheumatoid arthritis. Arthritis Rheum. 31,
315324 (1988).

References
Papers of special note have been highlighted as:
of interest
of considerable interest
1

Arnett FC, Edworthy SM, Bloch DA etal.

The American rheumatism association
1987 revised criteria for classification of

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Firestein G. Evolving concepts of

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Steinman L. A brief history of TH17,

thefirst major revision in the Th1/Th2

hypothesis of T cell-mediated tissue

damage. Nat. Med. 13, 139145 (2007).

Review with valuable references showing

the introduction of Th17 in the
pathophysiology of rheumatoid arthritis
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associated with the tofacitinib mechanism
of action.

329

Drug Profile

Zerbini & Lomonte

Annunziato F, Cosmi L, Santarlasci V etal.

Phenotypic and functional features of
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Sato K, Suematsu A, Okamoto K etal. Th17

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Kirkham BW, Lassere MN, Edmonds JP

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Liepe J, Skapenko A, Lipsky P etal.

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Nadkarni S, Mauri C, Ehrenstein MR. AntiTNF-a therapy induces a distinct regulatory

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Koch AE, Distler O. Vasculopathy and

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Lee DM, Kiener HP, Agarwal SK etal.
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McInnes IB, Liew FY. Cytokine networks:

towards new therapies for rheumatoid
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Breedveld FC, Weisman MH, Kavanaugh

AF etal. The PREMIER study: a
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patients with early, aggressive rheumatoid
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Genovese MC, Bathon JM, Martin RW

etal. Etanercept versus methotrexate in
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Maini RN, Breedveld FC, Kalden JR etal.
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15

Nishimoto N, Yoshizaki K, Miyasaka N

etal. Treatment of rheumatoid arthritis with
humanized anti-interleukin-6 receptor
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50(6), 17611769 (2004).

26

Meyer DM, Jesson MI, Li X etal.

Anti-inflammatory activity and
neutrophil reductions mediated by the
JAK1/JAK3 inhibitor, CP-690,550, in rat
adjuvant-induced arthritis. J.Inflamm. 7,
41 (2010).

16

Darnell JE Jr, Kerr IM, Stark GR.

JAKSTAT pathways and transcriptional
activation in response to IFNs and other
extracellular signaling proteins. Science 3,
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Paper showing tofacitinib as a potent

inhibitor of JAK1 and JAK3 with reduced
potency for JAK2 in a rat model.

27

Chrencik JE , Patny A, Leung IK etal.

Structural and thermodynamic
characterization of the TYK2 and JAK3
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413433 (2010).

Paper with good illustrations showing the

structural molecular interactions of JAK3
kinase domains in complex with
tofacitinib.

28

Krishnaswami S, Kudlacz E, Yocum S etal.

Effect of CYP2C19 polymorphism on the
pharmacokinetics of CP-690,550 a Janus
kinase inhibitor. AAPS J.11, 36 (2009)
(Abstract).

29

Chow V, Ni G, LaBadie R etal. Openlabel

study to estimate the effectfluconazole on
the pharmacok inetics of a JAK3 antagonist
(CP-690, 550) in the healthy adult
subjects. Clin. Pharmacol. Ther. 83, PI-93
(2008) (Abstract).

30

Chow V, Wilkinson B, LaBadie R etal.

Open label study of the pharmacokinetics
of a JAK3 antagonist (CP-690,550) and
single doses of a oral methotrexate in
rheumatoid arthritis subjects. Clin.
Pharmacol. Ther. 83, PI-92 (2008)
(Abstract).

31

Chow V, Krishnaswami S, Chan G.

Pharmacokinetics of CP-690,550, a janus
kinase inhibitor, in subjects with impaired
renal function and end-stage renal disease.
Clin. Pharmacol. Ther. 85, PII-86 (2009)
(Abstract).

32

Milici AJ, Kudlacz EM, Audoly L etal.

Cartilage preservation by inhibition of
Janus kinase 3 in two rodent models of
rheumatoid arthritis. Arthritis Res. Ther.
10(1), R14 (2008).

33

Ghoreschi K, Jesson MI, Li X etal.

Modulation of innate and adptative
immune responses by tofacitinib (CP690,550). J.Immunol. 186, 42344243
(2011).

34

Borie DC, Larson MJ, FloresMG etal.

Combined use of the JAK3 inhibitor CP690,550 with mycophenolate mofetil to
prevent kidney allograft rejection in
nonhuman primates. Transplantation
80(12), 17561764 (2005).

17

Ghoreschi K, Laurence A, OShea JJ.Janus

kinases in immune cell signaling. Immunol.
Rev. 228(1), 273287 (2009).

Review article explaining in detail the

JAKs action in transducing cytokine
signals. This is a comprehensive
explanation making it easier to understand
the role of these enzymes in the cellular
immunity response.
18

Leonard WJ, OShea JJ.Jacks and STATs:

biological implications. Annu. Rev.
Immunol. 16, 29322 (1998).

19

Rochman Y, Spolski R, Leonard WJ.New

insights into the regulation of T cells by g(c)
family cytokines. Nat. Rev. Immunol. 9,
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20

Bhan, Dari R, Kuriyan J. JAKSTAT

signaling. In: Handbook of Cell Signaling
(1stEdition). Bradshaw R, Dennis E (Eds).
Academic Press, NY, USA, 343347
(2003).

21

Russell SM, Tayebi N, Nakajima H etal.

Mutation of JAK3 in a patient with SCID:
essential role of JAK3 in lymphoid
development. Science 270, 797800 (1995).

22

Nosaka T, van Deursen JM, Tripp RA etal.

Defective lymphoid development in mice
lacking JAK3. Science 270, 800802 (1995).

23

Changelian PS, Flanagan ME, Ball DJ etal.

Prevention of organ allograft rejection by a
specific Janus kinase 3 inhibitor. Science
302, 875878 (2003).

24

Flanagan ME, Blumenkopf TA, Brissette

WH etal. Discovery of CP-690,550: a
potent and selective Janus kinase (JAK)
inhibitor for the treatment of autoimmune
diseases and organ transplant rejection.
J.Med. Chem. 53(24), 84688484 (2010).

An outstanding paper written by the

researchers responsible for the development
of tofacitinib. Summarizes all the initial
studies and the idea behind the focus on
JAK3 inhibition.
25

Karaman MW, Herrgard S, Treiber DK

etal. A quantitative analysis of kinase
inhibitor selectivity. Nat. Biotechnol. 26,
127132 (2008).

Expert Rev. Clin. Immunol. 8(4), (2012)

Tofacitinib for the treatment of rheumatoid arthritis

35

36

Kudlacz E, Perry B, Sawyer P etal. The

novel JAK-3 inhibitor CP-690550 is a
potent immunosuppressive agent in various
murine models. Am. J.Transplant. 4(1),
5157 (2004).
Corry R, Winn H, Russel P. Primarily
vascularized allografts of hearts in mice.
Transplantation 16(4), 343353 (1973).

37

Babany G, Morris RE, Babany I etal.

Evaluation of the invivo dose-response
relationship of immunosuppressive drugs
using a mouse heart transplant model:
application to cyclosporine. J.Pharmacol.
Exp. Ther. 244(1), 259262 (1988).

38

Borie DC, Hausen B etal. Nonhuman

primates to study the effects of
immunosuppressive drugs: report of a lifesupporting technique of renal
allotransplantation in Macaca fascicularis.
J.Surg. Res. 107, 6474 (2002).

39

Borie DC, Changelian PS, Larson MJ etal.

Immunosuppression by the JAK3 inhibitor
CP-690,550 delays rejection and
significantly prolongs kidney allograft
survival in nonhuman primates.
Transplantation 79, 791802 (2005).

40

Kremer JM, Bloom BJ, Breedveld FC etal.

The safety and efficacy of a JAK inhibitor
in patient with active rheumatoid arthritis
results of a double-blind, placebocontrolled PhaseIIa trial of three dosage
levels of CP-690,550 versus placebo.
Arthritis Rheum. 60(7), 18951905 (2009).

First PhaseII trial of tofacitinib treatment

in RA. The proof-of-concept monotherapy
study.
41

42

43

Coombs JH, Bloom BJ, Breedveld FC etal.

Improved pain, physical functioning and
health status in patients with rheumatoid
arthritis treated with CP-690,550, an orally
active Janus kinase (JAK) inhibitor: results
from a randomized, double-blind, placebocontrolled trial. Ann. Rheum. Dis. 69,
413416 (2010).
Kremer JM, Cohen S, Wilkinson BE etal.
A PhaseIIb dose-ranging study of the oral
JAK inhibitor tofacitinib (CP-690,550)
versus placebo in combination with
background methotrexate in patients with
active rheumatoid arthritis and an
inadequate response to methotrexate alone.
Arthritis Rheum. 64(4), 970981 (2012).
Fleischmann R, Cutolo M, Genovese MC
etal. PhaseIIb dose-ranging study of the
oral JAK inhibitor tofacitinib (CP-690,550)
or adalimumab monotherapy versus
placebo in patients with active rheumatoid

www.expert-reviews.com

arthritis with an inadequate response to

disease-modifying antirheumatic drugs.
Arthritis Rheum. 64(3), 617629 (2012).

Study comparing American College of

Rheumatology 20 responses in tofacitinib
arm, adalimumab (anti-TNF) arm and
placebo arm of RA patients treatment.

44

Tanaka Y, Suzuki M, Nakamura H etal.

Phase2 study of tofacitinib (CP-690, 550)
combined with methotrexate in patients
with rheumatoid arthritis and inadequate
response to methotrexate. Arthritis Care
Res. (Hoboken) 63(8), 11501158 (2011).

45

Fleischmann R, Kremer J, Cush J etal.

Phase3 study of oral JAK inhibitor
tasocitinib (CP-690,550) monotherapy in
patients with active rheumatoid arthritis.
Presented at: Annual Scientific Meeting of
the American College of Rheumatology.
Atlanta, GA, USA, 611 November 2010
(Abstract 4352).

46

van der Heijde D, Tanaka Y, Fleischmann

R etal. Tofacitinib (CP-690,550), an oral
janus kinase inhibitor, in combination with
methotrexate reduced the progression of
structural damage in patients with
rheumatoid arthritis: a 24month Phase 3
study. Arthritis Rheum. 63(S1017), 2592
(2011) (Abstract).

First study to show inhibition of

structural damage with tofacitinib in
patients with RA.

47

Burmester G, Blanco R, CharlesSchoemann C etal. Tofacitinib (CP690,550), an oral janus kinase inhibitor, in
combination with methotrexate, in patients
with active rheumatoid arthritis with an
inadequate response to tumor necrosis
factor-inhibitors: a 6month Phase 3 study.
Arthritis Rheum. 63(S279), 718 (2011)
(Abstract).

Study of tofacitinib in patients with

inadequate response to anti-TNF agents.

48

Connell CA, Riese RJ, Wood SP etal.

Tasocitinib (CP-690,550), an orally
available selective janus kinase inhibitor,
exhibits sustained safety and efficacy in the
treatment of rheumatoid arthritis over
24months. Artrhtis Rheum. 62(S473),
1129 (2010) (Abstract).

49

Connell CA, Riese RJ, Wood SP etal.

Tasocitinib (CP-690,550) appears to be
effective and tolerated when administered
either as long-term monotherapy or on
background methotrexate in patients with
rheumatoid arthritis. Arthritis Rheum.
62(S911), 2171 (2010) (Abstract).

Drug Profile

50

Wollenhaupt J, Silverfield JC, Lee EB etal.

Tofacitinib (CP-690,550), an oral janus
kinase inhibitor, in the treatment of
rheumatoid arthritis: open-label, long-term
extension studies up to 36months. Arthritis
Rheum. 63(Suppl. 10), S152S153 (2011)
(Abstract 407).

51

Cohen S, Radominski SC, Asavatanabodee

P etal. Tofacitinib (CP-690,550), an oral
Janus Kinase inhibitor: analysis of
infections and all-cause mortality across
Phase 3 and long-term extension studies in
patients with rheumatoid arthritis. Arthritis
Rheum. 63(Suppl. 10), S153 (2011)
(Abstract 409).

52

van de Sande MGH, de Hair MJH, van

der Leij C etal. Different stages of
rheumatoid arthritis: features of the
sinovium in the preclinical phase. Ann.
Rheum. Dis. 70, 772777 (2011).

Paper showing that development of

autoimmunity may precede synovial
inflammation suggesting a clue to
diagnosis before the appearance of clinical
symptoms.

53

Machado P, Castrejon I, Katchamart W

etal. Multinational evidence-based
recommendations on how to investigate
and follow-up undifferentiated peripheral
inflammatory arthritis: integrating
systematic literature research and expert
opinion of a broad international panel of
rheumatologists in the 3E Initiative. Ann.
Rheum. Dis. 70, 1524 (2011).

European initiative aimed to improve

clinicians investigation and follow-up of
arthritis at early stages of the disease. The
paper emphasizes the importance of early
discrimination between a benign course
and a more destructive disease.
54

Opar A. Kinase inhibitors attract attention

as oral rheumatoid arthritis drugs. Nat.
Rev. Drug Discov. 9(4), 257258 (2010).

55

Shuai K, Liu B. Regulation of JAKSTAT

signalling in the immune system. Nat. Rev.
Immunol. 3(11), 900911 (2003).

Websites
101

American College of Rheumatology.

www.rheumatology.org

102

The European League Against

Rheumatism.
www.eular.org

103

ClinicalTrials.gov.
http://clinicaltrials.gov/ct2/results?term=C
P+690+550+rheumatoid+arthritis

331