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REVIEWS

TypeI/II cytokines, JAKs, and new


strategies for treating autoimmune
diseases
Daniella M. Schwartz1, Michael Bonelli2, Massimo Gadina1 and John J. OShea1
Abstract | Cytokines are major drivers of autoimmunity, and biologic agents targeting cytokines
have revolutionized the treatment of immune-mediated diseases. Despite the effectiveness of
these drugs, they do not induce complete remission in all patients, prompting the development
of alternative strategies including targeting of intracellular signal transduction pathways
downstream of cytokines. Many cytokines that bind typeI and typeII cytokine receptors are
critical regulators of immune-mediated diseases and employ the Janus kinase (JAK) and signal
transducer and activator of transcription (STAT) pathway to exert their effect. Pharmacological
inhibition of JAKs blocks the actions of typeI/II cytokines, and within the past 3years therapeutic
JAK inhibitors, or Jakinibs, have become available to rheumatologists. Jakinibs have proven
effective for the treatment of rheumatoid arthritis and other inflammatory diseases. Adverse
effects of these agents are largely related to their mode of action and include infections and
hyperlipidemia. Jakinibs are currently being investigated for a number of new indications,
andsecond-generation selective Jakinibs are being developed and tested. Targeting STATs
couldbe a future avenue for the treatment of rheumatologic diseases, although substantial
challenges remain. Nonetheless, the ability to therapeutically target intracellular signalling
pathways has already created a new paradigm for the treatment of rheumatologic disease.

A fundamental insight gained over more than three importance in host defence and immune-mediated dis-
decades is that diverse cytokines are pivotal drivers of ease, cytokines such as TNF, IL1 and IL17 do not signal
rheumatoid arthritis (RA) and other autoimmune dis- via JAKs and STATs. However, JAKSTAT-dependent
eases13. Cytokine-targeting therapies developed on the cytokines can induce these cytokines and in this way
basis of these discoveries have dramatically changed also affect immune-mediated disease. In the first part of
the treatment options for patients with RA, psori the Review, we will discuss the roles of JAK-dependent
1
Molecular Immunology
asis, inflammatory bowel disease (IBD) and other dis cytokines in normal and aberrant immune responses,
&Inflammation Branch, orders46. Clearly, however, not all patients respond and then briefly review JAKSTAT signalling. The sec-
andTranslational adequately to these therapies, complete remission is not ond part of the Review focuses on the emergence of
Immunology Section, as common as one would hope, and cure remains an therapies targeting the JAKSTAT signalling pathway.
National Institute of Arthritis
elusive goal. These challenges suggest that alternatives to
&Musculoskeletal and Skin
Diseases, NIH, Building 10,
targeting cytokines extracellularly should be considered. Roles of typeI and typeII cytokines
9000 Rockville Pike, Indeed, the prospect of targeting intracellular pathways Cytokines that bind typeI and typeII receptors include
Bethesda, Maryland activated by cytokines is now a reality. interleukins, interferons (IFNs), IFN-like cytokines,
208921616, USA. In considering the cytokines that drive autoimmun- colony-stimulating factors, hormones, and growth fac-
2
Medical University
ofVienna, Department
ity, it is important to understand that the term cytokine tors (TABLE1). Some of these cytokines share receptor
ofRheumatology, encompasses structurally distinct factors that bind cellu- subunits and can be grouped on this basis.
WaehringerGuertel 1820, lar receptors belonging to at least seven families, which
1090Vienna,Austria. signal through very different pathways (FIG.1). In this TypeI cytokines in autoimmunity
Correspondence to D.M.S. Review, we focus on cytokines that drive autoimmune The common chain (c, also known as IL2 receptor
daniella.schwartz@nih.gov disease and that employ one particular pathway: the subunit) cytokines include IL2, IL4, IL7, IL9, IL15,
doi:10.1038/nrrheum.2015.167 Janus kinase (JAK) and signal transducer and activa- and IL21. The fundamental role of these cytokines
Published online 3 Dec 2015 tor of transcription (STAT) pathway7,8. Despite their in lymphocyte development is illustrated by primary

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Key points through the gp130 receptor subunit (encoded by IL6ST).


Among its many actions, IL6 drives the production of
Cytokines are major drivers of autoimmunity, and targeting cytokines has TNF and IL1, and induces the differentiation of type17
revolutionized the treatment of rheumatologic diseases helperT (TH17) cells (FIG.2). These cells are the major
Despite their success, biologic agents that target key cytokines are not completely producers of IL17, which acts synergistically with TNF
effective in all patients to promote activation of chondrocytes and fibroblast-like
TypeI and II cytokines signal through the JAKSTAT pathway, and pharmacological synoviocytes, production of metalloproteinases, and
inhibition of this signal transduction pathway with small molecules can block the joint destruction in RA1. Tocilizumab and other agents
actions of these cytokines in development target IL6 (TABLE1). Clinical trials are
JAK inhibitors, or Jakinibs, are effective for rheumatoid arthritis and other ongoing for multiple indications beyond RA, such as
immune-mediated diseases vasculitis and myositis (ClinicalTrials.gov identifiers
Many of the adverse effects of Jakinibs can be linked to action of the cytokines that NCT01450137 and NCT02043548, respectively). Other
are blocked gp130 cytokines include IL11, IL27, and IL31. IL11 is
Jakinibs are currently being investigated for a number of new indications, and involved in haematopoiesis and bone remodelling. IL31
second-generation selective Jakinibs are being developed and tested is produced by TH2 cells, mast cells and other leukocytes;
this cytokine has a role in skin barrier function and mye
loid development21. IL27 is also a gp130 cytokine but
immunodeficiency that arises from inactivating muta- primarily limits inflammation, including antagonizing
tions of c (encoded by IL2RG), termed Xlinked IL17 production2224 (see below).
severe combined immunodeficiency (XSCID). Many Related to the gp130 cytokines is the dimeric
c cytokines also have been implicated in diverse cytokine family, which includes IL12, IL23, and IL35.
autoimmune diseases. IL2 is the prototypic Tcell IL12 promotes the differentiation of IFNproducing
growth factor and has both proinflammatory and TH1 cells, whereas IL23 promotes IL17 production
anti-inflammatory effects. This cytokine is important and generation of TH17 cells. IL23 is important in the
for effector Tcells, upregulating production of other pathogenesis of psoriasis, IBD, and spondyloarthritis2.
cytokines and augmenting the cytolytic activity of CD8+ Targeting IL23 and IL12 with ustekinumab is effec-
Tcells and natural killer (NK) cells. Blockade of the IL2 tivefor psoriasis25 and has shown promise as a treatment
receptor with daclizumab is approved for the treatment forIBD26.
of transplant rejection and seems to be efficacious in
multiple sclerosis (MS)9,10. IL4 is found at elevated lev- TypeII cytokines in autoimmunity
els in the synovial fluid of patients with early RA but is The typeII cytokines comprise a large group of >30
absent in late disease11; generally, though, IL4 is thought signalling molecules including the typeI, II, and III
to be more important in driving allergic diseases. Both IFNs (IFN-, IFN-, IFN-, IL28, and IL29) and
IL7 and IL15 are important for lymphocyte homeo IL10related cytokines (IL10, IL19, IL20, IL22,
stasis and Tcell memory11,12 IL15 also regulates NK IL24, and IL26). A large body of evidence implicates
cells, whereas IL7 is important for the homeostasis of typeI IFNs in the development of autoimmunity: multi
other innate lymphoid cells13. Thymic stromal lympho ple rheumatologic diseases including RA, SLE, systemic
poietin (TSLP) shares the IL7 receptor chain as a sclerosis (SSc), and myositis are characterized by acti
receptor component; it has a role in Tcell development vation of typeI IFN signalling27,28. Mendelian disorders
and allergy12. IL9 is involved in atopy and IBD14. IL21 associated with upregulation of typeI IFN signalling also
promotes differentiation of follicular helper T (TFH) cells, present with severe inflammation and autoimmunity29.
which act on Bcells in germinal centres to promote anti Paradoxically, though, IFN is an approved therapy for
body class-switching15. Inactivating mutations of IL21 MS (as discussed below).
and IL21R result in immunodeficiency16. Because of IFN, the typeII IFN, also contributes to the patho
their role in class switching, TFH cells are thought to be genesis of autoimmune diseases, although the relative
important for diverse autoantibody-linked autoimmune contribution of TH1 versus TH17 cells is the subjectof
diseases including RA and systemic lupus erythematosus ongoing research. T H1 cells, the main producers
(SLE). Levels of IL21 are increased in the synovium and ofIFN, have been implicated in the development of
serum of patients with RA17. Targeting IL21 has been RA and in animal models of collagen-induced arth
investigated in phaseI trials of RA and Crohn disease, ritis (CIA)11. However, mice lacking the Ifng and Ifngr1
although results have not yet been reported18. genes are not protected from CIA, and IFN deficiency
The common chain cytokines include IL3, IL5, can even exacerbate the disease. IL20 is produced by
and granulocyte-macrophage colony-stimulating factor keratinocytes, neutrophils and fibroblast-like synovio
(GMCSF). Encoded by CSF2, GMCSF is a proinflam- cytes30, has been implicated in synoviocyte migration
matory growth factor with a key role in the generation, and osteoclast formation, and is upregulated in RA
survival, and activation of myeloid cells. It is produced by synovia31. PhaseII clinical trials targeting IL20 have
pathogenic Tcells, and a body of data points to its impor- shown encouraging results in the treatment of RA31.
tance in driving autoimmunity19. GMCSF blockade has IL20 produced by keratinocytes has been implicated
been effective for RA in phaseII clinicaltrials20. in the pathogenesis of psoriatic skin disease30. Other
IL6 is the prototypic proinflammatory cytokine, typeII cytokines, such as IL10 and IL22, have different
which, like a number of related cytokines, signals actions, bringing us to the good guy cytokines.

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Iniximab
Certolizumab
Adalimumab Secukinumab
Golimumab
Tocilizumab Etanercept Anakinra
Ustekinumab TNF Canakinumab
Mepolizumab Rilonacept
Type I/II IL-1 IL-17 SCF/RTK TGF- Fingolimod
Chemokine

Tofacitinib
JAK JAK
P P P Calcium
P STAT P Act I SMAD GDP mobilization
IP3


GTP PLC
GSK3
IKK
ATP
P
STAT
STAT

P
P SMAD Co-SMAD Cyclic AMP

C/EBP
MAP
P kinases DAG
IB P
C/EBP PKA PKC
NFB

AP1
P CREB
IB
P NFB
STAT
STAT

P P
SMAD P
ERK
C/EBP/
Nucleus

Figure 1 | Cytokines are grouped into superfamilies based on shared structural elements Natureof the receptors
Reviews they
| Rheumatology
bind. The major cytokine families are: the typeI/II cytokines, the TNF family, the IL1 family, the IL17 cytokines, the stem
cell factor/receptor tyrosine kinase (STF/RTK) cytokines, the transforming growth factor (TGF)- family cytokines, and
chemokines. The typeI/II cytokine families signal through Janus kinase (JAK) and signal transducer and activator of
transcription (STAT) pathways. When a cytokine binds to its cognate receptor, the receptor becomes activated. JAKs
autophosphorylate and transphosphorylate, causing STATs to be recruited to the activated receptor where they, in turn,
are phosphorylated. The STATs then dimerize and translocate to the nucleus where they initiate transcription.
FDA-approved medications blocking the different classes of cytokine receptor are denoted in pink boxes. C/EBP,
CCAAT/enhancer binding protein ; Co-SMAD, common-mediator SMAD; CREB, cyclic AMP response element-binding
protein; DAG, diacylglycerol; ERK, extracellular signal-regulated kinase; GSK3, glycogen synthase kinase 3; IB,
inhibitor of B; IKK, IB kinase; IP3, inositol 1,4,5-trisphosphate; MAP, mitogen-activated protein; NFB, nuclear factor B;
PK, protein kinase; PLC, phospholipase C.

Anti-inflammatory actions of cytokines this therapy can be complicated by rash and alopecia,
Although cytokines are clearly positive effectors of indicative of exacerbation of autoimmunity9,10,33.
immune responses and drivers of autoimmunity, many IL2 is not alone in having complex actions;
typeI and II cytokines also have anti-inflammatory many cytokines have both proinflammatory and
actions that need to be considered in the treatment anti-inflammatory properties. Other cytokines
of autoimmune disease. IL2 is a prime example: the with anti-inflammatory properties include IL10,
importance of this cytokine in promoting immune tol- IL22, and IL35. IL10 is perhaps the best character-
erance through upregulation of FOXP3 protein would ized of these anti-inflammatory cytokines: it suppresses
seem to indicate that IL2 inhibition might induce, Tcelldendritic cell/macrophage interactions11,34 and
rather than treat, autoimmunity32, but the efficacy of negatively regulates NLRP3 inflammasome activation
targeting IL2 in MS provides a very different view9,10. to ameliorate synovial inflammation in animal models35.
While daclizumab is efficacious in the treatment of MS, Mutations of IL10 and IL10R cause severe early-onset

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Table 1 | TypeI/II cytokines important for haematopoiesis and immunity


Cytokine Signalling JAKs Signalling STATs Immune function and potential role Blocking agent
inimmune-mediated disease (clinicalindication)
TypeI, common c cytokines
IL2 JAK1, JAK3 STAT3, STAT5 Enhances effector and regulatory Daclizumab
responses (transplantation, MS)
IL4 JAK1, JAK3 STAT6 Allergy and asthma (TH2mediated Dupilumab* (asthma)
diseases)
IL7 JAK1, JAK3 STAT3, STAT5 Tcell development and homeostasis N/A
IL9 JAK1, JAK3 STAT1, STAT3, STAT5 Atopic disease, IBD N/A
IL13* JAK1, JAK2, JAK3, STAT6 Airway hyperresponsiveness, goblet cell Lebrikizumab (asthma)
TYK2 metaplasia and mucus hypersecretion, Dupilumab* (asthma)
fibrosis
IL15 JAK1, JAK3 STAT3, STAT5 Induction of memory Tcells and NK cell N/A
proliferation
IL21 JAK1, JAK3 STAT1, STAT3, STAT5 Differentiation of TFH cells N/A
TypeI, common c cytokines
GMCSF JAK2 STAT3, STAT5 Growth of macrophages and N/A
granulocyotes, enhances T-cell and
dendritic-cell function, stimulation and
differentiation of stem cells
IL3 JAK2 STAT3, STAT5, STAT6 Differentiation of multipotent N/A
haematopoietic stem cells, proliferation
of all cells in the myeloid lineage
IL5 JAK2 STAT3, STAT5, STAT6 Allergy, asthma, eosinophilic disease Mepolizumab (asthma)
Benralizumab
Reslizumab
TypeI, gp130 cytokines
IL6 JAK1, JAK2, TYK2 STAT1, STAT3 Prototypic proinflammatory cytokine Toclizumab (RA, sJIA, pJIA)
Broadly relevant for many autoimmune Sarilumab
diseases ALX0061
Olokizumab
Sirukinumab
Siltuximab
Clazakinumab
IL11 JAK1, JAK2, TYK2 STAT3 Haematopoiesis, bone remodelling N/A
IL27 JAK1, JAK2, TYK2 STAT1, STAT2, STAT3, Regulation of B-cell and Tcell activity N/A
STAT4, STAT5
TypeI, dimeric cytokines
IL12 JAK2, TYK2 STAT4 TH1associated disease Ustekinumab (psoriasis, PsA)
IL23 JAK2, TYK2 STAT3, STAT4 TH17mediated disease Ustekinumab (psoriasis, PsA)
Tildrakizumab
Guselkumab
IL27 JAK1, JAK2 STAT1, STAT3 Enhance TH1 cell responses and inhibit N/A
TH17 cell responses
IL35 JAK1, JAK2 STAT1, STAT4 Anti-inflammatory responses N/A
TypeI, hormone-like cytokines
Erythropoietin JAK2 STAT5 Control of erythropoiesis Adverse effects of Jakinibs
Thrombopoietin JAK2 STAT1, STAT3, STAT5 Regulation of the differentiation of Adverse effects of Jakinibs
megakaryocytes and platelets
GCSF JAK2 STAT5 Bone marrow stimulation to produce stem Adverse effects of Jakinibs
cells and granulocytes
Growth hormone JAK2 STAT3, STAT5a Stimulation of cell division of N/A
chondrocytes and IGF1
Leptin JAK2 STAT3, STAT5a Coordination of energy homeostasis, N/A
increases satiety

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Table 1 (cont.) | TypeI/II cytokines important for haematopoiesis and immunity


Cytokine Signalling JAKs Signalling STATs Immune function and potential role Blocking agent
inimmune-mediated disease (clinicalindication)
TypeII, IFN family cytokines
IFN, IFN JAK1, TYK2 STAT1, STAT2, STAT4 Enhance immunity against infections Anifrolumab
anddrive autoimmunity Medi546 (SSc, SLE)
IFN JAK1, TYK2 STAT1 Enhance immunity against infections N/A
anddrive autoimmunity
IL28 JAK1, TYK2 STAT1, STAT2, STAT3, Enhance immunity against infections N/A
STAT4, STAT5
IL29 JAK1, TYK2 STAT1, STAT2, STAT3, Enhance immunity against infections N/A
STAT4, STAT5
TypeII, IL10 family cytokines
IL10 JAK1, JAK2, TYK2 STAT1, STAT3, STAT5 Anti-inflammatory actions N/A
IL19 JAK1, JAK2, TYK2 STAT3 Bcell activation N/A
IL20 JAK1, JAK2, TYK2 STAT3 Synoviocyte migration N/A
Osteoclast formation
IL22 JAK1, JAK2, TYK2 STAT1, STAT3, STAT5 Promote endothelial barrier immunity N/A
Augment IL17 function
Table1 includes selected typeI and typeII cytokines that are important for haematopoiesis, immune homeostasis, and immune-mediated disease, grouped on the
basis of shared structure/subunits. Agents listed are FDA-approved or in late-phase clinical trials; details are available at ClinicalTrials.gov.. GCSF, granulocyte
colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; IBD, inflammatory bowel disease; IFN, interferon; IGF1, insulin-like
growth factor 1; JAK, Janus kinase; Jakinib, JAK inhibitor; MS, multiple sclerosis; N/A, not applicable; NK cell, natural killer cell; pJIA, polyarticular juvenile idiopathic
arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis; sJIA, systemic-onset juvenile idiopathic arthritis; SLE, systemic lupus erythematosus; STAT, signal
transducer and activator of transcription; TFHcell, follicular helper Tcell; TH cell, helper T cell. *IL13 does not share the common c but shares the IL4 receptor
subunit (IL4R); dupilumab targets IL4R and therefore blocks both IL4 and IL13. Both IL12 and IL23 are composed of the p40 subunit; ustekinumab, which
targets p40, blocks both cytokines.

IBD36. IL22 is involved in epithelial barrier function receptors8,41 (TABLE 1). JAKs are kinases or phospho
and can augment IL17 function; elevated levels of this transferases, meaning they transfer phosphate from ATP
cytokine are associated with increased disease activity in to tyrosine residues of their substrates, an important acti-
RA37. IL27 can enhance TH1 cell differentiation, but also vation event within cells. One crucial attribute of JAKs is
antagonizes IL2 production, promotes IL10 production, their ability to deposit a phosphate on themselves (auto
and inhibits TH17 cell responses2224. IL27 is found at phosphorylation) or on other JAKs (transphosphory
increased levels in the serum and synovial fluid of patients lation). Cytokines induce JAK enzymatic activity by
with RA, but whether its role is predominantly proin- binding the extracellular portion of their cognate recep-
flammatory or anti-inflammatory is unclear24,38. However, tors. This modification enables a variety of signalling
recent data suggest that IL27 prevents the development molecules to recognize the activated receptor.
of ectopic lymphoid-like structures in arthritic joints39. When one considers the number of cytokines that
Even the IFNs, which are crucial for immune responses signal through JAKs, it is not surprising that mutations
to viral infections and heavily implicated in the patho and polymorphisms of genes encoding these kinases have
genesis of autoimmune diseases, have immunosuppres- been linked to diseases of immunity (TABLE 2). For exam-
sive effects; in fact, IFN is an approved treatment for ple, JAK3 mediates signalling for all the c cytokines;
MS40. Other good guy functions of cytokines include thus, inactivating mutations of JAK3 recapitulate the
the role of growth factors and hormones that regu- phenotype of c deficiency and cause SCID42,43. TYK2
late homeostasis and haematopoiesis. Erythropoietin, lossoffunction causes a milder immunodeficiency44.
thrombopoietin, granulocyte colony-stimulating factor A large body of evidence from genome-wide associ
(GCSF), growth hormone, and leptin, among others, ation studies has implicated JAKs in the pathogenesis of
signal via JAKs41. All these factors must be considered autoimmune diseases. TYK2 is linked to SLE and Crohn
carefully when designing small-molecule inhibitors of disease45,46, and JAK2 polymorphisms are associated with
JAKs, which will simultaneously and potently block the Behet disease47.
actions of multiplefactors. STATs comprise an important class of molecules that
transmit signals from typeI and II cytokine receptors to
Overview of JAKSTAT signalling the nucleus. STATs reside in the cytosol before activa-
The receptors bound by typeI and typeII cytokines tion. Upon stimulation by cytokines, STATs bind active
lack intrinsic catalytic activity; rather, these receptors phosphorylated receptors and are, in turn, phosphory
have an extracellular cytokine-binding domain and a lated by JAKs. This modification causes STATs to trans
cytoplasmic domain that associates with JAKs. There locate to the nucleus, where they bind DNA and activate
are four JAKsJAK1, JAK2, JAK3, and TYK2 (tyro the transcription of target genes. There are seven STATs:
sine kinase2)each associates with different cytokine STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and

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FLS Synovium
IL-15

TNF IFN-/ IL-7


IL-1 IL-6
IL-22

IL-23 Macrophage

DC
IL-2 TH1 IL-12
TH17 IL-15
G-CSF IL-18 IL-20
Chemokines IL-21
IFN-
GM-CSF
IL-21
IL-4
IL-17 TFH
IFN-
IL-17

Class
TNF
Auto- switching
IL-1
antibodies
IL-20 IL-6
Neutrophil Plasma cell B cell

ADAMTS Matrix degradation


Chondrocyte MMPs Cartilage destruction

Cartilage
FLS

IL-20

Bone resorption

Osteoclast Bone

Figure 2 | TypeI and II cytokines (red), which are blocked by Jakinibs, are major drivers of autoimmune
Nature diseases
Reviews | Rheumatology
such as rheumatoid arthritis. Within the rheumatoid joint, fibroblast-like synoviocytes (FLSs) are major sources of TNF,
IL1, IL6, and granulocyte colony-stimulating factor (GCSF). IL6, along with IL-1 and IL23, promotes the
differentiation of pathogenic type 17 helper T (TH17) cells. Pathogenic TH17 cells produce the neutrophil growth factor
granulocyte-macrophage colony-stimulating factor (GMCSF). GCSF and GMCSF drive neutrophil-derived production
of TNF and IL1. TH17 cells are also the major producers of IL17. TNF, IL17 and IL1 induce production of matrix
metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), which
degrade the cartilage matrix. Similarly, production of the typeI cytokine IL12 by macrophages and dendritic cells (DCs)
promotes the differentiation of pathogenic TH1 cells. TH1 cells produce IFN-, which activates macrophages. IL20 and
other cytokines promote bone resorption by osteoclasts. DCs also produce IL15, which promotes FLS survival and TH1
differentiation, and IL21, which promotes follicular helper T (TFH)-cell differentiation and antibody production.

STAT6. Like JAKs, the various STATs transmit signals for mutations of STAT3 cause hyper IgE syndrome (also
different cytokine receptors. However, a degree of func- known as Job syndrome), which is characterized by
tional promiscuity exists: in certain situations, one par- dermatitis, elevated levels of IgE, susceptibility to bac-
ticular STAT protein can transmit signals for cytokines terial pulmonary infection, connective tissue disorders,
that would usually signal through another STAT protein. and bone abnormalities49. Conversely, gainoffunction
Both activating and inactivating mutations of STATs STAT3 mutations cause early-onset lymphoproliferative
can cause abnormalities in immune function (TABLE 3). disease and autoimmunity50. STAT5 deficiency manifests
Lossoffunction mutations in STAT1 or STAT2 cause with immunodeficiency and autoimmunity, as well as
immunodeficiency41. STAT1 gainoffunction mutations dwarfism attributable to the role of STAT5 in mediating
lead to chronic mucocutaneous candidiasis via inhibi- growth-hormone signalling51,52. Genome-wide associ
tion of IL17 production41. Autoimmunity has also been ation studies have established links between STAT3 and
reported in association with STAT1 gainoffunction Behet disease47, Crohn disease53, and psoriasis53, whereas
mutations, likely due to increased signalling downstream STAT4 polymorphisms are associated with RA and SLE54.
of IFN-, IL21, and IL6 (REF.48). Dominant negative Finally, polymorphisms in STAT6, which mediates IL4

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Table 2 | JAKs associated with human disease have reasonable kinome selectivity. Interestingly, none of
the first-generation Jakinibs are good TYK2inhibitors56.
JAK Disease(s) associated with gain of function Disease(s) associated
with loss of function
Tofacitinib
JAK1 Acute lymphoblastic leukaemia, acute N/A The first Jakinib developed for the treatment of auto-
myelogenous leukaemia, solid organ
malignancies
immune diseases was tofacitinib, which inhibits JAK1,
JAK3 and, to a lesser extent, JAK2 (REF.57). After prom-
JAK2 Polycythemia vera, myelofibrosis, essential N/A ising results in preclinical and early-phase clinical trials
thrombocythemia, hypercoagulable state,
somatic mutations associated with acute and for various immune-mediated diseases41, tofacitinib was
chronic haematologic malignancies extensively evaluated in pivotal trials in 2012. Multiple
JAK3 Acute megakaryoblastic leukaemia, Tcell SCID, Jacobsen syndrome phaseII and III studies demonstrated that tofacitinib was
leukaemias and lymphomas effective for RA as monotherapy or in combination with
DMARDs, for treatment-naive or DMARD-refractory
TYK2 Cutaneous lymphoproliferative disorders, Primary
Tcellleukaemias immunodeficiency disease, and even for disease refractory to treatment
JAK, Janus kinase; N/A, not applicable; SCID, severe combined immunodeficiency;
with biologic agents5862. Tofacitinib was superior to
TYK,tyrosine kinase. methotrexate in the treatment of naive patients63 and as
effective as adalimumab62. Two clinical trials assessing
Table 3 | STATs associated with human disease MRI and radiographic responses in nearly 1,000 patients
indicated that tofacitinib halts structural damage and
STAT Disease(s) associated Disease(s) associated Disease(s) associated erosive disease61,63,64. Based on these findings, tofacitinib
with gain of function wih loss of function with polymorphism
was approved by the US FDA for the treatment of patients
STAT1 Chronic Susceptibility to N/A with RA with inadequate response to methotrexate.
mucocutaneous mycobacterial and Tofacitinib has also been found to be effective in the
candidiasis viral infections
treatment of psoriasis and psoriatic arthritis65, being non
STAT2 N/A Increased N/A inferior to etanercept6567. However, the FDA has declined
susceptibility to viral
infections to approve tofacitinib for psoriasis. This may be because
higher doses of tofacitinib (10mg twice daily) than the
STAT3 Lymphoproliferative Autosomal-dominant Behet disease, IBD, AS approved dose for RA (5mg twice daily) were required
disease and hyper IgE syndrome
autoimmunity, LGL for optimal efficacy. The higher dose (10mg twice daily)
was not approved by the FDA because of concerns
STAT4 N/A N/A RA, SLE
regarding adverse events68. Studies also indicate that
STAT5a, Somatic mutations Autoimmunity, N/A continuous therapy results in more durable remission,
STAT5b associated with LGL bleeding diathesis, although up to 60% of patients can recapture a response
immunodeficiency
anddwarfism when treated intermittently69. Tofacitinib is also an effi-
cacious treatment for ulcerative colitis70 and possibly for
STAT6 N/A N/A Asthma, atopy, high
serum IgE Crohn disease, although results in the latter are incon-
sistent71. In prophylaxis of kidney transplant rejection,
AS, ankylosing spondylitis; IBD, inflammatory bowel disease; LGL, large granulocytic
leukaemia; N/A, not applicable; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; tofacitinib preserves renal function better than stand-
STAT, signal transducer and activator of transcription. ard-ofcare with calcineurin inhibitors, by preventing
tubular atrophy and interstitial fibrosis72.
signalling, are associated with atopy and asthma55. Thus,
a large body of evidence points to a critical role for JAKs Ruxolitinib and baricitinib
and STATs in the pathogenesis of rare and common The JAK1 and JAK2 inhibitor ruxolitinib was actually the
disorders of human immunity. first FDA-approved Jakinib, for the treatment of myelo-
proliferative disease41. However, ruxolitinib seems to be
Jakinibs in autoimmune diseases efficacious in models of preclinical arthritis73, and results
The success of biologic therapies in treating auto of a phaseII trial in RA are promising (ClinicalTrials.gov
immunity notwithstanding, the prospect of new identifier NCT00550043).
alternativesnamely blocking key cytokines by tar- Another JAK1 and JAK2 inhibitor, baricitinib,
geting their signal transduction pathways with small has shown efficacy in the treatment of RA, in which
moleculesoffers a novel and exciting opportunity for settinglike tofacitinibit is effective in patients with
treating disease (FIG.2). This possibility was recognized disease refractory to treatment with DMARDs and TNF
in 1995 (REF.43), but the development of JAK inhibitors inhibitors7477. Baricitinib halts radiographic disease
(Jakinibs) faced several important challenges. One impor- progression, with significant differences in erosions and
tant consideration is that most Jakinibs act as competi- joint-space narrowing, particularly at the higher dose
tive inhibitors of ATP41 (FIG.3)and all kinases have some of 4mg twice daily, and to a lesser degree with 2mg
degree of homology. Despite such challenges, differences twicedaily7477.
in kinase structure can be capitalized upon to generate
inhibitors that exhibit some degree of specificity. First- Oclacitinib
generation Jakinibs (tofacitinib, ruxolitinib, baricitinib Oclacitinib is a nonselective Jakinib approved for the
and oclacitinib) inhibit more than one JAK but seem to treatment of eczema in dogs. Orally administered

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JAKs use ATP to phosphorylate substrates Jakinibs block ATP binding to JAKs
FERM FERM
SH2 SH2

N-lobe P P
N-lobe
N-lobe P N-lobe Jakinib

C-lobe C-lobe
C-lobe C-lobe

P P P P P P
Pseudokinase Pseudokinase
N Kinase N Kinase
C C
Figure 3 | JAKs are composed of several key domains including a tyrosine kinase domain, Nature pseudokinase domain,
Reviews | Rheumatology
FERM (band four-point-one, ezrin, radixin, moesin) domain, and SH2 (Src homology 2) domain. The tyrosine
kinase domain binds ATP hydrolysing it to ADP and catalyses both autophosphorylation and other substrates including
signal transducers and activators of transcription (STATs). JAK, Janus kinase (JAK) inhibitors (Jakinibs) bind to the pocket
ordinarily occupied by ATP, thereby preventing JAKs from using ATP and phosphorylating their substrates.

Jakinibs are not currently being tested for the treatment pneumococcus and VZV before initiating this therapy, as
of allergic diseases in humans; however, the efficacy of is also recommended with other biologicagents.
oclacitinib in canine atopic dermatitis78 demonstrates In renal transplant recipients, higher rates of BK
that inhibition of JAKs can disrupt key signalling path- polyomavirus infection were seen in those treated with
ways that drive allergic inflammation79. These findings tofacitinib than with ciclosporin, although the drugs
have paved the way for clinical trials of topical tofa were used in the setting of combination immuno
citinib for the treatment of atopic skin disease in humans suppressive therapy89. While most of these infections
(ClinicalTrials.gov identifier NCT02001181). do not result in nephropathy, a trend towards higher
rates of BK polyomavirus-associated nephropathy in
Adverse effects of Jakinibs tofacitinib-treated patients was observed89. Clinical tri-
As with other effective therapies in autoimmune dis- als and long-term extension studies have not revealed
ease, Jakinibs are not without side effects. Many of similar issues in patients with RA82,83, but clearly this
the adverse effects of Jakinibs can, like their therapeu- potential risk must be monitored as new Jakinibs emerge
tic efficacy, be directly traced to their mechanism of for various clinical indications and as part of combined
action: blocking JAK-dependent cytokine signalling. treatment regimens.
Because more patients have been treated with tofa
citinib than other agents, we know the most about this Lipid effects
drug; however, the adverse effect profile of baricitinib Increases in levels of total cholesterol, LDL cholesterol,
seemscomparable7477. and HDL cholesterol have been noted in clinical trials
of tofacitinib41,82,83 This side effect is also seen with IL6
Infection receptor (IL6R) blocker tocilizumab90,91 IL6 promotes
An obvious concern with the use of any immuno insulin resistance and redistributes fatty acids from the
modulatory drug is the risk of infection, and in clinical blood to peripheral tissues, thereby decreasing serum
trials increased rates of infections have been demon- lipids91,92. Thus, treatment-induced changes in lipid lev-
strated in tofacitinib-treated patients. These infections els may or may not correlate with rates of cardiovascu-
were mainly upper respiratory tract infections, urinary lar disease. The results of clinical trials and long-term
tract infections, and viral gastroenteritis. However, seri- extension data do not indicate an increased risk of cardio
ous cases of tuberculosis, fungal infection, Pneumocystis vascular disease with tofacitinib use82,92. On the contrary,
jirovecii pneumonia, and bacterial pneumonia were tofacitinib can improve arterial stiffness, suggesting that
reported as well 65,72,8083. Given the broad range of it might improve cardiovascular outcomes in patients
cytokines that can be affected by tofacitinib, this outcome with RA93. In this context, tofacitinib-induced hyper
was not unexpected. cholesterolaemia could be cardioprotective. Indeed,
The risk of infection with tofacitinib use is compar patients with RA commonly have low total, HDL, and
able to that with other biologic agents82,83, with one LDL cholesterol levels and a discordantly increased risk
exception: the risk of varicella zoster virus (VZV) infec- of cardiovascular disease92. Moreover, Jakinibs alter
tion seems to be increased82,84. This increase could be lipoprotein kinetics94 and increase LDL particle size94.
attributable to the effects of tofacitinib on IFN or IL15 Jakinibs also confer metabolic properties of brown fat
signalling, the latter being a key cytokine for NKcell to white adipocytes by uncoupling the respiratory chain
homeostasis85. However, NK cell counts are only mod- and increasing mitochondrial activity95, a novel and
erately reduced in tofacitinib-treated patients and do provocative mechanism by which JAK blockade might
not correlate with infection risk86,87. Tofacitinib-treated reduce cardiovascular risk. Needless to say, the meta
patients also have impaired responses to vaccination88, bolic effects of JAK blockade are complex and deserve
soclinicians are encouraged to immunize patients against furtherattention.

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Table 4 | Jakinibs being investigated for rheumatologic diseases malignancy96. However, as is the case with biologic
therapies, whether Jakinib-treated patients are truly
Drug Target(s) Status Disease(s) at increased risk of cancer is unclear. In RA trials, the
Ruxolitinib JAK1, JAK2 FDA approved RA risk of malignancy in tofacitinib-treated patients was
(INC424)
PhaseII Various cancers not significantly increased82. Although tofacitinib is
associated with anincreased risk of nonmelanoma skin
PhaseIIb Psoriasis (topical) cancer, the effect size is similar to that seen with other
Tofacitinib JAK3, JAK1, FDA approved RA biologic agents such as TNF inhibitors81. When Jakinibs
(CP690550) JAK2 have been used for transplant-rejection prophylaxis in
PhaseIII Psoriasis, ulcerative colitis
PhaseII Spondyloarthritis, JIA
combination with other immunosuppressive drugs, the
risk of developing post-transplant lymphoproliferative
Oclacitinib JAK1 FDA approved Canine allergic dermatitis disease (PTLD) isincreased72.
(PF03394197)
ABT494 JAK1 PhaseII RA, Crohn disease New applications for Jakinibs
Baricitinib JAK1, JAK2 PhaseII RA, psoriasis, diabetic The future of therapies that target JAKs and the
(INCB28050, nephropathy, cytokines that signal through them is only starting to
LY3009104) autoinflammatory disease emerge (TABLE4). One need only consider the example
Filgotinib JAK1 PhaseII RA, Crohn disease of tocilizumab to see the potential applicability of JAK
(GLPG0634) blockade to a wide variety of immune-mediated diseases.
INCB039110 JAK1, JAK2 PhaseII Psoriasis, RA Initially used for the treatment of RA, tocilizumab is now
Peficitinib pan-JAK PhaseII Psoriasis, RA approved foruse in polyarticular juvenile idiopathic
(ASP015K) arthritis (JIA) and systemic-onset JIA97,98 and has been
R333 JAK/SYK PhaseII Discoid lupus (topical) used successfully to treat large-vessel vasculitis99, poly
myalgia rheumatica100, amyloid A (AA) amyloidosis101,
GLG0778 JAK1 PhaseII SLE
spondyloarthritis102, SSc103, and myositis104, among other
GSK2586184 JAK1 PhaseII SLE, psoriasis rheumatologic diseases. As IL6 is clearly blocked by
Decernotinib JAK3 PhaseIIb RA existing Jakinibs, these diseases should be reasonable
(VX509) settings in which to test JAK blockade.
Table4 includes Jakinibs that are FDA-approved, or in clinical trials, for the treatment of Alopecia areata is characterized by an IFN and c
autoimmune diseases. JAK, Janus kinase; Jakinib, JAK inhibitor; JIA,juvenile idiopathic arthritis; cytokine gene signature88. Tofacitinib, ruxolitinib, and
RA,rheumatoid arthritis; SLE, systemic lupus erythematosus; SYK,spleen tyrosine kinase.
baricitinib have all been used successfully to treat alo
pecia areata and alopecia universalis105108, and clini-
Because all first-generation Jakinibs inhibit JAK2, cal trials in these diseases are ongoing (ClinicalTrials.
which mediates erythropoietin, thrombopoietin, IL11, gov identifiers NCT02299297, NCT02197455,
GCSF and GMCSF signalling, patients treated with NCT02312882, NCT01950780). Preliminary evi-
these agents can develop cytopenias, especially anaemia; dence indicates that tofacitinib could be equally effec-
generally, this effect is not necessarily a cause for discon- tive in the treatment of vitiligo109, and that inhibition
tinuation of treatment. Other adverse effects reported of JAKSTAT signalling causes hair growth through
in clinical trials include minimal elevations in serum initiation ofanagen110.
transaminases41 and reductions in glomerular filtration The presence of the typeI IFN gene signature in
rate80. Neither of these laboratory abnormalities seems SLE, myositis, primary Sjgren syndrome, and SSc, and
to indicate any substantial end-organ damage, with perhaps a subset of RA patients, suggests that Jakinibs
the possible exception of BK polyomavirus-associated might be useful in these settings27,28,111,112. A case of
nephropathy82. refractory dermatomyositis was indeed reported to
respond to treatment with ruxolitinib113. The potential
Other considerations for Jakinibs to treat IFN-mediated diseases has also
Although the adverse events attributed to Jakinibs in been suggested by preliminary data in patients with
clinical trials for rheumatologic diseases indicate an interferonopathiesmonogenic diseases characterized
acceptable safety profile, several additional factors war- by uncontrolled upregulation of typeI IFNs114. A com-
rant consideration. Cytokines such as IL10, IL22 and passionate use study of baricitinib in chronic atypical
IL27 have important anti-inflammatory actions; other neutrophilic dermatosis with lipodystrophy and ele-
cytokines such as IL2 have both inflammatory and vated temperature (CANDLE) and STING-associated
immunosuppressive actions. Whether suppression of vasculopathy with onset in infancy (SAVI) is ongoing115
these anti-inflammatory actions will be clinically rele (ClinicalTrials.gov identifier NCT01724580).
vant in the context of inflammatory cytokine blockade An important consideration involves the opti-
remains to be determined. mal dosing and route of administration for Jakinibs.
Finally, the potential role of JAK inhibition in Although the current paradigm of continuous low-level
tumour development warrants discussion. Because dosing is comparable to that of DMARDs and other
IFNs, IL12,and other cytokines contribute to the maintenance therapies, it is possible that Jakinibs might
elimination and destruction of tumours, prolonged be most effective when used in high doses to induce
blockade of JAKSTAT signalling might promote remission followed by tapering to much lower doses.

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Moreover, topical formulations of tofacitinib improve targeted several other tyrosine kinases120. At present,
symptoms of dry eye disease116, and are being investi- ~20Jakinibs are in clinical trials for various autoimmune
gated for psoriasis and eczema (ClinicalTrials.gov iden- conditions including autoinflammatory disease, RA,
tifiers NCT01831466, NCT02193815, NCT02001181, psoriasis and psoriatic arthritis, SLE, JIA, spondyloar-
and NCT00678561). If these formulations prove as thritis, discoid lupus, ulcerative colitis, atopic dermatitis,
efficacious as systemic therapy, they could funda- and diabetic nephropathy (ClinicalTrials.gov identi-
mentally alter the treatment of diseases that affect fiers NCT01458574, NCT01724580, NCT01687309,
a single organ systemincluding pulmonary and NCT01500551, NCT01597050, and NCT02001181).
gastrointestinaldiseases.
Targeting STATs?
Jakinibs: the next generation In principle, cytokine signalling could also by blocked by
The assessment of the adverse events associated with inhibiting STAT activation, interrupting STATreceptor
tofacitinib led the European Medical Agency to refuse interactions, blocking STAT dimerization, or interfer-
marketing approval for tofacitinib for the treatment of ing with STATDNA binding41,121. These strategies have
RA. Other agencies had a different view of the relative been considered especially in cancer, in which con-
risks and benefits of this drug. As with any immuno stitutive JAKSTAT activation is a common event41.
modulatory drug, the goal is to identify regimens that However, unlike JAKs, STATs are not enzymes, and
provide efficacy at the minimal effective dose. As more generating drug candidates suitable for clinical use
experience is gained with tofacitinib and other Jakinibs has been difficult owing to challenges of bioavail
in a range of disorders, we should have a better under ability, invivo efficacy, and selectivity; for instance,
standing of the risks and benefits of these agents, and STAT3, a heavily investigated target in the treatment of
perhaps more insights into optimal dosing and regimens solid-organ malignancy, has a high degree of homology
in real-world usage. Whether the assessment of the rela with STAT1. Moreover, STATs represent convergent end-
tive benefits and risks of baricitinib and other agents in points for multiple signalling pathways with critical roles
development will or will not be viewed similarly to those in tumour prevention and host defence122. These issues
of tofacitinib remains to be seen. must be considered if STATs are to be targeted in the
However, with the demonstrated efficacy of multiple treatment of rheumatologicdiseases.
first-generation Jakinibs that exhibit kinome selectivity
but target multiple JAKs, the question naturally arises Conclusions
whether targeting a single JAK would be superior. Might Cytokines that signal through JAKs and STATs are fun-
such agents exhibit similar efficacy with fewer adverse damental drivers of host defence, immunity, and inflam-
events? Conversely, though, agents that block fewer mation. Advances in the understanding of cytokine
JAKs by definition block fewer inflammatory cytokines, biology, and of the links between cytokine regulation and
which could negatively affect their therapeutic efficacy. autoimmunity, have sparked a revolution in the treat-
Indeed, development of second-generation Jakinibs with ment of rheumatologic diseases over the past 15years.
a greater degree of JAK selectivity is underway. PhaseI However, the continuing burden of immune-mediated
and II trials seem to indicate that the JAK1 inhibitor diseases clearly demonstrates that novel forms of therapy
filgotinib117 and the JAK3 inhibitor decernotinib118,119 are needed. The emergence of small-molecule targeted
are effective for the treatment of RA. Several important therapies represents a new era owing to the ability of
questions will need to be answered as these and other these agents to simultaneously block multiple signalling
selective Jakinibs emerge on the clinical scene. The pathways. Tofacitinib is the first targeted small molecule
apparent selectivity of these agents needs to be verified to be approved for use in rheumatologic diseases and is
invivo, by examining lymphoid, myeloid, and eryth- likely to be joined by a number of other Jakinibs. A new
roid compartments for signs that other JAKsespe- chapter in the treatment of immune-mediated diseases
cially JAK2are being affected. Furthermore, even has begun, in which the paradigm has been fundamen-
if an inhibitor is exquisitely selective for one JAK over tally shifted yet again. The next 5years will be a crucial
another, selectivity is not necessarily ensured across time, as we learn how to best use Jakinibs and other
the kinome. This was the case for a recently developed small-molecule inhibitors for the treatment of the vast
class of reversible covalent JAK3 inhibitors that also array of autoimmune diseases encountered by clinicians.

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Author contributions
leading to the abnormal lipid profile in patients with treatment of vitiligo: a pathogenesis-directed therapy.
All authors researched the data, provided a substantial
rheumatoid arthritis versus healthy volunteers and JAMA Dermatol. 151, 11101112 (2015).
contribution to discussions of the content, contributed to
reversal by tofacitinib. Arthritis Rheumatol. 67, 110. Harel,S. etal. Pharmacologic inhibition of JAKSTAT
writing the article, and reviewed/edited the manuscript before
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conversion of human adipocytes by JAK inhibition. 111. Bennett,L. etal. Interferon and granulopoiesis Competing interests statement
Nat. Cell Biol. 17, 5767 (2015). signatures in systemic lupus erythematosus blood. J.J.OS. declares that he and the US Government receive
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&Smyth,M.J. New insights into cancer 112. Banchereau,J. &Pascual,V. Type I interferon in J.J.OS. and M.G. and the US Government have had
immunoediting and its three component systemic lupus erythematosus and other autoimmune longstanding Cooperative Research and Development
phaseselimination, equilibrium and escape. diseases. Immunity 25, 383392 (2006). Agreements with Pfizer, which produces tofacitinib, a Janus
Curr.Opin. Immunol. 27, 1625 (2014). 113. Hornung,T. etal. Remission of recalcitrant kinase inhibitor.
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PressAnnouncements/ucm251572.htm (2011). pulmonary syndrome. N.Engl. J.Med. 371, 507518 FURTHER INFORMATION
98. Genentech. Medicine offers a new option for the (2014). ClinicalTrials.gov: http://www.clinicaltrials.gov
treatment of polyarticular juvenile idiopathic arthritis 115. Montealegre Sanchez,G.A. etal. Lipodystrophy and ALL LINKS ARE ACTIVE IN THE ONLINE PDF
(PJIA). Genetech [online], http://www.gene.com/media/ elevated temperatures (CANDLE): clinical

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