JAK/STAT pathway targeting in primary Sjögren syndrome

Abstract

Primary Sjögren's syndrome (pSS) is an autoimmune systemic disease mainly affecting exocrine glands and resulting in disabling symptoms, as dry eye and dry mouth. Mechanisms underlying pSS pathogenesis are intricate, involving multiplanar and, at the same time, interlinked levels, e.g., genetic predisposition, epigenetic modifications and the dysregulation of both immune system and glandular-resident cellular pathways, mainly salivary gland epithelial cells. Unravelling the biological and molecular complexity of pSS is still a great challenge but much progress has been made in recent years in basic and translational research field, allowing the identification of potential novel targets for therapy development. Despite such promising novelties, however, none therapy has been specifically approved for pSS treatment until now. In recent years, growing evidence has supported the modulation of Janus kinases (JAK) - signal transducers and activators of transcription (STAT) pathways as treatment strategy immune mediated diseases. JAK-STAT pathway plays a crucial role in autoimmunity and systemic inflammation, being involved in signal pathways of many cytokines. This review aims to report the state-of-the-art about the role of JAK-STAT pathway in pSS, with particular focus on available research and clinical data regarding the use of JAK inhibitors in pSS.

Full text

Review • DOI: 10.2478/rir-2022-0017 • 3(3) • 2022 • 95–102
RHEUMATOLOGY AND IMMUNOLOGY RESEARCH
95
Introduction
Primary Sjögren’s syndrome (pSS) is an autoimmune systemic
disease which mainly a󰀨ects exocrine glands and causes dis-
abling symptoms, such as dry eye and dry mouth.[1,2] Besides
sicca, fatigue and pain are the other most common symptoms
in pSS patients, together with a wide range of possible addi-
tional and highly heterogeneous clinical extra-glandular mani-
festations, potentially involving any organ.[1,2] Furthermore,
pSS patients are at higher risk than general population to
develop lymphoma, mainly a non-Hodgkin B cell lymphoma of
mucosa-associated lymphoid tissue (MALT) type.[3,4] Females
are most a󰀨ected by pSS than males, with a ratio 9:1, but an
increased risk of lymphoma development has been recent-
ly reported for the latter.[5] The histological hallmark of pSS,
i.e., the focal lymphocytic sialadenitis, observed in speci-
mens obtained through minor salivary gland (MSG) biopsy,
still represents, together with anti-SSA (Sjögren’s-syndrome-
related antigen A) autoantibodies, a crucial pillar for pSS
JAK/STAT pathway targeting in primary Sjögren
syndrome
Saviana Gandolfo1, Francesco Ciccia2,*
1Rheumatology Unit, Department of Internal Medicine, San Giovanni Bosco Hospital, Naples, Italy
2Department of Precision Medicine, Università della Campania Luigi Vanvitelli, Naples, Italy
Received May 18, 2022 accepted June 25, 2022
Primary Sjögren’s syndrome (pSS) is an autoimmune systemic disease mainly a󰀨ecting exocrine glands and resulting
in disabling symptoms, as dry eye and dry mouth. Mechanisms underlying pSS pathogenesis are intricate, involving
multiplanar and, at the same time, interlinked levels, e.g., genetic predisposition, epigenetic modications and the
dysregulation of both immune system and glandular-resident cellular pathways, mainly salivary gland epithelial cells.
Unravelling the biological and molecular complexity of pSS is still a great challenge but much progress has been made
in recent years in basic and translational research eld, allowing the identication of potential novel targets for therapy
development. Despite such promising novelties, however, none therapy has been specically approved for pSS treat-
ment until now. In recent years, growing evidence has supported the modulation of Janus kinases (JAK) - signal trans-
ducers and activators of transcription (STAT) pathways as treatment strategy immune mediated diseases. JAK-STAT
pathway plays a crucial role in autoimmunity and systemic inammation, being involved in signal pathways of many
cytokines. This review aims to report the state-of-the-art about the role of JAK-STAT pathway in pSS, with particular
focus on available research and clinical data regarding the use of JAK inhibitors in pSS.
Sjögren’s syndrome • JAK molecules • STAT molecules • cytokines
Abstract
Keywords
Address for correspondence:
*Francesco Ciccia, MD, PhD, Professor of Rheumatology, University della
Campania L. Vanvitelli, Via S. Pansini 5, 80127 Naples Italy. Telephone and
Fax: +390815666752. E-mail: francesco.ciccia@unicampania.it
classication.[6]
Mechanisms underlying pSS pathogenesis are intricate, in-
volving multiplanar and, at the same time, interlinked levels,
e.g., genetic predisposition, epigenetic modications, and
the dysregulation of both the immune system and glandular-
resident cellular pathways, mainly salivary gland epithelial
cells (SGECs).[1,7–9] SGECs are not only damaged by the in-
ammatory process but are leading actors actively involved in
several immune pathophysiology pSS processes.[7,8] Infectious
and/or exogenous agents might be involved in triggering the
disease in predisposed individuals, enhanced by endogenous
factors.[10] Unraveling the biological and molecular complexity
of pSS is still a great challenge, but much progress has been
made in recent years in the basic and translational research
eld, allowing the identication of potential novel targets for
therapy development. Despite such promising novelties,[11]
however, no therapy has been specically approved for pSS
treatment until now.[12]
In recent years, growing evidence has supported the modula-
tion of Janus kinases (JAK)–signal transducers and activators
of transcription (STAT) pathways as a treatment strategy for

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rheumatoid arthritis (RA) and spondyloarthritis (SpA), lead-
ing to the development of clinical trials and, nally, to the ap-
proval of di󰀨erent JAK inhibitors (JAK-i) agents for clinical use
in RA and SpA.[13–15] JAK-STAT pathway plays a crucial role in
autoimmunity and systemic inammation and are involved in
signal pathways of many cytokines, and, for this reason, an
increasing number of clinical trials with JAK-i have been per-
formed even on other immune-mediated systemic diseases
beyond RA and SpA, such as connective tissue diseases.[16]
This review aims to report the state of the art about the role of
JAK-STAT pathway in pSS, with particular focus on available
research and clinical data regarding the use of JAK-i in pSS.
JAK-STAT Pathway and pSS Cytokine Landscape
The family of JAK-STAT molecules, including 4 JAK intracel-
lular tyrosine kinases (i.e., JAK1, JAK2, JAK3, and TYK2)
and seven transcription factors STAT (STAT1, STAT2, STAT3,
STAT4, STAT5a and 5b, and STAT6), represents a crucial
system involved in the transduction of signaling of several
cytokines related to immune responses, inammation, cell
activation, and survival.[17] Following the cytokine binding to
its receptor on the cell membrane, JAK transfers phosphates
from ATP (adenosine triphosphate) to intracellular domains
of the cytokine receptor, to JAK members themselves, and
to other downstream signaling molecules, such as STAT, that
translocate to the nucleus and modulate the expression of
dened gene sets.[17]
JAK-STAT dysregulation has been associated with di󰀨erent
immune system disorders.[18] Therefore, JAK-i, which causes
competitive ATP binding and blocks the abovementioned cas-
cade of events and gene expression has become an excel-
lent novel therapeutic strategy in rheumatology.
Several JAK-i have been or are being developed, includ-
ing rst-generation pan-JAK-i, i.e., tofacitinb, baricitinib,
ruxolitinib, and pefacitinib and second-generation more se-
lective JAK-i, i.e., lgotinib, upadacitinib, and decernotinib.
Tofacitinib acts by blocking JAK1 and JAK3 but has also a
role in JAK2 and TYK2 inhibition and is the rst oral JAK-i
approved for the treatment of RA[19–21] and psoriatic arthritis
(PsA).[22] Baricitinib is a JAK1 and JAK2 inhibitor used in RA
treatment,[23] such as lgotinib[24,25] and upadacitinb,[26,27] that
inhibits more selectively JAK1. Given the high number of cy-
tokines signaling through JAK-STAT, the revolutionary impact
of oral anti-JAK small molecule therapy lies in being able to
simultaneously block multiple cytokines and the related path-
ways, e󰀨ectively overcoming the direct block of single cyto-
kines that is at the basis of therapies with biotechnological
anti-cytokine drugs (Figure 1). In the context of pSS, this also
translates into the possibility of nding and developing ef-
fective therapies that target multiple pathways with a single
drug, whereas anti-cytokine biotechnological therapies have
instead dramatically failed in several clinical trials.[12]
The cytokine landscape characterizing pSS is extremely com-
plex and heterogeneous. Among cytokines signaling through
JAK-STAT, IL-6, IL-7, IL-21, and IL-23 have been demonstrated
to be potentially involved in pSS pathogenesis. The classical
pro-inammatory cytokine IL-6 has been found to be increased
in serum, saliva, and tears of patients with pSS and linked to
the pathogenesis of the disease.[28–30] Despite the pathogenetic
contribution of IL-6 in crucial immune processes such as the
di󰀨erentiation and activation of both B and T cells, the use of
tocilizumab, a recombinant humanized monoclonal antibody act-
ing as an IL-6 receptor antagonist, did not improve systemic in-
volvement and symptoms over 24 weeks of treatment compared
with placebo in a multicenter double-blind randomized placebo-
controlled trial in pSS patients.[31] IL-21 is a key cytokine in the type
I interferon (IFN) signaling pathway, in the generation of follicu-
lar subtypes, and IL-17–producing T helper (Th) cells, as well as
in plasma cell di󰀨erentiation and B-cell activation. High levels of
IL-21 have been demonstrated in the pSS sera, which are cor-
related with lower memory B-cell and higher naïve B-cell per-
centages.[32,33] RNA sequencing of MSG also demonstrated
signicantly increased levels of IL-21 and IL-21-inducible genes
such as IL-21R, JAK3, STAT1, HLA-B, CCR7, and C-X-C motif
ligand 10 (CXCL10) in pSS patients.[34] The increased IL-21
signature gene expression was associated with an increased
EULAR Sjögren’s Syndrome Disease Activity Index score
(ESSDAI)[35] and increased enrichment of B cells, memory B
cells, CD4+ T cells, and CD8+ T cells.[34] Interestingly, the ex-
pansion of IL-21 T-follicular-helper (Tfh) under the control of
ICOS (inducible co-stimulator) has been demonstrated as a
characteristic of pSS with ectopic germinal centers and MALT
lymphoma.[36]
IL-23A is a pro-inammatory cytokine required for Th17 and
innate lymphoid cells (ILC) 3 maintenance and expansion
and the production of type 3 cytokines such as IL-17 and
IL-22. Intense IL-23 expression has been demonstrated,
Figure 1: Main cytokines signaling through JAK-STAT involved in pSS
pathogenesis.

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of the immune system.[51] The hyperexpression of IFN sys-
tems in pSS is sustained by chronic reverberating processes,
such as autoantigenic overload and lack of control mecha-
nisms, that act together with genetic susceptibility and epi-
genetic modications.[52] Despite the di󰀨erence between IFNs
in signaling via specic cell surface receptor complexes,
they activate some common downstream pathways, where
JAK-STAT is one of the most crucial ones among them.[51]
Targeting JAK-STAT can therefore result in the modulation
of biological consequences of IFN activation. In pSS, type
I IFN plays a central role in initiating and enhancing inam-
mation in the context of salivary glands, where it is mainly
released by plasmacytoid dendritic cells (pDCs) and SGECs
after an exogenous, likely viral or bacterial, or endogenous,
e.g., autoantigens, trigger.[52] By the expression of more than
2000 genes, the biological e󰀨ects of type I IFN are impressive
and range from innate responses, such as the maturation
of DC with expression of costimulatory molecules, antigen
presentation, and upregulation of chemokines, to T and B
lymphocyte stimulation and activation.[51,52] Among others, in
fact, following type I IFN release, crucial adaptive immune re-
sponses occur, e.g., the stimulation of CD8+ lymphocytes, the
di󰀨erentiation of Th1 and Th17 lymphocytes, the suppression
of T regulatory (Treg) lymphocyte activity, and the induction
of B-cell hyperactivity, by both enhancing the B-cell activating
factor (BAFF) release and lowering of B-cell receptor (BCR)
threshold required for B-cell activation.[52] B-cell dysregula-
tion is one of the most impacting pillars in pSS pathogenesis
leading to both autoimmunity and lymphoproliferation that
accounts for many clinical manifestations and the risk of lym-
phoma evolution in about 5%–10% of pSS patients.[3,4] Type
II IFN sources in pSS are mainly T lymphocytes, but also NK,
B cells, macrophages and, to a less extent, DC, being this
system involved in antimicrobial protection, apoptosis, in-
ammation and tissue damage.[51] Very novel data report the
presence of an amplication loop between interleukin IL-7,
a pivotal cytokine in T-cell responses and T-cell–dependent
activation of SGECs and B lymphocytes in pSS, and IFN-γ,
supporting the role of the IFN system as a bridge milestone
connecting leading actors in pSS pathogenesis, i.e., SGECs,
T and B cells.[45] Recently, many studies also focused on type
III IFN, with increasing evidence of possible contribution to
both autoimmune and malignant disorders.[53,54]
Classically, pSS has been indicated as a type I IFN-driven
disease,[52] but discrepancies in di󰀨erent IFN signatures
expression between peripheral blood and MSG biopsies
have been reported also in the same patient, with a predomi-
nant type I IFN signature in the former and type II in the lat-
ter samples.[46] Higher IFN-γ transcriptional levels were ob-
served in MSG biopsies of patients developing lymphoma,[46]
suggesting a possible contribution of IFN systems also in
the prediction of the risk of lymphoma evolution in pSS.[46,55]
Other authors reported 3 di󰀨erent subsets of IFN expression
in MSG biopsies from pSS patients, i.e., purely type I, purely
by immunohistochemical staining, in submandibular glands
of C57BL/6.NOD-Aec1Aec2 mice and in pSS salivary gland
biopsies within lymphocytic foci and on epithelial tissues.[37,38] IL-
23 increased expression is associated in pSS salivary glands
with the increased expression of IL-17 and IL-17 producing
cells, mainly Th17 and ILC3.[37] According to the increased
IL-23 expression, IL-22 and STAT3 are also signicantly
increased at both protein and mRNA levels in the inamed
salivary glands of patients with pSS and accompanied by the
expansion of IL-22-producing cells.[37] Interestingly, Barone
et al.[39] by using a virus-induced model of autoantibody for-
mation in the salivary glands of adult mice conrmed the role
of IL-22 in pSS pathogenesis, demonstrating that IL-22 pro-
vides a mechanistic link between mucosal infection, B-cell
recruitment, and humoral autoimmunity. IL-22 receptor en-
gagement was in fact necessary and su󰀩cient to promote
di󰀨erential expression of CXCL12 and CXCL13 in epithelial
and broblastic stromal cells that, in turn, is pivotal for B-cell
recruitment and organization of the TLOs (tertiary lymphoid
organs). Accordingly, IL-22 blockade impairs and reverses
TLO formation and autoantibody production.
An increasing body of evidence suggests also a signicant
role of IL-7 axis in pSS, by driving both T-cell responses
and B lymphoneogenesis. IL-7 and its receptor IL-7Rα lev-
els have been demonstrated to be increased in pSS salivary
glands, the latter correlating with the severity of sialadenitis,
and involved in the development of pSS ectopic lymphoid
structures.[40] Interestingly, the exogenous administration of
IL-7 was able to accelerate pSS onset in a mouse model,
whereas pSS development was prevented by blocking IL-
7Rα signal, suggesting that therapeutic intervention on this
axis, by a direct block or an indirect inhibition of downstream
molecules, e.g., JAK-STAT, might be useful in pSS.[41,42] By
signaling through its receptor featuring the common IL-7Rα
chain, in addition to a specic chain named TSLPR (Thymic
stromal lymphopoietin receptor), the pathway of thymic stro-
mal lymphopoietin (TSLP), a novel biomarker for pSS and
related lymphoproliferation,[43,44] also involves JAK-STAT, and
its e󰀨ects might be modulated by JAK-i agents. Furthermore,
very recent data reported that IL-7 secreted by SGECs under
IFN inuence may activate T cells in pSS, which in turn se-
crete IFN-γ, enhancing a vicious circle that amplies one of
the main pathogenetic system in connective tissue diseases,
i.e., IFN itself.[45]
Among such a rich cytokine networking in pSS, growing
evidence supports a prominent role of type I IFN (mainly
IFN-α and IFN-β), type II (IFN-γ), and, more recently, type III
(IFN-λ) also in pSS pathogenesis, based on studies report-
ing the upregulation of IFN-regulated genes (IRGs, proling
the so-called IFN signatures) both in peripheral blood and in
MSG biopsy specimens.[46–50] IFNs are primarily involved in
host defense against infections but also in cell di󰀨erentiation,
proliferation, survival, and death and are crucial regulators

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cells, broblasts, and endothelial cells.[63] CXCL10 and its re-
ceptor CXCR3 have been involved in the pathogenesis of
pSS since they are up-regulated in pSS MSG and contrib-
ute to the chemotaxis of immune cells and their accumula-
tion in the context of inamed salivary glands.[64–66] Beside
the strong expression of JAK1 and JAK2 in MSG biopsies of
pSS patients,[57] Aota et al.[57] demonstrated that baricitinib
signicantly inhibited IFN-γ-induced CXCL10 production in
an immortalized human salivary gland ductal-cell clone and
by a western blot analysis showed also its ability to strongly
inhibit the phosphorylation of STAT1 and, to a less extent,
of STAT3. These data suggested a possible role of JAK-i
baricitinib in pSS treatment.
Very recently, the e󰀩cacy and safety of baricitinib for active
pSS patients have been explored in a pilot non-controlled
trial.[67] This study enrolled 11 pSS patients, all fullling 2016
ACR (American college of rheumatology)/EULAR (European
Alliance of Associations for Rheumatology) classication cri-
teria for pSS, showing a ESSDAI of at least 5. The improve-
ment of ESSDAI of at least 3 points has been considered as
the minimal clinical improvement expected. Other measures,
such as European pSS Patient Reported Index (ESSPRI),
Phisycian Global Assessment Score (PGA), Immunoglobulin
G (IgG), and remission/improvement of single-organ mani-
festations have been also collected and evaluated. Patients
were treated with baricitinib 2 mg per day and followed up at
3 months and 6 months after starting the therapy. Baricitinib
treatment led to a signicant ESSDAI reduction, as did with
regard to the ESSPRI and PGA. At 6 months, 88.9% patients
achieved minimal clinical improvement of ESSDAI.[67] A de-
creasing trend in IgG and ESR (Erythrocyte sedimentation
rate) levels was also observed. Main clinical manifestations
showing improvement compared with baseline were skin
rash and arthritis, consistent with the study of baricitinib in ac-
tive SLE patients,[68] weight loss, anemia, and cytopenia. Two
pSS patients with interstitial lung disease (ILD) and cough,
short of breath, and dyspnea after exertion were relieved in
symptoms, together with an improvement of lung involve-
ment in follow-up HRCT (High-resolution computed tomog-
raphy) scan. A are of HBV (hepatitis B virus) was the only
adverse event reported.[67] Besides major limitations of the
study, mainly the absence of a control group, the treatment
with baricitinib appears promising in pSS, and high-quality
randomized controlled clinical trials are needed to conrm
these preliminary results.
Filgotinib
Lee et al.[69] demonstrated that lgotinib, a selective JAK1
inhibitor, suppressed in pSS the expression of IFN-related
genes and of BAFF in human SGECs, as well as the BAFF
production in salivary gland organoids. In addition, after l-
gotinib administration in mice models, both increased sali-
vary ow rates and amelioration of lymphocytic inltration of
type II, and a mixed type I/type II pattern and described a
link between these di󰀨erent patterns and peculiar clinical
manifestations.[47] More recently, a very innovative study[48]
proposed a new classication of pSS according to results ob-
tained from a huge multi-omic analysis performed on periph-
eral blood of pSS patients and healthy volunteers, highlight-
ing a clear centrality of IFN signatures in molecular subsetting
of pSS patients. Among 4 di󰀨erent identied clusters, namely
C1, C2, C3, and C4, those pSS patients belonging to C1,
C3, and C4 were sharply characterized by specic combi-
nations between di󰀨erent magnitudes of type I and type II
IFN expression.[48] Although an integration between periph-
eral blood- and tissue-derived data is mandatory in the next
future, considering that all crucial events for pSS develop-
ment and maintenance occur in salivary glands, this novel
approach is the rst step for developing precision medicine-
driven therapies overcoming heterogeneity issues of pSS
that led in the past to the failure of many clinical trials.[12,48,56]
With regards to IFN-λ, a higher expression in MSG from pSS,
compared with non-pSS sicca control subjects, has been
demonstrated,[49] and, more recently, a synergistic e󰀨ect be-
tween IL-29, which belongs to type III IFN system, and IFN-α
in the induction of BAFF and CXCL10 by prolonged STAT1
phosphorylation in salivary gland epithelium has been also
reported.[50]
Data regarding JAK and/or STAT expression in pSS salivary
glands are limited. Aota et al.[57] demonstrated a strong JAK1
and JAK2 expression, respectively, in ductal and acinar cells
of MSG biopsies of pSS patients by immunohistochemi-
cal analysis. STAT1[58,59] and STAT3[37,60,61] expression has
been found also to be increased in pSS MSG biopsies and
linked to IFN-α, IFN-γ, and IL-6 stimulation of the former[58,59]
and to IL-22 and IL-17 overexpression[37,60,61] of the latter.
Furthermore, very recent data demonstrated that STAT3 is
also implicated in epigenetic DNA methylation/hydroxymeth-
ylation processes in pSS, mostly a󰀨ecting IFN-α- and IFN-
γ-regulated genes, as well as the oxidative stress pathways,
and that JAK-i agents (AG490 and ruxolitinib) were able to
reverse the global DNA hydroxymethylation mediated by
IFNα, IFNγ, and H2O2 in human SGECs.[62]
JAK Inhibition in pSS
Baricitinib
There are no many basic research data about JAK-i in pSS.
A recent study[57] demonstrated that baricitinib, a JAK1 and
JAK2 inhibitor, suppressed the destruction of acinar cells in
the salivary gland of pSS patients by abrogating IFN-γ-induced
CXCL10 expression and CXCL10-dependent immune cell
inltration in human salivary gland ductal cells. CXCL10 is
a chemokine induced by IFN-γ via JAK-STAT during Th1 im-
mune responses, released by peripheral blood mononuclear

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salivary glands were reported,[69] suggesting that lgotinib
might be a novel therapy to directly target salivary gland
inammation and, possibly, lymphoproliferation in pSS
patients.
Results from a multicenter, double-blind placebo-controlled
randomized phase 2 clinical trial including an arm with
lgotinib, besides other agents (i.e., lanraplenib and tirabru-
tinib), in order to assess both safety and e󰀩cacy in patients
with active pSS (ESSDAI ≥ 5), have been very recently pub-
lished.[70] Patients randomized to the lgotinib arm received
the dosage of 200 mg per day for 48 weeks. The primary
endpoint was dened as the proportion of patients fullling
at week 12 both protocol-specied improvement and non-
worsening criteria, based on C-reactive protein (CRP) and
pSS-related symptoms, assessed by the visual analog scale
(VAS) of global disease, pain, oral dryness, ocular dryness,
and fatigue. Change in ESSPRI and ESSDAI was included as
a secondary endpoint and assessed at week 12 and week 24.
Exploratory e󰀩cacy endpoints included objective tests, such
as Schirmer’s test and salivary ow (unstimulated and stimu-
lated), treatment response on specic ESSDAI domains, and
ESSDAI score change from baseline in subgroups of patients.
Exploratory biomarker-related endpoint was the change from
baseline for selected peripheral biomarkers, e.g., IgA, IgG,
IgM, rheumatoid factor (RF) and CRP, B cell and plasma cell
subset, and IFN signature, for each patient at week 4, 12,
and 24.[70]
At week 12, 43.3% of the lgotinib group achieved the primary
endpoint, although no statistically signicant di󰀨erence was
found compared with the placebo arm.[70] Neither secondary
endpoint was met. However, some notable evidence emerged
from the trial. Change of ESSDAI appeared more pronounced
after lgotinib treatment in the pSS subgroup of patients with
baseline ESSDAI ≥ 14 or without disease-modifying antirheu-
matic drugs/corticosteroids. Moreover, by week 24, greater
decreases in RF, IgM, IgG, and IgA were seen in the lgotinib
group compared with placebo, and, very interestingly, the IFN
activity was signicantly reduced from baseline at week 4 and
week 12. Cytosolic DNA sensing and chemokine signaling
pathways were also reduced by lgotinib therapy. In explor-
atory analyses, the salivary rate and tear production resulted
stabilized at similar levels compared with baseline during the
treatment with lgotinib.[70] Finally, most adverse events were
not severe, and overall safety and tolerability were consistent
with the already known safety prole. In light of this, although
primary and secondary endpoints were not met, these obser-
vations support post hoc analyses in specic subgroups of
pSS patients, possibly guided by peculiar biomarkers, which,
together with a general deep revision of pSS outcome mea-
sures for clinical trials, already ongoing,[71] might lead to tar-
get more accurately pSS patients and potentially to prove e󰀩-
cacy of promising novel therapeutic agents, such as lgotinib,
for use in clinical practice.[70]
Tofacitinib
Autophagy is one additional altered mechanism in pSS,
which is involved in several homeostatic functions and both
in innate and adaptive immune responses.[72,73] Deciency of
autophagy has been associated with increased inammation
by IL-6 and accumulation of JAK-STAT components.[74] In a
recent study,[75] Barrera et al.[75] evaluated autophagy dysreg-
ulation in pSS and its link with JAK-STAT system by analyzing
MSG biopsies from both pSS patients and control subjects
and by generating autophagy-decient (ATG5 knockdown)
3 dimensional (3D) salivary glands acini, which were then
incubated in the presence or in absence of the JAK1 and
JAK3 blocking agent tofacitinib. MSG from pSS patients
showed decreased ATG5 expression, correlating negatively
with increased activation of STAT1 and STAT3. Increased ex-
pression of STAT1 and IL-6 correlated with ESSDAI and the
presence of anti-SSA antibodies.[75] ATG5-decient 3D-acini
showed also increased expression of pro-inammatory cyto-
kines such as IL-6, interestingly reversed by tofacitinib.[75]
Ruxolitinib
The biological e󰀨ects of ruxolitinib, a JAK1 and JAK2 inhibi-
tor, on mesenchymal stromal cells (MSCs), isolated from sali-
vary glands of both pSS patients and controls, have been
recently evaluated in vitro.[76] A ruxolitinib-mediated inhibi-
tion of IFN-γ-induced expression of MSC immunomodulatory
markers, such as HLA-DR (Major histocompatibility complex
(MHC) II cell surface receptor) expression, has emerged by
these experimental studies, together with the block of CD4+
T cell chemotaxis through the inhibition of MSC production of
CXCL9, CXCL10, and CXCL11, suggesting potential implica-
tions for ruxolitinib in pSS therapy.[76]
Conclusions
JAK-STAT inhibition has become in recent last years a new
therapeutic option approved for clinical use in immune-
mediated disorders and tested in an increasing number of
clinical trials for other autoimmune diseases, including pSS.
The variegate cytokine landscape signaling through the JAK-
STAT system and, among others, the prominent importance
of IFN pathways in both pSS pathogenesis and patient sub-
setting suggest the potential role of JAK-i in treating pSS by
modulating crucial molecular and biological events for the
disease development and maintenance. In vitro and in vivo
data seem to support this hypothesis, together with encour-
aging results from clinical trials, despite the inadequacy of
outcome measures available at the moment. However, many
e󰀨orts have still to be dedicated to more clearly elucidate the
e󰀨ects of blocking JAK-STAT pathways in pSS, not only in
the perspective of controlling inammation but also in that of
rescuing the homeostatic complex functions of the salivary
gland epithelium.[77]

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Conict of Interest
Francesco Ciccia is an Editorial Board Member of the journal. This article was subject to the journal’s standard procedures, with peer review
handled independently of this member and his research group.
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