The Journal of Allery and Clinical immunology

The emerging role of Janus kinase inhibitors in the treatment of autoimmune and
inflammatory diseases
William Damsky, MD, Danielle Peterson, MD, Julie Ramseier, BS, Badr Al-Bawardy,
Hyung Chun, Deborah Proctor, Vibeke Strand, Richard A. Flavell, Brett King, MD

1 The emerging role of Janus kinase inhibitors in the treatment of autoimmune and
2 inflammatory diseases
William Damsky MD*,1, Danielle Peterson MD1
Julie Ramseier BS1
Badr Al-Bawardy2
3 Hyung Chun3
4 Deborah Proctor2
Vibeke Strand4
Richard A. Flavell5,6, Brett King MD*,1 4

5 Department of Dermatology, Yale School of Medicine, New Haven, Connecticut, USA.
6 Division of Digestive Diseases, Yale School of Medicine, New Haven, Connecticut,
7 USA.
8 Division of Cardiovascular Medicine, Yale School of Medicine, New Haven,
9 Connecticut, USA.
10 Division of Immunology/Rheumatology, Stanford University School of Medicine, Palo
11 Alto, CA
12 Department of Immunobiology, Yale School of Medicine, New Haven, CT, USA.
13 Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT,
14 USA.
15 *Authors to whom correspondence should be addressed: Department of Dermatology,
16 Yale School of Medicine, 333 Cedar St, LCI 501, PO Box 208059, New Haven,
17 Connecticut, USA, 06510. Phone: 203-785-4092, Fax: 203-785-7637
24 WD is supported by a Career Development Award form the Dermatology Foundation.
25 BK is supported by the Ranjini and Ajay Poddar Fund for Dermatologic Diseases
26 Research. RAF is a Howard Hughes Medical Institute Investigator.

28 Competing Interests
29 DP, JR, BAB, DDP have no disclosures. WD has research support from Pfizer, has
30 served as a consultant for Eli Lilly and receives licensing fees from
31 EMD/Sigma/Millipore in unrelated work. HC receives research support from Pfizer. VS
32 serves as a consultant to Abbvie, Amgen Corporation, Arena, AstraZeneca, Bayer,
33 Blackrock, Bioventus, BMS, Boehringer Ingelheim, Celltrion, Concentric Analgesics,
34 Crescendo / Myriad Genetics, EMD Serono, Equilium, Eupraxia, Flexion, Galapagos,
35 Genentech / Roche, Gilead, GSK, Horizon, Ichnos, Inmedix, Janssen, Kiniksa, Kypha,
36 Lilly, Merck, MiMedx, MyoKardia, Novartis , Pfizer, Regeneron, Samsung, Samumed,
37 Sandoz, Sanofi, Servier, Setpoint, Tonix, UCB. BK is an investigator for Concert
38 Pharmaceuticals Inc, Eli Lilly and Company, and Pfizer Inc. RAF is a consultant for
39 GlaxoSmithKline and Zai Lab Limited. BK is a consultant to and/or has served on
40 advisory boards for Aclaris Therapeutics, Arena Pharmaceuticals, Bristol-Meyers
41 Squibb, Concert Pharmaceuticals Inc, Dermavant Sciences, Eli Lilly and Company,
42 Pfizer Inc, and VielaBio; he is on speaker’s bureau for Pfizer Inc, Regeneron and Sanofi
43 Genzyme.

47 Abstract
48 Autoimmune and inflammatory diseases are common, diverse, and they can affect
49 nearly any organ system. Much of the pathogenesis of these diseases relates to
50 dysregulated cytokine secretion. Historically, autoimmune and inflammatory diseases
51 have been treated with medications that non-specifically suppress the immune system.
52 Monoclonal antibodies that block the action of pathogenic cytokines emerged two
53 decades ago and have become widely useful. More recently, agents that simultaneously
54 block multiple pathogenic cytokines via inhibition of the downstream Janus kinase-
55 signal transducer and activator of transcription (JAK-STAT) pathway have emerged and
56 are becoming increasingly important. These targeted synthetic drugs, collectively
57 termed JAK inhibitors, are FDA approved in a few autoimmune disorders and are being
58 evaluated in many others. Here we review the biology of the JAK-STAT pathway and
59 the use of JAK inhibitors to treat autoimmunity across medical subspecialties.

95 Autoimmune diseases are diverse
96 The incidence of autoimmune and inflammatory diseases is on the rise. Autoimmune
97 disorders are currently estimated to affect 3-5% of the population in Western
countries.1–3 98 Autoimmunity and some inflammatory disorders are thought to develop as
99 a result of a complex and incompletely understood interplay among various factors.
100 Host genetics, microbiota, and environmental factors lead to dysregulated T and/or B
101 cell activity against the host causing tissue damage. Rare autoinflammatory syndromes
102 are caused by inherited mutations. Immune responses also play an important role in
103 atopic diseases, including asthma and atopic dermatitis, and will also be considered
104 herein. Despite the varied aspects of autoimmunity, secreted cytokines are thought to
105 play a central role in these diseases, which makes them amenable to treatment with
106 overlapping approaches.
107
108 Cytokines regulate immune and other responses
109 Cytokines are a group of structurally diverse secreted proteins produced by both
110 immune and other host cells that facilitate cellular communication. Cytokines are most
111 well known for their role in regulating immune responses, both protective and
112 autoimmune responses alike. Cytokines act on target cells through specific receptors.
113 For example, interferon-gamma (IFN-γ) produced by a T cell can bind to the IFN-γ
114 receptor on a macrophage and change its behavior. Cytokines can act in an autocrine,
115 paracrine, and occasionally endocrine manner. They are often given the designation
116 “interleukin”, abbreviated as “IL” (for example, IL-2). Not all cytokines, however, follow
117 this nomenclature; tumor necrosis factor alpha (TNF-α), IFN-γ, prolactin, and
118 erythropoietin are all cytokines.
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123 Non-specific immunosuppressive therapies
124 In the absence of a specific target, one way to suppress an aberrant immune response
125 is to globally suppress T cell immunity (Figure 1). Glucocorticoids are agents commonly
126 used to achieve this goal and likely represent the most significant advance ever made in
the treatment of autoimmune diseases.4
127 Glucocorticoids such as prednisone act rapidly,
128 but are very non-specific immunosuppressants, with broad activity against both immune
129 and other cell types.
130
131 As steroid receptors are expressed widely, adverse effects of glucocorticoids are
132 common and so their use in the management of chronic autoimmune diseases is
133 minimized as much as possible. Steroid-sparing immunosuppressants (anti-proliferative
134 agents and calcineurin and mTOR inhibitors) are often employed when long-term
135 therapy is needed. Agents such as thalidomide and lenalidomide are also sometimes
136 used and are thought to suppress TNF- α/NF-κB signaling (Figure 1). However,
137 collectively, these drugs are also relatively non-specific and not always adequate (Table

140 Molecularly targeted therapy: therapeutic monoclonal antibodies block the
141 activity of cytokines

142 Cytokine activity can be inhibited with therapeutic monoclonal antibodies and soluble
143 receptors (Figure 1 and Table 2). This class of medications is often referred to as
144 “biologics”. The first biologic approved for the treatment of autoimmune disease was
145 infliximab, a chimeric monoclonal antibody against TNF-α. It was approved by the Food
146 and Drug Administration (FDA) for treatment of Crohn’s disease in 1998 and then
rheumatoid arthritis (RA) in 1999.5
147 Since then, multiple TNF-α inhibitors have been
148 widely successful for the treatment of several diseases including RA, psoriasis and
149 psoriatic arthritis, spondyloarthritis, and inflammatory bowel disease (IBD). These
150 biologics have paved the way for other therapeutic antibodies, including inhibitors of IL-
151 4/13, IL-5, IL-6, IL-12/23, IL-17, and IL-23, among others.
152
153 Molecularly targeted therapy: small molecule inhibitors that block cytokine
154 signaling via the JAK-STAT pathway
155 Once a cytokine binds its receptor on the surface of a target cell, downstream signaling
156 ensues. Interrupting this signaling cascade is another way to inhibit cytokine activity.
157 The role of JAK inhibitors in this process and their use in treating autoimmune disease
158 is the focus of the remainder of the review.
159
160 Some cytokines signal via the JAK-STAT pathway
161 There are more than 200 cytokines. Cytokines and their receptors are grouped
162 according to their structure into different families (Table 3). The hematopoietin super
163 family of cytokine receptors encompasses a broad group that includes receptors for
164 immune (i.e. IL-2, IL-4, IFN-γ), hematopoietic (erythropoietin, thrombopoietin, GM-CSF)
165 and non-immune (i.e. prolactin, leptin, growth hormone) cytokines. There are more than
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50 hematopoietin family cytokines.6–9 166 These cytokines are also referred to as 4α-helical
167 cytokines, and they signal via the JAK-STAT pathway. Other cytokines and chemokines
168 signal via other, non-JAK-STAT dependent, mechanisms (Table 3).
169
170 The JAK-STAT pathway
171 The hematopoietin family of cytokine receptors lack intrinsic enzymatic activity and thus,
172 after cytokine binding, rely on JAK enzymes to transmit their signals intracellularly.
173 JAKs, or Janus kinases, were named based on two tandem kinase-like domains,
174 reminiscent of the two-headed mythical Roman god “Janus” and were discovered nearly
30 years ago.10 175 Humans have 4 JAK enzymes: JAK1, JAK2, JAK3, and tyrosine kinase
176 2 (TYK2). While JAK3 expression is largely restricted to immune cells, JAK1, JAK2, and
TYK2 are widely expressed.11 177 Specific JAKs selectively associate with specific cytokine
178 receptors in pairs (usually heterodimers) (Figure 2). For example, IFN-γ signals via the
179 IFN-γR (receptor), which associates with JAK1 and JAK2, whereas IL-2 signals via the
180 IL-2R, which associates with JAK1 and JAK3. Given that more than 50 cytokines rely on
181 these 4 JAKs, there is significant overlap in use of JAK proteins among cytokines
182 (Figure 2).
183
184 Cytokine binding induces receptor dimerization and activation of JAK kinase activity,
185 ultimately resulting in activation of STAT proteins (Figure 3). In humans, there are 7
186 STAT proteins (STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6).
187 Phosphorylation of STATs allows them to dimerize and translocate to the nucleus where
188 they act as transcription factors. As with the JAKs, there is both specificity but also
189 redundancy in STAT usage by specific cytokines. For example, binding of IL-4 to its
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190 receptor results in activation of STAT6 homodimers (via JAK1/JAK3), whereas binding
191 of IL-12 and IL-23 to their receptors results in activation of STAT4 homodimers (via
192 JAK2/TYK2). Specificities of STAT proteins in cytokine signaling has been reviewed in
detail elsewhere.12 193
194
195 Loss of cytokine-JAK-STAT signaling causes immunodeficiency
196 JAK-STAT signaling is required for proper immune function. Germline inactivation of
JAK1 or JAK2 is lethal.13–15 197 JAK3 inactivation causes autosomal recessive severe
198 combined immunodeficiency (SCID), characterized by lack of T and B cell activity.
199 Inactivation of IL2RG, an essential receptor component of multiple JAK-STAT
200 dependent cytokines (γc cytokines), also causes SCID. STAT-inactivating mutations can
manifest as both immunodeficiency and autoimmunity.12,16 201 Autoimmunity is thought to
result from loss of inhibitory cross talk between STATs.17 202 For example, Job syndrome
203 (hyper-IgE syndrome) is due to impaired STAT3 function and is characterized by
204 recurrent skin and sinopulmonary infections in addition to atopic dermatitis, high
Immunoglobulin E (IgE) levels, and eosinophilia.18 205
206
207 Overactivation of cytokine-JAK-STAT signaling causes autoimmune disease and
208 cancer
209 While inactivating mutations in JAKs and STATs can cause immunodeficiency,
210 activating mutations can lead to autoimmunity or cancer. For example, inherited STAT3
211 activating mutations cause autoimmune syndromes with phenotypes including neonatal
diabetes and lymphoproliferative disorders.19 212
213
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214 Additionally, polymorphisms in JAK and STAT genes and upstream JAK-STAT
215 dependent cytokines/receptors implicate this pathway in the pathogenesis of a wide
216 spectrum of autoimmune disorders (Table S1). For example, IL2RA polymorphisms are
217 associated with an increased risk for multiple sclerosis, Type I diabetes, and RA. IL-12,
IL-23, and TYK2 polymorphisms are common in psoriasis, Crohn’s disease and SLE.20 218
219 Atopic dermatitis and asthma are associated with IL-4, IL-4R, and STAT6
220 polymorphisms, consistent with the role of IL-4 and downstream JAK-STAT signaling in
Th2 responses.21 221 Indeed, in many autoimmune diseases, a variant of at least one JAK-
222 STAT-related gene has been described (Table S1).
223
224 Somatic gain-of-function mutations are also commonly found in JAK genes in a variety
of hematologic and solid tumors (reviewed elsewhere22 225 ). The mutations typically make
226 the JAK constitutively active, rendering the pathway always “on”. For example,
227 activating JAK2 mutations (most commonly V617F) are found in polycythemia vera,
essential thrombocytopenia, and myelofibrosis23–25 228 ; an observation leading to the
229 development of JAK inhibitors to treat these disorders, as discussed below.
230
231 JAK inhibitors are approved for the treatment of rheumatoid arthritis, psoriatic
232 arthritis, ulcerative colitis and myeloproliferative neoplasms
233 Five drugs are now FDA approved for the treatment of autoimmune diseases as well as
234 myeloproliferative disorders that harbor JAK activating mutations. Current JAK inhibitors
235 are called “Type I” kinase inhibitors, as they bind to the active conformation of the
236 enzyme and block the ATP binding pocket in the catalytic domain. They are orally
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237 administered small molecules (Table 2). While the first generation of JAK inhibitors
238 block multiple JAKs, some newer ones are more selective for individual JAKs.
239
240 Ruxolitinib and Fedratinib
241 Ruxolitinib was the first FDA approved JAK inhibitor and preferentially blocks JAK1 and
242 JAK2 (Table 4). It was FDA approved in 2011 for the treatment of the JAK2-mutant
myelofibrosis and subsequently for polycythemia vera.26,27 243 Recently, ruxolitinib was
approved for the treatment of acute graft-versus-host-disease (GVHD).28 244 Fedratinib is a
245 recently approved JAK2 inhibitor for the treatment of myelofibrosis.
246
247 Tofacitinib
248 Tofacitinib was the first JAK inhibitor developed to treat autoimmune disease and was
249 initially studied both in RA and for prevention of allograft rejection. Tofacitinib inhibits
JAK1 and JAK3 and to a lesser extent JAK2.29 250 It was FDA approved for the treatment of
RA in 2012 and subsequently psoriatic arthritis and ulcerative colitis.30,31 251
252
253 Baricitinib and Upadacitinib
254 Baricitinib is structurally similar to ruxolitinib, and baricitinib also inhibits JAK1 and
255 JAK2; it was FDA approved in 2018 for the treatment of RA. Upadacitinib is a JAK1
256 inhibitor, FDA approved in 2019 for RA. Filgotinib, another JAK1 inhibitor, is currently
257 under FDA review for the treatment of RA.
258
259 JAK inhibitors are being tested across the spectrum of autoimmune diseases
260 Dermatology: Alopecia areata, vitiligo, psoriasis and atopic dermatitis
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261 Alopecia areata (AA) and vitiligo are cutaneous autoimmune diseases that result from T
262 cell responses against hair follicles and melanocytes, respectively. These dermatologic
263 disorders are challenging to treat. Recently, identification of IFN-γ and IL-15 (JAK-
264 STAT-dependent cytokines) as central mediators of disease pathogenesis in these two
disorders32,33 265 paved the way for clinical evaluation of the efficacy of JAK inhibitors.
266 Open-label trials in both AA and vitiligo suggested efficacy of tofacitinib and ruxolitinib,
leading to large clinical trials, of which early results confirm efficacy.32,34–43 267 . JAK
268 inhibitors have shown efficacy and are in Phase 3 clinical trials in psoriasis (IL-12, IL-
23)44 and atopic dermatitis (IL-4, IL-13).45,46 269 . There is emerging evidence of efficacy of
270 JAK inhibitors for less common dermatologic disorders including lichen planus,
morphea, and granuloma annulare, among others (see Table S2).
47,48 271 Topically applied
272 JAK inhibitors clearly have a role in dermatology and are actively being investigated
273 (discussed briefly below).
274
275 Rheumatology: Inflammatory arthritis, sarcoidosis and lupus
276 Systemic lupus erythematosus (SLE) is a quintessential autoimmune disease and can
277 affect multiple organ systems. The pathogenesis of lupus is complex, but in part it is
278 related to JAK-STAT-dependent cytokines including Type I interferons (IFN-α/β), and
blocking JAK signaling ameliorates lupus in murine models.49 279 In a randomized trial of
280 314 patients with inadequately controlled SLE, treatment with baricitinib 4 mg resulted in
281 resolution of arthritis and rash in 67% of patients compared to 53% in the placebo group
after 6 months50 282 . JAK inhibitors have been used successfully in sporadic chilblain
lupus51 and for lupus-like manifestations of autoinflammatory disorders52,53 283 or
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284 “interferonopathies” (Figure 4). Additional clinical trials will help clarify the role of JAK
285 inhibition in the treatment of lupus.
286
287 Sarcoidosis is a multisystem disorder characterized by macrophage activation in tissue
288 resulting in granuloma formation and tissue damage. JAK-STAT-dependent cytokines,
particularly IFN-γ, are likely involved in pathogenesis,54 289 and we have recently shown
290 that treatment with tofacitinib in patients with recalcitrant cutaneous sarcoidosis resulted
in clinical and histologic remission of disease.55,56 291 Others have reported efficacy of
ruxolitinib.57–59 292 Clinical trials evaluating the efficacy of JAK inhibitors in sarcoidosis are
293 underway.
294
JAK inhibitors are FDA approved for RA and psoriatic arthritis30 295 . There is evidence of
296 efficacy of JAK inhibitors in juvenile idiopathic arthritis (JIA) and dermatomyositis and
297 they are additionally being trialed in axial spondyloarthropathy, systemic sclerosis
298 (SSc), polymyositis, and giant cell arteritis (Figure 4).
299
300 Gastroenterology: Inflammatory bowel disease
301 The cytokines IL-6, IL-12, IL-23, and IFN-γ are important mediators of IBD and signal via
the JAK-STAT pathway.60 302 Hence, JAK inhibition is an appealing treatment modality for
303 IBD. Tofacitinib was FDA approved for ulcerative colitis (UC) in 2018 and is currently
304 the only FDA approved JAK inhibitor for IBD. Tofacitinib has been shown to be effective
305 in inducing and maintaining clinical and endoscopic remission compared to placebo in
UC in both the TNF-inhibitor (TNFi) naïve and experienced patients.61 306 A phase 2 trial of
tofacitinib in Crohn’s disease (CD) failed to meet the primary endpoints.62 307 Study design,
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308 high placebo response rates and concomitant immunosuppressive therapy have been
309 hypothesized to underlie this failure. A recent systematic review and meta-analysis of
310 clinical trials of multiple JAK inhibitors (tofacitinib, filgotinib, pefecitinib, upadicitinib, TD-
1473) suggests that JAK inhibition can induce remission in CD.63 311 Selective JAK1
312 inihbitors such as filgotinib and upadicitinib have demonstrated efficacy in phase 2 trials
for CD and UC and are currently in phase 3 trials.64,65 313
314
315 JAK inhibitors will be an important part of and may even revolutionize the treatment
316 paradigm in IBD. In comparison to biologic agents, they are oral rather than intravenous
317 or injectable and have a rapid onset of action (Table 2). For example, improvement in
318 symptoms such as rectal bleeding and stool frequency were noted within 3 days of
starting tofacitinib in UC patients.66 319
320
JAK-STAT signaling may also be involved in NASH,67 321 and JAK inhibitors have been
322 reported to be effective in other disorders including eosinophilic esophagitis (IL-4, IL-5,
IL-13).68 323
324
325 Pulmonology: Asthma
326 Asthma is an atopic disorder characterized by a Th2 predominant immune response
327 and increased IL-4, IL-5, and IL-13 production and is thought to have overlapping
328 pathogenesis with atopic dermatitis. Although systemic use of JAK inhibitors has not yet
329 been pursued in asthma, inhaled JAK inhibitors are an area of great interest. For
330 example, iJak381, an inhaled JAK inhibitor is currently in clinical development for
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asthma.69 331 Additionally, study of JAK inhibitors in pulmonary diseases with fibrotic
332 manifestations are also being investigated (see below).
333
334 Hematology: Hemophagocytic lymphohistiocytosis, hypereosinophilic syndrome,
335 and graft-versus-host disease
336 Hemophagocytic lymphohistiocytosis (HLH) is a poorly understood syndrome
337 characterized by cytokine-driven macrophage activation leading to multi-organ failure
and high rates of mortality.70 338 Patients with HLH have marked elevation of many
339 cytokines (often referred to as a “cytokine storm”) in blood, including JAK-STAT
dependent cytokines such as IFN-γ, IL-2, and IL-6.71 340 Based on the efficacy of JAK
inhibitors in murine models of primary HLH72,73 341 and their known inhibitory effect on
342 cytokine signaling, JAK inhibitors have been used to treat both primary and secondary
HLH.74–77 343 Several clinical trials using JAK inhibitors in HLH are underway. JAK
344 inhibitors are also being evaluated in other settings with cytokine storm-like physiology
345 including in patients with moderate or severe SARS-CoV-2 infection.
346
347 Hypereosinophilic syndrome (HES) encompasses a group of disorders characterized by
increased eosinophil abundance and activation.78 348 HES, in many cases, is thought to be
driven by dysregulated IL-5, a prominent eosinophil cytokine.79 349 Tofacitinib and ruxolitinib
were effective in five patients with HES.80 350 Further clinical study is currently underway.
351 We and others have shown that tofacitinib effectively suppressed refractory drug
352 induced hypersensitivity syndrome, a severe drug reaction in which eosinophils play an
important role in pathogenesis.81,82 353

358 Cardiovascular: potential to suppress cardiac inflammation
359 Inflammation of cardiac muscle, otherwise known as myocarditis, can manifest
360 secondary to various infectious and noninfectious conditions, including after viral or
361 bacterial illnesses, related to inflammatory processes such as drug induced
362 hypersensitivity syndrome, and in response to emerging cancer therapeutics such as
363 immune checkpoint inhibitors. While the clinical presentation can be highly variable,
364 clinical outcomes may be devastating if not recognized in a timely manner. Current
365 treatment approaches include supportive measures to manage new onset heart failure
366 and/or arrhythmia.
367
368 Previously, immunosuppressive therapies have been evaluated for myocarditis with
369 varying degrees of success. Corticosteroids have not demonstrated reliable
370 improvement in clinical outcomes, and trials of cyclosporine and azathioprine also failed
to demonstrate benefit.84 371 JAK inhibition has yet to be tested in a randomized controlled
372 trial in myocarditis, but given its immunomodulatory profile, consideration of its use in
373 specific patient populations with myocarditis is warranted. We recently reported two
374 patients who developed myocarditis associated with drug induced hypersensitivity
375 syndrome; marked improvement in their LV ejection fraction closely correlated with use
of tofacitinib.85 376 While the utility of JAK inhibitors in this setting needs further evaluation,
377 this approach shows promise.

379 Tissue fibrosis
380 Tissue fibrosis is a feature of some autoimmune diseases including scleroderma and
381 idiopathic pulmonary fibrosis. The pathogenesis of tissue fibrosis is not completely
382 understood but may be a byproduct of uncontrolled inflammation. Although medical
383 therapy can lessen the aberrant immune response in these disorders, it can be difficult
384 to halt the pro-fibrotic cascade and no currently available therapies are thought to have
the ability to specifically prevent or reverse fibrosis.86 385 Interestingly, the JAK-STAT
386 pathway has been shown to be activated in autoimmune disorders where fibrosis is
observed, including SSc 87–89 and idiopathic pulmonary fibrosis.90 387 In mouse models of
SSc and liver fibrosis, JAK1 and STAT3 have been shown to control fibrosis.87,91 388
389 Although evaluation of JAK inhibitors in fibrotic disorders is in its infancy, we have
390 shown that tofacitinib treatment can result in clinically relevant reversal of fibrosis in
391 cutaneous fibrosing disorders such as generalized morphea and eosinophilic
fasciitis.92,93 392

394 GVHD often has fibrotic manifestations, and the JAK1/2 inhibitor, ruxolitinib, has been
used successfully in the treatment of both acute and chronic GVHD.83,94,95 395 In a series of
396 12 patients with sclerodermatous (fibrotic) GVHD, ruxolitinib was shown to result in
significant softening of sclerotic skin lesions in 8 out of 12 patients.96 397
398
399 Practical considerations with JAK inhibitor use

401 Screening of patients prior to and monitoring during therapy

402 Prior to starting treatment, the following evaluation should be performed: complete
403 blood count with differential (CBC), creatinine, liver function tests (LFTs), fasting lipid
404 panel, and tuberculosis screening. Screening for hepatitis A, B and C viruses and HIV
405 infection should be considered. Recommendations for laboratory monitoring during
406 treatment vary somewhat between JAK inhibitors (Table 4) but, in general, the following
407 monitoring is appropriate. After starting treatment, CBC and LFTs should be checked at
408 1 month and fasting lipid panel at 2-3 months. If fasting lipids are normal, then monitor
409 these only as the patient would normally be monitored. Thereafter, monitoring of CBC
410 and LFTs should be performed periodically. In general, cytopenias and other laboratory
411 anomalies are uncommon, are typically mild when they do occur, and are reversible
with cessation of therapy.97 412 In patients with bone marrow dysfunction (i.e.
413 myeloproliferative neoplasms), ruxolitinib dosing may be limited by platelet counts (a
414 dosing algorithm based on platelet counts is described in the package insert). Patients
415 should be screened for tuberculosis infection annually. Use of JAK inhibitors in patients
416 with a history of malignancy, blood clots, immunodeficiency, peptic ulcer disease, and
417 diverticulitis should be considered on a case-by-case basis (see below).
418
419 Vaccinations
420 Patients should not receive live vaccines while taking a JAK inhibitor. The Shingrix®
421 recombinant zoster vaccine and the pneumococcal and tetanus vaccines are safe in
patients already taking a JAK inhibitor and have been shown to be effective.98 422 Patients
423 whom are not immune to HAV or HBV may also benefit from vaccination before or
424 during use of a JAK inhibitor.
425
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426 Pregnancy, lactation, and pediatrics
427 Pregnant patients were excluded from studies involving JAK inhibitors and, based on
428 this, use of JAK inhibitors in pregnancy should be avoided. Some retrospective data in
this area is available.99 429 Similarly, use during lactation is also not advised. Use of JAK
inhibitors has been reported in pediatric patients with JIA100, GVHD101, AA102 430 , and auto￾inflammatory syndromes52,103 431 , though the numbers of patients are relatively small. JAK-
432 STAT signaling is required for growth hormone signaling and has important roles in
bone/skeletal development;104 433 therefore, until there are data from large clinical trials,
434 use of JAK inhibitors in pediatric patients should be considered on an individual basis.
435
436 Safety
JAK inhibitors seem to have comparable safety to TNF-α inhibitors.105 437 To date, the JAK
438 inhibitors approved for autoimmune diseases have a black box warning (see below).
439 While ruxoltinib does not have a black box warning, it is likely not because its safety
440 profile is different than other JAK inhibitors but because it is indicated for hematologic
441 diseases with high mortaility and that affect relatively few people (compared with
442 autoimmune diseases); relatively small risks of malignancy, infection, and thrombosis
443 may be considered differently in these populations. Only currently approved JAK
444 inhibitors will be considered below; fedracitinib, a new JAK2 inhibitor is not dicussed.
445 Needless to say but important to highlight is that as new JAK inhibitors emerge and this
446 class of medicine becomes increasingly used, the safety profile will become increasingly
447 well understood.
448
449 Malignancy
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450 As with TNF-α blockers, there is a theoretical risk that JAK inhibitors could impair
451 immune surveillance of incipient malignancy in the body, i.e. inhibtion of IFN-γ activity.
452 There is, however, no clearly increased risk of malignancy for either tofacitinib or
baricitinb in RA.105,106 453 Although the current data is reassuring, additional long-term
454 monitoring is required before the malignancy signal can be more comprehensively
455 assessed.
456
457 Infections
458 Rates of serious infections in patients taking JAK inhibitors are rather low and
comparable to biologic agents including TNF-α inhibitors.107 459 With tofacitinib, community-
460 acquired pneumonia, urinary tract infection, and skin and soft tissue infections were the
most common infections.108,109 461 There is an increased risk of herpes zoster in patients
taking JAK inhibitors.110 462 The incidence of herpes zoster in tofacitinib-treated UC patients
463 has been shown to be elevated in the maintance period (5.1% in the tofacitinib 10 mg
464 twice daily group vs 0.5% in the placebo group) but not in the induction period (0.6% in
the tofacitinib 10mg group vs 0.4% in the placebo group).111,112 465
466
467 Patients with latent tuberculosis may undertake treatment with isoniazid during JAK
inhibitor therapy, an issue considered in detail elsewhere.113 468 Development of
opportunistic infections is possible, but uncommon.113 469 Compared to other therapies,
470 such as monoclonal antibodies, JAK inhibitors have short half-lives and so the
471 immunomodulatory effect can be rapidly reversed when the effect of the drug is
472 temporarily undesirable in the setting of an acute infection (Table 2).
473
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474 Gastrointestinal perforation
475 Gastrointestinal perforation has been reported in patients taking JAK inhibitors, in
476 particular in the RA clinical trials. Although the mechanism of this effect is unclear, it has
477 also been observed with IL-6 blocking antibodies (and methotrexate), suggesting that
478 the effect might be IL-6 dependent. Many patients in RA trials were also taking
concomitant NSAIDs and/or prednisone. This topic has been recently reviewed114 479 .
480
481 Thrombosis
482 The black box warning for baricitinib, tofacitinib, and upadacitinib includes deep vein
thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis.115 483 For tofacitinib,
484 in particular, there was an increased risk in patients 50 years of age and older with at
485 least one cardiovascular risk factor and taking high-dose tofacitinib (10 mg twice daily);
486 these patients also had a higher risk of mortality.
487
488 Overall, the risk of DVT/PE and arterial thrombosis appears to be relatively low and may
489 be disease specific. In a post-hoc analysis of the pivotal UC clinical trials of tofacitinib,
VTE occurred in 5 patients and all had additional risk factors for VTE.116 490 Additional
491 studies will be needed to more accurately quantify these risks and define the
mechanism by which they occur. 117 492 Nonetheless, this risk should be discussed with
493 patients. The issue is complex and unresolved, but has been considered in detail by
Verden and colleagues.118 494

497 Currently approved JAK inhibitors are metabolized by CYP3A4 enzymes. Therefore,
498 concomitatnt use with strong inducers (e.g. rifampin) or inhibitors (e.g. ketoconazole) of
499 CYP3A4 would need to be carefully considered. In general, concomitant use with other
500 immunosuppressants is not advised, with the exception of methotrexate which can be
501 combined with JAK inhibitors, as in rheumatoid arthritis and other settings.
502
503 What’s coming: the future of JAK inhibitors
504 There are numerous JAK inhibitors in various stages of both pre-clinical and clinical
505 development. An overview of efforts to enhance efficacy and reduce adverse effects are
506 described below.

508 JAK specificity
509 The first generation JAK inhibitors inhibit multiple JAKs. More specific JAK inhibitors
510 (i.e. targeting JAK1, JAK3, or TYK2) are under development. Less activity against JAK2
511 may, for example, spare JAK2-dependent bone marrow toxicity while preserving
512 efficacy. Whereas targeting specific JAKs is predicted to reduce pleiotropy of these
513 drugs and reduce toxicity, it may also reduce efficacy (and may or may not limit toxicity
514 in practice). Yet other possibilities are agents that inhibit JAK proteins as well as other
515 kinases, e.g. JAK1 + SYK (laraplenib) and JAK3 + TEC (rittlecitinib).

517 Delivery
518 In some setting, alternate delivery of JAK inhibitors may improve their efficacy while
519 minimizing potential adverse effects. Farthest along in development are topical JAK
inhibitors in dermatology.119 520 Topical ophthalmic preparations have been evaluated in the
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clinic, for example in GVHD.120 521 Inhaled JAK inhibitors and JAK inhibitors with poor GI
522 absorption are being developed for asthma and IBD, respectively. For example, TD-
523 1473, an orally administerd gut-selective pan-JAK inhibitor, is designed to have poor
systemic absorption and has shown promising results in a phase Ib study in UC.121 524 526 Conclusions
527 Cytokines that signal via the JAK-STAT pathway appear to be dysregulated in most, if
528 not all, autoimmune and inflammatory diseases that have been studied to date. Gene
529 polymorphisms that confer risk of autoimmune disease are commonly found in JAK and
530 STAT genes, underscoring the central role that this pathway plays in autoimmunity.
531 Taken together, the growing number of diseases for which JAK inhibitors are
532 demonstrating efficacy, and the vast pipeline of JAK inhibitors in development, it is likely
533 that JAK inhibitors will become a backbone of the treatment armamentarium for
534 autoimmune diseases. These advances are central to the translational revolution that is
535 occurring in medicine, allowing clinicians to offer safer, more effective treatments to
536 their patients with autoimmune and inflammatory diseases.

Acknowledgements
539 BK is supported by the Ranjini and Ajay Poddar Fund for Dermatologic Diseases
540 Research. WD is supported by a Career Development Award from the Dermatology
541 Foundation. Figures were made with BioRender. Funding sources had no direct
542 involvement in this work. A medical writer or editor was not used.

References
558 1. Wang L, Wang F-S, Gershwin ME. Human autoimmune diseases: a
559 comprehensive update. J Intern Med [Internet]. 2015 Oct;278(4):369–95.
560 Available from: http://doi.wiley.com/10.1111/joim.12395
561 2. Cooper GS, Stroehla BC. The epidemiology of autoimmune diseases. Autoimmun
562 Rev [Internet]. 2003 May;2(3):119–25. Available from:
563 http://www.ncbi.nlm.nih.gov/pubmed/12848952
564 3. Bach J-F. The hygiene hypothesis in autoimmunity: the role of pathogens and
565 commensals. Nat Rev Immunol [Internet]. 2018;18(2):105–20. Available from:
566 http://www.ncbi.nlm.nih.gov/pubmed/29034905
567 4. HENCH PS, KENDALL EC, SLOCUMB CH, POLLEY HF. Effects of cortisone
568 acetate and pituitary ACTH on rheumatoid arthritis, rheumatic fever and certain
Journal Pre-proof
25
569 other conditions. Arch Intern Med (Chic) [Internet]. 1950 Apr;85(4):545–666.
570 Available from: http://www.ncbi.nlm.nih.gov/pubmed/15411248
571 5. Kornbluth A. Infliximab Approved for Use in Crohnʼs Disease: A Report on the
572 FDA GI Advisory Committee Conference. Inflamm Bowel Dis [Internet]. 1998
573 Nov;4(4):328–9. Available from:
574 https://academic.oup.com/ibdjournal/article/4/4/328-329/4753768
575 6. Gadina M, Le MT, Schwartz DM, Silvennoinen O, Nakayamada S, Yamaoka K, et
576 al. Janus kinases to jakinibs: from basic insights to clinical practice.
577 Rheumatology (Oxford) [Internet]. 2019 Feb 1;58(Supplement_1):i4–16. Available
578 from: http://www.ncbi.nlm.nih.gov/pubmed/30806710
579 7. Gadina M, Johnson C, Schwartz D, Bonelli M, Hasni S, Kanno Y, et al.
580 Translational and clinical advances in JAK-STAT biology: The present and future
581 of jakinibs. J Leukoc Biol [Internet]. 2018;104(3):499–514. Available from:
582 http://www.ncbi.nlm.nih.gov/pubmed/29999544
583 8. Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O’Shea JJ. JAK inhibition
584 as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug
585 Discov [Internet]. 2017 Dec;16(12):843–62. Available from:
586 http://www.ncbi.nlm.nih.gov/pubmed/29104284
587 9. Villarino A V, Kanno Y, O’Shea JJ. Mechanisms and consequences of Jak-STAT
588 signaling in the immune system. Nat Immunol [Internet]. 2017;18(4):374–84.
589 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28323260
590 10. Stark GR, Darnell JE. The JAK-STAT pathway at twenty. Immunity [Internet].
591 2012 Apr 20;36(4):503–14. Available from:
592 http://www.ncbi.nlm.nih.gov/pubmed/22520844
Journal Pre-proof
26
593 11. Kotyla PJ. Are Janus Kinase Inhibitors Superior over Classic Biologic Agents in
594 RA Patients? Biomed Res Int [Internet]. 2018;2018:7492904. Available from:
595 http://www.ncbi.nlm.nih.gov/pubmed/29862290
596 12. O’Shea JJ, Plenge R. JAK and STAT signaling molecules in immunoregulation
597 and immune-mediated disease. Immunity [Internet]. 2012 Apr 20;36(4):542–50.
598 Available from: http://www.ncbi.nlm.nih.gov/pubmed/22520847
599 13. Parganas E, Wang D, Stravopodis D, Topham DJ, Marine JC, Teglund S, et al.
600 Jak2 is essential for signaling through a variety of cytokine receptors. Cell
601 [Internet]. 1998 May 1;93(3):385–95. Available from:
602 http://www.ncbi.nlm.nih.gov/pubmed/9590173
603 14. Neubauer H, Cumano A, Müller M, Wu H, Huffstadt U, Pfeffer K. Jak2 deficiency
604 defines an essential developmental checkpoint in definitive hematopoiesis. Cell
605 [Internet]. 1998 May 1;93(3):397–409. Available from:
606 http://www.ncbi.nlm.nih.gov/pubmed/9590174
607 15. Rodig SJ, Meraz MA, White JM, Lampe PA, Riley JK, Arthur CD, et al. Disruption
608 of the Jak1 gene demonstrates obligatory and nonredundant roles of the Jaks in
609 cytokine-induced biologic responses. Cell [Internet]. 1998 May 1;93(3):373–83.
610 Available from: http://www.ncbi.nlm.nih.gov/pubmed/9590172
611 16. O’Shea JJ, Holland SM, Staudt LM. JAKs and STATs in Immunity,
612 Immunodeficiency, and Cancer. N Engl J Med [Internet]. 2013 Jan 10;368(2):161–
613 70. Available from: http://www.nejm.org/doi/10.1056/NEJMra1202117
614 17. Hu X, Chen J, Wang L, Ivashkiv LB. Crosstalk among Jak-STAT, Toll-like
615 receptor, and ITAM-dependent pathways in macrophage activation. J Leukoc Biol
616 [Internet]. 2007 Aug;82(2):237–43. Available from:
Journal Pre-proof
27
617 http://doi.wiley.com/10.1189/jlb.1206763
618 18. Zhang Q, Su HC. Hyperimmunoglobulin E syndromes in pediatrics. Curr Opin
619 Pediatr [Internet]. 2011 Dec;23(6):653–8. Available from:
620 https://insights.ovid.com/crossref?an=00008480-201112000-00015
621 19. Milner JD, Vogel TP, Forbes L, Ma CA, Stray-Pedersen A, Niemela JE, et al.
622 Early-onset lymphoproliferation and autoimmunity caused by germline STAT3
623 gain-of-function mutations. Blood [Internet]. 2015 Jan 22;125(4):591–9. Available
624 from: https://ashpublications.org/blood/article/125/4/591/33865/Earlyonset-
625 lymphoproliferation-and-autoimmunity
626 20. Enerbäck C, Sandin C, Lambert S, Zawistowski M, Stuart PE, Verma D, et al. The
627 psoriasis-protective TYK2 I684S variant impairs IL-12 stimulated pSTAT4
628 response in skin-homing CD4+ and CD8+ memory T-cells. Sci Rep [Internet].
629 2018 Dec 4;8(1):7043. Available from: http://www.nature.com/articles/s41598-
630 018-25282-2
631 21. Hershey GKK. IL-13 receptors and signaling pathways: An evolving web. J Allergy
632 Clin Immunol [Internet]. 2003 Apr;111(4):677–90. Available from:
633 https://linkinghub.elsevier.com/retrieve/pii/S0091674903006973
634 22. Thomas SJ, Snowden JA, Zeidler MP, Danson SJ. The role of JAK/STAT
635 signalling in the pathogenesis, prognosis and treatment of solid tumours. Br J
636 Cancer [Internet]. 2015 Jul 7;113(3):365–71. Available from:
637 http://www.nature.com/articles/bjc2015233
638 23. Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S, et al.
639 Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative
640 disorders. Lancet (London, England) [Internet]. 365(9464):1054–61. Available
Journal Pre-proof
28
641 from: http://www.ncbi.nlm.nih.gov/pubmed/15781101
642 24. James C, Ugo V, Le Couédic J-P, Staerk J, Delhommeau F, Lacout C, et al. A
643 unique clonal JAK2 mutation leading to constitutive signalling causes
644 polycythaemia vera. Nature [Internet]. 2005 Apr 28;434(7037):1144–8. Available
645 from: http://www.ncbi.nlm.nih.gov/pubmed/15793561
646 25. Kralovics R, Passamonti F, Buser AS, Teo S-S, Tiedt R, Passweg JR, et al. A
647 gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med
648 [Internet]. 2005 Apr 28;352(17):1779–90. Available from:
649 http://www.ncbi.nlm.nih.gov/pubmed/15858187
650 26. Verstovsek S, Kantarjian H, Mesa RA, Pardanani AD, Cortes-Franco J, Thomas
651 DA, et al. Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in
652 myelofibrosis. N Engl J Med [Internet]. 2010 Sep 16;363(12):1117–27. Available
653 from: http://www.ncbi.nlm.nih.gov/pubmed/20843246
654 27. Verstovsek S, Mesa RA, Gotlib J, Levy RS, Gupta V, DiPersio JF, et al. A double-
655 blind, placebo-controlled trial of ruxolitinib for myelofibrosis. N Engl J Med
656 [Internet]. 2012 Mar 1;366(9):799–807. Available from:
657 http://www.ncbi.nlm.nih.gov/pubmed/22375971
658 28. U.S. Food and Drug Administration. FDA approves ruxolitinib for acute graft-
659 versus-host disease. FDA NEWS RELEASE [Internet]. 2019; Available from:
660 https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-
661 ruxolitinib-acute-graft-versus-host-disease
662 29. Ghoreschi K, Jesson MI, Li X, Lee JL, Ghosh S, Alsup JW, et al. Modulation of
663 innate and adaptive immune responses by tofacitinib (CP-690,550). J Immunol
664 [Internet]. 2011 Apr 1;186(7):4234–43. Available from:
Journal Pre-proof
29
665 http://www.ncbi.nlm.nih.gov/pubmed/21383241
666 30. Berekmeri A, Mahmood F, Wittmann M, Helliwell P. Tofacitinib for the treatment of
667 psoriasis and psoriatic arthritis. Expert Rev Clin Immunol [Internet]. 2018 Sep
668 2;14(9):719–30. Available from:
669 https://www.tandfonline.com/doi/full/10.1080/1744666X.2018.1512404
670 31. U.S. Food and Drug Administration. FDA approves new treatment for moderately
671 to severely active ulcerative colitis. FDA NEWS RELEASE [Internet]. 2018;
672 Available from: https://www.fda.gov/news-events/press-announcements/fda-
673 approves-new-treatment-moderately-severely-active-ulcerative-colitis
674 32. Xing L, Dai Z, Jabbari A, Cerise JE, Higgins CA, Gong W, et al. Alopecia areata is
675 driven by cytotoxic T lymphocytes and is reversed by JAK inhibition. Nat Med
676 [Internet]. 2014 Sep;20(9):1043–9. Available from:
677 http://www.ncbi.nlm.nih.gov/pubmed/25129481
678 33. Rashighi M, Agarwal P, Richmond JM, Harris TH, Dresser K, Su M-W, et al.
679 CXCL10 is critical for the progression and maintenance of depigmentation in a
680 mouse model of vitiligo. Sci Transl Med [Internet]. 2014 Feb 12;6(223):223ra23.
681 Available from: http://www.ncbi.nlm.nih.gov/pubmed/24523323
682 34. Rothstein B, Joshipura D, Saraiya A, Abdat R, Ashkar H, Turkowski Y, et al.
683 Treatment of vitiligo with the topical Janus kinase inhibitor ruxolitinib. J Am Acad
684 Dermatol [Internet]. 2017 Jun;76(6):1054-1060.e1. Available from:
685 http://www.ncbi.nlm.nih.gov/pubmed/28390737
686 35. Joshipura D, Alomran A, Zancanaro P, Rosmarin D. Treatment of vitiligo with the
687 topical Janus kinase inhibitor ruxolitinib: A 32-week open-label extension study
688 with optional narrow-band ultraviolet B. J Am Acad Dermatol [Internet]. 2018
Journal Pre-proof
30
689 Jun;78(6):1205-1207.e1. Available from:
690 http://www.ncbi.nlm.nih.gov/pubmed/29438765
691 36. Rosmarin D, Pandya AG, Lebwohl M, Grimes P, Hamzavi I, Gottlieb AB, et al.
692 Ruxolitinib cream for treatment of vitiligo: a randomised, controlled, phase 2 trial.
693 Lancet [Internet]. 2020 Jul;396(10244):110–20. Available from:
694 https://linkinghub.elsevier.com/retrieve/pii/S0140673620306097
695 37. Simpson EL, Lacour J-P, Spelman L, Galimberti R, Eichenfield LF, Bissonnette R,
696 et al. Baricitinib in patients with moderate-to-severe atopic dermatitis and
697 inadequate response to topical corticosteroids: results from two randomized
698 monotherapy phase III trials. Br J Dermatol [Internet]. 2020 Aug;183(2):242–55.
699 Available from: http://www.ncbi.nlm.nih.gov/pubmed/31995838
700 38. Guttman-Yassky E, Thaçi D, Pangan AL, Hong HC-H, Papp KA, Reich K, et al.
701 Upadacitinib in adults with moderate to severe atopic dermatitis: 16-week results
702 from a randomized, placebo-controlled trial. J Allergy Clin Immunol [Internet].
703 2020 Mar;145(3):877–84. Available from:
704 http://www.ncbi.nlm.nih.gov/pubmed/31786154
705 39. Nakagawa H, Nemoto O, Igarashi A, Saeki H, Oda M, Kabashima K, et al. Phase
706 2 clinical study of delgocitinib ointment in pediatric patients with atopic dermatitis.
707 J Allergy Clin Immunol [Internet]. 2019;144(6):1575–83. Available from:
708 http://www.ncbi.nlm.nih.gov/pubmed/31425780
709 40. Kim BS, Sun K, Papp K, Venturanza M, Nasir A, Kuligowski ME. Effects of
710 ruxolitinib cream on pruritus and quality of life in atopic dermatitis: Results from a
711 phase 2, randomized, dose-ranging, vehicle- and active-controlled study. J Am
712 Acad Dermatol [Internet]. 2020 Jun;82(6):1305–13. Available from:
Journal Pre-proof
31
713 http://www.ncbi.nlm.nih.gov/pubmed/32057960
714 41. Kennedy Crispin M, Ko JM, Craiglow BG, Li S, Shankar G, Urban JR, et al. Safety
715 and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata.
716 JCI Insight [Internet]. 2016 Sep 22;1(15). Available from:
717 https://insight.jci.org/articles/view/89776
718 42. Mackay-Wiggan J, Jabbari A, Nguyen N, Cerise JE, Clark C, Ulerio G, et al. Oral
719 ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia
720 areata. JCI insight [Internet]. 2016;1(15):e89790. Available from:
721 http://www.ncbi.nlm.nih.gov/pubmed/27699253
722 43. Craiglow BG, King BA. Tofacitinib Citrate for the Treatment of Vitiligo. JAMA
723 Dermatology [Internet]. 2015 Oct 1;151(10):1110. Available from:
724 http://archderm.jamanetwork.com/article.aspx?doi=10.1001/jamadermatol.2015.1
725 520
726 44. Papp K, Gordon K, Thaçi D, Morita A, Gooderham M, Foley P, et al. Phase 2 Trial
727 of Selective Tyrosine Kinase 2 Inhibition in Psoriasis. N Engl J Med [Internet].
728 2018 Oct 4;379(14):1313–21. Available from:
729 http://www.nejm.org/doi/10.1056/NEJMoa1806382
730 45. Kim BS, Howell MD, Sun K, Papp K, Nasir A, Kuligowski ME. Treatment of atopic
731 dermatitis with ruxolitinib cream (JAK1/JAK2 inhibitor) or triamcinolone cream. J
732 Allergy Clin Immunol [Internet]. 2020 Feb;145(2):572–82. Available from:
733 https://linkinghub.elsevier.com/retrieve/pii/S0091674919313260
734 46. Silverberg JI, Simpson EL, Thyssen JP, Gooderham M, Chan G, Feeney C, et al.
735 Efficacy and Safety of Abrocitinib in Patients With Moderate-to-Severe Atopic
736 Dermatitis. JAMA Dermatology [Internet]. 2020 Jun 3; Available from:
Journal Pre-proof
32
737 https://jamanetwork.com/journals/jamadermatology/fullarticle/2766772
738 47. Gao W, McGarry T, Orr C, McCormick J, Veale DJ, Fearon U. Tofacitinib
739 regulates synovial inflammation in psoriatic arthritis, inhibiting STAT activation
740 and induction of negative feedback inhibitors. Ann Rheum Dis [Internet]. 2016
741 Jan;75(1):311–5. Available from:
742 http://ard.bmj.com/lookup/doi/10.1136/annrheumdis-2014-207201
743 48. Cotter DG, Schairer D, Eichenfield L. Emerging therapies for atopic dermatitis:
744 JAK inhibitors. J Am Acad Dermatol [Internet]. 2018 Mar;78(3):S53–62. Available
745 from: https://linkinghub.elsevier.com/retrieve/pii/S0190962217328207
746 49. Chan ES, Herlitz LC, Ali J. Ruxolitinib Attenuates Cutaneous Lupus Development
747 in a Mouse Lupus Model. J Invest Dermatol [Internet]. 2015 Sep;135(9):2338–9.
748 Available from: http://www.ncbi.nlm.nih.gov/pubmed/26134782
749 50. Wallace DJ, Furie RA, Tanaka Y, Kalunian KC, Mosca M, Petri MA, et al.
750 Baricitinib for systemic lupus erythematosus: a double-blind, randomised,
751 placebo-controlled, phase 2 trial. Lancet (London, England) [Internet].
752 2018;392(10143):222–31. Available from:
753 http://www.ncbi.nlm.nih.gov/pubmed/30043749
754 51. Wenzel J, van Holt N, Maier J, Vonnahme M, Bieber T, Wolf D. JAK1/2 Inhibitor
755 Ruxolitinib Controls a Case of Chilblain Lupus Erythematosus. J Invest Dermatol
756 [Internet]. 2016;136(6):1281–3. Available from:
757 http://www.ncbi.nlm.nih.gov/pubmed/26916391
758 52. Sanchez GAM, Reinhardt A, Ramsey S, Wittkowski H, Hashkes PJ, Berkun Y, et
759 al. JAK1/2 inhibition with baricitinib in the treatment of autoinflammatory
760 interferonopathies. J Clin Invest [Internet]. 2018;128(7):3041–52. Available from:
Journal Pre-proof
33
761 http://www.ncbi.nlm.nih.gov/pubmed/29649002
762 53. Vanderver A, Adang L, Gavazzi F, McDonald K, Helman G, Frank DB, et al.
763 Janus Kinase Inhibition in the Aicardi–Goutières Syndrome. N Engl J Med
764 [Internet]. 2020 Sep 3;383(10):986–9. Available from:
765 http://www.nejm.org/doi/10.1056/NEJMc2001362
766 54. Ramstein J, Broos CE, Simpson LJ, Ansel KM, Sun SA, Ho ME, et al. IFN-γ-
767 Producing T-Helper 17.1 Cells Are Increased in Sarcoidosis and Are More
768 Prevalent than T-Helper Type 1 Cells. Am J Respir Crit Care Med [Internet].
769 2016;193(11):1281–91. Available from:
770 http://www.ncbi.nlm.nih.gov/pubmed/26649486
771 55. Damsky W, Thakral D, Emeagwali N, Galan A, King B. Tofacitinib Treatment and
772 Molecular Analysis of Cutaneous Sarcoidosis. N Engl J Med [Internet].
773 2018;379(26):2540–6. Available from:
774 http://www.ncbi.nlm.nih.gov/pubmed/30586518
775 56. Damsky W, Thakral D, McGeary MK, Leventhal J, Galan A, King B. Janus kinase
776 inhibition induces disease remission in cutaneous sarcoidosis and granuloma
777 annulare. J Am Acad Dermatol [Internet]. 2019 Jun 8; Available from:
778 http://www.ncbi.nlm.nih.gov/pubmed/31185230
779 57. Rotenberg C, Besnard V, Brillet P-Y, Giraudier S, Nunes H, Valeyre D. Dramatic
780 response of refractory sarcoidosis under ruxolitinib in a patient with associated
781 JAK2-mutated polycythemia. Eur Respir J [Internet]. 2018;52(6). Available from:
782 http://www.ncbi.nlm.nih.gov/pubmed/30361243
783 58. Wei JJ, Kallenbach LR, Kreider M, Leung TH, Rosenbach M. Resolution of
784 cutaneous sarcoidosis after Janus kinase inhibitor therapy for concomitant
Journal Pre-proof
34
785 polycythemia vera. JAAD Case Reports [Internet]. 2019 Apr;5(4):360–1. Available
786 from: https://linkinghub.elsevier.com/retrieve/pii/S235251261930058X
787 59. Levraut M, Martis N, Viau P, Suarez F, Queyrel V. Refractory sarcoidosis-like
788 systemic granulomatosis responding to ruxolitinib. Ann Rheum Dis [Internet].
789 2019 Nov;78(11):1606–7. Available from:
790 http://www.ncbi.nlm.nih.gov/pubmed/31076391
791 60. Salas A, Hernandez-Rocha C, Duijvestein M, Faubion W, McGovern D, Vermeire
792 S, et al. JAK-STAT pathway targeting for the treatment of inflammatory bowel
793 disease. Nat Rev Gastroenterol Hepatol [Internet]. 2020 Jun;17(6):323–37.
794 Available from: http://www.ncbi.nlm.nih.gov/pubmed/32203403
795 61. Sandborn WJ, Su C, Sands BE, D’Haens GR, Vermeire S, Schreiber S, et al.
796 Tofacitinib as Induction and Maintenance Therapy for Ulcerative Colitis. N Engl J
797 Med [Internet]. 2017;376(18):1723–36. Available from:
798 http://www.ncbi.nlm.nih.gov/pubmed/28467869
799 62. Panés J, Sandborn WJ, Schreiber S, Sands BE, Vermeire S, D’Haens G, et al.
800 Tofacitinib for induction and maintenance therapy of Crohn’s disease: results of
801 two phase IIb randomised placebo-controlled trials. Gut [Internet].
802 2017;66(6):1049–59. Available from:
803 http://www.ncbi.nlm.nih.gov/pubmed/28209624
804 63. Ma C, Lee JK, Mitra AR, Teriaky A, Choudhary D, Nguyen TM, et al. Systematic
805 review with meta-analysis: efficacy and safety of oral Janus kinase inhibitors for
806 inflammatory bowel disease. Aliment Pharmacol Ther [Internet]. 2019;50(1):5–23.
807 Available from: http://www.ncbi.nlm.nih.gov/pubmed/31119766
808 64. Sandborn WJ, Feagan BG, Loftus E V, Peyrin-Biroulet L, Van Assche G, D’Haens
Journal Pre-proof
35
809 G, et al. Efficacy and Safety of Upadacitinib in a Randomized Trial of Patients
810 With Crohn’s Disease. Gastroenterology [Internet]. 2020 Jun;158(8):2123-
811 2138.e8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/32044319
812 65. Vermeire S, Schreiber S, Petryka R, Kuehbacher T, Hebuterne X, Roblin X, et al.
813 Clinical remission in patients with moderate-to-severe Crohn’s disease treated
814 with filgotinib (the FITZROY study): results from a phase 2, double-blind,
815 randomised, placebo-controlled trial. Lancet (London, England) [Internet].
816 2017;389(10066):266–75. Available from:
817 http://www.ncbi.nlm.nih.gov/pubmed/27988142
818 66. Hanauer S, Panaccione R, Danese S, Cheifetz A, Reinisch W, Higgins PDR, et al.
819 Tofacitinib Induction Therapy Reduces Symptoms Within 3 Days for Patients With
820 Ulcerative Colitis. Clin Gastroenterol Hepatol [Internet]. 2019;17(1):139–47.
821 Available from: http://www.ncbi.nlm.nih.gov/pubmed/30012431
822 67. Kaltenecker D, Themanns M, Mueller KM, Spirk K, Suske T, Merkel O, et al.
823 Hepatic growth hormone – JAK2 – STAT5 signalling: Metabolic function, non-
824 alcoholic fatty liver disease and hepatocellular carcinoma progression. Cytokine
825 [Internet]. 2019 Dec;124:154569. Available from:
826 http://www.ncbi.nlm.nih.gov/pubmed/30389231
827 68. Cheng E, Zhang X, Wilson KS, Wang DH, Park JY, Huo X, et al. JAK-STAT6
828 Pathway Inhibitors Block Eotaxin-3 Secretion by Epithelial Cells and Fibroblasts
829 from Esophageal Eosinophilia Patients: Promising Agents to Improve
830 Inflammation and Prevent Fibrosis in EoE. PLoS One [Internet].
831 2016;11(6):e0157376. Available from:
832 http://www.ncbi.nlm.nih.gov/pubmed/27310888
Journal Pre-proof
36
833 69. Dengler HS, Wu X, Peng I, Rinderknecht CH, Kwon Y, Suto E, et al. Lung-
834 restricted inhibition of Janus kinase 1 is effective in rodent models of asthma. Sci
835 Transl Med [Internet]. 2018;10(468). Available from:
836 http://www.ncbi.nlm.nih.gov/pubmed/30463918
837 70. Esteban YM, de Jong JLO, Tesher MS. An Overview of Hemophagocytic
838 Lymphohistiocytosis. Pediatr Ann [Internet]. 2017 Aug 1;46(8):e309–13. Available
839 from: http://www.ncbi.nlm.nih.gov/pubmed/28806468
840 71. Xu X-J, Tang Y-M, Song H, Yang S-L, Xu W-Q, Zhao N, et al. Diagnostic
841 Accuracy of a Specific Cytokine Pattern in Hemophagocytic Lymphohistiocytosis
842 in Children. J Pediatr [Internet]. 2012 Jun;160(6):984-990.e1. Available from:
843 https://linkinghub.elsevier.com/retrieve/pii/S0022347611012200
844 72. Das R, Guan P, Sprague L, Verbist K, Tedrick P, An QA, et al. Janus kinase
845 inhibition lessens inflammation and ameliorates disease in murine models of
846 hemophagocytic lymphohistiocytosis. Blood [Internet]. 2016 Mar
847 31;127(13):1666–75. Available from:
848 http://www.ncbi.nlm.nih.gov/pubmed/26825707
849 73. Maschalidi S, Sepulveda FE, Garrigue A, Fischer A, de Saint Basile G.
850 Therapeutic effect of JAK1/2 blockade on the manifestations of hemophagocytic
851 lymphohistiocytosis in mice. Blood [Internet]. 2016;128(1):60–71. Available from:
852 http://www.ncbi.nlm.nih.gov/pubmed/27222478
853 74. Zandvakili I, Conboy CB, Ayed AO, Cathcart-Rake EJ, Tefferi A. Ruxolitinib as
854 first-line treatment in secondary hemophagocytic lymphohistiocytosis: A second
855 experience. Am J Hematol [Internet]. 2018;93(5):E123–5. Available from:
856 http://www.ncbi.nlm.nih.gov/pubmed/29417621
Journal Pre-proof
37
857 75. Sin JH, Zangardi ML. Ruxolitinib for secondary hemophagocytic
858 lymphohistiocytosis: First case report. Hematol Oncol Stem Cell Ther [Internet].
859 2019 Sep;12(3):166–70. Available from:
860 http://www.ncbi.nlm.nih.gov/pubmed/28834694
861 76. Broglie L, Pommert L, Rao S, Thakar M, Phelan R, Margolis D, et al. Ruxolitinib
862 for treatment of refractory hemophagocytic lymphohistiocytosis. Blood Adv
863 [Internet]. 2017 Aug 22;1(19):1533–6. Available from:
864 http://www.ncbi.nlm.nih.gov/pubmed/29296794
865 77. Wang J, Wang Y, Wu L, Wang X, Jin Z, Gao Z, et al. Ruxolitinib for
866 refractory/relapsed hemophagocytic lymphohistiocytosis. Haematologica
867 [Internet]. 2019 Sep 12;haematol.2019.222471. Available from:
868 http://www.haematologica.org/lookup/doi/10.3324/haematol.2019.222471
869 78. Curtis C, Ogbogu P. Hypereosinophilic Syndrome. Clin Rev Allergy Immunol
870 [Internet]. 2016 Apr;50(2):240–51. Available from:
871 http://www.ncbi.nlm.nih.gov/pubmed/26475367
872 79. Sutton SA, Assa’ad AH, Rothenberg ME. Anti-IL-5 and hypereosinophilic
873 syndromes. Clin Immunol [Internet]. 2005 Apr;115(1):51–60. Available from:
874 http://www.ncbi.nlm.nih.gov/pubmed/15870021
875 80. King B, Lee AI, Choi J. Treatment of Hypereosinophilic Syndrome with Cutaneous
876 Involvement with the JAK Inhibitors Tofacitinib and Ruxolitinib. J Invest Dermatol
877 [Internet]. 2017;137(4):951–4. Available from:
878 http://www.ncbi.nlm.nih.gov/pubmed/27887955
879 81. Damsky WE, Vesely MD, Lee AI, Choi J, Meyer A-C, Chen M, et al. Drug-induced
880 hypersensitivity syndrome with myocardial involvement treated with tofacitinib.
Journal Pre-proof
38
881 JAAD Case Reports [Internet]. 2019 Dec;5(12):1018–26. Available from:
882 https://linkinghub.elsevier.com/retrieve/pii/S2352512619303571
883 82. Kim D, Kobayashi T, Voisin B, Jo J-H, Sakamoto K, Jin S-P, et al. Targeted
884 therapy guided by single-cell transcriptomic analysis in drug-induced
885 hypersensitivity syndrome: a case report. Nat Med [Internet]. 2020 Jan 20;
886 Available from: http://www.nature.com/articles/s41591-019-0733-7
887 83. Jagasia M, Perales M-A, Schroeder MA, Ali H, Shah NN, Chen Y-B, et al.
888 Ruxolitinib for the treatment of steroid-refractory acute GVHD (REACH1): a
889 multicenter, open-label phase 2 trial. Blood [Internet]. 2020 May 14;135(20):1739–
890 49. Available from:
891 https://ashpublications.org/blood/article/135/20/1739/452638/Ruxolitinib-for-the-
892 treatment-of-steroidrefractory
893 84. Mason JW, O’Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME,
894 et al. A clinical trial of immunosuppressive therapy for myocarditis. The
895 Myocarditis Treatment Trial Investigators. N Engl J Med [Internet]. 1995 Aug
896 3;333(5):269–75. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7596370
897 85. Damsky WE, Vesely MD, Lee AI, Choi J, Meyer A-C, Chen M, et al. Drug-induced
898 hypersensitivity syndrome with myocardial involvement treated with tofacitinib.
899 JAAD case reports [Internet]. 2019 Dec;5(12):1018–26. Available from:
900 http://www.ncbi.nlm.nih.gov/pubmed/31763425
901 86. Hinchcliff M, Varga J. Systemic sclerosis/scleroderma: a treatable multisystem
902 disease. Am Fam Physician [Internet]. 2008 Oct 15;78(8):961–8. Available from:
903 http://www.ncbi.nlm.nih.gov/pubmed/18953973
904 87. Chakraborty D, Šumová B, Mallano T, Chen C-W, Distler A, Bergmann C, et al.
Journal Pre-proof
39
905 Activation of STAT3 integrates common profibrotic pathways to promote fibroblast
906 activation and tissue fibrosis. Nat Commun [Internet]. 2017;8(1):1130. Available
907 from: http://www.ncbi.nlm.nih.gov/pubmed/29066712
908 88. Wang W, Bhattacharyya S, Marangoni RG, Carns M, Dennis-Aren K, Yeldandi A,
909 et al. The JAK/STAT pathway is activated in systemic sclerosis and is effectively
910 targeted by tofacitinib. J Scleroderma Relat Disord [Internet]. 2020 Feb 7;5(1):40–
911 50. Available from: http://journals.sagepub.com/doi/10.1177/2397198319865367
912 89. Khanna D, Bush E, Nagaraja V, Koenig A, Khanna P, Young A, et al. Tofacitinib
913 in Early Diffuse Cutaneous Systemic Sclerosis— Results of Phase I/II
914 Investigator-Initiated, Double-Blind Randomized Placebo-Controlled Trial. Arthritis
915 Rheumatol [Internet]. 2019;71(suppl 10). Available from:
916 https://acrabstracts.org/abstract/tofacitinib-in-early-diffuse-cutaneous-systemic-
917 sclerosis-results-of-phase-i-ii-investigator-initiated-double-blind-randomized-
918 placebo-controlled-trial/
919 90. Milara J, Hernandez G, Ballester B, Morell A, Roger I, Montero P, et al. The JAK2
920 pathway is activated in idiopathic pulmonary fibrosis. Respir Res [Internet].
921 2018;19(1):24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29409529
922 91. Tang L-Y, Heller M, Meng Z, Yu L-R, Tang Y, Zhou M, et al. Transforming Growth
923 Factor-β (TGF-β) Directly Activates the JAK1-STAT3 Axis to Induce Hepatic
924 Fibrosis in Coordination with the SMAD Pathway. J Biol Chem [Internet].
925 2017;292(10):4302–12. Available from:
926 http://www.ncbi.nlm.nih.gov/pubmed/28154170
927 92. Kim SR, Charos A, Damsky W, Heald P, Girardi M, King BA. Treatment of
928 generalized deep morphea and eosinophilic fasciitis with the Janus kinase
Journal Pre-proof
40
929 inhibitor tofacitinib. JAAD case reports [Internet]. 2018 Jun;4(5):443–5. Available
930 from: http://www.ncbi.nlm.nih.gov/pubmed/29984277
931 93. Damsky W, Patel D, Garelli CJ, Garg M, Wang A, Dresser K, et al. JAK inhibition
932 prevents bleomycin-induced fibrosis in mice and is effective in morphea patients.
933 J Invest Dermatol [Internet]. 2020 Jan; Available from:
934 https://linkinghub.elsevier.com/retrieve/pii/S0022202X2030018X
935 94. Zeiser R, Burchert A, Lengerke C, Verbeek M, Maas-Bauer K, Metzelder SK, et
936 al. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after
937 allogeneic stem cell transplantation: a multicenter survey. Leukemia [Internet].
938 2015 Oct;29(10):2062–8. Available from:
939 http://www.ncbi.nlm.nih.gov/pubmed/26228813
940 95. von Bubnoff N, Ihorst G, Grishina O, Röthling N, Bertz H, Duyster J, et al.
941 Ruxolitinib in GvHD (RIG) study: a multicenter, randomized phase 2 trial to
942 determine the response rate of Ruxolitinib and best available treatment (BAT)
943 versus BAT in steroid-refractory acute graft-versus-host disease (aGvHD)
944 (NCT02396628). BMC Cancer [Internet]. 2018 Nov 19;18(1):1132. Available from:
945 http://www.ncbi.nlm.nih.gov/pubmed/30453910
946 96. Hurabielle C, Sicre de Fontbrune F, Moins-Teisserenc H, Robin M, Jachiet M,
947 Coman T, et al. Efficacy and tolerance of ruxolitinib in refractory sclerodermatous
948 chronic graft-versus-host disease. Br J Dermatol [Internet]. 2017;177(5):e206–8.
949 Available from: http://www.ncbi.nlm.nih.gov/pubmed/28422274
950 97. Winthrop KL. The emerging safety profile of JAK inhibitors in rheumatic disease.
951 Nat Rev Rheumatol [Internet]. 2017 Apr;13(4):234–43. Available from:
952 http://www.ncbi.nlm.nih.gov/pubmed/28250461
Journal Pre-proof
41
953 98. Winthrop KL, Korman N, Abramovits W, Rottinghaus ST, Tan H, Gardner A, et al.
954 T-cell-mediated immune response to pneumococcal conjugate vaccine (PCV-13)
955 and tetanus toxoid vaccine in patients with moderate-to-severe psoriasis during
956 tofacitinib treatment. J Am Acad Dermatol [Internet]. 2018 Jun;78(6):1149-
957 1155.e1. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29080806
958 99. Clowse MEB, Feldman SR, Isaacs JD, Kimball AB, Strand V, Warren RB, et al.
959 Pregnancy Outcomes in the Tofacitinib Safety Databases for Rheumatoid Arthritis
960 and Psoriasis. Drug Saf [Internet]. 2016;39(8):755–62. Available from:
961 http://www.ncbi.nlm.nih.gov/pubmed/27282428
962 100. Ruperto N, Brunner HI, Zuber Z, Tzaribachev N, Kingsbury DJ, Foeldvari I, et al.
963 Pharmacokinetic and safety profile of tofacitinib in children with polyarticular
964 course juvenile idiopathic arthritis: results of a phase 1, open-label, multicenter
965 study. Pediatr Rheumatol Online J [Internet]. 2017 Dec 28;15(1):86. Available
966 from: http://www.ncbi.nlm.nih.gov/pubmed/29282090
967 101. González Vicent M, Molina B, González de Pablo J, Castillo A, Díaz MÁ.
968 Ruxolitinib treatment for steroid refractory acute and chronic graft vs host disease
969 in children: Clinical and immunological results. Am J Hematol [Internet]. 2019
970 Mar;94(3):319–26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30536806
971 102. Craiglow BG, Liu LY, King BA. Tofacitinib for the treatment of alopecia areata and
972 variants in adolescents. J Am Acad Dermatol [Internet]. 2017 Jan;76(1):29–32.
973 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27816292
974 103. Wheeland RG. Commentary: treatment of telangiectasia-an editorial. Dermatol
975 Surg [Internet]. 2010 Aug;36(8):1231. Available from:
976 http://www.ncbi.nlm.nih.gov/pubmed/20666809
Journal Pre-proof
42
977 104. Li J. JAK-STAT and bone metabolism. JAK-STAT [Internet]. 2013 Jul
978 1;2(3):e23930. Available from: http://www.ncbi.nlm.nih.gov/pubmed/24069548
979 105. Harigai M. Growing evidence of the safety of JAK inhibitors in patients with
980 rheumatoid arthritis. Rheumatology (Oxford) [Internet]. 2019 Feb
981 1;58(Supplement_1):i34–42. Available from:
982 http://www.ncbi.nlm.nih.gov/pubmed/30806708
983 106. Curtis JR, Lee EB, Kaplan I V, Kwok K, Geier J, Benda B, et al. Tofacitinib, an
984 oral Janus kinase inhibitor: analysis of malignancies across the rheumatoid
985 arthritis clinical development programme. Ann Rheum Dis [Internet]. 2016
986 May;75(5):831–41. Available from:
987 http://www.ncbi.nlm.nih.gov/pubmed/25902789
988 107. Strand V, Ahadieh S, French J, Geier J, Krishnaswami S, Menon S, et al.
989 Systematic review and meta-analysis of serious infections with tofacitinib and
990 biologic disease-modifying antirheumatic drug treatment in rheumatoid arthritis
991 clinical trials. Arthritis Res Ther [Internet]. 2015 Dec 15;17:362. Available from:
992 http://www.ncbi.nlm.nih.gov/pubmed/26669566
993 108. Cohen S, Radominski SC, Gomez-Reino JJ, Wang L, Krishnaswami S, Wood SP,
994 et al. Analysis of infections and all-cause mortality in phase II, phase III, and long-
995 term extension studies of tofacitinib in patients with rheumatoid arthritis. Arthritis
996 Rheumatol (Hoboken, NJ) [Internet]. 2014 Nov;66(11):2924–37. Available from:
997 http://www.ncbi.nlm.nih.gov/pubmed/25047021
998 109. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of
999 infection in patients with rheumatoid arthritis compared with controls: a
1000 population-based study. Arthritis Rheum [Internet]. 2002 Sep;46(9):2287–93.
43
1001 Available from: http://www.ncbi.nlm.nih.gov/pubmed/12355475
1002 110. Curtis JR, Xie F, Yun H, Bernatsky S, Winthrop KL. Real-world comparative risks
1003 of herpes virus infections in tofacitinib and biologic-treated patients with
1004 rheumatoid arthritis. Ann Rheum Dis [Internet]. 2016 Oct;75(10):1843–7.
1005 Available from: http://www.ncbi.nlm.nih.gov/pubmed/27113415
1006 111. Olivera PA, Lasa JS, Bonovas S, Danese S, Peyrin-Biroulet L. Safety of Janus
1007 Kinase Inhibitors in Patients With Inflammatory Bowel Diseases or Other Immune-
1008 mediated Diseases: A Systematic Review and Meta-Analysis. Gastroenterology
1009 [Internet]. 2020 May;158(6):1554-1573.e12. Available from:
1010 http://www.ncbi.nlm.nih.gov/pubmed/31926171
1011 112. Sandborn WJ, Panés J, D’Haens GR, Sands BE, Su C, Moscariello M, et al.
1012 Safety of Tofacitinib for Treatment of Ulcerative Colitis, Based on 4.4 Years of
1013 Data From Global Clinical Trials. Clin Gastroenterol Hepatol [Internet].
1014 2019;17(8):1541–50. Available from:
1015 http://www.ncbi.nlm.nih.gov/pubmed/30476584
1016 113. Winthrop KL, Park S-H, Gul A, Cardiel MH, Gomez-Reino JJ, Tanaka Y, et al.
1017 Tuberculosis and other opportunistic infections in tofacitinib-treated patients with
1018 rheumatoid arthritis. Ann Rheum Dis [Internet]. 2016 Jun;75(6):1133–8. Available
1019 from: http://www.ncbi.nlm.nih.gov/pubmed/26318385
1020 114. Jagpal A, Curtis JR. Gastrointestinal Perforations with Biologics in Patients with
1021 Rheumatoid Arthritis: Implications for Clinicians. Drug Saf [Internet]. 2018
1022 Jun;41(6):545–53. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29392593
1023 115. Taylor PC, Weinblatt ME, Burmester GR, Rooney TP, Witt S, Walls CD, et al.
1024 Cardiovascular Safety During Treatment With Baricitinib in Rheumatoid Arthritis.
Journal Pre-proof
44
1025 Arthritis Rheumatol (Hoboken, NJ) [Internet]. 2019 Jul;71(7):1042–55. Available
1026 from: http://www.ncbi.nlm.nih.gov/pubmed/30663869
1027 116. Sandborn WJ, Panés J, Sands BE, Reinisch W, Su C, Lawendy N, et al. Venous
1028 thromboembolic events in the tofacitinib ulcerative colitis clinical development
1029 programme. Aliment Pharmacol Ther [Internet]. 2019;50(10):1068–76. Available
1030 from: http://www.ncbi.nlm.nih.gov/pubmed/31599001
1031 117. Scott IC, Hider SL, Scott DL. Thromboembolism with Janus Kinase (JAK)
1032 Inhibitors for Rheumatoid Arthritis: How Real is the Risk? Drug Saf [Internet].
1033 2018;41(7):645–53. Available from:
1034 http://www.ncbi.nlm.nih.gov/pubmed/29500799
1035 118. Verden A, Dimbil M, Kyle R, Overstreet B, Hoffman KB. Analysis of Spontaneous
1036 Postmarket Case Reports Submitted to the FDA Regarding Thromboembolic
1037 Adverse Events and JAK Inhibitors. Drug Saf [Internet]. 2018 Apr;41(4):357–61.
1038 Available from: http://www.ncbi.nlm.nih.gov/pubmed/29196988
1039 119. Hosking A-M, Juhasz M, Mesinkovska NA. Topical Janus kinase inhibitors: A
1040 review of applications in dermatology. J Am Acad Dermatol [Internet]. 2018
1041 Sep;79(3):535–44. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29673776
1042 120. Kheirkhah A, Di Zazzo A, Satitpitakul V, Fernandez M, Magilavy D, Dana R. A
1043 Pilot Randomized Trial on Safety and Efficacy of a Novel Topical Combined
1044 Inhibitor of Janus Kinase 1/3 and Spleen Tyrosine Kinase for GVHD-Associated
1045 Ocular Surface Disease. Cornea [Internet]. 2017 Jul;36(7):799–804. Available
1046 from: http://www.ncbi.nlm.nih.gov/pubmed/28445193
1047 121. Sandborn WJ, Nguyen DD, Beattie DT, Brassil P, Krey W, Woo J, et al.
1048 Development of gut-selective pan-Janus kinase inhibitor TD-1473 for ulcerative
1076 Figure 1. Molecular mechanism of action of medications used to treat
1077 autoimmune disease. Monoclonal antibodies (biologics) interfere with binding of
1078 soluble proteins (i.e. cytokines) to their receptors on the cell surface. JAK inhibitors
1079 block the downstream intracellular effect that would otherwise be induced by cytokine –
1080 cytokine receptor interactions. mTOR inhibitors (sirolimus, everolimus) block the
1081 mTORC1 complex which is activated downstream of the T cell receptor. Calcineurin
1082 inhibitors (cyclosporine, tacrolimus) block calcineurin which is activated downstream of
1083 the T cell receptor. Thalidomide and lenalidomide may block some activity of TNF family
1084 cytokines through inhibiton of NF-κB. Corticosteroids have pleiotropic activity and inhibit
1085 inflammation at multiple levels. Anti-proliferative agents (methotrexate, mycophenolate,
1086 azathioprine) interfere with DNA synthesis in activated T cells.
1087
1088 Figure 2. Cytokine specificity for individual JAK proteins. Various cytokines signal
via distinct JAK proteins, as summarized here (adapted from Gadina 2018).7
1089 Boxes
1090 around cytokines represent structural similarity. EPO: erythropoietin, TPO:
1091 thrombopoietin, GH: growth hormone, PRL: prolactin. *Signals primarily via JAK1.
1092
1093 Figure 3. Overview of the JAK-STAT pathway. Binding of a cytokine to its receptor
1094 triggers engagement of the receptor by JAK proteins, phosphorylation of both the JAK
1095 and the receptor, and subsequent recruitment and activation (phosphorylation) of STAT
1096 proteins. Upon activation/phosphorylation, STATs dimerize and translocate to the
1097 nucleus where they drive changes in cell behavior through transcriptional effects. JAK

1098 inhibitors act by inhibiting the kinase activity of JAK proteins downstream of cytokine
1099 binding.
1101 Figure 4. JAK inhibitors are undergoing clinical evaluation in multiple disorders.
1102 JAK inhibitors have shown efficacy in and are undergoing more rigorous clinical
1103 evaluation in numerous autoimmune diseases. Diseases that are underlined already
1104 have at least one JAK inhibitor that is FDA approved for that indication. A full list of
1105 references can be found in Table S2. GVHD: graft versus host disease, DRESS: drug
1106 reaction with eosinophilia and systemic symptoms, DIHS: drug induced hypersensitivity
1107 syndrome, CANDLE: chronic atypical neutrophilic dermatosis with lipodystrophy and
1108 elevated temperature, SAVI: STING-associated vasculopathy with onset in infancy, JIA:
1109 Juvenile idiopathic arthritis, GCA: giant cell arteritis, AAV: ANCA associated vasculitis,
1110 RA: rheumatoid arthritis, PsA: psoriatic arthritis, IPF: idiopathic pulmonary fibrosis,
1111 NMO: neuromyelitis optica. Journal Pre-pro
1154 Table 4. Overview of FDA approved Upadacitinib JAK inhibitors. FDA approved JAK inhibitors,
1155 their indications, dosing, JAK specificity, safety issues, and monitoring
1156 recommendations. *With 10 mg twice daily dosing. If unchanged, monitoring as
1157 otherwise indicated. PsA: psoriatic arthritis, RA: rheumatoid arthritis, ET: essential
1158 thrombocythemia, PCV: polycythemia vera, GVHD: graft versus host disease: BID:
1159 twice daily, QD: once daily, LFT: liver function tests, CBC: complete blood count. Boxed
1160 warnings are in bold.