10.5826/dpc.1204a178
Backgrounds: Janus kinase inhibitors (JAKi) are anti-inflammatory medications suppressing Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway by inhibiting various cytokines receptors on the membrane of cells. Mutations and polymorphisms on JAK and STAT proteins can cause dysregulation in the balance of immune system, and ultimately result in autoimmune disorders.
Objectives: to record and summarize the overall efficacy and safety of JAKi in various autoimmune conditions such as alopecia areata (AA), psoriasis vulgaris (PV), psoriatic arthritis (PsA), atopic dermatitis (AD), vitiligo, hidradenitis suppurative (HS), lichen planus (LP), and pyoderma gangrenosum (PG).
Methods: A thorough review of articles was performed across PubMed and Google Scholar on meta-analyses, systematic reviews, clinical trials and case studies evaluating the treatment of autoimmune disorders such as AA, PV, PsA, AD, vitiligo, LP, HS, and PG with JAKi. Duplicated data and animal experiments or in vitro/ex vivo studies were excluded.
Results: all the reviewed articles reported beneficial effects of tofacitinib and ruxolitinib application in the treatment of disorders mentioned above with the autoimmune predisposition.
Conclusion: tofacitinib and ruxolitinib showed potential efficacy in treating several autoimmune disorders. Based on records in the reviewed studies, both medications had acceptable safety profiles; however, physicians are recommended to outweigh the risks and benefits of such treatments for each specific condition.
text/xml
2160-9381
2201
en
Azadeh Goodarzi
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Review
Various Applications of Tofacitinib and Ruxolitinib (Janus Kinase Inhibitors) in Dermatology and Rheumatology:  A Review of Current Evidence and Future Perspective
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Review
2022-10-31
2021-11-26
2022-10-31
2022-12-01
e2022178
Dermatol Pract Concept
Backgrounds: Janus kinase inhibitors (JAKi) are anti-inflammatory medications suppressing Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway by inhibiting various cytokines receptors on the membrane of cells. Mutations and polymorphisms on JAK and STAT proteins can cause dysregulation in the balance of immune system, and ultimately result in autoimmune disorders.
Objectives: to record and summarize the overall efficacy and safety of JAKi in various autoimmune conditions such as alopecia areata (AA), psoriasis vulgaris (PV), psoriatic arthritis (PsA), atopic dermatitis (AD), vitiligo, hidradenitis suppurative (HS), lichen planus (LP), and pyoderma gangrenosum (PG).
Methods: A thorough review of articles was performed across PubMed and Google Scholar on meta-analyses, systematic reviews, clinical trials and case studies evaluating the treatment of autoimmune disorders such as AA, PV, PsA, AD, vitiligo, LP, HS, and PG with JAKi. Duplicated data and animal experiments or in vitro/ex vivo studies were excluded.
Results: all the reviewed articles reported beneficial effects of tofacitinib and ruxolitinib application in the treatment of disorders mentioned above with the autoimmune predisposition.
Conclusion: tofacitinib and ruxolitinib showed potential efficacy in treating several autoimmune disorders. Based on records in the reviewed studies, both medications had acceptable safety profiles; however, physicians are recommended to outweigh the risks and benefits of such treatments for each specific condition.
Azadeh Goodarzi
2022/10/31
10.5826/dpc.1204a178
e2022178
Iran University of Medical Sciences (IUMS), RasoolAkram hospital, Department of Dermatology
2160-9381
Review
en
e2022178
Kochar B, Herfarth N, Mamie C, Navarini AA, Scharl M, Herfarth HH. Tofacitinib for the treatment of pyoderma gangrenosum. Clinical Gastroenterology and Hepatology. 2019;17(5):991-3.
Various Applications of Tofacitinib and Ruxolitinib (Janus Kinase Inhibitors) in Dermatology and Rheumatology:  A Review of Current Evidence and Future Perspective
https://dpcj.org/index.php/dpc/article/download/2201/1821
   Various Application of Tofacitinib and Ruxolitinib
     (Janus Kinase Inhibitors) in Dermatology and
   Rheumatology: A Review of Current Evidence and
                  Future Perspective
                                            Sara Sadeghi1, Azadeh Goodarzi1,2


1 Rasool Akram Medical Complex Clinical Research Development Center (RCRDC), Iran University of Medical Sciences, Tehran, Iran
2 Department of Dermatology, Faculty of Dermatology, Rasool Akram Medical Complex Clinical Research Development Center (RCRDC),
  School of Medicine, Iran University of Medical Sciences, Tehran, Iran



Key words: Tofacitinib, ruxolitinib, janus kinase inhibitors, skin, mucosa
Citation: Sadeghi S, Goodarzi A. Various Application of Tofacitinib and Ruxolitinib (Janus kinase Inhibitors) in Dermatology and
Rheumatology: A Review of Current Evidence and Future Perspective. Dermatol Pract Concept. 2022;12(4):e2022178.
DOI: https://doi.org/10.5826/dpc.1204a178
Accepted: February 1, 2022; Published: October 2022
Copyright: ©2022 Sadeghi et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding author: Azadeh Goodarzi, MD, Department of Dermatology, Associate Professor of Dermatology, Rasool Akram Medical
Complex Clinical Research Development Center (RCRDC), School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
E-mail: Azadeh_goodarzi1984@yahoo.com, Goodarzi.a@iums.ac.ir




  ABSTRACT             Introduction: Janus kinase inhibitors (JAKi) are anti-inflammatory medications suppressing Janus
                       kinase-signal transducer and activator of transcription (JAK-STAT) pathway by inhibiting various
                       cytokines receptors on the membrane of cells. Mutations and polymorphisms on JAK and STAT pro-
                       teins can cause dysregulation in the balance of immune system, and ultimately result in autoimmune
                       disorders.
                       Objectives: To record and summarize the overall efficacy and safety of JAKi in various autoimmune
                       conditions such as alopecia areata (AA), psoriasis vulgaris (PV), psoriatic arthritis (PsA), atopic derma-
                       titis (AD), vitiligo, hidradenitis suppurative (HS), lichen planus (LP), and pyoderma gangrenosum (PG).
                       Methods: A thorough review of articles was performed across PubMed and Google Scholar on
                       ­meta-analyses, systematic reviews, clinical trials and case studies evaluating the treatment of auto-
                        immune disorders such as AA, PV, PsA, AD, vitiligo, LP, HS, and PG with JAKi. Duplicated data and
                        animal experiments or in vitro/ex vivo studies were excluded.
                       Results: All the reviewed articles reported beneficial effects of tofacitinib and ruxolitinib application
                       in the treatment of disorders mentioned above with the autoimmune predisposition.




Review | Dermatol Pract Concept. 2022;12(4):e2022178                                                                                1
                     Conclusions: Tofacitinib and ruxolitinib showed potential efficacy in treating several autoimmune
                     disorders. Based on records in the reviewed studies, both medications had acceptable safety profiles;
                     however, physicians are recommended to outweigh the risks and benefits of such treatments for each
                     specific condition.




Introduction                                                      Objectives
The Janus kinase inhibitors are a category of anti-­ The development of JAKi in dermatology and rheumatology
inflammatory medications, targeting JAK-STAT pathways. is still in the early stage; however, there is favorable evidence
Many inflammatory cytokines function through the JAK-             about the utility of JAKi in treating some of the autoimmune
STAT pathways in the human body [1,2]. Cytokines are cru-         disorders. To prevent extensive efforts collecting data from
cial molecules working on the immune system regulation,           different studies to answer specific inquiries about such dis-
and their dysregulation might be important in the pathogen-       orders and medications, we performed a narrative review to
esis of autoimmune disorders [3].                                 summarize all the available evidence on the utility of JAKi in
    Genetic polymorphisms and different mutations can             treating AA, PV and PsA, AD, vitiligo, LP, HS, and PG.
occur within JAK-STAT pathways, resulting in several
­
forms of malignancies and autoimmune disorders, ie poly-          Methods
morphisms of JAK2 and STAT3 are involved in psoriasis
[4]. JAKi medications provide us with the possibility of          A thorough search was performed on PubMed, and Google
shutting down the impaired JAK-STAT pairs. Ruxolitinib            Scholar using combinations of the following MeSH terms:
and tofacitinib are the prototypes of JAKi. Ruxolitinib is        “tofacitinib,” “ruxolitinib,” “JAK inhibitors,” “Janus Kinase
a JAK1/2 selective inhibitor; it affects several parts of the     inhibitors,” “alopecia areata,” “psoriasis vulgaris,” “psori-
innate and adaptive immune system, including natural killer       asis arthritis,” “atopic dermatitis,” “vitiligo,” “hidradenitis
cells (NKc), dendritic cells, T-helpers, and regulatory T-cells   suppurative,” “pyoderma gangrenosum,” “lichen planus,”
[5]. Tofacitinib preferentially blocks JAK1/3 and, to some        “­lichen planopilaris.” A total of 672 publications were found.
degree, JAK2 and TYK2 [6].                                        After removing duplicates and non-suitable publications, we
    JAKi, like other medications, have adverse effects (AEs)      focused on the most recent and available pooled studies such
on the human body. JAKi suppress the immune system at             as systematic reviews and meta-analyses and then available
some levels, and their consumption increases the risk of some     clinical trials, observational and case studies.
infections such as herpes zoster (HZ). Vaccination against
HZ prior to the treatment with tofacitinib is recommended.        Results
Non-HZ opportunistic infections, including cytomegalovi-
rus, cryptococcus, histoplasmosis and clostridium difficile       Alopecia Areata
are also reported in JAKi recipients [5,7].                       Alopecia areata is a non-cicatricial alopecia with an autoim-
    There is a potential risk of increasing venous thrombo-       mune etiology, affecting approximately 2% of the general
embolism (VTE) events following the treatment with JAKi so        population. Histopathology assessment on the involved skin
it is recommended to avoid prescribing JAKi in patients with      showed lymphocytic infiltration around the hair follicles at the
age >50, previous VTE, hypercoagulability, smoking, cardio-       level of bulb or lower [9]. Immune system dysregulation results
vascular disease (CVD), long-term immobilization, recent          in hair follicles damage by T-cells and NKc. Moreover, auto-re-
trauma or surgery, paralysis, malignancy, obesity, frequent       activation of immune cells upregulates IFN-γ and cytokines
long flights, and hormonal therapy. A further consideration       and cause further cellular damage and inflammation [10].
is required to either avoid or prescribe JAKi with extra cau-        Excessive activation of JAK-STAT has a major effect
tion in patients with a history of cancer; however, there is      on maintaining the activation of CD8+ T-cells and NKc.
not enough evidence and data about the carcinogenicity of         ­Additionally, a low level of T-regulatory cells identified in AA
JAKi. Other AEs include anemia, reversible hyperlipidemia         patients, makes it impossible to suppress excessive amounts
and minimal elevation in liver transaminases and creatine         of cytokines. These complexes of immune dysregulations
phosphokinase (CPK) [7,8].                                        contribute to hair follicles damage [10,11].




2                                                                             Review | Dermatol Pract Concept. 2022;12(4):e2022178
   Yu et al reviewed 12 studies with 346 patients. In this           for the placebo recipients at weeks 16 - 24. Moreover, clini-
review 288 participants received oral tofacitinib and 58             cal efficacy was reported based on Dermatology Life Quality
received oral ruxolitinib. The outcome measurement was               Index (DLQI) and Nail Psoriasis Severity Index (NPSI). AEs
reported with the Severity of Alopecia Tool50 (SALT50),              such as hyperlipidemia, CPK elevation, anemia and lympho-
showing 66% overall improvement in all patients. There was           penia were observed in some patients [17].
no statistically difference when studies categorized by sex,            Tian et al meta-analyzed seven randomized clinical tri-
age and subtypes of AA (P = 0.81, P = 0.37 and P = 0.91,             als (RCTs) about oral tofacitinib in chronic plaque psoriasis.
respectively). The SALT50 rates were lower in patients who           Physician global assessment (PGA) and PASI 75 (4 s­tudies
received a shorter length of treatment but was not statisti-         reported PASI 90) showed denoting difference b
                                                                                                                  ­etween
cally significant (P = 0.25). The reported AEs were upper            the group of tofacitinib 5 mg/bid users and control group
respiratory tract infections (URTI), urinary tract infections        (P < 0.00001). The effectiveness of tofacitinib 10 mg/
(UTI), herpes simplex and herpes zoster infections, alteration       bid was also significantly distinct from the control group
of blood cells count, the elevation of liver aminotransami-          (P < 0.00001). Moreover, 5 mg/bid of tofacitinib showed less
nase and lipids; moreover, there were no fatal AEs [12]. In          efficacy than 10 mg/bid. Even though, there was no statis-
another meta-analysis, Hamilton et al reviewed ten different         tically significant difference in AEs between 5 and 10 mg
studies on the systemic and topical tofacitinib and ruxoli-          tofacitinib, more AEs were related to 10 mg/bid dosage [18].
tinib in children and teenage populations (age 1 – 17 years).        Further, it is recommended to conduct clinical trials on topi-
The review affirmed success for JAKi in children and teens           cal types of JAKi in treating PV.
with higher numbers of complete responders and smaller
numbers of poor responders compared to adults. AEs were              Psoriatic Arthritis
small and limited to mild infections, diarrhea and reversible        Approximately 19.4% of patients with psoriasis present
lab abnormalities [13]. In addition, Guo et al conducted a           joints involvement [19]. PsA manifestations include periph-
meta-analysis on 14 studies with 275 patients treating with          eral arthritis, enthesitis, axial disease, dactylitis, and skin
oral and topical tofacitinib. A complete response in 54.0%           characteristics [20]. No serology markers are available to
and partial response in 26.1% of patients were reported.             distinguish PsA from psoriasis; however, hyperlipidemia,
The AA relapse rates were 24.0% in the pooled results, and           gout, axial spondylopathy or allergic rhinitis are more com-
the main reason was medication discontinuation. A 7.2%               mon in PsA [19].
of patients presented AEs, and the most common AE was                   Companaro et al systematically reviewed three RCTs
URTI [14].                                                           studying oral tofacitinib. In these studies, 947 patients treated
                                                                     with tofacitinib and those who only received 5 mg/bid were
Psoriasis Vulgaris                                                   assessed in the review. The results at week 16 revealed a sig-
Psoriasis is a chronic autoimmune inflammatory disease with          nificant higher ACR20 (number of patients who achieved
the prevalence of 2% worldwide. Psoriasis has several sub-           ≥20% response rate to the treatment based on the Amer-
types, including plaque, guttate, inverse, and pustular. Over-       ican College of Rheumatology Index) response than pla-
activation of dendritic cells is responsible for the initial phase   cebo. Moreover, tofacitinib also presented statistically higher
of psoriasis and unbalanced elevated levels of cytokines such        ACR50, ACR70 and PASI75 response rates compared to
as IL-17, IL-21 and IL-22 (mostly Th17 and IL-23 driven              placebo, and Health Assessment Questionnaire-Disability
[15]) for the maintenance phase of inflammation. Medica-             Index (HAQ-DI) score and post-treatment fatigue assess-
tions such as tofacitinib and ruxolitinib targeting TNF-α,           ment showed lower rate, which means better response. Seri-
IL-23 and IL-17 and JAK/STAT pathways can be effective in            ous AEs were greater in the treatment group than the control
treating PV [16].                                                    group; however, it was not proved statistically [21].
   Kvist-Hansen et al conducted a systematic review on five             Paik et al reviewed tofacitinib efficacy in two well-designed
clinical trials (phase two and three trials) utilizing oral to-      parallel RCTs (phase 3) in PsA patients: the OPAL Broaden
facitinib to treat moderate to severe forms of PV. The effec-        with 442 patients for 12 months and the OPAL Beyond with
tiveness was calculated based on PASI75 (Psoriasis Area &            394 patients for six months. Patients received tofacitinib 5
Severity Index 75% reduction). In the phase two studies, the         or 10 mg/bid or placebo (or adalimumab 40 mg/sc combined
effectiveness of tofacitinib was reported 25% with 2 mg/bid,         with a csDMARD instead of placebo in OPAL Broaden) in
40.8% with 5 mg/bid, and 66.7% with 15 mg/bid compared               both trials. The efficacy of tofacitinib over placebo was eval-
to 2% efficacy in placebo. In the phase three studies, the ef-       uated with ACR20, ACR50, ACR70, HAQ-DI and PASI75.
fectiveness was reported 39.5% – 54.3% with 5 mg/bid and             After three months, tofacitinib 5 mg/bid recipients achieved
59.2% - 81.1% with 10 mg/bid compared to 5.6% - 12.5%                statistically significant ACR20 or ACR50 and HAQ-DI




Review | Dermatol Pract Concept. 2022;12(4):e2022178                                                                                3
scores than placebo in both trials, and in the OPAL Broaden         patients received oral tofacitinib 5 – 10 mg/bid for 12 – 40
study, significantly more patients treated with 5 mg/bid tofac-     weeks; 11 patients received topical tofacitinib 2% bid +
itinib achieved PASI75 score than placebo. After 12 months,         UVB phototherapy for 12 weeks, 21 patients received top-
minimal disease activity was attained in 37% of tofacitinib         ical ruxolitinib 1.5% bid for 12 – 38 weeks (in one study
5 mg recipients. A minimal progression in radiography was           UVB phototherapy was also added), and one patient re-
reported in the OPAL Broaden trial, and more than 90% of            ceived oral ruxolitinib 20 mg/bid for 20 weeks. Efficacy was
patients showed non-progression criteria [22]. All reviewed         assessed with Vitiligo Area and Severity Index (VASI) and
studies reported favorable safety and efficacy profiles of oral     facial Vitiligo Area and Severity Index (fVASI). Overall effec-
tofacitinib and ruxolitinib.                                        tiveness in the JAKi-alone recipients was reported as 57.8%
                                                                    good response, 22.2% partial and 20% none or minimal
Atopic Dermatitis                                                   response. Moreover, the response to the treatment with con-
Atopic dermatitis is the most common chronic inflamma-              current UVB phototherapy was statistically higher than JAKi
tory skin disease with 3% – 10% prevalence in adults and            alone (P < 0.001). The improvement turned more significant
15% – 25% in children. Moderate-to-severe AD can alter              (fVASI reduction) in facial vitiligo than other body sites
the health-related quality of life (HRQoL) because of sleep         (P < 0.001) when the studies were sub-grouped based on spe-
disturbance, purities and comorbid mental conditions. Mul-          cific body areas. No significant difference was observed be-
tiple inflammatory pathways and cytokines are involved in           tween different routes of JAKi administration (P = 0.1). AEs
the pathogenesis of AD, and they can be considered as ther-         were erythema, transient acne, hyperpigmentation, transient
apeutic targets [15,23].                                            hyperlipidemia, URTIs, weight gain and joint pain [27].
    Tsai et al conducted a meta-analysis on 15 RCTs and re-            In a case report, Komnitski et al presented a 40-year-old
viewed the efficacy and safety of JAKi in treating AD. Among        lady with vitiligo and rheumatoid arthritis receiving 5 mg
4,367 participants, 69 patients received topical tofacitinib        oral tofacitinib twice daily. After 2 years of the treatment
2% bid for 4 weeks, and 307 patients received topical rux-          without being sun-exposed, complete re-pigmentation of the
olitinib 0.15%, 0.5%, or 1.5% once daily, or 1.5% bid for           frontal and peri-labial were observed. Further, partial im-
8 weeks. In the tofacitinib study, efficacy was evaluated by        provement in the back of the neck and upper chest were also
Investigator Global Assessment (IGA), Eczema Area and               noted. No AEs were reported during the treatment in this
Severity Index (EASI-75%) and Body Surface Area (BSA)               case [28].
response. There were statistically significant higher rates
of achievement to IGA, EASI-75%, and BSA responses in               Lichen Planus
the treatment group compared to the control group. In as-           Lichen planus is a chronic inflammatory disorder that can
sessing topical ruxolitinib among 307 patients, efficacy was        involve derma, mucous, nail and hair follicles. The etiology
evaluated by pruritus numerical rating scale (pruritus-NRS)         of LP seems to be autoimmune with the incidence rate of
response. Participants in the treatment group disclosed sta-        2% – 3% [30]. The overactivation of CD8+ T-call lympho-
tistically greater rates of achieving pruritus-NRS response         cytes and dysregulation of CD4+ T-cells have been observed
than placebo recipients. Additionally, safety was reported          to play a major role in the pathogenesis of LP [30].
with Treatment-Emergent Adverse Events (TEAEs), showing                Damsky et al 2020 evaluated the benefit of oral tofac-
a higher rate of AEs in the treatment groups that was directly      itinib in a case series of three patients with erosive lichen
related to the length of treatment (24). Further, it is suggested   planus (ELP). Treatment with oral tofacitinib 5 mg/bid was
that topical JAKi are rational modalities in treating refrac-       initiated for all patients. Additional therapy with methotrex-
tory AD; however, more clinical trials are required to evalu-       ate and prednisolone was added to the therapeutic regimen
ate the long-term safety.                                           of patient #1 due to the refractory course of his condition.
                                                                    All patients showed dramatic improvements and complete
Vitiligo                                                            or near-complete remission while they were on tofacitinib.
Vitiligo is an autoimmune skin disease with acquired loss of        Discontinuation of tofacitinib in patient #1 resulted in ELP
function in epidermal melanocytes, resulting in depigmented         relapse even when he continued methotrexate and prednis-
white patches of skin. The unregulated activity of T-helper1        olone. Re-initiation of tofacitinib 5 mg/bid resulted again in
and high levels of IFN-γ, IL-9 and IL-10 seem to be the lead-       improvement in patient #1. Tofacitinib was tolerated well
ing cause of autoimmunity in vitiligo, and treatments aiming        with no reported AEs in any of the cases [31].
to lower the levels of ILs seem to be rationale [25,26].               Another case series by Yang et al reported the effec-
    Phan et al meta-analyzed data from nine case reports            tiveness of oral tofacitinib in ten patients with refractory
and case series to assess the pooled results about the efficacy     lichen planopilaris (LPP). Treatment with tofacitinib 5 mg/
and safety of JAKi in the treatment of vitiligo. Twenty-three       bid for 8 patients and 5 mg/tds for the other 2 patients,



4                                                                                Review | Dermatol Pract Concept. 2022;12(4):e2022178
with more severe disease, was commenced and continued            including adalimumab, tacrolimus, prednisolone, and rit-
for 2 – 19 months. Disease activity assessed by LPP activ-       uximab. Treatment was transitioned to oral tofacitinib
ity index (­LPPAI), and showed statistically significant im-     5 mg/bid: significant improvement was observed after two
provement compared to pre-treatment (P = 0.0014). One            weeks, and 95% improvement and sustained remission were
patient reported hair loss upon treatment discontinuation        reported at three months post-treatment [42].
(due to weight gain), which stabilized when medication was          Another case report was conducted by Kochar et al
re-started with a 5 mg/bid dosage [32]. A significant effi-      presenting three patients with refractory PG. The first two
cacy and low AEs were reported in the reviewed case series.      patients were treated with 5 mg of tofacitinib twice daily,
Large-scale and long-term studies are required to assess the     and no signs of disease activity and AEs were reported after
safety and efficacy of the treatment.                            12 months. The third patient commenced on tofacitinib
                                                                 5 mg/bid and concomitant steroid, and his PG lesions were
Hidradenitis Suppurativa                                         improved but not healed entirely within a month. Then ste-
Hidradenitis suppurativa is a chronic inflammatory disor-        roid was stopped, and tofacitinib up-titrated to 10 mg/bid
der in 1% of general population [33,34]. Pathogenesis of         and improvement continued [43]. Reviewed studies indi-
HS starts with cutaneous changes around hair follicles and       cated the effectiveness of oral tofacitinib in the treatment of
dysregulation of innate and adaptive immunity: elevated lev-     PG; however, more studies with larger scales are needed to
els of ILs following the overactivity of T-helpers, ultimately   assess the accuracy of this allegation.
affect neutrophils, macrophages and plasma cells. These
changes result in a vicious cycle of inflammation, pain, puru-
                                                                 Conclusions
lence, tissue destruction, and disfiguring scars [33-36]. JAKi
suppress the impacts of ILs, and thus they can be a potential    Tofacitinib and ruxolitinib showed potential efficacy in the
treatment for HS; however, limited studies aim to prove the      treatment of several autoimmune disorders. Based on a thor-
benefit of JAKi in treating HS.                                  ough review of the literature, it is concluded that both med-
   Savage et al reported two cases of HS treating with oral      ications have acceptable safety profiles; however, physicians
tofacitinib 5 mg/bid: a patient treated for one year and the     are recommended to outweigh the risks and benefits of the
other patient for three years. Both patients showed favor-       treatment for each specific condition. Further, there are not
able results: patient #1 was pain and drainage free after        enough data and studies about the benefit and safety of to-
11 months. Upon discontinuation at 12 months, the modest         facitinib and ruxolitinib in treating disorders such as HS, PG,
disease activity was observed, and tofacitinib re-treatment      and LP. We predict that JAKi will be utilized more broadly in
directed the disease to full remission. Patient #2 experienced   treating autoimmune disorders, and future reviews can be a
gradual remission over 3 years of treatment. At this time,       paradigm guideline helping clinicians to treat their patients.
localized herpes zoster infection was reported which was
controlled with intravenous valacyclovir. No other AEs were
                                                                 Acknowledgement
reported in either of the two patients [35].
                                                                 The authors would also like to express their gratitude to
Pyoderma Gangrenosum                                             Zeena Amini, for an extraordinary helpful comments during
Pyoderma gangrenosum is a rare, ulcerative and painful der-      the review process, and to the authorities of Rasool Akram
matological condition with a multifactorial pathogenesis.        Medical Complex Clinical Research Development Center
Diagnosis of PG is clinical after excluding other causes ie      (RCRDC)or their technical assistance.
infection, neoplasia, thrombophilia, and other inflammatory
conditions. PG often is related to other systemic inflamma-
tory conditions [37-40]. Pathophysiology of PG is not en-        References
tirely known; however, it represents dysregulation of the
                                                                 1. Choy EH. Clinical significance of Janus Kinase inhibitor se-
innate and adaptive immune systems: neutrophil dysfunc-             lectivity. Rheumatology (Oxford). 2019;58(6):953-962. DOI:
tion, JAK2 mutation, overexpression of integrin and dys-            10.1093/rheumatology/key339. PMID: 30508136. PMCID:
regulation of integrin signaling, and overproduction of ILs         PMC6532440.
seems to be involved in the course of PG [41].                   2. Damsky W, King BA. JAK inhibitors in dermatology: the promise
                                                                    of a new drug class. J Am Acad Dermatol. 2017;76(4):736-744.
   There are few studies about the efficacy of JAKi in treat-
                                                                    DOI 10.1016/j.jaad.2016.12.005. PMID: 28139263. PMCID:
ing PG; however, few case reports show potential benefits
                                                                    PMC6035868.
that need further large-scale RCTs. In a case report, Choi et    3. O’Shea JJ, Kontzias A, Yamaoka K, Tanaka Y, Laurence A.
al presented a patient with a history of cocaine abuse and          Janus kinase inhibitors in autoimmune diseases. Ann Rheum
10-month PG lesions refractory to other forms of treatment,         Dis. 2013;72 Suppl 2(0 2):ii111-ii115. DOI: 10.1136/



Review | Dermatol Pract Concept. 2022;12(4):e2022178                                                                           5
      annrheumdis-2012-202576. PMID: 23532440. PMCID:                              10.1177/0300060519847414. PMID: 31096817. PMCID:
      PMC3616338.                                                                  PMC6567701.
 4.   Cinats A, Heck E, Robertson L. Janus kinase inhibitors: a re-          19.   Su YJ. Early diagnosis of psoriatic arthritis among psori-
      view of their emerging applications in dermatology. Skin Therapy             asis patients: clinical experience sharing. Clin Rheumatol.
      Lett. 2018;23(3):5-9. PMID: 29772037.                                        2020;39(12):3677-3684. DOI: 10.1007/s10067-020-05132-1.
 5.   Elli EM, Baratè C, Mendicino F, Palandri F, Palumbo GA. Mecha-               PMID: 32468320. PMCID: PMC7648743.
      nisms underlying the anti-inflammatory and immunosuppressive           20.   Gladman D, Rigby W, Azevedo VF, et al. Tofacitinib for Psoriatic
      activity of ruxolitinib. Front Oncol. 2019;9:1186. DOI: 10.3389/             Arthritis in Patients with an Inadequate Response to TNF Inhib-
      fonc.2019.01186. PMID: 31788449. PMCID: PMC6854013.                          itors. N Engl J Med. 2017;377(16):1525-1536. DOI: 10.1056/
 6.   Hodge JA, Kawabata TT, Krishnaswami S, et al. The mecha-                     NEJMoa1615977. PMID: 29045207.
      nism of action of tofacitinib-an oral Janus kinase inhibitor for       21.   Campanaro F, Batticciotto A, Zaffaroni A, Cappelli A, Do-
      the treatment of rheumatoid arthritis. Clin Exp Rheumatol.                   nadini MP, Squizzato A. JAK inhibitors and psoriatic arthri-
      2016;34(2):318-328. PMID: 26966791.                                          tis: A systematic review and meta-analysis. Autoimmun Rev.
 7.   Agrawal M, Kim ES, Colombel J-F. JAK Inhibitors Safety in                    2021;20(10):102902. DOI: 10.1016/j.autrev.2021.102902.
      Ulcerative Colitis: Practical Implications. J Crohns Colitis.                PMID: 34274542.
      2020;14(Supplement_2):S755-S760. DOI: 10.1093/ecco-jcc/                22.   Paik J, Deeks ED. Tofacitinib: a review in psoriatic arthritis.
      jjaa017. PMID: 32006031. PMCID: PMC7395307.                                  Drugs. 2019;79(6):655-663. DOI: 10.1007/s40265-019-01091-
 8.   Bewersdorf JP, Jaszczur SM, Afifi S, Zhao JC, Zeidan AM. Beyond              3. PMID: 30895473.
      Ruxolitinib: Fedratinib and Other Emergent Treatment Options           23.   Rodrigues MA, Torres T. JAK/STAT inhibitors for the treatment
      for Myelofibrosis. Cancer Manag Res. 2019;11:10777-10790.                    of atopic dermatitis. J Dermatolog Treat. 2020;31(1):33-40.
      DOI: 10.2147/CMAR.S212559. PMID: 31920387. PMCID:                            DOI: 10.1080/09546634.2019.1577549. PMID: 30703333.
      PMC6935287.                                                            24.   Tsai HR, Lu JW, Chen LY, Chen TL. Application of Janus Kinase
 9.   Pratt CH, King LE, Messenger AG, Christiano AM, Sund-                        Inhibitors in Atopic Dermatitis: An Updated Systematic Review and
      berg JP. Alopecia areata. Nat Rev Dis Primers. 2017;3:17011.                 Meta-Analysis of Clinical Trials. J Pers Med. 2021;11(4):279. DOI:
      DOI: 10.1038/nrdp.2017.11. PMID: 28300084. PMCID:                            10.3390/jpm11040279. PMID: 33917069. PMCID: PMC8067719.
      PMC5573125.                                                            25.   Rothstein B, Joshipura D, Saraiya A, et al. Treatment of vitil-
10.   Dillon KL. A Comprehensive Literature Review of JAK Inhibi-                  igo with the topical Janus kinase inhibitor ruxolitinib. J Am
      tors in Treatment of Alopecia Areata. Clin Cosmet Investig Der-              Acad Dermatol. 2017;76(6):1054-1060.e1. DOI: 10.1016/j.
      matol. 2021;14:691-714. DOI: 10.2147/CCID.S309215. PMID:                     jaad.2017.02.049. PMID: 28390737.
      34211288. PMCID: PMC8242127.                                           26.   Wang Y, Li S, Li C. Clinical Features, Immunopathogenesis,
11.   Hordinsky MK. Overview of Alopecia Areata. J Investig                        and Therapeutic Strategies in Vitiligo. Clin Rev Allergy Immu-
      Dermatol Symp Proc. 2013;16(1):S13-S15. DOI: 10.1038/                        nol. 2021;61(3):299-323. DOI: 10.1007/s12016-021-08868-z.
      jidsymp.2013.4. PMID: 24326541.                                              PMID: 34283349.
12.   Yu D-A, Kim YE, Kwon O, Park H. Treatment outcome of oral              27.   Phan K, Phan S, Shumack S, Gupta M. Repigmentation in vit-
      tofacitinib and ruxolitinib in patients with alopecia areata: A sys-         iligo using janus kinase (JAK) inhibitors with phototherapy:
      tematic review and meta-analysis. Indian J Dermatol Venereol                 systematic review and Meta-analysis. J Dermatolog Treat.
      Leprol. 2021;87(5):621-627. DOI: 10.25259/IJDVL_975_19.                      2022;33(1):173-177. DOI: 10.1080/09546634.2020.1735615.
      PMID: 34379968.                                                              PMID: 32096671.
13.   Hamilton CE, Craiglow BG. JAK Inhibitors for the Treatment             28.   Komnitski M, Komnitski A, Komnitski Junior A, Silva de Cas-
      of Pediatric Alopecia Areata. J Investig Dermatol Symp Proc.                 tro CC. Partial repigmentation of vitiligo with tofacitinib,
      2020;20(1):S31-S36. DOI: 10.1016/j.jisp.2020.04.005. PMID:                   without exposure to ultraviolet radiation. An Bras Dermatol.
      33099381.                                                                    2020;95(4):473-476. DOI: 10.1016/j.abd.2019.08.032. PMID:
14.   Guo L, Feng S, Sun B, Jiang X, Liu Y. Benefit and risk pro-                  32418716. PMCID: PMC7335860.
      file of tofacitinib for the treatment of alopecia areata: a            29.   Shao S, Tsoi LC, Sarkar MK, Xing X, Xue K, Uppala R, et al.
      systemic review and meta-analysis. J Eur Acad Dermatol Ve-                   IFN-gamma enhances cell-mediated cytotoxicity against ke-
      nereol. 2020;34(1):192-201. DOI: 10.1111/jdv.15937. PMID:                    ratinocytes via JAK2/STAT1 in lichen planus. Sci Transl Med.
      31494993.                                                                    2019;11(511):eaav7561. DOI: 10.1126/scitranslmed.aav7561.
15.   He H, Guttman-Yassky E. JAK inhibitors for atopic dermati-                   PMID: 31554739. PMCID: PMC7285657.
      tis: an update. Am J Clin Dermatol. 2019;20(2):181-192. DOI:           30.   Damsky W, Wang A, Olamiju B, Peterson D, Galan A, King B.
      10.1007/s40257-018-0413-2. PMID: 30536048.                                   Treatment of severe lichen planus with the JAK inhibitor tofaci-
16.   Rendon A, Schäkel K. Psoriasis Pathogenesis and Treatment.                   tinib. J Allergy Clin Immunol. 2020;145(6):1708-1710.e2. DOI:
      Int J Mol Sci. 2019;20(6):1475. DOI: 10.3390/ijms20061475.                   10.1016/j.jaci.2020.01.031. PMID: 32018031.
      PMID: 30909615. PMCID: PMC6471628.                                     31.   Yang CC, Khanna T, Sallee B, Christiano AM, Bordone LA.
17.   Kvist-Hansen A, Hansen PR, Skov L. Systemic treatment of pso-                ­Tofacitinib for the treatment of lichen planopilaris: A case series.
      riasis with JAK inhibitors: a review. Dermatol Ther (Heidelb).                Dermatol Ther. 2018;31(6):e12656. DOI: 10.1111/dth.12656.
      2020;10(1):29-42. DOI: 10.1007/s13555-019-00347-w. PMID:                      PMID: 30264512. PMCID: PMC6585740.
      31893355. PMCID: PMC6994544.                                           32.    Scala E, Cacciapuoti S, Garzorz-Stark N, et al. Hidradeni-
18.   Tian F, Chen Z, Xu T. Efficacy and safety of tofacitinib for the              tis Suppurativa: Where We Are and Where We Are Going.
      treatment of chronic plaque psoriasis: a systematic review and                Cells. 2021;10(8):2094. DOI: 10.3390/cells10082094. PMID:
      meta-analysis. J Int Med Res. 2019;47(6):2342-2350. DOI:                      34440863. PMCID: PMC8392140.




6                                                                                          Review | Dermatol Pract Concept. 2022;12(4):e2022178
33. Sabat R, Jemec GBE, Matusiak Ł, Kimball AB, Prens E, Wolk K.              Dermatol Venereol. 2009;23(9):1008-1017. DOI: 10.1111/j.1468-
    Hidradenitis suppurativa. Nat Rev Dis Primers. 2020;6(1):18.              3083.2009.03199.x. PMID: 19470075.
    DOI: 10.1038/s41572-020-0149-1. PMID: 32165620.                     39.   Braswell SF, Kostopoulos TC, Ortega-Loayza AG. Pathophysiology
34. Savage KT, Santillan MR, Flood KS, Charrow A, Porter ML,                  of pyoderma gangrenosum (PG): an updated review. J Am Acad
    Kimball AB. Tofacitinib shows benefit in conjunction with other           Dermatol. 2015;73(4):691-698. DOI: 10.1016/j.jaad.2015.06.021.
    therapies in recalcitrant hidradenitis suppurativa patients. JAAD         PMID: 26253362.
    Case Rep. 2020;6(2):99-102. DOI: 10.1016/j.jdcr.2019.10.010.        40.   Alavi A, French LE, Davis MD, Brassard A, Kirsner RS. Pyo-
    PMID: 31993474. PMCID: PMC6974699.                                        derma gangrenosum: an update on pathophysiology, diagnosis
35. Zouboulis CC, Frew JW, Giamarellos-Bourboulis EJ, Jemec GBE,              and treatment. Am J Clin Dermatol. 2017;18(3):355-372. DOI:
    del Marmol V, Marzano AV, et al. Target molecules for future hi-          10.1007/s40257-017-0251-7. PMID: 28224502.
    dradenitis suppurativa treatment. Exp Dermatol. 2021;30 Suppl       41.   Choi AW, Abuav R, Rabizadeh SM, Ansari R, Marsch AF. Re-
    1:8-17. DOI: 10.1111/exd.14338. PMID: 34085329.                           calcitrant and severe pyoderma gangrenosum attributable to le-
36. Miller J, Yentzer BA, Clark A, Jorizzo JL, Feldman SR. Pyoderma           vamisole-adulterated cocaine and treated successfully with oral
    gangrenosum: a review and update on new therapies. J Am Acad              tofacitinib. JAAD Case Rep. 2020;6(9):939-941. DOI: 10.1016/j.
    Dermatol. 2010;62(4):646-654. DOI: 10.1016/j.jaad.2009.05.030.            jdcr.2020.07.035. PMID: 32923571. PMCID: PMC7475066.
    PMID: 20227580.                                                     42.   Kochar B, Herfarth N, Mamie C, Navarini AA, Scharl M, Her-
37. Crowson AN, Mihm MC, Jr., Magro C. Pyoderma gangrenosum: a                farth HH. Tofacitinib for the treatment of pyoderma gangreno-
    review. J Cutan Pathol. 2003;30(2):97-107. DOI: 10.1034/j.1600-           sum. Clin Gastroenterol Hepatol. 2019;17(5):991-993. DOI:
    0560.2003.00024.x. PMID: 12641787.                                        10.1016/j.cgh.2018.10.047. PMID: 30404036.
38. Ruocco E, Sangiuliano S, Gravina AG, Miranda A, Nicoletti
    G. Pyoderma gangrenosum: an updated review. J Eur Acad




Review | Dermatol Pract Concept. 2022;12(4):e2022178                                                                                       7
