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Scoping Review on the Use of Drugs Targeting JAK/STAT Pathway in Atopic Dermatitis, Vitiligo, and Alopecia Areata

  • Ana M. Montilla
  • Francisco Gómez-García
  • Pedro J. Gómez-Arias
  • Jesús Gay-Mimbrera
  • Jorge Hernández-Parada
  • Beatriz Isla-Tejera
  • Juan RuanoEmail author
Open Access
Review

Abstract

Introduction

The JAK/STAT signaling pathway is involved in the immune-mediated inflammatory skin diseases atopic dermatitis (AD), vitiligo, and alopecia areata (AA), and represents a potential target when developing treatments. So far, no drugs targeting this pathway have been approved for the treatment of dermatological diseases. We reviewed the use of drugs blocking the JAK/STAT pathway in the aforementioned diseases.

Methods

An a priori protocol was published. We used Joanna Briggs Institute Reviewer’s Manual methodology to conduct the review and PRISMA Extension for Scoping Review (PRISMA-ScR) to report results. MEDLINE, EMBASE, CINAHL, Scopus, and Web of Science databases were searched in a three-step approach on April 2019 by two researchers.

Results

Ninety-six mainly multicenter observational studies were included (66, 10, and 20 studies on AA, vitiligo, and AD, respectively). Tofacitinib and ruxolitinib were mainly used for the three diseases, and also upadacitinib, abrocitinib, baricitinib, cerdulatinib, delgocitinib, gusacitinib for AD, and baricitinib, PF-06700841, and PF-06651600 for AA. All patients with AD improved, whereas patients with vitiligo and patients with AA showed varied responses, including unresponsive cases. The safety profiles were similar for all drugs and diseases, mainly comprising mild or no adverse events.

Conclusions

Evidence on the efficacy and safety of drugs targeting the JAK/STAT pathway for the treatment of patients with AD, vitiligo, or AA is increasing but is still of low quality.

Keywords

Alopecia areata Atopic dermatitis Baricitinib Cerdulatinib Immune-mediated inflammatory skin diseases JAK/STAT pathway Ruxolitinib Tofacitinib Upadacitinib Vitiligo 

Introduction

Immune-mediated inflammatory skin diseases are a group of frequently associated disorders comprising atopic dermatitis (AD), vitiligo, and alopecia areata (AA), among others. AD is a chronic inflammatory skin disease associated with skin barrier dysfunction, intense pruritus, and eczematous skin lesions. Its estimated prevalence in industrialized countries is 15–30% in the pediatric population and 2–10% in the adult group [1]. Vitiligo is a chronic autoimmune disorder characterized by cutaneous depigmentation as a result of the destruction of melanocytes via cell-mediated immunity, affecting 1–2% of the population worldwide including children and adults [2]. AA is a multifactorial autoimmune disease in which an immune-mediated destruction of hair follicles in conjunction with genetic predisposition lead to non-scarring hair loss, typified by alopecic patches that can encompass the entire scalp in alopecia totalis or body in alopecia universalis [3]. It is one of the most prevalent autoimmune diseases with approximately 2% lifetime risk [4, 5].

These three diseases cause significant impairment in the quality of life of the patient and marked psychological distress derived from their associated symptoms and the stigma related to a highly visible skin condition [6, 7, 8]. This profound impact is not completely avoidable because the currently existing therapies are limited in efficacy and not exempt from undesirable side effects, which is the reason behind performing further research.

Since multiple molecules are involved in their pathogenesis, further knowledge of molecular cell biology has permitted the design of new drugs directed against key targets in signaling pathway regulation. In this sense, the Janus kinases (JAKs) and signal transducer and activator of transcription (STAT) proteins (JAK/STAT) pathway is one of a handful of pleiotropic routes used to transduce multiple extracellular signals involved in cell proliferation, differentiation, migration, and apoptosis [9]. The JAK pathways are believed to play an important role in inflammatory processes as they are involved in signaling for over 50 cytokines and growth factors, many of which drive immune-mediated conditions.

The JAK family is constituted by four types of cytoplasmic tyrosine kinases: JAK1, JAK2, JAK3, and TYK2 [10]. STAT, of which there are seven different subtypes (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6), is the other fundamental component of the cascade [11]. After being phosphorylated by JAK, STAT translocates to the nucleus to induce the transcription of specific genes (Fig. S1 of Supplementary Material). Alterations in the JAK/STAT pathway have been related to the pathophysiology of AD, vitiligo, and AA. In fact, some molecules, such as interleukins (IL)-2 and its family, IL-23, interferon alpha [12], and IL-17 [13], have demonstrated their importance in the development of dermatological diseases by direct or indirect regulation of this pathway. Therefore, drugs that act on this pathway [14] by selectively inhibiting one (filgotinib, JAK1; pacritinib, JAK2; decernotinib, JAK3) or more than one (tofacitinib, JAK1 and JAK3; ruxolitinib, baricitinib, JAK1 and JAK2) JAK protein [15] are promising for the treatment of the aforementioned diseases [14] (Table S7 of Supplementary Material).

So far, no JAK/STAT inhibitors have been approved for the treatment of dermatological diseases, although some of them (ruxolitinib and tofacitinib) are used in other illnesses, such as myelofibrosis and rheumatoid arthritis [16, 17]. However, the off-label use of these drugs showed promising results in the treatment of different skin diseases, including AA, AD, and vitiligo. Broadening our knowledge on the efficacy and safety profiles of these drugs and their application in dermatological diseases is essential to establish their risk–benefit balance.

A scoping review is a form of scientific methodology that addresses an exploratory research question, with the aim of mapping key concepts and gaps related to a defined area or field [18]. The development of JAK inhibitors for the treatment of AA, AD, and vitiligo is still in its early stages. In order to avoid the extensive efforts that would be needed to conduct studies aimed at answering specific questions, we considered it necessary to review the literature available to date. Therefore, we performed a scoping review to broadly summarize all the available evidence presented to date on the use of inhibitors of the JAK/STAT pathway in the treatment of AA, AD, and vitiligo diseases.

Methods

Protocol and Registration

We conducted this scoping review in accordance with the recently published a priori protocol [19]. Methodology to conduct scoping reviews by the Joanna Briggs Institute was followed [20] and results were presented using the recent Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews (PRISMA-ScR) [21].

Literature Search and Eligibility Criteria

Strategies for literature search and eligibility criteria are broadly described in the Supplementary Methods (Supplementary Material).

Data Chart

The relevant information for this review was extracted and summarized in a data chart developed by two reviewers. Characteristics of the studies, including information about author(s), year of publication, country, study design, registration, conflict of interest (COI), and funding, were displayed in separate tables for AA, AD, and vitiligo. Epidemiological aspects of the studies, including a classification based on the type (experimental or observational) and subtype of study, study population, sample size, as well as an evaluation of the efficacy and safety of drugs for each disease (intervention type, details of comparators, duration of the intervention, dosage, outcomes, and adverse events) were collected and displayed in tables. Finally, a table linking randomized clinical trial (RCT) protocols and the subsequently published articles was also created.

Report of Results

Results of the comprehensive search were presented in a PRISMA flow diagram. We organized the extracted data in several categories: indications, mechanism of action, efficacy, and safety and provided a clear explanation for each category. Finally, the results of the scoping review were presented in both diagrammatic and tabular forms, and in a descriptive format, accompanied by a narrative summary of the relation between the results and the review objective and question(s).

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors; thus, no ethical approval from institutional committees was required.

Protocol versus Overview

Our planned search strategy published in BMJ Open was compared with the final reported review methods. No differences were found.

Results

From 2197 articles (EMBASE + MEDLINE 1108; EMBASE 1048; MEDLINE 41) regarding the use of JAK/STAT-targeting drugs in dermatological diseases, after filtering duplicates and selecting studies according to title, abstract, and keywords, 116 studies met the criteria for full-text review (Fig. 1). Of these, 95 articles fulfilled the inclusion criteria and one article was included after reviewing the references of those studies. Thus, 96 studies, which included 66, 20, and 10 reports describing AA, AD, and vitiligo, respectively, were finally analyzed in the scoping review. A reference list of all articles with reasons for inclusion and exclusion is presented in Tables S2 and S3 of Supplementary Material.
Fig. 1

PRISMA flow diagram

Mapping Studies on Use of JAK Inhibitors

Atopic Dermatitis

Twenty studies [22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41] comprising 1851 patients with AD were published from 2015 to 2019 as full-text publications of abstracts presented at congresses (n = 11) or scientific manuscripts (n = 9) (Tables S4 and S8 of Supplementary Material). Seven studies (35%) previously registered an a priori protocol in a public registry. Sixteen (80%) were multicenter studies involving up to 38 different institutions. The average number of authors and affiliations per article was 7 (range 3–18) and 6 (range 1–38), respectively. Sixteen articles (80%) had at least one author who was working for a pharmaceutical company, with an average of five authors per article (range 0–16). Eight studies (40%) declared that one or more authors had conflicts of interest (CoIs), while another article (5%) denied any CoIs and 11 papers did not mention CoI (55%). Disclosures related to the funding sources were detailed only in seven articles (35%), including public sources (n = 1), pharmaceutical sources (n = 5), or none (n = 1).

Vitiligo

Ten studies [42, 43, 44, 45, 46, 47, 48, 49, 50, 51] comprising 62 patients with vitiligo were published between October 2015 and June 2018 as full manuscripts (n = 7), full-text publications of abstracts presented at congresses (n = 2), or letters (n = 1) (Tables S5 and S8 of Supplementary Material). Only three studies (30%) had an a priori protocol. Six (60%) were multicenter studies with up to four centers participating. The average number of authors and affiliations per article was 5 (range 2–13) and 2 (range 1–4), respectively. Authors from pharmaceutical industries were involved in three studies with an average number of one author (range 1–2). Three studies (30%) declared the existence of an author’s CoI, five articles (50%) declared having no CoI, and in another two (20%) this information was not available. Funding sources were described in five articles (50%) and were divided into public sources (n = 3), both public and pharmaceutical sources (n = 1) ,or none (n = 1).

Alopecia Areata

Sixty-six studies [49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114] comprising 950 patients with AA were published between May 2013 and May 2019 as full papers (n = 39), letters (n = 14), or full-text publications of abstracts presented at congresses (n = 11) (Tables S6 and S8 of Supplementary Material). Of those, 16 studies (24.2%) had previously published or registered an a priori protocol. The majority of studies were performed in the USA (n = 41) and 37 studies (56%) were multicenter involving up to five institutions. The number of authors per article ranged from 1 to 15, with an average of 4. Only 17 studies declared CoIs among their authors, whereas 29 studies stated not to have any, and 20 articles did not make any reference to this topic. Information on funding sources was available in 32 manuscripts, of which 15 were funded by public sources, one by academic and pharmaceutical industry, and 16 did not receive any funding.

Evidence of Efficacy and Safety of Treatment with JAK Inhibitors

Atopic Dermatitis

Twenty studies on the use of JAK inhibitors for the treatment of AD were identified, four of which followed an observational design (two case reports and two case series) and 16 followed an experimental design (three phase I and 13 phase II RCTs) (Table 1). The duration of observational studies ranged from 6 to 10 months. The phase I RCT study was performed for 7 days and phase II RCTs lasted for 4–16 weeks. The reviewed articles explored the efficacy and safety of a wide variety of drugs such as tofacitinib (three systemic, three topical), upadacitinib (five systemic), ruxolitinib (three topical), abrocitinib (two systemic), gusacitinib (one systemic), delgocitinib (one topical), baricitinib (one systemic), and cerdulatinib (one topical). Efficacy outcomes were assessed using several validated scales, such as Eczema Area and Severity Index (EASI), pruritus Numerical Rating Scale (NRS) score, Investigator’s Global Assessment (IGA), body surface area (BSA), Severity Scoring of Atopic Dermatitis Index (SCORAD), or Patient-Oriented Eczema Measure (POEM).
Table 1

Characteristics of primary clinical studies on atopic dermatitis

Study [references]

Type

Drug

Dosage

Administration route

Period (weeks)

Number of patients

Outcomes

Efficacy

Safety

1 [22]

RCT phase IIb

Upadacitinib

7.5/15/30 mg PO

Systemic

16

167

At week 16

 EASI score

 Pruritus NRS score

 EASI-75

EASI: 39.4%/61.7%/74.4% for UPA vs 23.0% placebo

NRS: 39.6%/ 48.0%/68.9% UPA vs 9.7% placebo

EASI-75: 28.6%/52.4%/69.0% UPA vs 9.8% placebo

Mild: Upper respiratory tract infection, AD exacerbation

Severe: appendicitis, pericoronitis, skin infection (all of them n = 1)

2 [23]

Case report

Tofacitinib

5 mg BID PO

Systemic

40

1

 NRS score

NRS score changed from 8/10 to 3/10

None

3 [24]

RCT phase II

Upadacitinib

7.5/15/30 mg QD PO

Systemic

16

163

At week 16

 SCORAD

 POEM

 ≥ 4 improvement in NRS

SCORAD: 33%/47%/60% UPA vs 12% placebo

POEM: 5.5/8.6/12.3 UPA vs 1.6 placebo

NRS: 24%/59%/53% UPA vs 6% placebo

Upper respiratory tract infection, AD exacerbation

4 [25]

RCT phase I

Tofacitinib

0.03%; 0.1%; 0.3%; 1%; 3%

Topical

1

66

 EASI score

 Pruritus NRS score

Clear and rapid improvement

White blood cell count decreased (n = 1 with 3% tofacitinib)

Erysipela (n = 1 with 1% tofacitinib)

AD exacerbation (n = 1 with 1% and n = 1 with 3%)

5 [26]

Case series

Ruxolitinib

NA

NA

NA

4

Clinical endpoints

Remarkable improvement

6 [27]

RCT phase II

Cerdulatinib

0.25%, 0.5%, 1%, or 3%

Topical

4

327

 EASI score

 Pruritus NRS score

 IGA score

 BSA

All doses had greater efficacy than vehicle in all studied efficacy parameters. Rapid significant pruritus NRS score reduction

Mild

7 [28]

Case report

Tofacitinib

5 mg BID PO

Systemic

24

1

 EASI score

EASI = 0 (complete remission) within 3 months

Upper respiratory tract infection

Diarrhea

8 [29]

RCT phase IIa

Tofacitinib

2%

Topical

4

69

 EASI score

 Pruritus NRS score

 IGA score

 BSA

Significant improvements vs vehicle across all efficacy endpoints

Mild and infrequent

9 [30]

Case series

Tofacitinib

5 mg/day or BID PO

Systemic

29

6

 SCORAD index

Decrease in SCORAD for all patients, maintained during follow-up period

None

10 [31]

RCT phase IIb

Ruxolitinib

1.5% QD; 1.5% BID

Topical

8

65

Serum proteomic changes from baseline

NA

Suspected herpes zoster-associated encephalitis during oral treatment with tofacitinib in alopecia universalis

11 [32]

RCT phase II

Upadacitinib

7.5 mg/15 mg/30 mg QD PO vs placebo

Systemic

16

167

 EASI score

 Pruritus NRS score

 Histological changes

Mean % improvements in EASI (39.4%, 61.7%, 74.4% vs 23% placebo) and pruritus NRS (39.6%, 48%, 68.9% vs 9.7% placebo)

Lesional and non-lesional biopsies from 50 patients: reduction of epidermal hyperplasia and number of dendritic cells, associated with clinical improvements, in upadacitinib 15 mg and 30 mg

NA

12 [33]

RCT phase II

Baricitinib

2/4 mg QD vs placebo PO

Systemic

16

124

 EASI-75

 Pruritus NRS score

 SCORAD

 IGA

 DLQI

 POEM

Achievement of EASI-50 (61% 4 mg, 37% placebo) was significant as early as week 4, although it was not significant for 2 mg vs placebo

EASI reduction at week 16: 65% for 2 mg and 4 mg vs 46% for placebo

Significant improvement in pruritus and sleep loss, as well as HRQoL measures

Adverse events were reported in 24 (49%) placebo, 17 (46%) baricitinib 2 mg, and 27 (71%) baricitinib 4 mg cases

Placebo: Lymphopenia (n = 3) and eczema

Baricitinib 2 mg: neutropenia (n = 1)

Baricitinib 4 mg: neutropenia (n = 5), white cell count decreases (n = 2), abnormal lymphocyte count, headache, eczema, benign polyp of the large intestine (n = 1)

13 [34]

RCT phase Ib

Gusacitinib

20/40/80 mg PO vs placebo

Systemic

4

36

 EASI-50

 EASI-75

 BSA

 Pruritus NRS score

 IGA

 POEM

EASI-50 (20%, 100%, 83% vs 22% placebo)

EASI-75 (0%, 71%, 33% vs 22% placebo)

Change in pruritus NRS score (− 1.3 ± 2.1, − 3.1 ± 2.7, − 4.7 ± 2.1 vs − 1.6 ± 1.8 placebo)

Adverse events were mild and similar across all groups, including headache, nausea, diarrhea, nasopharyngitis, back pain, mild hypertension, and low lymphocyte levels

14 [35]

RCT phase II

Upadacitinib

7.5/15/30 mg QD PO

Systemic

16

36

 EASI score

 Pruritus NRS score

 AEC

 Serum IgE

Mean percentage EASI reduction at week 16: 39.4%, 61.7%, 74.4% vs 23% placebo, all of them significant

Mean percentage pruritus NRS reduction at week 16: 39.6%, 48%, 68.9% vs 9.7% placebo, all significant

Week 16 AEC significantly lowered with 15 mg and 30 mg vs placebo, as early as week 2 (these changes strongly correlated with EASI)

Changes in IgE levels were not significant

NA

15 [36]

RCT phase II

Ruxolitinib

0.15% QD; 0.5% QD; 1.5% QD; 1.5% BID

Topical

8

111

 EASI score

 TARC/CCL17 levels

 AEC

 Serum IgE

Significant reduction of TARC/CCL17 levels with ruxolitinib 1.5% BID

Total serum IgE levels reduction with ruxolitinib 1.5% QD or BID

These changes did not predict ruxolitinib treatment response (percentage reductions in EASI)

NA

16 [37]

RCT phase IIb

Upadacitinib

7.5/15/30 mg QD PO

Systemic

16

166

 SCORAD

 Pruritus NRS score

 POEM

Mean improvement in SCORAD itch VAS: 3.3, 3.4, 4.7 vs 1.2 placebo

NA

17 [38]

RCT phase IIa

Tofacitinib

2%

Topical

4

67

 Pharmacokinetics

NA

For adult and pediatric patients with > 70% BSA, concentrations could exceed 12.4 ng/mL for ointment application rates > 2 mg/cm2

Additional safety monitoring requirements may have to be considered

18 [39]

RCT phase Ib

Cerdulatinib

0.4% BID

Topical

2

8

 EASI

 Histological, immune, and gene expression analyses

Significant clinical improvements (EASI improvement 65%), reversal of epidermal hyperplasia, reduced immune cell infiltration and AD‐related inflammatory gene expression

All treatment-related adverse events were grade 1 (34/35 events) or grade 2 (1/35 events), with no safety-related withdrawals

19 [40]

RCT phase IIb

Abrocitinib

10/30/100/200 mg QD PO

Systemic

12

267

 EASI-50/75/90

 Pruritus NRS score

 SCORAD

Significative changes in SCORAD (40.7% for 100 mg), in EASI (47.4% for 100 mg), and in pruritus NRS (25.4% for 200 mg; 20.7% for 100 mg)

EASI-50 achievement: 78.5% for 200 mg, 55.3% for 100 mg, and 27.4% for placebo

EASI-75 achievement: 63.7% for 200 mg, 41.6% for 100 mg, and 15.6% for placebo

EASI-90 achievement: 51.6% for 200 mg, 26.8% for 100 mg, and 10.3% for placebo

Adverse events and laboratory anomalies were found in 184 patients (68.9%). Serious AE were observed in 9 patients (3.4%). No deaths were registered

20 [41]

RCT phase IIb

Abrocitinib

10/30/100/200 mg QD PO

Systemic

12

267

 Pruritus NRS score

 PtGA

 POEM

 DLQI

200 mg significantly improved ALL outcomes. 100 mg only pruritus NRS, DLQI, and POEM

NA

AEC absolute eosinophil count, SCORAD Severity Scoring of Atopic Dermatitis Index, EASI Eczema Area and Severity Index, NRS Numerical Rating Scale, EASI-75 ≥ 75% reduction of basal EASI value, POEM Patient Oriented Eczema Measure, PGA Physician’s Global Assessment, PtGA Patient’s Global Assessment, HRQoL Health-Related Quality of Life, IGA Investigator’s Global Assessment, VAS visual analogue scale, QD once a day, BID twice a day, PO per os (oral), DLQI Dermatology Life Quality Index, BSA body surface area, NA not acquired

Significant improvement across all efficacy endpoints was evidenced in both experimental and observational studies. Furthermore, some studies evaluated relapse rate after a treatment discontinuation. Most studies did not report adverse events. Where they were reported, the majority were mild cases of upper respiratory tract infections, nasopharyngitis, AD exacerbation, erysipelas, headache, nausea, diarrhea, white cell count decrease (neutropenia, lymphopenia), or mild hypertension. There were four reports of severe adverse events: herpes zoster-associated encephalitis, appendicitis, pericoronitis, and skin infection.

Vitiligo

We identified ten studies about the use of JAK inhibitor drugs in vitiligo therapy. Seven of them were observational (four case reports, three case series), whereas three were open-label experimental studies (Table 2). Study length ranged from 3 to 10 months for observational studies and from 5 to 13 months for experimental studies. Regarding drug and administration route, seven articles were about tofacitinib (three systemic, one topical, three systemic/topical) and three were about ruxolitinib (two topical, one systemic). Seven studies (five observational, two experimental) set the percentage change in repigmentation (or percentage decrease in BSA) as their primary endpoint. Out of 17 patients in whom facial repigmentation was specifically studied, 14 (82%) showed different degrees of response. Concerning body repigmentation, which was assessed in 27 patients, 13 (48%) of them had an improvement; meanwhile, five patients experienced preferential repigmentation in sun-exposed areas. Three studies (one observational, two experimental) considered the improvement in Vitiligo Area Scoring Index (VASI) score as their main goal. These studies found that from a total of 20 patients, 14 (70%) had some improvement in VASI score, although with varied degrees, and one patient only showed a marginal improvement. Overall, 14 out of 20 patients (70%) responded to ruxolitinib and 11 out of 16 (68%) to tofacitinib.
Table 2

Characteristics of primary clinical studies on vitiligo

Article

Type, subtype of study

Drug

Dosage

Administration route

Period (weeks)

Number of patients

Outcomes

Efficacy

Safety

1 [42]

Open label

Ruxolitinib

1.5% BID

Topical

52

8

VASI score

PGA score

DLQI score

BSA

5/8 patients responded (facial VASI—mean improvement 92% ± 7.1 [n = 4], VASI—mean improvement: non-acral upper extremities 12.6% ± 19.5 [n = 3], trunk 16.7% ± 16.7 [n = 2])

Not statistically significant: PGA, DLQI, and BSA

Minor (erythema [n = 3], transient acne [n = 2])

2 [43]

Open label

Tofacitinib

2.5 mg BID PO

Systemic

NA

25

Repigmentation

NA

NA

3 [44]

Case series

Tofacitinib

5 mg BID PO

Systemic

12–18

2

Repigmentation

Facial repigmentation: nearly complete in case #1; 75% case #2

Body repigmentation: > 75% in case #1, 0% case #2

None

4 [45]

Case series

Tofacitinib

Topical 1.5%; 5 mg BID PO

Topical

12

2

Repigmentation

Facial and body repigmentation, preferential in sun-exposed areas

NA

5 [46]

Case series

Tofacitinib

5–10 mg BID PO

Systemic

40

10

Repigmentation

5/10 patients responded (BSA 5.4% decrease, 3 of them only in sun-exposed areas)

Upper respiratory tract infection [n = 2], weight gain [n = 1], arthralgia [n = 1], mild lipid elevation [n = 4]

6 [47]

Case report

Tofacitinib

Topical

Topical

NA

1

NA

NA

NA

7 [48]

Open label

Ruxolitinib

1.5% BID

Topical

20

11

VASI score

Repigmentation

8/11 patients responded (VASI 23% mean improvement, facial repigmentation [n = 8], periocular repigmentation [n = 2], non-acral upper extremities repigmentation [n = 3])

Erythema [72%], transient acne [n = 2]

8 [49]

Case report

Tofacitinib

5 mg BID PO

Systemic

24

1

VASI score

Only marginal improvement (VASI from 4.68 at baseline to 3.95 at 5 months)

Upper respiratory tract infection and diarrhea

9 [50]

Case report

Ruxolitinib

20 mg BID PO

Systemic

20

1

Repigmentation

51% facial repigmentation, repigmentation on other areas

NA

10 [51]

Case report

Tofacitinib

5 mg PO every other day; later, daily

Systemic

20

1

Repigmentation

Partial facial and upper extremities repigmentation, nearly complete in forehead and hands

None

BSA body surface area, DLQI Dermatology Life Quality Index, PGA Physician Global Assessment, VASI Vitiligo Area Severity Index, QD once a day, BID twice a day, PO per os (oral), NA not acquired

Adverse events, though infrequent and mild, included application-site irritation, folliculitis, hypertension, upper respiratory tract infections, herpes zoster infection, increased appetite, weight gain, or diarrhea.

Alopecia Areata

Sixty-six studies on drugs targeting the JAK/STAT pathway in AA were selected (Table 3). Most of them followed an observational design (30 case reports and 23 case series). There were also 13 experimental studies (7 open-label, 1 phase I, 5 phase II RCTs). Both observational and experimental studies lasted between 3 months and 3 years. Most manuscripts focused on the treatment with tofacitinib (41 systemic, 3 topical), ruxolitinib (9 systemic, 2 topical), or both tofacitinib vs ruxolitinib (4, both as topical and/or systemic). Two studies were found for baricitinib (systemic) and for both PF-06700841 and PF-06651600, two dual TYK2/JAK1 and JAK3/TYK2 family kinase inhibitors, respectively.
Table 3

Characteristics of primary clinical studies on alopecia areata

Study [references]

Type, subtype of study

Drug

Dosage

Administration route

Follow-up (weeks)

Number of patients

Outcomes

Efficacy

Safety

1 [52]

Case report

Tofacitinib

5 mg BID PO; later, 15 mg/day

Systemic

40

1

Hair regrowth

Near complete by 6 months, loss of regrown hair at 8 months

Herpes zoster

2 [53]

RCT phase II

Tofacitinib

5 mg to 10 mg BID PO

Systemic

72

12

≥ 50% regrowth

SALT score

≥ 50% regrowth (n = 8), overall SALT improvement (n = 11)

Hypertension (n = 1)

3 [23]

Case report

Tofacitinib

5 mg BID PO

Systemic

40

1

Hair regrowth

Hair regrowth on all affected body parts

None

4 [54]

Case series

Tofacitinib

2%

Topical

11

SALT score

Average SALT reduction of 32.3%

Application-site irritation (n = 1)

5 [55]

Open label

Tofacitinib

2.5 mg QD PO, modified according to response

Systemic

24/72

200

% change in SALT score

Eleven out of 12 patients attained a global overall improvement in SALT score at the end of treatment with results ranging from 12.1% to 100% regrowth, with an average 56.8% regrowth

None

6 [56]

Case series

Tofacitinib

10 mg PO

Systemic

≥ 16

33

Nail improvement

Improvement in nail changes in 11/15 patients (73.3%)

NA

7 [57]

Case report

Ruxolitinib

20 mg BID PO

Systemic

48

1

Hair regrowth

Complete regrowth (beard) and partial (50%) regrowth (scalp), maintained after 1 year

NA

8 [58]

RCT phase II

Tofacitinib

5 mg BID PO

Systemic

12

30

HRQoL scale

Skindex-16 scale

Significant improvement for all subjects

NA

9 [59]

Open label

Tofacitinib

2% BID

Topical

24

10

Hair regrowth

SALT score

Hair regrowth in 3 patients (61%, 18%, 25% improvement in SALT score)

Skin irritation, folliculitis

10 [60]

Case series

Tofacitinib

5 mg QD or BID PO

Systemic

20

2

SALT score

Patient 1: SALT 100 to 15 (85% change). Patient 2: SALT 100 to 10 (90% change)

Increased appetite, weight gain

11 [61]

RCT phase I

Tofacitinib, Ruxolitinib

Tofacitinib 2%

Ruxolitinib 1%

Tofacitinib 5 mg PO

Topical/systemic

28

16

Hair regrowth

Global photography

IGA score

PtGA

Partial regrowth (n = 6 with 2% T, n = 5 with 1% R, n = 10 with clobetasol propionate 0.05%, n = 0 with placebo)

None

12 [23]

Case report

Tofacitinib

5 mg BID PO

Systemic

24

1

Hair regrowth

Hair regrowth on scalp, beard, extremities, eyebrows, and eyelashes

Upper respiratory tract infections, diarrhea

13 [62]

Open label

Tofacitinib

5 mg BID PO

10 mg QD PO

20 mg QD PO

Systemic

30

32

SALT50

18/32 patients achieved SALT50

None

14 [63]

Case series

Ruxolitinib

5 mg BID to 30 mg QD

Systemic

56

2

Hair regrowth

Complete or nearly complete regrowth

None

15 [64]

Case series

Tofacitinib

Ruxolitinib

Tofacitinib 1%

Ruxolitinib 2%

Topical

NA

6

Hair regrowth

Partial regrowth in 4 patients (20%, 75%, 95%, 80%, respectively)

None

16 [65]

Case report

Ruxolitinib

0.6% nightly to BID

Topical

14

1

SALT score

Lack of improvement

None

17 [66]

Case report

Tofacitinib

5 mg PO

Systemic

20

1

Hair regrowth

Regrowth on scalp, eyebrows, and extremities

Increased appetite, weight gain

18 [67]

Case series

Tofacitinib

5 mg BID PO, increased by 5 mg per month

Systemic

36

13

Regrowth rate, response time

Rate 2–90%, mean (sd) 44.3% (31.9), median 50.5%. Response time 1–9 months, mean (sd) 4.2 (2.6) months

Morbilliform eruption, peripheral edema, lipid and liver abnormalities

19 [68]

Case report

Tofacitinib

NA

NA

40

1

Hair regrowth

Nail improvement

Near complete regrowth, mild nail improvement

None

20 [69]

Case series

Tofacitinib

NA

NA

16–52

13

Hair regrowth

Regrowth range 2–90%, mean 44.3%, median 50.5%

NA

21 [70]

Case report

Tofacitinib

5 mg BID PO

Systemic

32

1

Hair regrowth

Complete regrowth in scalp

None

22 [71]

Case series

Tofacitinib

5 mg BID PO

Systemic

48

8

Hair regrowth

SALT score

> 50% regrowth in scalp, eyebrows, eyelashes, and body hair (n = 8)

None

23 [72]

Case report

Tofacitinib

15 mg QD PO to 10 mg QD PO

Systemic

36

1

Hair regrowth

Significant regrowth in scalp and body. No regrowth in eyebrows and eyelashes

Herpes zoster

24 [73]

Case series

Tofacitinib

5 mg BID to 10 mg BID PO

Systemic

16–52

90

Hair regrowth

SALT score

69/90 patients with response, 52/90 patients achieved > 50% change in SALT score

Upper respiratory (28.9%) and urinary tract (3.3%) infections, tonsillitis (2.2%), headache (14.4%), acne (7.8%), fatigue (6.7%). Leukopenia (n = 1). LDL-c increase (n = 15)

25 [74]

Case report

Tofacitinib

5 mg BID PO

Systemic

12

1

Hair regrowth

No hair regrowth

NA

26 [75]

Case report

Tofacitinib

5 mg BID to 10 mg am + 5 mg nightly

Systemic

24

1

Hair regrowth

Complete hair regrowth throughout the entire body

None

27 [76]

Case report

Tofacitinib

5 mg BID PO

Systemic

36

2

Hair regrowth

Partial regrowth on scalp, eyebrows, and axillae

NA

28 [77]

Case series

Tofacitinib

NA

 

26

13

Hair regrowth

SALT score

Clinically significant regrowth (n = 9), mean SALT change 93%

Headache, upper respiratory infections, mild and transient increase in transaminases

29 [78]

RCT phase II

Tofacitinib

5 mg BID PO

Systemic

12

66

SALT score

36% were non-responders (< 5% SALT change), 32% intermediate responders (5–50% change), 32% strong responders (> 50% SALT change)

Grade I and grade II leukopenia

30 [79]

RCT phase II

Ruxolitinib

20 mg BID PO

Systemic

12–24

12

≥ 50% regrowth

Changes in mean SALT score

9/12 ≥ 50% regrowth 7/9 responders achieved > 95% regrowth. Mean SALT from 65.8% ± 28.0% (baseline) to 7.3% ± 13.5% (end of treatment)

Minor bacterial skin infections, upper respiratory or urinary infections, allergy, pneumonia, conjunctival hemorrhage, mild gastrointestinal symptoms. Lowered Hb (n = 1)

31 [80]

Case report

Tofacitinib

5 mg BID PO

Systemic

40

1

Hair regrowth

Nail improvement

At 10 months, complete hair regrowth, nail growth, and nail plate normalization

None

32 [81]

Case report

Tofacitinib

5 mg BID PO

Systemic

16

1

Hair regrowth

Nearly complete scalp hair regrowth. Significant regrowth in eyebrows and eyelashes. Near-complete hair loss at treatment cessation

None

33 [82]

Case report

Tofacitinib

5 mg BID PO

Systemic

128

1

Hair regrowth

Beard, body, scalp, eyebrow, and eyelash hair regrowth

None

34 [83]

Case report

Ruxolitinib

5 mg BID to 20 mg/day PO

Systemic

24

1

Hair regrowth

Progressive regrowth until complete recovery. Relapse after 6 months of durable remission after treatment end

Mild anemia

35 [84]

Case report

Ruxolitinib

0.6% BID

Topical

12

1

Hair regrowth

Nearly complete eyebrow regrowth, 10% scalp hair regrowth

None

36 [85]

Case report

Ruxolitinib

5 mg BID to 15 mg/day PO

Systemic

24

3

Hair regrowth

Nail improvement

Remission of nail changes (n = 3), hair regrowth (n = 2)

None

37 [49]

Case report

Ruxolitinib

20 mg BID PO

Systemic

20

1

Hair regrowth

85% scalp hair regrowth, maintained after 12 weeks from end of treatment

NA

38 [86]

Case report

Tofacitinib

5 mg BID PO

Systemic

16

1

Hair regrowth

Growth of short terminal pigmented hair after 3 months, which then completely disappeared within a month

NA

39 [87]

Case series

Tofacitinib

5 mg BID PO

Systemic

32

2

Hair regrowth

Beard, body, scalp, eyelash, and eyebrow hair regrowth in both patients

Viral infections, fatigue

40 [88]

Case report

Baricitinib

7 mg/day, later 7 mg am + 4 mg pm PO

Systemic

60

1

Hair regrowth

Complete scalp hair regrowth

NA

41 [89]

Case report

Ruxolitinib

15 mg BID PO

Systemic

40

1

Hair regrowth

Nearly complete regrowth durable at > 50 months

NA

42 [90]

Case series

Ruxolitinib

20 mg BID PO

Systemic

12–18

3

Hair regrowth

Nearly complete hair regrowth in all patients

NA

43 [91]

Case report

Tofacitinib

5 mg BID to 10 mg am + 5 mg nightly PO

Systemic

32

1

Hair regrowth

Complete hair regrowth at all body sites except extremities

None

44 [92]

Case series

Tofacitinib

5 to 10 mg BID PO

Systemic

12–18

6

Hair regrowth

Photography

SALT score

Physical examination

Nearly complete regrowth. Mean SALT score went from 77.9% to 25.5%

Acneiform eruptions (n = 2)

45 [93]

RCT phase II

PF-06651600, PF-06700841

PF-06651600: 200 mg QD during induction and 50 mg QD during maintenance

PF-06700841: 60 mg QD during induction and 30 mg QD during maintenance

Systemic

24

46

To evaluate changes in lesional scalp biomarkers

Gene-level changes (PF-06651600 and PF-06700841, respectively): 62% and 115% at week 12, 162% and 104% at week 24, vs 18% and 6% placebo. Downregulation of Th1, Th2 and IL-12/23 immune responses and upregulation of hair keratins. These changes correlated with clinical (SALT score) improvement

NA

46 [94]

Case report

Tofacitinib

5 mg BID PO

Systemic

36

1

Efficacy

Hair regrowth: complete hair regrowth at 5 months, maintained after 4 months of follow-up. Regrowth started in the area of contact dermatitis

NA

47 [95]

Case series

Tofacitinib

2.5 mg QD, then 2.5 mg QD for 4 days and 5 mg QD for 3 days each week

Systemic

48

3

Efficacy and safety

With 2.5 mg: unsatisfactory hair regrowth (< 20%)

When 2.5/5 mg: patient #1 > 90% regrowth; patient #2 > 50% by month 6; patient #3 > 50% by 21 months (complete regrowth of eyebrows and eyelashes and partial scalp hair)

Mild diarrhea. Upper respiratory tract infection

48 [96]

Case series

Tofacitinib

Patient #1: 5 mg BID. Then cycles of 5 mg BID PO 8 weeks/5 mg once daily 4 weeks/no treatment 10–12 weeks. Then 5 mg once daily 5 months/off drug 8 weeks/5 mg BID 8 weeks.

Patient #2: 5 mg BID PO

Systemic

3 years

2

Efficacy and safety

Patient #1: almost complete regrowth at 3 months, relapsing after 8–10 weeks of stopping drug. With the 3rd cycling pattern, almost complete regrowth and no relapses

Patient #2: complete regrowth after 2 months

No adverse effects

49 [97]

Case series

Tofacitinib, ruxolitinib

Tofacitinib 5 mg BID PO

Ruxolitinib 1.5% BID topical

Systemic/topical

52/16

2

Rebound effect after JAK inhibitor treatment discontinuation

Patient #1 on tofacitinib: SALT improvement from 60% to 25%. After discontinuation, relapse and SALT 90%

Patient #2 on ruxolitinib: SALT score improvement from 80% to 7%. After discontinuation, relapse and SALT > 99%

 

50 [98]

Case series

Ruloxitinib

10 to 25 mg BID PO

Systemic

20/124

8

Efficacy and safety

5/8 patients achieved complete or nearly complete regrowth. Mean SALT improvement of 98% (SD 4%). 3/8 patients: no regrowth

Mild adverse effects: upper respiratory infections, weight gain, acne, easy bruising, fatigue. One patient had decreased white blood cell count

51 [99]

Open label

Tofacitinib, ruxolitinib

Tofacitinib 5 mg BID PO

Ruxolitinib 20 mg BID PO

Systemic

36

75

Efficacy and safety

% change in SALT score: 93.8 ± 3.25 for ruxolitinib/95.2 ± 2.69 for tofacitinib. aRUXO group (38 patients): 3 low, 3 medium, 6 good, 18 excellent, 8 complete. Relapse: 28 (73.3%)

aTOFA group (n = 35): 4 low, 4 medium, 5 good, 16 excellent, 8 complete. Relapse: 26 (74.2%)

Adverse effects were infrequent and minor: leukopenia (n = 4), AST/ALT mild elevation (n = 5), serum triglycerides elevation (n = 2), cholesterol elevation (n = 1), acute infections (n = 25), mild gastrointestinal symptoms, headache, weight gain, fatigue

No differences between both drugs

52 [100]

Case series

Tofacitinib

5 mg BID PO

Systemic

24/60

4

Efficacy

Hair regrowth: complete (n = 2) after 3–6 months, 62% (n = 1), scarce (n = 1)

NA

53 [101]

Case series

Tofacitinib

5 mg BID PO, then decreased to 7.5 mg daily

Systemic

NA

63

Efficacy and safety

25/63 patients had > 90% SALT score change. Of these, 15/24 achieved 100% change in SALT score

Mild adverse effects: hyperseborrhea, upper respiratory infections, acneiform eruptions

54 [102]

Case report

Tofacitinib

5 mg BID PO

Systemic

24

1

Hair regrowth

40% regrowth

NA

55 [103]

Case report

Ruloxitinib

5 mg BID then 10 mg BID PO

Systemic

40

1

Hair regrowth

Nearly complete hair regrowth

NA

56 [104]

Case report

Tofacitinib

2% BID

Topical

32

1

Eyelashes regrowth

Nearly complete eyelashes regrowth

NA

57 [105]

Case report

Tofacitinib

5 mg BID PO

Systemic

24

1

Efficacy and safety

Complete regrowth of eyebrows and scalp hair (SALT of 0)

Mild headaches

58 [106]

Case series

Tofacitinib

5 mg QD

PO 5 mg BID PO

Systemic

16/108

11

Efficacy and safety

The mean SALT score improvement from baseline was calculated to be 61.18% (n = 10, range, 0–100%)

One patient developed hyperlipidemia and weight gain while on 11 mg extended release twice daily, which improved with exercise and diet changes while remaining on treatment. Other side effects included gastrointestinal symptoms and mild acne. One patient stopped treatment because of new-onset multiple sclerosis

59 [107]

Case series

Tofacitinib

Tofacitinib 5 mg BID PO, increased to 5 mg 3 times daily for 4 unresponsive patients, and then to 10 mg BID for one of these

Comparators: oral conventional treatment (steroids + cyclosporine) and diphenylcyclopropenone (DPCP)

Systemic/topical

24

74

Efficacy and safety

Median SALT change:

 3rd month: tofacitinib 34.6 (range 0–80), conventional 34.7 (0–89.2), and DPCP 0 (0–53.0)

 6th month: tofacitinib 36.5 (0–91.5), conventional 39.9 (0–91.6), and DPCP 0 (0–80)

SALT50 3rd month:

 Tofacitinib: 9 patients (50%), conventional: 7 patients (26.9%), DPCP: 1 patient (3.6%)

SALT50 6th month:

 Tofacitinib: 8 (44.4%), conventional: 9 (37.5%), DPCP: 3 (11.1%)

In the tofacitinib group, 6 patients (33.3%) suffered abdominal discomfort and acneiform eruption, most of them mild and transient

60 [108]

Case series

Tofacitinib

5 mg BID PO

Systemic

64

9

Efficacy and safety

3/9 patients responded (showing 25–75% regrowth at 6 months)

No significant clinical or laboratory adverse events

61 [109]

Open label

Tofacitinib

5 mg BID PO, increased to 10 mg BID PO in non-responders

Systemic

24

12

Efficacy

8/12 patients ≥ 50% hair regrowth, 3/12 partial < 50% regrowth, and 1 patient no regrowth

NA

62 [110]

Case series

Tofacitinib

5 mg BID PO

Systemic

28/36

4

Efficacy

Patient #1: progressive hair growth after 9 months

Patient #2: partial growth of scalp, eyebrow, and axillary hair

Patient #3: hair growth on scalp, eyebrows, and skin after 7 months

Patient #4: complete regrowth

NA

63 [111]

Case report

Tofacitinib

5 mg BID PO

Systemic

32

1

Efficacy and safety

Almost complete full body hair regrowth

No adverse effects or laboratory abnormalities

64 [112]

Open label

Tofacitinib

5 mg BID PO, then escalated to 10 mg BID PO

Systemic

24

12

Efficacy

7/12 patients achieved ≥ 50% regrowth (60% response rate)

NA

65 [113]

Open label

Tofacitinib

5 mg BID PO, then escalated to 10 mg BID PO

Systemic

24

12

Efficacy

8/12 patients ≥ 50% improvement (hair regrowth). Skin gene expression profiles and ALADIN scores correlated with clinical response

NA

66 [114]

Case report

Tofacitinib

5 mg BID PO

Systemic

20 + 8

1

Efficacy and safety

Complete hair regrowth. At 5 months treatment discontinuation because of herpes zoster infection. When resolved, tofacitinib was restarted but without clinical response at 2 months, then it was discontinued

Herpes zoster-associated encephalitis

ALADIN Alopecia Areata Disease Activity Index, HRQoL Health-Related Quality of Life, IGA Investigator’s Global Assessment, LDL-c low density lipoprotein cholesterol, PtGA Patient Global Assessment, SALT Severity of Alopecia Tool, BID twice a day, AST aspartate transaminase, ALT alanine transaminase, NA not acquired

aGrade of treatment response based on SALT reduction: low 0–24%, medium 25–49%, good 50–74%, excellent 75–99%, complete 100%

Efficacy outcomes were mainly measured by using Severity of Alopecia Tool (SALT) score in experimental studies, while the percentage of hair regrowth, at least 50% regrowth achievement, or HRQoL assessed by Skindex-16 scores were used to determine treatment efficacy in observational studies. Hair regrowth was observed in around 50% of patients, with some studies finding at least 50% hair regrowth. Some studies found a median frequency of hair regrowth of 50.5% (2–90%), and a mean response time of 4.2 (range 1–9) months. In some cases, relapse was observed after drug withdrawal. JAK inhibitors were generally safe and well tolerated in all AA studies. Reported adverse events included minor bacterial skin infections, peripheral edema, acneiform eruptions, upper respiratory or urinary tract infections, viral infections, tonsillitis, allergy, pneumonia, conjunctival hemorrhage, mild gastrointestinal symptoms, lipid and liver abnormalities, mild anemia, headache, fatigue, increased appetite, weight gain, and one case of leukopenia.

Discussion

Summary of Findings

This is the first scoping review which summarizes the available evidence on the use of JAK inhibitor drugs in patients with AD, vitiligo, and AA. Our results provide more insight about the gap that exists between specific therapeutical needs not covered by current therapies and the strategical value of these diseases in the R&D pipeline of pharmaceutical companies.

Some patterns were found after systematically reviewing evidence of using JAK-targeting drugs for AD, vitiligo, and AA. Most reviewed studies were related to AA disease, and just a few published studies about vitiligo were identified. In both cases, studies followed an observational design, mostly as small case series. Also, they mainly used systemic drugs, with tofacitinib followed by ruxolitinib, as the JAK inhibitors most frequently used. Although there are some planned or ongoing early phase RCTs for AA, no vitiligo study was associated with any current or completed RCT. Response to treatment was very variable among studies. In most vitiligo studies a positive therapeutic response was noted in 50% of patients, especially in sun-exposed areas. However, not standardized methods were used to assess the efficacy, and the period of follow-up was less than 6 months in most cases. In AA studies, a validated scale (SALT) was frequently used and the follow-up period was longer than in vitiligo studies. We noted two observations of JAK inhibitor response in many AA studies: first, many patients that achieved therapeutic efficacy needed to scale up or maintain treatment for an extended period of time; secondly, in many of these cases the achieved effect was lost after treatment was discontinued. As we observed different responses with different agents in different diseases, we shall consider selecting some specific types of JAK/STAT in different diseases on the basis of their pathogenic features. Finally, the number of published AD studies was intermediate between vitiligo and AA and mostly were associated with phase I/II RCTs, involving up to seven drugs/pharma companies and enrolling a total of 2098 patients. Improved methodological procedures were implemented (i.e., using several standardized tools for each study) to assess efficacy and safety outcomes more rigorously in AD studies as compared to those used for AA and vitiligo. Studies were mainly multicenter and multidisciplinary, especially related to AA, as they involved the largest number of medical specialties and were performed in a higher number of countries, most of them developed countries and mainly represented by the USA. Private funding sources were scarce, and most studies received financial support either from public sources or from none. Conflicts of interest were minimal.

Some factors may explain differences between clinical needs and pharma initiatives: prevalence, burden of disease, and current therapeutic options. The prevalence of vitiligo and AA is lower than that of AD. The burden of disease is higher for AD and AA, compared to that of vitiligo. Therapeutic options are not specifically targeted in any of the three cases. However, there are more current therapeutic options for AD as compared to those for AA and vitiligo. These facts could explain why most the pharmaceutical industry is more interested in developing clinical trials to assess targeted therapies with different drugs in the case of AD, as compared to AA and vitiligo. The increased burden of disease associated with AA could explain the great number of physician-initiated off-label observational studies.

Strengths and Limitations

Some years ago, a systematic review was published about the available data on the use of JAK inhibitors in cutaneous diseases [115]. Recently, two systematic reviews about JAK inhibitors were published, both of them focused on patients with AA and included 30 studies [116, 117]. After assessing these reviews using A MeaSurement Tool to Assess systematic Reviews (AMSTAR) 2 instrument [118], we found that the overall confidence in their results was critically low (data not shown). These reviews had more than one critical flaw and did not provide an accurate and comprehensive summary of the available studies. There are also some non-systematic reviews or literature reviews about JAK inhibitors for AA, AD, and vitiligo, all of them with an intrinsic lower methodological quality as compared with systematic reviews [119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133, 134].

In contrast to all the above, our review was conducted systematically according to the methodology planned in an a priori protocol published prior to study performance. This methodology followed the latest guidelines for conducting scoping reviews and at least two researchers participated in each of the phases. Authors were contacted to clarify certain details about primary data when necessary. Reporting was based on recommendations from the PRISMA Extension for Scoping Reviews. However, funding and time limitations only allowed for the inclusion of studies published in English in our analysis. Even though we believe that the literature search was complete and the performance of a three-stage search approach minimized the potential loss of relevant papers, there is still a possibility that we missed some manuscripts. Additionally, it was not possible to obtain all missing data or clarification of poorly detailed data from some articles we reviewed, even after contacting the authors. This was especially relevant in studies published in the form of abstracts, which we did not exclude. Furthermore, most of these selected studies were of low quality, owing to their observational designs and the high proportion of observational studies and their diversity of efficacy endpoints and outcome reporting forced us to organize and analyze the information into broader and less detailed categories. As a result of the large amount of information extracted from the search and the different designs of the included studies we were not able to do analysis comprising individual patients. Finally, we did not assess the quality of the studies included here, in terms of risk of bias, quality of evidence, and statistical analysis techniques.

Research Gaps

The small number of studies about the use of drugs targeting the JAK/STAT pathway in the treatment of AD and vitiligo contrasts with the great amount of available information on the use of these drugs in AA. Most of the reviewed studies were observational, which translated into a low quality of evidence, according to the GRADE system for grading the quality of evidence [117]. In addition to this, the absence of an a priori design published in a public repository, as occurs in the majority of included studies, could increase the bias risk and reduce analysis transparency, thus limiting the validity and reproducibility of results. Therefore, future studies should focus on improving study quality in order to achieve reliable evidence that could be applicable to clinical practice.

Considering these limitations, the use of JAK inhibitors for the treatment of AD, vitiligo, and AA is promising. The conditions of most participants with AD improved to some extent, while in vitiligo and AA studies both responders and non-responders were identified. Given the preferential repigmentation in sun-exposed areas that some patients with vitiligo experienced when treated with JAK inhibitors, the concomitant or sequential treatment of these patients with UV exposure and these drugs may result in a greater improvement compared to administration of the drug. Response rates to tofacitinib and ruxolitinib were similar in all the studied diseases, while efficacy evidence for other drugs (upadacitinib, baricitinib, cerdulatinib, abroticinib, delgocitinib, and gusacitinib) was scarce because of the small number of studies in which they were applied. It is imperative to establish a consensus on the best methodology (outcomes, validated scales, and time point for assessment) to measure efficacy, which will allow comparison of results between studies, especially in the case of vitiligo and AA, and AD to a lesser extent. Overall, JAK inhibitor drugs have shown short-term acceptable safety, even though they are not completely without adverse events. However, further phase III/IV RCTs are required to ensure more accurate efficacy and safety profiles of these drugs. In fact, there are currently several protocols of RCTs registered in ClinicalTrials.gov about JAK inhibitors for AA, AD, and vitiligo treatment, most of them promoted by the industry and still active and recruiting (Table S8 of Supplementary Material).

Conclusions

Evidence on the use of drugs targeting the JAK/STAT pathway for the treatment of dermatological diseases such as AD, vitiligo, and AA is growing but still mainly focused on observational or early phase experimental studies. Although existing results are promising, further studies are needed to ensure that the efficacy and safety parameters of these drugs are optimal for their use in clinical practice. These clinical trials studies should provide more accurate results by improving their design, standardization of scales, and the time of outcome measurement.

Notes

Acknowledgements

Funding

This work was supported, in part, by project ICI1400136 to JR, integrated into the National Plan of R+D+I 2008-2011 and cofinanced by the ISCIII-Subdirección General de Evaluación and European Regional Development Fund (ERDF), by project PIN-0316-2017 of the Consejería de Salud, Junta de Andalucía (Spain) to JR, and by Grant PP13/009 of Plan Propio de movilidad para investigadores del Instituto Maimonides de Investigacion Biomédica de Córdoba (IMIBIC). No funding was received from any pharmaceutical company. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published. The authors would like to thank Editage (http://www.editage.com) for English-language editing.

Authorship Contributions

Ana M. Montilla and Francisco Gómez-García contributed equally to this work.

Disclosures

Juan Ruano is a member of the journal’s Editorial Board. Ana M. Montilla, Francisco Gómez-García, Pedro J. Gómez-Arias, Jesús Gay-Mimbrera, Jorge Hernández-Parada, Beatriz Isla-Tejera have nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Data Availability

All data generated or analyzed during this study are included in this published article or as supplementary information file.

Open Access

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Supplementary material

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Supplementary material 1 (DOCX 544 kb)

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Copyright information

© The Author(s) 2019

Authors and Affiliations

  1. 1.Immune-mediated Inflammatory Skin Diseases GroupIMIBIC/Reina Sofía University Hospital/University of CórdobaCórdobaSpain
  2. 2.Department of DermatologyReina Sofía University HospitalCórdobaSpain
  3. 3.School of MedicineUniversity of CórdobaCórdobaSpain
  4. 4.Department of PharmacyReina Sofía University HospitalCórdobaSpain

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