Tofacitinib

Off-label studies on tofacitinib in dermatology: a review

Kyle Tegtmeyer, Jeffrey Zhao, Nolan J. Maloney, Giancarlo Atassi, Molly Beestrum & Peter A. Lio

To cite this article: Kyle Tegtmeyer, Jeffrey Zhao, Nolan J. Maloney, Giancarlo Atassi, Molly Beestrum & Peter A. Lio (2019): Off-label studies on tofacitinib in dermatology: a review, Journal of Dermatological Treatment, DOI: 10.1080/09546634.2019.1673877
To link to this article: https://doi.org/10.1080/09546634.2019.1673877

Published online: 03 Oct 2019.

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JOURNAL OF DERMATOLOGICAL TREATMENT
https://doi.org/10.1080/09546634.2019.1673877
REVIEW ARTICLE
Off-label studies on tofacitinib in dermatology: a review
Kyle Tegtmeyera , Jeffrey Zhaoa , Nolan J. Maloneyb , Giancarlo Atassia , Molly Beestruma and Peter A. Lioc,d
aDepartment of Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; bDivision of Dermatology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; cDepartment of Dermatology & Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; dMedical Dermatology Associates of Chicago, Chicago, IL, USA

ARTICLE HISTORY
Received 10 September 2019 Accepted 12 September 2019

KEYWORDS
Tofacitinib; off-label; psoriasis; inflammatory

Introduction
Tofacitinib citrate is an oral Janus kinase (JAK) 1/3 inhibitor ini- tially approved for rheumatoid arthritis in 2012, with additional indications for ulcerative colitis and active psoriatic arthritis (1). Inhibition of JAK 3 enzyme signaling interferes with downstream signal transducer and activators of transcription (STATs) function, which ultimately disrupts hematopoiesis and immune cell func- tion, including in T-, B-, NK, and mast cell populations (2–4). Within the field of dermatology, off-label trials of tofacitinib have been reported for various inflammatory and other conditions involving cell types that are heavily regulated by JAK1/3, such as psoriasis, alopecia areata, and atopic dermatitis. There are cur- rently a multitude of reported and active clinical trials utilizing tofacitinib for skin disorders; the goal of this review is to profile the current state of the literature for off-label and emerging uses of tofacitinib in dermatology.

Adverse effects of tofacitinib
Tofacitinib has a favorable side effect profile and is well-tolerated at therapeutic doses as an oral agent. Commonly reported adverse effects include upper respiratory tract infection and naso- pharyngitis in over 10% of patients, and less commonly (1–10%) diarrhea or gastrointestinal (GI) side effects, hypertension, head- ache, urinary tract infection (UTI), hypercholesterolemia, and anemia (5). More serious infections occasionally seen with tofaciti- nib use include herpes zoster and other rare opportunistic

infections such as candidiasis, likely secondary to tofacitinib’s immunosuppressive effects (6). Rare adverse events that have been reported include malignancies, such as lymphoma, EBV-asso- ciated post-transplant lymphoproliferative disorder in the setting of additional immunosuppression, and non-melanoma skin cancer (5,7–9). Due to these reported adverse events, tofacitinib is con- traindicated in the setting of potent immunosuppressive agents. Additionally, recent data from Phase 4 trials has implicated higher tofacitinib doses with increased risk of deep vein thromboses (DVTs) and pulmonary embolism (PE), and as such, caution is advised in higher-risk patient populations (10).

Off-label uses
Due to its potent anti-inflammatory effects noted in rheumatoid arthritis, ulcerative colitis and psoriatic arthritis, tofacitinib has been explored as a therapeutic option for many inflammatory dermatologic conditions. This includes psoriasis, alopecia, atopic dermatitis, vitiligo, and numerous others.

Materials and methods
A database search for articles and trials mentioning ‘tofacitinib’ was developed for the following databases: MEDLINE (PubMed), EMBASE (Embase.com), CINAHL Plus (EBSCO), Cochrane Library (Wiley), Scopus (Elsevier), Web of Science (Clarivate Analytics), Clinicaltrials.gov, and the WHO International Clinical Trials Registry

CONTACT Peter A. Lio [email protected] Department of Dermatology & Pediatrics, Northwestern University Feinberg School of Medicine, 363 W Erie Street, Suite 350, Chicago, IL 60654, USA
© 2019 Taylor & Francis Group, LLC

2 K. TEGTMEYER ET AL.

Figure 1. Article selection flowsheet for identifying articles detailing off-label uses of tofacitinib in the dermatology literature.

Platform. All abstracts were independently reviewed using Rayyan by two authors (K. T. and J. Z.), and only those describing an off- label use of tofacitinib for a dermatologic condition were retained (Figure 1). Articles written in languages other than English and conference abstracts were excluded from consideration. A full text screen was then conducted by two authors (K. T. and J. Z.). For inclusion, articles needed to describe clinical outcomes for patients attempting tofacitinib for an off-label dermatologic indi- cation. The current FDA indications for tofacitinib include rheuma- toid arthritis, ulcerative colitis, and psoriatic arthritis – all other conditions for which tofacitinib is used are considered off-label use for the purposes of this review (6). All articles meeting the above criteria were included, regardless of positive or nega- tive results.
This article is structured by level of available evidence for each indication for which Tofacitinib has been utilized. The strongest level of evidence includes randomized control trial (RCT) data, fol- lowed by open-label clinical trials, and case series or case reports.

Results
Highest level of evidence: RCT data and open-label trials
Randomized control trials (RCTs) of tofacitinib have been con- ducted for three off-label dermatologic conditions: plaque psoria- sis, alopecia areata (and variants), and atopic dermatitis. See Table 1 for more details on individual trials.

Psoriasis
Numerous RCTs assessing the efficacy of tofacitinib for psoriasis have been completed, including for both oral and topical routes of administration.
Two large RCTs looked at the efficacy of oral tofacitinib regi- mens for the treatment of chronic plaque psoriasis: Oral treatment Psoriasis Trial (OPT) Pivotal 1 and 2 (11). These studies found

significant improvements in psoriasis as measured by Physician’s Global Assessment (PGA) and Psoriasis Area and Severity Index (PASI) over placebo, and stronger effects among 10 mg twice daily (BID) dosing groups over 5 mg BID dosing (Table 1). A subgroup analysis of these studies found consistent results across all sub- groups, and noted lower response rates correlated with higher body weight and prior biologic use (12). A post-hoc analysis of these trials assessing for efficacy in treating nail psoriasis found that a significantly higher proportion of patients receiving 5 mg and 10 mg tofacitinib achieved Nail Psoriasis Severity Index (NAPSI) score improvements compared to control groups (13). NAPSI scores continued to improve from weeks 16 to 28 and remained roughly stable through week 52. A long-term follow up study looked at continued efficacy and safety after placebo patients were rerandomized into 5 mg or 10 mg tofacitinib treat- ment groups (14). A greater proportion of study participants achieved PASI75 by 28 weeks (versus 16 weeks), and a large pro- portion of those participants maintained PASI75 clearance at 24 months of treatment. Data from numerous other RCTs for oral tofacitinib and plaque psoriasis have been reported and are sum- marized in Table 1.
To date, three RCTs have been completed looking at efficacy of topical tofacitinib for the treatment of psoriasis. An intra-sub- ject placebo-controlled trial of 2%, 0.2%, and 0.02% tofacitinib failed to find a statistically significant difference in target plaque severity score (TPSS) versus placebo (15). However, the study authors note that tofacitinib was detected in placebo treated patches, indicating possible cross-contamination related to unsupervised patient application. Another RCT comparing two ointment formulations of tofacitinib to vehicle controls found sig- nificant improvements over vehicle control for one of the two for- mulations, with minimal adverse effects noted in all treatment groups (16). An RCT comparing treatment efficacy of 1% and 2% tofacitinib ointment to vehicle control found statistically signifi- cant improvement over control in Calculated Physician’s Global

Table 1. RCT and open-label trials on off-label use of tofacitinib.

tofacitinib vs mean change of 29.9%±6.46 (SE) for control (p<.001). PGA score of ‘clear’ or ‘almost clear’ at 4 weeks was 73%±7.7 (SE) for tofacitinib versus 22% ± 7.5 (SE) in control (p<.05) Alopecia areata RCT (16) 62.5% of patients achieved hair regrowth with 0.05% clobetasol propionate ointment versus 37.5% with 2% tofacitinib ointment and 31.3% with ruxolitinib ointment 28 weeks (tofacitinib 2% ointment versus others) Bokhari and Sinclair (18) Alopecia areata Open-label trial (66) NCT02197455, NCT02312882 32% achieved >50% SALT reduction, 32% achieved 5–50% SALT reduction, and 36% of patients saw no response. Longer duration of current alopecia episode
associated with worse improvement (p .025). 20 patients of 20 followed after cessation of tofacitinib experienced hair loss within 3 months

3 months (5 mg BID) Kennedy Crispin et al. (19)

Alopecia areata Open-label trial (10) NCT02812342 30% of patients demonstrated hair regrowth with an average SALT reduction of
34.6% (SD, 23.2%)

24 weeks (2% ointment) Liu et al. (22)

Alopecia areata Open-label trial (12) NCT02299297 66% of patients achieved SALT reduction >50%, 25% achieved SALT reduction of
5–50%, and 8% achieved no response. 6 of 7 patients followed were noted to
have shedding of hair following cessation of tofacitinib

6-18 months (5- 10 mg BID)

Jabbari et al. (20)

Alopecia areata Open-label comparison study (75)

Ruxolitinib 20 mg BID (n 38) versus tofacitinib 5 mg BID (n 37). 68.4% achieved excellent to complete response with ruxolitinib versus 64.9% with tofacitinib (p>.05). After drug cessation, 73.7% relapsed when taken off ruxolitinib versus
70.3% with tofacitinib (p>.05)

6 months (5 mg BID vs ruxolitinib)

Almutairi et al. (21)

Plaque Psoriasis (OPT Pivotal I)

Plaque Psoriasis (OPT Pivotal II)

RCT (901) NCT01276639 Significantly more patients achieved PGA response with 5 mg (41.9%) and 10 mg
(59.2%) versus placebo (9%) (p<.001). Significantly more patients achieved PASI 75 with 5 mg (39.9%) and 10 mg (59.2%) versus placebo (6.2%). Significantly more patients achieved PGA (17.3%, p<.001) and PASI 75 (19.2%, p<.001) on 10 mg versus 5 mg dosing RCT (960) NCT01309737 Significantly more patients achieved PGA response with 5 mg (46.0%) and 10 mg (59.1%) versus placebo (10.9%) (p<.001). Significantly more patients achieved PASI 75 with 5 mg (46%) and 10 mg (59.6%) versus placebo (11.4%). Significantly more patients achieved PGA (13.1%, p<.001) and PASI 75 (13.6%, p<.001) on 10 mg versus 5 mg dosing 16 weeks (5-10 mg BID) Papp et al. (11) 16 weeks (5-10 mg BID) Papp et al. (11) Plaque Psoriasis RCT (1106) NCT01241591 PASI75 response achieved by 39.5%±2.7 (SE) of patients on 5 mg tofacitinib, 63.6% ± 2.6 (SE) on 10 mg, 58.8%±2.7 (SE) on etanercept, and 5.6%±2.2 (SE) on placebo (all significant versus placebo, p<.0001). Significant difference between etanercept and 5 mg tofacitinib (19.3%±3.8 [SE], p<.0001), but not 10 mg dosage ( 4.8%±3.8 [SE], p .20). Significant PGA response seen in all treatment groups versus control; etanercept shows significant improvement in PGA score over 5 mg tofacitinib (19.2%±3.8 [SE], p<.0001), but not over 10 mg dosage (—1.9%±3.6 12 weeks (5-10 mg BID vs Etanercept) Bachelez et al. (27) Plaque Psoriasis RCT (674) NCT01186744 [SE], p .60) Patients randomized in initial treatment phase to tofacitinib 5mg or 10mg for 24 weeks; non-responders removed from study. Patients then randomized to placebo or previous tofacitinib dose, monitored for relapse (>50% reduction in PASI improvement from initial phase) for 24 weeks. Relapsed patients entered into retreatment phase for 16 weeks. Between 32.8% and 42.9% in placebo
groups did not relapse in withdrawal period. After 16 weeks of retreatment after relapse, 36.8% on 5 mg and 61.0% on 10 mg re-achieved PASI75

84-96 weeks (5- 10 mg BID)

Bissonnette et al. (28)

(continued)

epidermal thickness, Ki67 levels and KRT16 expression (p<.05). Gene expression changes evident after 1–3 days, decreased T-cell and dendritic cell populations noted after 1–2 weeks, and Il-23/Th17 pathway inhibition by week 4 Plaque Psoriasis RCT (197) NCT00678210 PASI and BSA improvements seen versus placebo group in all four body regions assessed (head & neck, upper limbs, trunk, lower limbs) (p<.0001). Head and neck regions appeared to improve most rapidly 12 weeks (2, 5, 15 mg BID) Menter et al. (30) Plaque Psoriasis RCT (94) NCT01519089 PASI75 response achieved by 62.8%±7.4 (SE) and 72.7%±6.7 (SE) of patients on 5 mg and 10 mg, respectively. PGA response achieved by 67.4%±7.1 (SE) and 68.2%±7.0 (SE), respectively. Differences between 5 and 10mg bid for both PASI75 and PGA response were not significant. In patients who achieved PASI75 response at week 16 with 10mg tofacitinib bid, 62.5%±8.9 (SE) maintained their response up to week 52; some decline in response across all groups noted in 4-week follow up period after drug cessation 52 weeks (5-10 mg BID) Asahina et al. (31) Plaque Psoriasis RCT (197) NCT00678210 Primary endpoint of PASI75 achieved in all treatment groups: 2% in placebo group, 25% [90% CI, 12.2–33.8] with 2 mg ( 23% versus placebo, p<.001), 40.8% [90% CI, 26.8–50.8] with 5 mg ( 38.8% versus placebo, p<.0001), and 66.7% [90% CI, 53.0–76.3] with 15 mg ( 64.7% versus placebo, p<.0001). Significant PASI75 improvements noted by week 4, stable though week 12 12 weeks (2, 5, 15 mg BID) Papp et al. (32) Plaque Psoriasis RCT (266) NCT01815424 Mean PGA improvements over baseline: 52.3% on 5 mg and 75.6% on 10 mg versus 19.3% in placebo. PASI75 achieved in 54.6% of patients on 5 mg and 81.1% on 10 mg versus 12.5% on placebo. Both dose groups were significantly different from placebo for both PGA and PASI75 endpoints (p<.0001). Of patients treated with 5 mg and 10 mg of tofacitinib, 76.8% and 84.9% respectively maintained PASI75, and 73.6% and 75.0% respectively maintained PGA improvements through week 52 52 weeks (5-10 mg BID) Zhang et al. (33) Plaque Psoriasis RCT (430) NCT01831466 Significant improvement over vehicle control seen at 8-week PGA-C assessment (response rate defined as PGA-C response of ‘clear or almost clear’ and 2 grade improvement from baseline). Comparing response rate to active treatment versus vehicle, BID dosing saw difference in response of 10.8% (80% CL, 3.1–18.5%) over control; QD dosing saw difference in response of 11.0% (80% CL, 3.8–18.2%) over control. No statistically significant differences evident at study completion at 12 weeks for PGA-C assessment. For 2% QD ointment, change from baseline in PASI was —9.2% (80% CL, —17.1 to —1.4) compared to control vehicle; change from baseline in PGA scores was —20.0% (80% CI, —31.4 to —8.7) compared to control vehicle 12 weeks (2%, 1% ointment) Papp et al. (17) Plaque Psoriasis RCT (71) NCT01246583 Significant improvement with tofacitinib ointment 1 over vehicle control 1 (LSM difference 12.9%, CL 25.0 to 0.7). No significant improvement seen in ointment 2 over vehicle control 2 (LSM difference 7.0, CL 20.6 to 6.6). Ointment 1 demonstrated significant improvement in induration and scaling, but not erythema over vehicle control 1; no significant difference in TPSS subscores with ointment 2 4 weeks (2% ointment) Ports et al. (16) Plaque Psoriasis RCT (81) NCT00678561 Intra-subject study. TPSS did not change significantly from contralateral vehicle control site in any treatment group throughout 4 weeks of study (p .28–.68). TPSS percent change from baseline also not significant from zero at any time 4 weeks (2%, 0.2%, 0.02% ointment) Ports et al. (15) point throughout 4 weeks of study (p¼.28–.95) BID: twice daily dosing; BSA: body surface area; CL: confidence limits; LSM: least squares mean; PASI: Psoriasis Area and Severity Index; PASI75: Psoriasis Area and Severity Index 75% improvement from baseline; PGA: Physician’s Global Assessment; PGA-C: Calculated Physician’s Global Assessment; SALT: Severity of Alopecia Tool; TPSS: Target Plaque Severity Score; QD: daily dosing. Table 2. Case series and case reports of treatment of alopecia with tofacitinib. Comorbid conditions Efficacy Time to onset of effect Length of known remission Serious adverse effects Citation (n 119) Analysis of eyebrow and eyelash alopecia. Complete eyebrow regrowth (41 of 119), partial eyebrow regrowth (50 of 119). Complete eyelash regrowth (46 of 119), partial eyelash regrowth (36 of 119) N/A 6 months or greater N/A Liu and King (34) AD (23 of 90), thyroid disease (19 of 90), vitiligo (9 of 90), RA (4 of 90) (n 90) Complete hair regrowth (13 of 90), >50% hair regrowth (25
of 90), partial hair regrowth (12 of 90), no response (15 of 90). Notably, those with current episode of alopecia >10 years were least likely to respond to therapy
(n 63) Complete hair regrowth (25 of 63), partial regrowth (27 of
63), minimal regrowth (8 of 63) and no response (3 of 63)

N/A 15 months URI (26 of 90), Herpes
Zoster (2 of 90), other
infection (7 of 90)

N/A 6–30 months Hyper-seborrhea (21 of
63) and URI (10 of 63)

Liu et al. (35)

Serdaroglu et al. (36)

AD, thyroid disease, dermographism

(n 33) 11 patients of 15 with nail involvement demonstrated symptomatic improvement. Average SALT reduction of 60.5% for scalp hair; 90.6% of patients experienced regrowth of body hair
(n 32) Complete hair regrowth (9 of 32), >50% hair regrowth (9 of
32), partial hair regrowth (6 of 32), no response (8 of 32)

5 months 11 months N/A Lee et al. (37)

2–10 months 4–17 months None Park et al. (38)

(n 18) Complete hair regrowth (2 of 18), >50% hair regrowth (6 of
18), partial hair regrowth (7 of 18), no response (3 of 18)

N/A 6 months Urticaria, palmoplantar desquamation

Shin et al. (39)

AD (5 of 13), thyroid
disease (1 of 13)

(n 13) Complete or near-complete hair regrowth (9 of 13), no response (4 of 13)

N/A 2–16 months URI (4 of 13) Craiglow et al. (40)

(n 13) At least 50% hair regrowth (7 of 13), partial hair regrowth (2
of 13) and no response (4 of 13)

1–9 months 0.5–13 months Morbilliform eruption
(1 of 13)

Ibrahim et al. (41)

(n 11) Complete or partial regrowth (3 of 11), minimal regrowth (5
of 11), no response (3 of 11)

N/A 8–76 weeks None Putterman and Castelo- Soccio (42)

(n 11) Complete hair regrowth (5 of 11), near-complete hair regrowth (2 of 11), no response (4 of 11)

4 days–3 months 4.5–27 months Multiple sclerosis, joint pain

Cheng et al. (43)

(n ¼ 8) All patients reported SALT score decrease by >50% 3 months 12–18 months None Castelo-Soccio (44)

(n 6) Significant hair regrowth in all patients. Return of alopecia in 1 patient after stopping tofacitinib
(n 5) Complete hair regrowth (1 of 5), partial hair regrowth (3 of 5) and no hair regrowth (1 of 5)

8 weeks 6 months None Shivanna et al. (45)

N/A 3–18 months None Bayart et al. (46)

Rheumatoid arthritis (2
of 4)

(n ¼ 4) Complete or near-complete hair regrowth 6–8 weeks 6–9 months None Scheinberg et al. (47)

(n 4) Complete hair regrowth (2 of 4), partial hair regrowth (1 of 4) and no hair regrowth (1 of 4)

3 months 15 months None Craiglow and King (48)

(n 3) >90% hair regrowth (1 of 3) and >50% hair regrowth (2 of 3) N/A 6–21 months URI and diarrhea Dai and Chen (49) (n 2) Near-complete hair regrowth 2 months 9 months None Scheinberg and
Ferreira (50)
(n ¼ 2) Near-complete hair regrowth N/A 5 months None Patel et al. (51)

(n 2) Complete or near complete hair regrowth noted 1–2 months 2 years Viral illness and fatigue
(1 of 2)

Gupta et al. (52)

Down syndrome (n ¼ 2) Complete hair regrowth 1 week 12 months None Rachubinski et al. (53) Plaque psoriasis (n ¼ 1) Complete clearance and partial clearance of psoriasis 2 months 8 months None Craiglow and King (54)

AD (n 1) Complete hair regrowth and subjective improvement of atopic dermatitis pruritis noted
AD and Vitiligo (n 1) Near-complete hair regrowth, complete remission of atopic
dermatitis, and no improvement in vitiligo

N/A 10 months None Morris et al. (55)

1 month 5 months URI and diarrhea Vu et al. (25)

(n 1) Complete hair regrowth 2 weeks 32 weeks None Kim and Kim (56)
(n 1) Near-complete hair regrowth 3 months 10 months None Hernandez-Montoya and Ruiz-Villaverde (57)
(n ¼ 1) Complete hair regrowth 1 month 6 months None Erduran et al. (58)
(n ¼ 1) Complete hair regrowth 1 month 10 months None Ferreira et al. (59)
(n ¼ 1) Complete hair regrowth 3 months 6 months None Brown and Skopit (60) (continued)

6 K. TEGTMEYER ET AL.

Assessment (PGA-C) scores at week 8, but not at study comple- tion (week 12) for 2% daily (QD) and twice daily (BID) dosing (17).

Alopecia areata
A randomized, double-blind RCT compared efficacy of hair regrowth of tofacitinib 2% topical ointment to ruxolitinib 1% oint- ment, clobetasol dipropionate 0.05% ointment, and vehicle con- trol (18). This study enrolled 16 patients, and all patients simultaneously received all four treatments to different skin areas (scalp and eyebrows). Clobetasol showed superior efficacy with 10 patients of 16 achieving hair regrowth where it was used, com- pared to 6 patients of 16 seeing regrowth with tofacitinib, and 5 patients seeing regrowth with ruxolitinib.
Four open-label trials using tofacitinib for alopecia have been reported to date, including three trials with oral tofacitinib, and one trial with topical tofacitinib ointment. One study involving 66 patients with hair loss >50% scalp hair loss gave oral tofacitinib
(5 mg BID) for 3 months and assessed for improvements in sever-
ity of alopecia tool (SALT) scores (19). Twenty-one patients achieved SALT improvement >50%, 21 patients achieved SALT improvement between 5 and 50%, and 24 patients did not respond to tofacitinib (SALT improvement <5%). Twenty patients with a strong response were followed for an additional three months after cessation of tofacitinib, and all experienced some rebound hair loss. Another open-label trial of 12 patients taking oral tofacitinib 5–10 mg BID found 66% of patients achieved SALT score reductions >50%, and 25% of patients achieved 5–50%
SALT reduction (20). Seven patients who achieved strong hair
regrowth (>50% SALT reduction) were followed after cessation of the trial period, and only 1 patient of 7 demonstrated durable hair regrowth without continuous tofacitinib dosing. An open-
label comparison study between oral tofacitinib and oral ruxoliti- nib found no significant difference in rates of hair regrowth and subsequent relapse after drug cessation (21). Lastly, an open-label study of 2% topical tofacitinib with 10 patients demonstrated hair regrowth in 30% of patients, with an average SALT score reduc- tion of 34.6% (22).
Many additional case series and case reports of alopecia areata patients treated with tofacitinib exist in the literature, including in both adult and pediatric patients. The results of those reports are detailed in Table 2.

Atopic dermatitis
An RCT of mild to moderate atopic dermatitis comparing 2% tofa- citinib to vehicle ointment demonstrated significantly greater treatment efficacy in terms of Eczema Area and Severity Index (EASI) scores at week 4, with an initial response evident by week 1 of treatment (23).
A study of 6 patients with moderate-to-severe atopic derma- titis treated with oral tofacitinib (5 mg BID) demonstrated a reduc- tion in scoring of atopic dermatitis (SCORAD) scores by 54.8% within the initial 14 weeks of treatment (24). An additional 66.6% reduction in SCORAD scores was noted in the following 15 weeks of treatment. Secondary endpoints included subjective improve- ment in pruritus and sleep quality over the course of this study. Notably, one patient with history of atopic dermatitis, alopecia and vitiligo was treated with tofacitinib, and saw complete remis- sion of atopic dermatitis symptoms within three months of treat- ment (25). The patient also demonstrated marked improvements in alopecia, with hair regrowth noted on the scalp, beard region, extremities, eyebrows and eyelashes. Improvements in vitiligo were more modest, with a decrease in vitiligo area scoring index (VASI) of 15.6%.

Table 3. Case series and case reports of off-label uses of tofacitinib.
Time to Length of Serious adverse
Disease Efficacy Adjunctive medication onset of effect known remission effects Citation
Actinic Dermatitis (n ¼ 1) Near complete clearance 2 months 12 months Herpes Zoster Vesely et al. (66)
Cutaneous Sarcoidosis (n ¼ 1) Complete remission 4 months 9 months None Damsky et al. (67) (n ¼ 2) Complete or near-complete response 2 months N/A N/A Damsky et al. (68)

Dermatomyositis (n 3) Roughly 50% improvement in CDASI score,
with improvement in pruritus, strength and fatigue noted

1 of 3 on HCQ 4 weeks 6–15 months None Kurtzman et al. (69)

(n 1) Remission of skin and join symptoms Prednisone 2 months N/A N/A Paik and Christopher-
Stine (70)

(n 4) Near-complete remission of skin and joint symptoms
(n 2) Near complete resolution of joint symptoms, partial clearance of cutaneous calcifications

Prednisone (all), IVIG (3 of 4)
1 of 2 on adjunctive MTX and Prednisone

3 months 3–6 months None Moghadam-Kia
et al. (71)
4 weeks 28 months None Wendel et al. (72)

Eosinophilic Fasciitis (n ¼ 1) Near complete resolution MTX N/A 12 months N/A Kim et al. (73)

Erosive
Pustular Dermatosis

(n ¼ 1) Near-complete resolution 4 weeks N/A N/A Leung et al. (74)

Granuloma Annulare (n ¼ 1) Complete clearance 2 months N/A N/A Damsky et al. (68)
Halo Nevus (n ¼ 2) Significant repigmentation 8 weeks 6–12 months None Hu et al. (75)

Hypereosinophilic Syndrome

(n ¼ 4) Complete or near-complete response Prednisone (3 of 4) N/A 3–13 months Herpes Zoster (1 of 4) King et al. (76)

Erythema Multiforme (n ¼ 1) Complete resolution N/A 8 months N/A Damsky and King (77)

Lichen Planopilaris (n 10) LPPAI score improvement of 30–94% for 8
patients; no improvement for 2 patients

Triamcinolone (4 of
10), HCQ (2 of 10),
Tacrolimus (1 of 10)

N/A 2–19 months None Yang et al. (78)

Morphea (n 1) Marked improvement of cutaneous and joint symptoms

Prednisone, ECP, MTX N/A 12 months N/A Kim et al. (73)

Nail Dystrophy (w/ Alopecia)

(n ¼ 2) Complete resolution of nail symptoms 4 months 10 months None Jaller et al. (79)
(n ¼ 3) Complete resolution of nail symptoms N/A 8 months None Dhayalan and King (80)

Palmoplantar Pustulosis (n ¼ 1) Improvement of cutaneous symptoms N/A N/A N/A Koga et al. (81)

Pyoderma Gangrenosum

(n ¼ 3) Complete or near-complete clearance Vedolizumab (1 of 3) 2 weeks 3 months N/A Kochar et al. (82)
(n ¼ 1) Near-complete clearance Infliximab 3 weeks N/A N/A Gregory et al. (83)

SAPHO Syndrome (n 1) Near-complete resolution of symptoms; all
inflammatory markers decreased to near- normal values

MTX 4 weeks 3 months None Yang et al. (84)

repigmentation noted versus phototherapy alone scoring index
no improvement for 5/10

(n ¼ 1) Near complete repigmentation
CDASI: Cutaneous Dermatomyositis Disease Area and Severity Index; ECP: extracorporeal photopheresis; HCQ: hydroxychloroquine; IVIG: intravenous immunoglobulin; LPPAI: Lichen Planopilaris Activity Index; MTX: Methotrexate; SAPHO: synovitis, acne, pustulosis, hyperostosis and osteitis

8 K. TEGTMEYER ET AL.

Table 4. Clinical trials on tofacitinib planned, in progress or completed and without published in a journal.
Disease Study type Number of patients (actual or estimated) Study number Citation
Cutaneous Sarcoidosis and Granuloma annulare Open-label trial 15 NCT03910543 (90)

Alopecia Areata RCT 19 NCT03800979 (91)

Dermatomyositis RCT 10 NCT03002649 (92)

Highest level of evidence: case series and case reports
There are numerous dermatologic conditions for which case reports on treatment with tofacitinib are available, including chronic actinic dermatitis, dermatomyositis, pyoderma gangreno- sum, and several others. In these case reports, tofacitinib is used as either a monotherapy, or in conjunction with other medica- tions. The results of these case series and case reports are detailed in Table 3.

Additional studies and clinical trials for off-label uses of tofacitinib
More clinical trials are currently underway for the use of tofaciti-
nib in dermatology. Table 4 details the list of clinical trials that are still recruiting patients and have not yet reported results.

Discussion
Literature of various strength of evidence describes off-label use of tofacitinib for a variety of dermatologic conditions. RCT evi- dence is available for the treatment of mainly psoriasis and alope- cia, with one trial indicating positive results for atopic dermatitis as well. Current evidence appears to favor oral tofacitinib over topical ointment formulations for the treatment of psoriasis. Given the strong body of evidence for psoriasis, Pfizer sought to expand its FDA indication for tofacitinib to include psoriasis. This was rejected by the FDA in 2015, with a Complete Response letter outlining safety concerns that Pfizer must address before continu- ing to seek approval for psoriasis as part of a supplemental New Drug Application (sNDA) (26). Additionally, a safety announcement from the FDA in early 2019 noted that phase 4 clinical trials have found an increased risk of deep vein thrombosis (DVT) and pul- monary embolism (PE) causing death in patients taking the 10 mg BID dosage, only currently approved for rheumatoid arthritis (10). Additional safety studies investigating this risk are currently underway, and the FDA hopes to report results by the end of 2019. Despite these safety concerns, there are currently few reports of serious adverse events among patients using tofacitinib for dermatologic conditions – most commonly herpes zoster, a known possible complication of tofacitinib. The vast majority of patients in this review noted no adverse effects, and the majority of adverse effects noted to date are minor infections, such as upper respiratory tract infections.
Overall, tofacitinib appears to be a relatively safe medication for many inflammatory dermatologic conditions. It appears to be efficacious, with reports of positive results available for all condi- tions included presently, although selection bias may overrepre- sent positive outcomes for conditions with only a few reported cases. Notably, tofacitinib was helpful for many patients in this study whose conditions were refractory to conventional therapies. Another advantage of this medication includes its availability in oral formulation, and its efficacy in certain scenarios in topical for- mulation; however, cost may be a limiting factor. Additionally, given concerns for infections and possible DVT/PE, patients taking oral tofacitinib should be monitored closely by treating physi- cians, in addition to receiving regular laboratory monitoring. Tofacitinib appears to be a possible candidate for treating many

dermatologic conditions refractory to other treatments, though further testing is recommended to better elucidate efficacy and optimal dosing regimens for these conditions, as well as to further clarify the adverse effect profile and safety of this immunosup- pressive agent.

Disclosure statement
Dr Lio has served as a consultant and speaker for Pfizer, a consult- ant and investigator for AbbVie, and a consultant for Eli Lilly. The other authors report no conflicts of interest.

ORCID
Kyle Tegtmeyer http://orcid.org/0000-0002-5828-6991 Jeffrey Zhao http://orcid.org/0000-0001-7046-5434 Nolan J. Maloney http://orcid.org/0000-0002-9722-5673 Giancarlo Atassi http://orcid.org/0000-0001-8543-3988 Peter A. Lio http://orcid.org/0000-0001-7600-0152

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