Real-World Efficacy and Safety of Oral Tofacitinib in Patients with Refractory Moderate to Severe Atopic Dermatitis: A Multicenter Retrospective Study

Abstract

Background
Atopic dermatitis (AD) has a complex etiology that includes Th2 polarization, which is accompanied by the cytokines IL4, IL-5, IL-13, and IL-31, as well as Th17 and Th22, and in chronic lesions, Th1 cells. Tofacitinib inhibits Th1-, Th2-, and Th17-associated cytokines by selectively blocking JAK1 and JAK3 receptors. We conducted a multicentric, retrospective chart analysis to study the efficacy and safety of tofacitinib in patients with moderate to severe refractory AD.

Materials and Methods
We included 16 adult patients (aged >18 years) with moderate to severe AD who had previously undergone systemic therapy with inadequate response. In the baseline, demographic data, previous treatment history, severity scores (eczema area and severity index [EASI] and SCORing Atopic Dermatitis [SCORAD]), and quality of life score (Dermatology Life Quality Index [DLQI]) were noted. Baseline blood investigations, including complete blood count, liver function test, renal function test, lipid profile, and interferon gamma release assay for tuberculosis, were done. Patients were followed up every month for 6 months that included documentation of severity scores, blood investigations, and DLQI. Any adverse events, if reported, were noted.

Result
All 16 patients completed the 6-month trial. Our patients were previously treated with cyclosporine (n = 10), methotrexate (n = 3), or both (n = 3). The mean EASI scores improved from 23.38 ± 9.56 at baseline to 8.50 ± 7.57 at the end of 6 months. The mean SCORAD score improved from 41.25 ± 8.69 at baseline to 14.93 ± 7.82 at the end of 6 months. Quality of life also improved as the mean DLQI improved from 15.18 ± 2.73 at baseline to 5.31 ± 4.11 at the end of the study period. No severe adverse reactions were noted, but 3 patients experienced dyslipidemia and 2 patients had altered bleeding time.

Conclusion
Tofacitinib is a safe and effective treatment option for recalcitrant moderate to severe adult AD.

Full text

292 © 2024 Indian Journal of Dermatology | Published by Wolters Kluwer - Medknow
ORIGINAL ARTICLE
Abstract
Background: Atopic dermatitis (AD) has a complex etiology that includes Th2 polarization,
which is accompanied by the cytokines IL4, IL-5, IL-13, and IL-31, as well as Th17 and
Th22, and in chronic lesions, Th1 cells. Tofacitinib inhibits Th1-, Th2-, and Th17-associated
cytokines by selectively blocking JAK1 and JAK3 receptors. We conducted a multicentric,
retrospective chart analysis to study the efficacy and safety of tofacitinib in patients
with moderate to severe refractory AD. Materials and Methods: We included 16 adult
patients (aged >18 years) with moderate to severe AD who had previously undergone
systemic therapy with inadequate response. In the baseline, demographic data, previous
treatment history, severity scores (eczema area and severity index [EASI] and SCORing Atopic
Dermatitis [SCORAD]), and quality of life score (Dermatology Life Quality Index [DLQI]) were
noted. Baseline blood investigations, including complete blood count, liver function test,
renal function test, lipid profile, and interferon gamma release assay for tuberculosis, were
done. Patients were followed up every month for 6 months that included documentation
of severity scores, blood investigations, and DLQI. Any adverse events, if reported, were
noted. Result: All 16 patients completed the 6-month trial. Our patients were previously
treated with cyclosporine (n = 10), methotrexate (n = 3), or both (n = 3). The mean EASI
scores improved from 23.38 ± 9.56 at baseline to 8.50 ± 7.57 at the end of 6 months. The
mean SCORAD score improved from 41.25 ± 8.69 at baseline to 14.93 ± 7.82 at the end of
6 months. Quality of life also improved as the mean DLQI improved from 15.18 ± 2.73 at
baseline to 5.31 ± 4.11 at the end of the study period. No severe adverse reactions were
noted, but 3 patients experienced dyslipidemia and 2 patients had altered bleeding time.
Conclusion: Tofacitinib is a safe and effective treatment option for recalcitrant moderate to
severe adult AD.
KEy Words: Refractory, severe atopic dermatitis, study, tofacitinib
Real‑World Ecacy and Safety of Oral Tofacitinib in Patients with
Refractory Moderate to Severe Atopic Dermatitis: A Multicenter
Retrospective Study
Sandipan Dhar, Abhishek De1, Aarti Sarda2, Kiran Godse3, Koushik Lahiri2
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Website: https://journals.lww.com/ijd
DOI: 10.4103/ijd.ijd_843_22
Background
Chronic skin inflammation and severe pruritus are the
hallmarks of atopic dermatitis (AD) that significantly
affects patients’ quality of life and is highly prevalent
in both children (15–30%) and adults (2–10%).[1] The
epidemiologic data on AD from India is insufficient.[2,3]
Atopic dermatitis has a complex etiology that includes
Th2 polarization, which is accompanied by the
cytokines IL4, IL-5, IL-13, and IL-31, as well as Th17,
Th22, and, in chronic lesions, Th1 cells.[4]
Emollients, topical corticosteroids, topical calcineurin
inhibitors, and phototherapy are the mainstays of
treatment for AD; however, moderate to severe AD is
frequently resistant to these treatments.[5] Although
immunomodulatory drugs (such as cyclosporine,
methotrexate, and azathioprine) had been tried in
refractory AD with varying degrees of effectiveness, a
better understanding of the pathogenesis has opened
the door to the prospect of the novel, targeted
therapies.[6]
In various inflammatory skin conditions, including AD,
the JAK inhibitors have been explored and proven to be
beneficial. Oclacitinib, a JAK1 selective inhibitor, was
From the Department of Pediatric
Dermatology, Institute of
Child Health, 1Department of
Dermatology, Calcutta National
Medical College, 2Department of
Dermatology, Wizderm Specialty
Clinic, Kolkata, West Bengal,
3Department of Dermatology,
Padmashree Dr. D Y Patil University,
Navi Mumbai, Maharashtra, India
Address for correspondence:
Dr. Sandipan Dhar,
Department of Pediatric
Dermatology, Institute of Child
Health, Flat 9C, Palazzo, 35,
Panditia Road, Kolkata - 700 029,
West Bengal, India.
E-mail: doctorsandipan@gmail.
com
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which allows others to remix, tweak, and build upon the work non‑commercially,
as long as appropriate credit is given and the new creations are licensed under
the identical terms.
For reprints contact: WKHLRPMedknow_reprints@wolterskluwer.com
How to cite this article: Dhar S, De A, Sarda A, Godse K, Lahiri K.
Real‑world efcacy and safety of oral tofacitinib in patients with refractory
moderate to severe atopic dermatitis: A multicenter retrospective study.
Indian J Dermatol 2024;69:292‑5.
Received: October, 2022. Accepted: April, 2024.
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Dhar, et al.: Tofacitinib in atopic dermatitis
Indian Journal of Dermatology | Volume 69 | Issue 4 | July-August 2024 293
first approved in 2013 for AD in dogs, and baricitinib was
later approved in November 2020 for AD in humans. Oral
upadacitinib, oral qbrocitinib, and topically administered
ruxolitinib are the other JAK inhibitors that the
United States Food and Drug Administration (US FDA)
recently approved.[7]
The topical use of tofacitinib citrate, a JAK 1/3
inhibitor, authorized for the systemic management
of moderate to severe rheumatoid arthritis, is being
studied in AD. Tofacitinib selectively blocks JAK1 and
JAK3 receptors that specifically inhibits Th1-, Th2-,
and Th17- associated cytokines.[8] We conducted a
multicentric, retrospective chart analysis to study
the efficacy and safety of tofacitinib in patients with
moderate to severe AD who showed an inadequate
response to systemic immunomodulators.
Materials and Methods
A retrospective chart analysis was conducted on patients
admitted in a total of 4 private clinics—3 in Kolkata
and 1 in Mumbai. The study comprised patients aged
above 18 years who had received oral tofacitinib for
at least 6 months. Patients with moderate to severe
AD who had previously received at least one systemic
immunomodulator with inadequate efficacy were given
oral tofacitinib. Inadequate efficacy of previous treatment
is defined by failure to decrease EASI score to 7 or less
for at least 8 weeks of treatment.
All of these patients have received oral tofacitinib
(Xeljanz™ tablets) at a dose of 1 tablet (5 mg) twice
daily.
The SCORing Atopic Dermatitis (SCORAD) and Eczema
Area and Severity Index (EASI) scores recorded in the
case sheets each month were compared to determine
effectiveness (i.e., baseline, 1, 2, 3, 4, 5, and 6 months).
In addition, the Dermatology Life Quality Index (DLQI)
questionnaire tool was used to evaluate the effect of
the patient’s quality of life at the baseline and 6-month
visit. Any therapy-related adverse events were recorded
during the twice weekly follow-up visits.
Each patient underwent a baseline laboratory
assessment prior to initiating tofacitinib, which
included a complete blood cell count, creatinine, liver
function test, lipid profile, coagulation profile, blood
biochemistry, QuantiFERON-TB Gold, and serologies for
HIV, hepatitis B, and hepatitis C. Every 4 weeks, tests
for the complete blood count, blood biochemistry, liver
function, and lipid profile were repeated during the
treatment.
Side effects were minimal in these 6 months of
follow-up. No severe adverse reactions were noted, but
3 patients experienced dyslipidemia and 2 patients had
altered bleeding time.
Result
A total of 16 patients’ records were collected for
this retrospective chart analysis. Of these, seven
patients (44%) were women and nine (56%) were
men. The age of these patients varied from 22 to
46 years (mean = 32.50 ± 7.58 years). These individuals
have all received at least one systemic immunomodulator
in the past with inadequate success rate. Of these
patients, 10 received cyclosporin treatment, 3 received
methotrexate treatment, and 3 received both cyclosporin
and methotrexate treatment.
All these patients were suffering from moderate to severe
AD and required systemic intervention. The baseline
EASI score in these patients varied from 13 to 38 with
the mean EASI being 23.38 ± 9.56. The baseline SCORAD
score varied from 28 to 55 with the mean SCORAD being
41.25 ± 8.69 [Table 1].
After 6 months of treatment, the mean EASI improved to
8.50 ± 7.57. Of these patients, 10 (62.5%) achieved EASI
75 (≥75% improvement from baseline) at the end of
6 months of treatment; 4 more patients (25%) achieved
EASI 50 response (≥50% improvement from baseline). In
addition, efficacy was demonstrated by the improvement
of SCORAD response after 6 months of treatment. The
mean SCORAD improved to 14.94 ± 7.82.
When EASI and SCORAD values were compared before and
after the administration of oral tofacitinib using paired
T-tests, the two-tailed P values for both scores were less
than 0.001, indicating a highly significant improvement
[Figures 1 and 2].
Similarly, paired T-test was done to compare the values
of DLQI before (15.19 ± 2.73) and after (5.31 ± 4.11)
the treatment to study the treatment effect on
the quality of life of these patients. The two-tailed
P value was less than 0.0001, indicating significant
improvement in the quality of life of the patients
treated with tofacitinib.
Discussion
For clinicians, managing moderate to severe AD has
always been challenging. Systemic immunomodulators
are recommended by Indian guidelines for people with
severe or recalcitrant AD. Cyclosporine, azathioprine,
and methotrexate are some of the other systemic
treatments that have been suggested in the Indian
context.[5] The US FDA has approved dupilumab as the
first targeted biologic medication for the treatment
of adults with moderate to severe AD. The authors
have published the first reports from India, where
dupilumab was successfully used to treat 25 adult
patients with AD.[6] However, due to its high price and
limited availability, the use of dupilumab in patients
with refractory AD in India has remained out of reach
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Dhar, et al.: Tofacitinib in atopic dermatitis
294 Indian Journal of Dermatology | Volume 69 | Issue 4 | July-August 2024
for most patients who actually need it. An alternative
therapy for AD that has fair price, adequate efficacy,
and a good safety profile is therefore extremely
desirable in the Indian context.
In this study, we present a group of 16 patients
who received oral tofacitinib treatment in 3 Indian
referral facilities for moderate to severe recalcitrant
AD. After receiving oral tofacitinib, skin eruptions of
most patients improved significantly. The erythema
subsided quickly and was followed by the reduction
of pruritus. Chronic lichenified lesions took longer to
improve.
It is not surprising that the JAK-STAT pathway plays a
part in cutaneous immune-mediated and inflammatory
diseases because it serves as an essential signaling
mechanism for several cytokines and growth factors.
Tofacitinib inhibits JAK 1 and JAK 3, which are required
for the signaling of cytokines such as IL-2, IL-4, IL-7,
IL-9, IL-15, and IL-21.
The pathogenesis of AD is mostly a Th2 immune
response, and IL-4 signaling is a crucial cytokine in
Th2 differentiation. The inhibitors JAK 1, JAK 3, and
STAT 6 are the possible targets for the therapy of AD
because they mediate IL-4 signaling. JAK 1/3 inhibition
should decrease IL-4 signaling, which should reduce Th2
response and improve AD symptoms.[9]
Alopecia areata and vitiligo are 2 autoimmune diseases
that have already been successfully treated with
tofacitinib citrate, an oral JAK 1/3 inhibitor, that is
licensed for the treatment of rheumatoid, psoriatic, and
inflammatory bowel disease.[10] However, the use of oral
tofacitinib in AD is still rarely documented. To the best of
Table 1: Six months follow‑up data of oral tofacitinib in the patients of AD
Baseline 1 month 2 months 3 months 4 months 5 months 6 months Remark
EASI 23.38±9.56 19.69±9.63 16.19±9.05 14.00±8.99 11.06±8.37 9.56±7.55 8.50±7.57 Paired t-test done. The two-tailed
P value is less than 0.0001.
SCORAD 41.25±8.69 34.93±8.92 29.88±9.00 25.75±8.64 22.31±8.34 19.50±7.83 14.94±7.82 Paired t-test done. The two-tailed
P value is less than 0.0001.
DLQI 15.19±2.73 5.31±4.11 Paired t-test done. The two-tailed
P value is less than 0.0001.
Figure 1: EASI 50 and 75 Response Over Time
Figure 2: Follow up data for 6 months
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Dhar, et al.: Tofacitinib in atopic dermatitis
Indian Journal of Dermatology | Volume 69 | Issue 4 | July-August 2024 295
our knowledge, there is only one small proof-of-concept
research that included 6 patients with AD. Tofacitinib
was given in a case series of 6 patients with moderate
to severe AD who had not responded to conventional
therapy. The series indicated a 66.6% drop in SCORAD
and a 69.9% decrease scores in pruritus during the 8
to 29 weeks of follow-up. All patients experienced a
reduction in erythema, edema, and lichenification as
well as a decrease in the region of eczema. No adverse
event was noted in the series.[9]
There is some evidence present in the literature on
the efficacy of topical tofacitinib in AD. A phase 2a,
double-blind, randomized control trial, with 2% topical
tofacitinib ointment was conducted involving 69 adults
with mild to moderate AD for 4 weeks. Patients were
randomly assigned in the ratio of 1:1 to a 2% tofacitinib
ointment and vehicle ointment twice daily. The EASI
score was reduced by 81.7% for tofacitinib versus 29.9%
for the placebo at the end of the study period. Topical
tofacitinib was well tolerated in these patients.[11]
To the best of our knowledge, this is the first instance
where a systemic JAK inhibitor has been used to treat AD
in Indian patients. The small sample size, retrospective
nature of data collection, lack of a placebo control
group, and concurrent use of topical corticosteroids are
various limitations of this study. However, this study
demonstrated that, with a reasonable safety profile,
oral tofacitinib therapy can significantly improve both
objective and subjective parameters of atopic eczema.
Conclusion
Tofacitinib is a promising agent for the treatment of AD.
Given the wide availability, reasonable cost, consistent
efficacy, and acceptable adverse effect profile, this
molecule can be an important option in the management
of moderate to severe adult AD, especially in patients
when cyclosporine or dupilumab is inadequate,
contraindicated, unaffordable, or unavailable. However,
prospective, long-term randomized controlled trials with
larger sample sizes are necessary to have reasonably
adequate data about the efficacy and safety of this new
molecule on the block in the management of severe and
recalcitrant AD.
Financial support and sponsorship
Nil.
Conicts of interest
There are no conflicts of interest.
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