
==== Front
Indian J Dermatol
Indian J Dermatol
IJD
Indian J Dermatol
Indian Journal of Dermatology
0019-5154
1998-3611
Wolters Kluwer - Medknow India

IJD-69-292
10.4103/ijd.ijd_843_22
Original Article
Real-World Efficacy and Safety of Oral Tofacitinib in Patients with Refractory Moderate to Severe Atopic Dermatitis: A Multicenter Retrospective Study
Dhar Sandipan
De Abhishek 1
Sarda Aarti 2
Godse Kiran 3
Lahiri Koushik 2
From the Department of Pediatric Dermatology, Institute of Child Health, Kolkata, West Bengal, India
1 Department of Dermatology, Calcutta National Medical College, Kolkata, West Bengal, India
2 Department of Dermatology, Wizderm Specialty Clinic, Kolkata, West Bengal, India
3 Department 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
Jul-Aug 2024
19 8 2024
69 4 292295
10 2022
4 2024
Copyright: © 2024 Indian Journal of Dermatology
2024
https://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, 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.
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
==== Body
pmcBackground

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.[23] 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 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].

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.	

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].

Figure 1 EASI 50 and 75 Response Over Time

Figure 2 Follow up data for 6 months

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 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 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.

Conflicts of interest

There are no conflicts of interest.
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