Abstract
Background:
The response of atopic dermatitis (AD) to different biologics and JAK inhibitors (JAKibs) is variable due to the varied immunological endotypes of AD.
Aim and Objectives:
To assess the effectiveness and adverse effect profile of tofacitinib in recalcitrant, moderate-to-severe AD patients and to compare the cost of therapy of tofacitinib with dupilumab.
Patients and Methods:
We retrospectively analyzed records of moderate to severe AD treated with tofacitinib monotherapy. The response to tofacitinib was assessed using clinical scores including Numerical Rating Scale (NRS), Scoring Atopic Dermatitis (SCORAD), and Eczema Area and Severity Index (EASI) at 4 weeks and 8 weeks of treatment. We also analyzed the duration of remission and time after which recurrences were seen after stopping tofacitinib. The cost of tofacitinib was compared with dupilumab.
Results:
Twelve cases of recalcitrant moderate–severe AD who had failed systemic agents [oral corticosteroids (n = 7), cyclosporine (n = 4), and azathioprine (n = 2)] were treated with tofacitinib monotherapy. There was a statistically significant reduction in SCORAD, EASI, and NRS scores at 4 weeks and 8 weeks of tofacitinib therapy [mean at baseline: 4 weeks: 8 weeks = SCORAD- 43.54: 22.74: 11.87 (P = 0.002); EASI-19.5: 6.45: 1.6 (P = 0.002); NRS-5.75: 3.25: 1.08 (P = 0.002)]. EASI 90 was achieved by 66% of patients in 8 weeks with treatment failure in one patient. The mean time to achieve complete/near complete resolution (n = 8) of the disease was 6.1 weeks (3-8 weeks). Relapse of the disease was noted in 4/11 (36.3%) patients. Side effects were observed in 5/12 (41.6%) patients (herpes zoster, dyslipidemia, anemia, impetigo, and thrombocytosis). The cost of therapy with dupilumab is 122 times higher than that of tofacitinib therapy (8 weeks treatment).
Limitations:
Small sample size and lack of tissue cytokines analysis pre- and post-treatment.
Conclusion:
Tofacitinib (pan JAK inhibitor) inhibits T helper 2 (Th2), Th1, Th17, and Th22 cell lines, and thus has potential for refractory AD. There is a need to generate tissue-based cytokine expression data in Indian patients with AD.
Keywords: Atopic dermatitis, cyclosporine, dupilumab, EASI, efficacy, JAK inhibitors, Th1, Th2, Th17, Th22, tofacitinib
Introduction
Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin condition with the associated pruritus negatively impacting the quality of life. The “outside-in” hypothesis postulates that epidermal barrier dysfunction triggers immune activation. In contrast, the “inside-out” hypothesis suggests that AD is primarily cytokine-driven with secondary skin barrier dysfunction.[1] The modern approach is based on an amalgamation of these two hypotheses.[2] The immunology of AD was firmly entrenched in a dominant role of T helper 2 (Th2) and its cytokines and chemokines (IL-4, IL-5, IL-13, CCL17, CCL18, and CCL22).[3] However, it is now known that there is also a Th22, Th1, and Th17 response, which suggests that a biological drug may not be the ideal choice in AD[4,5] and explains the efficacy of JAK inhibitors (JAKibs) which act on multiple cytokine families and Th cell lines.
There is a need for personalized medical intervention instead of a one-drug-for-all approach in AD.[6] Tofacitinib, being a pan JAK inhibitor (predominant inhibition on JAK3/1), would effectively suppress Th2 as well as Th22, Th1, and Th 17 cell lines. While topical tofacitinib (2% ointment) has been approved for use in mild to moderate atopic dermatitis in India,[7] it cannot be applied over large body areas and hence is not useful for moderate-to-severe AD.
It is pertinent to focus on the costs of treatment of AD, specifically moderate and severe disease, as this would determine patient adherence, which is an important and understated consideration.
Our primary objective was to assess the effectiveness and adverse effect profile of tofacitinib in recalcitrant and moderate-to-severe AD patients. A secondary objective was to compare the cost of therapy of tofacitinib with dupilumab (approved by the Central Drugs Standard Control Organisation, India) for moderate and severe AD.
Patients and Methods
We retrospectively analyzed institutional records of patients with moderate to severe AD (>10% body surface area and Scoring Atopic Dermatitis, SCORAD >20) treated with tofacitinib monotherapy at our tertiary center over a period of one year after obtaining ethics approval [674 (41/2023)] [Flowchart 1]. AD was diagnosed using UK working party’s diagnostic criteria.[8]
Flowchart 1.
Flow of study
Participants
We analyzed records of refractory moderate to severe AD patients treated with tofacitinib. All these patients were previously on various systemic agents and were either not controlled on them or had developed side effects due to these therapies.
The varied parameters noted were baseline and follow-up clinical details, dose and duration, and response to tofacitinib using the Numerical Rating Scale (NRS), SCORAD, and Eczema Area and Severity Index (EASI) at regular intervals (4 and 8 weeks). We also analyzed the duration of remission and time for recurrences seen after stopping tofacitinib. In addition, baseline and follow-up laboratory evaluations were carried out.
Cost effectiveness analysis
The mean cost of oral tofacitinib was taken from 1mg.com. To ensure consistency of data, two generic brands were chosen based on past experience of efficacy and cost considerations. The cost of therapy for the duration of treatment was compared with projected cost of dupilumab for the same duration. Dupilumab is the biological drug approved for use in India. The dose considered for calculation was 5 mg twice daily for tofacitinib for 8 weeks and 600 mg loading dose followed by 300 mg every two weeks for 8 weeks for dupilumab.
Statistical methods
The data were entered in Microsoft Excel® 2019 and analyzed using Statistical Package for Social Sciences (SPSS) software (IBM manufacturer, Chicago, USA, version 25.0). The presentation of the categorical variables was done in the form of number and percentage (%). The quantitative data were presented as the mean ± SD. The data normality was checked by using the Kolmogorov–Smirnov test. Nonparametric tests were used as data were not normal. The Wilcoxon signed rank test was used for comparison across follow-up. P value of less than 0.05 was considered statistically significant.
Results
Clinical and therapeutic details of 12 patients are elaborated in Supplementary File 1. The mean age of 12 patients included in the study was 12.72 ± 10.8 years, among them seven were females (58.33%) and five were males (41.67%) [Table 1]. The mean duration of disease was 3 years (6 months–5 years). Clinically, patients presented with moderate to severe pruritus, excoriations, erythema, oozing, and crusting [Figure 1]. All patients had previously failed/were intolerant to systemic therapy. Half of the patients had a history of other atopic diseases too [allergic rhinitis (n = 4) and bronchial asthma (n = 2)]. The vaccination status of all patients was appropriate for their age as per the national immunization schedule.
Table 1.
Demographic and clinical characteristics of patients treated with tofacitinib
| Baseline characteristics | Data |
|---|---|
| Mean age of patients (range) | 12.72±10.8 years (5-16 years) |
| Gender | |
| Males | 5 |
| Females | 7 |
| Clinical characteristics | |
| Mean duration of disease | 3 years (6 months-5 years) |
| Atopic co-morbidities | Allergic rhinitis (n=4) Bronchial asthma (n=2) |
| Previous treatment | Azathioprine (n=2) Cyclosporine (n=4) Oral corticosteroids (n=7) |
| Baseline NRS | 5.75±1.66 |
| Baseline SCORAD | 43.54±19.85 |
| Baseline EASI | 19.5±9.48 |
NRS: Numeric Rating Scale, SCORAD: Scoring Atopic Dermatitis, EASI: Eczema Area and Severity Index
Figure 1.
(a) and (b) A 5-year-old male child presented with recalcitrant atopic dermatitis for 3 months (erythema, scaling and crusting on face, limbs, and trunk) with NRS-9, SCORAD-46, and EASI-12. The patient was started on tofacitinib 5 mg once daily (c) and (d) Significant reduction in disease activity was noted after 8 weeks of tofacitinib 5 mg once daily. NRS-0, SCORAD-6, EASI-2
The mean starting dose of tofacitinib was 6.25 mg (5–10 mg once daily) and was maintained for 8 weeks, and escalated by 5 mg if there was no response after 4 weeks (10–15 mg). After complete/near complete remission, the dose was gradually tapered and maintained on 5 mg alternate day. Six patients showed complete remission with 5 mg once daily dosing, and thus, the dose was not escalated. Treatment with topical corticosteroids, moisturizer, and topical calcineurin inhibitors was continued during treatment with tofacitinib.
There was improvement in pruritus and quality of sleep, a decrease in the affected body surface area, erythema, excoriation, papulation/edema, and lichenification [Figure 1] with a significant reduction in severity scores at 4 weeks and 8 weeks of therapy [Table 2]. Eight patients showed near remission of symptoms (EASI90; 8 weeks), whereas three patients showed partial response (EASI75; 8 weeks). One patient failed tofacitinib therapy (5 mg thrice daily for 2 months).
Table 2.
Therapeutic details of 12 atopic dermatitis patients treated with tofacitinib monotherapy
| Drug | Data | ||||
|---|---|---|---|---|---|
| Mean dose of tofacitinib | |||||
| -Baseline | 6.25 mg (5-10 mg) | ||||
| -Maximum dose | 7 mg (5-15 mg) | ||||
| Mean duration of therapy (weeks) | 11.58 (2-24) | ||||
|
| |||||
| Scores | At baseline | At 4 weeks | At 8 weeks | ||
|
| |||||
| Mean (range) | Mean (range) | P | Mean (range) | P | |
|
| |||||
| SCORAD | 43.54±19.85 (19.4-75.5) | 22.74±6.82 (9-34.2) | 0.002* | 11.87±6.31 (6-27) | 0.002* |
| EASI | 19.5±9.48 (5.2-32) | 6.45±3.03 (4-12) | 0.002* | 1.6±1.11 (1.9-4) | 0.002* |
| NRS | 5.75±1.66 (3-8) | 3.25±0.87 (2-4) | 0.004* | 1.08±0.51 (0-2) | 0.002* |
| Side effects | 5/12 (41.6%) Anemia (n=2), thrombocytosis (n=1), hyperlipidemia (n=2), impetigo (n=1), and herpes zoster (n=1) |
||||
| Mean time to achieve complete/near complete resolution (n=8)# | 6.1 weeks (3-8 weeks) | ||||
| Relapse | 4/11 (36.3%) After a mean duration of 5.5 weeks (2-8 weeks) of tapering or stopping tofacitinib |
||||
SCORAD - Scoring Atopic Dermatitis; EASI - Eczema Area and Severity Index; NRS - Numerical Rating Scale. *Wilcoxon signed ranks test. #3 patients showed partial response and one patient failed tofacitinib
Side effects were noted in 5/12 (41.6%) patients including anemia (n = 2), thrombocytosis (n = 1), hyperlipidemia (n = 2), impetigo (n = 1), and herpes zoster (n = 1).
The mean time to achieve complete/near complete resolution (n = 8) of the disease was 6.1 weeks (3–8 weeks). Relapse of the disease was noted in 4/11 (36.3%) patients after a mean duration of 5.5 weeks (2-8 weeks) of tapering or stopping tofacitinib.
Economic costs
The mean cost of two brands of tofacitinib 5 mg tablet (1 mg.com) was Rs. 146.05/10 tablets [Tofajak™- Rs. 183.3/10 tablets and Tofasure™ –Rs. 108.8/10 tablets]. The total cost of therapy for the pre-defined daily dose of tofacitinib for 8 weeks was Rs. 2818. The therapy with Dupixent™ for 8 weeks (considering a loading dose of 600 mg followed by 300 mg once in 2 weeks) was projected to be Rs. 345300 (Rs. 57550/300 mg prefilled syringe), which is approximately 122 times higher than that of tofacitinib therapy.
Discussion
We found that tofacitinib achieved a EASI 90% by 8 weeks with a dose of 5-10 mg in majority of patients who had failed multiple systemic agents, with a statistical improvement in SCORAD, EASI, and NRS as early as 4 weeks. The data comparing the therapeutic response of AD patients (achieving EASI75/EASI90) to biologics and JAKibs [Table 3],[9,10,11,12,13] in conjunction with the impressive efficacy of tofacitinib in our population, wherein EASI 90 was achieved at 8 weeks, makes it a useful drug in AD.
Table 3.
Clinical trials and studies on the efficacy of biologics and JAK inhibitors in moderate–severe atopic dermatitis (comparison of EASI)
| Dupilumab | Abrocitinib | Upadacitinib | Baricitinib | Tofacitinib | |
|---|---|---|---|---|---|
| Reich et al.[9] (EASI90, 4 weeks) | 15% | 29% (200 mg/day) | |||
| Blauvelt[10] (EASI90, 16 weeks) | 38.7% | 60.6% (30 mg/day) | |||
| Simpson et al.[11] (EASI75, 12 weeks) | 40% (100 mg/day) 96% (200 mg/day) | ||||
| Gargiulo et al.[12] (EASI90) | 55.26% (week 8) 74.29% (week 16) | ||||
| Reich et al.[13] (EASI90, week 16) | 24% (4 mg) 17% (2 mg) | ||||
| Our study (EASI90, 8 weeks) | 66.6% |
EASI - Eczema Area and Severity Index
While the predominant cytokine implicated in AD is of the Th2 family (IL-4, IL-5, IL-10, IL-13), others include Th17 (IL-17A, IL-17F, IL-21), Th22 (IL-22) and Th1 (IFN-γ, IL-2, TNF-β) [Figure 2]. The Asian AD cohort tends to have a marked Th17 and Th22 expression as compared to the European cohort.[14] Thus 3 major CD4 Th subtypes (Th2, Th1, Th22 cells) are implicated in AD and the cytokine cell interaction is mediated via the JAK STAT pathway [Figure 2] accounting for the efficacy of JAKib.
Figure 2.
A schematic diagram that shows the varied CD4 subtypes implicated in AD and their cytokines. Notably, the cytokine families implicated mediate their action via varied JAK receptors highlighting the need for a pan JAK inhibitor for AD and showing the obvious lack of efficacy of biological drugs across all endotypes of AD
In addition, JAK inhibition has a marked antipruritic effect via the inhibitory effect on IL-4 (JAK1)[15] apart from modulation of the signaling of TRPV1 (transient receptor potential vanilloid receptor 1) expressed via the dorsal root ganglia.[16] A recent paper describes the role of tofacitinib in chronic pruritus of unknown origin which is an eloquent clinical translation of the in vitro data that validates the role of JAK inhibition in controlling itch.[17]
The role of biological drugs is based on enhanced expression of type 2 cytokines (including IL-4, IL-5, and IL-13) found in 50% of patients with AD.[18] Thus, this subset of patients could benefit from type 2–targeted treatments, including dupilumab (anti–IL-4/IL-13), tralokinumab, and lebrikizumab (anti–IL-13). However, as discussed and evident in Figure 2, there are other cytokines that are involved in AD, which necessitates the use of a drug that can inhibit multiple cytokines explaining the superiority of JAKibs over dupilumab.[9,19]
In India, the cost of therapy is crucial, and a world bank study on “out of pocket expenditure” (OOPE) noted that medicines accounted for a mean of 29.1% of OOPE among inpatients and 60.3% of OOPE among outpatients.[20] The proportion of mean annual health expenditure from the mean annual income was 15.6% for inpatient and 21.9% for outpatient services.[21] In fact, the NICE guidelines tend to assess novel treatments by their cost-effectiveness before allowing it to enter clinical practice. As highlighted by the recent GIRFT (Getting It Right First Time) report, novel systemic therapies are costly. For instance, dupilumab costs £1264.89 every 2 weeks according to the British National Formulary, with an annual cost per patient of £32887.[22] We have shown that tofacitinib would be markedly cheaper and possibly equally effective as biologicals, particularly dupilumab, which requires prolonged therapy to achieve EASI90 as observed in clinical trials and real-world studies.[9,10] Also [Table 3], EASI90 is achieved by dupilumab in 16 weeks, which in our study was achieved in 8 weeks with tofacitinib.
While varied JAKibs have been studied in AD (ruxolitinib, upadacitinib, abrocitinib), there are yet no head-to-head data between the JAKibs, specially tofacitinib, to guide clinicians on the ideal oral JAK inhibitor.
Tofacitinib is approved in juvenile idiopathic arthritis in children 2 years or older and prescribed based on weight [≤20 kgs: 3.2 mg twice daily, 20-39 kgs: 4 mg twice daily, and ≥40 kgs: 5 mg twice daily]. There is paucity of data on use of oral tofacitinib in pediatric AD. However, tofacitinib has been used safely in pediatric alopecia areata in doses as high as 15 mg and in children of less than 5 years age, with few minor side effects.[23,24]
While JAKibs have been shown to be effective and economical, there is a need for head-to-head trials both within the class and with existing systemic agents. Our work tends to address the latter as tofacitinib was effective even when other systemic agents failed. In addition, there is a need for more “dose tapering” (less frequent dosing/treatment cessation) data and a need to define desirable disease control (treat-to-target).
Limitations and Conclusion
Our limitations include small sample size and lack of tissue cytokines analysis pre and posttreatment. The ideal choice of JAKib or any systemic agent in AD should be based on analysis of tissue cytokines or JAK expression as the cytokine signatures of AD are phase, age, and race dependent. The strength of our work is that we used a cost-effective drug in a population that had failed systemic drugs with marked amelioration of disease severity that compares favourably with [Table 3] other drugs in this class. More data should be generated on tofacitinib specially as the drug is cheap, even though its use in AD will remain a “off label” indication like many other applications of oral JAkibs.
Conflicts of interest
There are no conflicts of interest.
Supplementary File 1.
Clinical and therapeutic details of atopic dermatitis patients treated with tofacitinib
| Patient | Age (years)/sex | Duration of AD (months) | Previous treatment | SCORAD | EASI | NRS | Maximum dose and duration of tofacitinib (weeks) | Time to achieve complete remission (weeks) | Adverse effects | Relapse |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 14/F | 6 | Cyclosporine | 69.2 | 30.4 | 9 | 10mg, 20 | Partial remission | Hyperlipidemia | - |
| 2 | 16/M | 60 | Cyclosporine | 75.5 | 32 | 10 | 10mg, 2 | 1 | - | - |
| 3 | 15/F | 24 | Azathioprine | 70.6 | 18.8 | 9 | 10mg, 24 | Partial remission | - | - |
| 4 | 10/F | 10 | OCS | 19.4 | 6 | 6 | 15mg, 8 | Failure | - | 2 weeks |
| 5 | 16/F | 60 | OCS | 20.1 | 9 | 6 | 5mg, 12 | 6 | Hyperlipidemia, anemia | - |
| 6 | 12/F | 60 | OCS | 53.3 | 5.2 | 8 | 5mg, 10 | 4 | Thrombocytosis | 8 weeks |
| 7 | 13/M | 48 | Azathioprine, OCS | 45.5 | 20 | 5 | 5mg, 12 | 8 | Impetigo | - |
| 8 | 9/M | 36 | OCS | 35 | 8.2 | 7 | 5mg, 10 | 3 | - | 7 weeks |
| 9 | 5/M | 12 | OCS | 46 | 12 | 9 | 5mg, 14 | 8 | - | - |
| 10 | 13/F | 20 | Cyclosporine | 28 | 7 | 7 | 10mg, 6 | 4 | - | - |
| 11 | 16/F | 36 | Cyclosporine | 30.9 | 8 | 8 | 10mg, 16 | Partial remission | Anemia, herpes zoster | - |
| 12 | 14/M | 60 | OCS | 29 | 7 | 6 | 5mg, 4 | 3 | - | 5 weeks |
SCORAD - Scoring Atopic Dermatitis; EASI - Eczema Area and Severity Index; NRS - Numerical Rating Scale; OCS - Oral corticosteroids
Funding Statement
Nil.
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