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

IJD-69-312
10.4103/ijd.ijd_1085_23
Original Article
An Open-Label, Investigator-Initiated, Single-Centre Pilot Study to Determine the Safety and Efficacy of Tofacitinib in Resistant Chronic Spontaneous Urticaria
De Abhishek
Pal Shrayan
Singh Sushil
Chakroborty Disha
Godse Kiran 1
From the Department of Dermatology, Calcutta National Medical College, Kolkata, West Bengal, India
1 Department of Dermatology, DY Patil University, Navi Mumbai, Maharashtra, India
Address for correspondence: Dr. Abhishek De, Flat 3A, Arcadia 1, Sonarpur Station Road, Kolkata, West Bengal - 700 103, India. E-mail: dr_abhishek_de@yahoo.co.in
Jul-Aug 2024
19 8 2024
69 4 312316
11 2023
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:

Chronic spontaneous urticaria (CSU) is a distressing skin condition characterized by the recurrent appearance of itchy hives. A subset of CSU patients remains resistant to conventional treatment with high-dose antihistamines. Tofacitinib, a Janus kinase inhibitor, has shown promise in various inflammatory skin diseases. We aimed to evaluate the efficacy of oral tofacitinib in patients with CSU resistant to antihistamines.

Methods:

This study examined data retrospectively from seven patients who were diagnosed with CSU and were treated with tofacitinib for at least six months. These patients initially exhibited resistance to treatment with four-fold up-dosed antihistamines. One of the patients was already on omalizumab, and another was tried on cyclosporine. The patients were administered oral tofacitinib at a dosage of 5 mg twice daily for six months. Patients were followed up monthly for disease control and side effects. The response to treatment was evaluated using the urticaria activity score over 7 days (UAS7) and urticaria control test (UCT). Paired t-tests were conducted to determine the statistical significance of the results using SPSS version 25 software.

Results:

Six out of the seven patients demonstrated a significant improvement in both UAS7 and UCT scores after six months of treatment with oral tofacitinib. The mean UAS7 score decreased from 24.86 at baseline to 3.83 at the study endpoint (P < 0.0001). Similarly, the mean UCT score increased from 0.57 at baseline to 14 at the study endpoint (P < 0.0001). The standard deviations for both measures were 4.85 and 0.98 at baseline and 3.1 and 3.1 at the study endpoint for UAS7 and UCT, respectively.

Conclusion:

In this six-month follow-up study, oral tofacitinib demonstrated significant efficacy in treating CSU patients’ resistant to high-dose antihistamines. Most patients experienced a remarkable reduction in urticaria activity and an improvement in disease control. These findings suggest that tofacitinib holds promise as a potential therapeutic option for this challenging subset of CSU patients. However, larger, randomized controlled trials are warranted to further investigate the long-term safety and effectiveness of tofacitinib in this population.

KEY WORDS:

Chronic spontaneous urticaria
JAK inhibitor
Janus kinase inhibitor
resistant urticaria
tofacitinib
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pmcIntroduction

Chronic spontaneous urticaria (CSU) is a debilitating skin condition characterized by the daily or nearly daily appearance of pruritic hives with or without angioedema, for 6 weeks or more.[12] Approximately 1% of the global population suffers from CSU which leads to major detrimental effects on many patients’ health-related quality of life.[3] Though a disease primarily of the skin, the effect of the disease is far wider, with many patients having a considerable impact on sleep quality, mental health, performance at work or school and even sexual functioning.[4] According to current consensus and guidelines, the first-line treatment for CSU is with a nonsedating second-generation H1-antihistamine. Second-generation H1-antihistamine can safely be up-dosed to 4 times the standard dosage in case of inadequate response.[56]

However, many patients still do not achieve adequate control of their symptoms, and less than half of patients are responding to the standard doses of H1-antihistamines. Anti-IgE monoclonal antibody like omalizumab is recommended as the next step in most algorithms, with concomitant use of H1-antihistamine.[7] However, the prohibitory high cost of omalizumab and the subcutaneous route of administration pose challenges to the healthcare infrastructure and the patients. An alternative molecule like cyclosporine was suggested in both Indian and international guidelines as either the second-line or the third-line treatment, however found limited place in the management of CSU because of its relatively high adverse events especially when used for longer duration.[68]

Considering the highly debilitating effects and the chronicity of CSU, while the options of agents for effective treatment are limited, the need for new therapies and the search for newer agents with novel mechanisms of action, higher efficacy and more favourable safety profiles are always on.[9]

Tofacitinib is a small molecule that inhibits the intracellular signalling of multiple key cytokines by blocking the JAK1/3 and thus interrupts the inflammatory cascade and showed its beneficial effects in patients with mast cell activation diseases, however has not been used extensively in CSU patients.[10] With this background, we did an open-label, investigator-initiated, single-centre prospective pilot study to determine the safety and efficacy of tofacitinib in treatment-resistant cases of CSU.

Materials and Methods

Study design

We conducted an open-label, investigator-initiated, single-centre pilot study to determine the safety and efficacy of tofacitinib in resistant cases of CSU which was conducted at a tertiary care centre in Eastern India in 2023. The was conducted for a total duration of six months where the patients were recruited for the first month and were followed up for 20 consecutive weeks for response to therapy.

We included clinically diagnosed cases of CSU (pruritus and wheals occurring daily or near-daily [>=3 times per week] for >=6 weeks) and refractory [defined by UCT <12] to the four-fold up-dosed second-generation antihistamines. We excluded patients with acute urticaria, angioedema without urticaria, patients who have taken steroids or immunosuppressive in the last 4 weeks, urticarial vasculitis, syndromic associations and ages below 12 years as well as special groups such as pregnancy.

Clinico-demographic data of all patients were recorded. Baseline investigations including complete hemogram, liver function tests, renal function tests, lipid profile and thyroid panels were performed. Urticaria activity score (UAS7) and urticaria control test (UCT) scores were recorded at baseline. Patients were given oral tablets of tofacitinib 5 mg twice daily for 4 weeks. A standard dose of second-generation antihistamine in the form of Bilastine 20 mg was given along with.

The subjects were followed up at 4 weekly intervals up to 20 weeks. All subjects were provided with a UAS7 and UCT standardized questionnaire at each visit to assess the efficacy of therapy. Complete hemogram, liver function test and lipid profile were repeated at monthly intervals for the first three months and subsequently at monthly intervals to assess the safety of the study medication. Patients were then given a tablet of tofacitinib (5 mg) twice daily for the subsequent 4 weeks at each visit.

Outcome measures

The primary outcome measures included standardized patient-related outcomes measure tools in CSU, the UAS7 scores and UCT scores which were assessed at each 4-weekly interval.

A UAS7 score of 1–6 and a UCT score of >=12 were considered well-controlled urticaria.

Secondary outcome measures included self-reported adverse events to the therapy and derangement of the laboratory parameters.

Statistical analysis

A total of seven patients were recruited during one month. Baseline demographic data and safety data are presented as mean and standard deviation with a 95% confidence interval. UAS and UCT scores are presented as mean with standard deviation at 95% confidence interval and median. Modified intention-to-treat analysis was carried out in patients reporting for at least one followup visit. The last observation was carried forward to address the missing data either due to dropouts or patients who achieved remission. Pre- and posttreatment laboratory values were compared in patients for whom both sets of data were available. MedCalc version 11.6 (Mariakerke Belgium: MedCalc Software, 2011) was used for statistical analysis.

Results

A total of seven patients with refractory CSU were included in the study. One of the patients dropped out of the study due to non-response to the study drug was assessed based on intention to treat analysis. The patient who dropped out was a 40-year-old male patient who dropped out after the 12th week and started on omalizumab. Reasons for the choice of tofacitinib over another second line of therapies were non-response to either omalizumab or cyclosporine in one patient each, hypertension in two patients, renal comorbidities in two patients and economic issues in one.

Out of seven patients, five were male patients and two were female patients. The mean age of the patients was 37.8 ± 8.9 years with a range of age varying from 26 years to 52 years. All of them received at least four-fold up-dosing of second-generation non-sedative antihistamines, either bilastine or fexofenadine. One of them received 300 mg of omalizumab every 4 weeks for three months before we switched on to tofacitinib because of an inadequate response. Another patient received cyclosporine at a dose of 3.5 mg/kg body weight per day for 8 weeks before we switched to tofacitinib because of an inadequate response [Table 1].

Table 1 Demographic and therapeutic data of patients of CSU who were treated with tofacitinib

Age	Sex	Duration of disease (months)	Treatment received	Associated Medical Condition	Reason for tofacitinib	Baseline	20 weeks	Final outcome	
	
UAS7	UCT	UAS7	UCT	
38	Male	18	4X antihistamine	Hypertension	Hypertension	28	0	5	14	Well-controlled	
44	Male	11	4X antihistamine, Cyclosporine	DM	Non-response	26	0	11	8	Uncontrolled	
52	Male	36	4X antihistamine	Renal comorbidities	Renal comorbidities	31	0	1	16	Completely controlled	
28	Female	14	4X antihistamine		Economic issues	19	2	4	14	Well-controlled	
40	Male	30	4X antihistamine	Hypertension	Hypertension	24	0	Started on omalizumab due to non-response	Drop out	
37	Female	48	4X antihistamine	Renal comorbidities	Renal comorbidities	28	2	0	16	Completely controlled	
26	Male	10	4X antihistamine, omalizumab		Non-response	18	0	2	16	Completely controlled	

The mean duration of the disease in all subjects was 23.8 ± 14.4 months with a baseline UAS7 score of 24.8 ± 4.8.

After five months (20 weeks) of follow-up, there was a statistically significant reduction from the baseline mean UAS7 scores from the first follow-up visit (P = 0.02) and continued to the fifth follow-up visit (P < 0.001) [Figure 1].

Figure 1 Mean reduction in UAS7 scores during therapy

A significant improvement was seen from the mean baseline UCT of 0.5 ± 0.97 to 12.0 ± 6.0 at the fifth follow-up visit (P < 0.001). A significant improvement in UCT was observed from the second follow-up onwards (P = 0.03) [Figure 2]. Of the seven patients, one dropped out due to inadequate response, three were in complete control of disease (UCT = 16), two were adequately controlled (UCT = 12 to 15) and one was uncontrolled.

Figure 2 Mean improvement in UCT scores during therapy

Laboratory parameters at the baseline and each visit were within normal limits. Tofacitinib was well-tolerated in all patients and none had to drop out from the study because of adverse events.

Discussion

Management of moderate to severe CSU remains a major challenge, According to the updated and revised 2021 guidelines by a joint initiative of the EAACI Dermatology Section, GA2LEN, EDF, WAO and CSACI, the first-line treatment for all cases of CSU should be the second-generation antihistaminics in usual dosage, and in case of inadequate control after 2–4 weeks, or in case of intolerable symptoms is up-dosed to up to 4 times the standard dosing of the second-generation antihistaminics is suggested. The second-line treatment, that is, omalizumab is considered in case of inadequate control after 2–4 weeks even after that, or still the symptoms are intolerable. However, if still the control is inadequate after six months or the patients are still unable to tolerate the symptoms, the guideline recommends moving to cyclosporine A as the third-line treatment.[8] In many patients, cyclosporine or omalizumab may either be contraindicated or prohibitively expensive. Also, there are concerns regarding the long-term use of agents such as cyclosporine A. Recently, ligelizumab which was introduced with lots of hyper and hope, had been withdrawn from further development in CSU because it failed to produce superior efficacy over omalizumab.[9]

All these suggested a requirement for alternative options beyond the conventional in the management of CSU, especially the refractory cases. Recently, small molecules of the Bruton tyrosine kinase inhibitors group such as Remibrutinib and Fenebrutinib have shown promising efficacy in controlling disease activity in CSU in randomized controlled trials.

Tofacitinib is an oral Janus kinases (JAK) inhibitor that inhibits JAK1, JAK2, JAK3 and to a lesser extent tyrosine kinase 2, thus inhibiting particularly those resulting from type I/II cytokine receptors-associated cytokines.

Tofacitinib has been successfully used for many other skin inflammatory and autoimmune skin conditions including psoriasis, atopic dermatitis, alopecia areata, vitiligo, lupus erythematosus and lichen planopilaris.[11]

Hence, we considered could be a therapeutic option in treatment-resistant CSUs as well, especially when we now understand that refractory CSUs are often associated with type 2b autoimmunity.

In our pilot study in cases of intractable CSU, a significant improvement was observed from the first follow-up visit at 4 weeks which was sustained to the end of therapy. All patients were treated with a standard dose of tofacitinib 5 mg twice daily. At least three patients of the seven we enrolled, were completely asymptomatic with tofacitinib; and two more were under good control. To the best of our knowledge, there was only one series with four patients of CSU and urticarial vasculitis treated with tofacitinib was published in an indexed journal. Their study showed despite the long-term unresponsiveness of various treatments in their patients, the addition of tofacitinib significantly improved the urticarial activity and ultimately led to tapering and discontinuation of cyclosporine or antihistamines. They concluded that tofacitinib appears to downregulate inflammatory phenomena associated with mast cells and might be a new therapeutic option for patients with refractory CSU or urticarial vasculitis.[12] Our study, though conducted only on CSU patients and included no patient with urticarial vasculitis, has similar findings, albeit with a larger number of patients.

Limitation

Our study is, however, limited by the small sample size and relatively short follow-up considering the long and chronic course of the disease. Future longitudinal randomized control trials against established therapeutic options like omalizumab or cyclosporine with longer follow-up periods may help delineate the relative efficacy and safety of tofacitinib in CSU.

Conclusion

Our study suggests promising efficacy, tolerability and good safety profile of tofacitinib in patients with CSU in a real-world setting and though done on a small number of patients and with a relatively short follow-up period. Our finding suggests tofacitinib may be considered a therapeutic option in CSU patients, especially the refractory ones where omalizumab or cyclosporine are either relatively contraindicated or have inadequate response. A larger cohort of patients in randomized controlled trials against more established therapeutic options over a longer period will confirm its true role in the therapeutic algorithm of CSU.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.
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1 Godse K De A Zawar V Shah B Girdhar M Rajagopalan M Consensus statement for the diagnosis and treatment of urticaria: A 2017 update Indian J Dermatol 2018 63 2 15 29527019
2 Shah B De A Sarda A Kochhar AM Dhoot D Deshmukh G Effect of bilastine on chronic spontaneous urticaria refractory to levocetrizine: Real world experience in India Dermatol Ther 2021 34 e14557 33210404
3 Datta S Singh S Sarda A De A Dhar S Role of patient-reported outcome measures in the management of chronic urticaria and angioedema Indian J Skin Allergy 2023 2 1 6
4 Fiallos LM Ojeda IC Thomsen S Giménez-Arnau A Sørensen JA Godse K Is there any relationship between chronic urticaria, its severity and alexithymia? J Allergy Clin Immunol 2023 151 AB333
5 Godse K Patil A De A Sharma N Rajagopalan M Shah B Diagnosis and management of urticaria in Indian settings: Skin allergy research society's guideline-2022 Indian J Dermatol 2022 67 732 43 36998850
6 De A Shah B Banodkar PD Dhoot D Chitnis K Barkate H Real-World Indian experience of switchover to Bilastine 40 mg/day in CSU patient refractory to other antihistamines at double dose Indian J Dermatol 2023 68 674 7 38371575
7 De A Chowdhury B Khemka M Sarda A Das S Biologics beyond boundaries: Innovative use of biologics in dermatology Indian J Dermatol 2021 66 314 7 34446957
8 Zuberbier T Abdul Latiff AH Abuzakouk M Aquilina S Asero R Baker D The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria Allergy 2022 77 734 66 34536239
9 Datta S Chakraborty D De A Ligelizumab: A novel molecule in the management of chronic spontaneous urticaria Indian J Skin Allergy 2023 2 14 7
10 Ahmed SS De A Sarda A Godse K Dhar S JAK inhibitors in dermatology Indian J Skin Allergy 2023 2 3 7
11 Dhar S Datta S De A Use of Janus kinase inhibitors in atopic dermatitis–An update Indian J Dermatol Venereol Leprol 2023 10 1 8
12 Mansouri P Mozafari N Chalangari R Martits-Chalangari K Efficacy of oral tofacitinib in refractory chronic spontaneous urticaria and urticarial vasculitis Dermatol Ther 2022 35 e15932 36226796
