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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 7  |  Issue : 1  |  Page : 7-11

Crisaborole for the treatment of atopic dermatitis in Indian patients: An evidence-based consensus statement


1 Department of Dermatology, Dr. DY Patil Medical College, Nerul, Navi Mumbai, Maharashtra, India
2 Department of Dermatology, Calcutta National Medical College, Kolkata, West Bengal, India
3 Department of Dermatology, The Medicity, Medanta Hospital, Gurugram, Haryana, India
4 Department of Dermatology, Apollo Hospital, Chennai, Tamil Nadu, India
5 Department of Dermatology, BJ Medical College, Ahmedabad, Gujarat, India
6 Department of Dermatology, Max Super Speciality Hospital, New Delhi, India
7 Department of Dermatology, Skin Diseases Center, Nashik, Maharashtra, India
8 Department of Dermatology, Krupa Shankar Skin Care Center, Mallige Hospital, Bengaluru, Karnataka, India
9 Department of Dermatology, MGM Medical College, Nerul, Navi Mumbai, India
10 Department of Pharmacology, Dr. DY Patil Medical College, Nerul, Navi Mumbai, India

Date of Submission18-Jun-2020
Date of Decision14-Dec-2020
Date of Acceptance15-Jan-2021
Date of Web Publication25-Jun-2021

Correspondence Address:
Kiran Godse
Department of Dermatology, Dr. DY Patil Medical College, Nerul, Navi Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijdd.ijdd_35_20

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  Abstract 


Atopic dermatitis is a chronic inflammatory dermatological condition associated with intense pruritus seen in all age groups and ethnic diversities. It can have a significant impact on the quality of life. The options for treatment include skincare, topical therapies, systemic therapies, and phototherapy. Treatment of atopic dermatitis may be associated with several challenges including suboptimal efficacy, risk of adverse events, and limited patient satisfaction. A better understanding of the pathophysiology of atopic dermatitis has resulted in the evaluation of many treatment options. Phosphodiesterase 4 plays a role in the pathogenesis of atopic dermatitis and hence can be a target for treatment. Crisaborole 2% ointment is a phosphodiesterase 4 enzyme inhibitor approved for the treatment of mild-to-moderate atopic dermatitis in patients above 2 years of age by the USFDA. Currently, it is not approved for use in Indian patients. In this article, the role and potential place of crisaborole in the management of atopic dermatitis in Indian patients based on global experience and evidence is discussed.

Keywords: Atopic dermatitis, crisaborole, efficacy, safety


How to cite this article:
Godse K, De A, Sharma N, Rajagopalan M, Shah B, Girdhar M, Zawar V, Shankar K, Godse G, Patil A. Crisaborole for the treatment of atopic dermatitis in Indian patients: An evidence-based consensus statement. Indian J Drugs Dermatol 2021;7:7-11

How to cite this URL:
Godse K, De A, Sharma N, Rajagopalan M, Shah B, Girdhar M, Zawar V, Shankar K, Godse G, Patil A. Crisaborole for the treatment of atopic dermatitis in Indian patients: An evidence-based consensus statement. Indian J Drugs Dermatol [serial online] 2021 [cited 2021 Dec 3];7:7-11. Available from: https://www.ijdd.in/text.asp?2021/7/1/7/319357




  Introduction Top


Atopic dermatitis is one of the common chronic inflammatory dermatological conditions encountered by primary care physicians as well as dermatologists.[1],[2],[3],[4],[5],[6] It is seen in all age groups as well as different ethnic populations. The disease affects children more than adults with a lifetime prevalence of about 15%–30% and 5%–10%, respectively.[1],[7] The prevalence in the elderly population of industrialized countries is about 3%–4%.[8] Atopic dermatitis can be associated with distressing symptoms of pruritus and cutaneous pain, increased risk of infections, and morbidity with impaired quality of life.[5],[8],[9],[10],[11] In addition to psychosocial impact,[1],[12] atopic dermatitis can also cause adverse economic consequences.[1],[13]


  Pathophysiology and Management of Atopic Dermatitis Top


Skin barrier defect, altered skin microbiome, and immune dysregulation are known to play an important role in the pathogenesis of atopic dermatitis.[2],[4],[12],[14],[15] Structural protein filaggrin deficiency can promote inflammation and infiltration of T cells. Neuroinflammation may play a role in itching in atopic dermatitis.[10] Amplification of several cytokine pathways has been suggested to play an important role in the pathogenesis of the disease. The important cytokine pathways involved in the disease pathogenesis include T helper (Th) 2, Th22, Th17, and Th1 pathways.[2] Phosphodiesterase-4, a cyclic AMP degrading enzyme,[16] is involved in the modulation of inflammation and epithelial integrity[17] and regulates cyclic adenosine monophosphate in cells.[2] Thus, this enzyme is involved in the regulation of pro-inflammatory cytokines and the activity of phosphodiesterase-4 is increased in the inflammatory cells in atopic dermatitis.[18] Considering this, its inhibition can be a promising target for the treatment of atopic dermatitis.[2],[17]

Treatment options for atopic dermatitis can be divided into three types; nonpharmacological treatment, topical treatment, and systemic therapies.[13] Good skincare remains central to the management of atopic dermatitis in all patients. Currently, several options including topical and systemic therapy are available for the treatment of atopic dermatitis with topical therapies being the mainstay.[19] The examples of topical agents include moisturizers, antihistamines,[20] calcineurin inhibitors, corticosteroids, and crisaborole.[21] Chronic use of topical steroids and calcineurin antagonists may be limited due to the risk of cutaneous adverse effects.[19] Topical corticosteroids may cause skin atrophy, telangiectasia, rosacea, and acne[2] whereas topical calcineurin inhibitors may be associated with burning and stinging and theoretical risk of malignancy.[2] In patients not responding to topical treatment, systemic agents[22] and phototherapy[18],[23] are the options. Examples of systemic agents include immunosuppressive therapies including cyclosporine, methotrexate, mycophenolate mofetil, corticosteroids, and other newer agents.[8] Examples of systemic immunomodulatory therapy include omalizumab, dupilumab, lebrikizumab, apremilast, nemolizumab, etc., whereas examples of topical agents include tofacitinib and crisaborole.[14] The examples of emerging therapy, i.e., JAK-STAT inhibitors include baricitinib, upadacitinib, ruxolitinib, and delgocitinib.[15] The factors considered for the selection of therapy include efficacy, safety profile, adherence, and effect on the quality of life.[22] Moisturizers/emollients, topical corticosteroids, and topical calcineurin inhibitors are among the first-line treatment options, whereas cyclosporine and phototherapy are recommended as second-line and third-line options, respectively.[23] Despite several available options, differences in efficacy and suboptimal patient satisfaction due to poor compliance and very high expectations from the patients demand newer agents for the management.


  Crisaborole 2% Ointment Top


Crisaborole 2% ointment is a nonsteroidal phosphodiesterase 4 inhibitor.[24],[25],[26],[27],[28],[29],[30],[31],[32]

A pharmacokinetic study in children with mild-to-moderate atopic dermatitis reported achievement of steady-state systemic concentrations by day 8. According to an in vitro study, crisaborole is highly (97%) bound to human plasma proteins. The drug is significantly metabolized into inactive metabolites which are excreted majorly through renal excretion.[33] The literature search did not yield reports on major drug interactions with crisaborole or its metabolite.

Crisaborole is a boron compound[30],[34] with the potential to reduce the requirement of topical corticosteroids.[13] Steroid phobia to topical steroids among general patients and parents of children with atopic dermatitis is a known phenomenon.[35],[36] Because of phobia in patients, even clinicians may hesitate to prescribe topical steroids. Reduction in the reduced dose of steroids will help clinicians to counsel the patients better and patients may accept the treatment more readily and which can potentially translate into better compliance and possibly better outcome. Thus, crisaborole can be a good option to address steroid phobia among patients as well as clinicians. Topical crisaborole has limited systemic absorption and exposure.[21],[37] Crisaborole is used twice daily for 28 days.[38]

The evidence for efficacy when used continuously for more than 28 days is not known from controlled trials. However, multiple treatment courses over 48 weeks have been studied in an open-label extension trial.[39]


  Efficacy in Atopic Dermatitis Top


Important aspects for evaluation of therapy include its overall efficacy, safety profile, the onset of action, sustained efficacy, and its impact on the underlying disease process. There are no randomized, double-blind comparative clinical trials in Indian patients with atopic dermatitis. Literature available from other countries is reviewed and analyzed to examine its efficacy, safety, and impact on the quality of life and its relevance in the Indian context. According to a literature review of randomized, blinded, vehicle-controlled trials, comparison among available topical agents is difficult due to different methodologies used in clinical trials. Clinical studies with crisaborole have shown its efficacy and manageable safety profile.[40]


  Onset of Action in Mild-to-Moderate Atopic Dermatitis Top


According to an analysis from two phase III studies, a significant number of patients in the crisaborole group reported early improvement in pruritus as compared to vehicle including at earliest assessment at day 2.[38] In another study involving 40 adults with mild-to-moderate atopic dermatitis, the use of crisaborole was associated with improvement in pruritus as early as 24 h.[29]


  Effect on Biomarkers of Atopic Dermatitis Top


Treatment with crisaborole results in a significant percentage improvement in lesional transcriptomic profile than vehicle at day 8 which was sustained until day 15. Treatment with crisaborole significantly modulated important biomarkers of atopic dermatitis including TH2 and TH17/TH22 pathways and epidermal hyperplasia. Overall, crisaborole was effective in normalizing the reversed biomarkers of skin inflammation and barrier function.[29]


  Clinical Efficacy in Mild-to-Moderate Atopic Dermatitis Top


Crisaborole has been evaluated in the treatment of mild-to-moderate atopic dermatitis in patients >2 years of age.[24] Efficacy and safety of crisaborole ointment was evaluated in two phase III randomized, double-blind, vehicle-controlled studies in patients >2 years of age with mild-to-moderate atopic dermatitis as judged by an Investigator's Static Global Assessment (ISGA) score. The treatment was given two times daily for 28 days. Significantly more number of patients in the crisaborole group achieved the primary endpoint, i.e., ISGA score success in both studies. In study 1, ISGA score success was achieved by 32.8% of patients receiving crisaborole versus 25.4% in the vehicle group (P =0.038). In second study, the rates were 31.4% and 18.0%, respectively (P < 0.001). The percentage of patients achieving clear or almost clear score in crisaborole and vehicle was 51.7% and 40.6% (P = 0.005) in the first study and 48.5% versus 29.7% in the second study (P < 0.001). Achievement of success for primary endpoint and improvement in pruritus was faster in the crisaborole group than the comparator group.[41]

A post hoc analysis of pooling results from two phase 3 studies to evaluate the efficacy of crisaborole in patients ≥2 years with mild-to-moderate atopic dermatitis (crisaborole [n = 1016] or vehicle [n = 506]) when given twice daily for 4 weeks reported significant improvement as compared to the vehicle as determined by mean changes in Atopic Dermatitis Severity Index score and percentage of treatable body surface area.[24] Crisaborole 2% ointment also provided sustained improvement in disease severity and pruritus.[18]

Callender et al. evaluated the efficacy and safety of crisaborole in patients with mild-to-moderate atopic dermatitis across racial and ethnic groups from a pooled post hoc analysis of two pivotal trials. The results suggested improvement in signs/symptoms and quality of life.[3]

Another open-label study evaluated the safety, effectiveness, and pharmacokinetics of crisaborole in 137 infants (3 to <24 months) with mild-to-moderate AD. Crisaborole was given twice daily for 4 weeks. Crisaborole was found to be effective in infants (3 to <24 months) with mild-to-moderate atopic dermatitis with systemic exposures similar to patients 2 or more years of age.[25]

A recently published meta-analysis of seven double-blind randomized clinical trials in the treatment of mild-to-moderate atopic dermatitis (n = 1869), as compared to topical vehicle, topical phosphodiesterase 4 inhibitors were associated with a significant reduction in target lesion score and a better response rate of clear or almost clear skin as assessed by investigators.[42]

Overall, results of clinical trials with crisaborole 2% topical ointment suggest that it can improve disease symptoms and clinical signs in patients with atopic dermatitis.[43]


  Effect on Quality of Life Top


Quality of life can be impaired in atopic dermatitis irrespective of severity. The results of two phase 3 studies among patients aged ≥2 years with mild-to-moderate atopic dermatitis demonstrated a clinically meaningful improvement in the quality of life of patients and their caregivers.[44] Crisaborole can be useful for improving the quality of life of patients with mild-to-moderate atopic dermatitis by a reduction in the severity of pruritus.[45]


  Tolerability of Crisaborole in Patients with Mild-to-Moderate Atopic Dermatitis Top


Crisaborole ointment 2% is well tolerated in patients with mild-to-moderate atopic dermatitis.[25] In a study involving Japanese adults with mild-to-moderate atopic dermatitis, crisaborole showed an acceptable safety profile.[28] Topical crisaborole has limited systemic exposure.[21],[37] Mild-to-moderate and transient painful reactions at the site of application are known with topical therapies including emollients, corticosteroids, calcineurin inhibitors, and phosphodiesterase 4 inhibitors. The incidence of such issues is higher with topical calcineurin inhibitors than with phosphodiesterase 4 inhibitor.[46] Minor adverse events associated with the use of crisaborole may include hypersensitivity reactions such as contact urticaria, irritation, pain, burning, and/or stinging at the site of application.[18],[28] No serious adverse events are reported in clinical trials.[43]

An open-label study involving patients from 3 months to 24 months of age reported treatment-emergent adverse events in 64.2% of patients, but most (98.9%) were mild/moderate. Treatment-related adverse events were reported in 16.1% of patients. Application site pain, discomfort, and erythema were the most commonly reported adverse events.[25]

Pooled post hoc analysis of two pivotal trials with crisaborole in patients with atopic dermatitis showed the incidence of adverse events between 7.1% and 8.5%.[3] A meta-analysis reported no difference in treatment-related adverse events or adverse events resulting in discontinuation between topical phosphodiesterase 4 inhibitors and topical vehicle.[42] In a 48-week safety study, the discontinuation rate due to treatment-emergent adverse events was 1.7%.[47]

A study involving healthy volunteers showed that crisaborole ointment application to sensitive skin areas is well tolerated.[48] It has no effect on skin thinning.[49] A 2-year study in animals suggested that crisaborole is not tumorigenic.[50] Apart from efficacy and safety considerations, financial implications to the patients should also be considered especially for chronic treatment. A study by Clark et al.[32] suggested modest pharmacy budget impact/savings with the adoption of crisaborole.


  Regulatory Approval Status Top


Crisaborole 2% ointment is approved by the US Food and Drug Administration for the treatment of mild-to-moderate atopic dermatitis in patients above 2 years of age.[33]

It belongs to pregnancy category B1. Adequate data about its use in pregnant women are not available. Animal studies have not shown harmful effects related to reproductive toxicity when used at maternally nontoxic doses. Information about secretion in human milk after topical application in breastfeeding is unknown. Breastfeeding mothers should avoid its application to the breast in order to prevent entry in the mouth of the newborn.[39]

It is recommended to apply as a thin layer to the affected areas. It should not be co-applied on the same areas with other topical medicines of atopic dermatitis medicines and hands should be washed after applying the medicine. Simultaneous use with other topical agents applied on different lesions has not been studied.

It is not yet approved for use in India.

Based on this available evidence from literature, crisaborole, once approved in India, may be considered as a choice for maintenance or sequential therapy in patients with mild-to-moderate atopic dermatitis. Consensus statements related to the use of crisaborole in Indian patients with atopic dermatitis are summarized in [Table 1].
Table 1: Consensus statements for use of crisaborole in Indian patients with atopic dermatitis

Click here to view



  Conclusion Top


Crisaborole ointment 2%, a nonsteroidal phosphodiesterase 4 inhibitor, is effective and well tolerated in the treatment of mild-to-moderate atopic dermatitis. Because of topical application, systemic exposure is minimal. Except for minor application site reactions, it is not associated with significant adverse events. It is not the treatment of choice for severe atopic dermatitis.[51]

Financial support and sponsorship

This activity was supported by the Skin Allergy Research Society India.

Conflicts of interest

There are no conflicts of interest.



 
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