Real-World Effectiveness and Safety of Dupilumab for the Treatment of Moderate to Severe Atopic Dermatitis in Indian Patients: A Multi Centric Retrospective Study.

INTRODUCTION: Treatment of moderate to severe atopic dermatitis (AD) is a real challenge for the dermatologists. Dupilumab is the first targeted biologic therapy approved for the treatment of children and adults with moderate-to-severe AD. The efficacy and safety of dupilumab in Indian patients is limited to date, it is necessary to assess the performance of this treatment in real clinical practice in the Indian context.
METHODOLOGY: Patients from three centers of India, two from Kolkata and one from Bangalore were included in the study for retrospective chart analysis. Efficacy was assessed by comparing the SCORAD and EASI and impact on quality of life was assessed by DLQI scores. All patients received standard doses of Dupilumab. Any side effect of the treatment was noted in the bi-weekly follow-up visit.
RESULTS: Twenty-five patients who were treated with dupilumab for at least 6 months were retrospectively included to study. The mean EASI score improved from 19.48 at baseline to 4.84 at six months. Seventeen patients (68%) achieved EASI 75 (≥75% improvement from baseline) at the end of 6 months of treatment. All these patients were earlier treated with at least one systemic immunomodulator without any significant improvement. The mean SCORAD score also improved with dupilumab treatment from 37.32 at baseline to 8.04 at six months. The improvement were found to be statistically significant (P < 0.001). The quality of life also improved significantly (P < 0.001) from a baseline mean of 17.08 at baseline to 6.52 at 6 months.
CONCLUSIONS: We observed significant efficacy, tolerability, and safety of dupilumab in Indian patients with AD in a real-world setting, which was similar to that shown in clinical trials in the western populations. Copyright:

Introduction

Atopic dermatitis (AD) is characterized by chronic inflammation of the skin with severe pruritus. AD has a high prevalence among children (15–30%) and adults (2–10%) with a substantial impact on the quality of life of patients.[1] Epidemilogic data on AD is inadequate.[2] Dhar and Kanwar's study of 672 children for epidemiologic and clinical features, a prospective study carried out over 6-year period still remains the largest series from India and subcontinent.[3]

The pathogenesis of AD is complex; with interleukin (IL)-4 and IL-13 playing a key role in the proinflammatory loop, decreasing the expression of structural proteins of the epidermis, and leading to the formation of inflammatory and very pruritic lesions.[4]

Treatment of AD poses a major challenge, particularly moderate to severe form of it. Recently Dupilumab became available internationally for the treatment of AD and showed high efficacy and tolerable safety in clinical trials. Dupilumab is a fully human monoclonal antibody that targets IL-4 receptor subunit a, the common subunit of the type 2 cytokines IL-4 and IL-13, blocking signaling of both cytokines and consequently inhibiting the entire type 2 pathway.[5]

Dupilumab has still not available freely in India, though recent Indian guidelines for the management of AD recommended its use as an option in the treatment-resistant moderate to severe patients of adult AD.[6]

However, we understand clinical trials have many limitations owing to inclusion and exclusion criteria, the real-world data can differ from the data obtained from clinical trials.

The efficacy and safety of dupilumab in Indian patients is limited to date, it is necessary to assess the performance of this treatment in real clinical practice in the Indian context.

Methodology

Patients from three centers of India, two from Kolkata and one from Mumbai were included in the study for retrospective chart analysis. Patients above 11 years who have received at least 6 months of dupilumab treatment were included in the study. Dupilumab was only given to patients moderate to severe patients of AD who were previously prescribed topical and at least one systemic immunomodulator with inadequate efficacy.

Efficacy was assessed by comparing the SCORAD (“SCORing Atopic Dermatitis”) and EASI (Eczema Area and Severity Index) scores recorded in the case-sheets every month (i.e., baseline, 1 month, 2 months, 3 months, 4 month, 5 months, and 6 months).

Also, the impact on the quality of life of the patients was assessed using DLQI (The Dermatology Life Quality Index) questionnaire tool at the baseline and at the 6 months visit.

All patients received one 600-mg loading dose of dupilumab. Then, starting 2 weeks later, 300 mg of dupilumab was administered subcutaneously every 2 weeks, in addition to treatment with topical corticosteroid and/or tacrolimus and emollient.

Any side effect of the treatment was noted in the bi-weekly follow-up visit.

Results

Twenty-five patients who were treated with dupilumab were retrospectively included to study the efficacy and safety of the medicine in the Indian population. Seventeen of these cases were treated in Kolkata and 8 of them were treated in Mumbai. Out of the 25 patients, 16 were male patients and 9 were female patients. The age of the patients varied between 15 to 31 years (Mean+/- standard deviation (SD) = 22.76 years+/- 4.61 years).

All these patients had moderate to severe atopic dermatitis inadequately responding to topical and at least one systemic modulators. Amongst topical treatments, topical corticosteroids were prescribed to all 25 patients and topical calcineurin inhibitors were prescribed to 21 of these patients. All of them were previously prescribed with cyclosporin at 3-5 mg/kg body weight for a minimum of 3 months at some point in their disease. Amongst other systemic immunomodulators, 6 had taken oral steroids (usually short courses not more than 6 weeks), 4 had taken oral methotrexate (6-8 months) previously.

Baseline EASI score in these patients varied from 14 to 29; with the mean EASI being 19.48 (SD = 4.16; standard error of the mean (SEM) =0.83). After six months of treatment mean EASI improved to 4.84 (SD = 2.23; SEM = 0.45). 17 patients (68%) achieved EASI 75 (≥75% improvement from baseline) at the end of 6 months of treatment [Figures 1 and 2].

Figure 1

Response of Dupilumab over 6 months demonstrated by EASI and SCORAD

Figure 2

EASI 75 response over 6 months in percentage of total cases

Baseline SCORAD score varied from 27-52; with the mean SCORAD being 37.32 (SD = 6.27; SEM = 1.25). After six months of treatment mean SCORAD improved to 8.04 (SD = 3.68; SEM = 0.74) [Figure 1].

Paired T-tests were done to compare before and after values of both EASI and SCORAD and the in the two-tailed P values were less than 0.001 for both scores, indicating highly significant improvement.

Similarly, paired T-test was done to compare the before (mean = 17.08, SD = 2.81, SEM = 0.56) and after (mean = 6.52, SD = 2.58, SEM = 0.52) values of DLQI. The two-tailed P value was less than 0.0001, indicating significant improvement in the quality of life of the patients treated with dupilumab [Table 1].

Table 1

Evaluation of efficacy of dupilumab with EASI, SCORAD and DLQI scores

	Baseline	1 month	2 months	3 months	4 months	5 months	6 months	Remark
EASI
Mean	19.48	14.32	10.80	8.56	7.08	6.04	4.84	Paired T test done. The two-tailed P value is less than 0.0001. The mean of EASI Before minus EASI after equals 14.64 95% confidence interval of this difference: From 13.23 to 16.05
Standard Deviation	4.16	4.34	3.97	3.68	3.46	2.76	2.23
Range	14-29						2-10
Standard error of Mean	0.83						0.45
SCORAD
Mean	37.32	23.56	18.24	14.28	11.92	10.16	8.04	Paired T test done. The two-tailed P value is less than 0.0001. The mean of SCORAD Before minus SCORAD after equals 29.28 95% confidence interval of this difference: From 27.06 to 31.50
Standard Deviation	6.27	8.00	7.14	6.37	5.98	4.85	3.68
Range	27-52						3-18
Standard error of Mean	1.25						0.74
DLQI
Mean	17.08						6.52	Paired T test done. The two-tailed P value is less than 0.0001. The mean of DLQI Before minus DLQI after equals 10.56. 95% confidence interval of this difference: From 9.86 to 11.26
Standard Deviation	2.81						2.58
Range	13-23						2-11
Standard error of Mean	0.56						0.52

Side effects were minimal, two patients had episodes of conjunctivitis which were treated accordingly in consultation with ophthalmologists. One of the patients complained of facial flushing and erythema and scaling with severe itching over erythematous patches. The patient was given two weeks of itraconazole 200 mg/day dose, with good clearance.

Hyperpigmentation caused by chronic AD were cleared in four patients of ours.

Discussion

Management of moderate to severe AD remained a challenge for physicians. Indian guidelines recommend systemic immunomodulators for severe or refractory AD.[6] To control severe AD a 2-3 week's course of antistaphylococcal antibiotics have long been recommended.[7] The concept is still held as a “skin infection group” of International Eczema Council (IEC) recommended it very recently in which the first author (SD) is a contributor.[8] Even the practice of use of a short course of oral corticosteroid has been recommended by a an expert group of IEC. The first author is a part of this expert group.[9] Among the various systemic therapies cyclosporine, azathioprine, and methotrexate are also been recommended in Indian scenario.[10] All these suggest that there has been a desperate attempt to control moderate to severe AD adequately with whatever treatment option available as of now.

Dupilumab is the first targeted biologic therapy approved by the United States Food and Drug Administration for the treatment of adults with moderate-to-severe AD whose disease is inadequately controlled by topical treatments, or when such treatments are not advisable.[4] The US FDA approval came in March 2017 for its use in patients of 18 years and above. Looking at the safety profile of the drug it was further approved by US FDA for children, 11–17 years in March 2019.[11] Finally it has been further approved by US FDA for its use in children above 6 years of age. This stepwise extension of recommended age range for the use of dupilumab by US FDA speaks volumes of its safety profile along with its efficacy as well.

We present a series of 25 patients (16 male and 9 female) with moderate-to-severe AD from 3 Indian reference institutions, between January 2018 and March 2020. In all patients, skin eruption improved greatly after receiving dupilumab [Figures 3a, b, 4a, b and 5a, b, 6a, b]. Erythema tended to disappear or be alleviated relatively rapidly, whereas chronic lichenified lesions took about 2-3 months to improve.

Figure 3

(a) A 19-year-old girl before the start of treatment. (b) A 19-year-old girl after the start of treatment

Figure 4

(a) A 16-year-old girl before the start of treatment. (b) A 16-year-old girl after the start of treatment

Figure 5

(a) A 13-year-old boy before the start of treatment. (b) A 13-year-old boy after the start of treatment

Figure 6

(a) A 23-year-old male before the start of treatment. (b) A 23-year-old male after the start of treatment

The efficacy of the treatment was evident from rapid improvements in SCORAD and EASI scores in most of our patients and after six months of treatment, there was a significant reduction in the severity scores. After 6 months of treatment, 68% of the patients achieved EASI75, indicating near-complete remission in the majority of our patients. These results were was similar to that shown in clinical trials.[121314]

In some patients, skin manifestations on the trunk and limbs improved faster, while skin manifestation on the face was comparatively refractory to treatment with dupilumab.

Hyperpigmentation caused by chronic AD cleared to a great extent in four patients of ours. This was not previously reported in the literature. Probably because hyperpigmentation is a feature/sequelae of AD in type IV and V skin, hence not reported from the western countries.

Concomitant treatment was prescribed according to clinical decision by the treating. Topical corticosteroids or calcineurin inhibitors were used in 25 patients at baseline, maintaining their use to week 24 in 19 cases. Antihistamine use also diminished from 14 to 6 patients during follow-up. No patients received concomitant systemic therapy.

Dupilumab also had a significant improvement in the quality of life of our patients which was evident from the changes in DLQI scores. Earlier, a randomized, placebo-controlled clinical trial demonstrated profound impact of dupilumab on the quality of life of the patients of AD.[15]

The safety profile was favorable, with two reported cases of mild conjunctivitis. The adverse event of conjunctivitis occurred 4-6 weeks after starting dupilumab. This was positively managed by the ophthalmologist with topical antihistamine eye drops, without dupilumab withdrawal. Similar cases of conjunctivitis were reported in earlier studies, most of these cases were associated with a history of allergic conjunctivitis in past.[16]

We had one patient with facial erythema; the distribution of the lesion was pointing towards a seborrheic dermatitis-like condition. The patient was prescribed oral itraconazole 200 mg daily for two weeks with complete clearance of the lesions. In subsequent months, the facial erythema did not recur. Though rare, similar cases of facial erythema were reported earlier.[17]

No injection-site reactions were reported. No patients have discontinued dupilumab due to serious adverse effects (SAE) as of 31 May 2020.

The value added by this multicenter, retrospective study comes from the necessity of real-world assessment of new treatments addressing AD, as their performance has only been proven in clinical trials. Also, dupilumab is relatively new in India, and till now no Indian data has been available.

The limitations of this study are the retrospective nature of the study, the small sample size, and the short follow-up period. Future studies should prospectively assess the real clinical practice response to dupilumab in a broader population with longer follow-up periods.

Conclusions

We observed significant efficacy, tolerability, and safety profile of dupilumab in Indian patients with AD in a real-world setting, quite similar to that shown in clinical trials in the western populations.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.