Allergic Contact Dermatitits Clinical Trial
Official title:
Anti-IL-17 a New Treatment for Contact Dermatititis
The purpose of this study is to assess the efficacy of anti-IL 17 treatment (secukinumab) in patients with known severe allergic contact dermatitis (ACD).
Purpose The purpose of this study is to assess the efficacy of anti-IL 17 treatment
(secukinumab) in patients with known severe allergic contact dermatitis (ACD).
Background ACD is an immune mediated disease characterized by itching, erythema, vesicles,
thickening and scaly skin, affecting a large part of the population in the world. A review
study from 2007 by Thyssen et al that summarizes studies from North Europe and North America
from 1966-2007 suggests that the prevalence to at least one allergen among these populations
was 21.2 % (range 12.5-40.6%)(1). The incidence of ACD is not static and differs in
countries(1), but in recent years there has been an increasing incidence of ACD caused by an
increasing number of environmental detergents(2, 3). For patients with severe ACD the
disease can be associated with difficulties performing daily activities, loss of sleep and
reduced life quality (DLQI)(4).
ACD is treated with moisturizing creams, topical steroids and in severe cases systemic
steroids, UVB, PUVA, azathioprin or alitretinoin. However, the drugs have severe side
effects and some patients with ACD do not respond to the already existing treatments. New
treatments are therefore highly needed. A group of these patients suffer from severe eczema
often resulting in impared lifestyle and not seldom loss of work(4).
The pathogenesis in ACD is a T-cell mediated delayed type hypersensitivity reaction,
consisting of a sensitization and an elicitation phase (5). In the sensitization phase an
exogen allergen(hapten) is entering the epidermis through a defect skin barrier. The
allergen is presented by the Langerhans cells to CD4+ and CD8+ T-cells in the lymphatic
nodes, which activates and increases the numbers of T-cells. The elicitations phase begins
when the patient once again is in contact with the allergen. The T-cells react with the
allergen and this releases cytokines such as IFN-ɣ followed by skin lesions and
inflammation. The IFN-ɣ is an important inflammatory cytokine, which is produced by CD4+ and
CD8+ T-cells during ACD in humans and mice(6, 7). However, in the last decades studies have
revealed that other inflammatory cytokines, such as IL-17 and IL-22 may be of importance in
the immune response to contact allergens(8-11). IL-17 is produced by T-helper (TH)17 cells,
innate cells as macrophages and dendrit cells and other cell types(12).
In mice both CD4+ and CD8+ T-cells producing IL-17 have been identified(13). A study by
Nakae et al where IL-17 deficient mice were generated and exposed to dinitroflorobenzene and
trinitrochlorobenzene, the mutants had a markedly reduced ear swelling compared to wild-type
mice, this suggesting that IL-17 plays a role in contact allergy (14).
In nickel allergic humans, CD4+ and CD8+ T-cells have been shown to produce IL-17 and an
increasing number of IL-17 producing cells have been found in tissue with eczematous
reaction(8). Our group and others have found nickel-specific Th1 and Th17 cells in
individuals with nickel allergy, but not in healthy controls(8, 9).
Our hypothesis is that since IL-17 appears to be involved in human ACD, anti-IL-17 treatment
(secukinumab) might have a beneficial effect in patients with ACD.
This study will evaluate secukinumab treatment in patients with known allergic contact
dermatitis. The study which is an interventional type will consist of two parts both
performed at Department of Dermato-allergology, Herlev and Gentofte Hospital, University of
Copenhagen, Hellerup, Denmark.
Study 1 Study 1 will include 10 patients with known allergy to nickel, but with no to low
grade of eczema at inclusion.
Before enrollment patients will be screened for eligibility (blood samples (8-10 ml),
Quantiferon TB Gold test, urine test for infection/pregnancy and chest x-ray to ensure that
there is no evidence of infections and/or malignancy)(15).
The patients will then be tested with two standard patch tests with nickel and vehicle at
the upper inner arm to confirm allergy. A photo and a biopsy (4 mm) from the patch test area
will be taken, a clinical examination and a skinfold measure to evaluate the grade of
dermatitis will be performed. The responses will be assessed clinically (at 48 h, 72 h and
day 7) after application and graded as negative (-), doubtful (?+), 1+, 2+, 3+ or 4+ using a
modified version of the International Contact Dermatitis Research (ICDRG) scoring system.
Patients will receive 300 mg secukinumab for s.c. injection (autoinjector) as a single dose,
administered by a nurse at Department of Dermato-allergology, Gentofte Hospital. After one
week the patients will be retested with nickel, photos and a biopsy from the patch test area
will be taken, a clinical examination and a skinfold measure will be performed to evaluate
the efficacy of secukinumab.
The study comprises 8 visits in total including screening
Study 2 Study 2 will include 10 patients with more than two known allergic contact allergies
and clinically moderate to severe (PGA≥3) allergic contact dermatitis at inclusion. Patients
will be treated open labeled for 8 weeks.
Before enrollment patients will be screened for eligibility (blood samples (20-25 ml),
Quantiferon TB Gold test, urine test for infection/pregnancy and chest x-ray to ensure that
there is no evidence of infections and/or malignancy)(15). Clinical degree of dermatitis
will be evaluated by using Physician Global Assessment score (PGA) as an instrument for the
severity of eczema with the following PGA levels: clear, almost clear, mild, moderate,
severe. Dermatology Life Quality Index (DLQI, appendix 1) and Patient's Global Assessment
score (PtGA, appendix 2) will be measured and photos of the eczema will be taken.
When test results from baseline clinical procedures are ready (7-14 days from screening
visit) patients eligible for inclusion will have a biopsy taken (4 mm, at eczema), PGA, PtGA
and DLQI will be performed and photos of eczema will be taken. This will be considered as
baseline. Afterwards treatment with 300 mg secukinumab for s.c. injection (autoinjector)
will initiate with the first dose administered by a nurse at Department of
Dermato-allergology, Gentofte Hospital. During the first four weeks patients will be treated
with secukinumab once a week. After this period secukinumab will be administered once a
month with last dose given at week 8. All doses of secukinumab besides the first dose will
be self-administered by the patients.
Two and four weeks from baseline another biopsy will be taken, PGA, PtGA and DLQI will be
performed and photos of eczema will be taken to evaluate the efficacy of secukinumab. At
week 4 another blood sample (12 ml) will be taken (cytokine level (IFN-ɣ and IL-17) will be
evaluated) Eight and twelve weeks from baseline, PGA, PtGA and DLQI will be performed and
photos will be taken to evaluate the efficacy of secukinumab. A follow up visit will be
performed 16 weeks from baseline where relapse, PGA, PtGA, DLQI and safety during the
treatment free weeks will be explored.
The study comprises 7 visits in total including screening
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Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment