Primary Objectives- To characterize the dermal immune response of healthy volunteers following a UV-B skin challenge- To characterize the dermal immune response of CLE patients following a UV-B skin challenge on non-lesional skin- To evaluate the…
ID
Source
Brief title
Condition
- Epidermal and dermal conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
- To characterize the dermal immune response of healthy volunteers following a
UV-B skin challenge
- To characterize the dermal immune response of CLE patients following a UV-B
skin challenge on non-lesional skin
- To evaluate the test-retest variability of the UV-B challenge in healthy
volunteers and CLE patients
Secondary outcome
- To evaluate disease-related characteristics and biomarkers in patients with
CLE compared to healthy volunteers
- To evaluate time-related changes in disease-related characteristics in
patients with CLE
Background summary
Cutaneous lupus erythematosus (CLE) is an autoimmune disease that can occur
isolated to the skin or as a manifestation of Systemic Lupus Erythematosus
(SLE) (Stannard et al., 2016). Subtypes of CLE, which differ in lesion
morphology and histopathology, include acute cutaneous LE (ACLE), subacute
cutaneous LE (SCLE), and chronic cutaneous LE (CCLE). CCLE can be further
subdivided into various subtypes including (but not limited to) cutaneous
discoid LE (CDLE) and LE profundus (LEP).
The pathogenesis and pathophysiology of CLE is not fully understood. The
current concept regarding the onset of the disease comprises a genetic
background predisposing to CLE triggered by factors such as UV light, which
leads to cellular stress and eventually to the release of DNA components in
keratinocytes (Fetter et al., 2022). Activation of both Toll-like receptor
(TLR)-dependent and TLR-independent inflammatory signalling cascades leads to
increased expression of several cytokines, in particular type I interferon
(IFN). Type I interferon mediates increased expression of proinflammatory
chemokines via the JAK-STAT pathway, leading to recruitment of cells, release
of cytokines and a chronic reactivation of innate immune pathways.
The UV-B *sun burn* model is an inflammatory pain model in which erythema is
induced on the skin by radiating the skin with UV-B light in a well-controlled
and reproducible manner. UV-B exposure drives an increase in skin perfusion,
followed by infiltration of immune cells into the skin. CHDR has applied this
model frequently in the field of inflammatory pain studies. UV-B causes
keratinocyte apoptosis by damaging DNA via strand breaks and pyrimidine dimer
formation. In addition, UV-B induces immunologic function and attracting of
inflammatory cells including IL-1, TNFa, ICAM-1 and histocompatibility II
molecules (e.g. HLA-DR) (Kim et al. 2013).
UV provocation in patients with SLE and/or CLE has been reported frequently in
literature to study photosensitivity. The last comprehensive literature review
was performed by Kim and Chone (2013) summarizing more than 700 patients and up
to a dose of 2xMEDx6 days. Minimal side effects were reported in a large
multicenter trial *Photoprovocation in cutaneous lupus erythematosus: a
multicenter study evaluating a standardized protocol of 1.5 MED*, Kuhn et al.
2011, where a general good tolerability was observed when a 4.5 cm2 section of
skin was irradiated with 1.5x MED for a total of three times over three
consecutive days.
Although there are some studies investigating the inflammatory response of the
skin to UV-B, the in-depth characterization of the immune response in healthy
volunteers as well as validation in a patient cohort with the purpose of
developing a rapid inflammatory model for drug development programs is still
lacking.
Therefore, the objective of this phase 0 study is to characterize the dermal
immune response of healthy volunteers and CLE patients following a UV-B skin
challenge on non-lesional skin compared to healthy volunteers, for later
integration into a phase 1 proof-of-mechanism study with a novel
immunomodulatory agent.
Study objective
Primary Objectives
- To characterize the dermal immune response of healthy volunteers following a
UV-B skin challenge
- To characterize the dermal immune response of CLE patients following a UV-B
skin challenge on non-lesional skin
- To evaluate the test-retest variability of the UV-B challenge in healthy
volunteers and CLE patients
Secondary Objectives
- To evaluate disease-related characteristics and biomarkers in patients with
CLE compared to healthy volunteers
- To evaluate time-related changes in disease-related characteristics in
patients with CLE
Study design
This is a single-center study in which 10 healthy volunteers and 6 cutaneous
lupus patients will be included to characterize the dermal immune response
following a UV-B challenge. After 5 healthy volunteers completed challenge
period 1, an interim analysis will commence to determine the optimal time point
for skin biopsy sampling focusing on the type I interferon response. This time
point will be implemented in the patient part.
Healthy volunteers
After the screening visit, in which the minimal erythema dose (MED) will be
determined, the skin of the upper back will be challenged with two-times MED
UV-B irradiation on three 1cm2 squares on the back in challenge period 1. Skin
punch biopsies of 4mm will be taken 3h, 6h and 24h post challenge. The site
that will be biopsied 24h post challenge will serve as imaging site to
characterize the inflammatory response following UV-B irradiation with several
non-invasive imaging tools. Imaging will also be performed on unchallenged skin
as control. Additionally, one control biopsy will be taken from unchallenged
skin of the upper back before the challenge at day 1. Two weeks after the first
challenge period, the second challenge period will commence in which one 1cm2
square on the back will be challenged with two-times MED UV-B irradiation and
biopsied 24h after the challenge to test repeatability. In total, five skin
punch biopsies will be taken from healthy volunteers.
CLE patients
After the screening visit, in which the MED will be determined, the skin of the
upper back will be challenged with two-times MED UV-B irradiation on one 1cm2
square on the back. This site will be biopsied at the optimal time point
determined after an interim analysis of data of five healthy volunteers. Two
weeks later, the same challenge will be performed to determine test-retest
variability. The inflammatory response following UV-B irradiation will also be
characterized with several non-invasive imaging tools. As control, imaging will
also be performed on unchallenged skin. One control biopsy will be taken from
unchallenged skin of the upper back during the first challenge period.
In total, three skin punch biopsies will be taken from the CLE patients.
Study burden and risks
Benefit
No medical benefit can be expected for the participants during the study.
Risk assessment
UV irradiation from sunlight is associated with an increased incidence of skin
cancer. UV irradiation contains a spectrum of wavelengths with UV-B being one
of the risk factors for skin cancer. The UV-B wavelength range used in this
study is the narrow band (NB) range 310-315nm, which is also used for
phototherapy of skin conditions such as psoriasis. In general, UV-B
phototherapy is a very safe treatment modality [Lee, 2005]. In a large study
aiming to define the long*term carcinogenic risk of NB*UV-B treatment in
humans, no significant association was found between NB*UV-B treatment and
basal or squamous cell carcinomas, or melanoma [Hearn, 2008]. Participants with
pre-existing risk factor for skin cancer will be excluded.
The UV-B test may induce post-inflammatory hyperpigmentation (PIH) in some
cases [Siebenga, 2019]. Typically, at centres performing the UV-B inflammatory
test, 3xMED (Minimum Erythemal Dose) of UV-B irradiation is applied to induce
sensitisation, however, long-lasting PIH has been associated with 3xMED. As
risk mitigation, participants with Fitzpatrick skin type IV, V or VI will be
excluded. Dose of UV irradiation will be at max 2xMED. The potential occurrence
of hyperpigmentation will be carefully monitored. Before study participation,
study participants will be thoroughly informed the potential risk of PIH at the
UV irradiation sites. CHDR has run multiple UV-B challenge studies over the
last 10 years, without any safety concerns. In only one of these studies, the
UV-B challenge was combined with a second inflammatory challenge. In the
present study, it could be argued that this is also the case: biopsies will be
collected from UV-B-inflamed skin. The biopsy will drive a wound healing
response comprising an inflammatory component. It is unknown whether the biopsy
procedure on UV-B-inflamed skin increases the risk for PIH. However, based on
in-house historical data CHDR has no indications for this.. In the public
domain, there are no reports of punch biopsy-driven PIH that the investigators
are aware of.
UV provocation in patients with SLE and/or CLE has been reported frequently in
literature to study photosensitivity. The last comprehensive literature review
was performed by Kim and Chone (2013) summarizing more than 700 patients and up
to a dose of 2xMEDx6 days. Minimal side effects were reported in a large
multicenter trial *Photoprovocation in cutaneous lupus erythematosus: a
multicenter study evaluating a standardized protocol of 1.5 MED*, Kuhn et al.
2011, where a general good tolerability was observed when a 4.5 cm2 section of
skin was irradiated with 1.5x MED for a total of three times over three
consecutive days. The UV-B exposed skin areas in this study will be limited to
1x1 cm squares on the back.
Study procedures
Albeit all study procedures are considered minimal invasive, participants can
experience pain and/or haematoma and in rare cases local infection during and
after a skin punch biopsy and/or venepuncture. For characterization of the
dermal immune response, skin biopsies are indispensable in this study. A skin
punch biopsy can possibly leave a lasting mark on the skin, therefore subjects
with a history of hypertrophic scarring or keloid will be excluded. Biopsies
will be taken in a minimally invasive manner. Since the diameter is only 4 mm
no stitching is necessary.
Zernikedreef 8
Leiden 2333CL
NL
Zernikedreef 8
Leiden 2333CL
NL
Listed location countries
Age
Inclusion criteria
Eligible healthy volunteers must meet all the following inclusion criteria at
screening:
1. Signed informed consent prior to any study-mandated procedure.
2. Male or female subjects,18-65 years of age at the time of signing informed
consent; in general, stable good health as per judgement of the investigator
based upon the results of a medical history, physical examination, vital signs,
ECG, and laboratory assessments performed at screening. Repeated laboratory
testing may be performed at the discretion of the clinical investigator.
3. Body mass index (BMI) > 18.0 and < 32.0 kg/m2.
4. Fitzpatrick skin type I-III (Caucasian).
5. No clinically significant skin disease as judged by the investigator.
6. No history of hypertrophic scarring or keloid.
7. Subject is willing to refrain from application of any topical product (e.g.,
ointments, cream or washing lotions) on the skin 24 hours prior to every study
visit day.
8. Subject is willing to refrain from any direct sun contact to the area being
challenged (back) for the duration of the study.
9. Subject has the ability to communicate well with the investigator in the
Dutch language and is willing to comply with the study requirements.
Eligible CLE patients must meet all the following inclusion criteria at
screening:
1. Signed informed consent prior to any study-mandated procedure.
2. Male or female CLE patients, 18-65 years of age at the time of signing
informed consent; in general, stable good health as per judgement of the
investigator based upon the results of a medical history, physical examination,
vital signs, ECG, and laboratory assessments performed at screening. Repeated
laboratory testing may be performed at the discretion of the clinical
investigators.
3. Body mass index (BMI) > 18.0 and < 35.0 kg/m2.
4. Fitzpatrick skin type I-III (Caucasian).
5. Patient has the ability to communicate well with the investigator in the
Dutch language and is willing to comply with the study requirements.
6. Subject is willing to refrain from application of any topical product (e.g.,
ointments, cream or washing lotions) on the skin 24 hours prior to every study
visit day.
7. Subject is willing to refrain from any direct sun contact to the area being
challenged (back) for the duration of the study
8. Participants must have a diagnosis of CLE that fulfils the following:
* Confirmed diagnosis by clinicopathological correlation.
* Receiving one of the following treatments for CLE (stable for a
minimum of 8 weeks):
* None
* Hydroxychloroquine
* Methotrexate
* Topical corticosteroids (for the target lesion there will be a wash
out of 2 weeks before the first challenge period)
Exclusion criteria
Eligible healthy volunteers must meet none of the following exclusion criteria
at screening:
1. (History of) immunological abnormality (e.g., immune suppression by
medication, auto-immune disease, auto-inflammatory disease) that may interfere
with study objectives, in the opinion of the investigator.
2. History of skin cancer (basal cell carcinoma, squamous cell carcinoma,
melanoma);
3. Diagnosis of systemic lupus erythematosus (SLE) according to the EULAR-ACR
criteria (2019) or substantial indication for systemic involvement.
4. Have any current and/or recurrent clinically significant skin condition,
including tattoos, in the skin area of interest (back).
5. Antibiotic use, operation, or intervention by surgeon/dentist within one
month before Day 1.
6. Positive hepatitis B surface antigen (HbsAg), hepatitis C antibody (HCV ab),
or human immunodeficiency virus antibody (HIB ab) at screening.
7. Participation in an investigational drug study within 3 months prior to
screening or more than 4 times a year.
8. Loss or donation of blood over 500mL within three months prior to
screening.
9. The use of any medication within 28 days prior to Day 1 (apart from the
allowed CLE-medication in patients), if the investigator judges it may
interfere with the study objectives.
10. History of alcohol abuse or consumption exceeding 5 standard drinks per day
on average within 3 months of screening. Alcohol consumption will be prohibited
from at least 24 hours preceding each study visit.
11. Positive urine test for drugs or history of drug abuse at screening. Urine
drug test may be repeated at the discretion of the investigator.
12. Pregnant, a positive pregnancy test, intending to become pregnant during
the study conduct, or breastfeeding.
13. (A history of) any clinically significant medical condition, factor or
abnormality that might interfere with study conduct or interpretation, as
judged by the investigator.
14. A minimal erythema dose (MED) higher than 355 mJ/cm2 at screening.
15. Any active or chronic and/or uncontrolled condition that, in the opinion of
the investigator, may influence study conduct or interpretation.
Eligible CLE patients must meet none of the abovementioned and following
exclusion criteria at screening:
1. Presence of a relevant skin infection or disease in the target areas other
than the observational disease (CLE), inclusively, but not limited to atopic
dermatitis, psoriasis vulgaris and dermatomycosis.
2. Having received treatments for CLE or any other disease within the following
intervals prior to Day 1:
a. < 2 weeks for topical treatment, e.g., corticosteroids at target
area(s).
b. < 6 weeks for systemic therapy with immunosuppressive agents (other
than hydroxychloroquine).
c. < 12 weeks for biologics.
d. < 8 weeks procedure or surgery in or close to the target areas.
e. < 3 months for chemotherapeutical treatment.
3. Low complement (C3 and/or C4) levels at screening (< ULN).
4. Positive ANA and anti-dsDNA and/or anti-SM antibodies at screening.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL85040.056.23 |