The Role of Interleukin-1 Beta Targeted Therapy for Patients Suffering From Allergic Contact Dermatitis: A Randomized Controlled Trial With Anakinra vs. Placebo
Phase: PHASE3
Conditions: Allergic Contact Dermatitis
Sponsor: Herlev and Gentofte Hospital

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Project protocol  
1 
 
2 
Title: The role of interleukin-1 beta targeted therapy for patients suffering from allergic contact 
3 
dermatitis: A randomized controlled trial with anakinra vs. placebo. 
4 
 
5 
Investigators: Kelvin Yeung, MD, Anders Boutrup Funch, MSc, Julie Friis Weber, Bsc, Claus 
6 
Zachariae, MD, DMSc, Carsten Geisler, MD, PhD, DMSc, Charlotte Menne Bonefeld, MSc, 
7 
PhD, DMSc, Lone Skov, MD, PhD, DMSc 
8 
 
9 
Sponsor: 
10 
Lone Skov, MD, PhD, DMSc. 
11 
Herlev and Gentofte Hospital 
12 
Department of Dermatology and Allergy 
13 
Gentofte Hospitalsvej 15, 2900 Hellerup 
14 
 
15 
GCP-monitor: 
16 
The GCP-unit at University of Copenhagen 
17 
Frederiksberg Hospital 
  
Nordre Fasanvej 57 
  
Skadestuevej 1, parterre 
 
2000 Frederiksberg 
  
 
18 
Initiation date: August 2022 
19 
Duration of study: The study is expected to last no longer than two years from approval.  
20 
Eudract-number: 2021-004750-39 
21 
NCT Number: NCT05498467 
22 
Study drug: Anakinra 
23 
 
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Purpose: Assessing the efficacy of anti-IL-1 treatment in patients with known nickel allergy. 
25 

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1. STUDY BACKGROUND AND RATIONALE 
26 
1.1. Background 
27 
Allergic contact dermatitis (ACD) is an inflammatory skin disease caused by cutaneous contact 
28 
with an allergen inducing a cell-mediated type 4 hypersensitivity immune reaction.  
29 
ACD is clinically characterized by erythema, pruritus, edema, blistering, thickening, and scaling 
30 
skin. The estimated prevalence of ACD to at least one contact allergen in North America and 
31 
North Europe is 21.2%(1), and in recent years the incidence of ACD has been increasing in 
32 
correlation with an increasing number of environmental detergents(2,3).  
33 
 
34 
ACD can affect the quality of life of patients by causing discomfort, social and occupational 
35 
limitations(4,5). The current treatment regimen of ACD consists of identification and elimination 
36 
of the eliciting contact allergen in combination with topical steroids and moisturizing creams. 
37 
Phototherapy and photochemotherapy can be complementary treatments for ACD patients 
38 
resistant to topical steroid treatment. In more severe cases of ACD systemic 
39 
immunosuppressant therapy may be needed such as glucocorticoids, disease-modifying anti-
40 
rheumatic drugs, and vitamin A derivatives. Systemic therapy has serious side effects and not 
41 
all patients with ACD respond well to the current treatments available, therefore there is a need 
42 
for exploring alternative forms of treatment for ACD(6).  
43 
 
44 
A specific subset of epidermal-resident memory CD8+ T (TRM) cells are generated locally in skin 
45 
exposed to contact allergens(7). The TRM cells are rapidly activated by re-exposure to the 
46 
specific allergen. Upon reactivation, TRM cells produce IFN-γ and IL-17A. The presence of TRM 
47 
cells correlates with an increased epidermal level of IL-1β during the challenge-response to 
48 
contact allergens, which seems to be mediated by the production of IFN-γ and IL-17A by the 
49 
TRM cells(7). Within the epidermis, both keratinocytes and Langerhans cells (LC) can produce 
50 
IL-1β. A central role of IL-1β in the response to contact allergens has been shown in numerous 
51 
studies, where defects in the IL-1 signaling pathway or blocking of IL-1 resulted in a decreased 
52 
challenge-response to contact allergens(8–13). IL-1β is involved in many different biological 
53 
functions central to immune responses to contact allergens. These include induction of the 
54 
production of various cytokines and chemokines by skin cells, up-regulation of MHC-II on 
55 
Langerhans cells (LC), and initiation of the migration of LC from the epidermis to the draining 
56 
lymph nodes(14,15). IL-1β potently increases the capacity of both dermal αβ and γδ T cells to 
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release IL-17A (16). However, it is not known if IL-1β plays a role in the maintenance and 
58 
function of epidermal TRM cells.  
59 
The recombinant IL-1 receptor antagonist anakinra is a well-explored drug and has been tested 
60 
in numerous rheumatic diseases such as rheumatoid arthritis, Still’s disease, ankylosing 
61 
spondylitis, psoriatic arthritis, systemic lupus erythematosus, and osteoarthritis(17). The RCT 
62 
described here will determine the effectiveness of anakinra in the treatment of ACD. A search of 
63 
the Controlled Trials Register indicates there are no current studies investigating anakinra as a 
64 
treatment for ACD.  
65 
1.2 Details of Investigational Medicinal Product 
66 
1.2.1 Description 
67 
This study will investigate the effects of anakinra (ATC code L04AC03) on the immune response 
68 
in humans with ACD. The medication of interest is labeled and used for the treatment of 
69 
rheumatoid arthritis and Still’s disease. Trained personnel at The Department of Dermatology 
70 
and Allergy, Herlev Gentofte Hospital will inject participants in the treatment group with the 
71 
medication subcutaneously. The brand of medication used: 
72 
• 
Kineret®, Swedish Orphan Biovitrum, 100 mg/0.67 mL, injectable fluid for s.c. 
73 
administration. 
74 
The pharmaceutical company will be notified about the trial. More details regarding the chemical 
75 
and pharmacological properties of the study drug can be found in the Summary of Product 
76 
Characteristics. 
77 
The control group will receive placebo in the form of sterile isotonic saline water injections. 
78 
• 
Sodium chloride Fresenuis Kabi 9 mg/ml 
79 
1.2.2 Packaging and Labelling 
80 
The study drug and placebo will be specially packaged and labeled by Region Hovedstaden’s 
81 
pharmacy and they will be the responsible unit for distribution of the study drug and placebo. 
82 
The administering personnel are unblinded to treatment but participants and investigators are 
83 
blinded to the treatment allocation. 
84 
1.2.3 Storage and administration 
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The study drug will be stored as per the manufacturer’s instructions at The Department of 
86 
Dermatology and Allergy, Herlev Gentofte Hospital. The clinical trials personnel at the hospital 
87 
will administer the medication and keep detailed administration records. Double checking of 
88 
medication will be performed. 
89 
1.2.4 Known Side Effects 
90 
Known side effects to anakinra are listed below: 
91 
>10%: Headache, local reaction at the site of injection 
92 
1-10%: Serious infections, neutropenia 
93 
0.1-1%: Allergic reactions (including angioedema and anaphylaxis) 
94 
 
95 
2. STUDY PURPOSE AND OBJECTIVES 
96 
2.1. Purpose 
97 
The purpose of this study is to characterize the clinical effect of inhibiting IL-1β in ACD, and to 
98 
investigate the role of IL-1β in the maintenance and function of epidermal TRM cells. We expect 
99 
that this knowledge can lead to the development of more specific treatments and potential cures 
100 
for patients with ACD.  
101 
2.2. Hypothesis 
102 
IL-1β is a key cytokine in immune responses to contact allergens. Epidermal-resident memory 
103 
CD8+ T (TRM ) cells lead to an increased production of IL-1β in skin cells upon challenge of the 
104 
skin with contact allergens. However, the effect of IL-1β on epidermal TRM cells is not known. 
105 
We hypothesis that a positive feedback loop exists where IL-1β from skin cells boost the 
106 
epidermal TRM cells to ensure their maintenance and increase their pathological effector function 
107 
in form of production of IFN-γ and IL-17A production that again stimulate the skin cells to 
108 
produce IL-1β.  
109 
2.3. Primary Objective 
110 
• 
To assess if there is a clinical difference in severity of ACD in participants treated with 
111 
anakinra compared to placebo measured by different scoring systems for ACD. 
112 
2.4. Secondary Objective 
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• 
To assess if there is a decrease in TRM function and inflammation after treatment with 
114 
anakinra compared to the control group, using following methods: flow cytometry, single cell 
115 
RNA sequencing, immunohistochemistry, ELISA, digital spatial profiling, and qPCR.  
116 
3. STUDY DESIGN 
117 
3.1. Overview 
118 
This study is a prospective. two-arm, double-blinded, parallel group, randomized controlled 
119 
clinical trial. Participants with known nickel allergy, but with minimal signs of dermatitis, will be 
120 
recruited to the study until 20 has completed the study. Before enrollment, participants will be 
121 
screened for eligibility (blood samples (20-25 ml), Quantiferon TB Gold test, and urine test for 
122 
infection/pregnancy and chest x-ray to ensure that there is no evidence of infections and/or 
123 
malignancy). Participants will be blinded to treatment and randomly allocated into two equally 
124 
sized groups. At baseline (day 0) all participants will be exposed to a two-chamber patch test on 
125 
the lower part of their back, with one chamber containing 5 % NiCl2 in petrolatum and one 
126 
chamber containing petrolatum. The patch testing will be repeated twice at the exact same skin 
127 
area, with an interval of 21 days between tests (day 21 and 42). One group (the control group) 
128 
will be treated with placebo (saline water) and the second group (the treatment group) will be 
129 
treated with anakinra before and during the second patch test (day 21) for six consecutive days 
130 
(day 20 to 25). Skin biopsies will be collected with 4 mm punch biopsies right before and 48 
131 
hours after the third patch test (day 42 and 44). The wounds will be closed with non-absorbable 
132 
sutures, and stitches will be removed after eight to ten days.  
133 
The study will be comprised of 12 visits in total, including screening. 
134 
3.2. Outcome Measures 
135 
3.2.1. Primary Outcome Measure 
136 
Photographs and clinical evaluation of the skin patch reactions will be performed on-site and 
137 
blinded, using the Investigators Globals Assessment (IGA) and International Contact Dermatitis 
138 
Research Group (ICDRG) scoring systems as instruments for classifying the severity of 
139 
dermatitis. Patient reported outcomes will include Patient’s Global Assessment Score (PtGA). 
140 
Treatment effect will be defined as a difference in score between the two groups on the scoring 
141 
systems used. 
142 
3.2.2. Secondary Outcome Measure 
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From each group, blood and biopsies from seven individuals will be used for single cell RNA 
144 
sequencing (sc-RNAseq), and/or digital spatial profiling. Skin biopsies from the remaining three 
145 
individuals will be used for immunohistochemistry, flowcytometry (staining with anti-CD3, anti-
146 
CD8, Ki67, anti-IL-1β) and/or qPCR (IFN-y, IL-17A and IL-1B). Treatment effect will be defined 
147 
as a reduction in number of T-cells, cytokines and proliferative markers in the treatment group 
148 
compared to placebo.  
149 
3.3. Stopping Rules and Discontinuation 
150 
The Department of Dermatology and Allergy, Herlev and Gentofte Hospital can discontinue the 
151 
trial at any time for failure to meet expected enrolment goals, for safety or any other 
152 
administrative reasons. Participants and The Regional Committee on Health Research Ethics 
153 
will be informed in given case. The following may result in the trial being terminated 
154 
• 
Major safety concerns. 
155 
• 
Insurmountable issues with trial conduct (e.g. poor recruitment, loss of resources). 
156 
3.4. Randomization and Blinding 
157 
3.4.1. Randomization 
158 
The randomization will be based on a computer-generated code using random permuted blocks 
159 
of varying size or by sealed envelope. Access to the sequence will be confined to Region 
160 
Hovedstadens Pharmacy. Participants will be allocated in a 1:1 ratio to the anakinra and 
161 
placebo treatment arms. The sequence of treatment allocations will be concealed until 
162 
interventions have all been assigned and recruitment, data collection, and all other trial-related 
163 
assessments are complete. 
164 
3.4.2. Blinding 
165 
The investigators and assessors will be blinded to treatment allocation until the results of the 
166 
outcome measurements are recorded. Only the administering personnel will be unblinded to 
167 
treatment allocation and know the allocation sequence. Trial participants will also be blinded to 
168 
treatment allocation until the end of trial.  
169 
3.5. Trial Management 
170 
The trial and all clinical procedures will be conducted at The Department of Dermatology and 
171 
Allergy, Herlev and Gentofte Hospital. All laboratory analyses of tissue specimens will be 
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analyzed at The LEO Foundation Skin Immunology Research Center, University of 
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Copenhagen. 
174 
3.6. Duration of Study and Participant Involvement 
175 
3.6.1. Duration of Participant Involvement in the Study 
176 
All participants will be in the study for two months, and the study will be comprised of 12 visits in 
177 
total ranging from 30 minutes to an hour per visit. 
178 
3.6.2. Duration of the Study 
179 
Recruitment will commence on Februar 2022 and is planned to continue until twenty participants 
180 
are recruited and randomized. The study is expected to last no longer than two years. 
181 
3.6.3. End of the Study 
182 
The end of study is defined as the last participant’s last visit. 
183 
3.7. Selection, Recruitment and Withdrawal of Participants 
184 
3.7.1. Participants 
185 
Participants over the age of 18 and with Fitzpatrick skin type 1 to 4 with known nickel allergy, 
186 
but with minimal signs of dermatitis, will be enrolled to the study. 
187 
3.7.2. Setting 
188 
The Department of Dermatology and Allergy, Herlev and Gentofte Hospital will be the primary 
189 
recruitment site. 
190 
3.7.3. Inclusion criteria 
191 
• 
Aged at least eighteen years old. 
192 
• 
Able to provide written informed consent. 
193 
• 
Have at least a ?+ reaction on the ICDRG scoring system when patch tested with nickel on 
194 
the lower back. 
195 
• 
Fitzpatrick skin type 1-4. 
196 
• 
Able to speak and understand Danish 
197 
3.7.4. Exclusion criteria 
198 
The following criteria will exclude the participants from the study: 
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Received any topical immunomodulating or immunosuppresive treatment on the lower back 
200 
two weeks prior, or applied crème/lotion on the lower back 24 hours prior to day 0 
201 
• 
Received systemic immunomodulating or immunosuppressive treatment four weeks prior to 
202 
day 0 
203 
• 
Any skin lesions at the area of interest such as nevi, scar tissue or pigment changes. 
204 
• 
Dermatitis and/or infection on their lower back 
205 
• 
Recent (3 months or less) administration of a live virus vaccine. 
206 
• 
Women of childbearing potential who are not taking adequate contraception or who are 
207 
pregnant, plan to become pregnant during the study duration or lactating.  
208 
• 
Taking part in any other intervention study. 
209 
• 
Has any other condition which would, in the Investigator’s opinion, deem the patient 
210 
unsuitable for participation in the study (e.g. condition requiring long term or frequent oral 
211 
steroid use). 
212 
• 
Presence of any condition or use of any medication which precludes the use of the study 
213 
drug. 
214 
• 
Allergy to any of the ingredients in the drug. 
215 
3.7.5. Retention of participants 
216 
To help retain participants in the study, in addition to being able to speak to the investigator, 
217 
participants will be able to telephone the investigator if they wish to discuss any aspect of the 
218 
study. For medical queries, the participant will be directed to a medical member of staff. 
219 
3.7.6. Withdrawal of participants from treatment and the study 
220 
Participants may be withdrawn from the trial either at their own request or at the discretion of the 
221 
Investigator. The participants will be made aware that this will not affect their future care. 
222 
Participants will be made aware (via the information sheet and consent form) that should they 
223 
withdraw the data collected to date may still be used in the final analysis. The reason for and 
224 
date of withdrawal will be recorded on the case report form. All participants who withdraw from 
225 
study treatment will be followed up for two weeks providing they have not withdrawn consent.  
226 
Participants may be withdrawn from the study for the following reasons:  
227 
• Withdrawal of consent.   
228 
• Later found to be ineligible. 
229 
3.7.7. Recruitment 
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The Department of Dermatology and Allergy, Herlev and Gentofte Hospital will recruit 20 
231 
participants with known nickel allergy by reviewing patient journal files and/or by advertisements 
232 
in newspapers, bulletin boards, social media platforms or relevant webpages. Recruitment of 
233 
participants will continue until 20 participants with a positive nickel allergy test (at least a +2 
234 
reaction on the ICDRG scoring system) have been included and completed the study. Prior to 
235 
enrollment participants will be screened for acute, chronic or recurring infections, malignant 
236 
diseases, latent or prior history of tuberculosis, granulocytopenia or conditions that increase the 
237 
risk of infection. 
238 
 
239 
3.7.8. Informed consent 
240 
All participants will provide written informed consent. Informed consent will be obtained from 
241 
each participant before they undergo any study procedure. Participants will be given details of 
242 
the study verbally in an undisturbed environment. Prior to the visit participants will be informed 
243 
that they have the right to bring an assessor of their choosing to the visit. If the participant is 
244 
interested in taking part they will be given time to read the full Participant Information Leaflet 
245 
and the investigator will answer any questions. Participants are allowed to bring an assessor 
246 
and to have a sufficient period of reflection of at least 24 hours and will be given an opportunity 
247 
to ask questions before signing the consent declaration. If participants wish, they can be 
248 
included in the study during the first visit. Those wishing to participate will be required to sign a 
249 
consent form before any study procedures are carried out.  Participants will be randomised to 
250 
receive one of two treatments. Participants will be reminded that they are free to withdraw their 
251 
consent at any time. Should there be any subsequent amendment to the final protocol, which 
252 
might affect a participant’s participation in the trial, continuing consent will be obtained using an 
253 
amended Consent form, which will be signed by the participant. 
254 
3.7.9 Informed Consent and Participant Information  
255 
The process for obtaining participant informed consent will be in accordance with the REC 
256 
guidance, and Good Clinical Practice (GCP) and any other regulatory requirements that might 
257 
be introduced.  
258 
The investigator or designee will discuss the study with the participant and also give them a 
259 
copy of the Participant Information Leaflet which will contain all the details of the study. There 
260 

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will be opportunity for the participant to ask questions about the study and the investigator or 
261 
designee will ensure the questions are fully answered.  
262 
The investigator or their nominee and the participant shall both sign and date the Informed 
263 
Consent Form before the person can participate in the study. The original will be kept in the 
264 
Investigator Site File, one copy given to the participant and a copy will be retained in the 
265 
participant’s hospital records.  
266 
The decision regarding participation in the study is entirely voluntary. The investigator or their 
267 
nominee shall emphasize to them that consent regarding study participation may be withdrawn 
268 
at any time without penalty or affecting the quality or quantity of their future medical care, or loss 
269 
of benefits to which the participant is otherwise entitled. No trial specific interventions will be 
270 
done before informed consent has been obtained.  
271 
The investigator will inform the participant of any relevant information that becomes available 
272 
during the study, and will discuss with them, whether they wish to continue with the study. If 
273 
applicable they will be asked to sign revised consent forms.  
274 
If the Informed Consent Form is amended during the study, the investigator shall follow all 
275 
applicable regulatory requirements pertaining to approval of the amended Informed Consent 
276 
Form by the REC and use of the amended form (including for ongoing participants).  
277 
Informed consent declaration S3 from The National Committee on Health Research Ethics will 
278 
be used.  
279 
 
280 
3.8. Study Treatment and Regimen 
281 
3.8.1. Study Treatment 
282 
At day 20 (week 3) participants will be randomized to receive either: 
283 
 
284 
 
285 
 
286 
Anakinra 100 mg/0,67 ml 
NaCl solution 9 mg/ml 
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Investigator and participants will be blinded to treatment allocation. The study drug and placebo 
287 
will be administered by unblinded personnel. The study drug or placebo will be administered 
288 
subcutaneously for six consecutive days, starting on day 20.  
289 
At any point, if the participant experiences a life-threatening adverse reaction, treatment will be 
290 
terminated. 
291 
 
292 
3.8.2. Rescue Medication 
293 
Use of any systemic or topical immunosuppressant/immune-modulating drugs is strongly 
294 
discouraged to prevent potential systemic effects not related to study intervention. Accidental 
295 
use of immunosuppressant or immune-modulating drugs during the study period will be 
296 
classified as a protocol deviation. 
297 
3.8.3. Prohibited concomitant medication 
298 
The administration of live virus vaccines and any form of immunosuppressive drug is not 
299 
permitted for all participants. Participants should continue to take medications for other 
300 
conditions as normal. However, if it is anticipated that the participant will need a live virus 
301 
vaccine during the intervention phase, they will be ineligible for entry into the study. 
302 
3.8.4. Caution with other concomitant medications 
303 
Concomitant use of other biological pharmaceuticals is not recommended due to an increased 
304 
risk of infection. 
305 
3.8.5. Adherence 
306 
To ensure adherence, designated personnel will administer the study drug. If a participant does 
307 
not adhere to the administration schedule, it will be classified as a protocol deviation. 
308 
3.8.6. Accountability 
309 
Personnel at the Department of Dermatology and Allergy, Herlev and Gentofte Hospital will 
310 
keep detailed records, including participant study number and name, treatment given, batch 
311 
number, expiry date, dose and date of administration. 
312 
3.8.7. Management of blood donation and risk of infection 
313 
During the study period, participants cannot donate blood as blood donors. Administration of the 
314 
study drug will be terminated if a participant gets an infection during the study period.  
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3.9. Study Visit Schedule and Procedures 
316 
3.9.1. Visit Schedule 
317 
The visit schedule ensures proper administration of study drug, and that the relevant data and 
318 
clinical procedures are collected and performed at appropriate time points.  
319 
Procedures, data collection, and drug 
administration 
Day  
0 
(screeni
ng)2 
Day 
2 
 
Day 
3 
Day 
20 
 
Day 
21 
Day 
22 
Day 
23 
Day 
24 
Day 
25 
Day 
42 
Day 
44 
Day 
45 
Clinical diagnosis of nickel allergy 
X 
 
 
 
 
 
 
 
 
 
 
 
Obtain informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Ascertain the participant is eligible for the 
study 
X 
 
 
 
 
 
 
 
 
 
 
 
Collect medical history and demographic 
data 
X 
 
 
 
 
 
 
 
 
 
 
 
Samples taken for routine blood and urine 
tests1 
 
X 
 
 
 
 
 
 
 
 
 
 
Routine chest X-ray 
 
X 
 
 
 
 
 
 
 
 
 
 
Record adverse reactions 
 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Patch testing 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Removal of patch test 
 
X 
 
 
 
 
X 
 
 
 
X 
 
Clinical evaluation of patch test reaction 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical photography 
X 
X 
X 
 
X 
 
X 
X 
 
X 
X 
X 
Collect skin biopsies 
 
 
 
 
 
 
 
 
 
X 
X 
 
Collect blood samples 
 
 
 
 
 
 
 
 
 
X 
X 
 
Give study diary to participant 
X 
 
 
 
 
 
 
 
 
 
 
 
Dispense either anakinra or placebo 
according to randomization schedule 
 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
Start study medication: anakinra or 
placebo 
 
 
 
X 
 
 
 
 
 
 
 
 
Stop study medication: anakinra or 
placebo 
 
 
 
 
 
 
 
 
X 
 
 
 
1Tests will include (but will not be restricted to) full red and white blood cell count, liver function tests, creatinine, HIV, hepatitis B 
320 
and C serology, urea and urine screen.  
321 
2And baseline if the patient wish to participate immediately  
322 
 
323 
3.9.2. Day 0: Screening 
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The initial visit will cover screening for eligibility and baseline assessments. For clarity, the 
325 
screening visit will be described here as one clinic visit. The following procedures will be carried 
326 
out at the screening visit:  
327 
• 
Give the participant information leaflet. Discuss the study and answer any initial 
328 
questions the participant may have. Allow patient sufficient time to consider their 
329 
participation in the study. Discuss the study with the participant further and answer any 
330 
questions about the study.  
331 
• 
Obtain consent from the patient before proceeding with the study.  
332 
• 
Physical examination and confirmation of clinical diagnosis of nickel allergy.  
333 
• 
Check patient meets all eligibility criteria.  
334 
• 
Record relevant medical history and demographic data.  
335 
• 
Give study diary to participant to record self-reported outcome measures, any medical 
336 
problems, health service usage and adherence with study protocol. 
337 
• 
Apply first set of patch tests containing nickel. 
338 
3.9.3. Day 2 and 3 visit 
339 
At the day 2 visit patch tests will be removed and clinical evaluation of patch test reactions 
340 
including photography will be performed. Following procedures will be performed during day 2 
341 
and 3. 
342 
• 
Removal of patch tests. 
343 
• 
Clinical evaluation of patch test reactions.  
344 
• 
Clinical photography of skin sites. 
345 
If positive patch test: 
346 
• 
Take samples for full blood cell count, kidney and liver function tests, plus any others 
347 
that are clinically indicated. Collect sample for urine screen (sediment, protein, hCG and 
348 
glucose). The results of these tests will not be collected or analysed but they should be 
349 
checked by the clinician as per routine practice and any clinically significant findings 
350 
treated accordingly and recorded on the medical history if appropriate.  
351 
• 
Perform routine chest X-ray to exclude any latent infectious disease. 
352 
3.9.4. Day 20 visit 
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The purpose of the day 20 visit is to initiate the study medication treatment and randomize 
354 
participants into the anakinra or placebo group. 
355 
The following procedures will be carried out at the day 20 visit: 
356 
• 
Physicial examination. 
357 
• 
Randomise participant. The participant will be randomised to receive either anakinra or 
358 
placebo.  
359 
• 
Initiate treatment 24 hours prior to the second set of patch tests with nickel chloride. 
360 
3.9.5. Day 21 visit 
361 
At this visit, participants will receive their second dose of study medication and a second set of 
362 
patch tests containing nickel chloride will be applied. 
363 
The following procedures will be carried out at the day 21 visit: 
364 
• 
Clinical evaluation of patch test reactions. 
365 
• 
Administration of the second dose of study medication right before patch testing. 
366 
• 
Application of second set of patch tests containing nickel chloride. 
367 
• 
Record adverse events. 
368 
3.9.6. Day 22 
369 
At this visit, participants will receive their daily dose of study medication. 
370 
The following procedures will be carried out at this visit: 
371 
• 
Administration of study medication. 
372 
• 
Record adverse reactions. 
373 
3.9.7. Day 23 
374 
This visit will comprise of patch test removal, clinical evaluation of patch test reactions and 
375 
administration of the daily dose of study medication. 
376 
The following procedures will be carried out at this visit: 
377 

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• 
Administration of study medication. 
378 
• 
Record adverse reactions. 
379 
• 
Patch test removal. 
380 
• 
Clinical evaluation of patch test reactions. 
381 
• 
Clinical photography. 
382 
3.9.8. Day 24 
383 
At this visit participants will receive their daily dose of study medication and clinical evaluation of 
384 
patch test reactions and clinical photography of skin sites will also be performed. 
385 
The following procedures will be carried out at these visits: 
386 
• 
Administration of study medication. 
387 
• 
Record adverse events. 
388 
• 
Clinical evaluation of patch test reactions. 
389 
• 
Clinical photography. 
390 
3.9.9. Day 25 
391 
This visit will be the last visit where participants receive study medication. 
392 
The following procedures will be carried out at these visits: 
393 
• 
Administration of study medication. 
394 
• 
Record adverse events. 
395 
• 
Stop study medication after administration. 
396 
3.9.6. Day 42, 44 and 45 visits 
397 
The remaining visits are at day 42, 44, 45.  
398 
At day 42, the following procedures will be carried out: 
399 
• 
Clinical evaluation of patch test reactions. 
400 
• 
Application of third set of patch tests containing nickel chloride. 
401 
• 
Collection of blood samples and skin biopsies for analysis. 
402 

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• 
Clinical photography. 
403 
At day 44, the following procedures will be carried out: 
404 
• 
Removal of patch tests 48 hours after application.  
405 
• 
Clinical evaluation of patch test reactions. 
406 
• 
Clinical photography. 
407 
• 
Collection of blood samples and skin biopsies for analysis and closure of wounds. 
408 
• 
Collect the completed study diary and record self-reported outcome measures, medical 
409 
problems, health service usage and adherence with study protocol. 
410 
At day 45, the following procedures will be carried out: 
411 
• 
Clinical evaluation of patch test reactions. 
412 
• 
Clinical photography. 
413 
4. STATISTICS 
414 
4.1. Methods 
415 
The analysis plan and statistical analysis will be carried out by the trial’s investigators. Any 
416 
deviations from the original plan will be documented and justified in the final report.  
417 
The results will be analyzed based on treatment code using a statistical analysis plan finalised 
418 
prior to revealing the coded allocation sequence. Only after the analysis is complete will the 
419 
actual treatment arms corresponding to the treatment codes be revealed. The analysis will be 
420 
conducted by per protocol. 
421 
 
422 
4.2. Sample size 
423 
A total of 20 participants will be recruited to the study (10 per arm). This should be sufficient to 
424 
detect a reduction in clinical score of at least one scoring point at 80% power and 95% 
425 
significance level.  
426 
 
427 
5. ADVERSE EVENTS 
428 
5.1. Definitions  
429 
An adverse event (AE) is any unfavourable and unintended sign, symptom, syndrome or illness 
430 
that develops or worsens during the period of observation in the study.  
431 

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An AE does include a / an:  
432 
1. Exacerbation of a pre-existing illness.  
433 
2. Increase in frequency or intensity of a pre-existing episodic event or condition.  
434 
3. Condition detected or diagnosed after study drug administration even though it may 
435 
have been present prior to the start of the study.  
436 
4. Continuous persistent disease or symptoms present at baseline that worsen following 
437 
the start of the study.  
438 
An AE does not include a / an:  
439 
1. medical or surgical procedure (e.g., surgery, endoscopy, tooth extraction, transfusion); 
440 
but the condition that lead to the procedure is an AE.  
441 
2. pre-existing disease or conditions present or detected at the start of the study that did 
442 
not worsen.  
443 
3. situations where an untoward medical occurrence has not occurred (e.g., 
444 
hospitalisations for cosmetic elective surgery, social and / or convenience admissions).  
445 
4. disease or disorder being studied or sign or symptom associated with the disease or 
446 
disorder unless more severe than expected for the participant’s condition.  
447 
5. overdose of concurrent medication without any signs or symptoms.  
448 
A Serious Adverse Event (SAE) is any adverse event occurring that results in any of the 
449 
following outcomes:  
450 
• 
Death  
451 
• 
life-threatening  
452 
• 
Inpatient hospitalisation or prolongation of existing hospitalisation  
453 
• 
Persistent or significant disability / incapacity  
454 
• 
A congenital anomaly or birth defect in the offspring of a participant  
455 
• 
Other medical events may be considered to be a SAE if they require medical or surgical 
456 
intervention to prevent one of the outcomes listed in this definition.  
457 
All adverse events will be assessed for seriousness, expectedness and causality (not related, 
458 
possibly related, probably related or definitely related). An adverse event whose causal 
459 
relationship to the study drug is assessed by the Chief Investigator as “possible”, “probable”, or 
460 

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“definite” is an Adverse Reaction (AR). If the AR is classed as serious then it is a Serious 
461 
Adverse Reaction (SAR). A distinction is drawn between serious and severe AEs. Severity is a 
462 
measure of intensity whereas seriousness is defined using the criteria above. Hence, a severe 
463 
AE need not necessarily be serious. All adverse events will be recorded and closely monitored 
464 
until resolution, stabilisation, or until it has been shown that the study medication or treatment is 
465 
not the cause. The summary product characteristics for Kineret® will be used as a reference 
466 
document to assess if an AE or SAE is expected or unexpected. 
467 
5.2. Causality  
468 
Not related or unlikely: a clinical event including laboratory test abnormality with temporal 
469 
relationship to trial treatment administration which makes a causal relationship incompatible or 
470 
for which other drugs, chemicals or disease provide a plausible explanation. This will be 
471 
counted as “unrelated” for notification purposes.  
472 
Possible: a clinical event, including laboratory test abnormality, with temporal relationship to 
473 
trial treatment administration which makes a causal relationship a reasonable possibility, but 
474 
which could also be explained by other drugs, chemicals or concurrent disease. This will be 
475 
counted as “related” for notification purposes.  
476 
Probable: a clinical event, including laboratory test abnormality, with temporal relationship to 
477 
trial treatment administration which makes a causal relationship a reasonable possibility, and is 
478 
unlikely to be due to other drugs, chemicals or concurrent disease. This will be counted as 
479 
“related” for notification purposes.  
480 
Definite: a clinical event, including laboratory test abnormality, with temporal relationship to trial 
481 
treatment administration which makes a causal relationship a reasonable possibility, and which 
482 
can definitely not be attributed to other causes. This will be counted as “related” for notification 
483 
purposes.  
484 
An AE whose causal relationship to the study investigational medical product (IMP) is assessed 
485 
by the Chief Investigator as “possible”, “probable”, or “definite” is an Adverse Drug Reaction.  
486 
With regard to the criteria above, medical and scientific judgment shall be used in deciding 
487 
whether prompt reporting is appropriate in that situation.  
488 

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5.3. Reporting of Adverse Events  
489 
Participants will be asked to contact the study site immediately in the event of any significant 
490 
adverse event. The Chief Investigator shall be informed immediately of any reportable serious 
491 
adverse reactions and shall determine seriousness and causality in conjunction with any 
492 
treating medical practitioners.  
493 
In the event of a pregnancy occurring in a trial participant or the partner of a trial participant 
494 
monitoring shall occur during the pregnancy and after delivery to ascertain any trial related 
495 
adverse events in the mother or the offspring. Where it is the partner of a trial participant 
496 
consent will be obtained for this observation from both the partner and her medical practitioner.  
497 
All serious adverse reactions will be recorded and reported to the Danish Medicines Agency 
498 
(DMA) and regional ethics committees (REC) as part of the regular mandatory reports. SUSARs 
499 
will be reported by e-form within the statutory timeframes to the DMA and REC as stated below. 
500 
The Chief Investigator shall be responsible for all adverse event reporting.  
501 
5.4. Suspected Unexpected Serious Adverse Reaction (SUSARs)  
502 
A serious adverse reaction (SAR) that is unexpected (i.e. not a known side effect of the study 
503 
drug) is classed as Suspected Unexpected Serious Adverse Reaction. All SUSARs will be 
504 
reported immediately to the Chief Investigator and will require expedited reporting to the 
505 
authorities as described below.  
506 
The Chief Investigator will:  
507 
• 
Assess the event for seriousness, expectedness and relatedness to the study IMP.  
508 
• 
Take appropriate medical action, which may include halting the trial.  
509 
• 
If the event is deemed a SUSAR, shall, within seven days, complete the CIOMS form 
510 
and send to the DMA.  
511 
• 
Shall inform the REC using the relevant reporting form found on the REC’s web page 
512 
within seven days of knowledge of the event.  
513 
• 
Shall, within a further eight days send any follow-up information and reports to the DMA 
514 
and REC.  
515 
• 
Make any amendments as required to the study protocol and inform the ethics and 
516 
regulatory authorities as required.  
517 

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5.5. Collection of Adverse Event Data  
518 
This study investigates a widely used drug, anakinra, for which the side-effect profile is well 
519 
established. For this reason, only adverse events that are known side-effects will be collected 
520 
(detailed in section 4.2.4, Known side effects) i.e. only adverse reactions will be collected. 
521 
At each mandatory study visit, the investigator will record whether the participant had 
522 
experienced any of the reportable adverse events. The investigator can also record any other 
523 
significant adverse events that are not listed if deemed clinically relevant.  
524 
All available sources of information will be used to collect information on adverse events 
525 
including hospital notes, the participant diary and discussion with the participant. Any adverse 
526 
events reported will be graded according to a modified version of the Common Terminology 
527 
Criteria for Adverse Events v3.0. 
528 
6. Ethics Committee and Regulatory Aspects  
529 
6.1. Ethical and Regulatory Approval  
530 
The trial will not be initiated before the protocol, informed consent forms and participant and 
531 
information sheets have received approval / favourable opinion from the DMA and REC.  
532 
The trial will be conducted in accordance with the ethical principles that have their origin in the 
533 
Declaration of Helsinki, 1996; the principles of Good Clinical Practice, in accordance with the 
534 
Medicines for Human Use Regulations, Statutory Instrument 2004, 1031 and its subsequent 
535 
amendments.  
536 
6.3. Case Report Forms  
537 
Each participant will be assigned a trial identity code number, allocated at randomisation, for 
538 
use on the case report forms (CRFs), other trial documents and the study database. The 
539 
documents and database will also use their initials (of first and last names separated by a 
540 
hyphen or a middle name initial when available) and date of birth (dd/mm/yy).  
541 
CRFs will be treated as confidential documents and held securely in accordance with 
542 
regulations. The investigator will make a separate confidential record of the participant’s name, 
543 

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date of birth, CPR-number, and Participant Trial Number, to permit identification of all 
544 
participants enrolled in the trial, in case additional follow-up is required.  
545 
All paper forms shall be filled in using black/blue ballpoint pen. Errors shall be lined out but not 
546 
obliterated by using correction fluid and the correction inserted, initialled and dated.  
547 
6.4. Direct access to source data / documents  
548 
The CRF and all source documents, including progress notes and copies of laboratory and 
549 
medical test results shall be made available at all times for review by the Chief Investigator and 
550 
inspection by relevant regulatory authorities (e.g. DMA).  
551 
6.5. Data Protection  
552 
Due respect for data protection and confidentiality will be maintained.  
553 
All trial staff and investigators will endeavour to protect the rights of the trial’s participants to 
554 
privacy and informed consent, and will adhere to the Data Protection Regulation and the Data 
555 
Protection Act. The CRF will only collect the minimum required information for the purposes of 
556 
the trial. CRFs will be held securely, in a locked room, or locked cupboard or cabinet. Access to 
557 
the information will be limited to the trial staff and investigators and relevant regulatory 
558 
authorities. Computer held data including the trial database will be held securely and password 
559 
protected. All data will be stored on a secure dedicated web server. Access will be restricted by 
560 
user identifiers and passwords (encrypted using a one way encryption method).  
561 
Information about the trial in the participant’s medical records / hospital notes will be treated 
562 
confidentially in the same way as all other confidential medical information. Following 
563 
information will be extracted from participants’ medical records: blood sample results, x-ray 
564 
description, urine sample result, age, gender, skin type, current and prior medical diseases, 
565 
medical disease predispositions and medical list. 
566 
Electronic data will be backed up every 24 hours to both local and remote media in encrypted 
567 
format.  
568 
6.6 Biobank  
569 

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Handling of biological samples and personal information will be kept in accordance to the GCP 
570 
standard and the Data Protection Regulation and the Data Protection act. Surplus material from 
571 
the biopsies will be kept in a research biobank for up to five years after study termination in case 
572 
it will be necessary to do any further analyses. After this period the samples will be destroyed. 
573 
All extra analyses will only be performed after approval from The National Committee on Health 
574 
Research Ethics. Biological material will not be sent to any other countries. 
575 
6.7 Procedures for breaking randomisation code 
576 
Sponsor will receive a set of coded envelopes with all randomization numbers and another set 
577 
of coded envelopes will be delivered seperatly together with the study drug/placebo. In case that 
578 
the treatment allocation needs to be revealed, the envelopes can be opened. The envelopes are 
579 
stored and available at the department 24/7. The investigator can be reached by telephone 
580 
24/7. 
581 
7. Quality Assurance and Audit  
582 
7.1. Insurance and Indemnity  
583 
Insurance and indemnity for trial participants and trial staff is covered within the hospital’s 
584 
liability insurance 
585 
7.2. Trial Conduct and Monitoring 
586 
This trial will be conducted in adherence with the protocol, International Conference on 
587 
Harmonisation Good Clinical Practice E6 (ICH-GCP) and the applicable regulatory 
588 
requirements. All study documents and standard operating procedures will be prepared to 
589 
ensure compliance with GCP.  
590 
The investigators will ensure that all study procedures are followed and any deviations 
591 
documented and investigated.  
592 
The study will be performed in accordance with GCP. The GCP-unit, Copenhagen 
593 
(Frederiksberg hospital, Nordre Fasanvej 57, Skadestuevej 1, parterre, 2000 Frederiksberg) will 
594 
monitor the study. The Danish Data Protection Agency will be notified about this study. 
595 

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7.3. Record Retention and Archiving  
596 
In compliance with the ICH-GCP guidelines, the Principal Investigator will maintain all records 
597 
and documents regarding the conduct of the study. These will be retained for at least 7 years or 
598 
for longer if required. If the responsible investigator is no longer able to maintain the study 
599 
records, a second person will be nominated to take over this responsibility.  
600 
7.4. Risk Assessment  
601 
There is little additional risk or benefit to the individual participant by entering this study. The 
602 
study drug is a standard treatment option for certain rheumatoid diseases and the risks 
603 
associated with the treatment are well documented with the most common being infection. 
604 
During the study we will be giving the study drug at the daily recommended dose. Risks related 
605 
to the clinical procedures in the study can be minor pain, bruise and infection when taking blood 
606 
samples. Minor pain and bruising during blood pressure measuring. Redness and irritation of 
607 
skin related to patch testing. Redness, irritation, minor risk of bleeding, infection and minor 
608 
scarring related to the biopsies. Minor radiation risk exposes the participant to about 0.1 mSv 
609 
(corresponding to 1-2 weeks of background radiation during chest x-ray. Background radiation 
610 
is 3 mSv/year). Participants in the study will receive either an active drug or placebo. The results 
611 
of this study will help inform clinical treatment decisions that will benefit society.  
612 
7.5. Confidentiality  
613 
Individual participant medical information obtained as a result of this study is considered 
614 
confidential. Participant confidentiality will be further ensured by utilising identification code 
615 
numbers to correspond to treatment data in the computer files.  
616 
Data generated as a result of this trial will be available for inspection on request by the 
617 
participating physicians, the ethics committees, host institutions and the regulatory authorities.  
618 
7.6. Ethical Considerations 
619 
Participants will be provided with written and oral information on this study and will only be 
620 
enrolled when given their written informed consent. The study will be designed in accordance to 
621 
the Helsinki-declaration. Herlev and Gentofte Hospital will ensure that collection and processing 
622 
of personal data comply with national legislation on data protection and privacy. Participants will 
623 

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not directly benefit from the study. All procedures (biopsy, blood tests and allergies) are 
624 
performed routinely in the department, anakinra is already used for individual patients with 
625 
autoinflammatory diseases. However, it will extend our knowledge about mechanisms involved 
626 
in ACD, which may lead to new treatments of the disease. Severe ACD is associated with 
627 
known reduced life quality, disruption of sleeping and affected work life. Thus, studies 
628 
investigating ACD are needed.  
629 
8. PUBLICATION AND DISSEMINATION POLICY  
630 
The results of the study will be submitted for publication in a peer review journal as soon as 
631 
possible after analysis. All investigators will be named in the acknowledgments, detailing their 
632 
role in the study. Participants will not be identified in any publications.  
633 
9. STUDY FINANCES  
634 
9.1. Funding source  
635 
This study is fully funded by the LEO Foundation and Aage Bang Foundation (DKK 1.070.000). 
636 
The University of Copenhagen administrates the economy. None of the investigators have any 
637 
commercial interests in the study. The LEO Foundation has no influence on this study. The 
638 
research conducted is fully independent of the LEO Foundation.  
639 
9.2. Participant stipends and payments  
640 
Participants will be economically compensated to participate in the trial since they will not 
641 
directly benefit from the study. Travel expenses will be covered for any costs incurred for 
642 
hospital visits. Participants will be compensated with 10.000 DKK for disadvantage, medical 
643 
treatment, visits, and skin biopsies upon completion of the study. The economical compensation 
644 
is taxable income. Participants will receive 500 DKK as compensation for their time if they’re 
645 
found non-eligible after the screening visit and participants who drop out prior to completion will 
646 
be economically compensated according to the number of visits and biopsies they have 
647 
participated in. 
 
648 

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10. REFERENCES 
649 
1.  
Thyssen JP, Linneberg A, Menné T, Johansen JD. The epidemiology of contact allergy in 
650 
the general population – prevalence and main findings. Contact Dermatitis [Internet]. 
651 
2007 Nov;57(5):287–99. Available from: http://doi.wiley.com/10.1111/j.1600-
652 
0536.2007.01220.x 
653 
2.  
Henrik Nielsen, Allan Linneberg, To N. Allergic Contact Sensitization in an Adult Danish 
654 
Population: Two Cross-sectional Surveys Eight Years Apart (The Copenhagen Allergy 
655 
Study). Acta Derm Venereol [Internet]. 2001 Jan 1;81(1):31–4. Available from: 
656 
https://medicaljournals.se/acta/content/abstract/10.1080/00015550116939 
657 
3.  
Simonsen AB, Deleuran M, Johansen JD, Sommerlund M. Contact allergy and allergic 
658 
contact dermatitis in children - A review of current data. Contact Dermatitis. 2011.  
659 
4.  
Kadyk DL, McCarter K, Achen F, Belsito DV. Quality of life in patients with allergic contact 
660 
dermatitis. J Am Acad Dermatol [Internet]. 2003 Dec;49(6):1037–48. Available from: 
661 
https://linkinghub.elsevier.com/retrieve/pii/S0190962203021121 
662 
5.  
Wang X, Shi XD, Li LF, Zhou P, Shen YW. Classification and possible bacterial infection 
663 
in outpatients with eczema and dermatitis in China. Med (United States). 2017;  
664 
6.  
Martin SF, Rustemeyer T, Thyssen JP. Recent advances in understanding and managing 
665 
contact dermatitis. F1000Research [Internet]. 2018 Jun 20;7:810. Available from: 
666 
https://f1000research.com/articles/7-810/v1 
667 
7.  
Schmidt JD, Ahlström MG, Johansen JD, Dyring-Andersen B, Agerbeck C, Nielsen MM, 
668 
et al. Rapid allergen-induced interleukin-17 and interferon-γ secretion by skin-resident 
669 
memory CD8 + T cells. Contact Dermatitis [Internet]. 2017 Apr;76(4):218–27. Available 
670 
from: http://doi.wiley.com/10.1111/cod.12715 
671 
8.  
Sutterwala FS, Ogura Y, Szczepanik M, Lara-Tejero M, Lichtenberger GS, Grant EP, et 
672 
al. Critical Role for NALP3/CIAS1/Cryopyrin in Innate and Adaptive Immunity through Its 
673 
Regulation of Caspase-1. Immunity [Internet]. 2006 Mar;24(3):317–27. Available from: 
674 
https://linkinghub.elsevier.com/retrieve/pii/S1074761306001403 
675 
9.  
Watanabe H, Gehrke S, Contassot E, Roques S, Tschopp J, Friedmann PS, et al. 
676 
Danger Signaling through the Inflammasome Acts as a Master Switch between Tolerance 
677 
and Sensitization. J Immunol [Internet]. 2008 May 1 [cited 2020 Aug 16];180(9):5826–32. 
678 

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Available from: 
679 
http://www.jimmunol.org/content/180/9/5826http://www.jimmunol.org/content/180/9/5826.f
680 
ull#ref-list-1 
681 
10.  
Weber FC, Esser PR, Müller T, Ganesan J, Pellegatti P, Simon MM, et al. Lack of the 
682 
purinergic receptor P2X7 results in resistance to contact hypersensitivity. J Exp Med 
683 
[Internet]. 2010 Nov 22 [cited 2020 Aug 16];207(12):2609–19. Available from: 
684 
www.jem.org/cgi/doi/10.1084/jem.20092489 
685 
11.  
Watanabe H, Gaide O, Pétrilli V, Martinon F, Contassot E, Roques S, et al. Activation of 
686 
the IL-1β-processing inflammasome is involved in contact hypersensitivity. J Invest 
687 
Dermatol. 2007 Aug 1;127(8):1956–63.  
688 
12.  
Vennegaard MT, Dyring-Andersen B, Skov L, Nielsen MM, Schmidt JD, Bzorek M, et al. 
689 
Epicutaneous exposure to nickel induces nickel allergy in mice via a MyD88-dependent 
690 
and interleukin-1-dependent pathway. Contact Dermatitis [Internet]. 2014 Oct 1 [cited 
691 
2020 Aug 16];71(4):224–32. Available from: https://pubmed.ncbi.nlm.nih.gov/25040758/ 
692 
13.  
Yeung K, Mraz V, Geisler C, Skov L, Bonefeld CM. The role of interleukin-1β in the 
693 
immune response to contact allergens. Contact Dermatitis [Internet]. 2021 Aug 10 [cited 
694 
2021 Aug 17]; Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/cod.13955 
695 
14.  
Enk AH, Angeloni VL, Udey MC, Katz SI. Inhibition of Langerhans cell antigen-presenting 
696 
function by IL-10. A role for IL-10 in induction of tolerance. J Immunol [Internet]. 1993 
697 
[cited 2020 Aug 16];151(5):2390–8. Available from: 
698 
http://www.ncbi.nlm.nih.gov/pubmed/8103065 
699 
15.  
Haraldsen G, Kvale D, Lien B, Farstad IN, Brandtzaeg P. Cytokine-regulated expression 
700 
of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion 
701 
molecule-1 (VCAM-1) in human microvascular endothelial cells. J Immunol. 1996;156(7).  
702 
16.  
Naik S, Bouladoux N, Wilhelm C, Molloy MJ, Salcedo R, Kastenmuller W, et al. 
703 
Compartmentalized control of skin immunity by resident commensals. Science (80- ) 
704 
[Internet]. 2012 Aug 31 [cited 2020 Aug 16];337(6098):1115–9. Available from: 
705 
/pmc/articles/PMC3513834/?report=abstract 
706 
17.  
A F, C G. At the horizon of innovative therapy in rheumatology: new biologic agents. Curr 
707 
Opin Rheumatol [Internet]. 2008 May [cited 2021 Aug 18];20(3):269–75. Available from: 
708 

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https://pubmed.ncbi.nlm.nih.gov/18388517/ 
709