SKIN Disease Profiling by an Exploratory, pRospective, Biomarker Study in dermatoloGY Practice (SKINERGY)

A Prospective, Multi-Center, Observational Biomarker Real-World Evidence Study for In-Depth Profiling of Patients With Chronic Immune-Mediated Inflammatory Skin Diseases in Daily Practice

The goal of this observational study is to comprehensively profile six immune-mediated inflammatory diseases, including atopic dermatitis (AD), plaque psoriasis (PSO), hidradenitis suppurativa (HS), cutaneous T-cell lymphoma subtype mycosis fungoides (MF), chronic spontaneous urticaria (CSU), and cutaneous lupus erythematosus (CLE) in daily practice. Data will be compared with data from healthy volunteers. This study is part of the larger NGID (Next Generation ImmunoDermatology) initiative, of which the main objective is to develop infrastructure that enables personalised patient care. The main questions the SKINERGY study aims to answer are:

• Which biomarkers can discriminate between responders and non-responders to treatment in patients with AD, CLE, CSU, HS, MF, and PSO?
• How do disease-related biomarkers in patients with AD, CLE, CSU, HS, MF, and PSO differ from those in healthy volunteers?
• Which (multi-omics) biomarkers are associated with disease subtypes and predict response or non-response to (targeted) therapies in daily clinical practice?
• How do biomarker profiles compare across different cohorts of patients with immune-mediated inflammatory skin diseases (AD, CLE, CSU, HS, MF, PSO)
• How do biomarker levels change over time in response to treatment in these patient populations?
• Which skin tissue biomarkers are associated with disease progression or treatment response?
• How do the genomic profiles of patients differ across diseases or correlate with treatment outcomes?
• Can additional imaging biomarkers enhance the characterization of disease profiles or treatment monitoring over time?

Researchers will compare both differences beween patients within a disease group in different treatment arms, as well as patients within the same treatment arm. Additionally, biomarker profiles of patients with different diseases will be evaluated. These comparisons will be made to see if shared or distinct biomarker patterns exist across diseases and treatments, which could inform patient stratification, optimize therapeutic decision-making, and identify potential targets for future interventions.

Participants will start medication according to national guidelines for the treatment of their inflammatory skin disease (AD: Cyclosporin A, anti-IL4/13, or anti-JAK; PSO: anti-TNF, anti-IL23, ani-IL17, anti-TYK2; HS: anti-TNF, anti-IL17; MF: CHLORM, TSC, PUVA-UV-B; CSU: anti-IgE, Cyclosporin A, anti-BTK*; CLE: TSC, HCQ, MTX)

*once approved and reimbursed in the Netherlands

Participants will:

• Take the prescribed medication for their skin disease (in line with standard care in the Netherlands).
• Visit the clinic for a study visit combined with their standard care appointment 3 times (baseline, month 3, and month 6. An additional 4th visit at month 12 is optional).
• Fill in an online set of questionnaires from home, 3 times during the study period (an additional 4th time is optional).
• Patients with CSU fill in the UAS7 (and if applicable the AAS7) daily for the study period.

Atopic dermatitis (AD), cutaneous lupus erythematosus (CLE), chronic spontaneous urticaria (CSU), hidradenitis suppurativa (HS), cutaneous T-cell lymphoma (CTCL, subtype mycosis fungoides, MF), and plaque psoriasis (PSO) are diverse immune-mediated inflammatory skin diseases with complex and often poorly understood pathophysiologies. Genetic, immunological, and environmental factors contribute variably across these conditions, leading to heterogeneous clinical presentations. Despite advances, the identification and validation of specific biomarkers remain limited, hampering precise diagnosis, disease subtyping, and treatment response prediction. For example, AD involves epidermal barrier defects and immune dysregulation; CLE features autoimmune mechanisms and diverse clinical subtypes; CSU results from mast cell activation; HS is driven by follicular occlusion and chronic inflammation; CTCL involves malignant T-cell proliferation in the skin; and PSO is characterized by immune-driven keratinocyte hyperproliferation. The Next Generation ImmunoDermatology project aims to address these challenges by deeply profiling these diseases to discover biomarkers that define disease endotypes and predict therapy response, ultimately enabling personalized treatment strategies.

The investigations will profile various aspects of the disease, including patient-reported outcomes, the clinician-reported outcomes, biophysical, imaging, cellular, microbiological, molecular, blood-based and tissue biomarkers.

This multicenter, open-label, longitudinal biomarker study follows 720 patients with six inflammatory skin diseases-AD, PSO, HS, CSU, CLE, and MF-for one year after starting standard-of-care treatment. Multimodal data are collected at baseline, 3, 6, and 12 months. An additional 120 healthy controls are included for baseline comparison and followed for 6 weeks. Each disease includes multiple treatment arms (N=40 per arm):

• AD: cyclosporine A; anti-IL-4/13 (dupilumab, tralokinumab, lebrikizumab); JAK1 inhibitors (upadacitinib, abrocitinib)
• PSO: anti-IL-23 (guselkumab, risankizumab, tildrakizumab); anti-IL-17 (secukinumab, ixekizumab, brodalumab, bimekizumab); anti-TNFα (adalimumab, certolizumab); TYK2 inhibitor (deucravacitinib)
• HS: anti-TNFα (adalimumab); anti-IL-17 (secukinumab, bimekizumab*)
• MF: topical chlormethine; topical corticosteroids; phototherapy (PUVA/UV-B)
• CSU: anti-IgE (omalizumab*); cyclosporine A; BTK inhibitors* (remibrutinib, rilzabrutinib)
• CLE: topical corticosteroids; hydroxychloroquine; methotrexate

Inclusion Criteria:

Patients:

1. Able to understand and provide a written informed consent prior to any study procedures
2. Male or non-pregnant female, ≥18 years of age
3. Patient is willing to refrain from extensively washing (including bathing, swimming) the target lesional skin 12 hours before every study visit day.
4. Patient is willing and able to comply with the study protocol
5. Female participants are willing to not get pregnant between M0 until M12, from study entry to the last study visit
6. The patient is willing to start the prescribed treatment.

Disease-specific inclusion criteria

For patients with AD:

To be eligible to participate in this study, a subject must meet all of the following criteria:

6. Diagnosis and history of chronic, moderate-to-severe AD (by the Eichenfield revised criteria of Hanifin and Rajka for at least 3 years before baseline visit.

7. Documented recent history (last 6 months) of eligibility for (local or systemic) treatment with immunosuppressants, biologics or JAK-inhibitors.

8. When applicable, documented recent history (last 6 months) of inadequate response to treatment with topical therapy, immunosuppressants, biologics or JAK-inhibitors.

9. Current treatment can include moisturizers, topical treatment and/or systemic treatments with preferable wash-out (see exclusion criterion #9). On-study treatment is at physician and patient discretion but must include eligibility to starting new systemic treatment.

10. EASI≥7 (moderate-to-severe disease) 11. At least one suitable target lesion at the discretion of the investigator 12. Intention to start treatment with cyclosporine A, dupilumab, tralokinumab, lebrikizumab or a JAK1-inhibitor (abrocitinib or upadacitinib)

For patients with CLE:

Participants must have a diagnosis of CLE, including SCLE, CDLE or LET that fulfil the following:

6. Confirmed CLE diagnosis by clinicopathological correlation. 7. An overall CLE Disease Area and Severity Index Activity (CLASI-A) Score ≥3 without counting any diffuse alopecia or oral ulcers.

8. Intention to start treatment with TCS, hydroxychloroquine or methotrexate (combination or mono-treatment).

If participating in the exploratory study with the skin biopsy: location of the lesion(s) selected for biopsy preferably outside the facial area (possible are e.g., neck, chest, back, limbs, scalp, ear etc.).

For patients with CSU:

6. Diagnosis of CSU (moderate to severe according to international guidelines (Zuberbier et al, 2022)) for ≥3 months and symptomatic disease despite treatment with second generation H1 antihistamines (up to fourfold the approved dose).

7.Patients currently on an antihistamine (up to fourfold the approved dose) must be on a stable dose for at least 2 weeks prior to day 1 and must maintain the same stable dose throughout the treatment period.

8. Intention to start (add-on to antihistamine) treatment of omalizumab, cyclosporine A or BTK inhibitor*. (*when approved and reimbursed in NL)

For patients with HS:

6. Patient with a history of signs and symptoms consistent with moderate-to-severe HS, based on IHS4 score (Zouboulis et al., 2017), for at least 1 year prior to baseline 7. Current treatment can include topical treatment. On-study treatment is at physician and patient discretion but must include eligibility to starting systemic treatment 8. Intention to start treatment with anti-TNF or anti-IL17 (secukinumab, bimekizumab*) *when approved and reimbursed in NL.

For patients with MF:

6. A confirmed diagnosis of CTCL MF type and stage classification via histology or clinicopathological correlation 7. For the stage IA-IIA CTCL patients: at least one patch and/or one plaque lesion is present 8. Intention to start treatment with topical chlormethine, topical corticosteroids or phototherapy (PUVA / UV-B).

For patients with PSO:

6. Diagnosed with chronic plaque psoriasis at least 6 months prior to study participation 7. PASI≥5 with at least one suitable target lesion at the discretion of the investigator 8. Current treatment can include moisturizers, topical treatment and/or systemic treatments with preferable wash-out. On-study treatment is at physician and patient discretion but must include eligibility to starting new systemic treatment 9. Intention to start treatment with biologics: anti-TNF, anti-IL23, anti-IL17 or anti-TYK2

Healthy volunteers:

All healthy volunteers must meet all of the following inclusion criteria:

1. Signed informed consent before any study-mandated procedure.
2. Male or non-pregnant female volunteers, ≥18 years of age
3. Subject is in stable good health as per judgement of the investigator based upon the results of medical history and assessments performed at baseline.
4. No clinically significant skin disease as judged by the investigator.
5. No history of hypertrophic scarring or keloid.
6. Subject is willing to refrain from extensively washing (including bathing, swimming) the skin 12 hours before every study visit.
7. Subject is willing and able to wash out and withhold any topical treatment (prescription and over-the-counter products) in the investigational area for 2 weeks prior to Day 1.
8. 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.
9. Subject is willing and able to wash out any antibiotic therapy for 14 days prior to Day 1.
10. Subject is willing and able to comply with the study protocol.
11. Female participants are willing to not get pregnant from study entry to the last study visit

Exclusion Criteria:

Patients:

1. Have any other relevant skin infection/disease in the treatment area other than the investigated skin disease.

2. Subjects who have received treatment with any non-marketed drug substance (that is, an agent which has not yet been made available for clinical use following registration) within 4 weeks prior to the baseline visit.

3. Any other condition, disease, or known factor that could interfere with the study conduct or the study objectives as per judgement of the investigator. 4. Having received treatments for the investigated skin disease within the following intervals prior to the start of the study is not a strict exclusion criterion since this is a real-world study. However, preferred intervals for washout are as follows:

   • 1 week for topical treatment, e.g. corticosteroids, retinoids, vitamin D analogs, calcineurin inhibitors
   • 4 weeks for phototherapy, e.g. UVB, PUVA, PDT
   • 4 weeks for non-biologic systemic treatment, e.g. retinoids, methotrexate, cyclosporine, JAK inhibitors
   • 8 weeks for radiotherapy or surgery in the treatment area
   • 8 weeks for biologics
   • 3 months for any systemic chemotherapeutical treatment

Disease specific exclusion criteria for patients with CLE:

5. Diagnosed with SLE

Disease specific exclusion criteria for patients with CSU:

5. Treatment with omalizumab within 8 weeks prior to Day 1 6. Urticarial or angioedema symptoms such as urticarial vasculitis, erythema multiforme, cutaneous mastocytosis (urticaria pigmentosa) and hereditary, acquired angioedema or drug-induced (e.g., due to C1 esterase inhibitor deficiency, ACE-inhibitor induced).

Disease specific exclusion criteria for patients with MF:

5. Ongoing uncontrolled active skin infection, other than secondary impetiginized CTCL lesions as judged by the investigator

Disease specific exclusion criteria for patients with PSO:

5. Having primarily erythrodermic, pustular or guttate psoriasis; 6. Having drug-induced psoriasis;

Healthy volunteers:

All healthy volunteers must meet none of the following exclusion criteria:

1. History of immunological abnormality (e.g. immune suppression, severe allergy, or anaphylaxis) that may interfere with study objectives as per judgement of the investigator.
2. History or symptoms of any uncontrolled, significant disease including (but not limited to), a neurological, psychiatric, endocrine, cardiovascular, respiratory, gastrointestinal, hepatic, or renal disorder that may interfere with the study objectives as per judgement of the investigator.
3. The use of systemic antibiotic therapy for >2 months in the past 12 months.
4. The use of any immunosuppressive or immunomodulatory therapy within the past 30 days prior to Day 1.

6. Loss or donation of blood over 500mL within three months prior to baseline. Participation in an investigational drug study within 3 months prior to baseline visit or more than 4 times a year.

7. History of alcohol consumption exceeding 5 standard drinks per day on average within 3 months prior to baseline. Alcohol consumption will be prohibited for at least 24 hours preceding each study visit.

8. Positive urine test for drugs or history of abuse at baseline. 9. Exposure to high doses of UV radiation is not permitted within 3 weeks of the first study visit until the end of the study 10. Extreme physical activities are not permitted within 48 hours before each study visit 11. Any other condition, disease, or known factor that could interfere with the study conduct or the study objectives as per judgement of the investigator.