Multi-Omic SignAtures of Inflammatory Cutaneous Diseases

Multi-Omic SignAtures of Inflammatory Cutaneous Diseases

The goal of this observational study is to identify the immune profile underlying various inflammatory skin diseases, through multi-omic procedures.

The main questions it aims to answer are:

1. What are the molecular and immune signatures of individuals with inflammatory skin disease?
2. Can these signatures reveal potential therapeutic targets for individuals with inflammatory skin disease?
3. How do patients' multi-omic signatures change before and after receiving systemic therapy?
4. Can the samples and data collected through this study provide a valuable bioresource for future skin disease research?

MOSAIC (Multi-Omic Signatures of Inflammatory Cutaneous Diseases) is a non-commercial, investigator-led, single-centre, prospective observational cohort study. Participants will be recruited at Guy's and St Thomas' NHS Foundation Trust, with University Hospitals Birmingham acting as a participant identification centre. The study will investigate individuals with a broad range of common and rare inflammatory skin diseases, including genetic skin diseases such as epidermolysis bullosa, alongside a healthy comparison cohort.

The study is based on the hypothesis that inflammatory skin diseases may share identifiable molecular and immune pathways, despite differences in their clinical presentation and underlying causes. By integrating molecular data with detailed clinical information, MOSAIC aims to identify and characterise disease-associated immune signatures, distinguish molecular subgroups or "endotypes", and identify potentially druggable pathways. The study will also investigate how molecular and immune profiles change following systemic treatment and will establish a well-characterised biological resource for future skin disease research. MOSAIC is observational: no treatment will be assigned or administered as part of the study, and participants will continue to receive clinical care according to usual practice.

Participants will undergo a detailed baseline assessment. Clinical information will include demographic characteristics, medical and family history, disease phenotype and duration, previous and current treatments, concomitant conditions and medications, relevant environmental factors, clinical assessments, patient- and clinician-reported information, and medical photography where applicable. Healthy participants will provide comparison data and samples at a single baseline visit.

Biological samples collected at baseline may include routine clinical blood samples, research blood samples and skin biopsies. Research blood will be used to isolate DNA, RNA, serum, plasma and peripheral blood mononuclear cells. Patients may provide samples from lesional and non-lesional skin, while healthy participants will provide site-matched control samples where possible. Subject to separate consent and clinical relevance, optional samples may include skin or mucosal swabs, stool, mucosal biopsies, scalp biopsies and skin that would otherwise be discarded during surgery. Relevant historical results obtained within six months before the baseline visit may be used where scientifically and clinically appropriate to reduce unnecessary repeat invasive procedures.

Patients who start, switch or stop a systemic therapy, or who experience a worsening of their disease, may be invited to attend optional longitudinal follow-up visits if they are not participating in another interventional study. Up to five optional follow-up visits may take place at clinically and scientifically relevant time points, such as Day 3, Week 1, Week 16, Month 6 and Month 12. The timing may be adapted according to the mechanism of the treatment or the specific research question. Follow-up assessments may include updated clinical and treatment information, examination, disease-specific assessments, medical photography and repeat collection of research samples. This will allow molecular profiles before and after treatment, or during changes in disease activity, to be compared. Clinical outcome information may be followed for up to five years after sampling to support longer-term correlation with molecular findings.

Samples may undergo single or multiple complementary analyses. These may include DNA sequencing and genotyping; epigenetic analysis; bulk, single-cell and spatial transcriptomics; NanoString profiling; proteomic, cytokine and metabolomic analysis; flow, spectral, imaging or mass cytometry; and functional ex vivo assays. Skin samples may also undergo histology, immunostaining, immunofluorescence, confocal imaging and cell-isolation procedures. Where appropriate, cells may be used in in vitro cultures, three-dimensional organotypic models, spheroids or organoids. Skin, mucosal and stool samples may also be analysed to characterise microbial composition and function. Multi-omic data will be integrated with clinical phenotype, disease activity, treatment exposure and longitudinal clinical information to identify shared and disease-specific pathways and potential therapeutic targets.

Participants found to have potentially actionable or druggable immune profiles may, with appropriate consent, be approached about separate interventional clinical trials. For example, eligible participants with epidermolysis bullosa may be considered for ART-EB, a separate clinical trial evaluating repurposed biological therapies. Molecular profiles generated through MOSAIC may be used as baseline information to support biological stratification and treatment matching in such studies. Participation in MOSAIC does not guarantee eligibility for, or entry into, an interventional trial, and separate informed consent will be required.

The planned case-to-control ratio prioritises the characterisation of heterogeneous inflammatory skin diseases while maintaining a feasible healthy comparison group. The protocol estimates that 300 inflammatory skin disease cases will provide approximately 84% power, using a two-sided 5% significance level, to identify a small-to-moderate effect across four disease subcategories, represented by a Cohen's w of 0.2. A subgroup of 100 cases would provide similar power to detect a larger effect of approximately Cohen's w 0.35 across four subcategories.

A detailed Statistical Analysis Plan will be prepared by the study statistician and finalised before database lock. Analyses will be tailored to the relevant clinical or molecular research question and may include parametric and non-parametric comparisons, linear or logistic regression, interaction testing, subgroup analyses and longitudinal analyses. These analyses will examine relationships between multi-omic signatures, clinical phenotypes, treatment exposure and changes over time.

Inclusion Criteria:

• Able to provide written informed consent prior to performing any protocol-related procedures, including screening.
• Adults (≥18 years) with confirmed diagnosis of inflammatory skin disease (defined as any skin disease with an inflammatory component, including but not limited to, genetic skin disease, such as EB), OR
• Adults age (≥18 years) without skin or systemic disease.

Exclusion Criteria:

• Inability to give written informed consent.
• Participants who have received topical corticosteroids to sites of biopsies (inflamed area of skin) for at least 2 weeks prior to tissue sampling.
• Inability to participate in study-specific procedures.
• Participants who are pregnant (confirmed on a positive urine pregnancy test) or breastfeeding
• Enrolment in any interventional study with systemic treatment within 3 months prior to baseline biopsy.