Biomarkers of Cancer-Associated Myositis (MIOSURFACE)

Plasma Membrane Antigens as Trigger in Cancer-associated Myositis

The project is about dermatomyositis (DM), an autoimmune disease characterized by inflammation in the skeletal muscles and skin. Patients with DM have an increased risk of cancer, with a cancer incidence between 5.5% and 42%. Cancers in these patients are one of the leading causes of death. Some myositis-specific autoantibodies have been discovered and some of them are associated with cancer development. However, DM patients negative for all the known autoantibodies can also develop cancer. The Investigator hypothesized that antibodies against plasma membrane antigens and soluble immune checkpoints can be responsible for the association between cancers and autoimmunity. Therefore, the present study aimed to identify novel antigens and immunological pathways in patients with DM with cancer versus patients with DM without cancer, to identify those patients who need cancer screening. The Investigators focus on soluble immune checkpoint molecules and autoantibodies directed against plasma membrane antigens.

Study Overview

• Status: Active, not recruiting
• Conditions: Dermatomyositis

Detailed Description

Several studies have reported an association between cancers and autoimmune diseases. Mechanisms underlying this association are largely unknown, but similarity between antigens expressed by cells in tissues targeted by autoimmune reactions and cancer cells is likely one of the drivers. Moreover, chronic inflammation can favor cancer onset.

Among autoimmune diseases, dermatomyositis (DM) has the highest association with cancers. About 25% of patients with DM, over 40 years old, have cancer at the time of diagnosis or develop cancer later. Common cancers include lung, breast, colon, prostate, and ovarian cancers. DM is a systemic inflammatory disease affecting skeletal muscle, skin, and other organs (e.g., lung). Cancer risk in patients with DM is higher compared to age- and sex-matched populations, both before diagnosis and in the three years following diagnosis (standardized incidence ratio: 3.8 - 17.29).

DM is characterized by autoantibodies. Autoantibodies against transcriptional intermediary factor TIF1-gamma, nuclear matrix protein (NXP2), and SUMO1 activating enzyme (SAE1) are detected more frequently in patients with paraneoplastic DM compared to patients without cancers and healthy controls. In contrast, autoantibodies against Jo-1 are detected less frequently. However, the identification of patients with increased cancer risk remains incomplete since DM patients negative for all known autoantibodies also have an increased risk. While TIF1-gamma, NXP2, and Jo-1 are intracellular antigens, plasma membrane antigens are more likely involved in cancer-associated DM due to their accessibility to antibodies.

Immune checkpoint molecules have emerged as key regulators of the immune system, crucial for self-tolerance and immune activation. They mainly act as ligand-receptor pairs, but several undergo alternative splicing, generating soluble isoforms. The production of soluble forms of immune checkpoints in DM is scarcely known.

Autoantibodies against extracellular antigens and soluble immune checkpoints may contribute to the association between cancers and autoimmunity. Identifying circulating markers deregulated in cancer-associated DM will enable the identification of patients at risk, facilitating timely screening and interventions.

Patients with dermatomyositis (DM) have an increased risk of developing tumors, making early detection crucial due to their worse prognosis. The currently known autoantibodies, such as anti-TIF1-gamma, anti-NXP2, and anti-SAE1, fail to identify all DM patients with associated tumors. Additionally, about 35% of DM patients are negative in standard autoantibody screenings but still exhibit a higher tumor risk. So far, the identified autoantibodies in cancer-associated DM target intracellular antigens, which are unlikely to have a direct pathogenic role as they cannot bind their targets under physiological conditions. Soluble immune checkpoints are believed to mediate the relationship between DM and cancer, potentially serving as biomarkers. The study hypothesizes that autoantibodies against cell surface antigens, which are more likely to be pathogenic, may be present in tumor-associated DM. It also proposes that changes in soluble immune checkpoint levels might contribute to DM-associated tumor development and could help identify at-risk patients.

This is a prospective and retrospective study. For the prospective part, serum samples will be collected at the time of enrollment, before the initiation of chemotherapy or immunotherapy. For the retrospective part, patients enrolled in the study must have an available serum sample stored at -80°C, and potentially a muscle biopsy, fixed in formalin and embedded in paraffin, taken during the diagnostic phase.

• Study Type: Observational
• Enrollment (Actual): 50

Contacts and Locations

Study Locations

• Italy
  • Bari, Italy, 70124
    • Azienda Ospedaliera Universitaria Consorziale Policlinico di Bari
  • Reggio Emilia, Italy, 42122
    • AUSL-IRCCS di Reggio Emilia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Patients diagnosed with DM during rheumatologic visits of the national health system

Description

Inclusion Criteria:

• Age > 40 years.
• Diagnosis of DM.
• Informed Consent

Exclusion Criteria:

• Chemotherapy at the time of the peripheral venous blood draw.
• Therapy with biologic drugs at the time of the peripheral venous blood draw.
• Necrotizing autoimmune myopathy.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
DM without cancer; Patients with DM who do not have cancer at diagnosis and in the 3-year follow-up period
DM with cancer; Patients with DM who have cancer at diagnosis or in the 3-years before or after DM diagnosis
Healthy controls; Subjects without known cancer, autoimmune diseases and infections

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Identification of autoantibodies against surface proteins in patients with dermatomyositis (DM) with and without cancer.	Serum samples from patients with DM with and without cancer will be tested for their ability to bind various cell lines surface antigens through immunofluorescence assays on live cells. Median fluorescence intensity will be evaluated. These analyses will determine whether there are differences in the levels of autoantibodies between the serum samples from patients with and without cancer. Potential autoantigens will be identified by immunoprecipitation of cell lysates with sera followed by mass spectrometry.	At enrollement
Identification of soluble immune checkpoint molecules in patients with dermatomyositis (DM) with and without cancer.	Levels of 14 soluble immune checkpoint molecules will be quantified in serum samples using the Magpix technology (ProcartaPlex Immuno-Oncology Checkpoint Panel 1). The target molecules include: BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PD-L1, PD-L2, TIM-3, CD28, CD80, CD137, CD27, and CD152. Concentrations of soluble immune checkpoints will be evaluated. These analyses will determine whether there are differences in the levels of these molecules between the serum samples from patients with and without cancer.	At Enrollment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Expression of autoantigens in muscle biopsy samples from DM patients and cancer samples	The expression of novel autoantigens will be tested using the immunohistochemistry technique in muscle biopsy samples from dermatomyositis (DM) patients, as well as in samples from ovarian, breast, and colon carcinomas, and normal tissues. Differences in the expression pattern of autoantigens between the DM patient samples and tumor samples will be identified	At Enrollment
Expression of autoantibodies against surface proteins in patients with dermatomyositis (DM) compared to healthy controls.	Median fluorescence intensities obtained after incubation of live cells with sera from DM patients will be compared to those obtained with sera from healthy subjects. These measurements will determine whether there are differences in the levels of these molecules between the serum samples from DM patients and healthy subjects.	At Enrollment
Expression of soluble immune checkpoint molecules in patients with dermatomyositis (DM) compared to healthy controls.	The levels of 14 soluble immune checkpoint molecules will be compared between serum samples from DM patients and healthy subjects. These measurements will determine whether there are differences in the levels of these molecules between the serum samples from DM patients and healthy subjects.	At Enrollment

Collaborators and Investigators

• Sponsor: Azienda USL Reggio Emilia - IRCCS

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2019
• Primary Completion (Actual): December 31, 2024
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: March 22, 2024
• First Submitted That Met QC Criteria: January 29, 2025
• First Posted (Actual): February 5, 2025

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: May 4, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Dermatomyositis; Immune Checkpoints; Autoantibodies; Cancer Risk
• Additional Relevant MeSH Terms: Musculoskeletal Diseases; Nervous System Diseases; Muscular Diseases; Neuromuscular Diseases; Connective Tissue Diseases; Skin Diseases; Myositis; Polymyositis; Skin and Connective Tissue Diseases; Dermatomyositis
• Other Study ID Numbers: 419/2019/OSS/AUSLRE

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No