Connective Tissue & Autoimmune

Principal Investigator:

Sonia Kamath, MD
Children’s Hospital Los Angeles
Keck School of Medicine of the University of Southern California (USC)

Overview:

Juvenile dermatomyositis (JDM) is a rare autoimmune disease, causing muscle weakness and rash. The skin findings are variable and are crucial to establishing the diagnosis, as they often occur months or years prior to muscle weakness. Some children have a classic rash affecting the eyelids and knuckles, while others have less common findings, such as scalp rash. To better understand the skin disease in JDM, we propose to evaluate the spectrum of initial skin findings. We will conduct a multi-center, retrospective review of children diagnosed with JDM to determine the prevalence of skin findings at initial presentation, whether the presenting skin findings can help identify patients who develop muscle disease, and whether skin findings vary by race/ethnicity. Our findings will inform future prospective studies to define distinct presentations of JDM, characterize long-term disease outcomes, and improve treatment approaches for JDM.

Status:

This project was funded by a 2020 PeDRA Research Grant.

Fellow

Henry Chen
UT Southwestern Medical Center

Mentor

Heidi Jacobe MD, MSCS
UT Southwestern Medical Center

Overview

Morphea, or localized scleroderma, is an idiopathic disorder of the skin and underlying tissue that produces permanent disability and functional impairment due to joint contracture and soft tissue loss. Notably, pediatric-onset morphea is associated with more severe features compared to adult-onset morphea, such as worsened morbidity and prolonged duration of disease, impairing growth and resulting in disfigurement. Morphea has remitting and relapsing periods of activity, marked by inflammation and fibrosis, and damage which produces atrophy. Activity is characterized by an inflammatory dermal and subcutaneous lymphocytic infiltrate manifesting clinically as erythema and edema. Inflammatory activity often overlaps with a fibrotic phase distinguished by dense collagen deposition with infiltration of inflammatory cells manifesting clinically as hardened, discolored plaques. Fibrosis and resultant atrophy of the skin, soft tissue, and bone result in functional impairment. As with other autoimmune disorders, the predominant driver of long-term morphea damage and disability is thought to be the magnitude and duration of the initial active phase, which likely facilitates subsequent damaging fibrosis. However, the dysregulation of immune and fibrotic pathways at single-cell resolution that contribute to these changes has not been systematically studied. The only widely tested treatment for morphea is a combination of corticosteroids and methotrexate, the use of which is substantially limited by toxicity, particularly in the pediatric population. Therefore, characterization of immune pathway aberrations at the single-cell level is quintessential in the identification of molecular targets for therapeutic development.

Aim 1: Identify dysregulated immune networks in morphea relative to matched healthy control skin.

Aim 2: Utilize identified dysregulated immune networks to determine association with disease trajectory and therapeutic response.

Status

This project was funded through a 2021 PeDRA Research Fellowship Grant.

Principal Investigator:

Reid Oldenburg, MD, PhD
University of California, San Diego

Overview:

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are catastrophic drug reactions that destroy the skin, surface of the eyes and lining of the mouth and genitals. Antibiotics, ibuprofen and anti-seizures medications can cause SJS and TEN. When these severe cutaneous adverse reactions occur, the causative medication must be stopped immediately. However, identifying a causative medication can be difficult, especially when children are taking multiple medications.

There is no available blood test that can identify drugs that cause SJS and TEN, making it difficult for doctors to continue prescribing important medications, or use similar medications. Our long term interest is to develop diagnostic blood tests that can safely be used to identify causative medications for SJS and TEN patients. Our current project will stimulate blood from SJS and TEN patients with known causative medications to identify inflammatory molecules that can be later be used to develop diagnostic tests.

Status:

This project was funded by a 2020 PeDRA Research Grant.

Principal Investigator:

Sonia Kamath, MD
Children’s Hospital Los Angeles
Keck School of Medicine of the University of Southern California (USC)

Overview:

Juvenile dermatomyositis (JDM) is a rare autoimmune disease, causing muscle weakness and rash. The skin findings are variable and are crucial to establishing the diagnosis, as they often occur months or years prior to muscle weakness. Some children have a classic rash affecting the eyelids and knuckles, while others have less common findings, such as scalp rash. To better understand the skin disease in JDM, we propose to evaluate the spectrum of initial skin findings. We will conduct a multi-center, retrospective review of children diagnosed with JDM to determine the prevalence of skin findings at initial presentation, whether the presenting skin findings can help identify patients who develop muscle disease, and whether skin findings vary by race/ethnicity. Our findings will inform future prospective studies to define distinct presentations of JDM, characterize long-term disease outcomes, and improve treatment approaches for JDM.

Status:

This project was funded by a 2020 PeDRA Research Grant.

Fellow

Laila Abbas
UT Southwestern Medical Center

Mentor

Heidi Jacobe, MD, MSCS
UT Southwestern Medical Center

Overview

Morphea, or localized scleroderma, is a neglected autoimmune disease of the skin and underlying tissue that produces permanent disability due to joint contracture and soft tissue loss. Approximately half of patients have disease onset in childhood, and pediatric morphea is associated with significant morbidity, with reported complications including loss of range of motion, joint deformity, facial disfigurement, and neurologic manifestations. Morphea has remitting and relapsing activity, marked by inflammation and fibrosis, and damage which produces atrophy. The overarching hypothesis of this project is that fibroblasts are constitutively activated in morphea and that both T cells and macrophages will promote activation of fibroblasts.

Aim 1: Determine constitutive expression of pro-fibrotic and inflammatory markers in fibroblasts derived from morphea lesions as compared to matched control specimens.

Aim 2: Co-cultures will be performed with combinations of healthy and morphea fibroblasts along with healthy and morphea derived T cells and macrophages to determine if these cells can potentiate fibroblast activation.

Status

This project was funded through a 2020 PeDRA Research Fellowship Grant.