Rheumatology

Grom / Thornton Lab

The Alexei Grom, MD / Sherry Thornton, PhD, Lab

Our lab’s main area of interest is systemic forms of juvenile arthritis. Specifically, we study the pathogenesis of rheumatic conditions such as juvenile idiopathic arthritis (JIA) and macrophage activation syndrome (MAS), a complication of JIA. Our work includes a strong translational component; along with studying the mechanisms behind these conditions, we are researching potential biomarker and imaging techniques that could accelerate the diagnosis and treatment process.

The broad goal of Dr. Grom’s research is to understand the molecular heterogeneity of Juvenile Idiopathic Arthritis (JIA) that would explain variability in clinical outcomes and risk for various complications of the disease. He is particularly interested in the pathways responsible for the increased incidence of macrophage activation syndrome (MAS) in systemic JIA (SJIA). Although relatively rare, this condition is potentially life threatening and remains a major cause of mortality in pediatric rheumatology. He developed a strong interest in MAS during his fellowship at Cincinnati Children’s Hospital Medical Center. At that time, it was recognized that MAS had strong clinical similarities with familial hemophagocytic lymphohistiocytosis, a constellation of autosomal recessive disorders all linked to various genetic defects in the cytolytic pathway. With the help of microarray technology, his group identified the gene expression signature of macrophage activation syndrome in patients with SJIA (P01 AR-048929). The analysis of this signature produced several candidate biomarkers for the early diagnosis of MAS. The clinical utility of these markers was then explored in the project funded through the NIH MCRC (P60-AR047884) and many of them are now used in routine clinical practice. His team has also identified new genetic markers associated with MAS. These markers have been explored using various next generation sequencing approaches (R01-AR059049). Using whole exome sequencing methodology, his group demonstrated an increased “burden” of rare variants in the cytolytic pathway in MAS patients compared to healthy controls suggesting that as in familial HLH, genetic variability in the cytolytic pathway contributes to MAS predisposition.

Using the single-cell RNA-Seq technology to study bone marrow macrophages in children with SJIA/MAS, his team implicated monocyte/macrophage IFNγ hyper-responsiveness and excessive activation of the IFN-induced signaling pathway in monocytes/macrophages as key pathways in MAS pathogenesis. These observations led to the recently completed Phase II-III clinical trials of the anti-IFNγ antibody emapalumab in MAS/SJIA where DR. Grom served as the North American PI. The results of these trials eventually secured a full FDA approval of emapalumab for the treatment of MAS in SJIA by the FDA.

With a team of collaborators at CCHMC (Drs. Grant Schulert and Christopher Towe), Dr Grom’s team has recently provided the first comprehensive clinical description of the new emerging life-threatening chronic pulmonary disease (SJIA-LD) in patients with SJIA that has features of alveolar proteinosis (PAP), endogenous lipoid pneumonia (ELP), and fibrosis. The group also provided the first detailed mechanistic look at SJIA-LD and found that this entity has distinct clinical and immunologic features from other lung disorders, including known causes of PAP or ELP, and represents a new inflammatory ILD (SJIA-LD). Most of these patients have a history of MAS, often recurrent. Furthermore, SC-RNA Seq using SJIA-LD lung biopsies reveals pathways overlapping with MAS.

The focus of Dr. Grom’s current research is refractory systemic JIA. Despite recently approved IL-1 and IL-6 blocking agents, about 20% of patients with SJIA develop a refractory disease course and fail to respond to all approved medications and require maintenance therapy with glucocorticoids. Single cell and special transcriptomics approaches are currently used to identify potential therapeutic targets specifically in this patient population. IL-18 has emerged as pivotal cytokine in this group of patients, and Dr. Grom now serves as a PI in Phase II clinical trials of new biologics targeting this cytokine.

Sherry Thornton’s research focuses on understanding the pathogenesis of arthritic diseases and cellular phenotyping. My research focuses on identification and characterization of genes involved in arthritis and functional analysis of these genes and their products through in vitro cellular assays and in vivo animal models of arthritis. Along with Dr. Grom, our laboratory has played an important role in analyzing cell types in samples from JIA and control populations and identifying the gene expression profiles from these samples. Discovery of biomarkers for rheumatic diseases is also a major focus of our research. Cytometric and cellular analyte analysis are used to determine cell types in PBMC from Juvenile Idiopathic Arthritis (JIA) subtypes; miRNA contributions to disease, as well as examine analytes in tears from JIA patients with uveitis and in synovial fluid from JIA patients. In animal models, I have investigated the contribution of angiogenic and hemostatic factors to the pathogenesis of arthritis and used flow cytometry to determine cell populations in inflamed synovium and cellular autoimmune responses in animal models of inflammatory arthritis. My research assesses biomarkers in serum, cells, tears, urine, and synovial fluid and utilizes high parameter cellular analysis of SJIA and MAS patients and provides data analysis of both high parameter flow and multiplex studies.

Contact the Grom / Thornton Lab

Division of Rheumatology
Location R Room 5543

Phone: 513-636-7663