Michael J. Ombrello, M.D.

Autoinflammatory diseases arise from inappropriate activation or regulation of innate immune pathways. Some result from variants in individual genes, whereas others have complex genetic architectures and marked variability in severity and treatment response. The TGGS uses human genetics to identify disease mechanisms, define the cellular programs through which they act, and translate these findings into endotypes, biomarkers, and therapeutic strategies.

Still's disease includes systemic juvenile idiopathic arthritis in children and adult-onset Still's disease in adults. Patients can develop prolonged fever, rash, arthritis, and multiorgan inflammation. Although IL-1 and IL-6 inhibitors can be highly effective, many patients do not achieve durable, steroid-free remission. Severe complications include macrophage activation syndrome and life-threatening lung disease associated with drug-associated immune reactions. These differences suggest that Still's disease includes biologically distinct inflammatory subsets rather than a single uniform process.

The TGGS was established in 2013 to investigate the genetic and molecular basis of Still's disease and related immune-dysregulatory disorders. In 2018, the section established a natural history protocol and dedicated Still's Disease Clinic at the NIH Clinical Center. The program supports longitudinal evaluation, family-based and cohort-scale genomics, serial biosampling, and recall of patients selected by genotype or molecular phenotype. These resources support progression from clinical observation to genomic discovery, functional investigation, molecular stratification, and therapeutic evaluation.

Current projects include:

• Defining the genetic architecture of Still's disease and its severe clinical subsets through family-based genomics and whole-genome sequencing.
• Determining how genetic variation alters innate immune signaling, cellular homeostasis, immune-cell trafficking, and inflammatory amplification.
• Identifying molecular endotypes associated with disease persistence, lung involvement, drug-associated immune reactions, and therapeutic response.
• Translating genetic and molecular findings into biomarkers, patient stratification, and mechanism-based treatments.
• Characterizing PLCG2-associated immune dysregulation through clinical, genomic, and functional studies.

Still's disease is both an important disorder and a rare-disease discovery system for inflammatory medicine. Detailed study of unusual patients can reveal mechanisms with strong biological signal; broader cohorts can determine how widely those mechanisms operate; and validated pathways can then be tested in more common inflammatory conditions. The TGGS seeks to improve the biological classification and treatment of Still's disease while identifying shared endotypes and therapeutic opportunities across immune-mediated disease.

Michael J. Ombrello, M.D., is a pediatric and adult rheumatologist, tenure-track investigator, and head of the Translational Genetics and Genomics Section (TGGS) in the NIAMS Intramural Research Program. His group integrates human genetics, functional immunology, and longitudinal investigation to explain differences in disease course and treatment response in children and adults with inflammatory disease. Still's disease serves as the central model for defining distinct endotypes and developing mechanism-based therapies. Still's disease provides a rare-disease model in which human genetics can reveal inflammatory mechanisms that can then be tested across more common immune-mediated conditions.

Dr. Ombrello earned his undergraduate and medical degrees from Saint Louis University. After combined training in internal medicine and pediatrics and in pediatric and adult rheumatology, he joined Dr. Daniel Kastner's group as an inaugural NIAMS Henry Metzger Scholar in Translational Medicine, subsequently completing additional postdoctoral training in the Inflammatory Disease Section of the National Human Genome Research Institute. He received the American College of Rheumatology Distinguished Fellow Award.

Dr. Ombrello has led genomic studies of Still's disease through the International Childhood Arthritis Genetics Consortium. His work established that systemic juvenile idiopathic arthritis has a genetic architecture distinct from other forms of childhood arthritis. His group identified genetic markers associated with response to IL-1-directed therapy and with severe drug-associated immune reactions to IL-1 and IL-6 inhibitors. The group also showed that rare variation in hemophagocytic lymphohistiocytosis-associated genes contributes to Still's disease without overt macrophage activation syndrome.

His group identified a type I interferon-high molecular endotype strongly associated with Still's disease-associated lung disease and drug-associated immune reactions. Recent work identified a new class of loss-of-function TNFRSF1A variants associated with Still's disease. Although these variants reduce conventional TNFR1 signaling and cell death, they paradoxically promote inflammation by disrupting receptor trafficking and cellular homeostasis. The mutant receptors accumulate in the Golgi apparatus and induce organelle stress via a mechanism distinct from that of TNFR1-associated periodic fever syndrome.

Dr. Ombrello was also a lead investigator in the first descriptions of human immune dysregulation caused by PLCG2 variants. His honors include the American Society for Clinical Investigation Young Physician Scientist Award, the NIH Fellows Award for Research Excellence, and NIAMS, NIAID, and NIH Director's awards. He is committed to mentoring scientists and physician-scientists; his trainees have advanced to careers in academia, research, industry, regulation, and clinical training.