Klemperer Lecture to Explore Rare Autoinflammatory Syndromes and Novel Treatment Strategies

Children with rare autoinflammatory conditions can be signposts for novel treatment pathways that benefit common diseases.

“Comprehensive genetic and immunologic evaluations of children with rare, systemic inflammatory diseases uncover defects in key innate immune pathways. These defects increase triggers and sensitize innate immune sensors, and have provided insights into pathomechanisms of sterile inflammation and clues to targeted treatment of sterile inflammation,” said Raphaela Goldbach-Mansky, MD, MHS, Chief of the Translational Autoinflammatory Diseases Section (TADS) at the National Institutes of Allergy and Infectious Diseases (NIAID). “Similar mechanisms also drive and amplify systemic inflammation in common diseases, such as COVID-19, other infections, even in arthritis. Sterile inflammation can aggravate common metabolic, neurodegenerative, and infectious diseases.”

During the Klemperer Memorial Lecture, When Misspellings Provide New Insights: Learning from Children with Rare Autoinflammatory Diseases, on Sunday, Nov. 17, Dr. Goldbach-Mansky will illustrate how pediatric discoveries have helped to link innate immune pathway dysregulation to systemic inflammation and progressive organ damage. The lecture will take place from 10:30–11:30 a.m. ET in Ballroom B of the Walter E. Washington Convention Center and be available on demand within 48 hours for registered ACR Convergence 2024 participants.

In the past 20 years, work on genetic diseases that present early in life has led to the identification of distinct inflammatory pathways and more than 90 monogenic diseases, many of which can be treated with targeted therapies, Dr. Goldbach-Mansky said. These insights have influenced treatment of COVID-19 and other common diseases.

Genetic analysis continues to unravel the mechanistic effects of immune cell mutations. Knowing disease-causing genes has significantly improved early diagnosis, and reconstructing activation pathways has identified novel treatment targets, some of which are being tested in clinical trials.

“Using a genetic approach that includes sequencing the patient and their parents has allowed us to identify genes that had not been associated with sterile inflammation and young children who may present with organ manifestations of sterile inflammation, such as aseptic meningitis, sterile lung inflammation, sterile joint disease, sterile muscle inflammation, often shortly after birth,” Dr. Goldbach-Mansky said. “Children are able to receive effective treatments early that prevent organ damage and give them a chance of survival and good quality of life.”

“Innate immune sensors not only spur immune responses in inflammatory and in hematopoietic blood cells, but may also be expressed in tissue cells, where they can alter cell fate. Further, in cells such as endothelial cells, disease-causing mutations can cause the production of inflammatory cytokines, cell de-differentiation, senescence, and/or cell death that lead to organ inflammation and damage, such as atrophy, fibrosis, tissue degeneration, and decreased tissue repair and growth, she explained.

Investigation of rare monogenic diseases has also led to the development of new biomarkers and treatment targets that spur drug development, Dr. Goldbach-Mansky added. These same biomarkers and treatment targets can inspire novel treatment approaches to more common diseases. Current trials of NLRP3 inhibitors to treat osteoarthritis (OA) and catastrophic antiphospholipid syndrome (CAPS) and drugs targeting the cGAS/STING nucleic acid-sensing pathway emerged from pediatric monogenic disease investigations and promise to improve treatment beyond rare autoinflammatory diseases, including some neuroinflammatory or other interferon-amplified diseases that occur in adults.

“I hope the lecture will help people recognize autoinflammatory symptoms and know more about treatment options for autoinflammatory features,” Dr. Goldbach-Mansky said. “Treating these pathways can reduce collateral organ damage.”