Raphaela T. Goldbach-Mansky, M.D., M.H.S.

Autoinflammatory diseases are a group of rare immune dysregulatory syndromes that present with unexplained fevers, rashes, joint pain, and inflammation in multiple organs, such as the central nervous system, the eyes, inner ears, bones, fat, blood vessels, lungs, and muscles. Many of the disease symptoms present very early in life, and patients do not have infections or malignacies. The discovery of single gene mutations, which modify the regulation of inflammatory pathways that are triggered by exogenous and endogenous "danger" molecules, has provided new concepts to understand this disease group. It also continues to provide us with new targets for intervention.

Dr. Goldbach-Mansky's translational autoinflammatory research program focuses on clinical and translational studies in children with early-onset autoinflammatory diseases. Her research team conducts studies in patients with IL-1-mediated autoinflammatory diseases—including neonatal onset multisystem inflammatory disease (NOMID) and deficiency of the IL-1 receptor antagonist (DIRA)—and in patients with IFN-mediated autoinflammatory diseases—including chronic atypical neutophilic dermatosis with lipodystrophy and elevated temperatures (CANDLE), STING- associated vasculopathy with onset in infancy (SAVI), and other autoinflammatory interferonopathies.

The research team also evaluates and studies patients with as yet undifferentiated autoinflammatory diseases who are difficult to treat. Their conditions are often uncharacterized but may be clinically similar to known autoinflammatory diseases.

The team applies a diagnostic approach that includes careful clinical evaluation, as well as genetics and immune evaluations, to characterize the immune dysregulation with the ultimate goal of finding better treatments for these patients. Clues from the pathogenic and genetic studies in patients with NOMID pointed to dysregulation in an innate immune pathway that regulates the release of the proinflammatory cytokine IL-1, and our clinical studies have led to the FDA's approval of the IL-1-blocking agent anakinra in the treatment of this condition in December 2012. Other molecular defects identified in our patients have become the target for new drug development, and these rare diseases have become models to understand the pathogenesis of more common inflammatory diseases.

Our program is part of the NIAID Clinical Genomics Program. Our goal is to use genetics as a diagnostic test for all patients seen to diagnose known diseases and to identify novel genetic variants that result or modify inflammatory disease phenotypes.

Our efforts to integrate insights gained from the disease pathogenesis with finding novel treatments. The NIH Clinical Center is uniquely suited to accommodate patients with rare autoinflammatory diseases by providing in- and outpatient care facilities, laboratory support, and first-class imaging modalities. TADS has established collaborations with specialists in other NIH institutes including the National Eye Institute, National Institute on Deafness and Other Communication Disorders, the dermatology branch at the National Cancer Institute, the National Human Genome Research Institute, and the radiology and physical therapy department at the Clinical Center. NIH facilities including the Trans-NIH Center for Human Immunology provide access to high-throughput technologies to study autoinflammatory disease pathways, all of which are necessary clinical and research tools to evaluate patients with complex autoinflammatory diseases.

Diseases We Study

Autoinflammatory diseases are conditions of excessive, uncontrolled inflammation. They are caused by over-activation of innate immune responses or a defect in stopping them. The dysregulated immune responses are triggered by a pathogen and/or danger signals that are released by damaged, dying, or stressed cells. The recognition of these triggers by innate immune sensors is coupled with the production of proinflammatory mediators. Uncontrolled inflammation can lead to life-threatening, systemic, sepsis-like conditions. If untreated inflammation becomes chronic, permanent organ damage can develop.

IL-1-mediated autoinflammatory diseases we study

Neonatal-Onset Multisystem Inflammatory Disease (NOMID)

NOMID presents at or around birth and is characterized by severe inflammation of the skin, the central nervous system (CNS), the inner ear, and the optic nerve. Sometimes bones are involved as well. NOMID is caused by mutations in NLRP3, an intracellular “danger” of pathogen recognition receptor (PRR). NOMID is at the most severe end clinically of a group of cryopyrin-associated periodic syndromes (CAPS) that also includes familial cold autoinflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS). If untreated or poorly treated, the ongoing inflammation in NOMID can lead to cognitive impairment and hearing and vision loss. Treatments blocking IL-1 are FDA approved for these conditions and can prevent the progression of organ damage. IL-1 blockade has become the standard of therapy.

Deficiency of the IL-1 Receptor Antagonist (DIRA)

DIRA presents with inflammation in skin and bones and, rarely, with CNS vasculitis. DIRA is caused by autosomal recessive mutations that lead to a loss of function of the IL1RN gene. The mutated gene in DIRA patients encodes a defective protein that can no longer block IL-1 signaling. Clinical studies assessing the long-term outcome of various IL-1-inhibiting medications and long-term outcomes are ongoing.

NLRC4-Mediated Macrophage Activation Syndrome (NLRC4-MAS)

We found that gain-of-function mutations in NLRC4—another inflammasome component—lead to a periodic fever syndrome, a condition with high levels of IL-1β and IL-18. High IL-18 levels indicate a predisposition to MAS.

Interferon (IFN)-mediated autoinflammatory diseases we study

In our ongoing efforts to understand the pathogenesis in patients who are resistant to IL-1-blocking treatments, we identified two monogenic diseases with strong interferon response signatures, CANDLE and SAVI.

Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated Temperatures (CANDLE)

We were part of an international collaboration that found that autosomal recessive loss-of-function mutations in proteasome components, including PSMB8 (6), cause CANDLE. In contrast to patients with IL-1-mediated diseases, CANDLE patients develop lipodystrophy, muscle inflammation, basal ganglion calcifications, and metabolic changes that are not seen in patients with IL-1-mediated diseases. The high interferon response gene expression in the blood of CANDLE patients suggests dysregulation of another innate immune mediator, Type I IFN.

STING-Associated Vasculopathy With Onset in Infancy (SAVI)

Our group recently found that gain-of-function mutations in TMEM173/STING cause SAVI, a disease that presents with vasculitis and vascular damage affecting fingers, toes, ears, and nose and with interstitial lung disease. The genetic mutations in SAVI, in TMEM173 that encodes an important adaptor protein called stimulator of IFN genes (STING), validate the notion that increased production of Type I IFN can cause an autoinflammatory phenotype through gain-of-function mutations in a potent regulator of IFNβ transcription.

Undifferentiated autoinflammatory diseases

Although we have come a long way, there are still many autoinflammatory conditions that we cannot diagnose and treat well. We find that some of these conditions seem to be caused by dysregulation in the cytokine pathways, including IL-1, IL-18, and IFN, although other inflammatory pathways can be activated. Understanding dysregulated innate immune pathways is crucial in finding new treatments. To evaluate patients with as yet poorly characterized autoinflammatory diseases, we use novel tools that include whole exome/genome sequencing, gene expression, cytokine and cell subset studies to find dysregulated inflammatory pathways that may become targets for novel treatment approaches.

Dr. Raphaela Goldbach-Mansky received her medical degree from the University Witten-Herdecke, Germany, in 1990 and completed a combined residency in internal medicine and pediatrics at Case Western Reserve University, Metro Health Medical Center. She completed her rheumatology fellowship training at NIAMS in 1999 and served as a staff clinician at NIAMS through 2008. Dr. Goldbach-Mansky is chief of the NIAID Translational Autoinflammatory Disease Studies (TADS) Unit. She leads the NIAID autoinflammatory disease clinic and has built a translational research program focusing on clinical and translational studies in children with early-onset autoinflammatory diseases. Together with Dr. Daniel Kastner (NHGRI) she founded the Translational Autoinflammatory Research Initiative (TARI) at NIH to improve research in patients with rare autoinflammatory diseases.

Dr. Goldbach-Mansky's research focus is on applying a systematic approach to the clinical and immunological study of autoinflammatory diseases. Her group uses targeted interventions to understand the role of specific inflammatory pathways in the pathogenesis of autoinflammatory diseases.