November 10-15

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ACR Convergence 2023

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Home // Lung inflammation could be the genetic disorder COPA syndrome, not rheumatic disease

Lung inflammation could be the genetic disorder COPA syndrome, not rheumatic disease


3 minutes

Paul W. Noble, MD
Paul W. Noble, MD

COPA syndrome is virtually indistinguishable from a variety of rheumatic diseases on initial examination. The first obvious symptom in many patients is lung inflammation that can be seen as juvenile or rheumatoid arthritis with interstitial lung disease, lupus, ANCA-associated vasculitis, or other common rheumatic diseases. In reality, COPA syndrome is an autosomal dominant genetic disease that was first identified in 2015.

“COPA has broadened our understanding of lung diseases,” said Paul W. Noble, MD, professor and chair of medicine, director of the Women’s Guild Lung Institute, and physician-in-chief at Cedars-Sinai Medical Center in Los Angeles. “It is more common in children than in adults, but we see it from neonates all the way to adults. And it can look like any number of autoimmune fibrosing lung diseases.”

Dr. Noble discussed different presentations of COPA syndrome compared to more familiar rheumatologic lung diseases during the special symposium What Every Rheumatologist Should Know About COPA Syndrome: A New Genetic Mimic of Rheumatic Disease on Sunday, Nov. 8. The session is available for replay to registered ACR Convergence attendees through March 11.

COPA syndrome is a dysfunction of lung epithelial cells producing surfactant, he said. The problem is that COPA imaging reflects the pathophysiology of the disease, which mimics many rheumatic and non-rheumatic fibrosing lung disorders.

R. Paul Guillerman, MD
R. Paul Guillerman, MD

CXR is too nonspecific to be helpful, but early stage CT imaging can show ground-glass opacities and recurrent pulmonary hemorrhage that progress to nodules and cysts with septal thickening, said R. Paul Guillerman, MD, professor of radiology at Baylor College of Medicine. A growing number of cysts and fibrosis may eventually require lung transplantation.

Typically, COPA onset comes before adolescence, often during the preschool years, Dr. Guillerman added, but the syndrome may not be recognized until the adult years, if ever. Most COPA patients have damage to multiple joints, often diagnosed as arthritis, in addition to pulmonary involvement.

A few patients also have renal involvement that can progress to end-stage kidney disease. Affected kidneys can be enlarged, normal-sized, or smaller than usual and are often hyperechoic.

“If you see a child with diffuse lung disease with evidence of pulmonary hemorrhage or lymphoid hyperplasia, especially if they present young, pre- or early school years, consider genetic testing for COPA,” Dr. Guillerman said.

Tony Shum, MD
Tony Shum, MD

In normal cells, COPA mediates transport from Golgi bodies to the endoplasmic reticulum (ER), said Tony Shum, MD, Associate Professor of Medicine, University of California, San Francisco, who first described COPA syndrome in 2015. Mutant COPA is unable to bind properly, resulting in a transport defect from the Golgi to the ER.

“COPA is ubiquitously expressed and is highly important for cell homeostasis,” Dr. Shum said.

STING-associated vasculopathy with onset in infancy (SAVI) is similar to COPA syndrome. Where COPA is the result of a transport defect from the Golgi to the ER, SAVI is the result of a transport defect from the ER to the Golgi.

Lung fibroblasts from COPA syndrome patients demonstrate STING (stimulator of interferon genes activation), Dr. Shum said. A mouse model developing lung disease that mirrors human COPA syndrome also shows STING pathway activation. Inhibiting STING blunts pathogenic interferon signaling in the mouse model and in COPA syndrome peripheral blood mononuclear cells.

“COPA is an interferonopathy resulting from STING disruption,” Dr. Shum said. “Until STING inhibitors are in use, JAK inhibitors have become standard of care, but we don’t know if they are more beneficial in early disease or in late disease. And we’ve had a lot of success with mycophenolate in preventing hemorrhage.”