Collaboration helped Klemperer lecturer build successful career in endometriosis research

Collaboration is the key to a long career filled with success and creativity, according to Peter Gregersen, MD, who delivered the Paul Klemperer, MD Memorial Lecture on Saturday. But don’t be surprised when collaboration leads in unexpected directions.

“I came to endometriosis by way of a collaborator,” said Dr. Gregersen, MD, Professor of Molecular Medicine at the Feinstein Institutes for Medical Research and the David and Barbara Zucker School of Medicine at Hofstra/Northwell. “You may not have thought much about endometriosis, but it could be tied to rheumatoid arthritis in various ways, including being a disease that could be sensitive to TNF blockade.”

Collaboration has long been the norm and the expectation in rheumatic disease research, Dr. Gregersen said during his lecture, 40 Years of Working in a Changing Research Landscape from RA to Endometriosis, which can be viewed by registered meeting participants through March 11, 2022.

Dr. Gregersen noted that the first histocompatibility workshop at Duke University in 1964 featured 23 investigators sharing data and insights on human leukocyte antigens, now called HLA, that had recently been discovered. Early work with antigens eventually led researchers into the genetics of autoimmune diseases and the North American Rheumatoid Arthritis Consortium (NARAC). NARAC tackled the genetics of RA with the help of more than 1,000 families with at least two siblings who had RA. By 2014, more than 100 loci associated with RA had been identified.

The overlap between genes and autoimmune diseases is complex. Crohn’s, celiac disease, juvenile idiopathic arthritis, multiple sclerosis, RA, lupus, spondyloarthropathies, type 1 diabetes, ulcerative colitis, and more share a bewildering array of genes, most active in multiple diseases. The Accelerating Medicines Partnership (AMP) hopes to help unravel parts of the puzzle using single-cell transcriptomics and mass cytometry to define different inflammatory cell states and associations in RA synovial tissues.

Endometriosis is at least as exciting and far less researched, Dr. Gregersen said. This chronic inflammatory disease has a poorly understood pathogenesis, a major genetic component, and is common yet commonly underdiagnosed with only a few unsatisfactory treatment options.

“This is a disease where a small advance can have a huge impact on treatment,” Dr. Gregersen said. “Endometriosis affects 5% to 10% of reproductive age women. Rheumatologists are seeing it even if they don’t know it.”

Retrograde menstruation is commonly accepted as the root of endometriosis, depositing multiple types of immune cells within the peritoneal cavity and forming lesions. Diagnosis currently requires laparoscopic surgery to inspect and biopsy lesions.

The culprit may be stromal cells altered by chronic endometrial inflammation in the uterus, Dr. Gregersen said. Inflamed stromal fibroblasts in endometriosis have high levels of TNF and/or IL-1β, similar to inflamed tissues in RA. Endometrial fragments found in menstrual effluent from patients with endometriosis have an overabundance of T cells and few NK cells.

“There are huge differences between people with endometriosis and normals,” Dr. Gregersen said. “And there is a lot of opportunity to address the chronic inflammation that is present in a lot of people with endometriosis to see if controlling inflammation reduces the progression and implantation of lesions. And I’m curious if people with both endometriosis and RA who take TNF inhibitors for their RA have seen any change in their endometriosis. Studies in primates suggest they could, but there are no studies in humans.”