Ami Shah, director, clinical and translational research, Johns Hopkins Scleroderma Center
Johns Hopkins researchers are making progress in their quest to understand why many patients get scleroderma and cancer concurrently. At the heart of their most recent findings, published earlier this year, are certain autoantibodies associated with cancer incidence, and others that protect against it.
“About 20% of patients in our scleroderma cohort have antibodies against RNA polymerase III,” says Ami Shah, associate professor of medicine at The Johns Hopkins University and first author of the paper published in Arthritis & Rheumatology. “They are 2.8 times more likely to get cancer than the general population. But we found that those who also have antibodies against RNA polymerase I are somewhat protected from that risk.”
As an autoimmune disease, scleroderma’s connection to cancer isn’t immediately obvious — except to scleroderma experts who see some of their patients develop cancer concurrently. The root causes of scleroderma are unknown, but work done by the Johns Hopkins team suggests an interesting hypothesis: Cancer triggers the autoimmune response, at least in a subset of patients.
In prior studies, these researchers found that 15% of scleroderma patients with autoantibodies against RNA polymerase III (RNA Pol III) have a concurrent cancer, and those cancers often manifest mutations in the POLR3Agene. The data suggests that mutation of the gene triggers an immune response against the abnormal protein produced. This immune response subsequently broadens to include normal versions of the protein, and this may lead to the excessive fibrosis typical of scleroderma.
But 85% of patients with anti-RNA Pol III antibodies do not have cancer. What makes them different?
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Searching for an answer, the Johns Hopkins Scleroderma Center followed a group of 168 patients with anti-RNA Pol III antibodies for five years, comparing those with and without detectable cancer. The research team found that 18.2% of those without cancer had autoantibodies against a large subunit of RNA polymerase I (anti-RPA194), compared to only 3.8% of those with cancer.
The rheumatology investigators collaborated with Marikki Laiho, a professor of radiation oncology and molecular radiation sciences at Johns Hopkins who has performed much work on RNA polymerase I (RNA Pol I) inhibitors as anticancer agents. RNA Pol I transcribes most ribosomal RNA, accounting for more than half of all RNA that cells produce. If the anti-RPA194 antibodies, which are extracellular, are able to access the RNA Pol I protein — which resides in the nucleus — and inhibit it, they could be potent anti-cancer agents. This question is being studied in the laboratory of Antony Rosen, vice dean for research and director of the Division of Rheumatology, and Livia Casciola-Rosen, professor of medicine in the Division of Rheumatology.
The team’s working hypothesis is that subclinical malignancies may trigger an anti-tumor immune response. Those patients who mount multiple orthogonal responses (creating antibodies against both RNA Pol I and RNA Pol III) may be more likely to eradicate the cancer. A byproduct of the anti-tumor immune response may be scleroderma.
“Clinically, our research raises several important questions,” says Shah. “If anti-RPA194 antibodies are protective against cancer, can they be harnessed as therapy? Can autoantibodies be used for cancer risk stratification for newly diagnosed scleroderma patients? If so, what cancer screening should be recommended for those at high risk? And, perhaps most importantly, if cancer is the trigger for these patients’ scleroderma, will treating it also treat the scleroderma? We have a lot more work ahead of us.”
The Johns Hopkins Scleroderma Center followed a group of 168 patients with anti-RNA Pol III antibodies for five years, comparing those with and without detectable cancer. The research team found that 18.2% of those without cancer had autoantibodies against a large subunit of RNA polymerase I (anti-RPA194), compared to only 3.8% of those with cancer.
Learn more at hopkinsscleroderma.org.