There is a clear need for more, and more effective, tests for antiphospholipid syndrome (APS). The current battery of lupus anticoagulant (LA), anti-cardiolipin antibody (aCL), and anti-β2-glycoprotein-I (aβ2GPI) is far from ideal.
“While these tests are widely available and clinically useful in the majority of cases, they are not enough,” said Laura Bertolaccini, PhD, senior research associate in vascular risk and surgery, King’s College School of Cardiovascular Medicine, London. “These tests do not recognize all APL antibodies.”
Dr. Bertolaccini opened Management and Future Directions for APS with a discussion of potential new tests to better identify APS. The session is available on demand to registered ACR Convergence 2020 attendees until March 11.
Between 1% and 2% of patients with clinical manifestations of APS are negative on the standard tests, Dr. Bertolaccini said. Efforts to develop tests that better identify more patients focus on different types of aβ2GPI and a combination of antiphosphatidylserine/prothrombin (aPS/PT) antibodies.
The ratio of aβ2GPI that recognizes domain I to species that recognize domains IV and V may identify pathogenic aβ2GPI, Dr. Bertolaccini said. The evidence that aPS/PT can improve both diagnosis and risk assessment in APS is stronger
“The jury is still out,” she said.
Clinicians should continue to follow current treatment recommendations for APS. It is tempting to abandon warfarin for the convenience of rivaroxaban or other direct oral anticoagulants (DOACs), but DOACs carry a high risk of recurrent thrombotic events in patients who are triple positive.
“I avoid DOACs in triple positive patients with VTE or ATE,” said Thomas L. Ortel, MD, PhD, professor of medicine and of pathology and chief of hematology, Duke University School of Medicine. “We have good evidence demonstrating a high risk of recurrent thrombotic events in triple positive patients on DOACs.”
There are no good data on warfarin versus DOACs in patients who are not triple positive, he added. DOACs are an option for these patients, but warfarin remains the preferred agent for most patients.
Those recommendations could change in the future. The entire approach to APS could, and should change, said Jason S. Knight, MD, PhD, associate professor of medicine, University of Michigan Medical School.
“We need to do a better job of getting out in front of APS,” Dr. Knight said. “Clinicians know that the current criteria are too restrictive. We don’t even classify APS until something pretty bad has already happened—thrombosis or pregnancy loss. We need to treat APS proactively rather than reactively.”
One approach is to treat APS at its source through immunomodulation.
On the innate immunity side, neutrophil extracellular traps (NETS) lead to thrombosis, a pathway that can be modified. A low-dose colchicine trial showed clear separation in mortality and other cardiovascular events starting at one year and continuing to the end of the trial.
“Colchicine seems to turn down the inflammasome,” Dr. Knight said. “This is something we might think about.”
Dipyridamole, an adenosine uptake inhibitor, may also modify innate immunity.
The drug forces neutrophil signaling toward non-inflammatory pathway and suppresses NETosis and other potentially pathogenic neutrophil activity. It is currently in trial to prevent exacerbation of respiratory status in COVID-19, but has not been studied in APS.
On the adaptive immunity side, any number of agents can modify B cell activity.
“Most of us have tried rituximab in APS,” Dr. Knight noted. “We can also target CD38 by repurposing drugs from myeloma to deplete plasmablasts.”
Other potential immunomodulators include hydroxychloroquine, belimumab, anti-interferon agents, and a variety of supplements.