“Antiphospholipid syndrome (APS) is a condition in which antibodies are not just markers of disease but also drive pathogenesis,” says Jason S. Knight, MD, PhD, Marvin and Betty Danto Research Professor of Connective Tissue Research and professor of internal medicine, Division of Rheumatology, University of Michigan Medical School, Ann Arbor. “As rheumatologists become aware of new treatments approved for antibody-mediated disorders that are typically treated outside our specialty, such as myasthenia gravis and immune thrombocytopenic purpura, they can consider whether some of these innovative approaches might eventually be repurposed for APS.”
Dr. Knight
Dr. Knight is the co-author of a review that is part of a series on immunology for rheumatologists published in Arthritis & Rheumatology (A&R).1 In this new installment, Dr. Knight and co-author Thalia G. Newman, BS, review APS and the emerging therapeutic opportunities of this antibody-mediated disease.2 Ms. Newman is a PhD candidate in immunology and studying for her MS in bioinformatics in Dr. Knight’s lab at the University of Michigan Medical School.
Insights for Rheumatologists
The review presents a clinical case of a patient with severe, relapsing APS. The authors provide an overview of the pathophysiology of this thrombo-inflammatory disorder, highlighting the role of anti-beta-2 glycoprotein I (anti-β2GPI) antibodies. They detail the significance of the β2GPI plasma protein in health and disease before discussing the formation of anti-β2GPI antibodies.
The review describes the proinflammatory signaling pathways downstream of anti-β2GPI antibodies and provides examples of anti-β2GPI antibody activation of pro-thrombotic cells. The authors cover other considerations in APS pathogenesis, discuss the direction of APS treatment and conclude with a follow-up of the clinical case.
Along with more than 50 references, the review includes two informative tables. One table details actively recruiting clinical trials of the following agents targeting B cells and/or plasma cells in patients with APS: zanubrutinib, telitacicept combined with rituximab, telitacicept alone, an anti-CD38 monoclonal antibody, anti-CD19 chimeric antigen receptor (CAR) T cells, anti-CD19 CAR-natural killer (NK) cells, belimumab and anti‑B cell maturation antigen (BCMA)/CD19 CAR T cells. The other table specifies the challenges and opportunities for the APS field.
Additionally, two figures and legends demonstrate antiphospholipid (aPL) antibody testing and the relevant clinical associations, as well as the mechanisms of prothrombotic cell activation by anti-β2GPI IgG antibodies.
Therapeutic Opportunities
Currently incurable, APS is “characterized by an increased risk of macrovascular thrombotic events in both venous and arterial beds, microvasculature injury, placental insufficiency, cardiac valve disease, thrombocytopenia and other morbid features,” the authors write.
Classification criteria include the clinical presentation and the stable presence of anti-β2GPI antibodies. The lupus anticoagulant test, also part of the criteria, yields positive results with high titers of certain antibodies, most notably anti-β2GPI antibodies and the anti-phosphatidylserine/prothrombin (anti-PS/PT) antibodies.
“Clinically available testing routinely informs the clinician about three anti-β2GPI isotypes: IgG, IgM and IgA. Of these, anti-β2GPI IgG is thought to be most relevant to [the] diagnosis and pathogenesis [of APS],” say the authors.
Meanwhile, the only treatment approach to reduce thrombosis in APS is systemic anticoagulation, usually with vitamin K antagonists, such as warfarin. However, up to one in five patients experience a macrovascular thrombotic event while on systemic anticoagulation. Additionally, anticoagulants fail to protect the microvasculature, causing organ deterioration in some patients.
“There is an unmet need for safe and effective therapies that can combat the inflammatory, anticoagulant-resistant manifestations of APS,” say the authors.
“Given the diverse and likely synergistic mechanisms downstream of APS autoantibodies, we will make the case that eliminating pathogenic autoantibodies is the only strategy likely to be fully effective in treating and eventually curing patients living with APS,” they add.
Patient Case Study
The case study follows a 37-year-old woman looking for guidance on how to manage her APS. Because she had a lower extremity deep vein thrombosis at age 19—linked to initiation of an oral contraceptive—and required six months of anticoagulation therapy, the patient has since avoided estrogen-containing medications.
At age 31, she saw a rheumatologist after developing inflammatory joint pain, particularly in her hands and wrists. Laboratory testing at that time revealed a mild elevation in the erythrocyte sedimentation rate (32 mm/hr), a positive anti-cardiolipin IgG antibody result of 92 IgG phospholipid (GPL) units and a positive lupus anticoagulant test result. Anti-β2GPI antibody testing did not take place and other lupus-
relevant laboratory tests came back negative. Although prescribed hydroxychloroquine, anticoagulation was not recommended, probably due to the thrombotic event 12 years prior. Several months later, testing for aPL antibody remained similarly positive.
At age 32, the patient presented with acute abdominal pain arising during recovery from an influenza-like illness. A computed tomography scan showed colonic ischemia requiring right colon resection, and colon pathology revealed minute organizing fibrin thrombi in superficial submucosal venules. The patient required temporary dialysis for acute kidney injury and a kidney biopsy indicated acute thrombotic microangiopathy. Persistent anti-cardiolipin IgG antibody and lupus anticoagulant positivity were confirmed with laboratory testing, which also showed positive anti-β2GPI IgG and IgA isotype antibodies. In‑patient treatment comprised unfractionated heparin, high-dose glucocorticoids and plasmapheresis.
At discharge, the patient received prescriptions for a prednisone taper and warfarin, while she continued taking hydroxychloroquine. After discharge, the patient’s creatinine stabilized to approximately 2.0 mg/dL.
At age 37, the patient reported shortness of breath and groundglass pulmonary infiltrates were found. Despite completing several courses of antibiotics over a few months, the dyspnea and infiltrates persisted. When hospitalized during an acute exacerbation of dyspnea, she presented with reduced hemoglobin and diffuse alveolar hemorrhage, confirmed as bronchoalveolar lavage. The patient’s breathing improved with glucocorticoids and plasmapheresis, and she received a prescription for a prednisone taper at discharge.
On referral to your clinic for further management, you added a rituximab course to her prednisone taper followed by a second round of rituximab after six months, while she continued taking warfarin and hydroxychloroquine. The patient experienced no further pulmonary hemorrhage flares, despite unchanged aPL antibody levels, but her kidney function deteriorated over the next two years. The patient is under consideration for a living-donor kidney transplant.
Key Takeaways
“IgG isotype antibodies recognizing the plasma protein beta-2 glycoprotein I are clearly pathogenic, activating a variety of effector cells to create the prothrombotic state inherent to APS,” Dr. Knight says.
“The microvascular manifestations of APS often progress despite treatment with anticoagulation, highlighting a subgroup of patients who are especially in need of new approaches to therapy.
“Rheumatologists (and patients) should feel optimistic that we are closer than we have ever been to trialing new therapeutic strategies that endeavor to impact APS closer to its antibody-mediated source,” Dr. Knight concludes.
Katie Robinson is a medical writer in New York.
Disclosures
Dr. Knight has received consulting fees from ArgenX, BioCryst, Jazz Pharma, Ouro Medicines, Roche, Roivant Sciences and Visterra/Otsuka, along with grant funding from Jazz Pharma and Visterra/Otsuka.
References
- Bucala R, Solomon DH. Immunology for the rheumatologist: Arthritis & Rheumatology introduces a new problem-based immunology review series with great educational potential. Arthritis Rheumatol. 2024 Jan;76(1):9–10.
- Newman TG, Knight JS. Antiphospholipid syndrome: An antibody-mediated disease with emerging therapeutic opportunities. Arthritis Rheumatol. 2025 May 19. Epub ahead of print.
