Experts in Complement-Mediated Diseases, APS, and Cutaneous Autoimmune Conditions Will Share Insights on Immune Mechanisms of Pathogenesis

An aberrant immune response, unable to differentiate self from foreign appropriately and efficiently, is a fundamental abnormality in autoimmune conditions. Studying signaling and metabolic pathways that modulate immune responses can help uncover novel approaches to autoimmune disease classification and treatment.

In the session Immunology for the Rheumatologist: Case-Based Illustrations of Key Pathways, to be held on Sunday, Nov. 17, from 10–11:30 a.m. ET in Room 147AB of the Walter E. Washington Convention Center, thought leaders will discuss how immunologic principles can help clarify diagnosis and treatment in rheumatology practice. The session will be available on demand within 48 hours for registered ACR Convergence 2024 participants.

Christoph Licht, MD, Head of the Division of Nephrology at The Hospital for Sick Children and Professor of Pediatrics at the University of Toronto, Canada, will share insights on complement-mediated diseases (CMDs).

“The complement pathway is an integral component of the innate immune system that is old, from a developmental perspective, and robust,” Dr. Licht said. “Over the past century, we have learned how defects and dysregulation of complement signaling are linked to specific diseases. The principles and insights uncovered through research focused on CMDs have now become more broadly applicable, with the understanding that the complement pathway is a modifiable biological system involved in multiple conditions relevant to not only nephrologists but also to rheumatologists.”

Dr. Licht will touch on several conditions to illustrate the role of the complement pathway.

“Complement blockers have now been developed for treating certain hematologic conditions, such as paroxysmal nocturnal hemoglobinuria (PNH), which is associated with overactive complement-driven hemolytic anemia, and atypical hemolytic uremic syndrome (aHUS), characterized by blood clots in organ microvasculature, primarily in the kidneys,” he said.

Dr. Licht is investigating complement blockers in complement C3 glomerulopathy (C3G), an inflammatory condition affecting kidney filters. Two complement pathway-targeted drugs are currently in phase 3 C3G clinical trials, with encouraging efficacy signals, according to Dr. Licht.

“The fourth therapeutic approach that leverages the complement pathway is in a systemic endothelial disease called antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, in which activated neutrophils attack the inner layer of blood vessels, the endothelium,” Dr. Licht explained. “While the role of autoantibodies in activating neutrophils in ANCA-associated vasculitis is well-established, until recently the role of the complement pathway in exacerbating ANCA-associated vasculitis was not appreciated. In ANCA-associated vasculitis, complement-targeted therapy would act as an adjunct treatment, to dampen complement system-mediated neutrophil recruitment and over-activation.”

Understanding the biology of the complement system has helped researchers develop targeted inhibitors that can be applied to restore homeostasis in conditions driven or exacerbated by specific dysfunction or deficits in this system, he noted.

“We have to take a learning step together and appreciate that when a patient is diagnosed, they are passing dynamically through stages of disease where the complement system may be relevant to different degrees at different disease stages along the clinical course,” Dr. Licht said.

Jason S. Knight, MD, PhD, the Marvin and Betty Danto Research Professor of Connective Tissue Research and Professor of Internal Medicine at the University of Michigan Medical School, will focus on the pathogenesis of antiphospholipid syndrome (APS).

“APS is an autoimmune disorder associated with an increased risk of blood clots and pregnancy loss,” Dr. Knight explained. “It is treated by both rheumatologists and hematologists, along with other subspecialists, depending on the patient’s needs.”

The mainstay of APS clinical management is anticoagulant medications. However, Dr. Knight noted that this approach addresses a symptom or manifestation rather than the root cause of the disease.

“While anticoagulants do typically improve patient outcomes by reducing the risk of clotting recurrence, there is a subgroup of patients where this symptom-oriented approach to treatment is insufficient,” he said.

The new 2023 joint ACR/EULAR research criteria for APS are bringing more attention to some underappreciated features of APS that often involve the microvasculature, for example, alveolar hemorrhage or APS nephropathy, Dr. Knight noted. Another example is small vessel occlusions in the skin, especially of the legs, which can lead to ulcers.

There is a significant unmet need for mechanism-informed treatments in patients with APS with these microvascular manifestations, he said. He also acknowledged that even patients who are doing relatively well on anticoagulants would typically prefer treatments that do not increase their risk of bleeding.

“I want to remind everyone of the autoantibody-mediated nature of APS and really encourage them to consider it akin to other autoantibody-mediated conditions that are not always grouped with rheumatologic diseases — for instance, immune thrombocytopenia, in which autoantibodies cause platelet destruction, or myasthenia gravis, in which antibodies form against nicotinic acetylcholine postsynaptic receptors at neuromuscular junctions, resulting in muscle weakness and fatigue,” Dr. Knight said. “At least some therapies that work for those conditions may also work for APS.”

Many new treatments for autoimmune diseases, like chimeric antigen receptor T-cell (CAR-T) therapy, are being developed as a potential way to reset the immune system.

“One wonders if such approaches could eventually cure disorders like APS,” Dr. Knight said. “In fact, I think APS should be near the top of the list of rheumatologic conditions where novel autoantibody-targeting therapies, including CAR-T therapy, should be explored.”

Victoria P. Werth, MD, Chief of Dermatology at the Philadelphia VA Hospital and Professor of Dermatology at the University of Pennsylvania/Penn Medicine, will discuss the interferon pathway in rheumatic skin disease.