The treatment of the serious, potentially fatal autoimmune clotting disorder antiphospholipid syndrome (APS) has, in general, been empiric and based on various approaches to inhibit the clotting system. Despite many clinical studies and progress in patient outcomes, the field has nevertheless lacked a solid foundation upon which to base decision making and the development of novel approaches. The reason? The fundamental mechanisms of disease remain unknown and efforts to mount basic and clinical research programs have been limited by organizational issues, insufficient funding, and lack of quantitative standards for antibody detection.
These problems have long been known, but only recently have they been aggressively addressed. In April 2010, the 13th International Congress on Antiphospholipid Antibodies (aPL) was held in Galveston, Texas, and emerging from this meeting was the newly formed APS Clinical Research Task Force (CRTF). Before and after the International Congress, the CRTF brainstormed, using published reports and the practical experience of task-force thought leaders, to gain insight into the challenges facing APS researchers. Following this activity, the CRTF held a summit in November 2010 to discuss their findings, which were shortly thereafter presented at the 2010 ACR Annual Scientific Meeting in Atlanta. The final CRTF report was subsequently published in the journal Lupus.1
In brief, as identified by the CRTF, the major impediments to the research, the development of novel agents, and the practice of evidence-based medicine in the setting of APS are these:
- aPL detection methods are not standardized;
- APS research cohorts are poorly controlled for baseline characteristics;
- Risk stratification by patient profiles are rarely incorporated in research protocols;
- Published studies are often retrospective, and not population based; and
- A lack of basic information about the mechanisms of aPL-mediated clinical events limits optimal study design.
Knowing What We Don’t Know
“This is the first effort to publish an official document about the limitations of APS research,” says CRTF co-chair, Doruk Erkan, MD, MPH, associate physician-scientist at the Barbara Volcker Center for Women and Rheumatic Diseases at Hospital for Special Surgery and assistant professor of Medicine at Weill Cornell Medical College, both in New York City. For a number of reasons, this is no small achievement. “Studying the disease is very difficult because, for the autoimmune disorders of lupus or rheumatoid arthritis (RA), you are following flares; here you are following thrombotic events, which are relatively rare.” More rare still are events among patients with primary APS—those who have a sustained aPL elevation without comorbid lupus or RA. “To effectively power a trial in this setting you would need thousands of patients,” Dr. Erkan notes.