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.
APS is associated with venous and arterial thromboembolism, recurrent pregnancy loss, valvular heart lesions, and thrombocytopenia. It is most often described as a comorbidity of lupus, with aPL detectable titers seen in up to 40% of lupus patients (aPL is a blanket term for lupus anticoagulant [LA], anticardiolipin antibodies [aCL], and anti-ß-glycoprotein-1 antibodies). Of note, while APS patients with lupus are usually women, the female predominance is less distinct in APS patients without other systemic autoimmune diseases (primary APS).
Importantly, the presence of an aPL does not necessarily correlate with clinical disease manifestations. “In the general population, thrombosis is multifactorial,” explains Dr. Erkan, “and we know it’s also true in APS. As many as half of these patients will have a trigger, another thrombosis risk factor at the time of their event—for example, use of birth control pills, a serious infection, or a recent surgical procedure.” Therefore, APS does not necessarily cause the clot, but it may make an individual more sensitive to clotting influences. This explains why the asymptomatic APS patient is at prothrombotic risk.
Given the variable relationship between serology and clinical manifestations, healthcare providers may be uncertain about how best to treat patients to prevent thrombotic events. “I asked this question in a survey of [congress] attendees—What are the three most important things you want know in APS?—and, overwhelmingly, everyone was interested in risk stratification.” In short, how do I know when to treat? For instance, there are APS patients with low aCL titer, says Dr. Erkan, “but we don’t think that’s clinically important. But then there are patients with very high titers in addition to positive LA test, yet the assumed increase in relative risk is not well defined.” Treating a clot is straightforward; managing risk is not.
Getting to Know You
The ideal of the CRTF in investigation is to first get everyone on the same page—a particular challenge when providers may work in different specialties. For lupus patients, APS is frequently identified by the rheumatologist, but it is the obstetrician who is following the women with an unexplained history of miscarriages; the neurologist is treating strokes; the hematologist, deep venous thrombosis; the cardiologist puzzles over valve damage in an otherwise healthy young man, and so forth. Often, APS is evidenced by an elevated activated partial thromboplastin time (aPT T) test prior to surgery. However, aPT T is not specifically informative, and the surgeon may never consider APS as a cause. “Even if you tell them that the patient has APS,” says Dr. Erkan, “they may not be aware of the risk of thrombosis associated with the disease.” This situation goes to the CRTF’s overall challenge of increasing awareness: “This is a commonly taught disease in medical school, but just a few weeks ago I got an email from a patient whose husband has been suffering multiple clots, and she’s the one who had to suggest to the physician to test for APS.”
Michael Lockshin, MD, director of the Barbara Volcker Center for Women and Rheumatic Disease at Hospital for Special Surgery in New York and CRTF co-chair, speaks to the flipside of awareness, which might be called unlearning. “A big part of the challenge is going to be getting all of the world speaking the same language, meaning that, for APS treatment there’s a British approach, an Italian approach, a German approach…” and while some of these geocentric paradigms are in agreement, others conflict, and none are sufficiently based on hard clinical data. “Erkan’s paper on aspirin and primary thrombosis prevention is one of the very few that was a really solid clinical trial. The field is full of case reports of ‘here’s my experience’ type data, yet only a handful of people who have systematically looked at the results. But if we don’t do it now, then when?”
A Call to ACTION
The concerns of Drs. Erkan and Lockshin betray a sense of urgency, and this is borne out by the post-CRTF phase in APS advocacy: the newly formed APS Alliance for Clinical Trials and International Networking (ACTION). The primary mission of APS ACTION is to facilitate high-quality, multicenter, multidisciplinary clinical research, which will be partially based on, and thereafter contribute to, an international APS registry. “The whole point is to have uniform definitions, joint recruitment, and standard treatment protocols so we can move forward,” says Dr. Lockshin. Specific tasks in moving toward this goal will be determined by APS ACTION subcommittees. Foci for these include clinical trial design; database creation, biospecimen sample collection, and funding initiatives, among others. APS ACTION currently includes 27 physicians from 19 international centers, and the goal is to increase the number of centers when the infrastructure is finalized. Drs. Erkan and Lockshin are two of the eight international members of the APS ACTION Executive Committee, which is chaired by Dr. Erkan.
The clinical trial subcommittee operates under the FINER criteria (Feasible, Interesting, Novel, Ethical, Relevant). Adhering to the Relevant, Novel, and Interesting should be easy enough, but Feasible? Yes, insists Dr. Lockshin, if you cast a wide enough net. “Any particular clinic probably can muster a couple hundred patients, of whom up to 50% would be eligible to enter a trial. But for statistical power you need to have a few times that number, so if we combine our clinical efforts we will be able to do these investigations.”
And Ethical? Can you not treat a control group that may have a known thrombotic risk? Standard treatment for those who have already had a thrombotic event is warfarin, used long term, or perhaps throughout life. APS in pregnancy is routinely treated with heparin, and for those with only aPL detected—it depends who you ask. “One of the things we’re seeing is that people don’t necessarily need to receive a medication if they have antibody only. I believe that ethically considered control groups are entirely possible.” says Dr. Lockshin.
For any trial, what Dr. Lockshin most wants to see is progress towards moving upstream: elucidation of the Novel. He wants to see the mechanistic studies that will point the way toward disease prevention. “What we’re doing right now is at the very end of the stream, anticoagulating. It’s preventing damage, but if we could get in much before that, before there’s any clotting occurring at all…” That’s the ACTION to take.
In a field that has few if any corporate sponsors (there are no anti-APS agents in any pipeline) funding is key, and in regards to APS ACTION, funding is personal, which helps answer the question: Why now? “A benefactor came along,” says Munther Khamashta, MD, PhD, director of the lupus research unit at King’s College London School of Medicine at St. Thomas’ Hospital in London, and APS ACTION Executive Committee Member. “For the last ten years we’ve been talking about international collaboration but we never had the clear opportunity to do it until this benefactor appeared—this person who had a family member who suffers from this disease—and what she wanted to know was this: Why don’t international experts talk to each other?” APS ACTION was the answer, and was supported by this funding.
Dr. Khamashta, based in the U.K. and having been in the APS field since its inception, can appreciate the obstacles to this international endeavor. Foremost among these is assay standardization. “This is a huge hurdle,” he says, going on to bluntly explain the reason: the inventor of the aPL test failed to get a patent. “Huge mistake. So, because it’s not a patented test, anyone can copy the recipe. This is why we have 50 different kits available in the market today without any kind of standards control.” Therefore, the first job of this international initiative, Dr. Khamashta says, has to be a standardization of the test. “Think about it, what is positive for me in the U.K. could be negative in New York, and borderline in Sydney.” That’s no way to treat, let alone do clinical research.
Also high on the soon-to-do list is to establish a decision tree of risk stratification, which is important for treatment and critical for clinical trial design. This goes to the very definition of APS. “When we started working with this syndrome 25 years ago, we thought the most prominent features were thrombosis in the lupus setting or problems during pregnancy,” says Dr. Khamashta, and to this day, in most clinics, this criteria for diagnosing APS remains in place. “But my colleagues and I are aware that by doing this, we are limiting ourselves to only clear-cut syndrome, completely ignoring other likely APS patients who may exhibit any of ten different disease manifestations.” Neurologic dysfunctions of seizure disorders or early-onset dementia may be a sign of APS, and so might valve problems. “A cardiologist may go ahead and do a valve replacement, but the real problem was sticky blood from APS. Yet, currently, you would not categorize that person as APS because of lack of evidence for thrombosis,” Dr. Khamashta notes. Current diagnostic criteria are simply not capturing the patients required to effectively treat the disease, or to populate a comprehensive clinical trial program.
Thanks to APS ACTION, these issues will soon be directly addressed. For now, the executive committee is in motion, coordinating the aims and activities of the APS ACTION subcommittees, with the short-term goal of establishing organizational structure. These components are slated to be in place, and ready for final review at EULAR 2011.
Neil Canavan is a journalist based in New York.
- Erkan D, Derksen R, Levy R, et al. Antiphospholipid syndrome clinical research task force report. Lupus. 2011; 20:219-224.
- Erkan D, Harrison MJ, Levy R, et al. Aspirin for primary thrombosis prevention in the antiphospholipid syndrome: A randomized, double-blind, placebo-controlled trial in asymptomatic antiphospholipid antibody-positive individuals. Arthritis Rheum. 2007;56:2382-2391.