Recent Developments in Managing and Treating Lupus and Antiphospholipid Syndrome (APS): Part II – APS

Adapted from a presentation at the SLE Workshop at Hospital for Special Surgery given by Dr. Kyriakos Kirou and Dr. Doruk Erkan


Doruk Erkan, MD, MPH

Doruk Erkan, MD, MPH

Associate Attending Rheumatologist, Hospital for Special Surgery
Associate Professor of Medicine, Weill Cornell Medical College
Associate Physician-Scientist, Barbara Volcker Center for Women and Rheumatic Disease

This summary, the second segment of this two-part presentation, focuses on antiphospholipid syndrome. For more information on lupus, please read Recent Developments in Managing and Treating Lupus and Antiphospholipid Syndrome (APS): Part I – Lupus.

Important Note: Information presented here is intended only to educate you and not to be used as therapeutic advice. Therapeutic decisions should be made closely with your treating rheumatologist as there is not one-size-fits-all therapy.


Antiphospholipid Syndrome: A Brief Overview

To understand the latest developments in treatment of antiphospholipid syndrome (APS), it is important to look at some of the basics related to antiphospholipid antibodies (aPL) and APS. Thus, after a brief discussion of aPL/APS-related general information, this presentation will review some of the potential new approaches that can be considered in the management of aPL-positive patients in the near future.

First, what is an antibody? Antibodies are proteins produced by the immune system in response to foreign substances such as chemicals, viruses, or bacterial toxins.

Secondly, what is an autoantibody? An autoantibody is an abnormal antibody production in the absence of a known foreign substance.

Antiphospholipid antibodies (aPL) are autoantibodies that can be positive in 2 - 5% of the general population, 30 - 40% of lupus patients, and approximately 15% of rheumatoid arthritis patients. So aPL are more common among lupus patients.

Having a positive aPL test does not mean the person has APS. The most common medical issues that can occur due to aPL are blood clots and pregnancy problems; if these problems develop in aPL-positive individuals, then the APS diagnosis is confirmed.

Blood clots can cause:

  • Stroke
  • Heart Attack
  • Deep vein thrombosis (formation of a blood clot in a deep vein; commonly effects the leg veins)
  • Pulmonary embolus (blockage of the main artery of the lung or one of its branches by a substance that has traveled in the bloodstream)

Pregnancy problems include:

  • Late pregnancy loss
  • Early pregnancy loss
  • Early delivery
  • Preeclampsia (high blood pressure & increased protein in the urine)
  • Growth Restriction in the uterus

Some of the other clinical problems related to aPL are:

  • Livedo reticularis (purple mottled skin rash)
  • Skin ulcers
  • Heart valve disease
  • Kidney disease
  • Autoimmune anemia
  • Low platelet counts (note: platelets are blood cells involved in the prevention of bleeding)
  • Memory problems

Antiphospholipid syndrome can occur as the primary disease or together with another systemic autoimmune disease (e.g., lupus).

As aPL-positive patients are at increased risk for cardiovascular events and blood clots, management of aPL-positive patients (with or without APS) involves two strategies: a) Prevention; and b) Treatment.

Primary prevention means the prevention of the first blood clot in aPL-positive patients with no history of blood clots. Secondary prevention means the prevention of the recurrence of a blood clot in APS patients.

Continuous monitoring of cardiovascular disease (CVD) and blood clot risk factors as well as patient education are crucial in aPL-positive patients to prevent first or recurrent blood clots.

The basic strategies to prevent blood clots are:

  • Monitoring and elimination of traditional cardiovascular disease (CVD) risk factors
  • Monitoring and elimination of venous thrombosis risk factors
  • Controlling lupus disease activity
  • Lifestyle changes as needed
  • Patient education

You can obtain more information about the prevention of blood clots in aPL-positive patients with the following HSS resources:

Anticoagulants (blood thinners) such as warfarin (Coumadin®) and heparin (Lovenox®) are used to treat blood clots in APS patients. Low dose aspirin and heparin are used to prevent recurrent pregnancy losses in APS patients with history of pregnancy loss.

Learn more about the treatment of APS by reading our article Antiphospholipid Syndrome (APS): Innovative Treatments Aimed at Improving Lives.

Potential New Approaches in APS Prevention/Treatment

There are other therapies that are currently under investigation for prevention and/or treatment of clots or pregnancy problems in patients with aPL. Many of these therapies are known as “immunomodulatory therapies,” which means that they interact with one’s immune system with the goal of decreasing or eliminating the production of the aPL. Some of the potential future immunomodulatory approaches include:

  • B-cell inhibition
  • Hydroxychloroquine
  • Statins
  • Complement inhibition

Hospital for Special Surgery has been conducting clinical studies regarding these potential future treatments.

B-cell Inhibition:

As discussed in the HSS article Antiphospholipid Syndrome (APS): Innovative Treatments Aimed at Improving Lives (which highlights some functioning mechanisms of these innovative treatment approaches), Dr. Erkan notes that B-cells are the cells that create autoantibodies, and the idea behind B cell inhibition is the fact that “if we can inhibit B cells, we can decrease the antibodies.”

Rituximab is one of the B cell inhibitor drugs that recognizes and attacks a specific region of mature B-cells (immune cells). It is already FDA-approved for treatment of certain types of cancers and moderate-to-severe rheumatoid arthritis. It has been used to treat immune-mediated anemia and thrombocytopenia in APS patients with anecdotal success; however, there are no definitive data that support the use of Rituximab in APS. The RITuximab Antiphospholipid Syndrome (RITAPS) Study at HSS is being undertaken to explore whether the Rituximab is effective against certain aPL-related clinical problems.

Hydroxychloroquine (HCQ):

Hydroxychloroquine (Plaquenil®) is an antimalarial drug which is used in the management of SLE patients. Hydroxychloroquine has anti-inflammatory effects and also inhibits platelet aggregation (platelets clumping together), which is a key step in blood clot formation. Hydroxychloroquine may reduce the thrombogenic properties (the tendency of blood to produce a clot) of aPL in mouse models, and it can also decrease the risk of blood clots in SLE patients. Hydroxychloroquine is possibly protective against blood clots in SLE by interfering with platelets, lowering lupus disease activity/inflammation, and reducing cardiovascular disease risk factors.

A study is being done at Hospital for Special Surgery and Montefiore Medical Center that explores the effect of hydroxychloroquine on a protein that protects against blood clots (Annexin A5) in aPL-positive patients.

Furthermore, clinical studies looking at the efficacy of hydroxychoroquine in aPL-positive patients are planned by the newly formed APS research network – APS ACTION.

Statins:

Statins are cholesterol-lowering agents that may be protective against blood clots by interfering with aPL binding to the walls of arteries or veins (based on mouse models). Currently, there is no definitive evidence that statins prevent clots in APS patients, but clinical studies are ongoing. A pilot study completed at HSS and University of Texas Medical Branch (UMTB) that explored the effects of Fluvastatin on Proinflammatory and Prothrombotic Markers in APS.

Complement Inhibition:

A “complement” is a protein that is part of the immune system. Based on mouse models, these proteins are involved in aPL-related blood clots and pregnancy problems. Thus, medications that inhibit or block these proteins may be useful in aPL-positive patients. There are no controlled clinical studies. One particular study at Hospital for Special Surgery is investigating the role of complement in pregnant aPL-positive patients.

Conclusion

Although it is promising that new treatments for aPL-positive patients are under investigation, controlled clinical studies with these agents are needed before they can be recommended in the management of aPL-positive patients. Also, it is important to note that aPL-positive patients present with variety of clinical manifestations (e.g., blood clots, pregnancy losses, low platelet counts) and the above medications may not be appropriate for every aPL-positive patient.

Also read the first segment of this two-part presentation: Recent Developments in Managing and Treating Lupus and Antiphospholipid Syndrome (APS): Part I – Lupus

Resources

If you have further questions on these studies, please contact:

Joann Vega – vegaj@hss.edu - 212.774.2795
Glendalee Ramon – ramong@hss.edu - 212.774.2808

Learn more about APS Clinical Trials on HSS.edu and the APS ACTION site.

Original summary by Stephen Rudolf, SLE Workshop Coordinator and Social Work Intern, with special acknowledgement to Pretima Persad, Manager, Mary Kirkland Center for Lupus Care, for her editorial review.


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