Introduction: The antiphospholipid syndrome (APS) is a heterogeneous disease expressed in a variety of ways, including venous thromboembolic disease (TED), with deep vein thrombosis (DVT) and pulmonary embolus (PE).[1] Anticoagulation therapy is usually adequate for these complications. However, when the disease is aggressive the routine anticoagulants may not successfully prevent TED. For this situation immunotherapy with immune globulin infusion, plasmapheresis, cyclophosphamide or steroids has been applied with variable success.[2-8] Experimental efforts have been reported to induce tolerance of the lymphocytes to beta 2 — glycoprotein 1.[9,10] This is a case report of a patient given rituximab immunotherapy with continued warfarin for warfarin resistant disease, with improvement in the concentrations of the involved antibodies and the clinical syndrome. This report gives a signal for the activity of this form of immunotherpay in treating aggressive versions of the antiphospholipid syndrome.

Case Report:This 59-year-old female came for hematology consultation in 2001 after having had two well documented pulmonary emboli and four well documented deep vein thrombi. An inferior vena cava filter had been placed in November 1999. Anticogulation with heparin and warfarin had been appropriately applied without success. Our evaluation demonstrated the antiphospholipid syndrome coupled with a positive lupus anticoagulant and antiplatelet antibody. Immunotherapy was considered appropriate. Because of concern about the long-term complications of steroids it was elected not to use that class of drugs. Azathioprine was given initially at 50 mg per day and later at 150 mg per day. Warfarin therapy was continued with target INR 2.5. The anticardiolipin and the antiphosphotidyl serine antibody titers did not fall, and she developed thrombosis in-situ in the pulmonary artery requiring emergency thrombectomy. A change in therapy was considered appropriate. Rituximab was begun at 375 mg/m2 by infusion weekly for four weeks. Maintenance therapy was repeated at approximate six-month intervals. Warfarin therapy was continued with target INR 2.5-3.0. Therapy was tolerated well. Table 1 demonstrates the antibody response to the rituximab therapy. (Antibody titers measured by Focus Diagnostics, Inc. Cypress, California 90630, using BINDAZYME Enzyme Immunoassay Kit from The Binding Site Ltd, Birmingham, England.) The lupus anticoagulant and antiplatelet antibody were no longer present. On this therapy she has had no further thrombotic events.

Discussion: This case report demonstrates a level of activity by rituximab immunotherapy for this life threatening disease. There was a reduction but not total resolution of the anticardiolipin and antiphosphotidyl serine antibodies, with a resolution of the lupus anticoagulant and antiplatelet antibody components of the syndrome. Thus there is a signal for activity of this drug for this syndrome. As with all single case reports, there can be only a limited level of confidence in the interpretation of the data. However, it does open the possibility for other more complete studies with larger number of patients, including determination of relationship between antibody titers and clinical expression of this hypercoagulation syndrome.

References:

1. Cuodrado MJ, Lopez-Pedrera C. Antiphospholipid syndrome. Clin Exp Med 2003; 3: 129-139.
2. Bletry O, Blanc AS, Piette AM. Value of intravenous immunoglobulin during antiphospholipid syndrome. Rev Med Interne 1999; 20 (suppl 4): 410-413.
3. Branch DW, Peaceman AM, Druzin M, et al. A multi-centered, placebo-controlled pilot study of intravenous immunoglobulin treatment of antiphospholipid syndrome during pregnancy. The Pregnancy Loss Study Group. Am J Obstet Gynecol 2000; 182:122-127.
4. Branch DW, Porter TF, Paidas JM, Belfort MA, Gonik B, Obstetric uses of intravenous immunoglobulin: success, failures, and promises. J Allergy Clin Immunol. 2001: 108 (suppl 4); 133-138.
5. Shoenfeld Y, Katz U. IVIG therapy in autoimmunity and related disorders: our experience with a large cohort of patients. Autoimmunity 2005; 38:123-137
6. von Baeyer H. Plasmapheresis in immune hematology: Review of clinical outcome data with respect to evidence based medicine and clinical experience. Ther Apher Dial 2003; 7:127-140.
7. Kawashima S, Toba T, Asada K. Selective removal of autoantibody and immune complex by plasma exchange. Nippon Rinsho 2004; 62:334-337.
8. Lavalle-Graef A, Villegas-Acosta L, Lavalle C. Trends of anticardiolipin antibodies after low dose methylprednisolone and cyclophosphamide treatment for systemic lupus erythematosus. Arch Med Res 2004; 35:421-427.
9. Merrill JT. LJP 1082: a toleragen for Hughes syndrome. Lupus 2004: 13: 335-338.
10. Cockerill KA, Iverson GM, Jones DS, Linnik MD. Therapeutic potential of toleragens in the management of antiphospholipid syndrome. Bio Drugs 2004; 18: 297-305

Table 1: Antiphospholipid antibody titers (U/ml) at baseline and following rituximab infusions.

N/A: Not Available.

• α Calibrated against the Louisville reference LAPL-GM200, with one unit defined as the binding activity of 1 μg/ml of an affinity purified IgG, IgM, or IgA anticardiolipin preparation from a standard serum.(8)
• β Diagnostics titers for antiphospholipid syndrome are ≥ 20 U/ml (9,10)
• γ Abnormal titers: ≥ 13 U/ml
• δ Abnormal titers: ≥11 U/ml.
• ε Abnormal titers: ≥ 25 U/ml.
• ζ Abnormal titers: ≥20 U/ml

Corresponding Author:
Murray Bern, MD
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Murray Bern, MD
830 Boylston Street
Chestnut Hill, Massachusetts 02467