Therapeutic Effect of Argatroban on Rheumatoid Vasculitis With Antiphosphatidylserine-Prothrombin Complex Antibody

Rheumatoid vasculitis (RV) is an inflammatory condition of the small and medium-sized vessels that affects a subset of patients with established rheumatoid arthritis (RA). Detection of antiphospholipid cofactor antibodies including antiphosphatidylserine-prothrombin complex (aPS/PT) antibodies in addition to the classic anticardiolipin antibodies and lupus anticoagulant (LAC) seems to be of considerable clinical importance.¹ Argatroban is a synthetic monovalent direct anticoagulant and thrombin inhibitor.²

A 70-year-old Japanese woman had a 35-year history of RA. Her disease had not responded well to treatment with intramuscular gold, methotrexate, D-penicillamine, azathioprine, or cyclosporine. She presented with a 2-week history of skin lesions with myalgias and arthralgias on her lower extremities. She complained of bilateral ankle numbness and a rapid increase in the intensity of her symptoms.

Examination revealed cutaneous ulcerations and livedo reticularis scattered over her legs. She developed leg ulcers along the lateral malleolus and pretibial region despite therapy with prednisone (20 mg/d) and salazosulfapyridine (1 g/d). The ulcers were deep and appeared mostly on the lower extremities during 3 weeks of therapy (Figure 1A).

According to the guidelines recommended by Brandt et al,³ the presence and levels of LAC were screened for by measuring diluted Russell viper venom time and kaolin clotting time, and confirmed by mixing studies and demonstration of phospholipid dependence. The presence and levels of IgG and IgM aPS/PT were determined with a specific enzyme-linked immunosorbent assay (Medical & Biological Laboratories, Nagoya, Japan). We found that IgM aPS/PT antibodies were present in the patient's serum at a high titer (70 U/mL), but IgG aPS/PT antibodies, LAC, anticardiolipin, and anti–β₂-glycoprotein I–dependent cardiolipin antibodies were not detected.

Two skin biopsy specimens were obtained from the ulcer edge on her lower extremities. Microscopic examination showed necrotizing vasculitis infiltrations and thrombosis in the small vessels through the dermis to the subcutaneous fat (Figure 2). Treatment with intravenous argatroban injection (2.0 μg/kg/min) was started, 2 h/d, and continued for 4 weeks leading to an improvement in symptoms, including a remarkable decrease in joint pain and swelling and a reduction in skin ulceration (Figure 1B). At 6 months' follow-up, there was no evidence of recurrence of the skin lesions.

Systemic glucocorticosteroids and/or nonsteroidal immunosuppressive agents represent the mainstay of therapeutic options for RV. However, long-term systemic administration of these compounds may be limited by severe adverse effects. Argatroban has been reported to have a safe and potent antithrombin action.² This antithrombin action is believed to reflect remarkable improvement in microcirculation. Our patient's response to this regimen indicates that recalcitrant vasculitic leg ulcers associated with RV may be successfully treated with argatroban.

To our knowledge, we describe the first patient with RV who also tested positive for aPS/PT antibodies. Anionic phospholipids such as cardiolipin and phosphatidylserine, which are not normally expressed on the surface of viable cells, are translocated to the surface of the plasma membrane of cells during apoptosis.⁴ Some studies have shown that prothrombin binds specifically to the surface of apoptotic cells.⁵ We suspect that prothrombin binds to apoptotic endothelial cells and combines with phosphatidylserine in the dermis. These complexes may cause aPS/PT antibody production, probably locally, in RV.

Correspondence: Dr Kawakami, Department of Dermatology, St Marianna University School of Medicine, 2-16-1 Sugao, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan (tami@marianna-u.ac.jp).

Financial Disclosure: None reported.