Successful treatment with bortezomib for refractory thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus

A 15-year-old girl presenting with arthritis, proteinuria, erythema, and headache was diagnosed with systemic lupus erythematosus (SLE) 8 years ago. She was treated with prednisone (initial dosage of 1 mg/kg daily), mycophenolate mofetil (0.75 g twice a day), and hydroxychloroquine (200 mg twice a day). Prednisone was tapered gradually, and she was in stable disease. Two years ago, she had a fever and consciousness disturbance. Her blood analysis showed anemia (hemoglobin [Hb]: 63 g/L), thrombocytopenia (platelet [PLT] count: 10 × 109/L), increased levels of lactate dehydrogenase ([LDH] 2272 U/L; normal: 0–250 U/L), bilirubin (Bil: 34.3 μmol/L; normal: 5.1–22.2 μmol/L), reticulocyte count (328.9 × 109/L; normal: 24–84 × 109/L), and serum creatine (Scr: 76 μmol/L; normal: 18–69 μmol/L). Numerous schistocytes were observed on the peripheral blood smear. The immunologic investigation showed a high titer of anti-double-stranded DNA (anti-dsDNA) and hypocomplementemia (complement 3: 0.383 g/L; normal: 0.73–1.46 g/L). Coombs test, antiphospholipid antibodies, and lupus anticoagulant were negative.

The diagnosis of thrombotic thrombocytopenic purpura (TTP) was considered due to hemolytic anemia, thrombocytopenia, elevated creatinine, and consciousness disturbance. Moreover, the serologic results of anti-DNA and complements indicated SLE flare. The activity and inhibitor of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif 13 (ADAMTS 13: activity 2%; normal: 42.16%–126.37%, inhibitor positive) confirmed the diagnosis of TTP associated with SLE flare. The patient was started on methylprednisolone (MP) pulse (1 g/ day for 3 days) and cyclophosphamide (CTX; 0.4 g/week). Meanwhile, plasma exchange (PE) was started. Her confusion improved, with the PLT count increased to 51 × 109/L and LDH reduced to 757 U/L. However, when MP was tapered to 80 mg/day, the PLT count and Hb level decreased again. The second course of MP pulse treatment was applied and PE was continued; but her condition did not improve. Refractory TTP associated with SLE was considered. She received bortezomib 1.3 g/m² once per week for 4 cycles, along with MP 60 mg daily, CTX 0.4 g/week and continued PE. The PLT count improved to 93 × 109/L, Hb increased to 83 g/L, and LDH reduced to 273 U/L. PE was stopped and MP was gradually tapered with CTX continuing. The patient was stable. The levels of Hb, PLT, Scr, Bil, LDH, and complement returned to the normal range. The titer of anti-dsDNA was negative. She was discharged. During a follow-up at 2 years, she remained stable (Figure 1).

Figure 1

The key laboratory findings and the treatments in the patient with TTP associated with SLE. CTX, cyclophosphamide; LDH, lactate dehydrogenase; MP, methylprednisolone; PE, plasma exchange; PLT, platelet; SLE, systemic lupus erythematosus; TTP, thrombotic thrombocytopenic purpura.

TTP is an acute and life-threatening condition that presents with microangiopathic hemolytic anemia, thrombocytopenia, fever, renal impairment, and neurological symptoms. Deficiency of the activity of ADAMTS 13, which is a von Willebrand factor (vWF) cleaving protease, plays a paramount role in TTP. SLE plays a vital role in the diagnosis of acquired TTP. The episode will be severe and lethal (mortality rate ranging from 34.1% to 62.5%) in TTP secondary to SLE.^[1] The diagnosis of TTP in patients with SLE might be challenging because both entities share similar clinical manifestations, and delayed diagnosis of TTP might cause fatal results.^[2] The tests for the activity and inhibitors of ADAMTS 13 are crucial for the diagnosis of TTP. Antibodies against the vWF-cleaving protease were frequently detected in the SLE patient, involved in the pathogenesis of concomitant TTP.^[3] As TTP is an acute and life-threatening condition, therapy should be started as soon as the diagnosis is made. The frontline treatments of TTP are steroid, immunosuppressor, and PE. Our patient received PE 23 times combined with treatments of MP pulse and intravenous CTX. However, she did not show improvement and was diagnosed with refractory SLE-associated TTP. Bortezomib is a selective proteasome inhibitor that leads to cell cycle arrest and apoptosis, and it is widely used to treat patients with multiple myeloma (MM). Moreover, in a mouse model of lupus, bortezomib had been shown to decrease plasma cells, activate the terminal unfolded protein response (UPR), ameliorate lupus nephritis, and prolong survival.^[4] In recent years, bortezomib has been used to treat patients with refractory TTP.^[5] Furthermore, some studies have investigated bortezomib as a treatment for patients with refractory SLE by targeting plasma cell and type-I interferon activity.^{[6, 7]} However, to our knowledge, bortezomib in the treatment of TTP induced by SLE has scarcely been reported. Herein, we report the case of successful treatment with bortezomib for refractory TTP associated with SLE. Prospective studies are needed to establish the efficacy and safety of bortezomib in SLE-related TTP.