Systemic lupus erythematosus (SLE) is usually treated with immunosuppressives and steroids. Autologous stem cell transplantation (auto-SCT) following immunoablative chemotherapy is a newer therapy for severe SLE.1, 2 Non-myeloablative auto-SCT has been studied in patients with SLE with promising results.2 Studies have reported 5-year disease-free survival of 50 and 55%, respectively.2 The treatment-related mortality ranged from 2 to 13%.2 Myeloablative allogeneic stem cell transplantation (MST) has been studied for SLE patients. However, high treatment-related mortality associated with MST mitigates the potential benefit and thus cannot be a routine choice of treatment for patients with SLE. Non-myeloablative allogeneic stem cell transplantation (NST) has been established as a novel approach for hematological malignancies or non-malignant disorders. We report a patient with refractory SLE who was treated successfully with allogeneic NST.
A 43-year-old Chinese woman was diagnosed with SLE in October 1997. She had positive anti-SSA, anti-ANA and anti-U1RNP. She was treated with prednisone at 10–30 mg/day for 6 years. She had avascular necrosis of the hip joint. She also developed clinical evidence of lupus nephritis in April 2002. At that time, she was treated with a course of high-dose cyclophosphamide at 1 g monthly for 6 months and methotrexate at 10 mg intravenous weekly for 4 weeks. Her symptoms of myalgia and low-grade fever persisted and became debilitating. She became bed-bound. She had an HLA-matched sibling. She consented to receive allo-SCT with non-myeloablative conditioning chemotherapy off clinical trial. Pre-transplantation laboratory data showed hemoglobin (Hb) 94 g/l, white blood cell (WBC) 3.0 × 109/l, platelets 124 × 109/l, anti-SSA+, anti-ANA+, anti-U1RNP+, C3 1.23 g/l, C4 0.1 g/l and ESR 110 mm/h. Her liver and kidney functions were normal.
The peripheral blood stem cells were collected after mobilization with G-CSF (10 μg/kg daily × 5 days). The conditioning regimen consisted of busulfan 4 mg/kg daily × 2 days, cyclophosphamide 50 mg/kg daily × 2 days and rabbit anti-thymocyte globulin 5 mg/kg daily × 4 days. Cyclosporin A (CsA) and mycophenolate mofetil (MMF) were given for graft-versus-host disease (GVHD) prophylaxis. The chimerism of peripheral blood mononuclear cells was evaluated using short-tandem-repeat analysis. She received a total of CD34+ dose at 4.5 × 106/kg from 6/6 HLA-matched sibling (brother) donors on December 19, 2003. The T-cell content in the infused allograft was not tested.
The hematological recovery was prompt. The days to neutrophil engraftment (ANC>0.5 × 109/l) and platelet engraftment (>50 × 109/l) were both +11. The donor chimerism was 100% on day +28. The patient received prophylactic antibiotics of gentamycin, norfloxacin, itraconazole and gancyclovir. She also received imipenem and amikacin for neutropenic fever. She did not require transfusion of blood products in this initial phase. She had no acute GVHD until day +70 when she stopped CsA herself. She had grade III acute GVHD with skin rash and diarrhea. She also had decreased blood counts with platelets <20 × 109/l. The skin and gut GVHD were controlled with tacrolimus and MMF. Later, low-dose CsA (25 mg daily) was used for maintenance. At 9 months after transplantation, laboratory examination showed negative study of anti-SSA, anti-ANA and anti-U1RNP. Blood counts of WBC and Hb were normal, and platelets were 60–80 × 109/l. She had no recurrence of SLE 26 months after transplantation. At the 26-month follow-up, she had WBC 7.24 × 109/l, Hb 96 g/l and platelets 198 × 109/l. She had normal urinalysis, liver and kidney functions, normal C3, C4, and normal IgG, IgA and IgM. She continued to require low-dose CsA for chronic GVHD of the oral mucosa.
Several reports have shown that auto-SCT was effective for severe SLE.1, 2 Non-myeloablative allogeneic stem cell transplantation for autoimmune disease (AID) has been shown to induce long-term remission through graft-versus-autoimmunity effect.3 Non-myeloablative allogeneic stem cell transplantation can induce full-donor chimerism with much less toxicity.
The patient in this case was refractory to methotrexate, high-dose cyclophosphamide and had debilitating complications from steroids. She also developed nephritis. She appeared to have benefited from the NST as she was free from steroid therapy and had no recurrence for more than 2 years. Our results suggest that allogeneic NST from a sibling donor for severe refractory SLE is well tolerated and may have curative potential.
This report may be the first case of NST carried out primarily for refractory SLE. Literature search revealed seven case reports on NST for AID (Table 1). Only four of these NSTs were carried out primarily for the AID, and the other three were carried out primarily for underlying hematologic malignancies. Six of the cases remained in remission of AID from 12 to 29 months. The case of autoimmune thrombocytopenic purpura did not go into remission until after the second NST with the conversion of full-donor chimerism,8 suggesting the importance of graft-versus-autoimmunne response. However, the threshold of donor chimerism needed for potential benefit is not clear at this time, as the two cases of AID with low donor chimerism (<50% donor) also were in remission for 29 and 17 months, respectively.4, 9 One of the two rheumatoid arthritis cases relapsed 10 months post-transplantation, even though full-donor chimerism was present and multiple myeloma was in complete remission.6 Chronic GVHD may present another challenge to some patients, as limited stage chronic GVHD was reported in four of the eight cases (including our case). In a retrospective analysis comparing patients who received NST with those who received MST, incidences of acute GVHD was lower in NST (64 vs 85%), but there was no differences in that of chronic GVHD (73 vs 71%).10 This analysis also showed that 1 year survival was superior for NST than MST (68 vs 50%; P=0.04). It appears that shorter duration and fewer use of systemic immunosuppressive therapy may be needed for GVHD after NST.10 Finally, owing to increased risk of severe GVHD, it still remains unknown whether NST for SLE from unrelated donor is beneficial or not. Clearly, further studies are needed on this promising approach of NST for AID.
Marmont AM, van Lint MT, Gualandi F, Bacigalupo A . Autologous stem cell transplantation for severe systemic lupus erythematosus of long duration. Lupus 1997; 6: 545–548.
Burt RK, Traynor A, Atatkute L, Barr WG, Rosa R, Schroeder J et al. Nonmyeloablative hematopoietic stem cell transplantation for systemic lupus erythematosus. JAMA 2006; 295: 527–535.
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Khorshid O, Hosing C, Bibawi S, Ueno N, Reveille J, Mayes MD et al. Nonmyeloablative stem cell transplant in a patient with advanced systemic sclerosis and systemic lupus erythematosus. J Rheumatol 2004; 31: 2513–2516.
Burt RK, Oyama Y, Verda L, Quigley K, Brush M, Yaung K et al. Induction of remission of severe and refractory rheumatoid arthritis by allogeneic mixed chimerism. Arthritis Rheum 2004; 50: 2466–2470.
Tapprich C, Fenk R, Schneider P, Bernhardt A, Haas R, Kobbe G . Early recurrence of rheumatoid arthritis after nonmyeloablative allogeneic blood stem cell transplantation in a patient with multiple myeloma. Bone Marrow Transplant 2003; 32: 629–631.
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Chakrabarti S, Handa SK, Bryon RJ, Griffiths MJ, Milligan DW . Will mixed chimerism cure autoimmune diseases after a nonmyeloablative stem cell transplant? Transplantation 2001; 72: 340–342.
Mielcarek M, Martin PJ, Leisenring W, Flowers MED, Maloney D, Sandmaier BM et al. Graft-versus-host disease after nonmyeloablative versus conventional hematopoietic stem cell transplantation. Blood 2003; 102: 756–762.
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