Letters to the Editor levels were respectively: IgG 750 and 924 mg/dl, IgA 395 and 110, IgM 426 and 144. In the evaluation of day 60 the MRA of the aortic arch branches showed recovery of the previous brachiocephalic artery stenosis and great improvement in the irregularities of the left carotid artery and the left subclavian artery (Fig. 1B). The patient was off any immunosuppression on day 400. Haematopoietic stem cell transplantation has been employed since 1996 for isolated refractory autoimmune diseases; more than 500 autologous transplants have been registered at the EBMT/EULAR data base in Basel [7] and about 150 have been performed in North and South America [8, 9]. Neurological diseases such as multiple sclerosis, and rheumatic diseases such as systemic lupus erythematosus, systemic sclerosis and adult and juvenile rheumatoid arthritis are currently the main indications for HSCT. Many other autoimmune diseases, including smalland medium-vessel arteritis [2, 3], have been successfully treated with autologous HSCT, but this is the first case of a largevessel arteritis submitted to this treatment. The mechanisms of therapeutic benefit of HSCT in autoimmune disease are currently under investigation and may include immunosuppression induced by high-dose chemotherapy and immunotherapy, tolerance induced by autologous stem cells or tissue repair mediated by transdifferentiated stem cells [9]. In the present case, inhibition of inflammatory activity is likely to be a consequence of immunosuppression by cyclophosphamide and ATG, but the surprisingly fast improvement in artery structure and function might be due to angiogenic properties of HSC, as hypothesized in HSCT for systemic sclerosis [10]. Although our patient still has a short follow-up and some arterial abnormalities, the encouraging results suggest that highdose chemo/immunotherapy associated with HSCT can modify the clinical course of severe and refractory large-vessel vasculitis.
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1. Johnston SL, Lock RJ, Gompels MM. Takayasu arteritis: a review. J Clin Pathol 2002;55:481–6. 2. Bacon PA, Carruthers D. New therapeutic aspects: hematopoietic stem cell transplantation. Best Practice Res Clin Rheumatol 2001; 15:299–13. 3. Fiehn C, Hensel M. High dose chemotherapy with hematopoietic stem cell transplantation in primary systemic vasculitis, Behc¸et’s disease and Sjogren’s syndrome. In: Burt RK, Marmont A (eds). Stem Cell Therapy for Autoimmune Diseases. Georgetown, TX: Landes Bioscience USA, 2004;411–18. 4. Voltarelli JC. Hematopoietic stem cell transplantation for autoimmune diseases in Brazil: current status and future prospectives. Rev Bras Hematol Hemoter 2002;24:206–11. 5. Voltarelli JC, Ouyang J. Hematopoietic stem cell transplantation for autoimmune diseases in developing countries: current status and future prospectives. Bone Marrow Transplant 2003;32:S69–S72. 6. Voltarelli JC, Oliveira MCB, Stracieri APBL, Godoi DF, Moraes DA, Coutinho MA. Autologous hematopoietic stem cell transplantation for Takayasu’s arteritis: report of the first case of the literature. Biol Blood Marrow Transplant 2004;10(Suppl 1):62. 7. Tyndall A, Koike T. High dose immunoablative therapy with hematopoietic stem cell support in the treatment of severe autoimmune disease: current status and future direction. Intern Med 2002;41: 608–12. 8. Voltarelli JC, Stracieri AB, Rodrigues MC et al. Outcome of autologous HSCT for severe and refractory autoimmune diseases in Brazil. Bone Marrow Transplant 2004;33:S145. 9. Burt RK, Slavin S, Burns WH, Marmont A. Induction of tolerance in autoimmune diseases by hematopoietic stem cell transplantation: getting closer to a cure? Blood 2002;99:768–84. 10. Burt RK, Oyama Y, Traynor A et al. Hematopoietic stem cell transplantation for systemic sclerosis with rapid improvement in skin scores: is neoangiogenesis occurring? Bone Marrow Transplant 2003;32:S65–S67.
Rheumatology
Key message Autologous haematopoietic stem cell transplantation may remit Takayasu’s arteritis.
Rheumatology 2004;43:1309–1310 doi:10.1093/rheumatology/keh308
Normalization of anticardiolipin antibodies following rituximab therapy for marginal zone lymphoma in a patient with Sjo¨gren’s syndrome
We are grateful to the multiprofessional team of the Bone Marrow Transplantation Unit of the University of Sa˜o Paulo Hospital at the Campus of Ribeira˜o Preto for superb care of the patient, to the referring physicians Maria Tereza M. Santos and Sergio S. Komessu, and to FAEPA-HCFMRP, FUNDHERP, FAPESP, Ministry of Health, CNPq and FINEP for financial support. The authors have declared no conflicts of interest. J. C. VOLTARELLI, M. C. B. OLIVEIRA, A. B. P. L. STRACIERI, D. F. GODOI, D. A. MORAES, M. A. COUTINHO, K. C. R. MALMEGRIM, A. C. SANTOS1 Bone Marrow Transplantation Unit and 1Division of Radiology, Department of Clinical Medicine, University Hospital (Hospital das Clı´nicas), School of Medicine of Ribeira˜o Preto, University of Sa˜o Paulo, Brazil Accepted 8 June 2004 Correspondence to: J. C. Voltarelli, Regional Blood Center (Hemocentro), Campus USP, 14051–140, Ribeira˜o Preto, Brazil. E-mail:
[email protected]
SIR, Sjo¨gren’s syndrome (SS) is associated with the development of lymphoma, most commonly marginal zone lymphoma (MZL), and antiphospholipid antibodies (aPL). While a diagnosis of SS places a patient at 44-fold increased risk of developing lymphoma, the association of SS with aPL is less often described [1, 2]. However, the occurrence of secondary antiphospholipid syndrome (APS) in patients with SS has been reported [3]. Few cases in the literature report the occurrence of both aPL and APS in non-SS patients with various forms of lymphoma [4–8]. Rituximab, a chimeric monoclonal CD20 antibody, has been used successfully to treat non-Hodgkin’s lymphoma and several autoimmune disorders, including systemic lupus erythematosus (SLE), rheumatoid arthritis, autoimmune thrombocytopenia and autoimmune haemolytic anaemia [9]. In addition, rituximab has recently been shown to improve lymphoma associated with SS, as well as the symptoms of SS itself [10]. We describe a case of normalization of anticardiolipin antibodies (aCL) in a patient with SS and secondary APS treated with rituximab for MZL. We feel that this report is of interest as it may relate to future uses of rituximab to treat APS, in particular the catastrophic APS. The patient is a 46-yr-old female who was diagnosed with SS in 1984. At that time, she had typical sicca symptoms, a positive minor salivary gland biopsy and an antibody
Rheumatology Vol. 43 No. 10 ß British Society for Rheumatology 2004; all rights reserved
Letters to the Editor
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TABLE 1. The patient’s aCL antibody titres (U/ml) before and after treatment with rituximab in January 2003 aCL antibody class
March 2001
July 2001
March 2003
October 2003
IgG IgM IgA
156.3 22.7 18.6
27.0 110.3 31.5
0.0 6.0 6.0
14.0 10.0 0.0
In 2001, positive IgG, IgM and IgA were >12.3, >12.9 and >16 U/ml, respectively. In 2003, positive IgG, IgM and IgA were 19, 10 and 15 U/ml, respectively.
profile consistent with the diagnosis (positive ANA, positive SSA/ SSB and positive high-titre RF). Initially, symptomatic treatment was successful. In 1995, the patient presented with left cervical lymphadenopathy, leading to a biopsy demonstrating marginal zone lymphoma (MALT). Staging bone marrow biopsy was negative, as were subsequent bone marrow biopsies. A right cervical lymph node excision in 1997 was consistent with MALT. In 2001, after presenting with acute pleuritic chest pain, the patient underwent evaluation for suspected pulmonary embolus. Imaging revealed a right common iliac deep venous thrombosis, without evidence of pulmonary embolus. Concurrent with the initiation of anticoagulation, an evaluation for a possible hypercoagulable state yielded positive aCL on two occasions. Lupus anticoagulant was negative on both occasions. She has continued on warfarin therapy for secondary APS without recurrent thromboembolic events to date. In 2002, the patient experienced recurrence of her pulmonary lymphoma by surveillance computed tomography (CT) and positron emission tomography (PET) scans. Upon surgical excision of this lesion, pathology again revealed marginal zone lymphoma. Due to continued recurrence of her lymphoma, rituximab was initiated in 2003 using a standard protocol. In addition to inducing stability of the lymphoma and decreasing her SS symptoms, rituximab normalized the patient’s previous high-titre ACL antibodies (Table 1). Follow-up CT and PET scans since administration of rituximab show no recurrence of disease. The patient will undergo a 2-yr maintenance regimen of rituximab at a minimum to continue to treat marginal cell lymphoma and her underlying connective tissue disease. In our patient, the normalization of aCL was fortuitous and not the reason for initiating rituximab therapy. To our knowledge, this is the first case report of such an association. We realize it is difficult to determine the cause of this patient’s deep venous thrombosis, which might have been either due to secondary APS (from underlying SS or lymphoma) or paraneoplastic, although the latter is rare. However, we feel that the high titre of the aCL is significant. In addition, we realize that aPL levels can vary over time, but such a dramatic decrease is probably due to the use of rituximab in this case. We feel that this case illustrates the effectiveness of rituximab in reducing high-titre aCL levels to a normal range. This finding, if validated by other case reports and trials, could have dramatic implications for the use of rituximab in treating and preventing complications due to APS, in particular catastrophic APS. In conclusion, rituximab could be used as primary therapy for this difficult syndrome. The views expressed in this case report are those of the authors and are not necessarily those of Walter Reed Army Medical Center, the Department of the Army, or the Department of Defense. The authors have declared no conflicts of interest. K. C. HARNER, L. W. JACKSON, J. J. DRABICK Walter Reed Army Medical Center, Washington, DC, USA Accepted 15 June 2004
Correspondence to: K. C. Harner, Walter Reed Army Medical Center, Rheumatology Clinic, Ward 77, 6900 Georgia Avenue, NW, Washington, DC 20307, USA. E-mail: kyle.harner@ na.amedd.army.mil 1. Kassan SS, Thomas TL, Moutsopoulos HM et al. Increased risk of lymphoma in sicca syndrome. Ann Intern Med 1978;89:888–92. 2. Asherson RA, Fei H, Staub HL, Khamashta MA, Hughes GRV, Fox RI. Antiphospholipid antibodies and HLA associations in primary Sjogren’s syndrome. Ann Rheum Dis 1992;51:495–8. 3. Ingram SB, Goodnight SH Jr, Bennet RM. An unusual syndrome of a devastating noninflammatory vasculopathy associated with anticardiolipin antibodies: report of two cases. Arthritis Rheum 1987;30:1167–72. 4. Onida P, Tresoldi M, Rugarli C. Anti-phospholipid-antibody syndrome associated with peripheral T-cell lymphoma. Am J Hematol 1997;55:167–8. 5. Ciaudo M, Horellou MH, Audouin J et al. Lupus anticoagulant associated with primary malignant lymphoplasmacytic lymphoma of the spleen: a report of four patients. Am J Hematol 1991;38:271–6. 6. Sciarra, Stasi R, Stipa E et al. Antiphospholipid antibodies: their prevalence, clinical significance and correlation with cytokine levels in acute myeloid leukemia and non-Hodgkin’s lymphoma. Recent Prog Med 1995;86:57–62. 7. Timuragaoglu A, Duman A, Ongut G, Saka O, Karadogan I. The significance of autoantibodies in non-Hodgkin’s lymphoma. Leuk Lymphoma 2000;40:119–22. 8. McGuire D, Zeidman A, Mittelman M. Non-Hodgkin’s lymphoma presenting with coagulopathy due to anti-phospholipid antibody syndrome. Leuk Lymphoma 1997;26:193–6. 9. Silverman GJ, Weisman S. Rituximab therapy and autoimmune disorders: prospects for anti-B cell therapy. Arthritis Rheum 2003;48:1484–92. 10. Somer BG, Tsai DE, Downs L, Weinstein B, Schuster SJ. Improvement in Sjogren’s syndrome following therapy with rituximab for marginal zone lymphoma. Arthritis Rheum 2003;49:394–8.
Rheumatology 2004;43:1310–1311 doi:10.1093/rheumatology/keh319
A case of successful pregnancy in a woman with systemic sclerosis treated with cyclosporin SIR, Systemic sclerosis (SSc) is a generalized connective tissue disease characterized by a strong female predilection. In our experience low-dose cyclosporin A (CyA) (1–3 mg/kg per day) provides a therapeutic option for patients with multivisceral involvement [1]. Its use during pregnancy in female transplant recipients has been proved to be safe, but there is little experience in autoimmune patients [2]. We present a case of successful pregnancy in a 25-yr-old woman with SSc who was treated with CyA. She presented to our department with severe Raynaud’s phenomenon attacks. Physical examination showed scleroderma skin changes proximal to the metacarpophalangeal joints and to the face. Mild restrictive lung disease associated with reduction of diffusion capacity for carbon monoxide, microvascular abnormalities (evaluated by nailfold videocapillaroscopy), a slight increase in renal vascular resistance and abnormal oesophageal motility were revealed by instrumental evaluation. Haematological parameters and urinalysis showed no significant abnormalities. Anti-topoisomerase 1 antibodies were positive. Anti-Ro (SSA), anti-La (SSB) and anticardiolipin antibodies were not found. Total functional haemolytic complement (CH 50) and C3 levels were decreased, while C4 level was normal.
Rheumatology Vol. 43 No. 10 ß British Society for Rheumatology 2004; all rights reserved
