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| | | Year : 2010 | Volume : 21 | Issue : 1 | Page : 109-112 | | | Response to rituximab in a refractory case of thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus | | | Faraz Azim Niaz, Aamer Aleem
Department of Medicine, Division of Nephrology and Division of Hematology/Oncology, College of Medicine, King Saud University, King Khalid University Hospital, Riyadh, Saudi Arabia
Click here for correspondence address and email | Date of Web Publication | 8-Jan-2010 | | |      | |  Abstract | | | Thrombotic thrombocytopenic purpura (TTP) is a serious disorder with a significant morbidity and mortality. Majority of cases of TTP are idiopathic, but some cases may be secondary to connective tissue diseases. TTP has been rarely associated with systemic lupus erythematosus (SLE) and may be refractory to treatment with plasma exchange, requiring immunosuppressive therapy. We describe a patient with TTP and SLE who was refractory to plasma exchange and corticosteroids but responded to anti-CD20 antibody rituximab with continued remission after eight months of follow-up. Rituximab appears to be an effective treatment in refractory cases of TTP associated with SLE. How to cite this article:
Niaz FA, Aleem A. Response to rituximab in a refractory case of thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus. Saudi J Kidney Dis Transpl 2010;21:109-12 |
How to cite this URL:
Niaz FA, Aleem A. Response to rituximab in a refractory case of thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2014 Mar 4];21:109-12. Available from: http://www.sjkdt.org/text.asp?2010/21/1/109/58783 |
| Introduction | |  |
Thrombotic thrombocytopenic purpura (TTP) is an uncommon disorder first described in 1924 by Moschowitz. [1] The majority of cases of TTP are idiopathic without an identifiable cause or associated illness. TTP may occur in association with various connective tissue diseases, but has rarely been associated with SLE. [2],[3] In most of the patients, SLE is usually diagnosed earlier and TTP develops, later but both can present simultaneously, or the TTP may develop with an exacerbation of SLE causing difficulty and delay in TTP diagnosis because of the overlapping features of these two disorders. [2],[4]
TTP is a serious disorder with high mortality if not treated. [5]
There is still a significant mortality with the current treatment strategies, and there is a need to explore new ones for patients who are refractory to the conventional treatment. [6],[7] Moreover, TTP associated with SLE is thought to be more resistant to plasma exchange, and early consideration to immunosuppressive therapy has been recommended. [8],[9] Rituximab is an anti-CD20 antibody, which has demonstrated effectiveness in many autoimmune disorders. [10]
Here we describe a patient who was diagnosed to have TTP and SLE simultaneously and was refractory to plasma exchange but showed a good response to rituximab.
| Case Report | | |
A 34-year-old Saudi woman presented to the emergency department at our institution during November, 2007 with one week history of fever and skin rashes all over the legs. A day prior to the admission, she suffered from an episode of generalized tonic-clonic convulsions followed by confusion and agitation. Her past medical history was unremarkable, but her sister was diagnosed to have SLE few years earlier.
On examination, the patient had normal vital signs, but revealed multiple ecchymotic patches on her both lower limbs. She was confused but there were no signs of meningeal irritation or focal neurological deficit. The rest of her examination was unremarkable. The laboratory investigations revealed the presence of anemia (hemoglobin (Hb) 5.9 g/dL), and severe thrombocytopenia (platelets count 9 Χ 10 9 /L). The coagulation profile was normal. The reticulocyte count was elevated to 12.4%. Liver function tests indicated total and indirect hyperbilirubinemia (total bilirubin: 50 ΅mol/L, indirect bilirubin: 30 ΅mol/L). Lactate dehydrogenase (LDH) was elevated at 1206 U/L (Normal: 100190). Peripheral blood smear revealed polychromasia and a significant number of schistocytes (fragmented red cells). A direct and indirect Coomb's tests were negative. The renal function tests were normal and urinalysis revealed proteinuria (0.83 g/day on 24-hour urine collection).
A computerized tomography (CT) scan of brain was normal. Serologic tests showed elevated ANA of 1:5120 and low C3 of 0.569 g/L (normal range 0.7-1.7), while C4, anti-dsDNA, Hepatitis B and C, and HIV were negative. All appropriate cultures were negative. On the basis of these findings, the patient was diagnosed to have thrombotic thrombocytopenic purpura along with SLE.
She was started on daily plasma exchange and received methylprednisolone 500 mg daily for 3 days followed by 60 mg (1 mg/kg) daily. She also received anticonvulsive therapy.
Her platelet count increased to 30 Χ 10 9 /L on the 5th day of treatment but dropped again to 12 Χ 10 9 /L the next day. There was no improvement till day 11. In view of the refractory disease, immunosuppressive therapy was considered and rituximab was started at a dose of 375 mg/m 2 weekly. Rituximab was tolerated well with no adverse events and the platelet count started to improve after three days of the first dose along with improvement in other parameters such as the reticulocyte count and LDH. Frequency of plasma exchange was reduced and then discontinued. Patient's laboratory parameters over the period of time are shown in [Table 1]. Platelet and LDH response to treatment in relation to time are shown in [Figure 1]. The patient received 3 weekly doses of rituximab and the fourth planned dose was not given because of an excellent response. She was also started on hydroxychloroquine and corticosteroids, which were tapered slowly over the next few months. ADAMTS-13 activity could not be tested initially because of non-availability; however, a sample tested few weeks later showed normal activity (> 70%). the patient remained well 8 months post therapy with normal laboratory parameters.
| Discussion | | |
TTP is a life-threatening disease with high mortality if not treated. [5] Treatment modalities, such as the plasma exchange, have decreased the mortality rate significantly from 90% to less than 20%. [6] For acute TTP, daily plasma exchange remains the initial treatment of choice in combination with corticosteroids. [6] Patients who do not respond well to this treatment require other modalities of treatment, usually an immunosuppressive therapy. TTP associated with SLE is rare but possibly under-diagnosed disease because of the overlapping features of both entities. [2] TTP secondary to SLE has been reported to be resistant to plasma exchange, and early cytotoxic therapy with cyclophosphamide has been recommended. [8],[9]
Rituximab is a chimeric, monoclonal antiCD20 antibody, which specifically depletes B cells. It has demonstrated effectiveness in various autoimmune hematological disorders including idiopathic TTP. [10] Treatment of refractory or relapsing TTP with Rituximab has been effective with lasting remissions. [11],[12] In a study by Scully et al, all 25 patients with idiopathic TTP attained complete clinical and laboratory remission in a median of 11 days after initiating rituximab. [13] There have been occasional reports of successful use of rituximab in refractory cases of SLE associated with TTP. [14],[15] In our patient, TTP and SLE were diagnosed simultaneously during the same admission. She was initially treated with daily plasma exchanges along with high dose corticosteroids without a good response. However, the patient responded successfully to weekly rituximab with clinical and laboratory improvement within few days after the first dose. Rituximab was chosen in this patient because of the recent encouraging reports of its effectiveness in this disorder and lesser potential toxicity when compared to cyclophosphamide. Because of the rarity of this disorder, comparative trials of rituximab with cyclophosphamide may not be possible. Because of this reason, case reports of rituximab efficacy as well as its failure, should be encouraged to define the role of this therapy in the management of SLE associated TTP cases, refractory to plasma exchange.
TTP is characterized by microthrombi in various organ systems due to presence of abnormally large Von Willibrand factor (vWF) multimers in the plasma. ADAMTS-13 is a metalloproteinase, which cleaves large vWF multimers into smaller, inactive monomers. [16] Reduced activity of ADAMTS-13 is associated with many disorders but markedly reduced activity (< 10%) is specific for TTP.[17] ADAMTS13 activity levels are not only helpful in initial diagnosis of TTP, but also useful in monitoring therapy, as it rises to higher levels in patients who achieve remission. In our patient, ADAMTS-13 activity could not be measured initially. However, a sample tested few weeks after rituximab therapy and clinical improvement, showed normal (> 70%) activity of ADAMTS13 consistent with clinical remission and a good response to rituximab therapy. The patient remains in remission after eight months of follow-up.
In conclusion, rituximab appears to be an effective treatment modality for refractory cases of TTP associated with SLE, and we recommend that the use of rituximab should be considered in this setting.
| References | | |
| 1. | Moschcowitz E. Hyaline thrombosis of terminal arterioles and capillaries: A hitherto undescribed disease. Proc N Y Pathol Soc 1924;24:21-4.  | | 2. | Aleem A, Al-Sugair S. Thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus. Acta Haematol 2006;115 (1-2):68-73. | | 3. | Caramaschi P, Riccetti MM, Pasini AF, Savarin T, Biasi D, Todeschini G. Systemic lupus erythematosus and thrombotic thrombocytopenic purpura. Report of three cases and review of literature. Lupus 1998;7:37-41. | | 4. | Dold S, Singh R, Sarwar H, Menon Y, Candia L, Espinoza LR. Frequency of microangiopathic hemolytic anemia in patients with SLE exacerbation: distinction from TTP, prognosis, and outcome. Arthritis Rheum 2005;53:982-5. [PUBMED] [FULLTEXT] | | 5. | Amorosi EL, Ultmann JE. Thrombotic thrombocytopenic purpura: Report of 16 cases and review of the literature. Medicine 1996;45:139-59. | | 6. | Rock GA, Shumak KH, Buskard NA, et al. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura: Canadian Aphresis Study group. N Eng J Med 1991;325:393-7. | | 7. | Torok TJ, Holman RC, Chorba TL. Increasing mortality from thrombotic thrombocytopenic purpura in the United States-analysis of nationnal mortality data, 1968-1991. Am J Hematol 1995;50:84-90. | | 8. | Vasoo S, Thumboo J, Fong KY. Thrombotic thrombocytopenic purpura in systemic lupus erythematosus: Disease activity and the use of cytotoxic drugs. Lupus 2002;11:443-50. [PUBMED] [FULLTEXT] | | 9. | Perez-Sanchez I, Anguita J, Pintado T. Use of cyclophosphamide in the treatment of thrombotic thrombocytopenic purpura complicating systemic lupus erythematosus: Report of two cases. Ann Hematol 1999;78:285-7. | | 10. | Franchini M, Veneri D, Lippi G, Stenner R. The efficacy of rituximab in the treatment of inhibitor-associated hemostatic disorders. Thromb Haemost 2006;96(2):119-25. | | 11. | Fakhouri F, Vernant JP,Veyradier A, et al. Efficiency of curative and prophylactic treatment with rituximab in ADAMTS 13-deficient thrombotic thrombocytopenic purpura: A study of 11 cases. Blood 2005;106:1932-7. [PUBMED] [FULLTEXT] | | 12. | Ahmad A, Aggarwal A, Sharma D, et al. Rituximab for treatment of refractory/relapsing thrombotic thrombocytopenic purpura (TTP). Am J Hematol 2004;77:171-6. [PUBMED] [FULLTEXT] | | 13. | Scully M, Cohen H, Cavenagh J, et al. Remission in acute refractory and relapsing thrombotic thrombocytopenic purpura following rituximab is associated with a reduction in IgG antibodies to ADAMTS-13. Br J Haematol 2007;136:451-61. [PUBMED] [FULLTEXT] | | 14. | Niewold TB, Alpert D, Scanzello CR, Paget SA. Rituximab treatment of thrombotic thrombocytopenic purpura in the setting of connective tissue disease. J Rheumatol 2006;33(6):1194-6. | | 15. | Limal N, Cacoub P, Sene D, Giuchard I, Piette JC. Rituximab for the treatment of thrombotic thrombocytopenic purpura in systemic lupus erythematosus. Lupus 2008;17:69-71. | | 16. | Levy GG, Motto DG, Ginsburg G. ADAMTS 13 turns 3. Blood 2005;106:11-7. | | 17. | Bianchi V, Robles R, Alberio L, Furlan M, Lammle B. von Willibrand factor-cleaving protease (ADAMTS 13) in thrombocytopenic disorders: a severely deficient activity is specific for thrombotic thrombocytopenic purpura. Blood 2002;100:710-3. |
Correspondence Address:
Faraz Azim Niaz
Department of Medicine, College of Medicine and King Khalid University Hospital,P.O. Box 7805, Riyadh 11472
Saudi Arabia
PMID: 20061703
[Figure 1]
[Table 1] | |
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