{"paper_id":"6fc45bf2-01f7-44a9-a7e7-e17587989489","body_text":"INTRODUCTION\nWhereas mild thrombocytopenia frequently occurs during\nan active stage of systemic lupus erythematosus (SLE) with-\nout causing bleeding tendency, severe immune thrombocy-\ntopenia, which can lead to a significant hematological prob-\nlem, is relatively uncommon in SLE. In the latter condition,\nsystemic corticosteroids are considered the first line treatment.\nWhen this therapeutic modality does not result in a sustained\nresponse, other therapeutic agents, including azathioprine,\nintermittent intravenous cyclophosphamide, cyclosporine,\ndanazol, dapsone, vincristine, and intravenous gamma glob-\nulin, have been reported to be efficacious in the treatment of\nthrombocytopenia in SLE. In addition, splenectomy may be\nindicated for SLE patients with severe thrombocytopenia who\nare refractory to corticosteroids and/or other agents described\nabove. However, these conventional therapeutic modalities\nmay cause significant side effects (1).\nMycophenolate mofetil (MMF), originally developed for\norgan transplantation, is a prodrug of mycophenolic acid,\nwhich blocks inosine monophosphate dehydrogenase, a cru-\ncial enzyme in purine synthesis. Consequently, mycophenolic\nacid inhibits lymphocyte proliferation and T-cell dependent\nantibody responses (2, 3). MMF has been reported to be effec-\ntive in mouse models of lupus nephritis (4). Moreover, recent\nrandomized controlled trials in humans have suggested that\nMMF could also be efficacious and safe in the management\nof proliferative lupus nephritis (5, 6). However, little informa-\ntion has been available regarding the role of MMF in the treat-\nment of immune thrombocytopenia complicated in SLE.\nHereby I describe a patient with SLE in whom thrombocy-\ntopeniawas refractory to corticosteroids, intermittent intra-\nvenous cyclophosphamide, azathioprine, cyclosporine, intra-\nvenous gamma globulin, danazol, and splenectomy, and whose\nplatelet counts eventually normalized during therapy with\nMMF. \nCASE REPORT\nIn November 2001, a 26-yr-old female was admitted with a\none-week history of pedal edema, nasal bleeding, and petechiae\non the lower limbs. She did not take any medications for\ncurrent illness. There was no medical history of photosensi-\ntivity, oral ulcer, and Raynaud’s phenomenon. On physical\nexamination, mildly anemic conjunctiva and petechiae and\npitting edema on the lower extremities were noted. Labora-\ntory studies at this time showed a hemoglobulin level of 9.8\nHyun Kyu Chang\nDivision of Rheumatology, Department of Internal\nMedicine, Dankook University, Cheonan, Korea\nAddress for correspondence\nHyun Kyu Chang, M.D.\nDivision of Rheumatology, Department of Internal\nMedicine, College of Medicine, Dankook University,\n16-5 Anseo-dong, Cheonan 330-715, Korea\nTel : +82.41-550-3915, Fax : +82.41-556-3256\nE-mail : hanks22@dankook.ac.kr\n883\nJ Korean Med Sci 2005; 20: 883-5\nISSN 1011-8934\nCopyright � The Korean Academy\nof Medical Sciences\nSuccessful Treatment of Refractory Thrombocytopenia with Mycoph e-\nnolate Mofetil in a Patient with Systemic Lupus Erythematosus\nWhile mild thrombocytopenia in systemic lupus erythematosus (SLE) is frequently\nseen in the context of active disease, severe thrombocytopenia causing significant\nbleeding is not that common. Corticosteroids are considered the first line therapy for\nsevere thrombocytopenia in SLE. Second-line therapeutic agents or splenectomy\nhave been reported to be effective for patients who fail to respond to steroids or those\nwho require moderate doses of steroids to maintain the platelet counts. Recent ran-\ndomized controlled studies have shown that mycophenolate mofetil (MMF) is an effi-\ncacious and safe therapeutic agent in patients with proliferative forms of lupus nephri-\ntis.However, little information has been available regarding the role of MMF in the\ntreatment of immune thrombocytopenia complicated with SLE. Hereby I describe a\npatient with SLE in whom thrombocytopenia was refractory to corticosteroids, inter-\nmittent intravenous cyclophosphamide, azathioprine, cyclosporine, intravenous gam-\nma globulin, danazol, and splenectomy, and whose platelet counts eventually nor-\nmalized during therapy with MMF. In this patient, thrombocytopenia is initially thought\nto be associated with active SLE involving major organ. However, after immunosup-\npressive agents were given, the refractory nature of thrombocytopenia seems to be\nan isolated phenomenon, independently of SLE activity.\nKey Words :Lupus Erythematosus, Systemic; Thrombocytopenia; mycophenolate mofetiI\nReceived : 1 September 2004\nAccepted : 3 November 2004\n\n884 H.K. Chang\ng/dL, a white blood cell count of 3,600/ L, and a platelet\ncount of 11,000/ L. Urinalysis revealed over 30 red blood\ncells per high-power field and 3+ proteinuria. Creatinine clea-\nranceand urinary total protein were 59 mL/min and 2.6 g/day,\nrespectively. The antinuclear antibody titer was 1:1,280 with\na homogenous pattern, the level of anti-double stranded DNA\nwas 420 IU/mL (normal, <5 IU/mL), and a profound hypo-\ncomplementemia was observed. IgM and IgG anticardiolipin\nantibodies and lupus anticoagulant were negative. Anti-plate-\nlet antibody was also negative. Renal biopsy showed a seg-\nmental endocapillary proliferation with active necrotizing\nlesions on some glomeruli, which was consistent with focal\nproliferative glomerulonephritis, class IIIB lupus nephritis.\nIn view of severe thrombocytopenia and the proliferative\nform of lupus nephritis, prednisolone (PD) 1 mg/kg, hydroxy-\nchloroquine 200 mg b.i.d., and monthly intravenous cyclophos-\nphamide500 mg/m\n2 were prescribed. She was discharged,\nsince the platelet counts rose to over 50,000/ L on these med-\nications.During initial six months of the follow-up, despite\n6 cycles of intravenous cyclophosphamide was monthly given,\nPD doses could not be tapered to below 20 mg/day to main-\ntain the platelet counts of over 50,000/ L.However, the pro-\nteinuria level decreased, and SLEDAI scores and serologic\nmarkers for disease activity improved. During the next 18\nmonths, several agents, including cyclosporine, azathioprine,\nintravenous gamma globulin and danazol were sequentially\ngiven to sustain the platelet counts, in combination with mod-\neratedoses of PD. However, she had to admit four times to\nthe hospital because of severe thrombocytopenia with the\nplatelet counts of below 10,000/ L and the development of\nspontaneous bleeding, such as epistaxis, petechiae, heavy men-\nstrual blood flow, and gingival bleeding, whenever the PD\ndoses decreased to less than 20 mg/day. However, there were\nno specific abnormal findings on the bone marrow biopsy.\nDuring this period, serologic markers for disease activity nor-\nmalizedand proteinuria also resolved, independently of the\nrefractory nature of thrombocytopenia. She, therefore, under-\nwentsplenectomy in September 2003, but failed to contribute\nto increment of the platelet counts to the adequate level. Spleen\nscintigraphy did not detect any evidences for accessory spleen\nand Howell-Jolly bodies were not found on a peripheral blood\nsmear, such that the possibility of the presence of accessory\nspleen was excluded.\nIn December 2003, MMF 500 mg b.i.d.and PD 40 mg/day\nwere then commenced. Within 2 weeks, the platelet counts\nincreased to over 100,000/ L. During the following three\nmonths, the platelet counts normalized and PD was success-\nfully tapered to 10 mg/day. In addition, clinical and serologic\nmarkers for SLE activity also remained stable. In June 2004,\nshe was very well on PD 5 mg/day and MMF 750 mg/day,\nwith stable disease activity and normal level of the platelet\ncounts.\nDISCUSSION\nIn general, the clinical features of thrombocytopenia in SLE\nare similar to those seen in other causes of thrombocytopenia,\nsuch as immune thrombocytopenic purpura (ITP). When the\nplatelet counts decreased to below 50,000/ L, spontaneous\nbleeding may occur. While mild thrombocytopenia in SLE is\nfrequently seen in the context of active disease, severe throm-\nbocytopenia causing significant bleeding is not that common\n(1). Two distinct subsets of SLE patients with thrombocytope-\nnia have been identified; one is related to an active disease of\nSLE, and the other is that thrombocytopenia is an isolated fin-\nding, independently of SLE activity (7). In the present patient,\nthrombocytopenia is initially thought to be associated with\nactive SLE involving major organ. However, after immuno-\nsuppressiveagents were given, the refractory nature of throm-\nbocytopeniaseems to be an isolated phenomenon, since other\nclinical and serologic markers for disease activity became im-\nproved.\nCorticosteroids are considered the first line therapy for severe\nthrombocytopenia in SLE. Although most patients with\nthrombocytopenia in SLE initially respond to this therapy,\nlong-term response has been reported to be sustained in only\n22% of patients (8). For patients who fail to respond to steroids\nor those who require moderate doses of steroids to maintain\nthe platelet counts, second-line therapeutic agents, includ-\ning azathioprine, intermittent intravenous cyclophosphamide,\ncyclosporine, danazol, dapsone, vincristine, and intravenous\ngamma globulin, have been described to be effective in the\ntreatment of steroids-resistant thrombocytopenia in SLE (1).\nOn the other hand, the efficacy of splenectomy in the treat-\nment of steroids-resistant thrombocytopenia in SLE is con-\ntroversial (1, 9). Several investigators have reported that\nsplenectomized patients with SLE may have a significantly\nhigher incidence of cutaneous vasculitis and serious infections\nwithout obvious benefits over those treated medically (10).\nIn contrast, since long-term responses by splenectomy in SLE\npatients with steroids-resistant thrombocytopenia have also\nbeen reported, splenectomy may be indicated for some patients\nrefractory to steroids or other second-line agents (1, 8, 11). \nIn the current patient, in spite of administrations of several\nimmunosuppressive or immunomodulating agents, moderate\ndoses of PD were required to maintain the platelet counts.\nMoreover, splenectomy failed to contribute to increment of\nthe platelet counts to the adequate level. However, severe,\nrefractory thrombocytopenia was successfully treated with\nMMF without any overt adverse effects.\nMMF is a potent immunosuppressant with good safety pro-\nfile,the commonest side effects being nausea, diarrhea, and\ndose-related leukopenia (2, 3). Recent randomized controlled\nstudies have shown that MMF is an efficacious and safe thera-\npeutic agent in patients with proliferative forms of lupus\nnephritis (5, 6). Moreover, there has been extensive use of\nMMF in several other autoimmune diseases, such as rheuma-\n\n\nTreatment of Refractory Thrombocytopenia with Mycophenolate Mofetil in Lupus 885\ntoid arthritis, psoriasis, and inflammatory eye disease (12).\nHowever, although little information has been available regard-\ning the role of MMF in the treatment of immune thrombo-\ncytopenia complicated with SLE, its immunomodulating func-\ntions,including selective inhibition of T and B cells prolifer-\nation, and suppression of antibody production and adhesion\nmolecule expression, are speculated to be an action of mech-\nanism for immune thrombocytopenia (2, 13). To date, there\nhas been only one formal report showing that steroids-refrac-\ntory thrombocytopenia in SLE successfully responded to MMF\n(13).The present patient seems to take much more refractory\ncourse of thrombocytopenia when compared with that patient.\nIn addition, in the case of ITP , there have been recent inves-\ntigationsindicating that MMF could be used as a second-line\nagent for the treatment of steroid-resistant ITP (14, 15). In\nthese previously published reports, MMF doses have usually\nbeen used in 2 g/day, which is a usual maintenance dosage\nused in other conditions. However, the MMF dosage was not\nincreased to 2 g/day, since the current patient responded well\nat lower dosage, 1 g/day. More studies are required which\ndosage of MMF is optimal for the management of thrombo-\ncytopenia in SLE.\nIn summary, I describe a patient with SLE in whom throm-\nbocytopenia was refractory to corticosteroids, intermittent\nintravenous cyclophosphamide, azathioprine, cyclosporine,\nintravenous gamma globulin, danazol, and splenectomy, and\nwhose platelet counts eventually normalized during therapy\nwith MMF. Further studies are required to confirm this obser-\nvation in a larger number of SLE patients with steroid-refrac-\ntory thrombocytopenia.\nREFERENCES\n1. Quismorio FP Jr.Hematologic and lymphoid abnormalities in sys-\ntemic lupus erythematosus. In: Wallace DJ, Hahn BH, editors,\nDubois’ lupus erythematosus. Philadelphia: Lippincott Williams &\nWilkins, 2002: 793-819.\n2. Allison AC, Eugui EM.Mycophenolate mofetil and its mechanisms\nof action. Immunopharmacology 2000; 47: 85-118.\n3. Adu D, Cross J, Jayne DR.Treatment of systemic lupus erythemato-\nsus with mycophenolate mofetil. Lupus 2001; 10: 203-8.\n4. Corna D, Morigi M, Facchinetti D, Bertani T, Zoja C, Remuzzi G.\nMycophenolate mofetil limits renal damage and prolongs life in\nmurine lupus autoimmune disease. Kidney Int 1997; 51: 1583-9.\n5. Chan TM, Li FK, Tang CS, Wong RW, Fang GX, Ji YL, Lau CS,\nWong AK, Tong MK, Chan KW, Lai KN.Efficacy of mycopheno-\nlate mofetil in patients with diffuse proliferative lupus nephritis. Hong\nKong-Guangzhou Nephrology Study Group. N Engl J Med 2000; 343:\n1156-62.\n6. Contreras G, Pardo V, Leclercq B, Lenz O, Tozman E, O\n’Nan P, Roth\nD. Sequential therapies for proliferative lupus nephritis. N Engl J Med\n2004; 350: 971-80.\n7. Miller MH, Urowitz MB, Gladman DD.The significance of throm-\nbocytopenia in systemic lupus erythematosus. Arthritis Rheum 1983;\n26: 1181-6.\n8. Arnal C, Piette JC, Leone J, Taillan B, Hachulla E, Roudot-Thoraval\nF, Papo T, Schaeffer A, Bierling P, Godeau B. Treatment of severe\nimmune thrombocytopenia associated with systemic lupus erythe-\nmatosus: 59 cases. J Rheumatol 2002; 29: 75-83.\n9. Alarcon-Segovia D. Splenectomy has a limited role in the manage-\nment of lupus with thrombocytopenia. J Rheumatol 2002; 29: 1-2.\n10. Rivero SJ, Alger M, Alarcon-Segovia D.Splenectomy for hemocy-\ntopenia in systemic lupus erythematosus. A controlled appraisal.\nArch Intern Med 1979; 139: 773-6.\n11. Homan WP, Dineen P. The role of splenectomy in the treatment of\nthrombocytopenic purpura due to systemic lupus erythematosus. Ann\nSurg 1978; 187: 52-6.\n12. Jayne D.Non-transplant uses of mycophenolate mofetil. Curr Opin\nNephrol Hypertens 1999; 8: 563-7.\n13. Vasoo S, Thumboo J, Fong KY.Refractory immune thrombocytope-\nnia in systemic lupus erythematosus: response to mycophenolate\nmofetil. Lupus 2003; 12: 630-2.\n14. Howard J, Hoffbrand AV, Prentice HG, Mehta A.Mycophenolate\nmofetil for the treatment of refractory auto-immune haemolytic anae-\nmia and auto-immune thrombocytopenia purpura. Br J Haematol\n2002; 117: 712-5.\n15. Hou M, Peng J, Shi Y, Zhang C, Qin P, Zhao C, Ji X, Wang X, Zhang\nM. Mycophenolate mofetil (MMF) for the treatment of steroid-resis-\ntant idiopathic thrombocytopenic purpura. Eur J Haematol 2003; 70:\n353-7.","source_license":"CC0","license_restricted":false}