{"paper_id":"60f16c6c-82ee-4fe5-b322-1e7d1e453818","body_text":"MEDITERRANEAN JO U R N A L  OF RHEUM\nATOLOGY\nLupus thrombocytopenia: pathogenesis and \ntherapeutic implications \nNikolaos Galanopoulos, Anna Christoforidou, \nZoe Bezirgiannidou\nMediterr J Rheumatol 2017; 28(1):20-6\nMEDITERRANEAN JOURNAL OF RHEUMATOLOGY   March 2017 | Volume 28 | Issue 1\nE-ISSN: 2529-198X\nMEDITERRANEAN JOURNAL \nOF RHEUMATOLOGY\nVolume 28    IssueMarch 2017 1\nAN EDITION OF GREEK R HEUM ATOLO GY SOCIETY A ND PROFE SSION AL ASSOCI ATION OF R HEUM ATOLO GISTS \nhttp://www.mjrheum.org\ne-ISSN: 2529-198X\n\n\nMEDITERRANEAN JOURNAL \nOF RHEUMATOLOGY\n28\n1\n2017\n20\nThis work is licensed  \nunder a Creative Commons  \nAttribution-NonCommercial  \n4.0 International License.\nSystemic Lupus Erythematosus (SLE) is a systemic au -\ntoimmune disorder that is frequently complicated by he-\nmatological manifestations such as hemolytic anemia, \nleukopenia and thrombocytopenia.1,2 These disorders are \nincluded in the diagnos-\ntic criteria of SLE both \nin the earlier (1982), as \nwell as in the revised \ncriteria of the American \nCollege of Rheumatolo-\ngy (2003), and the 2012 \nSystemic Lupus Inter -\nnational Collaborating Clinics (SLCC) criteria.3-5\nThrombocytopenia (<100x10 9/L) has been reported in \n20% to 40% of patients with SLE 2,6-8 and is usually at -\ntributed to an autoimmune mechanism similar to that of \nidiopathic immune thrombocytopenia (ITP). It may be the \nfirst manifestation of lupus in up to 16% of patients, pre-\nsenting months or as early as 10 years before diagno -\nsis.9,10 It can also be a complication of therapeutic agents \nsuch as azathioprine, methotrexate and rarely hydroxy -\nchloroquine. Severe thrombocytopenia (<20 to 50x109/L \naccording to study definition) is relatively rare, occurring \nin about 3-10% of patients. 11,12 Occasionally, thrombo-\nCite this article as: Galanopoulos N, Christoforidou A, Bezirgiannidou Z. Lupus thrombocytopenia: pathogenesis and therapeutic implications. \nMediterr J Rheumatol 2017;28(1):20-6.\n© Galanopoulos N, Christoforidou A, Bezirgiannidou Z\nKeywords: systemic lupus erythematosus, thrombocytopenia, mycophenolate mofetil, rituximab, \nthrombopoietin receptor agonists.\nCorresponding author:  \nAnna Christoforidou \nDepartment of Hematology \nUniversity Hospital of Alexandroupolis,  \nArea of Dragana 68100, Alexandroupolis, \nGreece. \nTel.: +30 2551351511 \nE-mail: annachristof@yahoo.gr\nABSTRACT\nSystemic Lupus Erythematosus (SLE) is frequently complicated by cytopenias. Thrombocytopenia is \nusually non severe and its frequency ranges from 20% to 40%. It is mostly an autoimmune process \ncaused by autoantibodies against platelet surface glycoproteins and it is associated with worse \nprognosis in SLE. It can also be a result of SLE treatment with azathioprine, methotrexate and \nrarely hydroxychloroquine or thrombotic microangiopathy or macrophage activation syndrome. \nIf thrombocytopenia is mild (>50x109/L) and there is no other evidence of disease there is no \nneed of therapy. Severe thrombocytopenia is less frequent and needs therapeutic management. \nCorticosteroids are the cornerstone of therapy. Continuous high dose oral prednisolone or pulse high \ndose methylprednisolone (MP) with or without intravenous immune globulin are used in the acute \nphase. Second line agents (hydroxychloroquine, danazol, azathioprine, cyclosporine, mycophenolate \nmofetil, cyclophosphamide, rituximab) are usually needed. Splenectomy is indicated for recurrent or \nresistant cases.  There are no evidence-based guidelines to facilitate selection of one drug over \nanother but certainly the co-existence of other systemic SLE manifestations must be taken into \naccount. Newer therapies are emerging although there is no consensus on the treatment of refractory \nlupus thrombocytopenia due to the absence of controlled randomized trials.  \nMediterr J Rheumatol 2017;28(1):20-6\nhttps://doi.org/10.31138/mjr.28.1.20\nArticle Submitted 28/11/2016; Revised Form 01/03/2017; Accepted 14/03/2017\nREVIEW\nLupus thrombocytopenia: pathogenesis and therapeutic implications \nNikolaos Galanopoulos, Anna Christoforidou, Zoe Bezirgiannidou\n1Outpatient Department of Rheumatology, University General Hospital of Evros (Alexandroupolis), Thrace, Greece \n2Department of Haematology, Democritus University of Thrace, Alexandroupolis, Greece \n\n21\nTITLE21\ncytopenia may be due to the development of thrombotic \nmicroangiopathy,13,14 antiphospholipid syndrome or sple-\nnomegaly with hypersplenism. Macrophage activation \nsyndrome should be suspected in patients with multiple \ncytopenias and fever with a rapid onset especially those \nwith juvenile SLE.15\nThrombocytopenia in SLE is associated with a worse \nprognosis and higher mortality from the disease. 12,16,17 It \nhas been linked with a severe disease course including \nneuropsychiatric disorders, renal involvement, hemolytic \nanemia and antiphospholipid syndrome.7,18 Most studies \nhave shown an association between thrombocytopenia \nand mortality, however a few did not found such a rela -\ntionship.1,19 In two large studies thrombocytopenia was \nthe only independent predictor for mortality in SLE. 16,20 \nThe leading cause of death in the Reveille et al. 20 study \nwas infection. It has been shown that it is not thrombocy-\ntopenia itself that influences survival, but its coexistence \nwith multiple organ damage and treatment related com-\nplications.12 A different presentation with a less severe, \nchronic form of thrombocytopenia, not related to disease \nactivity is also common, and appears to be less respon-\nsive to corticosteroid therapy.1 \nSLE has a significant genetic predisposition.21 In a prom-\ninent study by Scofield RH et al., families with even one \nmember with thrombocytopenic SLE seemed to be re -\npeatedly affected by a serious clinical phenotype that \nwas assigned to a familial form of the disease, associated \nwith genetic linkages at 1q22-23 and 11p13. 22 In these \nfamily pedigrees, even the non-thrombocytopenic SLE \npatients presented with multiple organ damage such as \nserositis, nephritis, neuropsychiatric disease, and hemo-\nlytic anemia.\nPATHOGENESIS \nAutoantibodies targeting antigenic glycoproteins on the \nplatelet membrane are central to the destruction of plate-\nlets in SLE.23-25 In some cases other autoantibodies such \nas antiphospholipid antibodies 26,27 and autoantibodies \nagainst thrombopoietin (TPO) or TPO receptor (c-mpl) \nare identified. 28-30 Antibody-coated platelets are sub -\nsequently removed by splenic and other reticular mac -\nrophages, through binding on their surface Fc gamma \nreceptor. \nAnti-IIb/IIIa antibodies, either circulating or platelet-bound \n(MAIPA method), are the most frequent finding, like in ITP , \nbut similar to ITP they are not specific for thrombocyto -\npenia, as their detection ranges from 30-70% in throm -\nbocytopenic patients and in contrast many patients \npositive for these antibodies do not ever develop throm-\nbocytopenia.31,32 However, in previously antibody-pos -\nitive patients recovering from thrombocytopenia after \nimmunosuppressive therapy, these antibodies disappear \nand reappear in relapses, thus indicating their pathoge -\nnetic role.23, 25 Antibodies against Gp Ia/IIa, HLA I and Gp \nIb/Ix complex are less frequently detected. \nSerum levels of TPO are higher in thrombocytopenic SLE \npatients compared to normal controls, and megakaryo -\ncytes are increased in their bone marrow. Nevertheless, \nantibodies against TPO and c-mpl have been identified \nin 23%-39% of patients. 25,28 These patients often have \nlower platelet counts, although their exact role in the \npathogenesis of thrombocytopenia remains obscure. In \nsome cases the development of anti-TPO antibodies is \nassociated with poor response to administration of cor -\nticosteroids (CS).30\nAntiphospholipid antibodies against cardiolipin, phos -\nphatidylinositol, prothrombin as well as lupus anticoag -\nulant are detected in a substantial proportion of patients \nwith SLE and thrombocytopenia31-33 and they are signifi-\ncantly associated with thrombocytopenia in many stud -\nies.34,35 Membrane phospholipids that cross-react anti -\ngenically with cardiolipin are exposed after cell damage \nand comprise the trigger for the development of anti-car-\ndiolipin antibodies.36\nFinally, autoantibodies against the CD40-ligand molecule \non the surface of T lymphocytes appear to have a role in \nthe development of thrombocytopenia in SLE. CD40-li -\ngant is linked to the CD40 antigen on the B lymphocytes \nsurface leading to their activation and autoantibody pro-\nduction. In a study by Nakamura et al. 37 such autoanti -\nbodies were detected in seven (6%) of 125 patients with \nSLE. The incidence of thrombocytopenia was higher \nin positive patients in comparison to the negative ones \n(100% vs 14%). \n  \nLABORATORY FINDINGS \nLaboratory investigation of patients with SLE and throm-\nbocytopenia begins with microscopic examination of \nperipheral blood smears for the estimation of platelet \ncount and size and the presence of schistocytes (frag -\nmented red blood cells). In case of coexistence of throm-\nbocytopenia and anemia the assessment of reticulocyte \ncount and direct Coombs test is warranted. Abnormal \nlymphocyte morphology as well as lymphadenopathy \nshould raise suspicion of a lymphoproliferative disease \nand prompt investigation with imaging studies, immuno-\nglobulin measurement, bone marrow and lymph node \nbiopsy.  Coagulation studies, LDH, bilirubin levels and \nantiphospholipid antibodies are also important to ex -\nclude TTP , disseminated intravascular coagulation and \nantiphospholipid syndrome.  \nThe measurement of antiplatelet antibodies may be re -\nquired in patients with severe thrombocytopenia, espe -\ncially in prednisone refractory ones. It should however be \nnoted that failure to detect them does not preclude au -\ntoimmune thrombocytopenia in patients with SLE. This \nfact along with the limited availability of these tests has \nmade their usefulness controversial.  \nHigh antibody titers against double-stranded DNA (an -\nLUPUS THROMBOCYTOPENIA: PATHOGENESIS AND THERAPEUTIC IMPLICATIONS\n\nMEDITERRANEAN JOURNAL \nOF RHEUMATOLOGY\n28\n1\n2017\n22\nMEDITERRANEAN JOURNAL \nOF RHEUMATOLOGY\n28\n1\n201722\nti-dsDNA) coupled with low levels of C3 and C4 advo -\ncate activity of SLE, although thrombocytopenia itself \nhas not been found to be associated with anti-dsDNA.11 \nOn the other hand low levels of  C3 or CH50 has been \nassociated with thrombocytopenia.12 \nBone marrow aspiration may be needed in severe or per-\nsistent thrombocytopenia, particularly when there is sus-\npicion of drug toxicity or hemophagocytosis or when it is \naccompanied by other cytopenias. Bone marrow findings \nare heterogeneous between studies, ranging from hypo- to \nhypercellular marrow and low, normal or high megakaryo-\ncyte number. Increased reticulin proliferation, lymphocy-\ntosis, plasmacytosis and morphological abnormalities of \nmegakaryocytes notably aggregation, reduced lobulation \nand pycnotic appearance, as well as necrotic lesions in the \nbone marrow stroma have been reported.25, 38\n \nTHERAPEUTIC MANAGEMENT \nThrombocytopenia in SLE may be acute in onset and \nextremely severe. Severe thrombocytopenia requires \nemergency therapy in order to eliminate hemorrhagic \ncomplications and achieve a complete or partial plate -\nlet response. Maintenance treatment is usually needed \nto prevent relapse. Initial treatment does not differ from \nITP . The decision to treat when thrombocytopenia is the \nsole disorder in SLE depends on the hemorrhagic man -\nifestations and platelet count. Generally, patients with a \nplatelet count > 50x109/l without bleeding manifestations \ndo not require treatment in the absence of coexistent he-\nmostatic disorders, anticoagulation treatment, trauma or \nmajor surgery.\nCorticosteroids are the cornerstone of initial treatment. \nHigh dose oral prednisolone or pulse high dose methyl -\nprednisolone (MP) with or without intravenous immune \nglobulin (IVIG) are used in the acute phase. Second line \nagents include hydroxychloroquine (HCQ), danazol, \nimmunosuppressive drugs like azathioprine (AZA), cy -\nclosporine (CSA), mycophenolate mofetil (MMF), cyclo -\nphosphamide (CYC), and biological therapies such as \nrituximab. The thrombopoietin receptor agonists romi -\nplostim and eltrombopag have been widely used for the \ntreatment of ITP and they also seem to have a role in \nSLE thrombocytopenia.  Splenectomy is indicated for re-\ncurrent or resistant cases. It should be noted that none \nof the above agents have been tested in a randomized \nfashion in the context of SLE thrombocytopenia.  \nIn a recent study, Jin-Hee Jung et al. 39 retrospectively \nexamined the clinical characteristics and prognosis of \n230 patients with SLE in regard to degree of thrombo -\ncytopenia and response to treatment. They found high -\ner mortality (15% vs 9%) among patients with severe \nthrombocytopenia (<20x109/l) and lower mortality in pa -\ntients with complete remission of thrombocytopenia after \ntreatment. No difference between therapeutic modalities \nwas found, regarding complete remission rate, except \na lower incidence of complete remission in the danazol \ngroup. Similarly, Ziakas et al. performed a case-control \nstudy in 632 patients and did not find a different relapse \nfree interval between patients receiving low or high inten-\nsity regimens (CS plus AZA vs CS plus CYC).12\nOther causes of thrombocytopenia beyond auto-im -\nmune will not be further discussed in the below section. \n \nFIRST LINE THERAPY  \nCorticosteroids \nCorticosteroids (CS) are administered at the conventional \ndose of 1-1.5 mg/kg of prednisone qd with subsequent \nslow tapering after achieving a stable platelet response or \nas pulses of methylprednisolone (MP) iv (500-1000 mg/\nday for 3 days). There is no significant advantage of the \nhigher dose MP scheme (3-5g), which may be associ -\nated with more complications like infections. 40 Anti-TPO \nreceptor antibodies may be associated with a subopti -\nmal response to CS.30 CS appear to produce a satisfac-\ntory response in the majority of patients, but eventually \nmost patients relapse.2,41 If there is no response after four \nweeks of CS therapy the patient is considered resistant \nand a second line treatment is sought.  \n \nIntravenous Immune Globulin (IVIG) \nIVIG is used in the acute management of the bleeding \npatient with severe SLE thrombocytopenia at a dose of \n1g/kg for 1 to 2 days, as recommended in the recent \n2011 American Society of Hematology guidelines for \nITP42 or at 400mg/kg for five consecutive days.43 It exerts \nits action by downregulating autoantibody production, \nneutralization of pathogenic autoantibodies by anti-id -\niotypic antibodies, inhibition of complement-mediated \ndamage, modulation of cytokine production, induction \nof apoptosis in lymphocytes, and modulation of both \nB- and T-lymphocyte function. Maintenance of remission \nafter repeated lower monthly doses has also been re -\nported.44 It is safely used in pregnancy. \n \nSECOND LINE THERAPY OR STEROID-SPARING \nAGENTS \nAlthough most patients initially respond to CS, respons -\nes are not sustained and eventually management calls \nfor second line agents. Alternative treatment is also war-\nranted in responding patients who experience debilitat -\ning side effects from prolonged CS use. These drugs are \nused alone or in combination with CS as steroid-sparing \nagents.  There are no evidence-based guidelines to facil-\nitate selection of one drug over another but certainly the \nco-existence of other systemic SLE manifestations must \nbe taken into account in order to select the appropri -\nate therapy. If thrombocytopenia is mild (>50x109/L) and \nthere is no other evidence of disease there is no need of \ntherapy.  \n\n23\nTITLE23\nLUPUS THROMBOCYTOPENIA: PATHOGENESIS AND THERAPEUTIC IMPLICATIONS\nHydroxychloroquine (HCQ)  \nA combination of HCQ and prednisone is effective in \nmany patients.41 Khellaf et al.45 studied the effect of HCQ \nin either SLE or only ANA positive patients with throm -\nbocytopenia and insufficient response to CS alone. The \ncoadministration of CS with HCQ resulted in an overall \nresponse rate of 60% with a higher rate noted in pa -\ntients with SLE compared to those with ANA only (83% \nvs 50%). Arnal et al. reported on the long-term results of \nHCQ plus CS in 11 patients failing CS alone, in 64% of \nwhom a lasting response was obtained.41\n \nDanazol \nDanazol is a synthetic androgen with a proven activity in \nmany types of \nthrombocytopenia including that of SLE. 46,47 Its mecha -\nnism of action is unclear but involves impairment of mac-\nrophage-mediated clearance of antibody-coated plate -\nlets via decreased Fc receptor expression.  It is a well \ntolerated drug, with the main side effects being hirsutism \nand an increased risk of thromboembolic episodes. The \nbest responses have been observed after prolonged \nadministration at a daily dose of 600-800mg, alone or \nin combination with AZA or CS. Following a stable re -\nsponse for at least 12 months the dose can be lowered \nor interrupted as it has been associated with lasting re -\nsponses even after discontinuation.48\n \nAzathioprine \nAZA is a steroid-sparing agent with sparse reports on  \nlupus thrombocytopenia, used alone or in combination \nwith CS.49,50 It is administered at a dose of up to 2mg/kg/\nday. If a response occurs, therapy should be continued \nat full doses for at least 12 months and then  tapered \ngradually. \n \nCyclosporine  \nIn a small number of patients with SLE and thrombocy -\ntopenia CSA appeared to be beneficial as a second line \nor steroid-sparing agent. 51,52 The optimal dose has not \nbeen defined and patients may respond in doses much \nlower than those used in transplantation (<3-5mg/kg/\nday). However, caution should be used because of its \nrenal toxicity.  \n \nCyclophosphamide  \nCyclophosphamide is of particular importance in the \ntreatment of severe refractory thrombocytopenia of \nSLE.52 It is administered in IV pulses (0,75-1 g/m 2 or \n10–15 mg/kg every 4 weeks for four to six months). In \nthe retrospective study of Boumpas et al.53 in 7 patients \nwith SLE and thrombocytopenia refractory to CS, CYC \nat a dose of  0,75-1 g/m 2 every 4 weeks resulted in all \npatients achieving CR within 2-18 weeks. In four patients \nthe subsequent administration of low dose prednisolone \nwas sufficient to maintain remission of thrombocytopenia \nthroughout a long follow up period (mean 5.6 years). Al -\nternatively, Park et al.54 applied the low dose CYC proto-\ncol (500 mg of CYC every two weeks for three months), \nas used in the Euro-Lupus Nephritis Trial, in 2 refractory \npatients achieving a good response which was main -\ntained thereafter by a combination of low dose prednis -\nolone with AZA or MMF. This lower dose can improve \ntolerability of CYC by reducing the risk of neutropenia. \n \nMycophenolate mofetil  \nMMF, a prodrug of mycophenolic acid, which inhibits \ninosine-5’monophosphate dehydrogenase, is an immu-\nnosuppressive drug successfully administrated both as \ntreatment of severe resistant thrombocytopenia and as \nmaintenance.55,56 Its main use has been lupus nephritis \nand it is less toxic than CYC. \n \nSplenectomy \nSplenectomy has been successfully performed is SLE \nthrombocytopenia.57 This procedure has been widely \nused, with excellent long-term results in recurrent ITP .58  \nHowever, in SLE there is a risk of a flare of the disease \nbecause the spleen is a prominent site of immune com -\nplexes’ clearance, and additionally a predisposition  to \ninfections due  to  the  often prolonged  use  of immu -\nnosuppressants in these patients. 1 Prophylactic vac -\ncinations against pneumonococcus sp, haemophilus \ninfluenza type B and meningitis are mandatory before \nthe procedure and antibiotic prophylaxis for at least two \nyears postsplenectomy are recommended, particularly in \npatients with additional chronic hypocomplementemia. \nEfficacy of splenectomy is controversial in SLE59 with one \nstudy reporting only 2 out of fourteen patients maintain -\ning response without the need of CS or other drugs. 60 \nThus, it is reserved for the most resistant cases. More \nstudies are needed to define the safety and efficacy of \nthe procedure. \n \nNOVEL THERAPIES \nRituximab  \nSLE is known to be associated with polyclonal B-cell \nhyper reactivity. Rituximab is a chimeric monoclonal an -\ntibody that binds to the CD20 antigen, found on the sur-\nface of B lymphocytes, inducing depletion of B cells. In \nSLE, it has been used at high doses of 1000 mg for one \nor multiple doses to as low as 100 to 200mg per week \nfor 1-4 doses,61-63 the lower doses reserved for patients \nwith cytopenias only. 64 Although retrospective or open \nlabel studies and case reports have shown efficacy over \n60% in lupus thrombocytopenia, optimal dose has not \nbeen defined and duration of response is somehow short \nlived.61,65 Newer, type II, anti-CD20 mAbs like obinotu -\nzumab may be more effective in this context due to more \npotent B cell depletion.66 On the other hand, results from \n\nMEDITERRANEAN JOURNAL \nOF RHEUMATOLOGY\n28\n1\n2017\n24\nMEDITERRANEAN JOURNAL \nOF RHEUMATOLOGY\n28\n1\n201724\ntwo randomized controlled studies (EXPLORER 67 and \nLUNAR68 trials) using rituximab in an intention-to-treat \nSLE have been disappointing 69 showing no significant \nbenefit over placebo showing no significant benefit over \nplacebo in BILAG scores and renal response respective-\nly. This unexpected outcome has been partially attribut -\ned to suboptimal trial design and concurrent therapies, \nbut it has also been speculated that a feedback effect, \ncharacterized by rising BAFF levels, may play a role to \npostrituximab SLE flares.69 The exact place of rituximab, \nregarding its use early or late in the course of thrombocy-\ntopenia remains to be defined by further studies. \n \nBelimumab \nBelimumab is a human IgG1 λ monoclonal antibody that \nbinds to and inhibits B-cell activating factor (BAFF), thus \ninhibiting the biological activity of B lymphocytes and \ninducing apoptosis of autoreactive B lymphocytes. 70 In \nSLE BAFF is overexpressed, enhancing the survival of B \nlymphocytes, including autoreactive B cell populations.71  \nIn the post hoc analysis of two Lupus phase III random-\nized trials, belimumab was significantly associated with \nless worsening in the haematological domain, but there \nare currently no trials of belimumab for immune thrombo-\ncytopenia or hematological disorders in general.70\n \nTHROMBOPOIETIN RECEPTOR AGONISTS \nRomiplostim and eltrombopag are thrombopoietin recep-\ntor agonists which exhibit their action by inducing prolif -\neration and differentiation of megakaryocyte progenitors, \nmaturation of megakaryocytes and increased platelet pro-\nduction.72 They have displayed excellent results in phase III \nrandomized trials73,74 and have been approved since 2008 \nas second line agents for ITP refractory to other treatments. \nSo far, the efficacy of these agents in lupus thrombocyto-\npenia has only been assessed in sparse case reports. In \none report a patient with Evans syndrome refractory to \nrituximab was successfully managed with romiplostim,75 \nwhereas in another case romiplostim facilitated response \nin a pregnant thrombocytopenic patient with SLE.76 Con-\ntrasting to these results a young SLE patient developed \nthrombotic microangiopathy with renal failure after romi-\nplostim therapy.77 Maroun et al. 78 reported on three pa -\ntients with SLE thrombocytopenia in which administration \nof eltrombopag was successful as steroid-sparing treat-\nment. Another patient with refractory thrombocytopenia \nachieved a complete response after eltrombopag treat -\nment.79 Eltrombopag was also efficient in a patient with \nlupus-associated amegakaryocytic thrombocytopenia. 80 \nThe thrombotic risk must be taken into account though. In \na recent report, a patient with antiphospholipid syndrome \npresented with fatal thrombotic complications one month \nafter starting eltrombopag for severe thrombocytopenia \nand while platelets had normalized.81 \nCONCLUSION \nThrombocytopenia (<100x10 9/L) has been reported in \n20% to 40% of patients with SLE and is usually attributed \nto an autoimmune mechanism similar to that of idiopathic \nimmune thrombocytopenia. It may be the first manifesta-\ntion of lupus in up to 16% of patients, presenting months \nor as early as 10 years before diagnosis. Many studies \nhave found an association between thrombocytopenia \nand a higher mortality from SLE, although the pattern of \nthrombocytopenia (severity, onset) is not clearly defined. \nThere are no evidence-based recommendations for the \ntreatment of SLE thrombocytopenia due to the absence \nof randomized controlled trials. Acute therapy of severe \nthrombocytopenia or for the bleeding patient is the same \nas in ITP , high-dose CS and IVIG-based, but maintenance \nusually calls for the addition of other immunosuppressive \ndrugs (hydroxychloroquine, danazol, azathioprine, cyc -\nlosporine, mycophenolate mofetil, cyclophosphamide), \nbecause response is often short-lived and patients have \nother organ involvement too. New drugs such as mono-\nclonal antibodies and thrombopoietin receptor agonists \nare emerging as steroid-sparing modalities but safety \nand efficacy have yet to be established.  Randomized \ncontrolled trials are needed to define the superiority of \nany second- line agent over the others. \n \nCONFLICT OF INTEREST\nThe authors of this manuscript declare no conflict of in -\nterest. \n \n \nREFERENCES\n1. Hepburn A L, Narat S, Mason J C. The management of peripheral \nblood cytopenias in systemic lupus erythematosus. Rheumatology \n(Oxford) 2010;49:2243-54.\n2. 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