Review
Management of immune cytopenias in patients with systemic lupus erythematosus — Old and new

https://doi.org/10.1016/j.autrev.2013.02.001Get rights and content

Abstract

There are various immune cytopenias associated with systemic lupus erythematosus (SLE). The most common one is anemia; however, there are different etiologies for the anemia caused by SLE. Anemia could be due to chronic disease, secondary to renal insufficiency, blood loss, drug induced or autoimmune hemolysis. There are other very rare causes of anemia secondary to SLE which include red cell aplasia, aplastic anemia, and microangiopathic hemolytic anemia. Treatment of the anemia would be according to the cause. Leukopenia, neutropenia, and lymphopenia are hematologic complications associated with SLE, and in majority of cases no treatment is required. Thrombocytopenia is one of the complications of SLE and is usually treated by steroids. However, there are significant numbers of patients which will either not respond to or relapse after treatment. This article summarizes immune cytopenias seen in patients with SLE, and it also discusses management of these cytopenias.

Introduction

Hematological involvement is common in SLE and no specific treatment is necessary in mild asymptomatic cases but close monitoring of cytopenia is warranted in most patients. Any significant changes in previous stable cell lineage parameters are considered to be an indication of SLE flare, and will need evaluation and close monitoring. This evaluation should include a detailed medical history for possible drug-induced myelosuppression, and in addition to stopping all medications which interfere with bone marrow function. Symptomatic treatment including transfusion therapy is required in cases with more severe hematological abnormalities. For the past 50 years, no new medication has been approved by FDA for SLE. Corticosteroids are considered the first line of treatment in severe cases for decades, and are effective in about 80% of SLE patients with hematological abnormalities. However, significant number of SLE subsets is resistant to conventional therapy and has high mortality and morbidity rates. There are second-line drugs such as immunomodulators and immunosuppressors for corticosteroid-resistant cases, but there is no randomized controlled clinical trial for most of these drugs and their use is anecdotal. Majority of these drugs are nonselective and have substantial toxicity. Moreover, there is no general agreement on definition of flare, response, and resistance and it is hard to compare the response rate of different drugs. More effective and less toxic drugs without any overt adverse effect still remain to be discovered [1], [2]. SLE is the most common cause (38–61%) of ICU admission among all autoimmune disorders and respiratory system is the most common involved organ [3]. In the next few paragraphs we will discuss the different hematologic manifestations of SLE and their treatments.

Section snippets

Autoimmune hemolytic anemia

Autoimmune hemolytic anemia (AIHA) with or without thrombocytopenia occurs in about 10% of SLE patients and is a common and serious complication in these cases [4], [5], [6], [7]. The warm type AIHA, mediated by IgG antibodies reacting in body temperature is the predominant type in patients with SLE while cold agglutinin AIHA is mediated by IgM complement-fixing antibody, which reacts at 4 °C. Patients with overt hemolysis present with anemia, elevated reticulocyte count, low haptoglobin,

Transfusion therapy in AIHA

Autoantibodies can potentially mask alloantibodies, and make it difficult to find the appropriate red blood cell by compatibility testing. However, sometimes clinicians face patients with progressive or severe symptomatic AIHA and reticulocytopenia that transfusion therapy is necessary and can be life-saving. Importantly transfusion should not be delayed in such situations. Most alloantibodies are directed against the blood group systems of Rh, Kell, Kidd, and Duffy. Occasionally, diluting the

Other types of anemia

Anemia of chronic disease is a frequent cause of anemia in patients with SLE. The pathogenesis is usually secondary to suppression of erythropoiesis by chronic inflammation [6]. Anemia is usually normochromic normocytic with a low reticulocyte count, elevated ferritin and low iron levels, and bone marrow iron is usually adequate. The major mediator of anemia of chronic disease is hepcidin which usually inhibits iron release from macrophages and absorption of iron from intestine, leading to

Leukopenia

Leukopenia is common in SLE and usually is secondary to lymphopenia, neutropenia or combination of both. Eosinopenia and basophilopenia are rare and have lesser clinical significance. Lymphopenia is common and T cell lymphopenia is the most common type of lymphopenias, and absolute lymphopenia correlates with SLE activity and high DNA antibody titers. Lymphopenia per se can predispose to autoimmunity and can also be a consequence of disease activity in the setting of active SLE. Concomitant

Thrombocytopenia

Thrombocytopenia is a common and important manifestation of SLE which has direct relation with its morbidity and mortality. It is mild to moderate most of the time and does not need any specific treatment. However, severe thrombocytopenia occurs in the context of active disease. There are growing evidences that show presence of at least two types of autoantibodies, anti GPIIb/IIIa, and anti thrombopoietin receptor (TPOR) antibodies are the major pathophysiologic mechanisms of thrombocytopenia

Treatment of TTP in SLE patients

Thrombotic thrombocytopenic purpura is a life threatening thrombotic microangiopathy (TMA) that needs high index of suspicion in SLE. TTP can be divided to primary or idiopathic and secondary to an underlying disorder. Severe ADAMTS13 deficiency or presence of its inhibitor is a manifestation of acute idiopathic TTP, relapses are frequent, and plasmapheresis is the standard of treatment. In a large study of patients with connective tissue disorders and TMA the percentage of patients with TMA

Splenectomy in SLE

Splenectomy is an invasive therapeutic modality and a frequent procedure for hematological manifestations of SLE but still the role of splenectomy in SLE associated hemocytopenia is not clear, and even some authors believe it is harmful. In one study, 30 unselected SLE patients with thrombocytopenic purpura and/or AIHA divided to two 15 groups of splenectomy and non-splenectomy and the result in a 19 months follow up for both groups were the same. However, cutaneous vasculitis, infections, and

Take-home messages

  • Anemia of chronic disorder is the most common type of anemia in SLE but autoimmune hemolytic anemia with high reticulocyte count is a SLE diagnostic criteria. Glucocorticoids are the main treatment of AIHA and about 96% of patients have initial response to glucocorticoids but rituximab, cyclosporine, IVIg, and cyclophosphamide have successfully been used in selective cases.

  • Transfusion may be problematic in AIHA, and even life threatening. Transfusion should be avoided and only be done

Disclosure

All authors do not have any conflict of interest to disclose.

Acknowledgment

The authors wish to thank Kathleen Kruger for her technical assistance.

References (99)

  • G.S. Habib et al.

    Pure red cell aplasia and lupus

    Semin Arthritis Rheum

    (2002)
  • L. Mouthon et al.

    Intravenous immunoglobulins in autoimmune- or parvovirus B19-mediated pure red cell aplasia

    Autoimmun Rev

    (2005)
  • M. Akhtari et al.

    Autoimmune neutropenia in adults

    Autoimmun Rev

    (2009)
  • K.A. Newman et al.

    Management of autoimmune neutropenia in Felty's syndrome and systemic lupus erythematosus

    Autoimmun Rev

    (2011)
  • B. Hellmich et al.

    Treatment of severe neutropenia due to Felty's syndrome or systemic lupus erythematosus with granulocyte colony-stimulating factor

    Semin Arthritis Rheum

    (1999)
  • A.J. Hakim et al.

    Autoimmune thrombocytopenia in primary antiphospholipid syndrome and systemic lupus erythematosus: the response to splenectomy

    Semin Arthritis Rheum

    (1998)
  • W.W. Coon

    Splenectomy for cytopenias associated with systemic lupus erythematosus

    Am J Surg

    (1988)
  • A.L. Hepburn et al.

    The management of peripheral blood cytopenias in systemic lupus erythematosus

    Rheumatology

    (2010)
  • K. Newman et al.

    Hematologic manifestations of systemic lupus erythematosus

  • Y. Shoenfeld et al.

    Hematologic manifestation

  • J.C. Nossent et al.

    Prevalence and significance of hematological abnormalities in patients with systemic lupus erythematosus

    Q J Med

    (1991)
  • M. Jeffries et al.

    Haemolytic anaemia in a multi-ethnic cohort of lupus patients: a clinical and serological perspective

    Lupus

    (2008)
  • E. Gomard-Mennesson et al.

    Treatment of isolated severe immune hemolytic anaemia associated with systemic lupus erythematosus: 26 cases

    Lupus

    (2006)
  • M. Abu-Shakra et al.

    Azathioprine therapy for patients with systemic lupus erythematosus

    Lupus

    (2001)
  • J.M. Pignon et al.

    Danazol in autoimmune hemolytic anemia

    Br J Haematol

    (1993)
  • A.C. Chan et al.

    Danazol therapy in autoimmune hemolytic anemia associated with systemic lupus erythematosus

    J Rheumatol

    (1991)
  • Y. Levy et al.

    A study of 20 SLE patients with intravenous immunoglobulin-clinical and serologic response

    Lupus

    (1999)
  • G. Zandman-Goddard et al.

    Intravenous immunoglobulin therapy and systemic lupus erythematosus

    Clin Rev Allergy Immunol

    (2005)
  • M.J. Leandro et al.

    An open study of B lymphocyte depletion in systemic lupus erythematosus

    Arthritis Rheum

    (2002)
  • B. Garvey

    Rituximab in the treatment of autoimmune haematological disorders

    Br J Haematol

    (2008)
  • J.H. Anolik et al.

    Rituximab improves peripheral B cell abnormalities in human systemic lupus erythematosus

    Arthritis Rheum

    (2004)
  • J. Merrill et al.

    Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER)

    Lupus

    (2011)
  • J.-E. Gottenberg et al.

    Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases

    Ann Rheum Dis

    (2005)
  • Y. Tanaka et al.

    A multicenter phase I/II trial of refractory systemic lupus erythematosus

    Mod Rheumatol

    (2007)
  • M.J. Leandro et al.

    B-cell depletion in the treatment of patients with systemic lupus erythematosus: a longitudinal analysis of 24 patients

    Rheumatology

    (2005)
  • K.G.C. Smith et al.

    Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis. Remission, relapse, and re-treatment

    Arthritis Rheum

    (2006)
  • J.A. Reynolds et al.

    Effects of rituximab on resistant SLE disease including lung involvement

    Lupus

    (2009)
  • S. Perrotta et al.

    Anti-CD20 monoclonal antibody (rituximab) for life-threatening autoimmune haemolytic anaemia in a patient with systemic lupus erythematosus

    Br J Haematol

    (2002)
  • F.J. Penalver et al.

    Rituximab is an effective and safe therapeutic alternative in adults with refractory and severe autoimmune hemolytic anemia

    Ann Hematol

    (2010)
  • D. Dierickx et al.

    Rituximab in auto-immune haemolytic anaemia and immune thrombocytopenic purpura: a Belgian retrospective multicentric study

    J Intern Med

    (2009)
  • C. Burton et al.

    Interstitial pneumonitis related to rituximab therapy

    N Engl J Med

    (2003)
  • E. Voog et al.

    Neutropenia in patients treated with rituximab

    N Engl J Med

    (2003)
  • P. Alba et al.

    Mycophenolate mofetil as a treatment for autoimmune haemolytic anaemia in patients with systemic lupus erythematosus and antiphospholipid syndrome

    Lupus

    (2003)
  • A. Mak et al.

    Mycophenolate mofetil for refractory haemolytic anemia in systemic lupus erythematosus

    Lupus

    (2005)
  • C.C. Mok

    Mycophenolate mofetil for non-renal manifestations of systemic lupus erythematosus: a systemic review

    Scand J Rheumatol

    (2007)
  • J. Howard et al.

    Mycophenolate mofetil for the treatment of refractory auto-immune haemolytic anaemia and auto-immune thrombocytopenic purpura

    Br J Haematol

    (2002)
  • O.W. Buetens et al.

    Red blood cell transfusion in autoimmune hemolytic anemia

    Curr Opin Hematol

    (2003)
  • M. Voulgarelis et al.

    Anaemia in systemic lupus erythematosus: aetiological profile and the role of erythropoietin

    Ann Rheumatol Dis

    (2000)
  • A. Winkler et al.

    High-dose intravenous cyclophosphamide treatment of systemic lupus erythematosus-associated aplastic anemia

    Arthritis Rheum

    (1988)
  • Cited by (73)

    • Systemic lupus erythematosus (I)

      2021, Medicine (Spain)
    View all citing articles on Scopus
    View full text