with the increasing use of agents that block the action of tumor necrosis factor ( tnf)- in the treatment of rheumatoid arthritis ( ra ) and other chronic immune - mediated inflammatory conditions , recognition of serious adverse events assumes greater importance even when they are rare . we report a patient with ra who presented with transient bone marrow ( bm ) aplasia associated with the first injection of etanercept , and review the literature on tnf - blocking agent - associated cytopenias . a 62-year - old woman was admitted with fatigue , fever ( 39  c ) , gingival bleeding , and a rash over her legs . she had a history of ra diagnosed 6  years prior when marked synovitis in more than ten large and small joints was found , associated with prolonged morning stiffness , elevated erythrocyte sedimentation rate ( esr ) and c - reactive protein ( crp ) , and strongly positive rheumatoid factor and anti - citrullinated peptide antibodies ( 250  iu / ml and 76.6 , respectively ) . her recent treatment included methotrexate ( 22.5  mg once a week with daily folic acid ) started on diagnosis , hydroxychloroquine ( 200  mg daily ) and a single first injection of etanercept ( enbrel 50  mg ) administered subcutaneously into the thigh 23  days prior to admission . previous treatment with leflunomide and adalimumab ( humira ) had failed and been discontinued months before etanercept was started . no other medications were used , and even methotrexate and hydroxychloroquine were discontinued by her rheumatologist when etanercept was commenced . one week after the injection , she reported malaise , lassitude , and low - grade fever ; those symptoms persisted over 2  weeks . a sudden appearance of high fever and rash led to her admission . on admission , she was febrile and tachycardic but stable , with unrewarding examination except for gingival bleeding , a profuse petechial rash over both legs and polysynovitis , which was not new . laboratory tests showed hemoglobin ( hb ) 7.5  g / dl ( normocytic ) , wbc 1.8    10/l with absolute neutrophil count ( anc ) 0.7    10/l , platelets 3    10/l , esr 172  mm / h , crp 76.8  mg / dl ( normal < 6  mg / dl ) , albumin 26 barr virus ( ebv ) , cytomegalovirus ( cmv ) , hepatitis viruses , parvovirus b-19 , and hiv were negative.fig . 1patient s bone marrow biopsy showing stroma and plasma cells ( more resistant to drug toxicity ) but absence of all other hematopoietic elements , consistent with transient aplasia patient s bone marrow biopsy showing stroma and plasma cells ( more resistant to drug toxicity ) but absence of all other hematopoietic elements , consistent with transient aplasia the patient was treated with platelets ( four times ) , packed cells ( 4  u ) , granulocyte colony - stimulating factor ( neupogen ) over 5  days , and broad - spectrum antibiotics . she was discharged on the 12th hospital day , afebrile and stable ( absolute neutrophil count [ anc ] 10.5    10/l ) , for ambulatory follow - up . one month later , the hb was 12.4  g / dl , white blood count ( wbc ) 13.7    10/l , and platelets 149    10/l . the patient resumed methotrexate treatment uneventfully for more than 6  months of follow - up . when serious adverse events ( saes ) associated with anti - tnf therapy are considered , attention is usually focused on an increased risk of infections ( in particular , reactivation of tuberculosis and opportunistic infections ) and malignancy , though the latter remains an unresolved concern . however , anti - tnf therapy - induced cytopenias constitute another sae that are potentially life threatening and mandate better recognition . for example , neutropenia was reported in 14.318.8  % of patients receiving a tnf inhibitor [ 35 ] . in most of the patients , neutropenia occurred after just 2  weeks of treatment , was mild ( mean 1.1    10/l ) , transient , and showed spontaneous resolution , allowing the original treatment to be continued in most ( 81  % ) patients . however , a few patients developed serious secondary infections ( 4/367 , 1.1  % ) . notably , asymptomatic drops in platelet counts ( mean 28    10/l ) were often associated . indeed , 19 patients with significant thrombocytopenia were identified in a recent review of the literature and , as in the case of neutropenia , almost all were due to either etanercept or infliximab . rarely , patients may develop both severe neutropenia and thrombocytopenia , whereas anemia is not usually a feature of this treatment . on the contrary , with amelioration of the underlying disease on anti - tnf therapy however , this therapy , especially etanercept and infliximab , may mediate a more life - threatening adverse event than neutropenia or thrombocytopenia , namely , aplastic anemia and pancytopenia . a few such patients have been identified in post - marketing reports , although the attribution of pancytopenia to the tnf inhibitor remains unclear . thus , etanercept and infliximab have been linked so far to just one case of aplastic anemia each , and several patients had developed pancytopenia or aplastic anemia , which could well have been related to anti - tnf therapy [ 1116 ] . most affected patients had ra , and the hematological sae occurred predominantly after the first tnf antagonist doses , becoming symptomatic soon after and usually responsive to drug discontinuation and supportive treatment ( table  1).table  1potentially life - threatening non - malignant hematological complications associated with tumor necrosis factor - inhibitor therapypatientsreferencesbackgroundtreatmentother potential drugssaestime intervaloutcomeremarks4/367 ptsvariedvariedunlikelysevere neutropenia with serious infectionnrrecoveredbm normal in 2 cases20mcrohn s spondylarthritisinfliximab [ 2nd]noneagranulocytosisnrresolved , recurred after retreatmentgranulocyte bound ab and neutrophil - specific bound ab60frainfliximab [ 3rd]unlikelyfever / chills and skin hemorrhages : profound neutropenia and thrombocytopenia7  weeksresolvedbm bx : hypoplasia2/61 ptsjuvenile i d . arthritisetanercept [ 1st in 1 pt]unlikelypancytopenia0.5 ; 12  monthsresolvedopen - label prospective study45fsclerodermainfliximab [ 1st]nonesevere pancytopenia and candida peritonitis3  weeksdiedtransient hs reaction at 6  days78mraetanercept ( > 17th dose)unlikelyaplastic anemia and sepsis<3  monthsresolved over 3  weeksbm bx+66mrainfliximab [ 1st]possiblesevere pancytopenia and bm hypoplasia with sepsis10  daysresolved over 2  weeksbm bx+32fcolitisinfliximab [ 1st]possible ( iv atb)severe pancytopenia6  daysresolved over 2  weeks32nrankylosing spondylitisinfliximab [ 1st]noneaplastic anemia4  daysresolved over 16  daysassociated skin vasculitis  bm bx+62fcurrentraetanercept [ 1st]unlikelytransient bm aplasia2  weeksresolved over 12  daysbm bx+ 
 ab antibodies , bm bone marrow , bx biopsy , f female , hs hypersensitivity , i d . idiopathic , iv atb intravenous antibiotics , m male , nr not reported , pt(s ) patient(s ) , ra rheumatoid arthritis , sae serious adverse event , + postive potentially life - threatening non - malignant hematological complications associated with tumor necrosis factor - inhibitor therapy 
 ab antibodies , bm bone marrow , bx biopsy , f female , hs hypersensitivity , i d . idiopathic , iv atb intravenous antibiotics , m male , nr not reported , pt(s ) patient(s ) , ra rheumatoid arthritis , sae serious adverse event , + postive our patient presented with symptoms and signs related to all three cytopenias : fatigue ( due to anemia ) ; fever that responded to broad spectrum antibiotics ( due to severe neutropenia ) ; and petechiae and gingival bleeding ( due to severe thrombocytopenia ) . the absence of concomitant drugs ( she had been receiving methotrexate and hydroxychloroquine for years ) as well as the temporal relationship between the appearance of her symptoms and the first injection of etanercept , strongly suggest a causal link . moreover , bm recovery from toxic injury corresponded to the discontinuation of etanercept , whereas methotrexate was later continued uneventfully for months . in contrast , in some of the other cases cited , drugs other than anti - tnf could have been responsible . other than listing all hitherto - reported cases of tnf blocking agent - associated aplastic anemia and pancytopenia , the literature review reveals the rarity of the association , considering that hundreds of thousands of patients have been treated . tnf is a pleiotropic cytokine , part of a complex cytokine network that regulates hematopoiesis and may affect bm stem cells differently under different circumstances [ 17 , 18 ] . on one hand , tnf ( and interferon  ) are overexpressed in the bm of patients with acquired aplastic anemia and can be involved in bm stem cell apoptosis and suppression of erythropoiesis [ 19 , 20 ] . thus , treatment with tnf antagonists can be a useful approach to the treatment of refractory aplastic anemia [ 2123 ] . on the other hand , under different conditions , tnf interacting with other cytokines directly enhances the clonal growth of bm progenitors and suppresses hematopoietic stem cell apoptosis [ 17 , 24 ] . thus , its blockade can also exert a deleterious effect on hematopoiesis . since autoimmune mechanisms are believed to have a key role in the pathogenesis of idiopathic aplastic anemia , the association between tnf - targeted therapies and induction of autoimmune diseases ( particularly , vasculitis and lupus predominantly with infliximab and etanercept ) is also a tenable mechanism . in conclusion , tnf antagonists for the treatment of ra show significant benefit and are generally safe in comparison with other disease - modifying anti - rheumatic drugs [ 2729 ] . bm suppression resulting in severe cytopenia , transient pancytopenia , or aplastic anemia is a well established but fortunately rare sae of anti - tnf therapy . since a steadily increasing number of patients are being treated for longer periods , any serious adverse effect , however rare , may be encountered . monitoring blood counts of patients starting treatment seems advisable , and we also suggest that patients should be instructed to consult their physician when unexplained fever , fatigue , or bleeding manifestations appear .
a patient with rheumatoid arthritis presented with increasing fatigue , fever , gingival bleeding , and petechial rash . 
 her symptoms started 1 week after the first injection of etanercept ( enbrel ) . 
 her only other medications ( methotrexate and hydroxychloroquine ) had been unchanged for years . 
 tests revealed severe pancytopenia and bone marrow aplasia . 
 she recovered with supportive treatment within 12  days . 
 the literature on serious blood dyscrasias associated with anti - tumor necrosis factor- therapy is reviewed , an intriguing postulated mechanism is discussed , and selective patient monitoring is recommended .