Rheumatology Advance Access originally published online on January 7, 2008
Rheumatology 2008 47(3):376-377; doi:10.1093/rheumatology/kem332
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Three significant cases of neutropenia with etanercept
Department of Rheumatology, Derbyshire Royal Infirmary, Derby, DE1 2QY, UK
Correspondence to: C. Deighton, Department of Rheumatology, Derbyshire Royal Infirmary, Derby, DE1 2QY, UK. E-mail: chris.deighton{at}derbyhospitals.nhs.uk
SIR, Current BSR guidelines do not recommend regular blood count monitoring for anti-TNF therapy [1] as studies have suggested no increase in adverse haematological events [2–4]. We have noted a minority (14.3%) of our patients becoming neutropenic (<2.0 x 109/l) on anti-TNF [5], predominantly asymptomatically [5]. However, not all episodes have been without concern. Here we describe three cases of significant neutropenia on etanercept.
A 57-yr-old lady with aggressive seropositive RA since 1984 was intolerant of multiple DMARDs. She was on methotrexate and prednisolone (<10 mg), but with persistent synovitis. An isolated episode of asymptomatic neutropenia of 1.26 during methotrexate therapy was documented. She started etanercept 25 mg twice weekly, with excellent response. She became neutropenic 7 weeks after first dose (1.76 x 109/l) and persisted throughout treatment, the lowest being 0.84 x 109/l. These episodes responded to increased prednisolone up to 5 mg. Bone marrow examination showed active haemopoiesis and white cell production with increased immature granulocyte production, suggesting peripheral neutrophil consumption. Because of the persisting neutropenia, she was changed to adalimumab 40 mg fortnightly. She was intermittently mildly neutropenic during the first 6 months, (lowest value 1.95 x 109/l) but with a higher average neutrophil count. She currently has a normal neutrophil count and good response to adalimumab.
A 50-yr-old lady with seropositive RA requiring maintenance prednisolone (10–20 mg) was intolerant of methotrexate, cyclosporin and azathioprine. She had previously documented asymptomatic neutropenia (0.42 x 109/l) prior to commencing DMARDs, and an asymptomatic neutropenia (0.35 x 109/l) was noted during cyclosporin treatment, rapidly responding to 10 mg prednisolone. Etanercept was started and she became neutropenic (0.17 x 109/l) 17 days after the first dose, with symptoms of sore throat, mouth ulcers and pyrexia. She was admitted for urgent intravenous tazocin and gentamicin. All cultures were negative. She required two doses of G-CSF to bring her neutrophil count over 1.0 x 109/l. Three months later, she had a persistent neutropenia (0.61 x 109/l), and has been maintained on 10 mg prednisolone since. A bone marrow examination showed normal cellularity with active white cell production and normal granulocyte precursors.
A 61-yr-old male diagnosed in 1998 with psoriatic arthritis was intolerant of sulphasalazine. He was found to be persistently leucopenic (total white cell counts around 3.1 x 109/l). In 2003, his bone marrow showed active marrow and normal granulocyte precursors, and he was started on methotrexate. He demonstrated a good initial response to methotrexate 7.5 mg weekly, but this was stopped due to neutropenia of 0.9 x 109/l. Cyclosporin was unsuccessful (gum hypertrophy and hypertension). Methotrexate was restarted, but with persisting asymptomatic neutropenia varying between 0.57 and 0.93 x 109/l. Methotrexate proved ineffective for the arthritis 6 months later. He was started on etanercept. He had an excellent clinical response, but with persistent neutropenia. Six months later, he presented to clinic with weight loss and left upper quadrant pain. Total white cell count was 8.9 x 109/l, with neutrophils of 6.79 x 109/l (very high for him). Ultrasound and CT scan showed multiple splenic abscesses. Blood cultures grew Staphylococcus aureus. Despite intensive intravenous antibiotics his C-reactive protein continued to rise and repeat CT showed no improvement. He had an elective splenectomy, complicated by post-operative sepsis and bleeding requiring repeat laparotomy and a 5-day ICU stay. Splenic histology confirmed staphylococcal abscesses. He made a full recovery, and is currently well, on no medication, with normal neutrophil counts.
There have been previous reports of neutropenia with anti-TNF agents. We have found only one other report with etanercept in an ankylosing spondylitis patient, with two positive rechallenges [6]. The patient also developed neutropenia after an infliximab infusion. Agranulocytosis and neutropenia have been described with infliximab [6–8], one case requiring inpatient stay for intravenous antibiotics until the cultures were negative. A recent study of 130 patients on anti-TNF showed a cytopenia rate of 12%, mainly leucopenias, with none leading to serious infection [9].
Our first patient had no sepsis, but the second showed a rapid and dramatic neutropenia, and though cultures were negative she behaved as if septic. The third patient had pre-existing neutropenia, and developed a dramatic and life-threatening infection with staphylococcal abscesses in a most unusual location. All three patients had normal bone marrow examinations, suggesting that the neutropenia may be due to peripheral consumption rather than a primary marrow disorder. All three patients were strongly positive for IgG ANA (1/1280, 1/5120 and >1/5120, respectively), though a previous analysis showed no evidence of an association between ANA and neutropenia in RA anti-TNF patients [5]. None of the patients had symptoms of Sjögren's syndrome. All three are negative for anti-neutrophil cytoplasmic antibodies, but we have not tested for other anti-leucocyte antibodies. The first patient has tolerated adalimumab far better than etanercept from a neutrophil perspective. The third patient has had a normal neutrophil count since his splenectomy. All three patients had episodes of neutropenia prior to their anti-TNF treatment, which significantly worsened with etanercept. We advise that all patients on anti-TNF agents should be monitored with regular full blood counts, with particular care for those with previously documented neutropenia [5]. We are not alone in this recommendation [9].
Disclosure statement: The Department of Rheumatology at Derbyshire Royal Infirmary has received sponsorship from Wyeth, Abbott and Schering Plough Pharmaceuticals for support of clinical meetings, and unrestricted grants from Wyeth and Schering Plough to support an anti-TNF audit clerk and research nurse. K.G. sits on an advisory board for Schering Plough, and has received honoraria for talks at symposia sponsored by Wyeth and Abbott. C.D. has previously sat on an advisory board for Schering Plough and received honoraria for talks at symposia sponsored by Wyeth and Abbott. All other authors have declared no conflicts of interest.
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 Top References |
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- Ledingham J, Deighton C. Update on the British Society of Rheumatology guidelines for prescribing TNF alpha blockers in adults with rheumatoid arthritis. Rheumatology (2005) 44:157–63.
[Free Full Text] - Furst D, Schiff M, Fleishmann R, et al. Results of safety trial of adalimumab in rheumatoid arthritis. J Rheumatol (2003) 30:2563–72.
[Abstract/Free Full Text] - Fleishmann R, Iqbal I, Nandeshwar P, Quiceno A. Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and risk of etanercept. Drug Safety (2002) 25:173–97.[CrossRef][Web of Science][Medline]
- Ang H, Helfgott S. Do the clinical responses and complications following etanercept or infliximab therapy predict similar outcomes with the other tumour necrosis factor-alpha antagonists in patients with rheumatoid arthritis? J Rheumatol (2003) 30:2315–8.
[Abstract/Free Full Text] - Rajakulendran S, Gadsby K, Allen D, et al. Neutropenia while receiving anti-tumour necrosis factor treatment for rheumatoid arthritis. Ann Rheum Dis. (2006) 65:1678–9.
[Free Full Text] - Montane E, Salles M, Barriocanal A, et al. Anti-tumor necrosis factor-induced neutropaenia: a case report with double positive rechallenges. Clin Rheumatol (2007) 26:1527–9.[CrossRef][Web of Science][Medline]
- Vidal F, Fontova R, Richart C. Severe neutropaenia and thrombocytopaenia associated with infliximab. Ann Intern Med (2003) 139:63.
- Favalli EG, Varenna M, Sinigaglia L. Drug-induced agranulocytosis during treatment with infliximab in enteropathic spondyloarthropathy. Clin Exp Rheumatol (2005) 2:247–50.
- Yazdani R, Simpson H, Kaushik VV. Incidence of cytopaenias with anti-TNF therapy. Rheumatology (2007) 46(Suppl. 1):i33.
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