Rheumatology Advance Access originally published online on July 4, 2006
Rheumatology 2006 45(10):1313-1314; doi:10.1093/rheumatology/kel204
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TNF
blocker-induced thrombocytopenia
Rheumatology, Queen Elizabeth Hospital, Gateshead, Tyne and Wear, UK
Correspondence to: S. K. Pathare. E-mail: skp1110{at}hotmail.com
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Introduction |
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 Top Introduction Case 1Case 2References |
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SIR, The use of tumour necrosis factor (TNF) antagonists has revolutionized the treatment of rheumatological diseases.
The key safety issues with TNF antagonists include infections, demyelinating disease, lupus-like syndromes [associated with the production of anti-nuclear antibody (ANA) and antibodies to double-stranded DNA (dsDNA)], congestive heart failure, malignancies and cytopenias [1, 2].
The prominent induction of ANA and anti-DNA autoantibody is not a pure class effect of TNF antagonist and is not associated with other serological and clinical signs of lupus [3]. Rare reports of patients developing pancytopenia and aplastic anaemia on infliximab and etanercept have been described. (E-mail communication with FDA, BSR Biologics register [4–7].)
Infliximab (a chimeric monoclonal antibody directed against TNF
), etanercept [a recombinant molecule comprising part of the human TNF receptor plus the constant region of human immunoglobulin G1 (IgG1) that binds to TNF] and adalimumab (an IgG1 monoclonal antibody that binds to TNF) are all in widespread use. We describe two patients who developed thrombocytopenia on one anti-TNF drug, which did not recur when switched to an alternative TNF antagonist.
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Case 1 |
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TopIntroductionCase 1Case 2References |
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A 44-yr-old lady was diagnosed with rheumatoid arthritis in 1997. She had failed several DMARDs including methotrexate (MTX) due to lack of efficacy or adverse events. She was commenced on etanercept (25 mg S.C. twice weekly) in January 2004. She was not on any other drugs that could cause thrombocytopenia. Her baseline blood counts (platelet count 271 x 109/l) were normal. After three doses of etanercept her platelet count fell to 38 x 109/l. Autoantibody screen as well as anti-platelet antibodies were negative. Her platelet count improved 9 days after stopping the drug. She commenced infliximab (3 mg/kg) but developed a rash after first infusion and was commenced on adalimumab (40 mg subcutaneously fortnightly) in August 2004. To date there has been no recurrence of the thrombocytopenia or any other side effect.
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Case 2 |
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A 56-yr-old lady was diagnosed with rheumatoid arthritis in 1979. She failed several disease modifying drugs (DMARDs) including combination therapy and optimum doses of MTX (which she had previously tolerated without adverse event). She was commenced on infliximab at a dose of 3 mg/kg with MTX at a dose of 5 mg, increasing to 10 mg over 3 months in October 2002. Pre-treatment blood counts were normal. Her treatment remained unchanged with good disease control until February 2005 when she experienced a sudden fall in platelet count (26 x 109/l) and developed positive ANA (1:160) and dsDNA (>200 IU/ml) autoantibody. Baseline ANA and dsDNA were negative. Two weeks prior to the onset of thrombocytopenia she had received a course of amoxycillin for a chest infection, which she had received previously without any adverse event. Infliximab and MTX were stopped. The platelet count recovered gradually over 1 month. By July 2005, the dsDNA titre had fallen to 51.4 IU/ml. She was commenced on etanercept 25 mg twice weekly subcutaneously once her platelet count had stabilized. She is now doing well, and to date she has not developed any side effects on etanercept.
Leucopenia and thrombocytopenia although not common, are recognized side effects of TNF blocking therapy. The exact mechanism of cytopenias as a result of TNF-blocker therapy is unclear. TNF regulates some pro-inflammatory cytokines such as interleukin (IL)-1, IL6, IL8 and granulocyte-macrophage-colony-stimulating factor, therefore, in theory, have the potential to block stem-cell differentiation with resultant bone marrow failure [8]. Other possible mechanisms include a lupus-like syndrome or direct marrow toxicity. In our second patient no other features of lupus were observed. Although it is possible that amoxyillin or MTX contributed to the development of thrombocytopenia, this seems unlikely given that she had received both drugs previously without adverse event.
We know that the clinical response may differ between anti-TNF agents, and the lack of response to one agent may not predict a lack of response to another [9]. Our small case series would suggest that thrombocytopenia induced by TNF-blocking agents are idiosyncratic reactions and not a class effect, and that it is safe to commence an alternative TNF-blocking agent in the event of the development of thrombocytopenia. It is, however, difficult to extrapolate this to any other adverse event based on these data.
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References |
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TopIntroductionCase 1Case 2References |
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- Keystone E. (2005) Safety of biologic therapies—an update. J Rheumatol 32:8–12.
- Cush JJ. (2003–04) Safety of new biologic therapies in rheumatoid arthritis. Bullet Rheum Dis 52:.
- de Ryke L, Baten D, Kruithof E, et al. (2005) Infliximab, but not etanercept, induces IgM anti-double stranded DNA autoantibodies as main antinuclear activity: biologic and clinical implications in autoimmune arthritis. Arthritis Rheum 52:2192–201.[CrossRef][Web of Science][Medline]
- Cush JJ and Spiera R. ( November 2000) Etanercept update in "Dear Doctor" letter. Hotline American College of Rheumatology http://www.rheumatology.org/research/hotline/1200etanercept.html.
- Vidal F, Fontova R, Richart C. (2003) Severe neutropenia and thrombocytopenia associated with infliximab. Ann Int Med 139E:238–9.[CrossRef]
- Menon Y, Cucurull E, Espinoza R. (2003) Pancytopenia in a patient with scleroderma treated with infliximab. Rheumatology 42:1273–4.
[Free Full Text] - Day R. (2002) Adverse reactions to TNF-alpha blockers in rheumatoid arthritis. Lancet 359:540–1.[CrossRef][Web of Science][Medline]
- Keystone EC. (2001) Tumor necrosis factor-alpha blockade in the treatment of rheumatoid arthritis. Rheum Dis Clin North Am 27:427–43.[CrossRef][Web of Science][Medline]
- Hansen KE, Hilderand JP, Genovese MC, et al. (2004) The efficacy of switching from etanercept to infliximab in patients with rheumatoid arthritis. J Rheumatol 31:1098–102.
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