Acquired Erythrocytosis on Treatment with Infliximab for Ankylosing Spondylitis

A 31 year-old male of Italian and German ethnicity with HLA-B27 positive ankylosing spondylitis (AS) was started on treatment with infliximab in May 2007 because of lack of response to nonsteroidal anti-inflammatory drugs (NSAIDs). His disease showed excellent response to infliximab. He had a 15-pack year smoking history. Prior to starting infliximab, his hemoglobin was 14.5g/dl, hematocrit 45.5% and platelet count 334 × 10³/μ L. He gradually developed erythrocytosis with hemoglobin 20.3g/dl, hematocrit 56.6% and platelet count 218 × 10³/μ L, and was referred to hematology clinic in July 2008. His peripheral blood smear was noted to be benign in appearance. Jak2 mutation was negative including exons 12/14 and erythropoietin level was normal. Bone marrow biopsy revealed erythroid hyperplasia and a mild increase in reticulin staining. He was started on aspirin and therapeutic phlebotomy, and his hematocrit decreased to 43.6%, and it has remained below 45% after 12 months of phlebotomy with continued treatment with infliximab.

Infliximab is a chimeric IgG1κ monoclonal antibody targeted against TNF-α. It is now used in the treatment of various inflammatory diseases. Hematologic dyscrasias associated with infliximab toxicity include leukopenia, neutropenia, thrombocytopenia, and pancytopenia.

We suggest a mechanism through which infliximab causes erythrocytosis based on a review of the literature. There is increasing evidence that cytokines such as TNF-α, IL-1, IL-6 and interferon-gamma are involved in inflammatory diseases. TNF-α has two opposing functions on a cell: destructive and protective mechanism. TNF binds to two cell surface receptors (TNFRI and TNFRII), which are located on hematopoietic cells, as well other cells. After binding, TNFRI primarily mediates programmed cell death through the activation of NF-κB but also has mild anti-apoptotic factors. TNFRII (lacks a death domain) interacts with TNF receptor associated factor 2 (TRAF-2). TRAF-2 activates JNK, which has an anti-apoptotic effect. TNF specifically modulates macrophage iron release as well as inhibits the formation of early red cell colonies in bone marrow. In addition it has a key role in inducing and sustaining tissue damage by activating the inflammatory cascade as well as stimulating angiogenesis. Bone marrow in patients with RA show significant increase in TNFRI and mild increase in TNFRII ^1,2.

Similarly, it has been demonstrated that patients with myelodysplastic syndromes (MDS) demonstrate increased TNF-α expression in bone marrow progenitor cells; in these patients, erythropoeisis is downregulated³. A study has shown that patients with MDS, treatment with infliximab may result in an increase in hemoglobin³. It may be that when TNF-α expression in the bone marrow is suppressed, an erythrocytosis, such as that in the case, may ensue. It has previously been documented that in patients with AS, anemia of chronic disease improves from baseline with infliximab⁴.

We have found no published report of secondary erythrocytosis in patients on infliximab. Our case demonstrates a possible association between infliximab therapy and secondary erythrocytosis, and we propose a possible mechanism of such an association. It is important that both rheumatologists and hematologists recognize this possible association in order to better recognize this potentially detrimental effect and initiate prompt treatment.

1. Sawanobori, M., Yamaguchi, S., Hasegawa, M. et al. Expression of TNF receptors and related signaling molecules in the bone marrow from patients with myelodysplastic syndromes. Leukemia Research 2003;27:583-591.

2. Papadaki, H. Kritikos, H. Valatas, V. Boumpas, D. Eliopoulos, G. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor- alpha antibody therapy. Blood 2002; 100:474-482.

3. Stifter, G, Heiss, S, Gastl, G, Tzankov, A, Stauder, R. Over-expression of tumor necrosis factor-alpha in bone marrow biopsies from patients with myelodysplastic syndromes: relationship to anemia and prognosis. Eur J Haematol 2005 Dec; 75(6):485-91.

4. Braun, J, van der Heijde D, et al. Improvement in hemoglobin levels in patients with ankylosing spondylitis treated with infliximab. Arthritis Rheum 2009 Aug 15; 61(8):1032-6.

No relevant conflicts of interest to declare.