Infliximab and Reactivation of Cerebral Toxoplasmosis
http://www.100md.com
《新英格兰医药杂志》
To the Editor: Post-marketing surveillance has revealed a higher incidence of reactivation of granulomatous infections — most notably, tuberculosis1 and histoplasmosis2 — in patients receiving the tumor necrosis factor (TNF-) inhibitor infliximab (Remicade, Centocor). Other opportunistic infections have been reported as well. Here we describe a patient receiving infliximab who had reactivation of cerebral toxoplasmosis.
The patient was a 36-year-old woman in whom rheumatoid arthritis was diagnosed in 2000. She was treated with prednisone at a dose of 10 mg per day, weekly methotrexate, and a high-dose nonsteroidal antiinflammatory drug for the first year. In early 2001, leflunomide (Arava, Aventis) was added at a dose of 20 mg per day. The patient's symptoms were not relieved, and the joint deformities progressed. In September 2001, low-dose infliximab was added to her regimen. The dose was slowly increased until she became asymptomatic (at 10 mg per kilogram of body weight intravenously every six weeks) in June 2004. She continued to receive the same low doses of prednisone, methotrexate, and leflunomide.
In January 2005, the patient had several days of diffuse headache, followed acutely by slurred speech, weakness in the left arm, and a grand mal seizure. Her examination was notable for left-sided facial droop and hemiparesis in the left upper extremity. Magnetic resonance imaging of the brain revealed two lesions within the right hemisphere (Figure 1). Immunostaining of brain-biopsy specimens revealed cysts with bradyzoites and tachyzoites of Toxoplasma gondii. The patient was seronegative for human immunodeficiency virus type 1, had normal leukocyte and CD4+ and CD8+ lymphocyte counts, and had normal immunoglobulin and complement levels. She had detectable serum IgG antibodies but no IgM antibodies to T. gondii, which suggested reactivation disease. The patient was treated with pyrimethamine, folinic acid, and dapsone instead of sulfadiazine, because of a known sulfa allergy. She quickly had substantial neurologic improvement.
Figure 1. Magnetic Resonance Image of the Brain of a Patient with Cerebral Toxoplasmosis.
The image, obtained in the axial plane with fluid-attenuated inversion recovery (FLAIR), shows two peripherally enhancing lesions in the right hemisphere.
The temporal proximity of the increase in the dose of infliximab and the reactivation of toxoplasmosis provides a reasonable likelihood that TNF- inhibition was the predisposing factor in this case. This hypothesis is further supported by the normal immunologic workup and the low doses of her other immunosuppressive medications. Although the process is incompletely understood, studies of murine models suggest a role for TNF- in host defense against toxoplasmosis.3 Antibody screening for T. gondii may be indicated in candidates for high-dose TNF-inhibitor therapy, with cautious consideration given to those who have evidence of latent infection. We suggest that toxoplasmosis needs to be in the differential diagnosis when patients receiving infliximab present with an appropriate constellation of signs and symptoms.
Jeremy D. Young, M.D.
Bradford S. McGwire, M.D., Ph.D.
Ohio State University Medical Center
Columbus, OH 43210
References
Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor -neutralizing agent. N Engl J Med 2001;345:1098-1104.
Wood KL, Hage CA, Knox KS, et al. Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med 2003;167:1279-1282.
Filisetti D, Candolfi E. Immune response to Toxoplasma gondii. Ann Ist Super Sanita 2004;40:71-80.
The above letter was referred to Centocor, the manufacturer of infliximab, which offers the following reply:
To the Editor: An increased risk of infection, including toxoplasmosis, is associated with immunosuppressive agents such as corticosteroids, azathioprine, methotrexate, leflunomide, and mercaptopurine and anti-TNF therapy.1,2,3,4 The patient with rheumatoid arthritis who is described in this case report was receiving concomitant corticosteroids, methotrexate, and leflunomide in addition to infliximab.
As of December 31, 2004, more than 2779 patients have received infliximab in clinical trials. Toxoplasmosis has not been reported in any of these study patients. Since the approval of infliximab by the Food and Drug Administration for Crohn's disease in 1998, for rheumatoid arthritis in 1999, for ankylosing spondylitis in 2004, and for psoriatic arthritis in 2005, nearly 650,000 patients have received infliximab. Post-marketing reports of toxoplasmosis in patients receiving infliximab through February 23, 2005, total seven cases of toxoplasmosis among 634,000 patients who received the drug (representing 1.6 million patient-years since first exposure).
For more than 13 years, the benefits of infliximab in the treatment of immune-mediated inflammatory diseases such as Crohn's disease and rheumatoid arthritis have been well established. Infliximab alters the course of these chronic diseases by producing clinical remission and closure of fistulas in Crohn's disease, by reducing the signs and symptoms of rheumatoid arthritis and preventing joint damage, and by reducing signs and symptoms of ankylosing spondylitis and psoriatic arthritis.4 Practitioners need to be prudent in considering the benefits and risks of all the therapeutic options, including anti-TNF agents, when developing a treatment plan for patients with Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis.
Peter E. Callegari, M.D.
Centocor
Malvern, PA 19355
References
Gonzalez-Vincent M, Diaz MA, Sevilla J, Madero L. Cerebral toxoplasmosis following etanercept treatment for idiopathic pneumonia syndrome after autologous peripheral blood progenitor cell transplantation (PBPCT). Ann Hematol 2003;82:649-653.
Re D, Reiser M, Bamborschke S, et al. Two cases of toxoplasmic encephalitis in patients with acute T-cell leukemia and lymphoma. J Infect 1999;38:26-29.
Nicholson DH, Wolchok EB. Ocular toxoplasmosis in an adult receiving long-term corticosteroid therapy. Arch Ophthalmol 1976;94:248-254.
Remicade. Malvern, Pa.: Centocor, 2002 (package insert).
The patient was a 36-year-old woman in whom rheumatoid arthritis was diagnosed in 2000. She was treated with prednisone at a dose of 10 mg per day, weekly methotrexate, and a high-dose nonsteroidal antiinflammatory drug for the first year. In early 2001, leflunomide (Arava, Aventis) was added at a dose of 20 mg per day. The patient's symptoms were not relieved, and the joint deformities progressed. In September 2001, low-dose infliximab was added to her regimen. The dose was slowly increased until she became asymptomatic (at 10 mg per kilogram of body weight intravenously every six weeks) in June 2004. She continued to receive the same low doses of prednisone, methotrexate, and leflunomide.
In January 2005, the patient had several days of diffuse headache, followed acutely by slurred speech, weakness in the left arm, and a grand mal seizure. Her examination was notable for left-sided facial droop and hemiparesis in the left upper extremity. Magnetic resonance imaging of the brain revealed two lesions within the right hemisphere (Figure 1). Immunostaining of brain-biopsy specimens revealed cysts with bradyzoites and tachyzoites of Toxoplasma gondii. The patient was seronegative for human immunodeficiency virus type 1, had normal leukocyte and CD4+ and CD8+ lymphocyte counts, and had normal immunoglobulin and complement levels. She had detectable serum IgG antibodies but no IgM antibodies to T. gondii, which suggested reactivation disease. The patient was treated with pyrimethamine, folinic acid, and dapsone instead of sulfadiazine, because of a known sulfa allergy. She quickly had substantial neurologic improvement.
Figure 1. Magnetic Resonance Image of the Brain of a Patient with Cerebral Toxoplasmosis.
The image, obtained in the axial plane with fluid-attenuated inversion recovery (FLAIR), shows two peripherally enhancing lesions in the right hemisphere.
The temporal proximity of the increase in the dose of infliximab and the reactivation of toxoplasmosis provides a reasonable likelihood that TNF- inhibition was the predisposing factor in this case. This hypothesis is further supported by the normal immunologic workup and the low doses of her other immunosuppressive medications. Although the process is incompletely understood, studies of murine models suggest a role for TNF- in host defense against toxoplasmosis.3 Antibody screening for T. gondii may be indicated in candidates for high-dose TNF-inhibitor therapy, with cautious consideration given to those who have evidence of latent infection. We suggest that toxoplasmosis needs to be in the differential diagnosis when patients receiving infliximab present with an appropriate constellation of signs and symptoms.
Jeremy D. Young, M.D.
Bradford S. McGwire, M.D., Ph.D.
Ohio State University Medical Center
Columbus, OH 43210
References
Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor -neutralizing agent. N Engl J Med 2001;345:1098-1104.
Wood KL, Hage CA, Knox KS, et al. Histoplasmosis after treatment with anti-tumor necrosis factor-alpha therapy. Am J Respir Crit Care Med 2003;167:1279-1282.
Filisetti D, Candolfi E. Immune response to Toxoplasma gondii. Ann Ist Super Sanita 2004;40:71-80.
The above letter was referred to Centocor, the manufacturer of infliximab, which offers the following reply:
To the Editor: An increased risk of infection, including toxoplasmosis, is associated with immunosuppressive agents such as corticosteroids, azathioprine, methotrexate, leflunomide, and mercaptopurine and anti-TNF therapy.1,2,3,4 The patient with rheumatoid arthritis who is described in this case report was receiving concomitant corticosteroids, methotrexate, and leflunomide in addition to infliximab.
As of December 31, 2004, more than 2779 patients have received infliximab in clinical trials. Toxoplasmosis has not been reported in any of these study patients. Since the approval of infliximab by the Food and Drug Administration for Crohn's disease in 1998, for rheumatoid arthritis in 1999, for ankylosing spondylitis in 2004, and for psoriatic arthritis in 2005, nearly 650,000 patients have received infliximab. Post-marketing reports of toxoplasmosis in patients receiving infliximab through February 23, 2005, total seven cases of toxoplasmosis among 634,000 patients who received the drug (representing 1.6 million patient-years since first exposure).
For more than 13 years, the benefits of infliximab in the treatment of immune-mediated inflammatory diseases such as Crohn's disease and rheumatoid arthritis have been well established. Infliximab alters the course of these chronic diseases by producing clinical remission and closure of fistulas in Crohn's disease, by reducing the signs and symptoms of rheumatoid arthritis and preventing joint damage, and by reducing signs and symptoms of ankylosing spondylitis and psoriatic arthritis.4 Practitioners need to be prudent in considering the benefits and risks of all the therapeutic options, including anti-TNF agents, when developing a treatment plan for patients with Crohn's disease, rheumatoid arthritis, ankylosing spondylitis, or psoriatic arthritis.
Peter E. Callegari, M.D.
Centocor
Malvern, PA 19355
References
Gonzalez-Vincent M, Diaz MA, Sevilla J, Madero L. Cerebral toxoplasmosis following etanercept treatment for idiopathic pneumonia syndrome after autologous peripheral blood progenitor cell transplantation (PBPCT). Ann Hematol 2003;82:649-653.
Re D, Reiser M, Bamborschke S, et al. Two cases of toxoplasmic encephalitis in patients with acute T-cell leukemia and lymphoma. J Infect 1999;38:26-29.
Nicholson DH, Wolchok EB. Ocular toxoplasmosis in an adult receiving long-term corticosteroid therapy. Arch Ophthalmol 1976;94:248-254.
Remicade. Malvern, Pa.: Centocor, 2002 (package insert).