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Considerable data have identified tumour necrosis factor α (TNFα) as a pivotal mediator in inflammatory processes, suggesting that it has a role also in the pathogenesis of some autoimmune diseases, such as rheumatoid arthritis (RA).1,2 Currently, two drugs that interfere with TNFα, infliximab and etanercept, have been extensively used for the treatment of patients with RA and other immunological disorders; both have been associated with a higher risk of serious infective complications.3–7
Listeria monocytogenes is a Gram positive intracellular organism seen almost always in neonatal sepsis, elderly meningitis, and in patients with chronic diseases and impairment of cellular immunity, which avoids the host immunity by a mechanism of cell to cell spreading.8
We report a case of Listeria meningitis in a 45 year old patient with RA. Methotrexate and cyclophosphamide had been given until 20 months before admission to hospital, when low grade renal failure developed and treatment was changed to monotherapy with etanercept 25 mg twice weekly. One day before admission, fever, malaise, headache, and progressive confusion developed.
At entry, examination showed a comatose state, neck stiffness, and fever (38.7°C). Deep tendon reflexes were symmetric, plantar responses were flexor. The findings on a computed tomographic scan of the brain were unremarkable. Blood laboratory analysis showed white blood cells 15×109/l (91% neutrophils), glucose 8.3 mmol/l, blood urea nitrogen 17.5 mmol/l of urea, creatinine 180 µmol/l, and no other significant abnormalities. Cerebrospinal fluid (CSF) showed pleocytosis (1.2×109 cells/l, lymphocyte 43%), high protein content (2.50 g/l), and glucose 3.6 mmol/l. Etanercept was withdrawn, and treatment with intravenous ceftriaxone (3 g/day), ampicillin (12 g/day), and dexamethasone (16 mg/day) was begun. Further results of the blood analysis obtained on the second day of hospitalisation showed an erythrocyte sedimentation rate (ESR) of 42 mm/1st h, C reactive protein (CRP) 411 mg/l, CD4+ cell count 1.41×109/l (CD4+/CD7+ 92%), CD8+ cell count 0.47×109/l (CD8+/CD38+ 42%), TNFα 32.9 ng/ml. On the fourth day, Listeria monocytogenes grew from CSF and blood cultures, ceftriaxone was discontinued, and dexamethasone slowly tapered.
During the next 4 days, the patient’s symptoms improved. Ampicillin was given for a total of 28 days, when full normalisation of the CSF variables had occurred. Blood analysis 2 and 4 months after meningitis, while the patient was taking only mild dose of prednisone (40 mg/day), showed a reduction of the ESR and CRP levels and a rise in TNFα (table 1).
The main concern about treatment of RA with TNFα neutralising agents is the possibility that latent tuberculosis may be unmasked; subsequent reports disclosed an increase in susceptibility for all infections sustained by intracellular agents. Infliximab, whose use is recommended in association with other immunosuppressive drugs, is implicated in the vast majority of cases.6,7 To our knowledge, etanercept has been associated with Listeria monocytogenes meningitis only in a 72 year old patient with RA receiving multiple immunosuppressive treatment (etanercept, prednisone, and methotrexate), and no case has been seen during monotherapy.9 A study of our patient’s lymphocyte subset showed that it did not change during the course of the disease. TNFα levels increased during the follow up, when etanercept was discontinued. Although there is no evidence about association between low TNFα levels and immunosuppression, in our case we suggest there may be an association between etanercept treatment and impairment of cell mediated immunity because of low TNFα circulating levels.
Screening before treatment for latent tuberculosis, close clinical evaluation of every febrile illness, and zero tolerance regimens against Listeria and other intracellular preventable pathogens may improve the long term outcome of patients treated with anti-TNFα agents.
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