Rheumatology Department and 1 Neurology Department, CHU A. Michallon, Grenoble, France
Correspondence to: L. Grange. E-mail: LGrange{at}chu-grenoble.fr
Sir, A 31-yr-old HLA-B27-positive White male had been suffering from refractory ankylosing spondylitis (axial and peripheral involvement) for the preceding 6 yr. He was treated daily with prednisone (20 mg), omeprazole (20 mg) and an analgesic composed of paracetamol, caffeine and dextropropoxyphene. The first infusion of infliximab at a dose of 3 mg/kg was administered over 2.5 h.
Rapidly after the initiation of the infusion, the patient experienced dizziness with a mild bilateral frontal headache. Seventy-two hours later the headaches intensified, becoming disabling and requiring hospitalization. Neurological examination and lumbar puncture were normal. A cerebral MRI angiogram showed thrombosis of the left lateral sinus (Fig. 1). The aetiological investigations for this cerebral thrombophlebitis were negative.
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The aetiologies of cerebral thromboses are numerous, with more than 75 documented causes. In more than 25% of cases, no aetiology is found. Certain inflammatory pathologies have been implicated, but it should be noted that to date ankylosing spondylitis does not seem to have been described in the literature. Each case normally has numerous aetiological factors causing the cerebral venous thrombosis. An accumulation of potential risk factors, which when taken separately would not lead to thrombosis, can result in a critical situation.
Infliximab is an anti-tumour necrosis factor-alpha (TNF-) antibody that is effective in the treatment of inflammatory pathologies, notably rheumatoid arthritis (RA) and ankylosing spondylitis. The reported side-effects are numerous but relatively mild in most cases. This agent is known to favour peripheral venous thromboses [18 cases reported in France up to April 2002 according to AFSSAPS (Association Française de Sécurité Sanitaire des Produits de Santé) data].
A review of the literature found three cases of peripheral thrombosis in a study of 65 Crohn's disease patients [1] and one case of peripheral thrombosis in a series of 36 RA patients treated with infliximab was reported by Yazici [2]. A peripheral thrombosis following the treatment of a patient with Behçet's disease (which is itself a potential aetiology for this complication) has been reported, as well as a case of multiple peripheral thromboses following infliximab treatment in a patient with sarcoid and antiphospholipid antibodies [3].
In our observation, infliximab was potentially responsible for this complication considering the chronology and the absence of other risk factors. To our knowledge this is the first case of cerebral venous thrombosis associated with anti-TNF therapy that has been described in the literature.
The pathophysiological mechanism is unknown. TNF- has a procoagulating activity via interleukin-6 (IL-6). In vitro, anti-TNF-
antibodies (cA2) block the procoagulating activity of certain HUVES cells exposed to TNF-
[4]. An in vivo prospective study of coagulation markers and fibrinolysis in 10 patients with active Crohn's disease treated with anti-TNF-
(10 mg/kg) showed that these anti-TNF-
antibodies (cA2) might stem from the procoagulating activity related to Crohn's disease by blocking the generation of thrombin linked to the increase in IL-6 (via TNF-
) [5].
Do anti-TNF- antibodies have a paradoxical procoagulating potential? The data in the literature report locoregional modifications after perfusion of anti-TNF-
in multiple sclerosis, with an increase in the white blood cell count and the IgG index in spinal fluid [6]. Jonsdottir et al. [7] underlined the emergence of statistically significant levels of anti-cardiolipin antibodies with anti-TNF-
, but with no real clinical significance.
While the exact relationship between infliximab and thromboses remains to be determined, the causes are probably multifactorial.
In conclusion, infliximab must be considered as a potential cause of cerebral venous thrombosis, and for any persistent headache in these circumstances a MRI angiogram is necessary to exclude this potentially serious pathology.
The authors have declared no conflicts of interest.
References
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