Rheumatology Advance Access originally published online on July 28, 2006
Rheumatology 2006 45(11):1445-1446; doi:10.1093/rheumatology/kel232
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Is TNF
really a good therapeutic target in motoneuronal degeneration? A case of amyotrophic lateral sclerosis in a patient with RA receiving infliximab
Arthritis Centre and1Department of Neurology, Northwick Park Hospital, London, UK
Correspondence to: Dr Magdalena Dziadzio, Arthritis Centre, Northwick Park Hospital, Watford Road, Harrow, HA1 3UJ, London, UK. E-mail: Magdalena.Dziadzio{at}nwlh.nhs.uk
SIR, Tumour necrosis factor-
(TNF-) has been implicated in the pathogenesis of various inflammatory conditions such as rheumatoid arthritis (RA), Crohn's disease and psoriasis. In these diseases, TNF- blockade is a successful and safe treatment option [1]. TNF- can be neurotoxic and has also been implicated in the pathogenesis of some central nervous system diseases where inflammation has recently emerged as a significant contributor to motor neuron damage [2]. TNF- acts as the main driver for neuroinflammation in amyotrophic lateral sclerosis (ALS). Animal studies [3–5] as well as phase II clinical trials are currently underway to test the validity of TNF- as a drug target in ALS [6].
Four cases of concomitant RA and ALS have been reported to date [7, 8] but the occurrence of the two diseases in the same patient is probably due to chance alone. Here we report a case of an RA patient who was diagnosed with ALS while receiving the anti-TNF- agent infliximab. ALS was rapidly progressive despite infliximab therapy.
An Asian man with non-insulin-dependent diabetes mellitus, hypertension, ischaemic heart disease and a permanent pacemaker was first seen in 1998 at the age of 68. He had a 9-month history of progressive symmetrical polyarthropathy involving the hands, wrists, shoulders, knees, ankles and feet with morning stiffness. A diagnosis of seropositive erosive RA was made and treatment with methotrexate (MTX) was started. However, he still required concomitant non-steroidal anti-inflammatory drugs (NSAIDs) and steroids. Sulphasalazine was added to his treatment without significant improvement. In August 2001, his disease remained active with a DAS28 score of 5.2. Treatment with infliximab 3 mg/kg 8-weekly was started and subsequently increased to 5 mg/kg. There was moderate improvement: although his DAS28 oscillated between 2.8 and 4.6, the patient stated that ‘he was feeling so much better!’ In autumn 2003, the patient suffered an infective episode and investigations also revealed raised prostate-specific antigen. Infliximab treatment was stopped. A diagnosis of benign prostatic hyperplasia with focal epithelial neoplasia was made. After careful review of the risk of prostate carcinoma in patients receiving immunosuppressive therapy, and considering a flare of RA and the patient's desire to continue infliximab, treatment was restarted in 2004. In March 2005, he developed a left foot drop. In January 2006, he noticed weakness of his right leg but no sensory symptoms. On examination, it was noticed that there was wasting of his quadriceps muscles and that reflexes were brisk throughout with extensor plantar response. A computed tomography (CT) scan of the cervical and lumbar spine showed mild degenerative changes and CT scan of the head and cerebro-spinal fluid examination were normal. Electromyography showed widespread denervation in the arms and legs with no fasciculation or fibrillation and normal motor and sensory conduction velocities. In March 2006, fasciculations were noted in the deltoid and scapular region and in both quadriceps. A diagnosis of ALS was made by a neurologist and treatment with riluzole was started. His disease has been progressive, with dysphagia and generalized weakness and wasting, and he is now wheelchair bound. Infliximab was stopped.
ALS is a progressive neurodegenerative disorder with selective upper and lower motor neuron loss. Information about the likely role of TNF- in ALS is provided by the transgenic ALS superoxide dismutase 1 (G93A SOD1) mouse model [3, 4] and the mnd mouse model [5]. Detectable TNF- mRNA and protein can be found in the brain and spinal cord of mnd mice but not in control mice; increased TNF- immunoreactivity is also detectable in G93A SOD1 transgenic mice (starting in the pre-symptomatic phase) [3]. Evidence in human disease includes increased TNF- immunoreactivity in post-mortem lumbar spinal cord sections of ALS patients [4] circulating serum TNF- and its soluble receptor levels [9]. However, no correlation between TNF- levels and disease severity or duration was found [9].
The results of clinical studies of TNF- blockade in ALS are awaited. Thalidomide, an anti-TNF- agent, was recently tested in G93A SOD1 transgenic mice, which showed improved survival, delayed disease onset and progression, and a reduction in TNF- protein and mRNA levels in spinal cords [4]. Currently, there are two clinical trials registered in 2005 at www.ClinicalTrials.gov [6]: a pilot German safety/efficacy study of oral thalidomide in patients with ALS and a USA phase II efficacy study of thalidomide in ALS in the setting of disease progression. Thalidomide is a small molecule, which can readily cross the blood-brain barrier, and acts differently to anti-TNF- monoclonal antibodies (mAbs) by inhibiting protein expression at the post-transcriptional level and by decreasing mRNA TNF- half-life from 30 to 17 minutes [10].
Despite earlier cautious enthusiasm [2], we found no reported data on anti-TNF- mAbs used in ALS either in animal models or in humans with ALS. The rationale for treating ALS with anti-TNF- mAbs remains unclear. No definite data regarding the relationship between serum and CNS TNF- levels in ALS are available and it is not known whether circulating TNF- blockade might exhibit any effect on CNS TNF- expression. Anti-TNF- mAbs are macromolecules and would be expected to have negligible brain access. On the other hand, anti-TNF- mAbs have shown protective effects in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis [2], but in contrast, anti-TNF- mAbs can worsen the disease in MS patients.
Treating patients who have ALS with anti-TNF- mAbs is certainly fraught with difficulties. ALS mimics the potential complications of RA with consequent diagnostic difficulties [7, 8], and increased susceptibility to infections in ALS may be dangerously aggravated by the immunosuppression of TNF- blockade. However, this incidental experience shows that ALS may develop and progress during TNF- blockade treatment sufficient to ameliorate RA. Further human experience with biological anti-TNF- agents and thalidomide may well be informative.
The authors have declared no conflicts of interest.
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