Rheumatology Unit, Hospital Donostia, 20014 San Sebastián, Spain
Correspondence to: J. Belzunegui. E-mail: belzunegui{at}chdo.osakidetza.net
SIR, Multifocal motor neuropathy (MMN) with conduction block is a rare autoimmune demyelinating disorder. Its diagnosis is based on clinical, laboratory and electrophysiological findings. Clinically, MMN is characterized by a slowly progressive asymmetric weakness of the limbs without sensory loss. Immunoglobulin M anti-GM1 titres may be elevated. Electrophysiological studies reveal motor conduction blocks at sites not prone to compression with normal sensory responses [1].
On the other hand, neurological and demyelinating events have been reported in association with the use of tumour necrosis factor-alpha (TNF-) antagonists [2]. Because these latter cannot penetrate the bloodbrain barrier, a proposed mechanism by which they exacerbate demyeliniting diseases is the activation of peripheral autoreactive myelin-specific T cells, which subsequently could enter the central nervous system and provoke demyelination. We report a patient with rheumatoid arthritis who developed MMN. Its onset coincided temporally with the initiation of infliximab therapy.
The patient was a 34-yr-old woman who had had chronic hepatitis C for 5 years and who had suffered from a severe symmetric polyarthritis since December 2001. At that moment, laboratory data showed erythrocyte sedimentation rate 55 mm/h (range 16 mm/h), rheumatoid factor 27 IU/l (range 014 IU/l) and serum cryoglobulin levels 0.14 g/l (range 00.037). Antinuclear antibodies were negative. Despite different regimens of aurothiomalate, sulphasalazine, cyclosporin and methotrexate, joint pain and swelling persisted. In June 2003 infliximab monotherapy (3 mg/kg) was started at a standard loading dose (0, 2, 6, 14 weeks). After four infusions (cumulative dose 720 mg) clinical remission was obtained but the patient was admitted with progressive weakness involving both hands and the right foot. Neurological examination revealed severe motor distal deficit at these levels without sensory loss, and decreased osteotendinous reflexes. Laboratory data showed erythrocyte sedimentation rate 20 mm/h, haemoglobin 124 g/l (range 120160 g/l), leucocyte count 5.4 x 109/l [range (4.510.6) x 109/l], platelet count 354 x 109/l [range (140400) x 109/l], aspartate amino transferase 17 IU/l (range 531 IU/l), aspartate alanine transferase 24 IU/l (range 531 IU/l), creatine phosphokinase 26 IU/l (range 20170 IU/l). Antinuclear antibodies were negative. The remaining biochemical parameters and urine analysis showed normal results. Serum cryoglobulin levels were 0.089 g/l. IgM antiganglioside antibodies were positive at high titre (1:640). The electromyographic pattern was compatible with a pure motor polyneuropathy with conduction block. The patient was treated with intravenous immunoglobulins with complete recovery of the muscle strength within a few weeks. Infliximab was definitively discontinued. Six months later arthritis was reactivated, muscle strength was normal and antiganglioside antibodies were negative. A regimen of subcutaneous anakinra (100 mg/day) was initiated with good response.
Despite the fact that high levels of TNF have been found in multiple sclerosis plaques and cerebrospinal fluid, development and exacerbation of demyelinating diseases like multiple sclerosis, GuillainBarré syndrome and optic neuritis have been described in association with the TNF receptor fusion proteins lenercept and etanercept, and also with the TNF-specific antibody infliximab. Current guidelines are to avoid the use of anti-TNF drugs in individuals with a history of demyelinating disease [2]. Clinicians should also be cautious with its use in those with a family history of multiple sclerosis. As in our case, a neurological disorder usually appears a few weeks or months after starting treatment [2]. The overall number of patients with new-onset demyelinating events on anti-TNF therapy appears to be small. These data argue against a true association of events and anti-TNF drugs. However, these episodes can be silent, making it difficult to asses the exact number of affected individuals [3].
MMN is a neurological demyelinating disorder which usually appears to be an isolated entity. However, it has been described in association with Hashimoto thyroiditis [4], B-cell lymphoma [5, 6] and infections caused by Campylobacter jejuni [7]. To our knowledge, it has not been reported as a complication of anti-TNF therapy.
Assessing the likelihood of a causal connection between an environmental exposure and an adverse event, the five primary elements of attribution reported by Miller et al. [8] include: 1, temporal association; 2, lack of likely alternative explanations; 3, dechallenge; 4, rechallenge; 5, biological plausibility. Analysing the second and fifth elements, we cannot exclude a possible role of cryoglobulins in the development of MMN in our case, because demyelinating polyneuropathies have been described in association with mixed cryoglobulinaemia [9]. The fourth element is not available to study because infliximab was not reinitiated. However, temporal association and dechallenge (improvement in symptoms following discontinuation of the drug) suggest that infliximab, rather than cryoglobulin, is related to the development of the neurological complication in our case. Hepatitis C infection and cryoglobulins were recognized at least 5 and 2 yr respectively before the demyelinating event occurred, and after only four doses of infliximab. Furthermore, the levels of cryoglobulins decreased after infliximab infusions. On the other hand, discontinuation of infliximab therapy was followed by a quick recovery of the muscle strength. Thus, we conclude that infliximab is probably the agent responsible for the development of MMN in this patient.
The authors have declared no conflicts of interest.
References
|