BUFFALO, NY, and CALGARY, Alberta – Biologic therapies directed against tumor necrosis factor (TNF)-α inhibitors have revolutionized treatment of inflammatory arthritis but have also been associated with occasional neurologic problems. Two recent studies^1,2 from groups in Buffalo, New York, and Calgary, Alberta, suggest that clinicians should be alert for signs of peripheral or central neuropathies in patients treated with these drugs.

"It is becoming increasingly apparent that [treatment] with the TNF antagonists has the potential to cause injury to both the central and peripheral nervous systems," Alan N. Baer, MD, co-author of a new study published in Arthritis & Rheumatism, told CIAOMed. "Physicians need to be aware that peripheral nerve disease can be a potential consequence of TNF antagonist therapy. The manifestations of peripheral nerve disease can be quite variable, but generally include paresthesias, distal limb weakness, numbness and other forms of sensory impairment, loss of tendon reflexes, and poor balance."

After encountering a rheumatoid arthritis (RA) patient who developed the Miller Fisher variant while taking infliximab, Dr. Baer and colleagues from the State University of New York at Buffalo examined cases of Guillain-Barré syndrome derived from US Food and Drug Administration (FDA) postmarketing data. The index patient presented after 21 months of infliximab with ataxia and dysarthria, which worsened after each infliximab infusion. After 6 months this patient developed areflexic flaccid quadriplegia despite treatment with intravenous methylprednisolone. The Miller Fisher variant of Guillain-Barré, which is characterized by ataxia, external ophthalmoplegia, and areflexia, was diagnosed after electrodiagnostic testing.

The index patient improved after two courses of intravenous immunoglobulin (IVIG), 0.4 gm/kg/day, but was not able to walk without assistive devices until 6 months later. At 17 months after hospitalization double-stranded DNA and RNP autoantibodies had returned to undetectable levels.

Fifteen more cases found in FDA postmarketing data

In the FDA database Dr. Baer identified 15 more patients who had developed Guillain-Barré syndrome following TNF inhibitor therapy (nine were treated with infliximab, five with etanercept, and one with adalimumab). Median time from first dose of TNF inhibitor to onset of Guillain-Barré was 4 months, and six of the 15 patients had antecedent events such as upper respiratory tract infection, flu-like illness, or low-grade fever.

Thirteen of the 15 patients were treated for the syndrome with plasmapheresis, IVIG, and/or corticosteroids. Symptoms resolved completely in three patients, resolved partly in nine patients, continued unabated in one patient, and had unknown resolution in three patients.

A second study, led by Julie Jarand, MD, of the Department of Medicine at the University of Calgary, Alberta, reports three cases of RA patients who developed neurological disease associated with infliximab treatment. Two of these patients had axonal polyneuropathies; one had a "very prominent motor axon demyelination." One patient had mild sensory symptoms before taking infliximab, developed severe neuropathy following infliximab treatment, and remained ataxic 9 months after discontinuation of infliximab despite intravenous corticosteroid treatment.

"There was improvement, but incomplete recovery in all three patients concurrent with discontinuation of infliximab," Dr. Jarand reports.

Does TNF-α provide a needed nerve signal?

Dr. Jurand and colleagues suggest the possibility that "constitutive TNF-α provides ongoing signaling support to peripheral neurons, and its sequestration with infliximab or mRNA degradation with thalidomide interrupts such support to cause neuropathy."

"Demyelination is a feature of many, but not all, of the syndromes that have developed in the reported patients (eg, optic neuritis, multiple sclerosis, chronic inflammatory demyelinating polyneuropathy, Guillain-Barré and Miller Fisher syndromes, and axonal polyneuropathy)," Dr. Baer told CIAOMed.

"It is a paradox that inhibition of TNF can be of dramatic therapeutic benefit for certain inflammatory conditions such as rheumatoid arthritis, Crohn's disease, and psoriatic arthritis, yet prove harmful for patients with multiple sclerosis, lupus, and congestive heart failure," Dr. Baer said. "TNF-alpha is known to have both anti-inflammatory and immunosuppressive actions. Altering the balance of these effects in a susceptible host or in a unique microenvironment (such as the central nervous system) could explain the variable effects of TNF antagonism. We clearly need to know more about the role of TNF-alpha in the peripheral and central nervous systems," he noted, adding, "As Jarand et al suggest, constitutive TNF-alpha may be essential to the maintenance of the integrity of the peripheral neurons."

Both studies agree that clinicians should be extremely cautious about giving infliximab to patients with preexisting polyneuropathy or demyelinating disease.

References

1. Shin I-SJ, Baer AN, Kwon HJ, et al. Guillain-Barré and Miller Fisher syndromes occurring with tumor necrosis factor-? antagonist therapy. Arthritis Rheum. 2006;54:1429-1434.
2. Jarand J, Zochodne DW, Martin LO, et al. Neurological complications of infliximab. J Rheumatol. 2006;3:1018-1020.