CLEVELAND — Tumor necrosis factor-α blockade should not be instituted in patients with known multiple sclerosis and should be used with caution in patients with family histories or other risk factors for MS, according to Jeffrey A. Cohen, M.D., a neurologist at the Cleveland Clinic.
In addition, physicians should be alert to uncommon central nervous system manifestations in patients receiving tumor necrosis factor (TNF) blockade for their inflammatory diseases, he said at a meeting on the treatment of autoimmune and inflammatory disorders.
TNF inhibitors currently approved by the Food and Drug Administration include the monoclonal antibodies infliximab (Remicade) and adalimumab (Humira) and the fusion protein etanercept (Enbrel).
TNF blockade both prevents and abrogates demyelinating disease in vitro and in animal studies. However, in humans, TNF blockade actually increased MS activity, said Dr. Cohen, citing data from two studies of infliximab and the discontinued lenercept. “In addition, treatment of other diseases for which TNF inhibitors are highly effective, including rheumatoid arthritis, Crohn's disease, and psoriasis, on rare occasions leads to CNS inflammatory demyelinating syndromes,” said Dr. Cohen at a summit sponsored by the Cleveland Clinic.
Failure of a TNF antagonist therapy in MS may be due to pleiotropic aspects of TNF actions, he noted. “In the CNS, TNF mediates cellular apoptosis and tissue damage, has important immunoregulatory functions, and is involved in tissue repair and regeneration. This experience reminds us that in the development of novel therapeutics, one must be cautious in extrapolating from animal models to human disease and from the results in one human disease to another,” he said.
Discussion of restarting therapy in patients who have been taken off a TNF inhibition because they developed a CNS manifestation involved a hypothetical case representing a composite of patients created for teaching purposes: a 32-year-old woman with a 5-year history of active Crohn's disease unresponsive to 6-mercaptopurine, mesalamine (Pentasa), and budesonide. She was started on infliximab and responded after the third infusion with complete resolution of abdominal pain and cramping and with a marked reduction in the frequency of bowel movements.
“After 12 months of therapy, she developed gait imbalance and numbness and tingling of the hands and feet that worsened over several weeks, making it difficult for her to walk,” Dr. Cohen said. The patient's Crohn's disease remained quiescent. A cranial nerve exam was normal, and the woman had normal strength, mild spasticity in the legs, diffuse hyperreflexia with right Babinski's sign, mild ataxia of the arms and legs, decreased position sense in the hands and feet, and moderate gait ataxia.
The patient's erythrocyte sedimentation rate was 55, she did not have a lupus anticoagulant, her B12 and copper were normal, and an antibody test was negative. An MRI of the cervical spine showed an ovoid lesion in the spinal cord at C3–4 with mild diffuse enhancement. A lumbar puncture showed mild mononuclear cell pleocytosis, normal glucose, mildly elevated protein, normal IgG index, and no oligoclonal bands Dr. Cohen said.
Infliximab therapy was discontinued, and the woman was treated with intravenous methylprednisolone for three days, with the dose tapered over 2 weeks. “Within 12 weeks, the neurologic symptoms had completely resolved,” said Dr. Cohen. “Repeat MRI showed resolution of enhancement of the spinal cord lesion and no other lesions in the brain or spinal cord. Her original Crohn's symptoms recurred, however, and did not respond to MTX [methotrexate] or budesonide. Her symptoms improved on prednisone 60 mg/day but returned when the dose was tapered. She said she had felt much better on infliximab and asked about the possibility of restarting it,” said Dr. Cohen. “The decision to restart infliximab must be based on weighing the risks from Crohn's disease and whether other treatment options exist versus the risk of a recurrent neurologic complication.”
“The differential diagnosis of neurologic manifestations in patients with immune mediated inflammatory disorders treated with TNF inhibitors is broad and includes neurologic complications of the underlying disease, neoplastic or infectious complications of TNF inhibitors, and direct neurologic complications of TNF inhibitors. Reported neurologic complications of TNF inhibitors include CNS demyelinating syndromes, aseptic meningitis, seizures, ischemic optic neuropathy, and demyelinating peripheral neuropathies,” according to Dr. Cohen.
“CNS demyelination can occur anytime after an anti-TNF agent is started, and clinical manifestations reflect the anatomic site of involvement. Demyelination has been reported with all TNF antagonists and thus appears to be a class effect.”
In terms of the nervous system, Dr. Cohen recommends avoiding TNF blockade for patients who are known to have MS or who might be at risk of MS; nor should TNF inhibitor infusions be given to patients who have had a previous clinically isolated CNS syndrome without the formal diagnosis of MS or to patients who have cranial MRIs that look suggestive of MS but do not yet have clinical manifestations, advised Dr. Cohen.