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Etanercept Induced Multiple Sclerosis and Transverse Myelitis To the Editor: Etanercept is a tumor necrosis factor-a (TNF-a) antagonist used in rheumatoid arthritis (RA). Several studies have raised the possibility that etanercept may have unexpected side effects such as demyelinating neurological disorders1. We describe a 58-year-old Caucasian woman who presented with a 9-day history of left lower extremity weakness that progressed to bilateral lower extremity weakness and numbness, along with a tingling sensation in both hands. She was unable to walk without assistance and was in a wheelchair on presentation. This numbness progressed to involve most of her body, from her chest down to her toes bilaterally, as well as both hands and wrists. She reported that she slipped and fell a few days prior to these symptoms and twisted her back, without significant neurological symptoms at that time. Magnetic resonance imaging (MRI) of the cervical spine showed a 1.5 cm focal area of high signal intensity seen on T2 weighted images at the C3–C4 level (Figure 1). She was started on oral steroids without a significant improvement prior to the MRI of the cervical spine.
She had a 5-year history of RA. Because methotrexate was only of partial benefit she was switched to etanercept, which she continued for more than one year, with dramatic improvement in her joint symptoms. Etanercept was discontinued at hospital admission. She had no history of multiple sclerosis (MS) or any neurological disease. Neurological examination revealed intact cranial nerves. Decreased sensitivity to light touch was noted in the left leg. Hip flexors, hamstrings, dorsi, and plantar flexors of the feet had decreased strength at about 4/5 in the left leg, 5/5 at the hip flexors, quads, hamstrings, dorsi, and plantar flexors of the right leg. Deltoid, biceps, and triceps had 5/5 strength. Straight leg raising test was negative bilaterally. Deep tendon reflexes were brisk in the left lower extremity with a positive Babinski's sign, but otherwise normal. A mild dysmetria was noted in her left upper extremity. MRI of the brain showed multiple areas of increased signal intensity involving the deep white matter (Figure 2).
Cerebrospinal fluid analysis showed white blood cell count was 13 cells/ml (90% lymphocytes), glucose 92 mg/dl, total protein 27 mg/dl, IgG 2.94 mg/dl, IgG index 1.05, and VDRL nonreactive. Oligoclonal bands were positive. Bacterial, viral, and fungal studies were negative. The presumptive diagnosis was MS with transverse myelitis induced or worsened by etanercept. Etanercept was discontinued and the patient was started on intravenous methylprednisolone. She improved significantly during the next 5 days, with partial resolution of her weakness and numbness. She was again able to walk without assistance. She was discharged on tapering doses of prednisone. Three weeks after discharge she had normal gait. She denied any persistent numbness. Motor examination showed 5/5 strength in all muscle groups of all extremities. Deep tendon reflexes were +2 in all extremities. Babinski's sign was negative bilaterally. Followup brain MRI one year later showed no change in the pattern of periventricular demyelinization. There was no abnormal enhancement of these changes to suggest active MS. Findings were compatible with old lesions. TNF-a stimulates collagenase and prostaglandin E2 production by human synovial cells2, induces bone resorption3, inhibits bone formation and proteoglycan synthesis4, stimulates resorption of proteoglycan, stimulates fibroblast proliferation, and increases production of interleukin 6 (IL-6), IL-8 and granulocyte macrophage-colony stimulating factor. TNF-a is primarily a product of synovial macrophages in RA and is present in rheumatoid synovial fluid and serum. Etanercept, a soluble TNF-a receptor fusion protein that binds TNF-a, provides substantial benefit to patients with RA when compared to placebo5. Efficacy is similar to that of methotrexate but of more rapid onset and is recommended for patients with an inadequate response to methotrexate alone6,7. The incidence of demyelinating disease in patients receiving etanercept (31 per 100,000 patients per year) appears to be higher than in the general population (4–6 per 100,000 per year). Symptoms include confusion, ataxia, paresthesia, optic neuritis, hemiparesis, and transverse myelitis. Transverse myelitis is defined as the development of spinal cord dysfunction over hours or days in patients in whom there is no evidence of a compressive lesion. The initial symptoms are paresthesias, back pain, or leg weakness. Patients presenting with acute complete transverse myelitis have a risk of MS of only 5–10%. However, partial or incomplete myelitis is a much more common clinical entity and more relevant to MS; 57–72% of patients with acute partial myelitis as an initial presentation have cranial MRI abnormalities consistent with MS8,9. Lenercept is another recombinant TNF receptor fusion protein. A double-blind, placebo-controlled phase II study was conducted in 168 patients, most with relapsing-remitting MS, to evaluate whether lenercept would reduce new lesions on MRI. The number of lenercept-treated patients experiencing exacerbations was significantly increased compared with patients receiving placebo (p = 0.007) and their exacerbations occurred earlier (p = 0.006)10. It seems reasonable to avoid the use of anti-TNF-a agents in patients with established demyelinating disease and to immediately discontinue therapy and pursue diagnostic tests in any patient with suspected demyelination.
NAWAR AL SAIEG, MD, Resident, Department of Internal Medicine, Western Reserve Care System; MICHAEL J. LUZAR, MD, Associate Professor of Medicine, Northeastern Ohio Universities College of Medicine, Director, Division of Rheumatology, Forum Health, Youngstown, Ohio, USA.
REFERENCES 1. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001;44:2862-9. 2. Dayer JM, Beutler B, Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med 1985;162:2163-8. 3. Bertolini DR, Nedwin GE, Bringman TS, et al. Stimulation of bone resorption and inhibition of bone formation in vitro by human tumour necrosis factors. Nature 1986;319:516-8. 4. Saklatvala J. Tumour necrosis factor a stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 1986;322:547-9.
5. Blumenauer B, Judd M, Cranney A, et al. Etanercept for the 6. Moreland LW, Baumgartner SW, Schiff MH, et al. Treatment of rheumatoid arthritis with a recombinant tumor necrosis factor receptor (p75)-Fc fusion protein. N Engl J Med 1997;337:141-7.
7. Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept 8. Morrissey SP, Miller DH, Kendall BE, et al. The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. A 5-year follow-up study. Brain 1993;116 Pt 1:135-46.
9. Ford B, Tampieri D, Francis G. Long-term follow-up of acute 10. The Lenercept Multiple Sclerosis Study Group and The University of British Columbia MS/MRI Analysis Group. TNF neutralization in multiple sclerosis: Results of a randomized, placebo-controlled multicenter study. Neurology 1999;53:457-65.
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