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Peripheral Mononeuropathy with Etanercept Use: Case Report

To the Editor:

Tumor necrosis factor-a (TNF-a) antagonist therapy has been associated with central and peripheral polyneuropathy demyelinating syndromes such as multiple sclerosis, Guillain-Barre syndrome, Miller-Fischer syndrome, and chronic inflammatory demyelinating polyneuropathy (CIDP)¹. This is the first report of a patient with inflammatory arthritis who developed peripheral mononeuropathy taking etanercept.

A 43-year-old Caucasian man was initially diagnosed with psoriatic arthritis (PsA) in 1997. His past course of treatment had been challenged by intolerance and inefficacy of different therapeutic modalities. He was initially treated with methotrexate (MTX) with a good response. However, he experienced adverse effects including headaches, nausea, vomiting, and diarrhea and he discontinued MTX therapy.

Two years later, during a severe flare of the psoriasis and arthritis, cyclosporine was used as monotherapy and later in combination with leflunomide, with good disease control. However, he developed hypertension on cyclosporine therapy and it had to be discontinued. Biologic agents including alefacept, infliximab, and etanercept were also used. They either controlled the arthritis but not the psoriasis or they were not efficacious at all.

The patient was evaluated in our rheumatology clinic in October 2005 for management of recalcitrant PsA. Etanercept in combination with leflunomide was initiated, which controlled his arthritis and psoriasis. However, he discontinued the etanercept after 12 weeks due to lack of insurance coverage. Thereafter, etanercept treatment was resumed on 3 more occasions over the course of a year based on his insurance coverage.

Eight weeks after reinitiating etanercept and leflunomide therapy for the fourth time, he presented with acute-onset numbness in the ulnar aspect of his left hand, fourth and fifth digits. His neurological examination showed mildly decreased left hand intrinsic motor strength (4/5) and diminished pinprick sensation on his left fifth digit. His mental status, ambulation, cranial nerves II-XII, coordination, deep tendon reflexes, motor strength, and sensation were intact. Given the distribution of findings, he was diagnosed with ulnar neuropathy. He denied any precipitating factors, including trauma or prolonged positioning of the arm. Etanercept was suspected to be the culprit and it was discontinued. Electromyography (EMG) was performed, which revealed left demyelinating ulnar mononeuropathy with evidence of approximately 80% conduction block localized to the segment between the elbow and the axilla (in the arm). There was no evidence of left cervical motor radiculopathy. Peripheral demyelinating mononeuropathy secondary to etanercept was the entertaining diagnosis. After etanercept was discontinued, no other medications were started until he reported improvement of his neuropathy 6 weeks later. During this time, he continued taking leflunomide, which had been started 6 months before. However, leflunomide as monotherapy did not control his inflammatory arthritis activity. Therefore, 9 weeks after discontinuation of his etanercept, he was started on cyclosporine in addition to leflunomide, but this regimen also failed to control his PsA. He was also offered a followup with neurology, but since his neuropathy was markedly improving off etanercept he declined it, and followup EMG/nerve conduction studies were not obtained.

Ulnar neuropathy is commonly seen with traumatic nerve injuries^2,3 and with nerve entrapment at the elbow, which can occur without any obvious inciting factor or anatomical predisposition⁴. While PsA has been associated with entrapment neuropathies⁵, as a consequence of local inflammation, psoriasis has not been associated with peripheral neuropathies. This patient's neurological symptoms started 8 weeks after etanercept use, which is earlier than the reported average time for demyelinating conditions associated with anti-TNF-a. His symptoms improved after the drug was discontinued, which supports an association between the use of the TNF-a antagonist and his neurological symptoms. This is in accord with the findings of Mohan, et al, who reported partial or complete resolution of symptoms after discontinuation of anti-TNF-a therapy⁶.

Drug-induced peripheral neuropathy seems like the most plausible diagnosis based on symptom improvement after drug discontinuation and lack of other possible causes such as trauma, metabolic abnormalities, and other underlying disease process⁷. In addition, the EMG was not consistent with nerve entrapment at the elbow. At the onset of his symptoms, the patient was also taking amlodipine and hydroxyzine and using triamcinolone acetonide ointment. He had also previously taken MTX, leflunomide, and cyclosporine. Among these medications at the doses used by this patient, leflunomide has been associated with peripheral neuropathy¹¹, most commonly in patients with rheumatoid arthritis⁸. It usually manifests as paresthesias with normal NCS⁹. In some patients, nerve conduction studies and EMG may show sensorimotor axonal neuropathy, but not demyelinating neuropathy as in this case¹⁰. Our patient's neuropathy improved 6 weeks after etanercept was withdrawn, although he continued taking leflunomide, which had been started 6 months before the neuropathy. This timeframe, the demyelinating expression of his neuropathy, and the improvement of his symptoms after withdrawal of etanercept, while he continued taking leflunomide, make etanercept more likely to have caused the neuropathy as compared to leflunomide.

Different outcomes have been reported when patients are rechallenged with the offending drug, with either worsening of neurological status on magnetic resonance imaging⁶ or no symptom recurrence on reexposure. The outcome of some of the cases who were rechallenged was confounded by the underlying disease and it was difficult to draw any conclusion¹². Rechallenge with anti-TNF-a was not attempted in our case.

Initially, TNF-a inhibitors were thought to be neuroprotective by counteracting with TNF-a, since the latter has been shown to cause axonal myelin degeneration and oligodendrocyte necrosis in central nervous system explants¹³. This notion was further compounded by studies in a well established murine model for human multiple sclerosis (MS) in which anti-TNF antibody was shown to prevent autoimmune demyelination from occurring¹⁴. But further murine studies were conflicting and a TNF-knockout mouse model revealed that these mice suffered from severe neurologic impairment and high mortality, with histological evidence of extensive demyelination and monocytic cell infiltration. The severity of the neurologic disease in TNF-a-deficient mice¹⁵ markedly improved after reinstitution of TNF-a, which is thought to promote remyelination through its influence in the proliferation of oligodendrocyte progenitors¹⁶.

In subsequent human studies, patients with MS treated with TNF-a inhibitors also had an unexpected increase in the number of gadolinium-enhancing lesions¹⁷ and in the number of MS exacerbations¹⁸. This led to the theory that TNF-a has a protective role in limiting the extent of immune-mediated inflammation and demyelination.

TNF-a inhibitors are being widely used in the treatment of rheumatic and inflammatory bowel diseases. They represent a major breakthrough in the treatment of these diseases, but they have also been associated with some potentially serious adverse effects, one of which is demyelination. For this reason, TNF-a inhibitors are contraindicated in patients with central demyelinating disorders. Individual susceptibility must account for the variable responses to TNF-a inhibitors and to the onset of demyelinating diseases in some people, but these mechanisms are still not completely understood. Although the occurrence of demyelinating syndromes associated with TNF-a inhibitors seems rare, the true incidence is unknown and it may be underreported. Nevertheless, TNF-a inhibitors are still promising drugs in the treatment of autoimmune inflammatory disorders, and their use is becoming more widespread. By reporting a new adverse effect associated with etanercept treatment, we aim to increase public awareness and patient safety.

BEATRIZ YAE HANAOKA, MD; JAMES LIBECCO, MD; MARY RENSEL, MD; RULA A. HAJJ-ALI, MD, Department of Rheumatic and Immunologic Diseases, Center of Vasculitis Care and Research, Cleveland Clinic Foundation, Cleveland, Ohio, USA. Address reprint requests to Dr. R.A. Hajj-Ali, Department of Rheumatic and Immunologic Diseases, Center of Vasculitis Care and Research, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: Hajjalr@ccf.org

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