Is there a relationship between gabapentin/valproate treatment and drug-induced SLE?/nA 47-year-old

Fråga: Is there a relationship between gabapentin/valproate treatment and drug-induced SLE?

A 47-year-old woman with a history of epilepsy since childhood, Raynaud disease, and arthralgia has been treated with sodium valproate (Orfiril) since eight years and gabapentin (Neurontin) since 1998-08-24. The dose of gabapentin was gradually increased to 2000 mg. Tremor, swelling of the hands and feet as well as involuntary movements developed and the dose was reduced (1200 mg) and thereafter withdrawn two months after the initiation of treatment. Four weeks after the withdrawal the patient presented with a severe polyarthritis (fingers, wrists, elbows and knees) and was admitted to a hospital. An extensive laboratory investigation revealed anemia, a marked inflammatory reaction with hypoalbuminemia and a moderately reduced GFR. Serology showed positive ANA-reactivity, sm autoantibodies and antihistone antibodies. The patient´s clinical condition as well as her laboratory parameters improved upon steroid treatment. ANA-positivity and antihistone antibodies were still present two months after admission. The final diagnosis was idiopathic SLE or drug-induced SLE.

Sammanfattning: There is no convincing time relationship between the gabapentin treatment and the present illness. Symptoms appeared before gabapentin treatment was started. Also, the deterioration that led to hospitalisation occurred one month after the withdrawal of gabapentin. With the exception of a few case reports in swedis and WHO database gabapentin has not been associated with SLE. Although antihistone antibodies are characteristic of drug-induced SLE, they do occur in idiopathic SLE. Further, drug-induced SLE usually subsides after withdrawal of the offending agent. This was not the case in this patient. The patient seems to have a lupus diathesis as suggested by a history of arthralgia and Raynaud´s phenomenon. The possibility that this underlying diathesis has been unmasked by gabapentin treatment cannot be totally excluded. Drug-induced SLE is a rather well-described side-effect of valproate. However, the time-relationship between treatment and symptoms is weak in the present case.

Svar: The incidence of drug-related lupus-like syndrome is eight per cent or less for anticonvulsants (1). We have found a couple of case reports of valproate-induced SLE in the literature. A 30-year-old woman developed arthralgia, muscle weakness, fatigue and fever after treatment with valproic acid for one year (1500 mg/day) and ethosuximide (750 mg/day). Laboratory values indicated systemic lupus erythematosus (SLE). Symptoms disappeared six weeks after discontinuation of drug treatment (2). A 47-year-old man was treated with phenytoin and primidone and valproate was added. One month later he developed fever, malaise and trombocytopenia and laboratory evidence of SLE. He improved one month after discontinuation of phenytoin and valproate. A 28-year-old woman experienced fever and lymphadenopathy after phenytoin treatment. After four months of valproate treatment she developed confusion, joint pain, more seizures and laboratory signs of SLE. Discontinuation of treatment led to improvement. Rechallenge of valproate led to return of the laboratory signs (3). An 18-year-old boy developed fever, lymphadenopathy, leucopenia and a positive ANA test four weeks after intake of valproate (800 mg/day). Symptoms began to resolve two weeks after withdrawal (4). A 30-year-old man with epilepsy and mental retardation was treated with valproate (500 mg four times daily). Two months later he developed thrombocytopenia with leucopenia and chronic hemolytic anaemia, positive ANA, rheumatoid factor, anti-NIA, circulating immune complexes and antihistone antibodies. The patient improved after dechallenge of valproate (5).

In the Swedish Adverse Drug Reactions Advisory Committee´s database (SWEDIS) we found no cases of SLE in treatment with gabapentin, nor with valproate (SADRAC). There were two cases of oedema in treatment with gabapentin and one case due to valproate. We found no data in the literature of oedema after gabapentin treatment. In the WHO database we found three unvalidated cases of SLE in treatment with gabapentin, and 33 cases associated with valproate.

The case has been reported to SADRAC and assessed as unclassifiable. 1 Davies DM, editor. Textbook of adverse drug reactions. 4th ed. Oxford: Oxford University Press; 1991. page 501 2 Gigli GL, Scalise A, Pauri F, Silvestri G, Diomedi M, Placidi F, Pomponi MG, Masala C: Valproate-induced systemic lupus erythematosus in a patient with partial trisomy of chromosome 9 and epilepsy. Epilepsia 1996; 37: 587-588 3 Bleck TP, Smith MC: Possible induction of systemic lupus erythematosus by valproate. Epilepsia 1990; 31: 343-345 4 Park-Matsumoto UC, Tazawa T: Valproate induced lupus-like syndrome. J Neurol Sci 1996; 143: 185-186 5 Asconape JJ, Manning KR, Lancman ME: Systemic lupus erythematosus associated with use of valproate. Epilepsia 1994; 35: 162-163