Has adalimumab (Humira) or vaccination against hepatitis A and B (Twinrix) been associated with dem

Fråga: Has adalimumab (Humira) or vaccination against hepatitis A and B (Twinrix) been associated with demyelinating diseases such as multiple sclerosis or acute disseminated encephalomyelitis?

The question concerns a 55-year-old woman with rheumatoid arthritis and hypothyreosis. She initiated treatment with adalimumab, and was given three injections within four weeks. Ten days after the first injection she also received her third dose of vaccination against hepatitis A and B. Two days after her last adalimumab injection (and three weeks after her vaccination), she sought medical care due to dizziness, diplopia and balance disturbances, symptoms that were worsened with a severe deterioration of her neurological symptoms. There were suspicions about brainstem infarction and herpes encephalitis, and she was therefore first treated with heparin infusions and later aciclovir. The aciclovir treatment was discontinued seven days later, since her creatinine had increased (from 85 to 217). The day after she was comatose. A magnetic resonance imaging was done eleven days after the first symptoms appeared, and there were signs of demyelinating disease. The patient was improving. Treatment with human immunoglobulin (Octagam) was initiated. She had no known previous history of neurological symptoms or heredity of multiple sclerosis. The neuroradiologist reports spreaded signal changes in white matter both infratentorial and supratentorial with high signal intensity on T2-wheighted magnetic resonance imaging.

Sammanfattning: There are some reports of demyelinating diseases both after tumor necrosis factor-alfa inhibitor treatment and hepatitis B vaccinations in the literature. A causal relationship has not been established. However, acute disseminated encephalomyelitis has been associated with previous immunisation.

Svar: Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating syndrome of acute or subacute onset, affecting multifocal areas of the CNS with a polysymptomatic onset, in patients without a history of neurologic symptoms (1). In severe cases the onset is abrupt and the progression rapid (hours or days). The mortality is up to 30 percent, and of those surviving up to 20 percent has remaining neurological impairment of varying degree (2). Acute disseminated encephalomyelitis can be hard to distinguish from initial presentation of multiple sclerosis. However, the simultaneous onset of disseminated symptoms and signs is common in acute disseminated encephalomyelitis and rare in multiple sclerosis. Meningismus, drowsiness, coma or seizures suggest acute disseminated encephalomyelitis rather than multiple sclerosis. Acute disseminated encephalomyelitis is frequently associated with a previous immunisation (postvaccinal encephalomyelitis) or infections (mainly virus infections) (3), and symptoms are usually seen within 4-18 days after vaccination or infection (2). There are a few cases diagnosed as acute disseminated encephalomyelitis after hepatitis vaccinations in the literature. In a retrospective study with children diagnosed with acute disseminated encephalomyelitis, two patients (out of 31) had received hepatitis B vaccination three to six week before symptoms occurred (4). In a study eight patients with confirmed CNS inflammation occurring less than ten weeks after hepatitis B vaccination were followed for 18 months. Initially the CNS demyelinisation was suggestive of acute disseminated encephalomyelitis rather than multiple sclerosis. However, persistent inflammatory activity was observed both clinically and on magnetic resonance imaging, which makes it more probable to be multiple sclerosis (5). A 40-year old man, with a history of recurrent acute disseminated encephalomyelitis, was admitted due to dizziness, nausea, vomiting and diplopia six weeks after his first hepatitis B vaccination. His condition worsened and he developed partial seizures. He improved 15 days later, but had some residual symptoms (6). One case of acute and irreversible loss of vision two weeks after vaccination against hepatitis A, hepatitis B and yellow fewer has been published (7). There are no cases diagnosed as acute disseminated encephalomyelitis after adalimumab, infliximab or etanercept administration in the published literature.

Adalimumab is a tumor necrosis factor (TNF) alfa inhibitor registered in Sweden in 2003. Three cases of demyelination (one case of optic neuritis and two cases of paresthesias) have been reported in clinical studies. Two of these had complete recovery after drug discontinuation and the third had residual lower extremity numbness (8,9). One report of multiple sclerosis-like syndrome has been reported (judged as possible) to the Swedish adverse drug reaction register (out of a total of 64 reports) (10). The manufacturer recommends caution of administration of adalimumab to patients with demyelinating disease (11).

Tumor necrosis factor-alfa has been implicated in multiple sclerosis pathogenesis, and therefore a tumor necrosis factor-alfa inhibitor, lenercept, was studied in 168 patients with multiple sclerosis to evaluate whether it would reduce new lesions. No significant differences were seen on magnetic resonance imaging. However, lenercept was found to increase the multiple sclerosis attack frequency within the first month of treatment. It significantly increased multiple sclerosis exacerbations and the exacerbations occurred earlier compared to placebo. This effect was more pronounced in high doses (50 and 100 mg) than in low doses (10 mg) (12). In another report, the effect of infliximab was studied in two multiple sclerosis-patients with an aggressive disease. An increased number of lesions compared to baseline were seen after treatment. A rise in the IgG index and in the number of CSF lymphocytes was seen, maybe suggesting that infliximab triggers an immune activation. However, there was no reported clinical worsening of the disease (13).

There are some more reports of development of symptoms of demyelinating disease for the two other tumor necrosis factor-alfa inhibitors, etanercept and infliximab, in the published literature. In the FDA adverse events reporting system 19 patients with demyelinating disease in connection to tumor necrosis factor-alfa inhibitor treatment was found (etanercept 17, and infliximab 2). The average time between initiation of therapy and onset of symptoms, which included paresthesia, optic neuritis, confusion, walking- and bladder difficulties, was five months (varying between 1 week and 15 months). Discontinuation of tumor necrosis factor-alfa inhibitor therapy was followed by complete or partial improvement in all patients where follow-up was available (14 patients). In one case, reexposure to etanercept caused worsening of neurological status (14). Other cases with development of symptoms of demyelinating disease in connection to etanercept and infliximab treatment have been published. The symptoms came 4 weeks to 20 months after initiation of therapy (15,16,17). In one case symptomatic improvement was seen after discontinuation (17). One patient had a family history of multiple sclerosis (16). In the Swedish adverse drug reaction register there are four reports of multiple sclerosis-like syndrome for etanercept (out of 275 reports) and none for infliximab (out of 515 reports). The symptoms in these reports came after two weeks to nine months after initiation of therapy. In two cases resolution of symptoms is described after drug discontinuation (10).

The question about a link between hepatitis B vaccination and multiple sclerosis has been widely discussed, and this has previously been answered in Drugline. Most studies do not find an association between the vaccine and multiple sclerosis. Two studies in France and one in England showed a non-significant correlation between the vaccination and the development of multiple sclerosis (18). In 1997 WHO issued a statement saying that there was no evidence that hepatitis B vaccine causes multiple sclerosis. This was based on several facts; the virus itself does not cause multiple sclerosis, none of the post-marketing surveillance studies had shown any evidence of an increased risk, the French data showed an incidence of 0.6 cases/100000 vaccines, which is a lower rate than expected in the population (1-3 cases/100000) and the available scientific data did not demonstrate a causal relationship (19). One recently published case-control study found an increased risk of multiple sclerosis in patients vaccinated with hepatitis B vaccination. There were 163 cases of multiple sclerosis and 1604 controls. Eleven patients in the vaccinated group got multiple sclerosis, and the odds ratio of multiple sclerosis for vaccination within three years compared to no vaccination was 3.1 (95% CI 1.5; 6.3) (20). The selection process used in this study has, however, been questioned (21). Any documentation about hepatitis A vaccination and an increased risk of multiple sclerosis has not been found.

There are some patients who have a predisposition for developing demyelinating diseases. Multiple sclerosis and RA have similar pathophysiologic and ethiologic features, and there might be an association between these two autoimmune diseases. Occasional reports discussing this potential connection have been found in the literature (22,23,24).

The present case is more suggestive of acute disseminated encephalomyelitis than multiple sclerosis. Since acute disseminated encephalomyelitis frequently has been associated with previous immunisation, this might have been caused by the vaccination against hepatitis. However, the possibility that adalimumab has caused the event cannot be excluded. We can neither exclude aciclovir as a contributor to the course of this event, sii