Interferon beta

Systematic reviews

In a meta-analysis of seven trials in 1215 patients with relapsing–remitting multiple sclerosis, there was a modest effect of recombinant interferon beta on the rate of clinical exacerbation at 1 year of treatment, but no clear clinical benefit beyond 1 year [ ]. Compared with placebo, the most common adverse reactions were flu-like symptoms (48% versus 28%), injection-site reactions (62% versus 14%), nausea and vomiting (32% versus 20%), hair loss (36% versus 2.5%), leukopenia (6% versus 0.6%), thrombocytopenia (3.5% versus 0.5%) and increased alanine aminotransferase activity (9% versus 3%).

Cardiovascular

Cardiovascular adverse reactions to interferon beta include isolated reports of severe Raynaud’s phenomenon [ ] and acute myocarditis [ ].

Fatal capillary leak syndrome has been reported [ ].

• A 27-year-old woman had an 8-month history of relapsing–remitting neurological symptoms and a monoclonal gammopathy. She started to take interferon beta-1b for multiple sclerosis, but had marked somnolence 30 hours after a single injection. She rapidly became unresponsiveness, and hemodynamic tests showed low central venous and pulmonary capillary wedge pressures with generalized peripheral edema, ascites, and bilateral pleural effusions. She died within 80 hours after injection from multiple organ failure. At postmortem she was found to have C1 esterase inhibitor deficiency.

In the light of the possible effects of interferon beta on cytokine release and complement activation, a cytokine-mediated reaction was discussed as the cause of the capillary leak syndrome in this case.

Respiratory

Bronchiolitis obliterans with organizing pneumonia has been reported in a patient taking interferon beta [ ].

• A 49-year-old man had a progressive unproductive cough and right hemithoracic pain after 3 months of interferon beta-1a 30 micrograms/week for multiple sclerosis. A CT scan showed a right basal pulmonary infiltrate and transbronchial biopsies showed features consistent with bronchiolitis obliterans with organizing pneumonia. The lesions resolved fully on interferon beta-1a withdrawal and prednisone treatment.

Nervous system

Although direct toxic effects of natural interferon beta on the nervous system have been regarded as a possible risk of intraventricular and/or intratumoral injection [ ], interferon beta is considered to be markedly less neurotoxic than interferon alfa [ ].

Although headache was not specifically identified as an adverse effect of interferon beta in pivotal trials, the frequency, duration, and intensity of headache increased during the first 6 months of treatment in 65 patients [ ]. There was a 35% probability of aggravated headaches in patients with pre-existing headaches.

The possible deleterious effects of interferon beta-1b on increased spasticity have been examined in 19 patients with primary progressive multiple sclerosis, 19 untreated matched patients, and 10 patients treated with interferon beta-1b for relapsing–remitting multiple sclerosis [ ]. Patients with primary progressive multiple sclerosis had frequent (68%) and clinically relevant increased spasticity (seven required oral baclofen), usually after about 2 months of treatment, whereas only two (11%) of the untreated patients and none of the patients with relapsing–remitting multiple sclerosis had similar disabling spasticity. Seven patients had to discontinue treatment after 6 months because of spasticity, and symptoms improved over several months after withdrawal. The authors suggested that this possible adverse effect should be taken into account in clinical trials because it could mask the positive clinical effects of interferon beta-1b.

Neurosarcoidosis has been reported in a patient with chronic hepatitis C who was treated with interferon beta.

• A 56-year-old woman developed numbness and difficulty in swallowing and in closing her left eye several weeks after starting interferon beta for chronic hepatitis C [ ]. She had facial paresthesia, a left facial nerve palsy, dysphagia, and signs of radiculopathy on the left side. Serum angiotensin-converting enzyme activity was raised. She had bilateral hilar lymphadenopathy without interstitial changes and increased radiogallium uptake in hilar lymph nodes and the parotid glands. Although the cerebrospinal fluid was normal, a diagnosis of neurosarcoidosis was considered, and she recovered completely after interferon beta withdrawal and glucocorticoid therapy.

Moderate exacerbation of multiple sclerosis sometimes occurs in the first 3 months of interferon beta treatment.

• A 21-year-old man had an acute and very severe clinical relapse, with multiple disseminated demyelinating lesions and axonal injury on MRI and cerebral biopsy, after the third injection of interferon beta-1a [ ].

Whether this case was due to interferon beta or resulted from spontaneous exacerbation was open to question.

There is an association between multiple sclerosis and central nervous system tumors.

• A 19-year-old woman with multiple sclerosis had a concomitant right intraventricular tumor, consistent with meningioma on an MRI scan [ ]. Two years after the start of treatment with interferon beta, a brain MRI scan showed enlargement of the intraventricular mass and a relative increase in the number of white matter lesions without significant clinical deterioration. She underwent almost total resection of the mass. A papillary meningioma was confirmed histologically.

This association could have been coincidental. However, meningiomas have been previously reported in two patients with multiple sclerosis, with progression during treatment with interferon-beta [ ]. Based on immunohistochemistry, the meningioma was speculated to have resulted from enhanced platelet-derived growth factor receptors and/or down-regulated transforming growth factor receptors on the tumor itself.

Sensory systems

Retinal complications of interferon alfa in chronic viral hepatitis patients are well known, but few cases have been described with interferon beta.

• Bilateral retinopathy with similar features to those observed with interferon alfa has been reported in a 40-year-old woman treated with interferon beta-1b for multiple sclerosis [ ].

In 49 patients, there was reversible otological impairment with tinnitus, mild-to-moderate hearing loss, or both in respectively 8%, 16%, and 20% of patients after administration of interferon alfa or interferon beta [ ]. These disorders tended to occur more frequently in patients on high cumulative doses, but led to withdrawal of treatment in only two patients.

Psychological, psychiatric

See also Interferons

There have been reports of depression, suicidal ideation, and attempted suicide in patients receiving interferon beta [ , , ]. The lifetime risk of depression in patients with multiple sclerosis is high, and there has been a lively debate about whether interferon beta causes or exacerbates depression in such patients. Impressions of a possibly raised incidence of depression among patients treated with interferon beta for multiple sclerosis should be interpreted in the light of the spontaneous tendency to depressive disorders and suicidal ideation, which is encountered even in patients with untreated multiple sclerosis. Moreover, no raised incidence of these complications has been recorded in some studies [ , ]. A critical review of the methodological limitations in studies that assessed mood disorders in patients on disease-modifying drugs for multiple sclerosis may help explain the widely divergent results from one study to another [ ]. Some results have argued against a specific role of interferon beta in the risk of depressive disorders.

Although isolated reports of psychotic delusional symptoms and depression continue to be published [ ], recent controlled trials or longitudinal studies have not provided evidence of an increase in depression scores or in the rate of depression in patients treated with interferon beta [ ]. In a meta-analysis of seven trials in 1215 patients with relapsing–remitting multiple sclerosis, the incidence of depression was 16% and did not differ between interferon-beta and controls, but the scales used to assess depression were specified in only three trials [ ]. Using a public reimbursement database for multiple sclerosis, the prevalence and incidence of depression and depression scores were not different in 163 patients treated with interferon beta or glatiramer, but the study was poorly controlled for potential biases [ ]. Overall, the current data suggest that interferon-beta is not substantially associated with depression.

A multicenter comparison of 44 and 22 micrograms of interferon beta-1a and placebo in 365 patients showed no significant differences in depression scores between the groups over a 3-year period of follow-up [ ]. In 106 patients with relapsing–remitting multiple sclerosis, depression status was evaluated before and after 12 months of interferon beta-1a treatment [ ]. According to the Beck Depression Inventory II scale, most of the patients had minimum (53%) or mild (32%) depression at baseline, and depression scores were not significantly increased after 1 year of treatment. There were no cases of suicidal ideation. In another study of 42 patients treated with interferon beta-1b, major depression at baseline was found in 21% of patients and was associated with a past history of psychiatric illness in most cases [ ]. Major depression was not considered as an exclusion criterion for interferon beta treatment when patients were on antidepressant therapy. There was a three-fold reduction in the prevalence of depression over the 1-year course of interferon treatment, suggesting a possible beneficial effect of treatment on mood. Finally, a single subcutaneous injection of interferon beta-1b did not alter cognitive performance and mood states in eight healthy volunteers [ ].

The emotional state of 90 patients with relapsing–remitting multiple sclerosis has been carefully assessed with a battery of psychological tests at baseline and after 1 and 2 years of treatment with interferon beta-1b [ ]. In contrast to what was expected, and despite the lack of controls, there was significant improvement in emotional state, as shown by significant reductions in scores of anxiety and depression over time. In addition, there was no effect of low-dose oral glucocorticoids in a subgroup of 46 patients.

Depression has been quantified by telephone interview in 56 patients with relapsing multiple sclerosis 2 weeks before treatment, at the start of treatment, and after 8 weeks of treatment [ ]. Patients with a high depressive score 2 weeks before treatment significantly improved on starting treatment and returned to baseline within 8 weeks, whereas the depression score in non-depressed patients remained essentially unchanged. The investigators therefore suggested that patients’ expectations had temporarily resulted in improvement of depression, and that increased depression during treatment is more likely to reflect pretreatment depression.

The clinical features, management, and prognosis of psychiatric symptoms in patients with chronic hepatitis C have been reviewed using data from 943 patients treated with interferon alfa (85%) or interferon beta (15%) for 24 weeks [ ]. Interferon-induced psychiatric symptoms were identified in 40 patients (4.2%) of those referred for psychiatric examination. They were classified in three groups according to the clinical profile: 13 cases of generalized anxiety disorder (group A), 21 cases of mood disorders with depressive features (group B), and six cases of other psychiatric disorders, including psychotic disorders with delusions/hallucinations (n = 4), mood disorders with manic features (n = 1), and delirium (n = 1) (group C). The time to onset of the symptoms differed significantly between the three groups: 2 weeks in group A, 5 weeks in group B, and 11 weeks in group C. Women were more often affected than men. There was no difference in the incidence or nature of the disorder according to the type of interferon used. Whereas most patients who required psychotropic drugs were able to complete treatment, 10 had to discontinue interferon treatment because of severe psychiatric symptoms, five from group B and five from group C. Twelve patients still required psychiatric treatment for more than 6 months after interferon withdrawal. In addition, residual symptoms (anxiety, insomnia, and mild hypothymia) were still present at the end of the survey in seven patients. Delayed recovery was mostly observed in patients in group C and in patients treated with interferon beta.

One debatable case of visual pseudo-hallucinations occurred only, but not reproducibly, within 30–60 minutes after interferon beta-1a injection in a 37-year-old woman with disseminated encephalomyelitis [ ].