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Interferons

The interferons and glatiramer acetate are collectively described as ‘disease-modifying agents’. Their action is such that they are intended to modify the course of the disease rather than make a difference to current symptoms. Interferons belong to a class of chemical messengers in the body. The messenger chemicals called eicosanoids and cytokines have a role in regulating the function of the immune system. Some of these messengers promote inflammation and some suppress it. Interferons belong to the cytokine class of chemicals. The interferons in general have anti-viral actions, effects on the immune system, and inhibit the growth of tumours. It is not certain which action is responsible for their therapeutic effect in MS. The interferons have also been used in treating hepatitis C, malignant melanoma and granulomatous disease. In these diseases, there is usually considerable discussion with the patient before embarking on treatment with interferons because of the serious side effects they can cause.

The Interferon Trials

There has now been a large number of randomized controlled trials studying the effects on MS of interferon therapy. Most of the work has been on interferon beta-1b (IFN-b1b) and interferon beta-1a (IFN-b1a), although interferon alpha-2a (IFN-a2a) has also been studied. It is worth going over the most important of these trials in a little detail to get a sound understanding of the pros and cons of this form of treatment for MS.

The first large-scale study was by the IFNB Multiple Sclerosis Study Group, published in Neurology in 1993.1 This was a study of 372 patients in eleven centres. Patients were randomly assigned to receive placebo (inactive injection), IFN-b1b 1.6 million units, or IFN-b1b 8 million units, given by sub-cutaneous injection every second day for 2-3 years. The relapse rate for the placebo (untreated) group was quite high at 1.27 relapses per year. With the lower dose of interferon, the relapse rate was reduced about 8 per cent to 1.17 relapses a year, and with the bigger dose, was reduced by about 34 per cent to 0.84 relapses a year. Because the number of patients in the study was quite large, the differences were significant, with p values of 0.01 and 0.009 respectively, so the differences were unlikely to have occurred by chance. The severity of relapses was also shown to be reduced significantly.

Two years later, the same investigators presented further follow-up of these patients.2 Patients were now studied for up to five years. Interferon continued to reduce the relapse rate, by about a third in the higher dose group, and the MRI evidence supported this, with untreated patients developing many more new lesions. In contrast, treated patients did not suffer significantly more lesions. However, differences were not significant at the p<.05 level after the second year, and only five patients completed the five years of the study. Importantly, the five year study failed to show any significant decrease in progression of disability.

One of the difficulties in this trial was the size of the placebo response. This is something that is not often mentioned in discussions about the interferon or other drug studies, but there is every reason to suspect that the placebo response will be quite large in MS. In addition, the natural history of the disease is that the number of annual relapses falls over time. This makes it hard to assess whether a drug is making any difference to what would have normally happened. In this study, taking data directly from the reported results, from the end of the first year to the fifth year in the study, the placebo group went from an annual relapse rate of 1.44 to 0.81, a 44% reduction. The high dose interferon group went from 0.96 in the first year to 0.57 in the fifth, a 41% reduction. The authors responded to this by stating that ‘This phenomenon diminishes the statistical power to demonstrate a significant treatment effect in the later years of this and other relapse-prevention trials’. There are other interpretations of this data. One could argue that placebo had a greater effect after the first year of study than the drug.

Despite the apparent reduction in number of relapses overall in the treated groups, and MRI evidence that there were significantly fewer new MS lesions, the investigators were unable to detect any difference in the progression of disability between the treated and untreated groups in either the two year or the five year study. An editorial on both studies in the prestigious British Medical Journal in 1996 commented on the fact that the drug had been hurriedly licensed for use in the UK on the basis of these studies.3 It concluded that its licensing was a very ‘high risk strategy’ and ‘We remain in total ignorance of the long term benefits and side effects of interferon beta in patients with multiple sclerosis’.

These findings have largely been reproduced in subsequent interferon studies, with minor differences. One of the difficulties in interpreting the findings of these studies has been that, although there is clear evidence of a decrease in relapse rate, the effects on the progression of disability in general have been disappointing. Only one trial, the European interferon B-1b trial, this trial being in secondary progressive MS rather than relapsing-remitting MS, showed an effect on progression to disability.4 The delay in progression achieved with three years of interferon treatment was of the order of 9-12 months, with a drop in the percentage of patients becoming wheelchair bound from 25 per cent for the placebo group to 17 per cent for the interferon group.

A large number of treated patients developed antibodies against the interferons (neutralising antibodies or NABs) which reduced the effectiveness of the treatment, mostly making it equivalent to no treatment at all. A study of 101 patients taking interferons from the National Neurology Hospital in London published in 2003 reported that over a 26 month period, 38% of Rebif treated patients, and 44% of Betaferon treated patients developed neutralising antibodies.5 None of the Avonex treated patients did. The down side however for patients taking Avonex in this study was that none of them remained relapse-free for the period of study, whereas 19% of the Betaferon treated patients did, along with 27% of the Rebif treated patients. Overall the authors were disappointed to report that nearly half of the patients treated with interferons had continuing evidence of disease activity, either with disabling relapses or insidious progression of the illness, over the relatively short period of study.

More recently, a Swiss study over four years showed that neutralizing antibodies to Avonex also reduced the effectiveness of therapy6, and another Swiss study over two years also showed that neutralizing antibodies during Rebif thearpy were common and reduced treatment effectiveness.7 Italian researchers concluded that the development of neutralising antibodies significantly influenced the effectiveness of interferon beta.8 A 2007 Expert Panel report concluded that ‘neutralising antibody testing is a critical component of care for MS patients because it provides information on one of the most important factors determining clinical responsiveness to IFNbeta therapy’.9 People taking interferons should ask their neurologist about this.

In all the interferon studies, many patients have had side-effects, and subsequently pulled out of treatment. This means regular blood testing to detect any abnormalities caused by the drug. Because the studies have gone for up to five years at a maximum, we don’t know how long these benefits will be sustained. Finally the benefit is relatively small.
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Side-effects of Interferon Therapy

Adverse reactions include injection site reactions, flu-like symptoms, CNS disturbances including depression and suicidal ideation, leucopenia (low white cell count), elevated liver enzymes and severe hypersensitivity reactions. Most patients do not get most of these effects. Flu-like illness, however, is very, very common. So is headache.10 Most people find that they feel ill on the day of injection, with an acute flu-like syndrome consisting of fever, chills, headache, muscle pains, joint pains, nausea, and perhaps vomiting and diarrhoea. These effects can be to some extent minimised with other drugs again. However, most people are loath to take another drug to offset the side-effects of the first drug. These drugs, such as ibuprofen, of course have their own side-effects.

Most people find that they gradually become tolerant of the flu-like side-effects. Rather more serious are the other side-effects referred to above, and the fact the interferon can impair fertility, and should not be used during pregnancy. Much has been written about the potential for increased risk of depression with the interferons. This is particularly important given how common depression is in MS, and how it can worsen the physical disease. Depression is a well known side effect of interferon alpha treatment; its occurrence with the interferon betas used in MS is less well established, but the risk appears real.11

One side effect about which little is written is loss of hair. Over a third of patients had hair loss in the studies in which this was reported.12,13 Indeed in one of the studies, over half the patients had this distressing symptom in the first six months of treatment. Importantly few of the interferon studies have reported the side effects of these drugs after two years, so we have little knowledge about the long term side effects of taking these drugs.

One of the few to do so was a large Canadian study.14 This followed up 844 patients on all the interferons over six years in British Columbia. They found that over a third (36.9%) of patients on the interferons developed liver disease as measured by elevations in liver enzymes. This was a considerably higher rate than reported in the clinical trials of the agents.

Several other side-effects have been reported and are potentially very serious. Thyroid disease is very common in people taking the interferons. In one large long term follow up study, 24% of patients taking the interferons for MS developed thyroid dysfunction, mostly under-activity of the thyroid, and 23% developed thyroid autoimmunity.15 Most (two thirds) developed this within the first year of treatment. So patients on the interferons should have their thyroid function monitored closely while on therapy, particularly in the first year.16 Other serious potential side-effects are pancreatitis17, skin problems18 and peripheral neuropathy which can produce neurological effects difficult to distinguish from MS.19 It seems that the side-effects of interferon are more common in younger patients and those with smaller body size.

Interferons should be stopped by women with MS who are taking them if they try to get pregnant. One large study showed very significant increases in the rate of stillbirths and low birth weight babies to women taking interferons.20 There were also significant fetal malformations. Other serious concerns have been raised about the potential for the occurrence of cancers in long term users of interferons. Although not statistically significant, one study showed a trend to more cancers in people with MS who were on interferons.21
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Concerns About the Interferon Studies

One major concern with the methodology of all the interferon studies is that, because the side effects of the interferons are so prominent, many, if not most patients receiving interferon as opposed to inactive placebo guess correctly that they are taking the active drug. This is of concern in studies which are supposed to be blinded, that is the participants are not meant to know whether they are getting the active drug or placebo, nor are their doctors.

The placebo effect in general is the term applied to the benefit that patients get when they expect to get better knowing they are receiving an active treatment. This effect can often be quite large, as it has been in a number of clinical trials in MS including the original interferon B trial.1 The placebo effect may result in substantial improvements in the course of a disease, and when a study is effectively ‘unblinded’ because people know that they are getting the active drug, it raises the distinct possibility that the beneficial effects seen in the study may be partly or even completely due to the placebo effect. That is, the drug itself may not be particularly effective in treating the disease at all, and the benefits are being caused by patients expecting to get better. If patients know they are getting the active treatment, it is also very likely that this information will be transmitted to the treating doctors, introducing bias into their assessments.

In the IFNB five year study for example2, 80% of patients in the high dose interferon group correctly guessed their treatment. This seriously weakens the conclusion that interferon was effective in that study, as the placebo effect may have played a major role in producing this apparent benefit. Another major weakness of the study was the high rate of patient drop out, with 20% of those in the high dose group opting to drop out of the study, or be unavailable for follow up and subsequent analysis. A real possibility when the drop out rate is so high is that the patients who continued to deteriorate despite treatment gave up and left the study. This would have the effect of artificially making the treatment look better than it really was by leaving those who did well in the study and available for final analysis.

This was in fact the only one of the interferon studies to report what happened to patients who dropped out. They had a higher relapse rate, more active disease, and became more disabled than those who remained in the study. An Italian group of neuroepidemiologists led by Filippini formally reviewed all the interferon studies to assess their adequacy.22 They found that the evidence from the studies was not strong enough to draw any conclusions about the benefit of interferons beyond the first year of treatment, and that even in the first year, the interferons could only be said to slightly reduce the number of patients who had relapses.

They noted that the commonest problem with the studies was the high rate of patient drop out, leaving only three quarters of those patients enrolled in the studies they reviewed available for final analysis. They also found that the evidence that the interferons delayed or prevented disease progression was inconclusive. This is supported by more recent evidence looking at the experience of 1 173 patients in Italy with the three common formulations of interferon, Betaferon, Rebif and Avonex.23 These researchers showed that at 4 years, despite falls in relapse rates, there was still on average a significant increase in disability. They showed that approximately one in five of the patients on Betaferon pulled out of therapy because of side effects, that being approximately three times the number of patients pulling out who were on the other drugs. Filippini and his colleagues concluded in their formal review of the interferon studies that side effects were common and that these side effects had a negative effect on the patients’ quality of life.

A number of neurologists are becoming concerned about what they call the uncritical acceptance of interferons as long term therapy for MS despite all the trials on its use being short term.24 They argue that essentially this is an untested approach, extrapolating long term effectiveness of a therapy from short term studies. They also argue that there is no convincing evidence that the interferons prevent disease progression, or positively affect common problems such as fatigue, pain, depression and cognitive impairment. These problems are often the most significant determinants of quality of life for people with MS, and often determine whether people with MS can continue to work.

Concerns about the long term use of interferons have led to a powerful statement by French neurologists.25 In response to Filipinni’s work suggesting there was little evidence that they were effective longer than one year, Clanet and Cucheratt stated: ‘If neurologists agree that these compounds have a moderate effect, but that the effect needs to be confirmed in long-term (5-10 year) trials, patients and their doctors deserve an explanation…’
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Overview

Interferon has been hailed as exciting new therapy, and it has been said that MS is now a treatable disease. This is only partly true. The studies are all drug company-sponsored, reducing our confidence in their conclusions, and have methodological problems particularly related to blinding and drop outs. More importantly, the benefit is small, and it may not prevent the progression of disability significantly. Most importantly, side-effects are common and can be severe.
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  1. The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing-remitting multiple sclerosis. 1. Clinical results of a multicenter, randomized, double-blind, placebo-controlled trial. Neurology 1993; 43:655-661
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