Interferons (Avonex, Rebif and Betaferon or Betaseron) belong to a class of messengers that play a role in regulating the immune system. These are used in the treatment of multiple sclerosis.
Beta-Interferons belong to a class of chemical messengers in the body called eicosanoids and cytokines, which help regulate the function of the immune system (some promote inflammation and some suppress it).
Interferons, which belong to the cytokine class of chemicals, generally have anti-viral actions, affect the immune system, and inhibit tumor growth, but it is not clear 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.
Introduced into clinical practice in the mid-1990s, the interferon-beta medications (Betaferon, Rebif, Avonex, Plegridy, Extavia) were the first of the DMDs used to treat RRMS. Offering a modest relapse rate reduction of around 30 per cent, they are self-injected, ranging in frequency from alternate days to once weekly.
Interferon was first discovered in 1957 and is made by our own cells when exposed to viruses, ‘interfering’ with their replication. Asides from their anti-viral properties the interferons also inhibit the growth of tumours and act on the immune system to reduce levels of inflammation. They are also used to treat hepatitis C, malignant melanoma and granulomatous diseases (e.g. TB)
In MS, the exact mechanism of action of interferons is complex and unclear, but appears to be related to its effect on altering the balance between pro and anti-inflammatory immune system messengers (cytokines), as well preventing white cells from crossing the blood-brain barrier and damaging myelin. It may also be due to an effect on the cells that regulate the immune response (T-reg cells), and by destroying those T cells that are primed to attack the body (auto-reactive T cells).
The side-effects of interferons are common and can have a marked detrimental effect on quality of life. Most people develop flu-like symptoms on the day of injection, with fever, chills, muscle pain, nausea and perhaps vomiting and diarrhoea. The majority of people become more tolerant of this over time, but more serious side-effects such as liver and thyroid disease, (hence the need for regular blood monitoring) as well as depression are also well documented. Around one third of patients develop hair loss, and injection site reactions are not uncommon. Pancreatitis is a rare but very serious potential side-effect.
The original studies into interferons were not designed to assess their long-term effectiveness, and their side effect profile has limited this research, as patients often know they are being given the active drug rather a placebo, therefore introducing bias to both patients and doctors. Those that remained in the studies then often knew they were getting the active drug, leading to the very real possibility that the placebo effect was responsible for part, or even all, of the beneficial effects.
Drop-out rates as high as 28% have been quoted within five years of starting treatment, and the initial follow-up trials at 2 and 5 years concluded that interferons had little or no effect on disability progression.
In 2018 however, long-term data demonstrated for the first time that those people taking interferons for 10 years gained on average an extra 4 years before requiring the regular use of a cane (EDSS 6.0). Much of the benefit appeared to be derived from the first two years of treatment, which then gradually plateaued and was sustained.
A large number of randomized controlled trials (RCTs) have studied the effects of interferon therapy on MS.
The first large-scale study was by the IFNB Multiple Sclerosis Study Group, published in Neurology in 1993.In this study of 32 patients in 11 centers, patients were randomly assigned to receive a placebo or one of two dosage levels via subcutaneous injection every other day for 2-3 years. The relapse rates were:
The severity of relapses was also significantly reduced.
Two years later, the same investigators presented follow-up findings on these patients, which extended the study’s period to up to five years. Interferon continued to reduce the relapse rate, by about a third in the high-dose group. MRI evidence supported this: untreated patients developed many newer lesions, while treated patients did not. However, only five patients completed the full five years of the study. Importantly, the 5-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 not often mentioned in discussions about drug studies, but there is every reason to suspect that the placebo response will be high in MS. In addition, the natural history of the disease is that the number of annual relapses falls over time, which makes it hard to assess whether a drug is making a difference.
In this study, taking data directly from the reported results, from the end of the first year to the fifth year, 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, ‘This phenomenon diminishes the statistical power to demonstrate a significant treatment effect in the later years of this and other relapse-prevention trials.’
One could also argue that the placebo had a greater effect after the first year of study than the drug did.
Despite the apparent reduction in relapses and MRI evidence showing 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 2-year or the 5-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. It concluded that licensing it was a very ‘high risk strategy, ‘noting, ‘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 difficulty in interpreting the findings of these studies has been that, despite clear evidence of a decrease in relapses, the effects on the progression of general disability have been disappointing.
Only one trial showed an effect on progression to disability: The European interferon B-1b trial, which focused on secondary progressive MS rather than relapsing-remitting MS. The delay in progression achieved with three years of interferon treatment was around 9 to 12 months, and the percentage of patients who became wheelchair-bound dropped from 25% for the placebo group to 17% for the interferon group.
A large number of treated patients developed neutralizing antibodies (NABs) against the interferons, which dramatically reduced the treatment’s effectiveness. A 2003 study from the National Neurology Hospital in London reported that, of 101 patients taking interferons over a 26-month period, 38% of Rebif-treated patients and 44% of Betaferon-treated patients developed neutralizing antibodies. None of the Avonex-treated patients did.
The downside for patients taking Avonex in this study was that none 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 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 4-year Swiss study showed that neutralizing antibodies to Avonex also reduced the effectiveness of therapy, while another Swiss study conducted over 2 years showed that neutralizing antibodies during Rebif therapy were common and reduced treatment effectiveness.
Italian researchers concluded that the development of neutralizing antibodies significantly influenced the effectiveness of interferon beta. A 2007 Expert Panel report concluded that ‘neutralizing 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.’ 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 indicates regular blood testing to detect any abnormalities caused by the drug. Because the studies have lasted a maximum of five years, we don’t know how long these benefits will be sustained.
Finally, the benefit is relatively small
Adverse reactions include injection site reactions, flu-like symptoms, central nervous system (CNS) disturbances (including depression and suicidal ideation), leucopenia (low white cell count), elevated liver enzymes and severe hypersensitivity reactions.
Most patients do not experience most of these effects, but flu-like illness and headache are very common. Most people 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 diarrhea. These effects can be minimized to some extent with other drugs, but most people resist taking another drug to offset the first drug’s side effects. Of course, these secondary drugs, such as ibuprofen, have their own side effects.
Most people gradually become tolerant of the flu-like side effects. The other side effects referred to above are more serious, as is the fact that 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.
Little is written about hair loss on these drugs. More than a third of patients had hair loss in the studies in which this was reported. In one study, more than half the patients experienced hair loss in the first six months of treatment. Importantly, few interferon studies have reported the side effects of these drugs after two years, so we have little knowledge about long-term side effects.
One of the few to do so was a large Canadian study that followed 844 patients on all the interferons over a 6-year period in British Columbia. More than a third (36.9%) of patients on the interferons in this study developed liver disease, as measured by elevations in liver enzymes. This was considerably higher than the rate reported in the agents’ clinical trials.
Several other reported side effects are potentially very serious, including thyroid disease, which is very common in people taking interferons. In one large long-term follow-up study, 24% of patients taking interferons for MS developed thyroid dysfunction (mostly under-activity of the thyroid), and 23% developed thyroid autoimmunity. 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.
Other serious potential side effects are pancreatitis, skin problems and peripheral neuropathy – which can produce neurological effects that resemble those of MS. Interferon’s side effects seem to be more common in people who are younger and also those who are smaller.
Women with MS who are trying to get pregnant should stop taking interferons. One large study showed very significant increases in stillbirths and low-birth-weight babies among women taking interferons. There were also significant fetal malformations.
Other serious concerns have been raised about the potential for cancer in long-term users of interferons. Although not statistically significant, one study showed a trend toward more cancers in people with MS who were on interferons.
One major concern with the methodology of all the interferon studies is that, because the interferons’ side effects are so prominent, patients receiving interferon often guess correctly that they are taking the active drug rather than the placebo. This is of concern in studies that are supposedly blinded, because neither participants nor their doctors should know whether they are getting the active drug or placebo.
The placebo effect describes the benefit patients get when they expect to improve because they think they are receiving an active treatment. This effect can be quite significant, as it has been in a number of clinical trials in MS, including the original interferon B trial. The placebo effect may result in substantial improvements in the course of a disease, and when a study is effectively ‘unblinded’ because people know they are getting the active drug, it raises the possibility that beneficial effects seen in the study are 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 result from patients’ expectations of improvement. If patients know they are getting the active treatment, that information is likely to be transmitted to the treating doctors, thus introducing bias to their assessments.
In the IFNB 5-year study for example, 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 dropout rate: 20% of those in the high-dose group quit or became unavailable for follow-up and subsequent analysis. When the drop-out rate is so high, it’s very possible that the patients who continued to deteriorate despite treatment just gave up and left the study. That attrition would make the treatment look more effective than it really was, because only those who did well remained available for final analysis.
This was in fact the only interferon study to report what happened to patients who dropped out. They had a higher relapse rate, their disease was more active, and they became more disabled than those who’d remained in the study. An Italian group of neuroepidemiologists led by Filippini formally reviewed all the interferon studies to assess their adequacy. 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 most common problem with the studies was the high rate of patient drop-outs, because only three-quarters of those who enrolled in the studies reviewed by this group were available for final analysis. They also found that evidence that the interferons delayed or prevented disease progression was inconclusive. This is supported by more recent evidence that looks at the experience of 1,173 patients in Italy with the 3 common formulations of interferon:Betaferon, Rebif and Avonex.
These researchers showed that at 4 years, despite declining relapse rates, there was still on average a significant increase in disability. They showed that approximately 1 in 5 patients on Betaferon pulled out of therapy because of side effects; that’s roughly 3 times as many dropouts as seen in other drug studies. Filippini and his colleagues concluded in their formal review of the interferon studies that side effects were common and 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 the fact that all the trials on its use have been short-term. They argue that extrapolating long-term effectiveness of a therapy from short-term studies is an untested approach.
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 they 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. 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 to 10 year) trials, patients and their doctors deserve an explanation….’
1. All the studies have been sponsored by drug companies, which reduces our confidence in their conclusions
2. The studies have methodological problems, particularly related to blinding and drop-outs
3. The benefit interferons provide is small, and it may not significantly prevent the progression of disability
4. Most importantly, side effects are common and can negatively affect your quality of life
