Multiple Sclerosis (MS) is a

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1 The role of interferon beta in multiple sclerosis management David J Rog MRCP, John P Mottershead MRCP, Greater Manchester Neurosciences Centre, Hope Hospital, Stott Lane, Manchester, M6 8HD SPL Multiple Sclerosis (MS) is a multi-focal disease of the central nervous system (CNS), characterised by inflammation, demyelination and axonal degeneration. It is the leading cause of disability in young adults in the UK, affecting about people. MS is estimated to cost the UK economy 1.2 billion a year, including 150 million at a direct cost to the NHS. 1 The initiating event for the first attack of MS is unknown, although polygenetic susceptibility and environmental factors both play a role. 2 It is thought that systemic T-lymphocytes become auto-reactive, migrating to, and penetrating, the blood/brain barrier through the interplay of chemokines, adhesion molecules and metalloproteinases. Once inside the blood/brain barrier, the T-lymphocytes interact with antigen-presenting cells, macrophages and B-lymphocytes, resulting in inflammation and tissue damage. A diagnosis of MS requires evidence of dissemination of CNS lesions in both time and space, and the exclusion of other possible conditions. Differential diagnoses include: sarcoidosis, systemic lupus erythematosis and spinocerebellar ataxia. Although traditional diagnostic criteria required two clinical episodes before a diagnosis of MS can be made, the recently revised McDonald criteria 3,4 allow dissemination to be confirmed by Magnetic resonance image (MRI) of the brain of a woman suffering from multiple sclerosis. Demyelinating lesions, due to the destruction of the myelin sheath around the axons of nerve cells, appear as the bright circular regions towards the centre of the brain. Magnetic Resonance Imaging (MRI) in the presence of only one clinical episode (see Table 1). DISEASE MANAGEMENT Cerebrospinal fluid electrophoresis demonstrates oligoclonal IgG bands in over 90 per cent of cases. Visual evoked potentials with a characteristic delay in impulse latency (in the context of a preserved amplitude) can be used as circumstantial evidence for demyelination in diagnostically challenging situations, for example in primary progressive MS. Management of MS has, until the mid-1990s, been limited to the treatment of relapses (largely with corticosteroids) and of some symptoms, such as bladder and bowel dysfunction, spasticity, pain and sensory phenomena (see Table 2), with varying degrees of success. Symptoms from a relapse typically last two to six weeks and remit, sometimes completely. Half of relapses, however, cause long-lasting deficits. Resolved symptoms can reappear transiently with rises in body temperature, for example at the time of an intercurrent infection. Eighty per cent of patients, especially young women, experience a relapsing-remitting (RRMS) FUTURE PRESCRIBER VOL 7(3) 15

2 course at disease onset, subject to well-defined relapses in neurological function with partial or complete recovery. The initial relapse rate of about one per year decreases over time, but, after around 10 years, half of RRMS patients have entered the secondary progressive phase. Secondary progressive MS (SPMS) results in accumulating neurological deficit, associated with oligodendroglial and neuronal cell loss. Primary progressive MS (PPMS) affects only around 10 per cent of patients, and typically has an older age of onset. PPMS is characterised by progression from onset and most patients do not experience relapses. Sustained disability in all types of MS mainly occurs in the progressive phase of the illness. Long-term natural history studies of people with MS have demonstrated that after 15 years about half of patients require at least a stick to walk 100 yards. 5 Life expectancy from disease onset, however, is at least 25 years and the majority of patients die from unrelated causes. The Expanded Disability Status Scale (EDSS) 6 is the most commonly used disability scale in MS. It is an ordinal non-linear scale and is based upon neurological examination and/or an estimation of walking ability. Although often criticised, it was used in the pivotal (IFN-ß) trials and Clinical presentation Two or more attacks; objective clinical evidence of 2 or more lesions Additional Data Needed for MS Diagnosis None a Two or more attacks; objective clinical evidence of 1 lesion Disseminated in space, demonstrated by MRI b, or Two or more MRI-related lesions consistent with MS plus positive CSF c, or Await further clinical attack implicating a different site One attack; objective clinical evidence of 2 or more lesions Dissemination in time, demonstrated by MRI e, or second clinical attack One attack; objective clinical evidence of 1 lesion (mono-symptomatic presentation; clinically isolated syndrome) Dissemination in time, demonstrated by MRI e, or Two or more MRI-detected lesions consistent with MS plus positive CSFc and dissemination in time, demonstrated by MRI, or second clinical attack Insidious neurological progression suggestive of MS One year disease progression (retrospectively or prospectively determined) and two of the following: a. Positive Brain MRI (nine T2 lesions or four or more T2 lesions with positive VEP d ), b. Positive spinal cord MRI (two focal T2 lesions), c. Positive CSF c If criteria indicted are fulfilled, the diagnosis is multiple sclerosis (MS); if the criteria are not completely met, the diagnosis is possible MS ; if the criteria are fully explored and not met, the diagnosis is not MS. a No additional tests are required; however, if tests (magnetic resonsance imaging [MRI], cerebral spinal fluid (CSF)) are undertaken and are negative, extreme caution should be taken before making a diagnosis of MS. Alternative diagnoses must be considered. There must be no better explanation for the clinical picture. b MRI demonstration of space dissemination must fulfill the criteria derived from Barkhof et al and Tintore et al c Positive CSF determined by oligoclonal bands detected by established methods (preferably isoelectric focusing) different from any such bands in serum or by a raised IgG index d Abnormal visual evoked potential of the type seen in MS (delay with a well-preserved wave form) e There are two ways to show dissemination in time: a. Detection of gadolinium enhancement at least 3 months after the onset of initial event. b. Detection of a new T2 lesion if it appears at any time compared with a reference scan at least 30 days after the onset of thew initial clinical event Adapted from Polman C, et al. Ann Neurol 2005;58: Table 1. McDonald diagnostic criteria for multiple sclerosis 4 16 FUTURE PRESCRIBER VOL 7(3)

3 The protean symptoms of MS reflect damage to the brain and spinal cord and include: fatigue sensory symptoms including pain, sensory loss and parasthesiae motor symptoms including weakness, tremor and ataxia bladder, bowel and sexual dysfunction brainstem syndromes, especially affecting eye movement optic nerve dysfunction cognitive problems Table 2. The protean symptoms of MS is the primary outcome measure in the Risk Sharing Scheme that is discussed later. An estimate of EDSS grading is shown in Table 3. PHARMACOLOGY AND MODE OF ACTION Interferons form part of the group of intracellular messengers known as cytokines, and they possess antiviral, antiproliferative, anti-tumour and immunomodulatory properties. 7 is induced by cytokines such as interleukin-1 and -2 and tumour necrosis factor released by activated T-cells, macrophages, and by some viruses. Studies of IFN-ß in MS began in the late 1970s, and three formulations have since been licensed for treatment of MS in the UK. IFN-ß- 1a (Avonex and Rebif), which have identical sequences to human IFN-ß, and IFN-ß-1b (Betaferon), which differs from human IFN-ß by being nonglycosylated and having one amino acid substitution (see Table 4). The pivotal randomised, placebo-controlled trials of Avonex, 8 Betaferon 9 and Rebif 10 in RRMS: included between 301 and 560 patients initially lasted two years, but were extended demonstrated annual relapse rate reductions over placebo of per cent (placebo group rates ranged from 0 9 to 1 2, and IFN-ß treated patients from 0 61 to 0 78 relapses per year). The reduction in relapse rate and also a reduction in MRI lesions are robust and were demonstrated in all the pivotal trials of IFN-ß. However, the effect of IFN-ß on accumulation of disability remains unclear. Some of the trials do appear to show a modest effect of IFN-ß on disability progression, but some of this may be due to left-over effects of relapses being more common in the placebo group. Longer-term trials would be required to examine whether IFN-ß reduces, or delays, the onset of SPMS. A Cochrane review concluded that if the disability of all patients who were lost to follow-up worsened (a worst-case scenario) any significant effects of IFN-ß on disability would be lost. 11 SECONDARY PROGRESSIVE MS Studies of Betaferon in SPMS have yielded conflicting results. The European study was stopped early, on the recommendation of the independent advisory board, after its 718 patients had received at least 24 months of treatment, because a significant effect on disability was seen. The study found it was taking 9 12 months longer for treated patients to reach a sustained increase in disability (by one EDSS point) compared with controls. 12 However, a larger trial in the USA, of 939 patients with SPMS treated with Betaferon, showed no benefit on disability. 13 These patients had a longer duration of MS, and fewer relapses in the two years before the study and during the trial, than the European cohort. A three year study using Rebif, whose patients again had longer disease duration, fewer relapses and were older than the European Betaferon cohort, also failed to demonstrate an effect on disability progression. 14 These results imply that any effect of IFN-ß on disability in the European study may have been due to an effect on relapses rather than disease progression. Although IFN-ß may have delayed cerebral atrophy (thought to be an MRI marker of disability progression) in one study, 15 another suggested similar rates of cerebral atrophy in IFN-ß and placebo groups. 16 RISK SHARING SCHEME In 2002, the National Institute for Health and Clinical Excellence (NICE) concluded that IFN-ß was not a cost-effective treatment for MS and, therefore, could not be recommended. 17 As a result a Risk Sharing Scheme came into being, to provide IFN-ß more cost-effectively, and to monitor the clinical benefits for patients receiving IFN-ß treatment over a period of 10 years. 18 The Risk Sharing Scheme also examines the effects of glatiramer acetate (Copaxone) in a similar way. The eligibility criteria match those of the Association of British Neurologists: 19 adult patients with two or more significant relapses in the previous two years; for RRMS, patients are able to walk 100 yards without aid or rest; and for SPMS, patients are able to walk at least 10 metres with any aid. It is estimated between 7500 and 9000 or 15 per cent of patients with MS in the UK will be eligible, with an annual cost to the NHS of around Minimally disabled, unlimited walking ability Moderate disability walks unaided between 100m and 500m Requires unilateral or bilateral assistance to walk Wheelchair bound with increasing upper limb disability and reliance on others for activities of daily living Table 3. Expanded Disability Status Scale (simplified) FUTURE PRESCRIBER VOL 7(3) 17

4 Product Dose Frequency and route of Initial annual (Manufacturer) administration cost per patient to Risk Sharing Scheme 7 Avonex (Biogen Idec) 30µg Once weekly intramuscularly 8502 Betaferon (Schering) 250µg Alternate days subcutaneously 7259 Rebif (Serono) 22µg or 44µg thrice weekly subcutaneously 7513 or 8942 Table 4. Characteristics of IFN-ß preparations available in the UK million. 18 However, if outcomes for any individual product fall short of those expected, payments from that point will be reduced on a sliding scale (to be agreed in advance) sufficient to restore the average cost per quality adjusted life year (QALY) to an acceptable level of cost-effectiveness for the remaining period of the scheme around per QALY. The Risk Sharing Scheme has been criticised for methodological issues such as lack of blinding, comparison with a historical Canadian control group, lack of clarity in determining the power of the study and planned follow-up of dropouts, and concentration on expensive treatments to the detriment of other (cheaper) therapies. 20 CLINICALLY ISOLATED SYNDROMES Clinically isolated syndromes (CIS) include optic neuritis, transverse myelitis and brainstem lesions. When they occur in the presence of two or more asymptomatic MRI lesions, on T2-weighted scans, there is nearly a 90 per cent chance of developing clinically definite MS, ie a second clinical episode, within 10 years. 21 Three studies have examined the effect of IFN-ß treatment on patients after one CIS: CHAMPS (Avonex 30µg, weekly); 22 ETOMS (Rebif 22µg, once-weekly, an unusually low dose), 23 and BENE- FIT (Betaferon 250µg, alternate days), currently only published in abstract form (see Table 5). 24 Despite treatment about a third of patients still convert to clinically defined MS (CDMS) within two years. The CHAMPIONS study followed up patients from the CHAMPS study for up to five years, who received Avonex either immediately or after a delay of two years (at the end of the blinded study). Over the follow-up period, there was a 35 per cent reduction in conversion to CDMS in patients treated immediately (unadjusted Study and Product and dose Period or Percentage of patients p-value number of randomised study developing clinically patients definite MS (2nd clinical episode) Active Placebo CHAMPS Avonex 30µg once weekly 3 years 35% 50% p=0.002 (383) ETOMS Rebif 22µg once weekly 2 years 34% 45% p=0.047 (308) BENEFIT Betaferon 250µg alternate 3 years 28% 45% p< (468) days Table 5. Summary of IFN-ß in clinically isolated syndromes hazard ratio 0.65, 95% CI: , p=0.03), and the authors state that few patients developed major disability within five years (87 per cent with EDSS 2.5). 25 CHAMPS also demonstrated relative reductions in new, enlarging or gadolinium-enhancing lesions and volume of brain lesions at 18 months and this effect was apparent as early as six months into treatment. Similarly, ETOMS demonstrated significant reductions in MRI activity (p<0.001) and BENEFIT showed a significant reduction in the number of newly active (p<0.0001) and gadolinium enhancing lesions at 12 and 24 months (p<0.0001), in the treated groups. 26 LONG-TERM BENEFITS OF IFN-ß There are no long-term, prospective, placebo-controlled studies of IFN-ß in MS. However, the London Ontario cohort from the pivotal Betaferon trial in RRMS has 16 years of follow-up data on more than 80 per cent of the 372 patients originally recruited, and has been published in abstract form. 27 The preliminary results are suggestive of a worse outcome in the original placebo group (most patients in the placebo group were eventually treated with Betaferon). For example, 63 per cent of patients who were randomised to Betaferon 250µg on alternate days were ambulant compared with 55 per cent of patients who initially received placebo (full statistical analysis is not yet published). NEUTRALISING ANTIBODIES TO IFN-ß The injection of proteins with biological activity such as erythropoietin, insulin and interferons is known to be associated with the development of neutralising 18 FUTURE PRESCRIBER VOL 7(3)

5 antibodies (NAbs) in a proportion of patients. These NAbs have the potential to abrogate the positive effects of the treatment in question. In several clinical trials of IFN-ß in MS, NAB positive patients had significantly higher relapse rates than NAB negative patients. 9,14,28 Recent European Federation of Neurology guidelines recommend that patients treated with IFN-ß should be regularly tested for the development of NAbs. 29 It is considered unlikely that patients with consistently high NAB levels will continue to benefit from treatment with IFN-ß and the guidelines therefore recommend stopping treatment in these patients. NAbs develop most frequently in patients treated with Betaferon (23 42 per cent), least frequently in patients treated with Avonex ( per cent) and at an intermediate rate in patients treated with Rebif (13 24 per cent). 29 The optimal method of managing patients with NAbs remains controversial. CONCLUSION IFN-ß has been shown to reduce relapse rates by approximately 30 per cent in patients with RRMS, and also to reduce the development of new lesions on MRI. It has also been shown to delay the conversion to MS in patients presenting with clinically isolated syndromes. To date, however, there have been no positive studies of therapeutic agents in PPMS, and IFN-ß is probably largely ineffective in patients with SPMS. The data on patients with long-term disability are less convincing, but the UK Department of Health Risk Sharing Scheme has been designed to investigate the long-term effects of IFN-ß treatment. REFERENCES 1. Homes J, Madgwick T, Bates D. The cost of multiple sclerosis. Br J Med Econ 1995;18: Compston A, Coles A. Multiple Sclerosis. Lancet 2002;359(9313): McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. 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