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NNTs for multiple sclerosis

Bandolier has been asked on more than one occasion to visit the difficult area of beta-interferon treatment for multiple sclerosis (MS). It is a hard subject - because the disease is itself awful, treatments have limited efficacy, and cost-benefit calculations are riven with hard decisions. But more evidence is emerging, and so, with much trepidation, it seemed that perhaps the time had come to see if NNTs could be calculated for clinical outcomes understandable to most of us.

One of the difficult issues is that of clinical outcomes versus surrogate markers from brain imaging. Frequent MRI scanning of the brains of patients with MS provides a dynamic picture of the disease process. Areas with increased water content seen on the T2-weighted images, known to some as "unidentified bright objects", appear in the cortical matter with surprising frequency. They enlarge, shrink, and often disappear at intervals of two to eight weeks. Most, possibly over 80% of them, are silent, in that they have no link to episodes of appreciable neurological deficit.

When biopsied, these lesions show inflammatory responses with invading T-cells and activated macrophages. Demyelination of nerves may be subtle, or frank, and repair processes are often seen. Plaques in brain tissue of people with evolved MS seen at post mortem show almost complete demyelination and an absence of inflammatory processes [1].

Many MS lesions are reversible and asymptomatic, but as one attack follows another repair mechanisms may fail and areas of permanent damage (plaques) enlarge or coalesce. Irreversible difficulties with gait, coordination, vision, and bladder and bowel control accumulate. Areas of demyelination, and of axonal loss, interrupt impulse conduction along nerve tracts. If the optic nerve is involved, vision will be compromised. If pyramidal tracts are involved, spasticity and weakness will follow, possibly leading to an inability to walk. If cerebellar pathways are involved, there may be loss of coordination. If sensory pathways are involved, there may be dysaesthesia or frank loss of sensation. If the pathways controlling bladder and bowel function are involved, there may be urinary and faecal incontinence.


Interferon-ß interferes with the local inflammatory processes. It may impede those processes involved with initiating or propagating the immune response, or enhance those which end an episode. This is an area of immense complexity, and the important point is that interferon-ß1b can be shown to have pharmacological properties which should be beneficial in MS. The question is whether these benefits transfer from the laboratory to the clinic.

Secondary progressive MS

This study [2] involved 718 patients who had clinically or laboratory-supported definite MS in the secondary progressive phase, with two relapses or a 1-point deterioration in the Extended Disability Severity Scale ( EDSS ) in the previous two years. The EDSS score had to be between 3.0 and 6.5 at entry, with no relapse or deterioration in the month before starting treatment. Patients were randomised between interferon-ß1b 8MIU subcutaneously every other day for 36 months, with lower doses in the first 15 days, and intermittent dose interruption, if indicated.

Outcomes were assessed at a planned interim time when all patients had 24 months of treatment. It was stopped at this point because of clear evidence of efficacy. The primary outcome was confirmed neurological deterioration by a 1-point deterioration in the EDSS scale, from baseline, on two consecutive visits at least three months apart. For patients with greater disability and an initial EDSS score of ≥6.0 a 0.5 increase was regarded as confirmed neurological deterioration. These outcomes were assessed by a neurologist not involved with the ongoing management of MS patients and who had no knowledge of the treatment assignment. A number of prespecified secondary endpoints were also used, which included time to becoming wheelchair bound (EDSS of 7.0), annual relapse rate, use of steroids, hospital inpatient episodes, and MRI T2 lesion volume.


Over 80% of patients had baseline EDSS scores of ≥4.0. The main results are shown in Table 1, with number needed to treat based on an intention-to-treat analysis of all patients randomised.

Table 1: Effects of treatment for two years with Inferferon ß-1b on various clinical outcomes in a randomised trial in 718 patients with secondary progressive multiple sclerosis (Intention to treat analysis) [2]
Event Relative Benefit (95%CI) NNT (95%CI)
Prevent confirmed progression 0.78 (0.66 to 0.92) 9.2 (5.5 to 28)
Prevent becoming wheelchair bound 0.68 (0.51 to 0.91) 13 (7.2 to 49)
Prevent moderate or severe relapse 0.82 (0.70 to 0.96) 11 (6.0 to 46)
Prevent MS-related steroid use 0.79 (0.70 to 0.89) 7.0 (4.7 to 14)
Prevent any hospital admission 0.80 (0.66 to 0.97) 16 (7.3 to no benefit)

Analysis when all patients had been treated for at least 24 months showed that, counting any patients lost to follow up as deteriorated, 178/358 (50%) of patients given placebo deteriorated, compared with 140/360 (39%) with interferon-ß1b. The NNT to prevent progression over two years was 9.2 (95% confidence interval 5.5 to 28). The treatment effect (relative benefit) was consistent across all baseline EDSS scores. This was equivalent to a delay of about 12 months in progression over two to three years.

Interferon-ß1b reduced the incidence of patients becoming wheelchair-bound (EDSS score of 7). With interferon-ß1b 60/360 (17%) of patients became wheelchair-bound, compared with 88/358 (26%) with placebo. The NNT was 13 (95% CI 7.2 to 49).

Interferon-ß1b reduced the incidence of patients having moderate or severe relapses. With interferon-ß1b 203/360 (56%) of patients had either no relapse or only a mild relapse, compared with 168/358 with placebo. The NNT was 11 (95% CI 6.0 to 46).

Interferon-ß1b reduced the incidence of patients needing high-dose steroids. With interferon-ß1b 167/360 (46%) of patients did not require steroids, compared with 115/358 (32%) with placebo. The NNT was 7.0 (95% CI 4.7 to 14).

Interferon-ß1b reduced the incidence of patients needing any hospital admission. With interferon-ß1b 193/360 (54%) of patients needed no hospital admission, compared with 169/358 (48%) with placebo. The NNT was 16 (95% CI 7.3 to no benefit, though in the paper this was a statistally significant difference using different statistical tests).

Interferon-ß1b reduced the cumulative mean number of new lesions detected by MRI. The mean lesion volume increased by 8% with placebo, but declined by 5% with interferon-ß1b. These results were statistically significant at more than the 1 in 10,000 level.

Adverse effects

Interferon-ß1b was associated with increased rates of adverse effects. There were mostly those of the 'flu syndrome associated with interferons, injection site inflammation and reaction, and increased muscle tone. While about 60% of patients receiving interferon-ß1b had 'flu-like symptoms in the first three months of treatment, this reduced to 10-20% after six months.

Relapsing/remitting MS

Another study [3] examined the effects of interferon-ß1a in relapsing/remitting disease. This was well conducted and randomised 560 patients with EDSS scores of 0 to 5 to placebo, 22 μg or 44 μg of interferon-ß1a subcutaneously three times a week over two years. Neurological examinations were done every three months and MRI twice a year.

Outcomes included the number of relapses, progression of disease by at least 1 EDSS point confirmed after three months, use of steroids and hospital admissions, as well as MRI outcomes.


The main results are shown in Table 2. The relapse rate over two years was lower for both doses of interferon-ß1a than for placebo with an NNT to prevent any relapse of 6.2 (4.1 to 13) for the higher dose. Time to first relapse was delayed by three and five months with the 22 μg and 44 μg doses respectively.

Table 2: Effects of treatment for two years with Inferferon ß-1a on various clinical outcomes in a randomised trial in 560 patients with relapsing/remitting multiple sclerosis [3]
    22 µg dose 44 µg dose
Event Relative Benefit (95%CI) NNT (95%CI) NNT (95%CI)
Prevent any relapse   9.1 (5.2 to 37) 6.2 (4.1 to 13)
Prevent moderate or severe relapse 0.82 (0.70 to 0.96) 5.4 (3.5 to 12) 5.1 (3.4 to 10)
Prevent MS-related steroid use 0.79 (0.70 to 0.89) 7.0 (4.1 to 23) 5.9 (3.7 to 14)

Both doses appeared to be equally effective in preventing a moderate or severe relapse over two years, with NNTs of 5.4 (3.5 to 12) and 5.1 (3.4 to 10) for 22 μg and 44 μg doses respectively.

Both doses were effective in preventing the need for steroids, with NNTs of 7.0 (4.1 to 23) for 22 μg and 5.9 (3.7 to 14) for 44 μg. There was an overall reduction in the number of hospital admissions for the 44 μg dose.

Interferon-ß1a reduced the cumulative mean number of new lesions detected by MRI. The mean lesion volume increased by 10.9% with placebo, but declined by 1.2% with 22 μg and by 3.8% with 44 μg (Figure).

Injection site reactions were higher with the interferon-ß1a than with placebo, but other adverse effects, like headache and influenza-like symptoms, were not different between the groups.


How are these results to be judged? It is about more than just NNTs and outcomes. The results are good without being startling, but the costs are high. Patients with MS and their carers, and decision-makers in the NHS may well view the results differently, in part because of the high treatment costs. It is possible for these treatment to appear to be good value for individuals and/or society as a whole while appearing to be poor value in the NHS.

The remarkable results of interferons in reducing the number of brain lesions and of the number of new lesions, a feature of both these studies, needs to be put in perspective. MRI scans appear, without too much thought, to be just another surrogate end point. But in other circumstances we have seen surrogate end points to be the bees' knees, as with viral load in HIV infection ( Bandolier 41 and 49 ) . There seems to be a missing link here, that between the MRI results and long term effects, or perhaps we have to wait for results from audits of patients treated with interferon, or open label extensions of these and other studies.


  1. BG Arnason, A Dayal, ZX Qu et al. Mechanism of action of interferon-ß in multiple sclerosis. Springer Seminars in Immunopathology 1996 18: 125-148.
  2. L Kappos and European Study Group. Placebo-controlled multicentre randomised trial of interferon ß1b in treatment of secondary progressive multiple sclerosis. Lancet 1998 352: 1491-7.
  3. GC Ebers & PRISMS Study Group. Randomised double-blind placebo-controlled study of interferon-ß1a in relapsing/remitting multiple sclerosis. Lancet 1998 352: 1498-504.

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