Interferon beta in multiple sclerosis: how much BENEFIT?

Despite pivotal trials of the disease-modifying agents interferon beta and glatiramer acetate, worldwide approval by licensing agencies, and a growing trend to treat all patients with early multiple sclerosis, controversy still exists about who and when to treat. 1,2 When a person presents to a neurologist for evaluation of a fi rst event (clinically isolated syndrome) suggestive of multiple sclerosis, the treating physician has a daunting task when making a rational therapeutic recommendation. He or she has to assimilate evidence-based medical facts, knowledge of the natural history of the disease, pharmaceutical promotional material, imperfect diagnostic criteria, and the patients' wishes. Does the evidence support the use of a disease-modifying agent without delay? For patients with limited clinical or radiographic disease dissemination, or when patients are reluctant to begin parenteral treatment, is a watchful waiting or delayed approach inappropriate? The magnitude of clinical benefi t in terms of disability prevention is an important consideration in the therapeutic decisionmaking process, in view of the fi nancial cost, adverse eff ects, patients' reluctance to begin long-term parenteral therapy, and the fact that patients with multiple sclerosis might do well for decades without treatment. 1,3,4 Trials have focused on accessible outcomes of relapse behaviour and MRI variables of disease activity, and have shown only partial benefi t on disability progression over the short term. 5,6 Objective interpretation of clinical eff ect is obscured when statistical analyses in large randomised trials emphasise relative risk reductions and their p values, rather than the magnitude of benefi t (eg, numbers needed to treat, absolute risk reductions). A key issue, for both multiple sclerosis and clinically isolated syndrome, is whether disease-modifying agents have any long-term benefi t on accumulation of disability. The CHAMPS, 7 ETOMS, 8 and BENEFIT (2-year placebo-controlled phase) 9 studies showed that treatment with interferon beta reduced the rate of conversion to clinically defi nite multiple sclerosis within 2 years of clinically isolated syndrome. The benefi ts, however, were modest. The number of patients needed to treat to prevent one from developing clinically defi nite multiple sclerosis at 2 years was six (BENEFIT) and at 3 years was seven (CHAMPS). Whether delaying the second attack has any long-term eff ect on disability remains unclear. To answer the disability question, we must rely on extension trials which, although imperfect (unblinding of patients and evaluators, drop-outs, and assumptions from missing data), are the best we have. 5 …