Barts-MS rose-tinted-odometer: ★★★★★★ (6-star bull’s blood red #8a0303)
Yesterday’s post on using cladribine to prevent CIS from converting to MS and whether this is MS prevention or an MS cure generated a robust debate. Good, this was the purpose of the post; i.e. to get you thinking.
As you are aware that as the diagnostic criteria for MS evolve many people diagnosed with CIS in the past actually have MS when the new diagnostic criteria are applied retrospectively. This then allows you to see how well cladribine works in preventing conversion to MS in the small subgroup of subjects who have ‘CIS’ and not MS when they were treated with cladribine.
The subjects who were still CIS after applying the newer McDonald diagnostic criteria showed that cladribine’s treatment effect improved with a reduction in risk of conversion to clinically definite MS by 63% on low-dose cladribine and by 75% on high-dose cladribine compared to placebo. I am not sure the MS community has clocked how effective cladribine really is when used early.
This post-hoc analysis also suggests that people with CIS treated with lower doses of cladribine actually do better than those on higher doses. The dose-effect is pretty clear when you look at the time to next attack or three-month confirmed disability worsening. Have we optimised the dose of cladribine? When you are trying to prevent/cure MS maybe not!
Any predictions? I predict that a proportion of patients with CIS treated early with cladribine may never go on to have a second attack or disability progression and hence are prevented from developing MS or cured of their MS, depending on how you define MS. Anyone taking bets?
Freedman et al. The efficacy of cladribine tablets in CIS patients retrospectively assigned the diagnosis of MS using modern criteria: Results from the ORACLE-MS study. Mult Scler J Exp Transl Clin. 2017 Oct 9;3(4):2055217317732802.
Background: Multiple sclerosis (MS) diagnostic criteria have changed since the ORACLE-MS study was conducted; 223 of 616 patients (36.2%) would have met the diagnosis of MS vs clinically isolated syndrome (CIS) using the newer criteria.
Objective: The objective of this paper is to assess the effect of cladribine tablets in patients with a first clinical demyelinating attack fulfilling newer criteria (McDonald 2010) for MS vs CIS.
Methods: A post hoc analysis for subgroups of patients retrospectively classified as fulfilling or not fulfilling newer criteria at the first clinical demyelinating attack was conducted.
Results: Cladribine tablets 3.5 mg/kg (n = 68) reduced the risk of next attack or three-month confirmed Expanded Disability Status Scale (EDSS) worsening by 74% vs placebo (n = 72); p = 0.0009 in patients meeting newer criteria for MS at baseline. Cladribine tablets 5.25 mg/kg (n = 83) reduced the risk of next attack or three-month confirmed EDSS worsening by 37%, but nominal significance was not reached (p = 0.14). In patients who were still CIS after applying newer criteria, cladribine tablets 3.5 mg/kg (n = 138) reduced the risk of conversion to clinically definite multiple sclerosis (CDMS) by 63% vs placebo (n = 134); p = 0.0003. Cladribine tablets 5.25 mg/kg (n = 121) reduced the risk of conversion by 75% vs placebo (n = 134); p < 0.0001.
Conclusions: Regardless of the criteria used to define CIS or MS, 3.5 mg/kg cladribine tablets are effective in patients with a first clinical demyelinating attack. ClinicalTrials.gov registration: The ORACLE-MS study (NCT00725985).
General Disclaimer: Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust and are not meant to be interpreted as personal clinical advice.