ClinicSpeak: relapses after switching from natalizumab to DMF

Is the reduction in lymphocyte counts on DMF associated with its therapeutic efficacy? #MSBlog #MSResearch #ClinicSpeak

"The study below shows rebound occurs in approximately a third of MSers on stopping natalizumab despite starting DMF (Tecfidera). These observation confirm another study that we discussed in detail on this blog last year (see here 20 Dec 2015). The main problem with this study is that DMF was started an average of 50 days after stopping natalizumab; this is too long. We know from studies on using fingolimod post-natalizumab that starting fingolimod as soon as possible (less than 4 weeks) is the best strategy for prevent rebound. In the past I have even proposed on this blog that with DMF we may need to overlap it with natalizumab to make sure it is working when natalizumab stops working, i.e. 3-4 months after the last natalizumab infusion (How bold is Biogen?; 11-Jan-2015)."

"An interesting observation is that in patients without relapses the lymphocyte counts decreased more significantly compared to those who had relapses. This hints at a drop in lymphocyte counts are associated with the efficacy of DMF. Biogen tell us this is not the case based on a simple analysis of their data comparing relapse rates in trial subjects with and without a lymphopaenia. I have ask Biogen many time to analyse their data differently, but have yet to see an in-depth analysis that satisfies me. Based on this paper a simple question would be to see what the average lymphocyte counts are in year-1 on DMF in subjects who were NEDA compared to those who had disease activity. Importantly, my dermatology colleagues are adamant that in psoriasis therapeutic response to fumarates is linked to the level of lymphopaenia (see Wain et al. below). As lymphopaenia is linked to the complication of PML on DMF,  you can see from a commercial perspective why Biogen don't want any link to be established between the reduction in lymphocyte counts on DMF and therapeutic efficacy. I am sure if Biogen won't answer this question the community will do it for us; there is enough interest out there and pwMS on DMF to get the answer very quickly."

Epub: Zurawski et al. Relapse frequency in transitioning from natalizumab to dimethyl fumarate: assessment of risk factors. J Neurol. 2016 May 18.

Background: Risk of relapse after natalizumab (NAT) cessation and switch to dimethyl fumarate (DMF) is unknown. 

Objective: The objective of this paper is to identify the risk and associated risk factors for relapse after switching from NAT to DMF in relapsing-remitting multiple sclerosis. 

Methods: Patients (n = 30) were treated with NAT for ≥12 months and then switched to DMF in a mean of 50 days. Patient age, annualized relapse rates (ARR), Expanded Disability Status Scale scores (EDSS), and lymphocyte counts were assessed. 

Results: Overall, eight patients (27 %) had relapses after switching to DMF. Five patients (17 %) suffered severe relapses with multifocal clinical and radiological findings. New lesions by MRI (T2 hyperintense or enhancing) were observed in 35 % of patients. Relapses occurred at a mean of 3.5 months after NAT cessation. Patient age and elevated ARR prior to NAT use were significantly associated with risk of relapse after switch to DMF. Once on DMF for 4 months prior to relapse, lymphocyte count decreased more significantly in patients without relapses than those with relapses. 

Conclusions: Switching from NAT to DMF correlated with increased relapses. Young patient age, high ARR and stability of lymphocyte counts were risk factors for relapse after transition from NAT to DMF.

Psoriasis; image form Wikipedia

Wain et al. Treatment of severe, recalcitrant, chronic plaque psoriasis with fumaric acid esters: a prospective study. Br J Dermatol. 2010 Feb 1;162(2):427-34.

BACKGROUND: Fumaric acid esters (FAE) are used in Germany as a first-line systemic treatment for chronic plaque psoriasis, with proven efficacy and low toxicity. Their use in the U.K. is variable, and they remain unlicensed. Consequently, efficacy and safety data from U.K. patients is limited and their place in the psoriasis treatment armamentarium is unclear.

OBJECTIVES: To examine the efficacy and safety of FAE in a prospective cohort of U.K. patients with severe, treatment-recalcitrant, chronic plaque psoriasis.

METHODS: A single-centre, open, nonrandomized, prospective study was performed in a regional referral centre for patients with severe psoriasis. Outcomes were measured by the Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), blood investigations and adverse events monitoring.

RESULTS: Eighty patients were recruited. Fifty-nine per cent were taking a concomitant oral antipsoriatic agent; 20% achieved a PASI-50, 8% a PASI-75 and 4% a PASI-90 on intention-to-treat analysis at 3 months with an overall, statistically significant, reduction in PASI from 13.9 + or - 9.0 to 11.3 + or - 9.2 (P < 0.0001). At 3 months, lymphopenia was seen in 33% of the cohort with significantly lower counts in patients responsive to FAE (P = 0.008). In addition, by 3 months, 36% of concomitant antipsoriatic medication had been stopped and 25% of doses had been reduced without loss of disease control. Side-effects (most commonly diarrhoea, abdominal pain and flushing) were reported by 74% of patients resulting in cessation of FAE in 36%.

CONCLUSIONS: FAE is a useful alternative treatment option in patients with severe, treatment-resistant, chronic plaque psoriasis and can allow dose reduction, and subsequent cessation, of other, potentially more toxic agents.

CoI: multiple