Fumaderm®, a mixture containing DMF as well as other different monoethyl fumarate salts, has been approved for the treatment of psoriasis since the early 1990s, and dermatological experience suggests a favourable safety profile with more than 185 000 patient years. However, PML cases have been reported recently during psoriasis treatment with fumaric esters [125-128], although confounding factors were identified in these cases. Two cases had experienced long-lasting lymphopenia without treatment adaption, as recommended [126, 127]; the other cases had a history of sarcoidosis, cancer, previous mAb (efalizumab) and immunosuppressive (methotrexate) BIBW2992 nmr treatment [128]. Tecfidera®, also

with differences regarding galenics, is approved for MS. Thus far, no signal for opportunistic infections such as PML have been reported from the clinical programme or the short post-marketing interval (US) with Tecfidera®. The regular assessment of leuco- and lymphocyte counts is sensible and may serve treatment surveillance. At 1 year of treatment, leuco- and lymphocyte counts decreased by 10–12% and 28–32%

(mean), respectively; 4–5% of patients experienced DAPT total lymphocyte counts below 0·5 × 109 per litre [123, 124]. As in other DMD treatments, regular MRI under DMF therapy will be reasonable for both therapy monitoring and determining effectiveness. Mitoxantrone (MX, Ralenova®/Novantrone®) has been approved for the treatment of secondary progressive and progressive relapsing MS following two placebo-controlled trials [19, 129] and two studies comparing MX or MX in combination with methylprednisolone (MP) to MP alone [130, 131]. Data on MX in primary progressive MS (PPMS) is discouraging [132-134], but has gained relevance in NMO treatment [24, 25]. Although not formally approved, MX has been used in children with aggressive forms of MS [135]. Different treatment Plasmin protocols may be an influencing factor for SADR development,

especially in terms of therapy-related acute leukaemia (TRAL) [136]. Whereas an intravenous infusion every 3 months according to the placebo-controlled, double-blind, randomised, multicentre, phase III trial of mitoxantrone in secondary progressive multiple sclerosis (MIMS) protocol [129], including dose adaption according to leucocyte nadir, is used widely in Germany, dose regimens differ substantially and may not include regular dose adaption [137, 138]. Additional differences may comprise pre- or co-treatments [37]. Thus, MP co-treatment has been shown to increase intracellular MX dosage in vitro [139], and may thus increase cellular toxicity. Treatment de-escalation should be considered after 1 year of clinical and paraclinical stability of disease to minimize the risk of at least partially dose-dependent SADRs (e.g. cardiotoxicity).