Management of breakthrough disease in patients with multiple sclerosis: when an increasing of Interferon beta dose should be effective?

Abstract

BackgroundIn daily clinical setting, some patients affected by relapsing-remitting Multiple Sclerosis (RRMS) are switched from the low-dose to the high-dose Interferon beta (IFNB) in order to achieve a better control of the disease.PurposeIn this observational, post-marketing study we reported the 2-year clinical outcomes of patients switched to the high-dose IFNB; we also evaluated whether different criteria adopted to switch patients had an influence on the clinical outcomes.MethodsPatients affected by RRMS and switched from the low-dose to the high-dose IFNB due to the occurrence of relapses, or contrast-enhancing lesions (CELs) as detected by yearly scheduled MRI scans, were followed for two years. Expanded Disability Status Scale (EDSS) scores, as well as clinical relapses, were evaluated during the follow-up period.ResultsWe identified 121 patients switched to the high-dose IFNB. One hundred patients increased the IFNB dose because of the occurrence of one or more relapses, and 21 because of the presence of one or more CELs, even in absence of clinical relapses. At the end of the 2-year follow-up, 72 (59.5%) patients had a relapse, and 51 (42.1%) reached a sustained progression on EDSS score. Overall, 85 (70.3%) patients showed some clinical disease activity (i.e. relapses or disability progression) after the switch.Relapse risk after increasing the IFNB dose was greater in patients who switched because of relapses than those switched only for MRI activity (HR: 5.55, p = 0.001). A high EDSS score (HR: 1.77, p < 0.001) and the combination of clinical and MRI activity at switch raised the risk of sustained disability progression after increasing the IFNB dose (HR: 2.14, p = 0.01).ConclusionIn the majority of MS patients, switching from the low-dose to the high-dose IFNB did not reduce the risk of further relapses or increased disability in the 2-year follow period.Although we observed that patients who switched only on the basis on MRI activity (even in absence of clinical attacks) had a lower risk of further relapses, larger studies are warranted before to recommend a switch algorithm based on MRI findings.

Overview of the management of relapsing−remitting multiple sclerosis and practical recommendations

“…Finally, a prospective longitudinal observational study from Argentina reported reductions in the annualized relapse rate of 57%−78% according to subgroup in the 3‐year period after patients had been switched from low‐dose to high‐dose IFN‐β ( n = 31), from IFN‐β to either GA ( n = 52) or mitoxantrone ( n = 13) or from GA acetate to IFN‐β ( n = 16) . In contrast, an observational study from Italy documented no benefit after 2 years’ follow‐up in 121 patients who were switched from low‐dose IFN‐β to high‐dose, high‐frequency IFN‐β because of breakthrough disease .…”

“…Some but not all studies investigating switching between first-line therapies in relapsingÀremitting MS have reported positive outcomes [10][11][12][13][14], and generalizability is further hampered by small sample sizes and methodological variation. A retrospective analysis reported significant (P < 0.05) decreases in annualized relapse rates for 90 patients treated with IFN-b or GA who were switched to an alternative first-line agent (IFN-b/IFN-b, IFN-b/GA, GA/IFN-b) due to suboptimal response [10].…”

“…patients had been switched from low-dose to high-dose IFN-b (n = 31), from IFN-b to either GA (n = 52) or mitoxantrone (n = 13) or from GA acetate to IFN-b (n = 16) [13]. In contrast, an observational study from Italy documented no benefit after 2 years' follow-up in 121 patients who were switched from low-dose IFN-b to high-dose, high-frequency IFN-b because of breakthrough disease [14]. In a separate study, these same Italian investigators reported significant differences after 24 months in the proportions of patients who were free from relapse (P < 0.0001), disability progression (P = 0.0045), MRI activity (P = 0.0003) and combined activity (P < 0.0001) following escalation to second-line natalizumab compared with switching between first-line immunomodulators (IFN-b/IFN-b, IFN-b/GA, GA/ IFB-b) after patients had failed first-line treatment.…”

Come modificare la terapia nel paziente experienced

“…Lo studio osservazionale retrospettivo di Rio et al [33] ha valutato pazienti sottoposti a un cambio di terapia immunomodulante di prima linea per risposta non ottimale, evidenziando una riduzione dell'attività clinica di malattia anche in caso di shift orizzontale verso altro farmaco di prima linea. Un altro studio osservazionale ha invece riportato come lo shift all'interno della prima linea, da una bassa dose di interferone a un'alta dose, operato per scarsa risposta clinica (presenza di una ricaduta o di lesioni captanti alla RM) non riduca l'attività di malattia nei 2 anni successivi [36]. Un terzo studio osservazionale, post-marketing e prospettico ha valutato la risposta al trattamento con natalizumab versus altri immunomodulanti in pazienti non-responders a un precedente trattamento con farmaco di prima linea [37].…”

Optimizing therapy early in multiple sclerosis: An evidence-based view

“…14,15,37,38 It is evident that in some patients IFN β and GA do not adequately control MS disease activity. 15,[17][18][19]39 Given the limited evidence supporting switching between different IFNs and/or GA 16,[40][41][42] and the lack of consistent disability reduction with long-term treatment with IFNs, [43][44][45] cycling between IFNs and GA may not be advisable. Thus, patients with breakthrough disease activity on first-line therapies seem to benefit more from a switch to a therapy with higher efficacy.…”