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Changing therapeutic strategies and persistence to disease-modifying treatments in a population of multiple sclerosis patients from Veneto region, Italy
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Changing therapeutic strategies and persistence to disease-modifying treatments in a population of Multiple Sclerosis patients from Veneto region, Italy Antonio Marangi , Gabriele Farina , Virginia Vicenzi , Stefano Forlivesi , Francesca Calabria , Fabio Marchioretto , Antonio Forgione , Francesca Rossi , Gianola Stenta , Marika Vianello , Alberto Gajofatto , Maria Donata Benedetti PII: DOI: Reference:
S2211-0348(20)30080-8 https://doi.org/10.1016/j.msard.2020.102004 MSARD 102004
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
12 May 2019 18 January 2020 7 February 2020
Please cite this article as: Antonio Marangi , Gabriele Farina , Virginia Vicenzi , Stefano Forlivesi , Francesca Calabria , Fabio Marchioretto , Antonio Forgione , Francesca Rossi , Gianola Stenta , Marika Vianello , Alberto Gajofatto , Maria Donata Benedetti , Changing therapeutic strategies and persistence to disease-modifying treatments in a population of Multiple Sclerosis patients from Veneto region, Italy, Multiple Sclerosis and Related Disorders (2020), doi: https://doi.org/10.1016/j.msard.2020.102004
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Highlights
Dimethylfumarate and fingolimod represent the most prescribed DMTs
54,8% of patients stopped their treatment within the last follow-up Dimethylfumarate use predicted higher persistence at 24 months Glatiramer acetate and azathioprine had the highest persistence at last follow-up Longer disease duration was predictive of an increased risk of DMT discontinuation
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Changing therapeutic strategies and persistence to disease-modifying treatments in a population of Multiple Sclerosis patients from Veneto region, Italy Antonio Marangi1*, Gabriele Farina2, Virginia Vicenzi3, Stefano Forlivesi4, Francesca Calabria4, Fabio Marchioretto5, Antonio Forgione6, Francesca Rossi7, Gianola Stenta1, Marika Vianello8, Alberto Gajofatto2, Maria Donata Benedetti9
1
Neurology Unit, St. Bortolo Hospital, Vicenza, Italy
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Department of Neurosciences, Biomedicine and Movement Sciences, Section of Neurology
B, University of Verona, Verona, Italy 3
Genetics and Molecular Biology Unit, St. Bortolo Hospital, Vicenza, Italy
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Section of Neurology A, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
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IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy
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Neurology Unit, Pederzoli Hospital, Peschiera del Garda, Verona, Italy
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Neurology Unit, Mater Salutis Hospital (AULSS9), Legnago, Verona, Italy
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OU Neurology, Cà Foncello Hospital, Treviso, Italy
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Section of Neurology B, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
*Corresponding Author Antonio Marangi Neurology Unit St Bortolo Hospital Viale Rodolfi 37, 36100, Vicenza, Italy Tel +390444753675 E-mail: [email protected]
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Abstract Background: The availability of new disease-modifying treatments (DMTs) in the last years has changed the therapeutic strategies used in Multiple Sclerosis (MS). We aimed to describe trend in DMTs utilization and persistence to treatment in a large sample of patients attending 10 MS centres from four provinces of Veneto, Italy. Methods: Demographic, clinical and DMTs information of patients regularly followed from January 2011 to August 2018 were recorded and analysed. Persistence at 12, 24 months and at last follow-up was assessed by Kaplan Meier survival analysis. Multivariable Cox- proportional hazard model was used to identify predictors of persistence. Results: Of 3025 MS patients 65.7% were in treatment al last follow-up. Dimethylfumarate (DMF) was the most prescribed single drug among first-line and fingolimod among secondline DMTs. In the cohort of 1391 cases starting any DMT since 2011 12.9% stopped within 6 months, 24% within 12 and 40.3% within 24 months. Disease duration > 5 years at therapy start was predictive of greater risk of discontinuation, while age and sex were not. DMF use was predictive of higher persistence at 12 and 24 months, but not at last follow-up when azathioprine and glatiramer acetate showed the highest persistence compared to other DMTs. Side effects represented the main reason of discontinuation. Conclusion: The use of the new oral DMTs greatly increased since their approval but persistence in the long-term is not better than with old drugs. The treatment choice is still a challenge both for patients and their doctors.
Keywords: Observational studies; Epidemiology; Multiple Sclerosis; Persistence to Treatment; Italy
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1.1 Introduction Over the past decade, MS therapeutic armamentarium has increased considerably to include so far eleven approved disease modifying therapies (DMTs) with varying degrees of efficacy in reducing disease activity (Filippini et al., 2013; Torkildsen et al., 2016). In this crowded pharmacologic landscape, the lack of head-to-head comparisons among different DMTs, along with the absence of well established prognostic markers to predict disease course and response to medications, makes it challenging to choose the appropriate therapy in each individual case (Multiple Sclerosis Coalition 2017). Moreover, DMTs differ by route of administration, dosing schedule, tolerability and safety, all aspects that impact patients’ persistence on therapy (Cramer et al., 2008; Ivanova et al., 2012; Romer and Zettl, 2018; World Health Organization 2003). This scenario is further complicated by the lack of evidence about the long term benefit of DMTs on reducing disability accumulation, along with the scanty amount of information about the safety profile of the latest approved DMTs (Auricchio et al., 2017; Cramer et al., 2008; Filippini et al., 2013; Ivanova et al., 2012; Multiple Sclerosis Coalition 2017; Romer and Zettl, 2018; World Health Organization 2003) . Observational studies on large cohorts of patients are useful to depict the changing pattern of DMTs prescriptions over time, patients and neurologists preferences in the choice of drug, persistence to treatment, benefit and adverse effects (Evans et al., 2016; Lanzillo et al., 2018; Lattanzi et al., 2017; Melesse et al., 2017; Setayeshgar et al., 2019). The purpose of this observational study was to evaluate the changing strategies in drug utilization over the last years and the persistence to different DMTs including azathioprine in a large sample of MS cases from Veneto region, Italy.
1.2 Methods
1.2.1 Study Population
Patients attending the MS centres of the Hub and Spoke network from the Italian provinces of Verona, Vicenza, Treviso and Belluno, covering a population of 2,877,030 inhabitants (https://www.tuttitalia.it/veneto/statistiche/popolazione-andamento-demografico, 2018) were the population frame of this study. According to the diagnostic and therapeutic guidelines for the management of MS adopted from Veneto Region in 2015, a precoded case form has to be filled in by the neurologists taking charge of patients in the Spoke centres and sent yearly to
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the Hub centre of reference. For the purpose of this study the data, collected retrospectively from January 2013 to March 2016 and prospectively updated from April 2016 to August 2018, were sent to the Hub centre of Verona to be analysed. The spreadsheet collects information on demographic and clinical data, including disability at last follow-up measured by the Expanded Disability Status Scale (EDSS) (Kurtzke, 1983), disease course, clinical and Magnetic Resonance Imaging (MRI) disease activity in the last twelve months; chronological history of MS treatments for each patient including reasons for discontinuation indicated as follows: lack of efficacy, side effects, safety protocol, patient’s choice, pregnancy or stability. In Italy at the time of study glatiramer acetate (GA), interferon beta (IFN-beta) 1a/1b and peginterferon beta-1a, teriflunomide, dimethyl fumarate (DMF) were approved as first-line therapies, while fingolimod, natalizumab, alemtuzumab, mitoxantrone as second-line therapies. Azathioprine and cyclophosphamide are also prescribed and reimbursed for MS in Italy (Gazzetta Ufficiale Italiana 2016) while rituximab is used off-label.
1.2.2 Inclusion criteria All patients with a diagnosis of clinically isolated syndrome (CIS), relapsing remitting (RR), primary progressive (PP) or secondary progressive (SP) MS according to 2010 McDonald criteria (Polman et al., 2011) regularly attending the aforementioned MS centres were included in the study. Patients with diagnoses of demyelinating diseases other than MS or CIS were excluded.
1.2.3 Outcomes The study outcomes were to describe DMT utilization and persistence to treatment throughout the study period, 2011-2018. For the analysis, we chose to include patients who started a DMT (“index therapy”), any time after January 2011 (year of the approval of fingolimod as the first oral drug specific for MS in Italy). Persistence to treatment was defined as the median time in months between the beginning and the withdrawal of a given DMT. The reasons for DMT discontinuation were defined as 1) inefficacy (clinical and/or MRI activity and/or disability progression), 2) side effects related to DMTs, 3) drug interruption according to standardized protocols (e.g. positivity for anti-JCV testing after 24 months of natalizumab treatment, or a limiting dose of 120 mg/m2 for mitoxantrone), 4) autonomous decision of the patient, 5) desire of motherhood, 6) clinical stability.
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1.2.4 Statistical analysis Absolute counts and percentages are provided for categorical variables, while means, standard deviation (SD), and medians for continuous variables as appropriate. Differences between groups were analysed by using the chi-square and ANOVA tests. Persistence to therapy was analysed by the Kaplan-Maier survival method, using the log-rank test for comparisons between groups. The cumulative time in treatment was defined as the interval in months between DMT onset and discontinuation or last follow-up, whichever came first, in reference to any assigned drug since 2011. Potential predictors of persistence were gender, age at therapy onset (≤35 or >35 years), disease duration at therapy onset (≤2, 3-5, 6+ years) and type of prescribed DMT. Multivariable Cox-proportional hazard model was used to analyse the associations between potential predictors and persistence to treatment at 12 and 24 months, and at last follow-up. Hazard ratios and 95% confidence intervals (CI) were reported as estimates of association. The adopted level of statistical significance was α= 0.05 (two-sides test). Statistical analyses were performed by using IBM SPSS v. 21. 1.3 Results
1.3.1 Overall population of cases The general characteristics of 3025 MS patients, 2013 women (66.5%), mean age at last follow-up 48.2 (±12.4) years, are reported in Table 1. At the last follow-up 1989 cases (65.7%) were on treatment, 1482 (74.5%) with a first-line and 507 (25.5%) with a second-line therapy. DMF was the most prescribed single drug among first-line therapies (433 cases, 29% of this group), while fingolimod was the most used second-line DMT (270 patients, 53% of second line cases). 1.3.2 Trend in DMTs utilization The cohort selected to analyse DMT utilization and persistence included 1391 patients (66.5% women, mean age at therapy 40.4±11.6 years) who started any DMT since January 2011 (Table 2). Figure 1 shows the changing profile of treatments in this cohort of cases over the years: the decline in first-line injective drugs prescriptions was evident mostly for IFNs as a group (from 56% in 2011-2012 to 15% in 2017-2018), while the newly approved DMF rapidly overtook the other treatments (up to 48% in 2017-2018). Second-line treatments as cyclophosphamide and rituximab also increased to 8% in the last four years. About 49% (n 681) of
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this cohort were naïve cases (missing information, n=9): they had a lower EDSS score at last follow-up (median 1.5) and shorter disease duration at the index therapy onset (median 3 years) compared to not naïve patients (median EDSS 2.5, median disease duration 6 years) (p<0.001). The median time of follow-up since index therapy was 36 months (range 1- 84 months), significantly longer in not naïve compared to naïve patients (42 versus 24 months, p<0.001). 1.3.3 Persistence to treatment In all, 757/1382 patients (54.8%) (time on DMT missing in 9 cases), discontinued their treatment: 180 (13%) within 6 months mostly for side effects (65%), 334 (24.2%) within 12 months and 560 (40.5%) within 24 months from onset (Figure 2). Persistence by type of treatment at last follow-up, at 12 and 24 months and overall median persistence in months (95% CI) are shown in Table 3. Discontinuation rate was significantly lower in DMF and higher for second-line DMTs treated cases (p<0.001, chi-square test). Overall median persistence was lower in teriflunomide cases (p=0.001, log rank test), for which discontinuation was mostly due to side effects, although the number of treated cases with this DMT was low. Second-line treatments different from natalizumab and fingolimod were also associated to higher discontinuation at 12 and 24 months, mostly for therapeutic protocols related to safety (mitoxantrone and cyclophosphamide) (p<0.01, chi-square test). In order to exclude the possible confounding effect of progressive cases, we also performed a subgroup analysis regarding RR patients (No 1191, 85,6%), whose discontinuation rate of 54,3% (647/1191) turned out ot be equal to what we found in the entire population of patients. Similarly, persistence for each DMT was generally comparable to that seen in the general cohort of subjects (data not shown). Kaplan Meier analyses showed that persistence was longer in cases with shorter disease duration at index therapy (p<0.001, log rank test), in patients treated with fingolimod or natalizumab compared to other second-line DMTs (p<0.001, log rank test), and in DMF or azathioprine treated cases compared to those in teriflunomide (p<0.001, log rank test) (Figure 3 A,B,C). No difference in persistence between IFNs subtypes was evident, while a longer persistence in GA versus IFNs treated cases was of borderline significance (Figure 3 D,E). When considering the long-term overall persistence, no differences were found between injective and oral first-line DMTs (Figure 3 F). Median time in treatment (index DMT) was 15 months (range 1-84), significantly longer in naïve compared to not naïve cases (median 17.5 and 14 months, respectively (p<0.001). As shown in the Cox analysis (Table 4), a disease duration over 5 years at the time of index therapy onset was predictive of increased risk of treatment
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discontinuation, while sex and age were not. At 12 and 24 months first-line oral DMTs considered as a group, and DMF as single drug, were associated to a significantly higher persistence compared to injectable or second-line DMTs. However, at last follow-up this difference was lost, while azathioprine and GA showed better persistence compared to other DMTs, and teriflunomide was associated to a higher risk of discontinuation. 1.3.4 Reasons for DMTs discontinuation Side effects were the most frequent reason for discontinuing DMT (298/757 cases, 39%), followed by lack of efficacy (265 cases, 35%), safety protocol (65 cases, 8.5%), patient’s choice (43 cases, 5.6%), pregnancy (31, 4.1%) and disease inactivity (9 cases, 1.2%) (unknown reason in 46 cases, 6%). Among first-line drugs side effects were more common with teriflunomide (61%) or DMF (60%) while lack of efficacy with self-injectable DMTs compared to oral drugs (mean percentage respectively 38 and 30% (p<0.05) (Figure 4). In the natalizumab group, 65% of patients discontinued because of safety reason (JCV positive serology) and only 5% because of lack of efficacy. Fingolimod cases displayed 50% of inefficacy, with 32% of these patients previously treated with natalizumab. Overall, treatment discontinuation due to lack of efficacy occurred later (17 months, 95% CI 14-20) than withdrawal due to adverse events (11 months, 95% CI 9-13) (p < 0.001, log rank test). After discontinuation of any firstline DMT, 23% of patients remained off treatment, 49% switched to another DMT of the same line while in 26% an escalation to a second-line drug was decided (no information in 10 cases). Among patients who discontinued their second-line therapy, 24% remained off treatment, 42% switched to another second-line DMT and 31% shifted down to a first line therapy (no information in 6 cases). Fig. 5 shows therapeutic strategies by reason of discontinuation.
1.4 Discussion To our knowledge this is the first Italian observational study to analyse the trend in prescriptions over the last years and to include an old drug similar in effects to IFN-beta, i.e. azathioprine (Massacesi et al., 2014), in the analysis of persistence to treatment.
Near-
ly 66% of the 3025 patients were on DMT therapy at last follow-up. A similar proportion, 62%, was found in the Stockholm County (Eriksson et al., 2018), while 51% of patients registered at MS clinics in British Columbia were in treatment (McKay et al., 2016). A recent update from a longitudinal cohort of MS cases in U.S.A. reported an increase in DMT use from 55.3% in 2000 to 61.5% in 2009 (Minden et al., 2019). Considering the low median EDSS (2.0) at last follow-up, it is evident that in our patients DMTs were largely used in the less se-
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vere forms of MS. In other studies based on administrative databases this information was unavailable (Eriksson et al., 2018; Minden et al., 2019). The trend of prescriptions in the cohort of cases starting any DMT since 2011 reflects the sequential introduction and reimbursement in Italy of the oral drugs for MS (fingolimod in 2011, terifunomide in 2014 and DMF in 2015). The concomitant decline of the old first-line injective DMTs (mostly IFN-beta) was observed everywhere, from British Columbia where the first-generation DMTs decreased by 30% (Setayeshgar et al., 2018) to Sweden where DMF and fingolimod approval impacted significantly DMT prescriptions (Eriksson et al., 2018), to Japan where the share of fingolimod in 2015 (26%) was comparable with that of IFN (28%) (Ogino et al., 2017). More than half of our patients stopped their DMT at some point of follow-up, and this was also confirmed in the subanalysis restricted to only RR patients. Interestingly, in 39% of cases discontinuation was due to side effects. These findings are in line with an observational study on 486 MS patients which found that 46% of participants discontinued or modified their DMT within 2.5 years from drug introduction (Longbrake et al., 2016), while in a recent multicenter Italian study the rate of discontinuation at 12 months with first-line DMTs was 20% (Lanzillo et al., 2018). In a Canadian population study about 18% of 4830 MS subjects receiving IFNs or GA discontinued their treatment within 12 months (Evans et al., 2016) while in a large retrospective French cohort almost 40% of cases stopped injectable DMTs at 24 months (Defer et al., 2018). We did not find substantial differences in persistence between IFN beta formulations, least of all a favourable relation with a lower frequency of administration as previously observed (Correia et al., 2016). A higher persistence in GA versus IFN treated cases was already suggested (Zhornitsky et al., 2015), although several studies showed that the effectiveness of injectable DMTs was quite similar (Bartolome-Garcia et al., 2019; Defer et al., 2018; Longbrake et al., 2016; Melesse et al., 2017). Our Cox analysis showed that first-line oral DMTs were predictive of higher persistence compared to injectable DMTs only at 12 and 24 months but not at last follow-up, and azathioprine and GA were surprisingly associated to better persistence. Although oral DMTs were expected from both patients and neurologists as convenient alternatives to injective drugs, several studies did not find differences in the discontinuation rate between oral and injectable DMTs (Ferraro et al., 2018; Lanzillo et al., 2018; Longbrake et al., 2016). In a recent Canadian cohort study the rate of discontinuation to oral DMTs was 20% by 12 months (Setayeshgar et al., 2019), similar to that found previously for injective DMTs in the same population (Evans et al., 2016). Fingolimod in our cases was not so favourably associated to persistence as
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reported in other studies (Kalincik et al., 2019; Lattanzi et al., 2017), likely due to the high proportion of switching from natalizumab, and this was also demonstrated by the subanalysis restricted to RR patients, which confirmed the high discontinuation rates with this drug (60% at last follow-up). Interestingly, an important issue for fingolimod turned out being naïve for any previous DMT, since 40 of the 42 patients who did not stop the drug had not been exposed to other previous DMTs. However, it should be noted that studies showing a higher persistence rate for fingolimod compared to self-injectable DMTs might have been conditioned by possible conflicts of interest (Johnson et al., 2017; Kantor et al., 2018). It is evident that persistence decreases with the increasing duration of follow-up. On the other hand, the availability of new treatments may increase the possibility to try other therapies, considering that in our, as in other studies, the main reason of stopping DMTs were side effects (Ferraro et al., 2018; Longbrake et al., 2016; Zhornitsky et al., 2015. Among our patients discontinuing DMTs, the choice of another first or second line drug was strictly related to the reason of discontinuation, with escalation towards a more potent drug as the common choice in case of disease activity, and “lateral” switch in case of side effects. Finally, we found that a longer disease duration at the time of index therapy onset was predictive of an increased risk of discontinuation, as already observed (Melesse et al., 2017), while age and sex were not. Other studies observed a higher DMT discontinuation in younger patients (Ferraro et al., 2018; Longbrake et al., 2016; Melesse et al., 2017; Zhornitsky et al., 2015) and in women (Lanzillo et al., 2018; Zettl et al., 2017). Limitations of our work include the typical biases of retrospective design, i.e. missing data, for the correction of which we excluded from the analysis frankly inaccurate patients’ forms; the non-enforceability of our findings for the general MS population, as proven by the underrepresentation of progressive variants, probably because of the lack of approved treatments at the time of the study. Secondly, given the tendency of a certain number of MS patients to search for experimental treatments outside the regional or provincial boundaries, a proportion of cases may be missed. Thirdly, the number of cases in teriflunomide was low, limiting conclusions on its use. Furthermore, information about EDSS score at the starting of index therapy, a potential predictor of treatment discontinuation, was lacking. In conclusion, although the therapeutic strategies in MS have changed dramatically over the last years, persistence in the long-term remains a concerning factor in this disease. These findings suggest the need for detecting well-defined predictive markers of long-term response to the treatment, which still represents a challenge both for patients and their doctors.
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Statement of Ethics The current study respected the ethical principles depicted in the Declaration of Helsinki. The study protocol has been approved by ethics committees of the coordinating Hub centre of Verona and the Hub centres of Vicenza and Treviso. No data used in the analyses contained any patient identifiers.
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Conflicts of interest:
AM, GF, VV, SF, FC, FM, AF, FR, GS, MV and MDB have no conflicts of interest. AG received research support funding and advisory board honoraria from Merck.
Funding Sources This study was funded by a grant from Regione Veneto (RSF2014-00000415). The funder had no role in study design, data collection and analysis, and manuscript preparation
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Contributions AM: acquisition, analysis, and interpretation of data, drafting of the manuscript, critical revision of the manuscript content. GF, VV: acquisition of data, database implementation, critical revision of the manuscript content. SF: conception and design of the study, critical revision of the manuscript content. FC, FF, AF, FR, GS, MV, AG: acquisition of data, critical revision of the manuscript content. MDB: conception and design of the study, acquisition, analysis, interpretation of data, critical revision of the manuscript content. Acknowledgments The authors would like to thank Dr Loredana La Mantia for her useful comments and suggestions.
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17
60
50
%
40
30
20
10
0 2011-2012 IFNs
GA
Natalizumab
2013-2014 Fingolimod
2015-2016 Other second-line
2017-2018 AZA
DMF
Teriflunomide
Fig. 1 Trend in drug prescription from 2011 to 2018 in the cohort of 1391 MS cases starting DMTs since January 2011. DMT= disease modifying treatment; GA= glatiramer acetate; DMF = dimethyl fumarate
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Total MS cases n=3025 Excluded cases starting DMT before 2011 n=1634 Persistence cohort starting DMT since 2011 n=1391 180 cases discontinued DMT ≤ 6 months 158 cases censored 334 cases discontinued DMT ≤ 12 months 309 cases censored 560 cases discontinued DMT ≤ 24 months 422 cases censored
n = 338
Missing time in DMT n=9 > 6 months of DMT therapy n=1044
n = 643
> 12 months of DMT therapy n=739
n = 982
> 24 months of DMT therapy n=400
Fig. 2 Flowchart of the MS cases included in the persistence analysis.
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Fig. 3 A. Kaplan Meier survival analyses by disease duration at index therapy
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Fig. 3 B. Kaplan Meier survival analyses by second-line DMTs
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Fig. 3 C. Kaplan Meier survival analyses by first-line oral DMTs
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Fig. 3 D Kaplan Meier survival analyses by IFNs different formulations
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Fig. 3 E Kaplan Meier survival analyses by first-line injective DMTs
24
Fig. 3 F Kaplan Meier survival analyses by first-line oral or injective DMTs
25
Fig. 4 Reasons for treatment discontinuation by DMTs
26
27
Fig. 5 Therapeutic strategies after discontinuation because of inefficacy (A) or side effects (B)
28
Table 1. General characteristics of the overall group of MS patients (N=3025) Sex (n, %) Women 2013 66.5% Men 1012 33.5% Age at last follow-up (yrs, mean±SD)(range) 48.2 ±12.4 (16-88 yrs) Type of MS (n, %)° CIS RR SP PP Age at disease onset (yrs, mean±SD)
185 6.1% 2213 73.2% 402 13.3% 200 6.5% 32.9±10.8
Median disease duration at last follow-up (range)
12 yrs (1 mo.-68 yrs)
Median EDSS at last follow-up (range)
2.0
In DMT* at last follow-up (n, %)** First-line drugs Second-line drugs Type of DMT at last follow-up (n, %) IFNBs DMF GA Fingolimod Natalizumab Azathioprine Teriflunomide Other second-line DMT°° Other first-line DMT Any DMT onset 1992-2000 2001-2005 2006-2010 2011-2014 2015-2018
1991 1484 507
65.8% 74.5% 25.5%
493 433 315 270 188 133 89 49 21
24.8% 21.7% 15.8% 13.6% 9.4% 6.7% 4.5% 2.4% 1.1%
91 224 613 821 570
3.9% 9.7% 26.4% 35.4% 24.6%
Patients never treated with DMTs
706
23,3%
(0-9)
° CIS= Clinically Isolated Syndrome, RR= Relapsing-Remitting, SP= Secondary Progressive, PP= Primary Progressive; Radiologically Isolated Syndrome (RIS) in 19 cases; unknown MS type in 6 cases * Disease-modifying treatment ** no information in 89 cases (3%); no treatment in 945 cases (31%) °° alemtuzumab n=17, cyclophosphamide n=7, ocrelizumab n=17, rituximab n=8
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Table 2. Characteristics of the cohort of 1391 patients who started any DMT since January 2011 Sex (n, %) Women
925
66.5%
Men
466
33.5%
Age at last follow-up (yrs, mean±SD)(range) Age at disease onset ((yrs, mean±SD) RRMS§ (n, %)
44.4±11.6 (18-79yrs) 32.6±10.7 1191
Median EDSS at last follow-up (range) In DMT^ at last follow-up (n, %)
2.0
85.6% (0-8.5)
1202
86.4%
First-line injective drugs
442
36.8%
First-line oral drugs*
455
37.9%
Second-line drugs
305
25.4%
No DMT
704
50.6%
1 DMT
336
24.2%
2 DMT
222
16.0%
3 or more DMT
124
8.9%
2011-2012
373
26.8%
2013-2014
447
32.2%
2015-2016
423
30.4%
2017-2018
148
10.6%
Number of treatments before the current one (n, %)**
Year of index therapy onset
Age at onset of index therapy (yrs, mean±SD)** Median disease duration at index therapy (range)° Median follow-up since index therapy onset (months, range) Naïve cases at index therapy (n, %)
40.4±11.6 5 yrs (1 month-52 yrs) 36 (1-84) 681
49.0%
within 6 months
180
12.9%
within 12 months
334
24.0%
within 24 months
560
40.3%
within last follow-up
757
54.8%
Cases discontinuing index therapy (n, %)
§ Relapsing Remitting MS ^ Disease-modifying treatment * Oral methotrexate in 10 PP cases included ** missing in 5 cases; ° missing in 35 cases
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Table 3. Persistence by type of treatment in the cohort of 1391 MS patients who started DMT since January 2011 Cases who Median persisCases who discontinuated DMTs within (%) Number discontinuated tenc time in -----------------------------------------------------Drug° of cases DMTs (%) months (95% CI) 6 months 12 months 24 months All IFNs
485
296 (61.0)
27 (24-32)
60 (12.4)
115 (23.7)
200 (41.2)
IFNB-1a 22 mcg
165
97 (58.8)
29 (24-37)
13
(7.9)
36 (21.8)
65 (39.4)
IFNB-1a 44 mcg
106
65 (61.3)
29 (22-35)
10
(9.4)
24 (22.6)
41 (38.7)
IFNB-1a i.m
144
90 (62.5)
23 (16-30)
25 (17.4)
40 (27.8)
66 (45.8)
70
44 (62.9)
30 (20-39)
12 (17.1)
15 (21.4)
28 (40.0)
GA
261
123 (47.1)
33 (26-40)
26 (10.0)
48 (18.4)
88 (33.7)
DMF
245
78 (31.8)**
25 (19-30)
35 (14.3)
50 (20.4)
72 (29.4)
IFNB-1b
Teriflunomide
39
24 (61.5)
13 (7-19)*
12 (30.8)*
17 (43.6)*
24 (61.5)*
Azathioprine
72
36 (50.0)
46 (30-62)
12 (16.7)
20 (27.8)
25 (34.7)
Fingolimod
113
71 (62.8)
25 (21-29)
10
(8.8)
23 (20.4)
48 (42.5)
Natalizumab
96
68 (70.8)
24 (22-26)
10 (10.4)
21 (21.9)
48 (50.0)
Other second-line DMT§
59
50 (84.7)**
12 (11-13)*
13 (22.0)
34 (57.6)*
47 (79.7)*
25 (24-28)
180 (13.0)
334 (24.2)
560 (40.5)
Overall DMTs°°
1382^
757 (54.8)
° missing DMT type in 5 cases, °°missing time in therapy in 9 cases; § cyclophosphamide n=48, mitoxantrone n=5, alemtuzumab n=3, ocrelizumab n=3; ^16 cases with other therapies included; * p < 0.01, ** p<0.001 (chi-square and log rank tes
31
Table 4. Cox proportional hazard ratio of time to DMT discontinuation at 12 months, at 24 months and at last follow-up in the cohort of 1391 cases starting any DMTs since January 2011 At 24 months
At 12 months Covariate
Adjusted HR (95% CI)
p value
At last follow-up
Adjusted HR (95% CI)
p value
Adjusted HR (95% CI)
p value
Sex Female
Reference
Male
1.10 (0.85-1.41)
Reference 0.46
1.10 (0.91 -1.33)
Reference 0.33
1.09 (0.93 -1.29)
0.27
Age at therapy onset <35 yrs 35+ yrs
Reference 0.96 (0.74-1.26)
Reference 0.79
0.86 (0.70-1.06)
Reference 0.16
0.95 (0.80-1.13)
0.59
Disease duration at therapy onset 0-2 yrs
Reference
3-5 yrs
1.22 (0.85-1.76)
0.29
Reference 1.30 (0.99-1.70)
0.054
1.43 (1.14-1.80)
0.002
6+ yrs
1.70 (1.26-2.29)
< 0.001
1.62 (1.30-2.02)
< 0.001
1.70 (1.41-2.04)
<0.001
DMTs:
Reference
.
IFNs
Reference
GA
0.63 (0.45-0.89)
0.009
Reference 0.80 ( 0.62- 1.04)
0.091
Reference 0.77 (0.62-0.95)
0.015
Natalizumab
1.09 (0.68-1.75)
0.72
0.84 (0.61-1.15)
0.27
1.19 (0.91-1.56)
0.20
Fingolimod
0.70 (0.44-1.10)
0.12
0.89 (0.64-1.23)
0.48
1.01 (0.77 -1.32)
0.95
DMF
0.48 (0.35-0.68)
<0.001
0.55 (0.42-0.72)
<0.001
1.04 (0.80-1.35)
0.75
Teriflunomide
0.87 (0.51-1.51)
0.63
1.06 (0.67-1.65)
0.82
1.99 (1.28-3.09)
0.002
Azathioprine
0.82 (0.50-1.35)
0.44
0.82 (0.53-1.27)
0.38
0.68 (0.47 -0.97)
0.032
DMTs: First-line injective
Reference
First-line oral
0.69 (0.53-0.90)
0.006
Reference 0.71 (0.58-0.88)
0.002
Reference 1.07 (0.87-1.30)
0.52
Second-line
0.99 (0.70-1.38)
0.93
0.90 (0.71-1.13)
0.36
1.19 (0.98-1.45)
0.082
32
*44 cases with missing values; DMT = Disease-modifying treatment; HR= hazard ratio; IFNs= all types of IFNs; GA= glatiramer acetate; DMF = dimethylfumarate. Statistical significant value are in bold, borderline in italic
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Changing therapeutic strategies and persistence to disease-modifying treatments in a population of Multiple Sclerosis patients from Veneto region, Italy Antonio Marangi , Gabriele Farina , Virginia Vicenzi , Stefano Forlivesi , Francesca Calabria , Fabio Marchioretto , Antonio Forgione , Francesca Rossi , Gianola Stenta , Marika Vianello , Alberto Gajofatto , Maria Donata Benedetti PII: DOI: Reference:
S2211-0348(20)30080-8 https://doi.org/10.1016/j.msard.2020.102004 MSARD 102004
To appear in:
Multiple Sclerosis and Related Disorders
Received date: Revised date: Accepted date:
12 May 2019 18 January 2020 7 February 2020
Please cite this article as: Antonio Marangi , Gabriele Farina , Virginia Vicenzi , Stefano Forlivesi , Francesca Calabria , Fabio Marchioretto , Antonio Forgione , Francesca Rossi , Gianola Stenta , Marika Vianello , Alberto Gajofatto , Maria Donata Benedetti , Changing therapeutic strategies and persistence to disease-modifying treatments in a population of Multiple Sclerosis patients from Veneto region, Italy, Multiple Sclerosis and Related Disorders (2020), doi: https://doi.org/10.1016/j.msard.2020.102004
This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.
Highlights
Dimethylfumarate and fingolimod represent the most prescribed DMTs
54,8% of patients stopped their treatment within the last follow-up Dimethylfumarate use predicted higher persistence at 24 months Glatiramer acetate and azathioprine had the highest persistence at last follow-up Longer disease duration was predictive of an increased risk of DMT discontinuation
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Changing therapeutic strategies and persistence to disease-modifying treatments in a population of Multiple Sclerosis patients from Veneto region, Italy Antonio Marangi1*, Gabriele Farina2, Virginia Vicenzi3, Stefano Forlivesi4, Francesca Calabria4, Fabio Marchioretto5, Antonio Forgione6, Francesca Rossi7, Gianola Stenta1, Marika Vianello8, Alberto Gajofatto2, Maria Donata Benedetti9
1
Neurology Unit, St. Bortolo Hospital, Vicenza, Italy
2
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Neurology
B, University of Verona, Verona, Italy 3
Genetics and Molecular Biology Unit, St. Bortolo Hospital, Vicenza, Italy
4
Section of Neurology A, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
5
IRCCS Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy
6
Neurology Unit, Pederzoli Hospital, Peschiera del Garda, Verona, Italy
7
Neurology Unit, Mater Salutis Hospital (AULSS9), Legnago, Verona, Italy
8
OU Neurology, Cà Foncello Hospital, Treviso, Italy
9
Section of Neurology B, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
*Corresponding Author Antonio Marangi Neurology Unit St Bortolo Hospital Viale Rodolfi 37, 36100, Vicenza, Italy Tel +390444753675 E-mail: [email protected]
2
Abstract Background: The availability of new disease-modifying treatments (DMTs) in the last years has changed the therapeutic strategies used in Multiple Sclerosis (MS). We aimed to describe trend in DMTs utilization and persistence to treatment in a large sample of patients attending 10 MS centres from four provinces of Veneto, Italy. Methods: Demographic, clinical and DMTs information of patients regularly followed from January 2011 to August 2018 were recorded and analysed. Persistence at 12, 24 months and at last follow-up was assessed by Kaplan Meier survival analysis. Multivariable Cox- proportional hazard model was used to identify predictors of persistence. Results: Of 3025 MS patients 65.7% were in treatment al last follow-up. Dimethylfumarate (DMF) was the most prescribed single drug among first-line and fingolimod among secondline DMTs. In the cohort of 1391 cases starting any DMT since 2011 12.9% stopped within 6 months, 24% within 12 and 40.3% within 24 months. Disease duration > 5 years at therapy start was predictive of greater risk of discontinuation, while age and sex were not. DMF use was predictive of higher persistence at 12 and 24 months, but not at last follow-up when azathioprine and glatiramer acetate showed the highest persistence compared to other DMTs. Side effects represented the main reason of discontinuation. Conclusion: The use of the new oral DMTs greatly increased since their approval but persistence in the long-term is not better than with old drugs. The treatment choice is still a challenge both for patients and their doctors.
Keywords: Observational studies; Epidemiology; Multiple Sclerosis; Persistence to Treatment; Italy
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1.1 Introduction Over the past decade, MS therapeutic armamentarium has increased considerably to include so far eleven approved disease modifying therapies (DMTs) with varying degrees of efficacy in reducing disease activity (Filippini et al., 2013; Torkildsen et al., 2016). In this crowded pharmacologic landscape, the lack of head-to-head comparisons among different DMTs, along with the absence of well established prognostic markers to predict disease course and response to medications, makes it challenging to choose the appropriate therapy in each individual case (Multiple Sclerosis Coalition 2017). Moreover, DMTs differ by route of administration, dosing schedule, tolerability and safety, all aspects that impact patients’ persistence on therapy (Cramer et al., 2008; Ivanova et al., 2012; Romer and Zettl, 2018; World Health Organization 2003). This scenario is further complicated by the lack of evidence about the long term benefit of DMTs on reducing disability accumulation, along with the scanty amount of information about the safety profile of the latest approved DMTs (Auricchio et al., 2017; Cramer et al., 2008; Filippini et al., 2013; Ivanova et al., 2012; Multiple Sclerosis Coalition 2017; Romer and Zettl, 2018; World Health Organization 2003) . Observational studies on large cohorts of patients are useful to depict the changing pattern of DMTs prescriptions over time, patients and neurologists preferences in the choice of drug, persistence to treatment, benefit and adverse effects (Evans et al., 2016; Lanzillo et al., 2018; Lattanzi et al., 2017; Melesse et al., 2017; Setayeshgar et al., 2019). The purpose of this observational study was to evaluate the changing strategies in drug utilization over the last years and the persistence to different DMTs including azathioprine in a large sample of MS cases from Veneto region, Italy.
1.2 Methods
1.2.1 Study Population
Patients attending the MS centres of the Hub and Spoke network from the Italian provinces of Verona, Vicenza, Treviso and Belluno, covering a population of 2,877,030 inhabitants (https://www.tuttitalia.it/veneto/statistiche/popolazione-andamento-demografico, 2018) were the population frame of this study. According to the diagnostic and therapeutic guidelines for the management of MS adopted from Veneto Region in 2015, a precoded case form has to be filled in by the neurologists taking charge of patients in the Spoke centres and sent yearly to
4
the Hub centre of reference. For the purpose of this study the data, collected retrospectively from January 2013 to March 2016 and prospectively updated from April 2016 to August 2018, were sent to the Hub centre of Verona to be analysed. The spreadsheet collects information on demographic and clinical data, including disability at last follow-up measured by the Expanded Disability Status Scale (EDSS) (Kurtzke, 1983), disease course, clinical and Magnetic Resonance Imaging (MRI) disease activity in the last twelve months; chronological history of MS treatments for each patient including reasons for discontinuation indicated as follows: lack of efficacy, side effects, safety protocol, patient’s choice, pregnancy or stability. In Italy at the time of study glatiramer acetate (GA), interferon beta (IFN-beta) 1a/1b and peginterferon beta-1a, teriflunomide, dimethyl fumarate (DMF) were approved as first-line therapies, while fingolimod, natalizumab, alemtuzumab, mitoxantrone as second-line therapies. Azathioprine and cyclophosphamide are also prescribed and reimbursed for MS in Italy (Gazzetta Ufficiale Italiana 2016) while rituximab is used off-label.
1.2.2 Inclusion criteria All patients with a diagnosis of clinically isolated syndrome (CIS), relapsing remitting (RR), primary progressive (PP) or secondary progressive (SP) MS according to 2010 McDonald criteria (Polman et al., 2011) regularly attending the aforementioned MS centres were included in the study. Patients with diagnoses of demyelinating diseases other than MS or CIS were excluded.
1.2.3 Outcomes The study outcomes were to describe DMT utilization and persistence to treatment throughout the study period, 2011-2018. For the analysis, we chose to include patients who started a DMT (“index therapy”), any time after January 2011 (year of the approval of fingolimod as the first oral drug specific for MS in Italy). Persistence to treatment was defined as the median time in months between the beginning and the withdrawal of a given DMT. The reasons for DMT discontinuation were defined as 1) inefficacy (clinical and/or MRI activity and/or disability progression), 2) side effects related to DMTs, 3) drug interruption according to standardized protocols (e.g. positivity for anti-JCV testing after 24 months of natalizumab treatment, or a limiting dose of 120 mg/m2 for mitoxantrone), 4) autonomous decision of the patient, 5) desire of motherhood, 6) clinical stability.
5
1.2.4 Statistical analysis Absolute counts and percentages are provided for categorical variables, while means, standard deviation (SD), and medians for continuous variables as appropriate. Differences between groups were analysed by using the chi-square and ANOVA tests. Persistence to therapy was analysed by the Kaplan-Maier survival method, using the log-rank test for comparisons between groups. The cumulative time in treatment was defined as the interval in months between DMT onset and discontinuation or last follow-up, whichever came first, in reference to any assigned drug since 2011. Potential predictors of persistence were gender, age at therapy onset (≤35 or >35 years), disease duration at therapy onset (≤2, 3-5, 6+ years) and type of prescribed DMT. Multivariable Cox-proportional hazard model was used to analyse the associations between potential predictors and persistence to treatment at 12 and 24 months, and at last follow-up. Hazard ratios and 95% confidence intervals (CI) were reported as estimates of association. The adopted level of statistical significance was α= 0.05 (two-sides test). Statistical analyses were performed by using IBM SPSS v. 21. 1.3 Results
1.3.1 Overall population of cases The general characteristics of 3025 MS patients, 2013 women (66.5%), mean age at last follow-up 48.2 (±12.4) years, are reported in Table 1. At the last follow-up 1989 cases (65.7%) were on treatment, 1482 (74.5%) with a first-line and 507 (25.5%) with a second-line therapy. DMF was the most prescribed single drug among first-line therapies (433 cases, 29% of this group), while fingolimod was the most used second-line DMT (270 patients, 53% of second line cases). 1.3.2 Trend in DMTs utilization The cohort selected to analyse DMT utilization and persistence included 1391 patients (66.5% women, mean age at therapy 40.4±11.6 years) who started any DMT since January 2011 (Table 2). Figure 1 shows the changing profile of treatments in this cohort of cases over the years: the decline in first-line injective drugs prescriptions was evident mostly for IFNs as a group (from 56% in 2011-2012 to 15% in 2017-2018), while the newly approved DMF rapidly overtook the other treatments (up to 48% in 2017-2018). Second-line treatments as cyclophosphamide and rituximab also increased to 8% in the last four years. About 49% (n 681) of
6
this cohort were naïve cases (missing information, n=9): they had a lower EDSS score at last follow-up (median 1.5) and shorter disease duration at the index therapy onset (median 3 years) compared to not naïve patients (median EDSS 2.5, median disease duration 6 years) (p<0.001). The median time of follow-up since index therapy was 36 months (range 1- 84 months), significantly longer in not naïve compared to naïve patients (42 versus 24 months, p<0.001). 1.3.3 Persistence to treatment In all, 757/1382 patients (54.8%) (time on DMT missing in 9 cases), discontinued their treatment: 180 (13%) within 6 months mostly for side effects (65%), 334 (24.2%) within 12 months and 560 (40.5%) within 24 months from onset (Figure 2). Persistence by type of treatment at last follow-up, at 12 and 24 months and overall median persistence in months (95% CI) are shown in Table 3. Discontinuation rate was significantly lower in DMF and higher for second-line DMTs treated cases (p<0.001, chi-square test). Overall median persistence was lower in teriflunomide cases (p=0.001, log rank test), for which discontinuation was mostly due to side effects, although the number of treated cases with this DMT was low. Second-line treatments different from natalizumab and fingolimod were also associated to higher discontinuation at 12 and 24 months, mostly for therapeutic protocols related to safety (mitoxantrone and cyclophosphamide) (p<0.01, chi-square test). In order to exclude the possible confounding effect of progressive cases, we also performed a subgroup analysis regarding RR patients (No 1191, 85,6%), whose discontinuation rate of 54,3% (647/1191) turned out ot be equal to what we found in the entire population of patients. Similarly, persistence for each DMT was generally comparable to that seen in the general cohort of subjects (data not shown). Kaplan Meier analyses showed that persistence was longer in cases with shorter disease duration at index therapy (p<0.001, log rank test), in patients treated with fingolimod or natalizumab compared to other second-line DMTs (p<0.001, log rank test), and in DMF or azathioprine treated cases compared to those in teriflunomide (p<0.001, log rank test) (Figure 3 A,B,C). No difference in persistence between IFNs subtypes was evident, while a longer persistence in GA versus IFNs treated cases was of borderline significance (Figure 3 D,E). When considering the long-term overall persistence, no differences were found between injective and oral first-line DMTs (Figure 3 F). Median time in treatment (index DMT) was 15 months (range 1-84), significantly longer in naïve compared to not naïve cases (median 17.5 and 14 months, respectively (p<0.001). As shown in the Cox analysis (Table 4), a disease duration over 5 years at the time of index therapy onset was predictive of increased risk of treatment
7
discontinuation, while sex and age were not. At 12 and 24 months first-line oral DMTs considered as a group, and DMF as single drug, were associated to a significantly higher persistence compared to injectable or second-line DMTs. However, at last follow-up this difference was lost, while azathioprine and GA showed better persistence compared to other DMTs, and teriflunomide was associated to a higher risk of discontinuation. 1.3.4 Reasons for DMTs discontinuation Side effects were the most frequent reason for discontinuing DMT (298/757 cases, 39%), followed by lack of efficacy (265 cases, 35%), safety protocol (65 cases, 8.5%), patient’s choice (43 cases, 5.6%), pregnancy (31, 4.1%) and disease inactivity (9 cases, 1.2%) (unknown reason in 46 cases, 6%). Among first-line drugs side effects were more common with teriflunomide (61%) or DMF (60%) while lack of efficacy with self-injectable DMTs compared to oral drugs (mean percentage respectively 38 and 30% (p<0.05) (Figure 4). In the natalizumab group, 65% of patients discontinued because of safety reason (JCV positive serology) and only 5% because of lack of efficacy. Fingolimod cases displayed 50% of inefficacy, with 32% of these patients previously treated with natalizumab. Overall, treatment discontinuation due to lack of efficacy occurred later (17 months, 95% CI 14-20) than withdrawal due to adverse events (11 months, 95% CI 9-13) (p < 0.001, log rank test). After discontinuation of any firstline DMT, 23% of patients remained off treatment, 49% switched to another DMT of the same line while in 26% an escalation to a second-line drug was decided (no information in 10 cases). Among patients who discontinued their second-line therapy, 24% remained off treatment, 42% switched to another second-line DMT and 31% shifted down to a first line therapy (no information in 6 cases). Fig. 5 shows therapeutic strategies by reason of discontinuation.
1.4 Discussion To our knowledge this is the first Italian observational study to analyse the trend in prescriptions over the last years and to include an old drug similar in effects to IFN-beta, i.e. azathioprine (Massacesi et al., 2014), in the analysis of persistence to treatment.
Near-
ly 66% of the 3025 patients were on DMT therapy at last follow-up. A similar proportion, 62%, was found in the Stockholm County (Eriksson et al., 2018), while 51% of patients registered at MS clinics in British Columbia were in treatment (McKay et al., 2016). A recent update from a longitudinal cohort of MS cases in U.S.A. reported an increase in DMT use from 55.3% in 2000 to 61.5% in 2009 (Minden et al., 2019). Considering the low median EDSS (2.0) at last follow-up, it is evident that in our patients DMTs were largely used in the less se-
8
vere forms of MS. In other studies based on administrative databases this information was unavailable (Eriksson et al., 2018; Minden et al., 2019). The trend of prescriptions in the cohort of cases starting any DMT since 2011 reflects the sequential introduction and reimbursement in Italy of the oral drugs for MS (fingolimod in 2011, terifunomide in 2014 and DMF in 2015). The concomitant decline of the old first-line injective DMTs (mostly IFN-beta) was observed everywhere, from British Columbia where the first-generation DMTs decreased by 30% (Setayeshgar et al., 2018) to Sweden where DMF and fingolimod approval impacted significantly DMT prescriptions (Eriksson et al., 2018), to Japan where the share of fingolimod in 2015 (26%) was comparable with that of IFN (28%) (Ogino et al., 2017). More than half of our patients stopped their DMT at some point of follow-up, and this was also confirmed in the subanalysis restricted to only RR patients. Interestingly, in 39% of cases discontinuation was due to side effects. These findings are in line with an observational study on 486 MS patients which found that 46% of participants discontinued or modified their DMT within 2.5 years from drug introduction (Longbrake et al., 2016), while in a recent multicenter Italian study the rate of discontinuation at 12 months with first-line DMTs was 20% (Lanzillo et al., 2018). In a Canadian population study about 18% of 4830 MS subjects receiving IFNs or GA discontinued their treatment within 12 months (Evans et al., 2016) while in a large retrospective French cohort almost 40% of cases stopped injectable DMTs at 24 months (Defer et al., 2018). We did not find substantial differences in persistence between IFN beta formulations, least of all a favourable relation with a lower frequency of administration as previously observed (Correia et al., 2016). A higher persistence in GA versus IFN treated cases was already suggested (Zhornitsky et al., 2015), although several studies showed that the effectiveness of injectable DMTs was quite similar (Bartolome-Garcia et al., 2019; Defer et al., 2018; Longbrake et al., 2016; Melesse et al., 2017). Our Cox analysis showed that first-line oral DMTs were predictive of higher persistence compared to injectable DMTs only at 12 and 24 months but not at last follow-up, and azathioprine and GA were surprisingly associated to better persistence. Although oral DMTs were expected from both patients and neurologists as convenient alternatives to injective drugs, several studies did not find differences in the discontinuation rate between oral and injectable DMTs (Ferraro et al., 2018; Lanzillo et al., 2018; Longbrake et al., 2016). In a recent Canadian cohort study the rate of discontinuation to oral DMTs was 20% by 12 months (Setayeshgar et al., 2019), similar to that found previously for injective DMTs in the same population (Evans et al., 2016). Fingolimod in our cases was not so favourably associated to persistence as
9
reported in other studies (Kalincik et al., 2019; Lattanzi et al., 2017), likely due to the high proportion of switching from natalizumab, and this was also demonstrated by the subanalysis restricted to RR patients, which confirmed the high discontinuation rates with this drug (60% at last follow-up). Interestingly, an important issue for fingolimod turned out being naïve for any previous DMT, since 40 of the 42 patients who did not stop the drug had not been exposed to other previous DMTs. However, it should be noted that studies showing a higher persistence rate for fingolimod compared to self-injectable DMTs might have been conditioned by possible conflicts of interest (Johnson et al., 2017; Kantor et al., 2018). It is evident that persistence decreases with the increasing duration of follow-up. On the other hand, the availability of new treatments may increase the possibility to try other therapies, considering that in our, as in other studies, the main reason of stopping DMTs were side effects (Ferraro et al., 2018; Longbrake et al., 2016; Zhornitsky et al., 2015. Among our patients discontinuing DMTs, the choice of another first or second line drug was strictly related to the reason of discontinuation, with escalation towards a more potent drug as the common choice in case of disease activity, and “lateral” switch in case of side effects. Finally, we found that a longer disease duration at the time of index therapy onset was predictive of an increased risk of discontinuation, as already observed (Melesse et al., 2017), while age and sex were not. Other studies observed a higher DMT discontinuation in younger patients (Ferraro et al., 2018; Longbrake et al., 2016; Melesse et al., 2017; Zhornitsky et al., 2015) and in women (Lanzillo et al., 2018; Zettl et al., 2017). Limitations of our work include the typical biases of retrospective design, i.e. missing data, for the correction of which we excluded from the analysis frankly inaccurate patients’ forms; the non-enforceability of our findings for the general MS population, as proven by the underrepresentation of progressive variants, probably because of the lack of approved treatments at the time of the study. Secondly, given the tendency of a certain number of MS patients to search for experimental treatments outside the regional or provincial boundaries, a proportion of cases may be missed. Thirdly, the number of cases in teriflunomide was low, limiting conclusions on its use. Furthermore, information about EDSS score at the starting of index therapy, a potential predictor of treatment discontinuation, was lacking. In conclusion, although the therapeutic strategies in MS have changed dramatically over the last years, persistence in the long-term remains a concerning factor in this disease. These findings suggest the need for detecting well-defined predictive markers of long-term response to the treatment, which still represents a challenge both for patients and their doctors.
10
Statement of Ethics The current study respected the ethical principles depicted in the Declaration of Helsinki. The study protocol has been approved by ethics committees of the coordinating Hub centre of Verona and the Hub centres of Vicenza and Treviso. No data used in the analyses contained any patient identifiers.
11
Conflicts of interest:
AM, GF, VV, SF, FC, FM, AF, FR, GS, MV and MDB have no conflicts of interest. AG received research support funding and advisory board honoraria from Merck.
Funding Sources This study was funded by a grant from Regione Veneto (RSF2014-00000415). The funder had no role in study design, data collection and analysis, and manuscript preparation
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Contributions AM: acquisition, analysis, and interpretation of data, drafting of the manuscript, critical revision of the manuscript content. GF, VV: acquisition of data, database implementation, critical revision of the manuscript content. SF: conception and design of the study, critical revision of the manuscript content. FC, FF, AF, FR, GS, MV, AG: acquisition of data, critical revision of the manuscript content. MDB: conception and design of the study, acquisition, analysis, interpretation of data, critical revision of the manuscript content. Acknowledgments The authors would like to thank Dr Loredana La Mantia for her useful comments and suggestions.
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23. Ogino M, Okamoto S, Ohta H, et al. Prevalence, treatments and medical cost of multiple sclerosis inJapan based on analysis of a health insurance claims database. Clinical and Experimental Neuroimmunology 2017:8:318–326 24. Longbrake EE, Cross AH, Salter A. Efficacy and tolerability of oral versus injectable disease-modifying therapies for multiple sclerosis in clinical practice. Mult Scler J Exp Transl Clin 2016 Jan-Dec:2 25. Defer G, de Seze J, Bouee S, et al. Outcomes and treatment management of a French cohort suffering from multiple sclerosis: A retrospective epidemiological study. Mult Scler Relat Disord 2018 Oct;25:276-281. 26. Correia I, Marques IB, Sousa M, et al. Predictors of first-line treatment persistence in a Portuguese cohort of relapsing-remitting multiple sclerosis. J Clin Neurosci 2016; Nov;33:73-78. 27. Zhornitsky S, Greenfield J, Koch MW, et al. Long-term persistence with injectable therapy in relapsing-remitting multiple sclerosis: a 18-year observational cohort study. PLoS One 2015;10(4):e012382. 28. Bartolome-Garcia E, Usarralde-Perez A, Sanmartin-Fenollera P, et al. Persistence and adherence to interferon and glatiramer acetate in patients with multiple sclerosis. Eur J Hosp Pharm 2019;26:23–28. 29. Ferraro D, Camera V, Baldi E, et al. First-line disease-modifying drugs in relapsingremitting multiple sclerosis: an Italian real-life multicenter study on persistence. Curr Med Res Opin 2018; 34:1803-1807. 30. Kalincik T, Kubala Havrdova E, Horakova D, et al. Comparison of fingolimod, dimethyl fumarate and teriflunomide for multiple sclerosis. J Neurol Neurosurg Psychiatry 2019; Apr;90(4):458-468 31. Johnson KM, Zhou H, Lin F, et al. Real-World Adherence and Persistence to Oral Disease-Modifying Therapies in Multiple Sclerosis Patients Over 1 Year. J Manag Care Spec Pharm 2017;23(8):844-52. 32. Kantor D, Johnson K, Vieira MC, et al. Real-world persistence with fingolimod for the treatment of multiple sclerosis: A systematic review and meta-analysis. J Neurol Sci 2018;388:168-174. 33. Zettl UK, Schreiber H, Bauer-Steinhusen U, et al; BETAPATH Study Group. Baseline predictors of persistence to first disease-modifying treatment in multiple sclerosis. Acta Neurol Scand 2017;136:116-121.
16
17
60
50
%
40
30
20
10
0 2011-2012 IFNs
GA
Natalizumab
2013-2014 Fingolimod
2015-2016 Other second-line
2017-2018 AZA
DMF
Teriflunomide
Fig. 1 Trend in drug prescription from 2011 to 2018 in the cohort of 1391 MS cases starting DMTs since January 2011. DMT= disease modifying treatment; GA= glatiramer acetate; DMF = dimethyl fumarate
18
Total MS cases n=3025 Excluded cases starting DMT before 2011 n=1634 Persistence cohort starting DMT since 2011 n=1391 180 cases discontinued DMT ≤ 6 months 158 cases censored 334 cases discontinued DMT ≤ 12 months 309 cases censored 560 cases discontinued DMT ≤ 24 months 422 cases censored
n = 338
Missing time in DMT n=9 > 6 months of DMT therapy n=1044
n = 643
> 12 months of DMT therapy n=739
n = 982
> 24 months of DMT therapy n=400
Fig. 2 Flowchart of the MS cases included in the persistence analysis.
19
Fig. 3 A. Kaplan Meier survival analyses by disease duration at index therapy
20
Fig. 3 B. Kaplan Meier survival analyses by second-line DMTs
21
Fig. 3 C. Kaplan Meier survival analyses by first-line oral DMTs
22
Fig. 3 D Kaplan Meier survival analyses by IFNs different formulations
23
Fig. 3 E Kaplan Meier survival analyses by first-line injective DMTs
24
Fig. 3 F Kaplan Meier survival analyses by first-line oral or injective DMTs
25
Fig. 4 Reasons for treatment discontinuation by DMTs
26
27
Fig. 5 Therapeutic strategies after discontinuation because of inefficacy (A) or side effects (B)
28
Table 1. General characteristics of the overall group of MS patients (N=3025) Sex (n, %) Women 2013 66.5% Men 1012 33.5% Age at last follow-up (yrs, mean±SD)(range) 48.2 ±12.4 (16-88 yrs) Type of MS (n, %)° CIS RR SP PP Age at disease onset (yrs, mean±SD)
185 6.1% 2213 73.2% 402 13.3% 200 6.5% 32.9±10.8
Median disease duration at last follow-up (range)
12 yrs (1 mo.-68 yrs)
Median EDSS at last follow-up (range)
2.0
In DMT* at last follow-up (n, %)** First-line drugs Second-line drugs Type of DMT at last follow-up (n, %) IFNBs DMF GA Fingolimod Natalizumab Azathioprine Teriflunomide Other second-line DMT°° Other first-line DMT Any DMT onset 1992-2000 2001-2005 2006-2010 2011-2014 2015-2018
1991 1484 507
65.8% 74.5% 25.5%
493 433 315 270 188 133 89 49 21
24.8% 21.7% 15.8% 13.6% 9.4% 6.7% 4.5% 2.4% 1.1%
91 224 613 821 570
3.9% 9.7% 26.4% 35.4% 24.6%
Patients never treated with DMTs
706
23,3%
(0-9)
° CIS= Clinically Isolated Syndrome, RR= Relapsing-Remitting, SP= Secondary Progressive, PP= Primary Progressive; Radiologically Isolated Syndrome (RIS) in 19 cases; unknown MS type in 6 cases * Disease-modifying treatment ** no information in 89 cases (3%); no treatment in 945 cases (31%) °° alemtuzumab n=17, cyclophosphamide n=7, ocrelizumab n=17, rituximab n=8
29
Table 2. Characteristics of the cohort of 1391 patients who started any DMT since January 2011 Sex (n, %) Women
925
66.5%
Men
466
33.5%
Age at last follow-up (yrs, mean±SD)(range) Age at disease onset ((yrs, mean±SD) RRMS§ (n, %)
44.4±11.6 (18-79yrs) 32.6±10.7 1191
Median EDSS at last follow-up (range) In DMT^ at last follow-up (n, %)
2.0
85.6% (0-8.5)
1202
86.4%
First-line injective drugs
442
36.8%
First-line oral drugs*
455
37.9%
Second-line drugs
305
25.4%
No DMT
704
50.6%
1 DMT
336
24.2%
2 DMT
222
16.0%
3 or more DMT
124
8.9%
2011-2012
373
26.8%
2013-2014
447
32.2%
2015-2016
423
30.4%
2017-2018
148
10.6%
Number of treatments before the current one (n, %)**
Year of index therapy onset
Age at onset of index therapy (yrs, mean±SD)** Median disease duration at index therapy (range)° Median follow-up since index therapy onset (months, range) Naïve cases at index therapy (n, %)
40.4±11.6 5 yrs (1 month-52 yrs) 36 (1-84) 681
49.0%
within 6 months
180
12.9%
within 12 months
334
24.0%
within 24 months
560
40.3%
within last follow-up
757
54.8%
Cases discontinuing index therapy (n, %)
§ Relapsing Remitting MS ^ Disease-modifying treatment * Oral methotrexate in 10 PP cases included ** missing in 5 cases; ° missing in 35 cases
30
Table 3. Persistence by type of treatment in the cohort of 1391 MS patients who started DMT since January 2011 Cases who Median persisCases who discontinuated DMTs within (%) Number discontinuated tenc time in -----------------------------------------------------Drug° of cases DMTs (%) months (95% CI) 6 months 12 months 24 months All IFNs
485
296 (61.0)
27 (24-32)
60 (12.4)
115 (23.7)
200 (41.2)
IFNB-1a 22 mcg
165
97 (58.8)
29 (24-37)
13
(7.9)
36 (21.8)
65 (39.4)
IFNB-1a 44 mcg
106
65 (61.3)
29 (22-35)
10
(9.4)
24 (22.6)
41 (38.7)
IFNB-1a i.m
144
90 (62.5)
23 (16-30)
25 (17.4)
40 (27.8)
66 (45.8)
70
44 (62.9)
30 (20-39)
12 (17.1)
15 (21.4)
28 (40.0)
GA
261
123 (47.1)
33 (26-40)
26 (10.0)
48 (18.4)
88 (33.7)
DMF
245
78 (31.8)**
25 (19-30)
35 (14.3)
50 (20.4)
72 (29.4)
IFNB-1b
Teriflunomide
39
24 (61.5)
13 (7-19)*
12 (30.8)*
17 (43.6)*
24 (61.5)*
Azathioprine
72
36 (50.0)
46 (30-62)
12 (16.7)
20 (27.8)
25 (34.7)
Fingolimod
113
71 (62.8)
25 (21-29)
10
(8.8)
23 (20.4)
48 (42.5)
Natalizumab
96
68 (70.8)
24 (22-26)
10 (10.4)
21 (21.9)
48 (50.0)
Other second-line DMT§
59
50 (84.7)**
12 (11-13)*
13 (22.0)
34 (57.6)*
47 (79.7)*
25 (24-28)
180 (13.0)
334 (24.2)
560 (40.5)
Overall DMTs°°
1382^
757 (54.8)
° missing DMT type in 5 cases, °°missing time in therapy in 9 cases; § cyclophosphamide n=48, mitoxantrone n=5, alemtuzumab n=3, ocrelizumab n=3; ^16 cases with other therapies included; * p < 0.01, ** p<0.001 (chi-square and log rank tes
31
Table 4. Cox proportional hazard ratio of time to DMT discontinuation at 12 months, at 24 months and at last follow-up in the cohort of 1391 cases starting any DMTs since January 2011 At 24 months
At 12 months Covariate
Adjusted HR (95% CI)
p value
At last follow-up
Adjusted HR (95% CI)
p value
Adjusted HR (95% CI)
p value
Sex Female
Reference
Male
1.10 (0.85-1.41)
Reference 0.46
1.10 (0.91 -1.33)
Reference 0.33
1.09 (0.93 -1.29)
0.27
Age at therapy onset <35 yrs 35+ yrs
Reference 0.96 (0.74-1.26)
Reference 0.79
0.86 (0.70-1.06)
Reference 0.16
0.95 (0.80-1.13)
0.59
Disease duration at therapy onset 0-2 yrs
Reference
3-5 yrs
1.22 (0.85-1.76)
0.29
Reference 1.30 (0.99-1.70)
0.054
1.43 (1.14-1.80)
0.002
6+ yrs
1.70 (1.26-2.29)
< 0.001
1.62 (1.30-2.02)
< 0.001
1.70 (1.41-2.04)
<0.001
DMTs:
Reference
.
IFNs
Reference
GA
0.63 (0.45-0.89)
0.009
Reference 0.80 ( 0.62- 1.04)
0.091
Reference 0.77 (0.62-0.95)
0.015
Natalizumab
1.09 (0.68-1.75)
0.72
0.84 (0.61-1.15)
0.27
1.19 (0.91-1.56)
0.20
Fingolimod
0.70 (0.44-1.10)
0.12
0.89 (0.64-1.23)
0.48
1.01 (0.77 -1.32)
0.95
DMF
0.48 (0.35-0.68)
<0.001
0.55 (0.42-0.72)
<0.001
1.04 (0.80-1.35)
0.75
Teriflunomide
0.87 (0.51-1.51)
0.63
1.06 (0.67-1.65)
0.82
1.99 (1.28-3.09)
0.002
Azathioprine
0.82 (0.50-1.35)
0.44
0.82 (0.53-1.27)
0.38
0.68 (0.47 -0.97)
0.032
DMTs: First-line injective
Reference
First-line oral
0.69 (0.53-0.90)
0.006
Reference 0.71 (0.58-0.88)
0.002
Reference 1.07 (0.87-1.30)
0.52
Second-line
0.99 (0.70-1.38)
0.93
0.90 (0.71-1.13)
0.36
1.19 (0.98-1.45)
0.082
32
*44 cases with missing values; DMT = Disease-modifying treatment; HR= hazard ratio; IFNs= all types of IFNs; GA= glatiramer acetate; DMF = dimethylfumarate. Statistical significant value are in bold, borderline in italic
33