Original Paper Eur Neurol 2014;71:233–241 DOI: 10.1159/000356786
Received: August 13, 2013 Accepted: October 27, 2013 Published online: January 25, 2014
From High- to Low-Frequency Administered Interferon-Beta for Multiple Sclerosis: A Multicenter Study Luca Prosperini a, b Chiara Rosa Mancinelli a Carlo Pozzilli a, b Maria Grazia Grasso c Alessandro Clemenzi c Sara Collorone b Simona Pontecorvo b, i Ada Francia b Veronica Villani d Tatiana Koudriavtseva d Fabio Buttari c, e Diego Centonze c, e Giancarlo Di Battista f Giovanni Frisullo g Simonetta Galgani h Claudio Gasperini h a
S. Andrea Hospital, Sapienza University, b Department of Neurology and Psychiatry, Sapienza University, c S. Lucia Foundation, IRCSS, d Neurology Unit, Regina Elena National Cancer Institute, e Department of Neurosciences, Tor Vergata University, f Neurology Unit, S. Filippo Neri Hospital, g Department of Neurology, University of Sacred Heart, h Department of Neurosciences, S. Camillo-Forlanini Hospital, Rome, and i IRCSS NeuroMed Institute, Pozzilli, Italy
Key Words Multiple sclerosis · Interferon-beta · Adherence · Frequency reduction · Disability
Abstract Objectives: To investigate whether clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) who required a reduction of administration frequency of interferon-beta (IFNB) were similar to those of patients who did not. Methods: We identified three subgroups of patients under treatment for 24 months with subcutaneous (sc) high-frequency IFNB-1a or -1b: those continuing to receive IFNB according to the drug label (recommended frequency group), those reducing the administration frequency of sc IFNB-1a or -1b (reduced frequency group), and those switched to once weekly intramuscular (im) IFNB (switched group). All patients were followed for further 24 months. The occurrence of relapse, MRI activity and disability worsening were considered as outcome measures. Results: We identified 308 patients, 201 in the recommended frequency group, 70 in the reduced frequency group, and 37
© 2014 S. Karger AG, Basel 0014–3022/14/0716–0233$39.50/0 E-Mail [email protected] www.karger.com/ene
in the switched group. Patients in the reduced frequency group had increased risk for relapses (HR = 1.95, p < 0.001) and MRI activity (HR = 1.41, p < 0.001), while patients in the switched group had increased risk for relapses (HR = 1.67, p = 0.012), but not for MRI activity (HR = 1.26, p = 0.08) than those in the recommended frequency group. Predictors for disease activity re-start after the reduction of IFNB administration frequency were younger age, higher pre-IFNB relapse rate, and reducing sc IFNB frequency to twice weekly rather than switching to im IFNB-1a once weekly. Conclusion: Our findings discourage the reduction of sc IFNB administration frequency, especially in younger patients with a higher preIFNB relapse rate. However, switching to im IFNB-1a may be considered in some selected cases. © 2014 S. Karger AG, Basel
Introduction
Multiple sclerosis (MS) is a life-long disease that requires long-lasting treatment to avoid relapses and accumulation of disability, especially in patients affected by a relapsing-remitting (RR) course. Although interferonLuca Prosperini MS Center, S. Andrea Hospital Department of Neurology and Psychiatry, Sapienza University Viale dell’Università, 30, IT–00185 Rome (Italy) E-Mail luca.prosperini @ uniroma1.it
beta (IFNB) treatment has convincingly demonstrated its beneficial effect in modifying the disease course of RR MS [1–3], it is often associated with poor tolerated side effects, such as flu-like syndrome and injection-site reactions [4]. Over the course of their treatment, IFNB-treated patients are often likely to face challenges to their adherence, i.e. the extent to which a person’s behavior corresponds with agreed recommendations from a healthcare provider [5]. It has been reported that 17–46% patients discontinue IFNB, especially within the first 6 months to 2 years from the beginning [6]. Although a relevant proportion of patients discontinue IFNB due to lack of efficacy, an equally relevant proportion does this due to poor tolerability [6, 7]. Furthermore, injection-related problems (anxiety, tiredness, injection-site pain or reactions) are other important reasons for non-adherence to IFNB, together with forgetting to administer, even in patients treated for more than 2 years [8–10]. A proportion ranging from 23 to 46% of patients treated with immunomodulating injective drugs have been reported as not adherent to IFNB treatment, in terms of both recommended dose and timing [7]. Adherence rates tend also to decline with increasing frequency of injection [8, 9, 11, 12]. In the daily clinical setting, some patients may require switching from high-frequency subcutaneous (sc) IFNB to intramuscular (im) IFNB-1a once weekly (ow). Alternatively, a reduction of administration frequency of sc IFNB-1a or -1b can sometimes be intentionally (to reduce intolerable side effects) or unintentionally (in the case of forgetting to administer) adopted by patients [8–10]. However, the long-term consequences on disease activity of reducing administration frequency of sc IFNB are still largely unknown. In this multicenter, retrospective, post-marketing study, we aimed to investigate whether clinical and magnetic resonance imaging (MRI) outcomes of patients who required a reduction of IFNB frequency were similar to those of patients who did not. Potential predictors for experiencing relapses, disability progression and/or MRI activity after the reduction of IFNB frequency were also investigated.
Methods Data from eight MS Centers in Rome were collected. To be enlisted in this study, patients must have the following characteristics: age from 18 to 65 years (inclusive); diagnosis according to McDonald criteria [13], with RR disease course; Expanded Disability Status Scale (EDSS) [14] score from 0 to 6.5 (inclusive), and
234
Eur Neurol 2014;71:233–241 DOI: 10.1159/000356786
regular follow-up from the diagnosis to more recent neurological assessment. Patients had also to be treated with one of the currently available IFNB formulations as first-line therapy, such as sc IFNB-1b 250 μg every other day (eod) or sc IFNB-1a 22 or 44 μg three times per week (tpw), without experiencing relapses, disability progression or MRI activity from IFNB start to 24 (±6) months. Among them, we identified three groups of patients: (1) those who continued to receive high-frequency sc IFNB-1a or -1b according to the drug label (recommended frequency group); (2) those who required a reduction of IFNB frequency, spontaneously dropping the administration frequency of sc IFNB-1a or -1b to twice weekly (reduced frequency group), and (3) those who switched to im IFNB-1a ow (switched group). To be allocated in the reduced frequency group or switched group, a patient had to change treatment regimen after 24 (±6) months from IFNB start owing to poor tolerability, including persistent flu-like symptoms, injection-site reaction or anxiety, tiredness of taking injections. Adherence and persistence were assessed as patient-reported information. Patients whose data on compliance, adherence and persistence to treatment were not available or not well documented over time were not considered in the analyses. Lastly, patients with previous exposure to immunosuppressant or experimental agents, and those who reduced the IFNB administration frequency for reasons other than poor tolerability (e.g. leukopenia, liver enzyme increase, thyroid abnormalities, mood disorders) were excluded. All patients were followed up for a further 24 months from the transition time-point, i.e. the clinical assessment nearest to an entire 24-month period of IFNB treatment (for the recommended frequency group), or the time at which the administration frequency of IFNB was reduced, i.e. after 24 (±6) months from IFNB start (for the reduced frequency group and switched group). Clinical and MRI data were retrospectively collected and stored into an electronic database (after obtaining informed consent from each patient). Patient management was conducted in accordance with the International Conference on Harmonization Guidelines of Good Clinical Practice and the Declaration of Helsinki. Given its retrospective design, this study in no way interfered in the care received by patients. Outcome Definition The following outcomes were considered over the 24-month follow-up after the transition time-point: (i) occurrence of relapse(s); (ii) presence of MRI activity, and (iii) sustained EDSS worsening. A relapse was defined as the appearance or reappearance of one or more symptoms attributable to MS, accompanied by objective deterioration on neurological examination lasting at least 24 h [13]. MRI activity was defined as the presence of one or more contrast-enhancing lesions during the 24-month follow-up. The development of new or enlarged T2-hyperintense was not considered as outcome measure since we could not be confident in reliable comparisons of MRI scan over time owing the multicenter design of this study. Sustained EDSS worsening was defined as a 1.5-point increase (if the previous EDSS score was 0), or a 1-point increase (if the previous EDSS score was
Received: August 13, 2013 Accepted: October 27, 2013 Published online: January 25, 2014
From High- to Low-Frequency Administered Interferon-Beta for Multiple Sclerosis: A Multicenter Study Luca Prosperini a, b Chiara Rosa Mancinelli a Carlo Pozzilli a, b Maria Grazia Grasso c Alessandro Clemenzi c Sara Collorone b Simona Pontecorvo b, i Ada Francia b Veronica Villani d Tatiana Koudriavtseva d Fabio Buttari c, e Diego Centonze c, e Giancarlo Di Battista f Giovanni Frisullo g Simonetta Galgani h Claudio Gasperini h a
S. Andrea Hospital, Sapienza University, b Department of Neurology and Psychiatry, Sapienza University, c S. Lucia Foundation, IRCSS, d Neurology Unit, Regina Elena National Cancer Institute, e Department of Neurosciences, Tor Vergata University, f Neurology Unit, S. Filippo Neri Hospital, g Department of Neurology, University of Sacred Heart, h Department of Neurosciences, S. Camillo-Forlanini Hospital, Rome, and i IRCSS NeuroMed Institute, Pozzilli, Italy
Key Words Multiple sclerosis · Interferon-beta · Adherence · Frequency reduction · Disability
Abstract Objectives: To investigate whether clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) who required a reduction of administration frequency of interferon-beta (IFNB) were similar to those of patients who did not. Methods: We identified three subgroups of patients under treatment for 24 months with subcutaneous (sc) high-frequency IFNB-1a or -1b: those continuing to receive IFNB according to the drug label (recommended frequency group), those reducing the administration frequency of sc IFNB-1a or -1b (reduced frequency group), and those switched to once weekly intramuscular (im) IFNB (switched group). All patients were followed for further 24 months. The occurrence of relapse, MRI activity and disability worsening were considered as outcome measures. Results: We identified 308 patients, 201 in the recommended frequency group, 70 in the reduced frequency group, and 37
© 2014 S. Karger AG, Basel 0014–3022/14/0716–0233$39.50/0 E-Mail [email protected] www.karger.com/ene
in the switched group. Patients in the reduced frequency group had increased risk for relapses (HR = 1.95, p < 0.001) and MRI activity (HR = 1.41, p < 0.001), while patients in the switched group had increased risk for relapses (HR = 1.67, p = 0.012), but not for MRI activity (HR = 1.26, p = 0.08) than those in the recommended frequency group. Predictors for disease activity re-start after the reduction of IFNB administration frequency were younger age, higher pre-IFNB relapse rate, and reducing sc IFNB frequency to twice weekly rather than switching to im IFNB-1a once weekly. Conclusion: Our findings discourage the reduction of sc IFNB administration frequency, especially in younger patients with a higher preIFNB relapse rate. However, switching to im IFNB-1a may be considered in some selected cases. © 2014 S. Karger AG, Basel
Introduction
Multiple sclerosis (MS) is a life-long disease that requires long-lasting treatment to avoid relapses and accumulation of disability, especially in patients affected by a relapsing-remitting (RR) course. Although interferonLuca Prosperini MS Center, S. Andrea Hospital Department of Neurology and Psychiatry, Sapienza University Viale dell’Università, 30, IT–00185 Rome (Italy) E-Mail luca.prosperini @ uniroma1.it
beta (IFNB) treatment has convincingly demonstrated its beneficial effect in modifying the disease course of RR MS [1–3], it is often associated with poor tolerated side effects, such as flu-like syndrome and injection-site reactions [4]. Over the course of their treatment, IFNB-treated patients are often likely to face challenges to their adherence, i.e. the extent to which a person’s behavior corresponds with agreed recommendations from a healthcare provider [5]. It has been reported that 17–46% patients discontinue IFNB, especially within the first 6 months to 2 years from the beginning [6]. Although a relevant proportion of patients discontinue IFNB due to lack of efficacy, an equally relevant proportion does this due to poor tolerability [6, 7]. Furthermore, injection-related problems (anxiety, tiredness, injection-site pain or reactions) are other important reasons for non-adherence to IFNB, together with forgetting to administer, even in patients treated for more than 2 years [8–10]. A proportion ranging from 23 to 46% of patients treated with immunomodulating injective drugs have been reported as not adherent to IFNB treatment, in terms of both recommended dose and timing [7]. Adherence rates tend also to decline with increasing frequency of injection [8, 9, 11, 12]. In the daily clinical setting, some patients may require switching from high-frequency subcutaneous (sc) IFNB to intramuscular (im) IFNB-1a once weekly (ow). Alternatively, a reduction of administration frequency of sc IFNB-1a or -1b can sometimes be intentionally (to reduce intolerable side effects) or unintentionally (in the case of forgetting to administer) adopted by patients [8–10]. However, the long-term consequences on disease activity of reducing administration frequency of sc IFNB are still largely unknown. In this multicenter, retrospective, post-marketing study, we aimed to investigate whether clinical and magnetic resonance imaging (MRI) outcomes of patients who required a reduction of IFNB frequency were similar to those of patients who did not. Potential predictors for experiencing relapses, disability progression and/or MRI activity after the reduction of IFNB frequency were also investigated.
Methods Data from eight MS Centers in Rome were collected. To be enlisted in this study, patients must have the following characteristics: age from 18 to 65 years (inclusive); diagnosis according to McDonald criteria [13], with RR disease course; Expanded Disability Status Scale (EDSS) [14] score from 0 to 6.5 (inclusive), and
234
Eur Neurol 2014;71:233–241 DOI: 10.1159/000356786
regular follow-up from the diagnosis to more recent neurological assessment. Patients had also to be treated with one of the currently available IFNB formulations as first-line therapy, such as sc IFNB-1b 250 μg every other day (eod) or sc IFNB-1a 22 or 44 μg three times per week (tpw), without experiencing relapses, disability progression or MRI activity from IFNB start to 24 (±6) months. Among them, we identified three groups of patients: (1) those who continued to receive high-frequency sc IFNB-1a or -1b according to the drug label (recommended frequency group); (2) those who required a reduction of IFNB frequency, spontaneously dropping the administration frequency of sc IFNB-1a or -1b to twice weekly (reduced frequency group), and (3) those who switched to im IFNB-1a ow (switched group). To be allocated in the reduced frequency group or switched group, a patient had to change treatment regimen after 24 (±6) months from IFNB start owing to poor tolerability, including persistent flu-like symptoms, injection-site reaction or anxiety, tiredness of taking injections. Adherence and persistence were assessed as patient-reported information. Patients whose data on compliance, adherence and persistence to treatment were not available or not well documented over time were not considered in the analyses. Lastly, patients with previous exposure to immunosuppressant or experimental agents, and those who reduced the IFNB administration frequency for reasons other than poor tolerability (e.g. leukopenia, liver enzyme increase, thyroid abnormalities, mood disorders) were excluded. All patients were followed up for a further 24 months from the transition time-point, i.e. the clinical assessment nearest to an entire 24-month period of IFNB treatment (for the recommended frequency group), or the time at which the administration frequency of IFNB was reduced, i.e. after 24 (±6) months from IFNB start (for the reduced frequency group and switched group). Clinical and MRI data were retrospectively collected and stored into an electronic database (after obtaining informed consent from each patient). Patient management was conducted in accordance with the International Conference on Harmonization Guidelines of Good Clinical Practice and the Declaration of Helsinki. Given its retrospective design, this study in no way interfered in the care received by patients. Outcome Definition The following outcomes were considered over the 24-month follow-up after the transition time-point: (i) occurrence of relapse(s); (ii) presence of MRI activity, and (iii) sustained EDSS worsening. A relapse was defined as the appearance or reappearance of one or more symptoms attributable to MS, accompanied by objective deterioration on neurological examination lasting at least 24 h [13]. MRI activity was defined as the presence of one or more contrast-enhancing lesions during the 24-month follow-up. The development of new or enlarged T2-hyperintense was not considered as outcome measure since we could not be confident in reliable comparisons of MRI scan over time owing the multicenter design of this study. Sustained EDSS worsening was defined as a 1.5-point increase (if the previous EDSS score was 0), or a 1-point increase (if the previous EDSS score was
