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Interferon-beta-1a treatment has a positive effect on quality of life of relapsing–remitting multiple sclerosis: Results from a longitudinal study
Journal of the Neurological Sciences
The impact of interferon beta (IFNβ) therapy on a patient's quality of life (QoL) has not been completely clarified. This multicenter, independent, observational and longitudinal study was aimed to evaluate the impact of different pharmaceutical formulations of IFNβ-1a on QoL in patients affected by relapsing–remitting multiple sclerosis (RRMS).
The multiple sclerosis quality of life-54 questionnaire was used to assess patients' QoL.
394 (66%) patients completed the two-year study; 152 were treated with IFNβ-1a i.m. weekly injected (group a), 152 with IFNβ-1a 44 μg s.c. injected three times a week (group b) and 90 were untreated (group c). After two years, a significant increase was found in the physical health composite score (Δ = + 3.1 in group a, Δ = + 3 in group b, p < 0.05 in both), mental health composite score (Δ = + 4.7 in group a, Δ = + 5.5 in group b, p < 0.001 in both), in eight MSQoL sub-items of group a and in seven sub-items in group b. Conversely, the untreated group showed a slight decrease in seven domains. The variable “therapy with DMDs” was associated with improved QoL.
QoL of RRMS could be improved by IFNβ-1a treatment, despite natural history data which seem to demonstrate that QoL could get worse over the time.
Keywords: Multiple sclerosis, Quality of life, Interferon beta-1a, EDSS, MSQoL-54, Relapse.
Multiple sclerosis shows a number of needs which are not completely satisfied by the use of interferon beta (IFNβ), , and . It is generally believed that IFNβ could impact and deteriorate the quality of life (QoL) of people with MS, , and . IFNβ therapy is known to be associated with both systemic and local adverse effects and , which can also occur after decades of treatment, as shown by several extension phase III and post marketing studies and . Thus, discontinuation of treatment is frequent, particularly in the first few months after starting IFNβ therapy  . The main reasons leading to the suspension of therapy are forgetting to administer the injection, perceived lack of efficacy, and side effects and . Various strategies to improve adherence and mitigate the negative impact of IFNβ have been successfully suggested including educative programs, injection devices and dedicated nurse assistance, , and . The impact of IFNβ-therapy on the patient's QoL has not been completely clarified, as there are conflicting evidences among the studies, , , , , , , , , and . Nevertheless, the majority of the authors confirmed the positive influence of treatment with IFNβ on QoL, , , and .
Main aim of our study was to longitudinally investigate the global impact of different pharmaceutical formulations of IFNβ-1a therapy on QoL in a large sample of Italian patients affected by RRMS. Secondarily, we evaluated whether occurrence of exacerbation and EDSS variation could influence QoL of treated and untreated MS patients.
2. Methods/patients section
2.1. Study design
This was an independent, non-sponsored, multicenter, national, observational and longitudinal study. A contract research organization (Medepha, Genoa, Italy) housed the database and performed the statistical analyses.
Longitudinal evaluation was carried out for a period of two years, from January 2004 to December 2006 in 40 Italian MS centers. Patients were assessed at each center every six months. T0 was the baseline evaluation at enrolment; T1–T2–T3–T4 represent the successive evaluations; T5 was the last evaluation, performed 2 years after the T0 baseline assessment.
Patients with a clinically or laboratory-supported definite diagnosis of RRMS, , and had to satisfy the following inclusion criteria: expanded disability status scale (EDSS)  score 1.0–5.5; 18 years or older; able to give written informed consent; and naïve to treatment with IFNβ. Patients who had been treated with steroids the month before inclusion were not enrolled. Other exclusion criteria were progressive course of the disease, liver or renal disease, or serious concomitant diseases. The sample was subgrouped in patients without exacerbations and patients with one or more exacerbations. Patients were also stratified as worsened or stable-improved on their EDSS score. At each center, principal investigators (PI) selected consecutive referral patients who were eligible for this study and who were suitable for treatment with IFNβ. It must be pointed out that in 2004–2006, IFNβ-1a was considered as the drug of first choice because of the higher frequent occurrence of neutralizing antibodies (NABs) in patients treated with IFNβ-1b  .
Ethical consent was provided by the Ethical Committee of the University of Catania, which approved the protocol. Successively, each MS center involved in the study submitted the study protocol to their local ethical committee. Before the enrolment, each patient gave their informed written consent to participate in the study.
Delta variations of MSQoL-54 sub-items were considered as an outcome measure investigating the impact of either different IFNβ formulations or the no treatment status on MS patients QoL.
Exacerbations and EDSS status were considered as possible variables influencing QoL.
Age, sex, education, disability and IFNβ treatment were considered as variables included in the model to identify possible predictors of QoL of these patients.
The disease specific multiple sclerosis quality of life-54 questionnaire (MSQoL-54)  , validated in the Italian version  was used to assess the QoL of all patients. Two composite scores, physical health (PHCS) and mental health (MHCS), can be derived from a weighted combination of scale scores. In addition, there are the following subscales: physical function (PH), role limitation physical (RP), role limitation emotional (RE), bodily pain (BP), emotional well-being (EWB), energy (E), health perception (HP), social function (SF), cognitive function (CF), health distress (HD), sexual function (SxF), change in health (CH), satisfaction with sexual function (SSxF), and overall quality of life (OQoL).
The study was open; drug choice was at the discretion of PIs at each center as reported above; having similar group sizes was tried to make easier the comparability of results in complete respect to both inclusion and exclusion criteria. Patients were treated with IFNβ if they satisfied the criteria to be included in treatment (i.e.at least two relapses within the past 2 years).
2.7. Study size
This was not a randomized, double blind and controlled study; thus it was not necessary to have the power size for the primary outcome. It represented an observational study, from true clinical practice, with the additional objective of investigating the impact of IFNβ on RRMS patients' QoL.
2.8. Statistical methods
Statistical analyses were performed for patients satisfying all the inclusion criteria. The Likert method was adopted to assemble MSQoL 54 scale scores and the raw scores were transformed into 0–100 scales. A better score was considered as the patients' higher health-related quality of life (HRQoL). Longitudinal variations of MSQoL-54 domains between T0 and T5 were evaluated with the Wilcoxon test.
Univariate linear regression and multivariate, with a significance level of p < 0.05 were used to evaluate the relationship between the composite scores and the variables EDSS, years of education, sex, age and therapy with DMDs. ANOVA and Wilcoxon test were used to analyze QoL scores between groups.
Analyses of variance of MSQoL domains among the groups were performed by the Kruskal–Wallis test.
Six hundred and forty-eight (648) consecutive outpatients, attending 40 Italian MS centers were included in this prospective study ( Fig. 1 ).
Data referring to 55 patients out of 648 were not considered because they did not fulfill the inclusion criteria or because the medical case reports were incomplete. Of 593 patients, we considered data referring to 394 patients who completed the 2-year study (66.4%); baseline characteristics were found to be similar between all the eligible patients and the analyzed cohort ( Table 1 —p < 0.05). Only patients treated with IFNβ-1a were chosen; those in treatment with IFNβ-1b or glatiramer-acetate were not analyzed because of their very small sizes.
|Eligible PTS||Analyzed cohort||Lost to follow up|
|no. = 593||no. = 394||no. = 199|
|N. (%)||N. (%)||N. (%)|
|Male||178 (30)||118 (30)||60 (30)|
|Female||415 (70)||276 (70)||139 (70)|
|18–30 years||173 (29)||114 (29)||59 (30)|
|31–40||233 (39)||142 (36)||91 (46)|
|41–50||140 (24)||106 (27)||34 (17)|
|> 50||46 (8)||32 (8)||14 (7)|
|0–2||417 (70)||276 (70)||141 (71)|
|2.5–3.5||134 (23)||91 (23)||43 (22)|
|4–5.5||42 (7)||27 (7)||15 (7)|
|Employed||368 (62)||244 (62)||124 (62)|
|Housewife||118 (20)||79 (20)||39 (20)|
|Student||45 (7)||32 (8)||13 (6)|
|Unemployed||50 (8)||35 (9)||15 (7)|
|Missing data||12 (2)||4 (2)||8 (4)|
|0–5 years||27 (4)||24 (6)||3 (1)|
|6–8||167 (28)||110 (28)||57 (29)|
|9–13||315 (53)||209 (53)||106 (53)|
|Degree||81 (14)||51 (13)||30 (15)|
|Missing data||3 (1)||3 (1)|
|0–2 years||338 (57)||219 (56)||119 (60)|
|3–5||126 (21)||87 (22)||39 (19)|
|6–10||66 (11)||44 (11)||22 (11)|
|> 10||58 (10)||41 (10)||17 (8)|
|Missing data||5 (1)||3 (1)||2 (1)|
One hundred ninety-nine patients were not included in the final analysis because 89 were lost to follow-up, 35 underwent treatment escalation (14 patients with azathioprine, 13 with cyclophosphamide, 8 with mithoxantrone), 27 were switched with IFNβ-1b, 4 with glatiramer-acetate, 21 changed their home city, 19 withdrew their informed consent and 4 worsened their neurological conditions.
Patients started IFNβ-1a therapy within one month from the enrolment; after 2 years, 152 (38.5%) out of 394 were treated with Avonex (Group A); 152 (38.5%) with Rebif 44 (Group B); and 90 (23%) did not assume any medication (Group C). MSQoL-54 delta variations between baseline and T5 represented the main outcome of this study.
3.2. Main results
At baseline, there are no significant differences of the MSQoL domains among the three groups.
Table 2 shows the variation of the MSQoL domains between baseline and T5 in both the composites scores.
p < 0.05.
p < 0.001.
A significant increase of subjectively perceived QoL was found in RP, RE, EWB, HD and CH ( Table 3 ).
p < 0.05.
p < 0.001.
p < 0.0001.
At T5, 211 (54%) out of 394 patients had no relapse, 167 (42%) had one or more relapses, whereas incomplete data for relapse occurrence were collected in 16 patients (4%). Apost-hocstratified analysis showed that the quality of life of patients without exacerbations was higher than those with exacerbations in all domains except CF ( Fig. 2 ).
Among patients with one or more exacerbations, the Avonex group reported a significant increase in the RE, SF, SSxF, and CH and the Rebif group in the MHCS, HP, RP, RE, EWB, HD, and CH ( Fig. 3 ).
Regarding EDSS changes, 275 out of 394 (70%) scored an EDSS between 0 and 2 at T0 and after 2 years, 266 (67%) patients had an EDSS between 0 and 2. Apost-hocanalysis stratifying for EDSS evidenced that patients with stable or improved EDSS scored significantly better than those with worsened EDSS in the PHCS, MHCS, PH, RP, BP, EWB, E, SF, CF, CH and OQoL ( Fig. 4 ).
Among patients with worsened EDSS, the Avonex group reported a significant increase in the RP, HD, CH, and SSxF; the Rebif group significantly increased in the RP, BP, and CH ( Fig. 5 ).
At T5, the variables EDSS (p < 0.0001), “education” (p = 0.002) and “therapy with IFNβ” (p = 0.002) were found to be significant predictors of improvement of both MHCS and PHCS ( Table 4 ).
|EDSS||− 7.2||< 0.0001||− 11.29||< 0.0001|
|Sex||− 2.62||0.009||− 2.06||0.03|
|Age||− 1.64||0.101||− 2.74||0.006|
|Therapy with IFNβ||3.11||0.002||3.01||0.002|
Changes of composite scores (PHCS and MHCS) of patients treated with IFNβ-1b or glatiramer-acetate or who underwent treatment escalation are shown in Table 5 .
|Other DMDs||Treatment escalation|
|31 patients||35 patients|
|Baseline||2 years||Baseline||2 years|
|PHCS||60.9 ± 17.56||57.4 ± 19.7||62.7 ± 13.8||63.0 ± 15.5|
|MHCS||58.7 ± 25.9||57.5 ± 25.4||62.7 ± 19.3||60.9 ± 24.0|
Our study showed that both IFNβ-1a and IFNβ-1b were found to exert a positive influence on RRMS patients' QoL. These differences were found in all MSQoL domains and were more prominent in HD, CH and EWB. These domains mainly consist of items investigating the emotional field and the psychological component of the patient QoL. The influence and the true weight of the psychological factors on the overall QoL of people with MS had already been highlighted by some authors  . Focusing on the composite scores, higher significant changes were found in MHCS than in PHCS. Therefore in our opinion, it seems that IFNβ therapy could determine a beneficial effect on the psychological profile, and then it can lead to coping better with the challenges of a chronic disease such as MS. The psychological support could impact the physical aspects of the patient. Therapy with IFNβ (in this study limited to two different IFN formulations) could have exerted a protective role on MS patients' QoL. As previously reported, our study showed that the occurrence of relapse and EDSS progression were linked to the deterioration of QoL and . The negative effects of “clinical parameters” (new relapses and EDSS progression) on QoL were more evident in untreated patients. In our study, untreated patients with one or more exacerbations showed an overall worsening in almost all MSQoL-54 domains. On the contrary, despite the exacerbation occurrence, most MSQoL-54 domains increased in both treated groups. Furthermore untreated patients without relapse showed a slight but significant worsening of QoL in three domains (BP, HP, SSxF). With this in mind, it could be hypothesized that IFNβ treatment could provide a sort of psychological support that helps the patient feeling “adequately taken cared of” in front of a negative event (new relapse, EDSS progression, MRI worsening).
The variable “EDSS” was found to be the strongest significant predictor of worsening of both the composite scores ( Table 3 ).
Untreated patients showed an EDSS worsening with higher frequency than that reported in treated patients; in untreated patients there was a decrease in most MSQoL-54 domains (Fig. 6). Instead, in treated patients EDSS deterioration did not determine a general detrimental effect on QoL. In this subgroup several MSQoL-54 domains in the Avonex group and a few in the Rebif group decreased.
The variable “education” was found to be a significant predictor of improved QoL. It is conceivable that higher education levels could provide a stronger ability to cope with the challenges of MS  .
This study was not randomized. It was mainly aimed to mirror the real clinical practice and to evaluate the longitudinal effects of IFNβ-1a on QoL over time in comparison with untreated patients. The benefits of interferon beta on QoL could partly be explained by the fact that patients were participating in a clinical study investigating the effects of specific therapy on QoL. The study was carried out in a limited cohort of patients, roughly two thirds who had provided their written informed consent to participate and so, a considerable amount of patients was not included in the final analysis. The study examined the impact of just two different formulations of interferon on QoL and results were compared to a group of untreated patients who were considered as potentially benign by their treating neurologists. Unfortunately patients on IFNβ-1b or glatiramer acetate were fewer to allow any comparison with other groups.
The results of our study confirm the benefits of interferon beta on QoL, although the impact of the side effects on QoL may undoubtedly be detrimental and . We further have to consider that the QoL is hardly impaired in the early stages of MS  ; in this phase, patients usually experience a discouraging feeling after a recent diagnosis of a chronic disease with an unpredictable course. To have found that treatment with interferons may improve QoL and that the QoL of untreated patients deteriorate should be presented to every patient, when communicating the diagnosis and discussing with them therapeutic options  . This communicative issue assumes a crucial role to help patients to overcome the difficult phase that follows the diagnosis, achieving as soon as possible an acceptable adjustment to the new order of their lives.
Patients who experienced relapse or disability progression could need more support or other interventions to maintain a satisfying compliance and adherence to therapy. The occurrence of a relapse may determine a reduction of either the hopeful expectations or the successful compliance toward the IFN-beta treatment. Besides, a new relapse may contribute to stigmatize the disease and its pathological processes.
Treatment with DMDs was able to improve MSQoL and may minimize the negative impact of new relapses and disability progression. Overall, the positive influence of IFNβ on QoL was finally confirmed with multiple linear regression, in which the variable “therapy with IFNβ” was found to be a significant predictor of improvement of both the composite scores ( Table 3 ). Although the study was not randomized, placebo controlled, and double blind, the chance to have examined a group of untreated patients could have partly reduced the possible bias of lack of randomization. Nonetheless it should be emphasized that the study was performed in accordance with the Recommendations of the Good Clinical Practice.
Summarizing, the results of our study suggest that:
- a) IFNβ-1a therapy has a positive impact on QoL in early RRMS patients suitable for treatment with IFNβ-1a
- b) IFNβ-1a therapy may minimize the negative effects of both exacerbation occurrence and EDSS progression on QoL.
These findings could be of major importance in clinical practice to prevent a discouraging feeling in front of the perspective of a long duration therapy with uncertain efficacy and side effects.
The authors thank all patients and participants in this study:
City (Main investigator, co-investigators)
Catania (Patti, Fiorilla, Vecchio, Pappalardo); Roma (Pozzilli, Onesti); Cagliari (Marrosu, Cocco); Ascoli Piceno (Ragno, Scarcella, Sirocchi); Ancona (Provinciali, Danni, Sgolastra); Parma (Visintini, Saviola); Catanzaro (Quattrone, Valentino, Sibilla); Roma (Gasperini); Gallarate (Ghezzi, Baldini); Bergamo (Rottoli); Bari (Trojano, Paolicelli); Napoli (Florio, Campese); Roma (Grasso); Milano (Martinelli, Rodegher, Radaelli); Padova (Gallo, Marangoni); Roma (Di Battista, Ferraro); Vicenza (Bortolon); Fidenza (Montanari, Pesci); Trieste (Zorzon, Zivadinov); Firenze (Amato); Bologna (Stecchi, Balugini); Trieste (Zadini); Genoa (Mancardi, Uccelli); Genoa (Solaro); Cuneo (Perla); Grosseto (Plewnia); Empoli (Guidi); Messina (Bramanti, Di Gangi); Pisa (Meucci, Fioretti); Napoli (Brescia Morra, Carrieri); Modena (Merelli, Casoni); Pozzilli (Bellantonio, Fantozzi); Latina (Lazzaro); Roma (Caramia, Boffa); Perugia (Urciuoli, Brufoli); Milano (Caputo, Mendozzi); Palermo (Salemi, Gennuso); Palermo (Cottone); Caltanissetta-Cefalù (Grimaldi); Torino (Durelli, Verdun).
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a Department DANA GF Ingrassia, Neurosciences Section, Multiple Sclerosis Centre, University of Catania, Catania, Italy
b Department of Rehabilitation, S. Marta & S. Venera Hospital, Acireale, Catania, Italy
c Multiple Sclerosis Centre, Unit of Neurology, Fidenza- S. Secondo Hospital, Fidenza, Parma, Italy
d Multiple Sclerosis Centre, S. Andrea Hospital, Sapienza University of Rome, Rome, Italy
Corresponding author at: Department DANA GF Ingrassia, Neurosciences Section, Multiple Sclerosis Centre, University of Catania, Via Santa Sofia 78, 95123 Catania, Italy. Tel.: + 39 095 3782620, + 39 3386270548; fax: + 39 095 3782832.
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