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Quality of life in adults with multiple sclerosis: a systematic review

Objective In recent years, quality of life (QoL) in multiple sclerosis (MS) has been gaining considerable importance in clinical research and practice. Against this backdrop, this systematic review aimed to provide a broad overview of clinical, sociodemographic and psychosocial risk and protective factors for QoL in adults with MS and analyse psychological interventions for improving QoL. Method The literature search was conducted in the Scopus, Web of Science and ProQuest electronic databases. Document type was limited to articles written in English, published from January 1, 2014, to January 31, 2019. Information from the selected articles was extracted using a coding sheet and then qualitatively synthesised. Results The search identified 4886 records. After duplicate removal and screening, 106 articles met the inclusion and exclusion criteria for qualitative synthesis and were assessed for study quality. Disability, fatigue, depression, cognitive impairment and unemployment were consistently identified as QoL risk factors, whereas higher self-esteem, self-efficacy, resilience and social support proved to be protective. The review analysed a wide spectrum of approaches for QoL psychological intervention, such as mindfulness, cognitive behavioural therapy, self-help groups and self-management. The majority of interventions were successful in improving various aspects of QoL. Conclusion Adequate biopsychosocial assessment is of vital importance to treat risk and promote protective factors to improve QoL in patients with MS in general care practice.

-Comprehensive and robust search strategy as well as strict inclusion criteria to cover all the relevant evidence.
-Careful and standardized assessment of risk of bias in all 106 included studies.
-Heterogeneity of studies only allows for qualitative synthesis of results.

Introduction
Multiple Sclerosis (MS) is a chronic neurodegenerative condition, characterized by a wide range of symptoms and a highly unpredictable prognosis, which can severely affect patients quality of life (QoL). [1][2][3][4] The constitution of the World Health Organization (WHO) declares health as "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity". [5] QoL is a multidimensional concept that encompasses the domains included in the cited definition of health. [1,6] Its introduction in the medical literature dates back to 1960 [7] with a continuously growing relevance up to now. [8] In recent years, the number of published research on MS QoL has highly increased. [1,9] Besides providing practitioners useful information on the impact of symptoms and therapy on patients life, QoL is a predictor of disease progression. [10,11] Considering its relevance in health care research and practice, there is an urgent need to synthetize the available scientific evidence. This systematic review aims at analysing risk and protective factors related to QoL in MS as well as relevant psychological interventions.

Methodology
The current systematic review was completed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. [12] Ethical approval (or informed consent) was not necessary because the present study is a review of prior publications.

Search strategy
The systematic search focused on journal articles published between 2014, January 1 st to 2019, January 31 st . The data bases consulted were: Scopus, Web of Science and ProQuest, the search was performed in February and March 2019.
The following key words were used: ("multiple sclerosis") AND ("quality of life" OR "health-related quality of life" OR "well-being" OR "wellbeing" OR "life satisfaction"). The search terms were markedly wide to guarantee the greatest coverage of literature. The search field was limited to "title/abstract" and language was limited to "English".
There is no published systematic review on this topic in Cochrane Library.

Study selection
Firstly, title and abstract screening was carried out to identify suitable articles for full text screening. The screening process was performed independently by two investigators. Any disagreement about study selection was resolved by consensus with a third reviewer.
Inclusion criteria were set as following: 1. Studies primarily focusing on QoL determinants as well as psychological interventions to improve QoL.
2. Study participants aged above 18 years with a confirmed MS diagnosis.
The following exclusion criteria were applied: 1. Non-psychological intervention.

2.
No primary research studies (systematic reviews, meta-analysis, protocols or clinical guidelines were excluded).

Quality assessment
The methodological quality of the included studies was appraised based on a well-established standardized 12-items Checklist. [13] Every item represents a methodological feature: inclusion/exclusion criteria, methodology/design, attrition rate, attrition between groups, exclusions after, follow up, occasion of measurements, pre/post measures, dependent variables, control techniques, construct definition and imputing missing data. The codification criteria proposed by the checklist authors was followed. No article was excluded in the quality appraisal phase.

Data abstraction
Data extraction from selected articles was carried out based on a coding sheet. The coding sheet was previously elaborated and piloted by consensus. The extracted information includes: title, authors and publication year, country (city), design, sample characteristics, studied variables and measurement tools, main results and conclusions. After the extraction process was completed, the obtained information was independently reviewed by two authors to avoid mistakes and missing data.
Conducting a meta-analysis was not possible due to the heterogeneity of study designs and outcomes, so a narrative synthesis was undertaken.

Literature screening
A total of 4886 articles were initially identified from SCOPUS, Web of Science and ProQuest. After removing duplicates and abstract analysis, 188 studies were eligible for full text screening. Finally, 106 were selected for the narrative analysis. The selection process is detailed in a PRISMA flow diagram ( Figure 1).

Study characteristics
The included articles were analyzed according to their primary and secondary outcomes. Concerning the articles objectives, 70 studies aimed at analyzing risk and protective factors for QoL (Table 2), 11 focused on the development of QoL at different ages and time points in disease history (Table 3) and 25 studied the effect of a psychological intervention on QoL in MS (Table 4).
All the included articles employed standardized and validated QoL measurement; 64 studies evaluated QoL with a generic measure and 50 studies made use of a disease-specific measure. Short Form Health Survey 36 (SF-36) was mainly used (n = 29) as a generic measure and Multiple Sclerosis Quality of Life-54 (MSQoL-54) (n = 28) as a disease-specific measure. Finally, 11 studies used more than one measure to evaluate QoL. The study designs were mostly cross-sectional (n = 74), and sample sizes ranged from 7 to 74451 participants.
In the following section a summary of the main findings from the included articles is provided.

Risk and protective MS QoL factors
Factors influencing PwMS QoL are summarized in Table 2.
Diverse cognitive impairments, for instance, cognitive fatigue, memory loss and planning/organization dysfunction, were recognized as risk factors by a number of studies. [28,39,41,42,[54][55][56] Sgaramella et al [57] showed that the preservation of executive functioning is a protective factor of QoL.
Congruently with this finding, Boogar et al [24] recognized a positive treatment experience as a protective factor.

Disease history
Some of the selected studies examined QoL in MS at the earliest years. According to Possa et al [84] , in the first year of diagnosis QoL assessed by MCS and physical composite score (PCS) decreased. Stern et al [85] showed the worst QoL in the youngest group of MS patients.
During the first three years of diagnosis, Calandri et al [86] found that problem solving and avoidance coping have a positive effect on QoL. Nourbakhsh et al [87] also studied factors influencing the development of QoL in the first three years. The results showed that higher baseline levels of fatigue and depression predicted worse QoL assessed by the PCS, whereas lower cognitive functioning and higher fatigue predicted worse MCS.
Another study focused on QoL in MS at an advanced age. Buhse et al [88] identified neurological impairment, physical disability, depression, and the comorbidity with thyroid disease as risk factors for worse QoL assessed by PCS in an elderly MS sample. On the contrary, being widowed and employed was identified as a protective PCS factor.
Regarding MS progression, Kinkel et al [89] pointed out that a second clinical event consistent with clinically defined MS, higher EDSS at the time of diagnosis and an earlier MS onset predicted a decrease in PCS 10 years after the diagnosis. Besides, Bueno et al [90] indicated that a progression from benign MS to non-benign MS predicted a decrease in PCS 25-30 years after the diagnosis.

Interventions
The details of the selected articles of psychological interventions are presented in Table 4.

Based on Mindfulness
All intervention programs showed improvements in QoL at some evaluation point and at least in some QoL domains.
A body-affective mindfulness intervention increased the general QoL score up to 6 months after the treatment. [95] Three studies investigated mindfulness-based stress reduction programs and two studies showed a significant increase in QoL after the treatment. [96][97][98] One study [98] resulted just in a small and insignificant increase after the treatment and at the follow up 3 months after the intervention.
Moreover, the community based mindfulness program treatment resulted in a significant increase in MCS. [99] Finally, mindfulness-based cognitive therapy did not show significant differences in general QoL between the control and the experimental group, but it showed significant differences in the following aspects of QoL: health distress, mental well-being, role limitation due to emotional problems and cognitive performance. [100]

Cognitive-behavioral
A wide spectrum of cognitive behavioral interventions were analysed.
In a study by Case et al [101] the experimental group underwent 10 weekly sessions of 1 hour of healing light guided imagery. The results revealed a greater increase of QoL in the intervention group compared to the active control group exposed to 10 hours of positive journaling.
Blair et al [102] focused their intervention on emotion regulation. The design consisted on 16 bi-weekly sessions of 1.5 hours during 8 weeks. The intervention resulted in a significant increase in QoL 6 months after the treatment.
The interventions by Calandri et al [103] and Graziano et al [104] applied a comparable design. Participants were divided into two subgroups based on age. The intervention comprised 4-5 sessions of 2 hours over the course of 2 months, and 1 follow up session 6 months after the treatment. Calandri et al [103] also included 1 follow up session 12 months after the treatment. The intervention group experienced an increase in QoL at the follow up in both studies.
Three studies [105][106][107] focused their intervention on depressive symptoms. Kiropoulos et al [105] and Chruzander et al [106] found improvements in QoL at post-treatment and follow up assessment points. Kikuchi et al [107] also found a posttreatment improvement but did not reach significant levels.
Two of the retrieved studies based their intervention on Acceptance and Commitment Therapy (ACT). Pakenham et al [108] implemented an 8 weeks session program aimed to train resilience. The results showed an increase in QoL after the treatment and 3 months later. Besides, Proctor et al [109] implemented an 8 weeks intervention comprising telephone calls plus self-help ACT books. No significant increase of QoL was observed.

Based on social and group support
Among interventions founded on social and group support, the following made an impact on QoL in MS.
Abolghasemi et al [110] implemented a 12 sessions Supportive-expressive therapy program, which resulted in an improvement of QoL.
Jongen et al [111] investigated an intensive social-cognitive wellness program, which involved the inclusion of the partner or another significant informal caregiver. The results showed an increase in MCS 1, 3 and 6 months post- 20 treatment, and in PCS 6 months after the treatment. The results of the program were evaluated again 12 months after the treatment. The relapsing-remittent MS group displayed an increase in PCS and MCS. [112] Eliášová et al [113] found in MS patients an improvement across several QoL domains after attending Self-help groups, in comparison to patients who did not visit Self-help groups. Liu et al [114] detected an increase in physical and psychological QoL in women with MS after participating in a 1 hour twice a week 8 weeks Hope based group therapy program.

Based on symptoms and self-management
Two studies analyzed a self-management fatigue group therapy. Mulligan et al [115] study reported positive but not significant changes in QoL after the treatment. Thomas et al [116] reported significant positive changes in physical health assessed by the Multiple Sclerosis Impact Scale (MSIS-29) and vitality as measured by the SF-36 in the intervention group 12 months after the treatment.
In addition to fatigue self-management, Ehde et al [117] focused in their intervention on pain and depression selfmanagement. The results were compared to an educational program. There was a higher QoL post-treatment and 12 months follow-up score in the self-management group. Feicke et al [118] implemented a program focused on MS selfmanagement. As in Ehde et al [117] improvements in QoL were maintained at 6 months follow up.

Discussion
Firstly, the present systematic review was intended to identify risk and protective factors of QoL in MS. The results showed that investigations tend to focus on the assessment of functional impairment by the EDSS [14][15][16][17][18][19][20][21][22][23][24] . As expected the number and severity of symptoms and the associated impairment appeared to play a crucial role for QoL.
The applied coping strategies obviously influence QoL in MS, however the effect depends on the specific circumstances of disease history. For example, problem solving and avoidance coping, normally classified as opposed strategies, both seemed to have a positive effect on MCS in the first three years of diagnosis. [86] However, in general strategies associated with denial [40,68] and avoidance of disease challenges such as problem avoidance, [60,70] behavioral disengagement, [40,69] distancing, [70] self-distraction, [68] social withdrawal, [60] wishful thinking, [60] were associated with a lower QoL. On the other hand strategies based on acceptance and active commitment such as active coping, humor, problem resolution, cognitive positive restructuring, and emotional expression led to higher QoL in MS. [40,60,[68][69][70][71] Obviously, there is a close connection between the active confrontation of illness challenges and specific personalitybased convictions, such as a high self-efficacy. In accordance a higher self-efficacy [40,77] , self-esteem [77] , and sense of coherence [78] improved QoL in MS.
Regarding sociodemographic influences on QoL, not surprisingly unemployment proved to be a major risk factor [19,23,43,56,83] as well as a low socioeconomic status [24] and financial difficulties [26] . In keeping with the negative influence of the scarcity of resources, lack of access to therapy was also identified as a risk factor. [19,20] This systematic review second aim was to study QoL in MS patients at different times of disease history. Two studies showed the diminishment of QoL in MS patients in its earliest stage. [84,85] This might have to do with the fact that patients being diagnosed with a severe and chronic disease need a certain time to come to terms with this emotional shock. The oscillation between avoidance and problem solving, which both have a positive influence in the first three years after diagnosis, [86] may stand for this inner struggle. In older patients neurologic impairment and physical disability, [86] which represent the age-associated increase in physical impairment, were identified as risk factors for QoL in MS.
Finally, the third aim of this review was to analyze psychological interventions for the improvement of QoL in MS.
Eight of the included intervention studies specifically aimed at the treatment of depressive symptomatology [95,[99][100][101]104,[106][107] by either mindfulness-based or cognitive-behavioral approaches both of which proved to be successful. Three studies were specifically directed towards the treatment of fatigue [101,115,116] by light guided imagery or selfmanagement programs. The imagery approach as well as the self-management group intervention were successful, whereas the individual self-management program did not show a significant improvement.
A variety of mindfulness-based approaches [96][97][98] aimed at stress. reduction as well as a Community based intervention [99] . Three of the four studies showed some kind of improvement of QoL, among these the only study with a control group.
Several of the investigated interventions had the objective to reinforce protective factors in MS patients. Graziano et al [104] focused on identity redefinition, sense of coherence and self-efficacy. Pakenham et al [108] implemented a program based on resilience training, and the program by Blair et al [102] focused on the improvement of emotion regulation. All studies were successful in improving QoL confirming the alternative focus on protective factors instead of risk factors.
Interventions based on social support concentrate on the reinforcement of the social network. A wide spectrum of these approaches was investigated in MS, as for example, self-help groups [113] , hope based group therapy [114] , supportive-expressive therapy [110] , and social cognitive training with support partners [111,112] . All interventions aimed to help people overcome MS barriers in daily living by strengthening the social support and resulted in the improvement of some aspects of QoL. This is consistent with above mentioned studies [81,82] pointing out the relevance of social support and participation as a protective factor for QoL.

Limitations
The main limitation of this study was the unfeasibility to carry out a quantitative synthesis of the results, due to the heterogeneity of studies methodologies and designs. Due to the vast amount of topics and limited resources we had to restrict our search on a five year period up to January 2019.

Conclusions
This review was conducted to give a broad overview over QoL in MS. The findings show the importance of clinical, psychosocial and demographic variables as risk and protective factor for QoL. A variety of psychological interventions ranging from mindfulness-based and cognitive-behavioral approaches to self-help groups were identified as promising options to improve QoL addressing these factors. These findings have important clinical implications. A sound biopsychosocial assessment of MS patients in daily clinical practice is necessary to ensure the possibility of identifying risk factors for QoL early on and to recommend evidence-based psychological interventions to improve or stabilize QoL.

Competing Interests
The authors declare that there is no conflict of interest.

Funding
This study was financially supported by the program of Formation of University Professor of Ministry of Education, Culture and Sport of Spain grant number: FPU 17/04240.

Patient and public involvement
No patient involved.      1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45 46 Study records: Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review 5 Selection process 11b State the process that will be used for selecting studies (such as two independent reviewers) through each phase of the review (that is, screening, eligibility and inclusion in meta-analysis) 5 Data collection process 11c Describe planned method of extracting data from reports (such as piloting forms, done independently, in duplicate), any processes for obtaining and confirming data from investigators 5 Data items 12 List and define all variables for which data will be sought (such as PICO items, funding sources), any pre-planned data assumptions and simplifications 5 Outcomes and prioritization 13 List and define all outcomes for which data will be sought, including prioritization of main and additional outcomes, with rationale 5

Risk of bias in individual studies
14 Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be done at the outcome or study level, or both; state how this information will be used in data synthesis 5 Data synthesis 15a Describe criteria under which study data will be quantitatively synthesised x 15b If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling data and methods of combining data from studies, including any planned exploration of consistency (such as I 2 , Kendall's τ) x 15c Describe any proposed additional analyses (such as sensitivity or subgroup analyses, meta-regression) x 15d If quantitative synthesis is not appropriate, describe the type of summary planned

Method
The literature search was conducted in the Scopus, Web of Science and ProQuest electronic databases. Document type was limited to articles written in English, published from January 1, 2014 to January 31, 2019. Information from the selected articles was extracted using a coding sheet and then qualitatively synthesized.

Results
The search identified 4886 records. After duplicate removal and screening, 106 articles met the inclusion and exclusion criteria for qualitative synthesis and were assessed for study quality. Disability, fatigue, depression, cognitive impairment, and unemployment were consistently identified as QoL risk factors, whereas higher self-esteem, selfefficacy, resilience and social support proved to be protective. The review analyzed a wide spectrum of approaches for QoL psychological intervention, such as mindfulness, cognitive-behavioral therapy, self-help groups and selfmanagement. The majority of interventions were successful in improving various aspects of QoL.

Conclusion
Adequate biopsychosocial assessment is of vital importance to treat risk and promote protective factors to improve QoL in patients with MS in general care practice.

Key words
Multiple sclerosis, quality of life, protective and risk factors, mental and physical quality of life.

Strengths and limitations of this study
-This is the first systematic review of risk factors and psychological intervention for quality of life in multiple sclerosis in over a decade.
-A comprehensive and robust search strategy and strict inclusion criteria were employed to cover all the relevant evidence.
-Careful standardized risk of bias was assessed in all 106 studies included.
-Due to heterogeneity of the studies only qualitative synthesis of results was possible.
-The huge number of publications made it necessary to limit the time span to the five-year period from January 1, 2014 to January 31, 2019.

Introduction
The Constitution of the World Health Organization (WHO) declares health to be "…a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." [1] Quality of life (QoL) is a multidimensional concept that encompasses the domains included in this definition of health. [2,3] Its introduction in medical literature dates back to 1960 [4] , with its importance continuously growing to date. [5] Multiple Sclerosis (MS) is a chronic neurodegenerative condition, characterized by a wide range of symptoms and a highly unpredictable prognosis, which can severely affect patient QoL. [6][7][8] MS patients tend to report lower QoL than the general population. [9][10][11][12] This diminished QoL may be due to their impaired functioning in daily living, more so if the help of caregivers is required, impeding family relations, work and social dynamics. [13,14] The impact of MS on QoL can be affected by numerous disease-related factors, such as disability level or MS type, and individual factors such as social support, education, age or employment. [15][16][17][18] Identification of risk and protective factors is a key point in implementing strategies to improve patient QoL. [7] In this context, all influences must be considered to contribute to QoL in MS. [7,19] In addition to providing practitioners with useful information on the impact of symptoms and therapy on the patient's life, QoL is also an indicator of treatment success and a predictor of disease progression. [20][21][22] In view of its relevance in healthcare research, the need to compile and condense available scientific evidence on the subject is urgent. Against this backdrop, this systematic review gives a comprehensive overview of risk and protective factors related to QoL in MS as well as relevant psychological interventions. The growing number of studies on this subject [2,22] provides a vast amount of data, which due to the inconsistency of findings, needs careful assessment to come to evidence-based conclusions.

Methodology
This systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. [23] As a review of prior publications, ethical approval (or informed consent) was unnecessary. A review protocol is available from the corresponding author upon request.

Search strategy
The systematic search focused on journal articles published between January 1, 2014 to January 31, 2019. The Scopus, Web of Science and ProQuest databases were searched in February and March 2019. The key words used were ("multiple sclerosis") AND ("quality of life" OR "health-related quality of life" OR "well-being" OR "wellbeing" OR "life satisfaction"). The search terms were intentionally broad to ensure wide coverage of the literature. The search field was limited to "title/abstract" and language was limited to "English".
There is no published systematic review on this topic in the Cochrane Library.

Study selection
First, title and abstract were screened to identify suitable articles for full text review. The screening process was performed independently by two researchers. Any disagreement about study selection was resolved by consensus with a third reviewer.
Inclusion criteria were the following: 1. Studies primarily focusing on QoL determinants and psychological intervention to improve it.
2. Study participants aged over 18 with a confirmed MS diagnosis.
The following exclusion criteria were applied: 1. Nonpsychological intervention.
2. Not primary research studies (systematic reviews, meta-analyses, protocols and clinical guidelines were excluded).
3. Studies on the development and validation of QoL measurement instruments.
4. QoL risk or intervention studies for healthy behavior, cognitive rehabilitation, physical activity or pharmacological treatment.
5. Studies on comorbidity with another illness or mental health diagnosis.
6. Sample selection based on a special condition (for example: only employees or MS patients under certain pharmacological treatment).
7. Studies not using a validated QoL measurement tool.

Quality assessment
The methodological quality of the studies was appraised with a well-established standardized 12-item checklist, [24] in which every item represents a methodological feature: inclusion/exclusion criteria, methodology/design, attrition rate, attrition between-groups, exclusions after, follow-up, occasion of measurements, pre/post measures, dependent variables, control techniques, construct definition and imputing missing data. The codification criteria proposed by the checklist authors was used. No article was excluded from quality appraisal.

Data abstraction
Data were extracted from selected articles based on a previously designed coding sheet. The pilot study was approved by consensus. The information extracted included: title, authors and publication year, country (city), design, sample characteristics, study variables and measurement tools, main results and conclusions. After extraction, the information was independently reviewed by two authors to avoid errors or omitting data.
A meta-analysis was not possible due to the heterogeneity of study designs and outcomes, so a narrative synthesis was undertaken.

Literature screening
A total of 4886 articles were initially identified from SCOPUS, Web of Science and ProQuest. After removal of duplicates and abstract analysis, 188 studies were eligible for full text review. Finally, 106 were selected for the narrative analysis. The selection process is detailed below in a PRISMA flow diagram ( Figure 1).

Methodological quality
Methodological quality scores using the 12-item checklist are summarized in Table 1.

Study characteristics
The articles included were analyzed by their primary and secondary outcomes. Seventy studies analyzed QoL risk and protective factors (Table 2), 11 focused on the development of QoL at different ages and times in the disease (Table 3), and 25 studied the effect of psychological intervention on QoL in MS (Table 4).
All as a disease-specific measure. Finally, 11 studies used more than one measure to evaluate QoL. The study designs were mostly cross-sectional (n = 74), and sample sizes ranged from 7 to 74451 participants.
The main findings of the articles are summarized below.

Risk and protective MS QoL factors
Factors influencing MS patients QoL are summarized in Table 2.
A diversity of cognitive impairments, for instance, cognitive fatigue, memory loss and planning/organizational dysfunction, were recognized as risk factors by a number of studies. [39,50,52,53,[65][66][67] Sgaramella et al. [68] showed that maintaining executive functioning was a protective factor of QoL. This was also the only study on the important subject of cognitive reserve and QoL.

Personality domains
The role of personality domains was explored in several studies. Cyclothymic and depressive temperament were associated with a lower QoL in MS, in contrast to hyperthymic temperament, which was associated with higher QoL. [77] Another study recognized extraversion as a personality trait related to higher QoL levels. [69] Cioncoloni et al. [34] recognized introverted personality as a risk factor for QoL in MS, and finally, type D personality was another relevant factor. [78]
Coping strategies were also identified as relevant mediator variables. Problem-focused, emotion-focused, and stopping unpleasant emotion coping strategies were partial mediators between fatigue [83] or type D personality [84] and QoL as measured by the mental composite score (MCS).

Other psychological factors
According to Van Damme et al., [85] acceptance of the illness is a protective factor for QoL. The role of flexible adjustment and tenacious goal pursuit in achieving personally blocked goals was not as clear, although their findings showed a trend towards a positive relationship.
Resilience was confirmed as a protective factor of QoL in MS. [27,86] Moreover, Koelmel et al. [87] highlighted its role as a mediator variable in the relationship between social support and MCS.
High levels of self-efficacy, [51,88] self-esteem, [88] illness identity [88] and sense of coherence [89] correlated with higher QoL, and self-esteem mediated in the relationship of social support with MCS. [90] Ultimately, cognitive fusion, the extent to which people feel fused with or attached to their thoughts, mediated the relationship between stigma and QoL in MS. [91]

Social factors
Social support [92] and participation [93] were positively related with QoL. Several mediators in this relationship were mentioned above.

Demographic factors
Employment was found to be the leading sociodemographic factor influencing QoL. Several studies displayed an association between unemployment and lower QoL. [30,34,54,67,94] Others showed a positive correlation between jobs adapted to disability, [94] job match and job satisfaction, [41] high employment status, [33,41] and QoL in MS. Low socioeconomic status [35] and financial straits [37] were also risk factors for lower QoL. Brola et al. [30,31] noted that not having access to an adequate pharmacological treatment put QoL in danger. Congruent with this finding, Boogar et al. [35] found a positive treatment experience to be a protective factor.
Other sociodemographic variables related to poorer QoL in MS were male sex, [37] old age, [30,31] unmarried or living with significant others, [37] whereas a higher education was a protective factor. [33] Table 3 summarizes the characteristics of studies focusing on QoL at different ages and times in the disease history.

Disease history
Some of the selected studies examined QoL in MS in its early years. According to Possa et al. [95] , QoL decreased in the first year of diagnosis, as assessed by the MCS and physical composite score (PCS). Stern et al. [96] found the worst QoL in the youngest group of MS patients.
Calandri et al. [97] found that during the first three years from diagnosis, problem-solving and avoidance coping strategies had a positive effect on QoL. Nourbakhsh et al. [98] also studied factors influencing the development of QoL in the first three years. Their results showed that higher baseline levels of fatigue and depression predicted worse QoL as assessed by the PCS, whereas lower cognitive functioning and higher fatigue predicted a worse MCS.
Another study on QoL in MS by Buhse et al. [99] focused on old age. These authors identified neurological impairment, physical disability, depression, and comorbidity with thyroid disease as risk factors for worse QoL as assessed by the PCS in a sample of elderly MS patients. On the contrary, being widowed and employed were identified as protective PCS factors.
In a longitudinal study, Kinkel et al. [100] showed that a second clinical event consistent with clinically defined MS, higher EDSS at the time of diagnosis and an earlier MS onset predicted a decrease in PCS 10 years after diagnosis.
Bueno et al. [101] also showed that progression from benign MS to non-benign MS predicted a decrease in PCS 25-30 years after diagnosis.
Some longitudinal predictors of QoL identified have been: longer MS duration predicted worse QoL two years later, [102] and worse EDSS predicted worse QoL two, [102] six, [103] and ten [104] years later. Depression predicted worse QoL six [103] and ten [104] years later, and stronger pain [105] and cognitive impairment [104] predicted worse QoL ten years later.

Interventions
Details of the selected articles on psychological intervention are presented in Table 4.

Mindfulness-based therapies
All mindfulness-based therapy intervention programs showed improvement in QoL at some evaluation point and at least in some QoL domains. Body-affective mindfulness intervention increased the general QoL score up to six months after treatment. [106] Of the three studies on mindfulness-based stress reduction programs, two showed a significant increase in QoL after treatment. [107][108][109] One study [109] only produced a small, insignificant increase after treatment and at the three-month follow-up.
A community-based mindfulness program resulted in a significant increase in MCS. [110] Finally, mindfulness-based cognitive therapy did not show any significant difference in general QoL between the control and the experimental group, however, it did show significant differences in QoL: in health distress, mental wellbeing, role limitation due to emotional problems and cognitive performance. [111]

Cognitive-behavioral
A wide spectrum of cognitive behavioral interventions was analyzed.
In a study by Case et al., [112] the experimental group attended 10 one-hour weekly sessions of healing light guided imagery. They found a greater increase in QoL in this group than with 10 hours of positive journaling in the active control group.
Blair et al. [113] focused intervention on emotion regulation. The design consisted of 16 1.5-hour biweekly sessions for eight weeks. The intervention resulted in a significant increase in QoL six months after treatment.
Interventions by Calandri et al. [114] and Graziano et al. [115] had a comparable design. Participants were divided into two subgroups by age. Intervention comprised four-five two-hour sessions over the course of two months, and one followup session six months after treatment. Calandri et al. [114] also included one follow-up session 12 months after treatment.
At follow-up, the intervention groups in both studies had experienced an increase in QoL.
Two of the studies based intervention on Acceptance and Commitment Therapy (ACT). Pakenham et al. [119] implemented an eight-week program aimed at training in resilience. QoL increased at treatment end and at three-month follow-up. Proctor et al. [120] implemented an eight-week intervention comprising telephone calls and self-help ACT books. No significant increase in QoL was observed.

Social and group support
The following social support and group interventions had an impact on QoL in MS.
Jongen et al. [122] tested an intensive social-cognitive wellness program involving the partner or other significant informal caregiver. The results showed an increase in the MCS at one, three and six months from treatment, and in the PCS six months after treatment. The results of the program were evaluated again 12 months after treatment. The relapsing-remittent MS group showed an increase in PCS and MCS. [123] Eliášová et al. [124] found more improvement across several QoL domains in MS patients after self-help group sessions than in patients who did not attend the self-help groups. Liu et al. [125] detected an increase in physical and psychological QoL in women with MS after participating in a hope-based group therapy program for one-hour twice a week for eight weeks.

Symptom and self-management-based therapies
Two studies analyzed a fatigue self-management group therapy. Mulligan et al. [126] reported positive, but not significant, changes in QoL after their treatment. Thomas et al. [127] reported significant positive changes in physical health assessed by the Multiple Sclerosis Impact Scale (MSIS-29) and vitality as measured by the SF-36 in the intervention group 12 months after the treatment.
In addition to fatigue self-management, Ehde et al. [128] focused in their intervention on pain and depression selfmanagement. The results were compared to an educational program. There was a higher QoL post-treatment and 12month follow-up score in the self-management group. Feicke et al. [129] implemented a program focused on MS selfmanagement. As in Ehde et al., [128] improvements in QoL were still maintained at six-month follow up.

Other psychological intervention
LeClaire et al. [130] implemented a five-week positive psychology program. The results showed only a significant improvement in the SF-36 vitality subscale.
Regarding sociodemographic influences on QoL, not surprisingly, unemployment, a low socioeconomic status [35] and financial difficulties [37] proved to be major risk factors [30,34,54,67,94] . In keeping with the negative influence of the scarcity of resources, lack of access to therapy was also identified as a risk factor. [30,31] The second aim of this systematic review was to study QoL in MS patients at different times during their disease history. Two studies showed diminishing QoL in MS patients in its early stage. [95,96] This might have to do with the fact that patients being diagnosed with a severe chronic disease need a certain time to come to terms with this emotional shock. Oscillation between avoidance and problem-solving, which both have a positive influence in the first three years after diagnosis, [97] may be behind this inner struggle. In older patients, neurological impairment and physical disability, [97] which represent the age-associated increase in physical impairment, were identified as risk factors for QoL in MS.
Finally, the third aim of this review was to analyze psychological interventions for the improvement of QoL in MS.
Symptomatic improvement of psychopathology usually at the center of psychotherapy outcome studies, was not the primary focus of our review. [131] Eight of the intervention studies specifically treated depressive symptomatology, [106,[110][111][112]115,[117][118] either with mindfulness-based or cognitive-behavioral approaches, both of which proved to be successful. Three studies were specifically directed towards the treatment of fatigue [112,126,127] by light guided imagery or selfmanagement programs. Both the imagery and self-management group intervention approaches were successful, whereas the individual self-management program did not show significant improvement.
A variety of mindfulness-based approaches [107][108][109] and a Community-based intervention were directed at stress reduction. [110] Three of the four studies showed some kind of improvement in QoL, including the only study with a control group.
Several of the interventions were designed to reinforce protective factors in MS patients. Graziano et al. [115] focused on identity redefinition, sense of coherence and self-efficacy. Pakenham et al. [119] implemented a program based on resilience training, and the program by Blair et al. [113] focused on the improvement of emotion regulation. All of them were successful in improving QoL, confirming the alternative focus on protective factors instead of risk factors.
A wide spectrum of interventions based on social support concentrated on reinforcement of the social network of MS patients, for example, self-help groups, [124] hope-based group therapy, [125] supportive-expressive therapy, [121] and social cognitive training with support partners. [122,123] All interventions aimed at helping people overcome MS barriers in daily living by strengthening their social support, improving some aspects of QoL. This is consistent with the studies mentioned above [92,93] and emphasizes the importance of social support and participation as a protective factor for QoL.

Limitations
The main limitation of this study was the impossibility of carrying out a quantitative synthesis of the results, due to the heterogeneity of methodologies and designs in the articles included. Due to the vast number of topics and limited resources our search was restricted to a five-year period through January 2019.

Conclusions
This

Authors Contribution
Irene   4 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale.

4-5
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

4-5
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

4-5
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

5
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

5
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.

Strengths and limitations of this study
-This is the first systematic review of risk factors and psychological intervention for quality of life in multiple sclerosis in over a decade.
-A comprehensive and robust search strategy and strict inclusion criteria were employed to cover all the relevant evidence.
-Careful standardized risk of bias was assessed in all 106 studies included.
-Due to heterogeneity of the studies only qualitative synthesis of results was possible.

Introduction
The Constitution of the World Health Organization (WHO) declares health to be "…a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity." [1] Quality of life (QoL) is a multidimensional concept that encompasses the domains included in this definition of health. [2,3] Its introduction in medical literature dates back to 1960 [4] , with its importance continuously growing to date. [5] Multiple Sclerosis (MS) is a chronic neurodegenerative condition, characterized by a wide range of symptoms and a highly unpredictable prognosis, which can severely affect patient QoL. [6][7][8] MS patients tend to report lower QoL than the general population. [9][10][11][12] This diminished QoL may be due to their impaired functioning in daily living, more so if the help of caregivers is required, impeding family relations, work and social dynamics. [13,14] The impact of MS on QoL can be affected by numerous disease-related factors, such as disability level or MS type, and individual factors such as social support, education, age or employment. [15][16][17][18] Identification of risk and protective factors is a key point in implementing strategies to improve patient QoL. [7] In this context, all influences must be considered to contribute to QoL in MS. [7,19] In addition to providing practitioners with useful information on the impact of symptoms and therapy on the patient's life, QoL is also an indicator of treatment success and a predictor of disease progression. [20][21][22] In view of its relevance in healthcare research, the need to compile and condense available scientific evidence on the subject is urgent. Against this backdrop, this systematic review gives a comprehensive overview of risk and protective factors related to QoL in MS as well as relevant psychological interventions. The growing number of studies on this subject [2,22] provides a vast amount of data, which due to the inconsistency of findings, needs careful assessment to come to evidence-based conclusions.

Methodology
This systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. [23] As a review of prior publications, ethical approval (or informed consent) was unnecessary. A review protocol is available from the corresponding author upon request.

Search strategy
The systematic search focused on journal articles published between January 1, 2014 to January 31, 2019. The Scopus, Web of Science and ProQuest databases were searched in February and March 2019. The key words used were ("multiple sclerosis") AND ("quality of life" OR "health-related quality of life" OR "well-being" OR "wellbeing" OR "life satisfaction"). The search terms were intentionally broad to ensure wide coverage of the literature. The search field was limited to "title/abstract" and language was limited to "English". The complete research string is reported under There is no published systematic review on this topic in the Cochrane Library.  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59

Study selection
First, title and abstract were screened to identify suitable articles for full text review. The screening process was performed independently by two researchers. Any disagreement about study selection was resolved by consensus with a third reviewer.
Inclusion criteria were the following: 1. Studies primarily focusing on QoL determinants and psychological intervention to improve it.
2. Study participants aged over 18 with a confirmed MS diagnosis.
The following exclusion criteria were applied: 1. Nonpsychological intervention.
2. Not primary research studies (systematic reviews, meta-analyses, protocols and clinical guidelines were excluded).
3. Studies on the development and validation of QoL measurement instruments.
4. QoL risk or intervention studies for healthy behavior, cognitive rehabilitation, physical activity or pharmacological treatment.
5. Studies on comorbidity with another illness or mental health diagnosis.
6. Sample selection based on a special condition (for example: only employees or MS patients under certain pharmacological treatment).
7. Studies not using a validated QoL measurement tool.

Quality assessment
The methodological quality of the studies was appraised with a well-established standardized 12-item checklist, [24] in which every item represents a methodological feature: inclusion/exclusion criteria, methodology/design, attrition rate, attrition between-groups, exclusions after, follow-up, occasion of measurements, pre/post measures, dependent variables, control techniques, construct definition and imputing missing data. The codification criteria proposed by the checklist authors was used. No article was excluded from quality appraisal.

Data abstraction
Data were extracted from selected articles based on a previously designed coding sheet. The pilot study was approved by consensus. The information extracted included: title, authors and publication year, country (city), design, sample characteristics, study variables and measurement tools, main results and conclusions. After extraction, the information was independently reviewed by two authors to avoid errors or omitting data.

Literature screening
A total of 4886 articles were initially identified from SCOPUS, Web of Science and ProQuest. After removal of duplicates and abstract analysis, 188 studies were eligible for full text review. Finally, 106 were selected for the narrative analysis. The selection process is detailed below in a PRISMA flow diagram (Figure 1).

Study characteristics
The articles included were analyzed by their primary and secondary outcomes. Seventy studies analyzed QoL risk and protective factors (Table 2), 11 focused on the development of QoL at different ages and times in the disease (Table 3), and 25 studied the effect of psychological intervention on QoL in MS (Table 4).
All the articles included employed standardized and validated QoL measurement instruments; 64 studies evaluated QoL with a generic measure and 50 studies made use of a disease-specific measure. The Short Form Health Survey 36 (SF-36) was mainly used (n = 29) as a generic measure and Multiple Sclerosis Quality of Life-54 (MSQoL-54) (n = 28) as a disease-specific measure. Finally, 11 studies used more than one measure to evaluate QoL. The study designs were mostly cross-sectional (n = 74), and sample sizes ranged from 7 to 74451 participants.
The main findings of the articles are summarized below.

Risk and protective MS QoL factors
Factors influencing MS patients QoL are summarized in Table 2.
A diversity of cognitive impairments, for instance, cognitive fatigue, memory loss and planning/organizational dysfunction, were recognized as risk factors by a number of studies. [39,50,52,53,[65][66][67] Sgaramella et al. [68] showed that maintaining executive functioning was a protective factor of QoL. This was also the only study on the important subject of cognitive reserve and QoL.

Personality domains
The role of personality domains was explored in several studies. Cyclothymic and depressive temperament were associated with a lower QoL in MS, in contrast to hyperthymic temperament, which was associated with higher QoL. [77] Another study recognized extraversion as a personality trait related to higher QoL levels. [69] Cioncoloni et al. [34] recognized introverted personality as a risk factor for QoL in MS, and finally, type D personality was another relevant factor. [78]
Coping strategies were also identified as relevant mediator variables. Problem-focused, emotion-focused, and stopping unpleasant emotion coping strategies were partial mediators between fatigue [83] or type D personality [84] and QoL as measured by the mental composite score (MCS).

Other psychological factors
According to Van Damme et al., [85] acceptance of the illness is a protective factor for QoL. The role of flexible adjustment and tenacious goal pursuit in achieving personally blocked goals was not as clear, although their findings showed a trend towards a positive relationship.
Resilience was confirmed as a protective factor of QoL in MS. [27,86] Moreover, Koelmel et al. [87] highlighted its role as a mediator variable in the relationship between social support and MCS.
High levels of self-efficacy, [51,88] self-esteem, [88] illness identity [88] and sense of coherence [89] correlated with higher QoL, and self-esteem mediated in the relationship of social support with MCS. [90] Ultimately, cognitive fusion, the extent to which people feel fused with or attached to their thoughts, mediated the relationship between stigma and QoL in MS. [91]

Social factors
Social support [92] and participation [93] were positively related with QoL. Several mediators in this relationship were mentioned above.

Demographic factors
Employment was found to be the leading sociodemographic factor influencing QoL. Several studies displayed an association between unemployment and lower QoL. [30,34,54,67,94] Others showed a positive correlation between jobs adapted to disability, [94] job match and job satisfaction, [41] high employment status, [33,41] and QoL in MS. Low socioeconomic status [35] and financial straits [37] were also risk factors for lower QoL. Brola et al. [30,31] noted that not having access to an adequate pharmacological treatment put QoL in danger. Congruent with this finding, Boogar et al. [35] found a positive treatment experience to be a protective factor.
Other sociodemographic variables related to poorer QoL in MS were male sex, [37] old age, [30,31] unmarried or living with significant others, [37] whereas a higher education was a protective factor. [33] [62] Labiano-Fontcuberta et al (2015) [74] Cross     Table 3 summarizes the characteristics of studies focusing on QoL at different ages and times in the disease history.

Disease history
Some of the selected studies examined QoL in MS in its early years. According to Possa et al. [95] , QoL decreased in the first year of diagnosis, as assessed by the MCS and physical composite score (PCS). Stern et al. [96] found the worst QoL in the youngest group of MS patients.
Calandri et al. [97] found that during the first three years from diagnosis, problem-solving and avoidance coping strategies had a positive effect on QoL. Nourbakhsh et al. [98] also studied factors influencing the development of QoL in the first three years. Their results showed that higher baseline levels of fatigue and depression predicted worse QoL as assessed by the PCS, whereas lower cognitive functioning and higher fatigue predicted a worse MCS.
Another study on QoL in MS by Buhse et al. [99] focused on old age. These authors identified neurological impairment, physical disability, depression, and comorbidity with thyroid disease as risk factors for worse QoL as assessed by the PCS in a sample of elderly MS patients. On the contrary, being widowed and employed were identified as protective PCS factors.
In a longitudinal study, Kinkel et al. [100] showed that a second clinical event consistent with clinically defined MS, higher EDSS at the time of diagnosis and an earlier MS onset predicted a decrease in PCS 10 years after diagnosis.
Bueno et al. [101] also showed that progression from benign MS to non-benign MS predicted a decrease in PCS 25-30 years after diagnosis.
Some longitudinal predictors of QoL identified have been: longer MS duration predicted worse QoL two years later, [102] and worse EDSS predicted worse QoL two, [102] six, [103] and ten [104] years later. Depression predicted worse QoL six [103] and ten [104] years later, and stronger pain [105] and cognitive impairment [104] predicted worse QoL ten years later.

Interventions
Details of the selected articles on psychological intervention are presented in Table 4.

Mindfulness-based therapies
All mindfulness-based therapy intervention programs showed improvement in QoL at some evaluation point and at least in some QoL domains. Body-affective mindfulness intervention increased the general QoL score up to six months after treatment. [106] Of the three studies on mindfulness-based stress reduction programs, two showed a significant increase in QoL after treatment. [107][108][109] One study [109] only produced a small, insignificant increase after treatment and at the three-month follow-up.
A community-based mindfulness program resulted in a significant increase in MCS. [110] Finally, mindfulness-based cognitive therapy did not show any significant difference in general QoL between the control and the experimental group, however, it did show significant differences in QoL: in health distress, mental wellbeing, role limitation due to emotional problems and cognitive performance. [111]

Cognitive-behavioral
A wide spectrum of cognitive behavioral interventions was analyzed.
In a study by Case et al., [112] the experimental group attended 10 one-hour weekly sessions of healing light guided imagery. They found a greater increase in QoL in this group than with 10 hours of positive journaling in the active control group.
Blair et al. [113] focused intervention on emotion regulation. The design consisted of 16 1.5-hour biweekly sessions for eight weeks. The intervention resulted in a significant increase in QoL six months after treatment.
Interventions by Calandri et al. [114] and Graziano et al. [115] had a comparable design. Participants were divided into two subgroups by age. Intervention comprised four-five two-hour sessions over the course of two months, and one followup session six months after treatment. Calandri et al. [114] also included one follow-up session 12 months after treatment.
At follow-up, the intervention groups in both studies had experienced an increase in QoL.
Two of the studies based intervention on Acceptance and Commitment Therapy (ACT). Pakenham et al. [119] implemented an eight-week program aimed at training in resilience. QoL increased at treatment end and at three-month follow-up. Proctor et al. [120] implemented an eight-week intervention comprising telephone calls and self-help ACT books. No significant increase in QoL was observed.

Social and group support
The following social support and group interventions had an impact on QoL in MS.
Jongen et al. [122] tested an intensive social-cognitive wellness program involving the partner or other significant informal caregiver. The results showed an increase in the MCS at one, three and six months from treatment, and in the  1  2  3  4  5  6  7  8  9  10  11  12  13  14  15  16  17  18  19  20  21  22  23  24  25  26  27  28  29  30  31  32  33  34  35  36  37  38  39  40  41  42  43  44  45  46  47  48  49  50  51  52  53  54  55  56  57  58  59  60   F  o  r  p  e  e  r  r  e  v  i  e  w  o  n  l  y 21 PCS six months after treatment. The results of the program were evaluated again 12 months after treatment. The relapsing-remittent MS group showed an increase in PCS and MCS. [123] Eliášová et al. [124] found more improvement across several QoL domains in MS patients after self-help group sessions than in patients who did not attend the self-help groups. Liu et al. [125] detected an increase in physical and psychological QoL in women with MS after participating in a hope-based group therapy program for one-hour twice a week for eight weeks.

Symptom and self-management-based therapies
Two studies analyzed a fatigue self-management group therapy. Mulligan et al. [126] reported positive, but not significant, changes in QoL after their treatment. Thomas et al. [127] reported significant positive changes in physical health assessed by the Multiple Sclerosis Impact Scale (MSIS-29) and vitality as measured by the SF-36 in the intervention group 12 months after the treatment.
In addition to fatigue self-management, Ehde et al. [128] focused in their intervention on pain and depression selfmanagement. The results were compared to an educational program. There was a higher QoL post-treatment and 12month follow-up score in the self-management group. Feicke et al. [129] implemented a program focused on MS selfmanagement. As in Ehde et al., [128] improvements in QoL were still maintained at six-month follow up.
Regarding sociodemographic influences on QoL, not surprisingly, unemployment, a low socioeconomic status [35] and financial difficulties [37] proved to be major risk factors [30,34,54,67,94] . In keeping with the negative influence of the scarcity of resources, lack of access to therapy was also identified as a risk factor. [30,31] The second aim of this systematic review was to study QoL in MS patients at different times during their disease history. Two studies showed diminishing QoL in MS patients in its early stage. [95,96] This might have to do with the fact that patients being diagnosed with a severe chronic disease need a certain time to come to terms with this emotional shock. Oscillation between avoidance and problem-solving, which both have a positive influence in the first three years after diagnosis, [97] may be behind this inner struggle. In older patients, neurological impairment and physical disability, [97] which represent the age-associated increase in physical impairment, were identified as risk factors for QoL in MS.
Finally, the third aim of this review was to analyze psychological interventions for the improvement of QoL in MS.
Symptomatic improvement of psychopathology usually at the center of psychotherapy outcome studies, was not the primary focus of our review. [131] Eight of the intervention studies specifically treated depressive symptomatology, [106,[110][111][112]115,[117][118] either with mindfulness-based or cognitive-behavioral approaches, both of which proved to be successful. Three studies were specifically directed towards the treatment of fatigue [112,126,127] by light guided imagery or selfmanagement programs. Both the imagery and self-management group intervention approaches were successful, whereas the individual self-management program did not show significant improvement.
A variety of mindfulness-based approaches [107][108][109] and a Community-based intervention were directed at stress reduction. [110] Three of the four studies showed some kind of improvement in QoL, including the only study with a control group.
Several of the interventions were designed to reinforce protective factors in MS patients. Graziano et al. [115] focused on identity redefinition, sense of coherence and self-efficacy. Pakenham et al. [119] implemented a program based on resilience training, and the program by Blair et al. [113] focused on the improvement of emotion regulation. All of them were successful in improving QoL, confirming the alternative focus on protective factors instead of risk factors.
A wide spectrum of interventions based on social support concentrated on reinforcement of the social network of MS patients, for example, self-help groups, [124] hope-based group therapy, [125] supportive-expressive therapy, [121] and social cognitive training with support partners. [122,123] All interventions aimed at helping people overcome MS barriers in daily living by strengthening their social support, improving some aspects of QoL. This is consistent with the studies mentioned above [92,93] and emphasizes the importance of social support and participation as a protective factor for QoL.

Limitations
The main limitation of this study was the impossibility of carrying out a quantitative synthesis of the results, due to the heterogeneity of methodologies and designs in the articles included. Due to the vast number of topics and limited resources our search was restricted to a five-year period through January 2019.

Conclusions
This review was intended to give a broad overview of QoL in MS. The findings show the importance of clinical, psychosocial and demographic variables as QoL risk and protective factors. A variety of psychological interventions ranging from mindfulness-based and cognitive-behavioral approaches to self-help groups addressing these factors were identified as promising options for improving QoL. These findings have important clinical implications. A sound biopsychosocial assessment of MS patients in daily clinical practice is necessary to ensure the possibility of early identification of QoL risk factors and evidence-based psychological intervention is recommended to improve or stabilize QoL.

4-5
Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched.

4-5
Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated.

Supplement Digital Content A
Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis).

5
Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators.

5
Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made.

Risk of bias in individual studies
12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis.