Impact of autologous HSCT on the quality of life and fatigue in patients with relapsing multiple sclerosis

In this study, we aimed to assess the quality of life, fatigue, anxiety, and depression after Autologous haematopoietic stem cell transplantation (AHSCT) and to investigate its impact of on separate domains of health status and fatigue in patients with multiple sclerosis (MS). Overall, 18 patients with highly active relapsing MS (mean age 36.3 years, 83.3% female) underwent the AHSCT in Vilnius Multiple Sclerosis center, and we prospectively collected Short Form 36, Health Survey Questionnaire, Fatigue Descriptive Scale, and Hospital Anxiety and Depression Scale beforeand Month3, 12, and 24 after AHSCT. The median score of Expanded Disability Status Scale at Month3 after transplant improved in 14 patients (77.8%). A significant improvement in physical functioning, vitality, and pain was found at Month3 after AHSCT (p < 0.05), which was sustained until Month12 and 24. The improvement in fatigue score was found at Month12 after AHSCT, which was sustained until Month24. Decrease in EDSS score had a positive impact on the better HRQoL outcomes, especially physical and social outcomes. Thus, AHSCT improved quality of life and reduced symptoms of fatigue in patients with highly active relapsing MS. The improvement was determined earlier in the domains of QoL than in the fatigue.

www.nature.com/scientificreports/ in fatigue 15,16 . However, fatigue is subjective and varies over the course and severity of the disease, which makes its measurement challenging. The incidence of psychopathological disorders, especially depression and anxiety, is high in MS, often, higher than in other chronic neurological disorders 17,18 . Clinical studies suggest that more than half of the patients with MS have symptoms of depression and anxiety, which negatively impacts all HRQoL domains. The depressive symptoms in MS also correlate with fatigue 19,20 .
Treatment targeting HRQoL and fatique in MS have had mixed levels of success. Some treatments aim to address comorbidities that might contribute to MS such as depression, anxiety, and spasticity or pain treatment through various pharmacologic mechanisms. There is also data showing that disease modification thorough immune modulation or suppression can improve fatigue, reduce anxiety, and improve QoL in patients with MS. During the last 30 years, autologous hematopoetic stem cell transplantation (AHSCT) was proposed as a treatment for severe autoimmune diseases and is a promising alternative treatment for highly active MS 21,22 .
Since AHSCT is an innovative therapy in the treatment of highly active MS, there is an urgent need for studies which can assess not only the effectiveness and safety of the treatment, but also its impact on the patients' QoL, fatigue, anxiety and depression. Further data is being provided regarding AHSCT in MS treatment; however, despite the wide recognition of the importance of evaluating the emotional aspects, most studies apply the clinical approach.
The study aimed to assess the QoL, fatigue, anxiety and depression after AHSCT in patients with MS and to investigate the impact of AHSCT on the separate domains of health status and fatigue in these patients after AHSCT.

Results
Patients. Eighteen patients treated with AHSCT were included in the study. HRQoL, depression, anxiety and fatigue were assessed in these patients before AHSCT, and thereafter, at Month 3, 12 and 24. Demographic and clinical characteristics of the patients at baseline are provided in Table 1.
Two patients of 18 (11.1%) had one relapse and one patient of 18 patients (5.6%) had two relapses during the first year after AHSCT. One patient of 18 (5.6%) had one relapse and one patient of 18 (5.6%) had two relapses during the second year after AHSCT. The annualized relapse rate dropped from 2.7 before AHSCT to 0.17 in the first year and to 0.11 in the senond year after AHSCT.
Comparing the mean score on the Expanded Disability Status Scale (EDSS) at the four time points (preAH-SCT, M3, M12 and M24), significant improvement was assessed at Month3 after AHSCT (p < 0.05) and EDSS score remained stable at Months 12 and 24 (Fig. 1). The median EDSS score at Month 3 with a minimal change from baseline of 0.5 points improved after transplant in 77.8% of patients; however, in 22.8% of patients EDSS, did not change. Sustained disability improvement was found in 12 (66.7%) of 18 patients at Month 12 and in 11 (61.1%) of 18 patients at Month 24. An improvement in all domains of Short Form 36 (SF-36) Health Survey Questionnaire was observed at the first follow-up, that is, Month3 after AHSCT. The improvement was sustained until Month 12 and 24 (Fig. 2).
A significant improvement was observed in physical functioning, vitality, and pain at Month 3 after AHSCT (p < 0.05) ( Table 2). The median physical functioning score improved by 18.4, vitality by 20 and pain by 36.7 at first follow-up after AHSCT (p < 0.05), which was sustained until the end of the study. In 22.8% of patients, who did not show improvement in EDSS score, the scores of physical functioning and vitality did not change after AHSCT. In this patients, the significant improvement in pain score was observed at Month12 after AHSCT (p < 0.05): the mean score improved by 51.8 at Month 12 compared with the baseline. 9 patients (50.0%) had moderate and 7 patients (38.9%) had severe depression before AHSCT. 13 patients (72.2%) had moderate anxiety and 1 patient (5.6%) had severe anxiety before AHSCT.
Unlike the scores on the HRQoL questionnaires, where significant improvement was found at Month 3, the improvement in fatigue score was found at Month 12 after AHSCT, and this improvement was sustained Median EDSS score before AHSCT (IQR) 6.0 (6.0-6.5) www.nature.com/scientificreports/ www.nature.com/scientificreports/ until Month 24. The improvement in fatigue score was also observed at Month3; however, it was not significant (p > 0.05). The anxiety and depression scores were stable before AHSCT and at Month 3, 12, and 24 after AHSCT (Table 3). In 22.8% of patients, who did not have improvement in their EDSS score, their score on fatigue and anxiety also did not change after AHSCT. However, there was significant improvement in depression score in these patients at Month 12 after AHSCT (p < 0.05): the mean score decreased by 7.25 at Month 12 compared with the baseline. Only significant independent variables (p < 0.05) were included in the models.

Discussion
The primary aim of the study was to assess the QoL, fatigue, anxiety, and depression in patients with MS after AHSCT. Since 1997, a number of trials on AHSCT in patients with MS and its efficacy and safety have been reported 21,22 . However, only two trials provide their data according to QoL 23,24 and one trial on fatigue 25 in patients with MS after AHSCT. In this study, we analysed the HRQoL and fatigue owing to MS by following up with 18 patients with MS on whom AHSCT was performed in one center. Moreover, we emphasized, on the impact of AHSCT on health status and fatigue in patients with MS post transplant. Evidence from multiple studies indicates that AHSCT is a highly effective treatment alternative for highly active relapsing MS [26][27][28] . The current analysis shows that in patients with relapsing MS who do not respond   www.nature.com/scientificreports/ to prior high efficacy DMT adequately, AHSCT provides disability stabilization as well as early disability regression 26,29 . Our results support previous published data, showing the ability of AHSCT to reduce the disability and to sustain the disability stability for long time [26][27][28] . MS is a chronic and potentially disabling disease that significantly affects patients' QoL. In MS, QoL is impaired partly owing to physical disability, and partly due to MS-associated fatigue, and depression. Mostly, patients with MS require life-long treatments that can cause major side-effects. Assessing the impact of these interventions on QoL and fatigue is important because it highlights the patient's perspective on the overall effect of the treatment. Our results show that AHSCT improves HRQoL and fatigue in people with highly active relapsing MS. Absolute scores of all SF-36 domains increased at Month 3 after AHSCT and remained stable at Month 12 and 24, whereas the SF-36 domains physical functioning, vitality and pain were significantly affected by the treatment. Unlike other studies that showed significant improvement in all domains of SF-36 one year after AHSCT 6,23,24 , we found earlier improvement in HRQoL in patients MS. The lack of significance in other domains, like general health, role limitation because of physical and emotional problems, and social functioning, may be related to a relatively small sample size. In contrast to the scores of HRQoL questionnaires, the improvement in fatigue score was found later, and significant improvement was observed at Month 12 after AHSCT, which sustained until Month 24. However, non-significant decline in anxiety score was observed at Month 3, which indicates increased anxiety in patients in the early phase after transplant. Slight decline in anxiety and later improvement in fatigue score suggest that AHSCT using intermediate intensity lymphoablative conditioning regimen may negatively impact anxiety and fatigue in patients with MS in early phases after the AHSCT procedure. Previously published data have proved the negative impact of AHSCT on cognition in the early phase after AHSCT (month 2 and 3 after AHSCT) [29][30][31] ; however, other comorbidities like fatigue and anxiety in MS are likely to be affected in the early phase after transplantation.
In almost one quarter of patients who showed no improvement in physical disability, the fatigue and anxiety scores also did not improve after AHSCT either. However, we found significant improvement in depression scores at Month 12 after transplant. Our data support that AHSCT has benefits on the disease stability and even can improve other comorbidities.
We also found an association between lower EDSS and improvement in physical and social functioning as well as role limitations owing to physical problems, during the last follow-up after AHSCT. The current analysis shows that in patients with highly active relapsing MS, disability regression is the main value that has a positive impact on HRQoL outcomes, especially physical and social outcomes. We did not find the value that could have a positive impact on fatigue scores after AHSCT; however, previous studies have demonstrated that better social outcomes are associated with reduction in fatigue score 25 .
The main limitation of this study was the relatively low sample size. Therefore, the results of this study cannot be generalized; further research is needed to replicate these findings. Furthermore, there was no comparative control group and the assessment was performed in one center. However, we did not identify any controlled study, with the exception of one small randomised controlled trial 32 in which a comparative group is used to assess the results of AHSCT.

Conclusions
AHSCT improved quality of life and reduced symptoms of fatigue in patients with highly active relapsing MS. The improvement was determined earlier in the domains of QoL than in the fatigue. A significant improvement in physical functioning, vitality, and pain was found at Month 3 after AHSCT (p < 0.05) in patients with MS, and this improvement was sustained until Month 12 and 24. The improvement in fatigue score was found at Month 12 after AHSCT, which was sustained until Month 24. Primarily, reduction of the EDSS score had a positive impact on the better HRQoL outcomes, especially physical and social outcomes.

Methods
The Lithuanian Bioethics Committee approved the study in 2011 (2011-01-27 No.: L-12-01/2), the permission to continue the study was granted by the Lithuanian Bioethics Committee in 2018 (2018-02-22 No.: 6B-18-41). All methods were carried out in accordance with relevant guidelines and regulations. All participants provided written informed consent. The AHSCT procedure is performed at our hospital as routine clinical practice for highly active relapsing patients with MS who do not respond to the second line MS treatment. Highly active MS patients in the case of AHSCT were defined the patients who experienced at least two relapses and had disability progression of at least 2.0 points according EDSS in the last year.
Participants underwent peripheral blood stem cells mobilization: cyclophosphamide was administered, subcutaneous filgrastim was started on day + 7 and peripheral blood stem cell apheresis procedure were targeted on day + 12 after cyclophosphamide. Collected cells were cryopreserved and stored. The conditioning regimen was intravenous cyclophosphamide and rabbit antithymocyte globulin 29 .
Patient eligibility. The inclusion criteria were: diagnosis of highly active relapsing MS; aged 18 years and over; performed AHSCT and completed SF-36, Hospital Anxiety and Depression Scale (HADS), and Fatigue Descriptive Scale (FDS) questionnaires before AHSCT and during the period defined by the evaluation, and participants willing to cooperate voluntarily with the research. Neurologic assessment. Neurologic assessment was scheduled for all patients at baseline, Month 3, 12 and 24 after AHSCT. Neurological disability was assessed with EDSS 33 . Confirmed significant disability change was defined as disability increase from study baseline, measured by EDSS: increase of ≥ 1.0 points if baseline EDSS was ≤ 5.5 points or an ≥ 0.5-point increase if baseline EDSS was > 5.5 points. Anxiety and depression assessment. HADS was used to assess anxiety and depression. It was completed at baseline, Month 3, 12, and 24 after AHSCT. HADS is a brief self-administrated two-dimensional questionnaire, which is one of the most widely used tool to screen anxiety and depression among patients with different disorders 36 . Previous studies have shown that HADS is an appropriate screening instrument for patients with MS [37][38][39] . Of the 14 questions-seven reflect anxiety (Hospital Anxiety and Depression Scale-Anxiety [HADA subscale]) whereas the rest reflect depression (Hospital Anxiety and Depression Scale-Depression (HADD subscale)). A total subscale score of > 8 points out of a possible 21 indicate considerable symptoms of depression or anxiety. Mauchly's test of sphericity was used to test whether or not the assumption of sphericity was met in a repeated measures ANOVA. Linear regression was used to assess the impact of different demographic and clinical factors on the disability regression. A significance level p < 0.05 was accepted.

Data availability
The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.