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Tolf A, Gauffin H, Burman J, Landtblom AM, Flensner G. Experiences of being treated with autologous haematopoietic stem cell transplantation for aggressive multiple sclerosis: A qualitative interview study. PLoS One 2024; 19:e0297573. [PMID: 38324607 PMCID: PMC10849216 DOI: 10.1371/journal.pone.0297573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 01/08/2024] [Indexed: 02/09/2024] Open
Abstract
BACKGROUND Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used as a treatment for aggressive multiple sclerosis (MS) and has the potential to induce long-term remission and resolution of disease activity. Despite the extensive research on treatment outcome after AHSCT, the experience of living with MS after AHSCT has not been previously described in the scientific literature. The aim of this study was to explore long-term lived experience of people with MS treated with AHSCT. METHODS AND FINDINGS To exclude selection bias, all persons treated with AHSCT for MS at Uppsala University Hospital, Sweden, between 2004 and 2007 (n = 10), were asked to participate in the study, and all accepted. Open-ended interviews were conducted, digitally recorded, transcribed verbatim, and then subjected to qualitative content analysis with an inductive approach. Five main themes emerged from the interviews: (I) being diagnosed with MS-an unpredictable existence; (II) a new treatment-a possibility for a new life; (III) AHSCT-a transition; (IV) reclaiming life; and (V) a bright future accompanied by insecurity. AHSCT was described by the participants in terms of a second chance and an opportunity for a new life. The treatment became a transition from a state of illness to a state of health, enabling a previous profound uncertainty to wane and normality to be restored. Although participants of different age and sex were included, the main limitation of this study is the relatively small number of participants. Also, the inclusion of persons from one centre alone could restrict transferability of the results. CONCLUSIONS The results give a first insight into lived experience following a highly effective induction treatment for MS, and the experience of not having MS anymore. Underpinned by previously described outcome following AHSCT, the results of this study challenge the current view on MS as a chronic disease with no possible cure.
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Affiliation(s)
- Andreas Tolf
- Department of Medical Sciences, Neurology, Uppsala University, Uppsala, Sweden
- Department of Neurology, Uppsala University Hospital, Uppsala, Sweden
| | - Helena Gauffin
- Department of Biomedical and Clinical Sciences (BKV), Faculty of Medicine and Health Sciences, Linköping University, Linköping, Sweden
- Department of Neurology, Linköping University Hospital, Region Östergötland, Linköping, Sweden
| | - Joachim Burman
- Department of Medical Sciences, Neurology, Uppsala University, Uppsala, Sweden
- Department of Neurology, Uppsala University Hospital, Uppsala, Sweden
| | - Anne-Marie Landtblom
- Department of Medical Sciences, Neurology, Uppsala University, Uppsala, Sweden
- Department of Neurology, Uppsala University Hospital, Uppsala, Sweden
| | - Gullvi Flensner
- Department of Caring Sciences, University West, Trollhättan, Sweden
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2
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Sai Santhosha Mrudula A, Avula NL, Ahmed SK, Salian RB, Alla D, Jagannath P, Polasu SS, Rudra P, Issaka Y, Khetan MS, Gupta T. Immunological outcomes of autologous hematopoietic stem cell transplantation for multiple sclerosis: a systematic review. Ann Med Surg (Lond) 2024; 86:421-432. [PMID: 38222726 PMCID: PMC10783339 DOI: 10.1097/ms9.0000000000001490] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Accepted: 10/30/2023] [Indexed: 01/16/2024] Open
Abstract
Background Autologous hematopoietic stem cell transplantation (AHSCT) is an extensive procedure that allows for the depletion of the immune system and its restoration from hemopoietic stem cells. The approach has been modified for the treatment of severe immune-mediated illnesses, including multiple sclerosis (MS), after being initially devised for the treatment of hematological malignancies. Objective This systematic review aims to determine and consolidate the information on the short-term and long-term immunological effects of AHSCT on the cellular level in MS patients. Methods The PubMed, Scopus, and Web of Science servers were used to conduct a systematic search in compliance with the PRISMA guidelines. The results were tabulated and analyzed. Results A total of 17 studies (10 clinical trials, 6 cohort studies, and 1 case-control study) were included in the final analysis, and 383 MS patients were analyzed. A significant decline in the cell count of CD4 T cells was reported when compared to the CD8 T cells, B cells, and NK cells. B cell count returned to baseline in 71.4% of the studies at the end of 6 months. The NK cell count was found to be above the baseline in 62.5% of studies. Conclusion AHSCT has been proven to be one of the most effective treatment modalities for MS in recent studies. However, debilitating complications due to immunological outcomes of the procedure have led to increased morbidity. Further research into this domain will help boost the success rate and efficacy of AHSCT.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Trisha Gupta
- Government Doon Medical College, Dehradun, Uttarakhand
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3
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Msheik A, Assi F, Hamed F, Jibbawi A, Nakhl AM, Khoury A, Mohanna R, Gerges T, Atat R. Stem Cell Transplantation for Multiple Sclerosis: A 2023 Review of Published Studies. Cureus 2023; 15:e47972. [PMID: 38034162 PMCID: PMC10686127 DOI: 10.7759/cureus.47972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/30/2023] [Indexed: 12/02/2023] Open
Abstract
This comprehensive literature review underscores the potential of stem cell transplantation (SCT) as a therapeutic intervention for multiple sclerosis (MS). By amalgamating evidence from various sources, including randomized controlled trials (RCTs), observational, retrospective, and comparative studies, this review offers a holistic understanding of SCT's effectiveness, safety, and feasibility in diverse contexts of MS management. SCT has shown promise in mitigating disease activity and progression, particularly in relapsing-remitting MS (RRMS). RCTs like the high dose immunoablation and autologous hematopoietic stem cell transplantation in MS (ASTIMS) versus mitoxantrone therapy in severe multiple sclerosis and multiple sclerosis international stem cell transplant (MIST) trials reveal SCT's capacity to reduce new lesion occurrences and inflammatory activity. However, variability exists in disability score improvements among these studies. Observational and retrospective investigations further affirm SCT's potential, highlighting decreased relapse rates, enhanced expanded disability status scale (EDSS) scores, and a noteworthy proportion of patients achieving no evidence of disease activity (NEDA). The initial literature search using all of the search items produced a total of 3,636 articles. After title, abstract, and article type screening and article retrieving, 147 articles were assessed for eligibility using the inclusion criteria. At the end of the literature search, 37 articles met the eligibility criteria. They were included in our review according to preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. Patients treated with hematopoietic stem cell transplantation (HSCT) present lower progression and relapse rates, suppression of inflammatory activity, and a greater reduction in T2 lesions on MRI than those treated with disease-modifying therapies (DMTs). In summary, while SCT presents promise as a therapeutic option for MS, its deployment should be tailored to individual patient characteristics, disease stages, and responses.
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Affiliation(s)
- Ali Msheik
- Neurological Surgery, Faculty of Medicine Lebanese University, Hadath, LBN
| | - Farah Assi
- Infectious Diseases, Faculty of Medicine Lebanese University, Beirut, LBN
| | - Faten Hamed
- Pharmacology, Lebanese International University, Beirut, LBN
| | - Ali Jibbawi
- Pediatric Medicine, Saint Georges Hospital, Beirut, LBN
| | - Anna-Marina Nakhl
- Medicine and Surgery, Faculty of Medicine Lebanese University, Beirut, LBN
| | - Anthony Khoury
- Medicine and Surgery, Faculty of Medicine Lebanese University, Beirut, LBN
| | - Rami Mohanna
- Medicine and Surgery, Faculty of Medicine Saint-Joseph University, Beirut, LBN
| | - Teddy Gerges
- Anesthesia, Winchester Anesthesia Associates, Boston, USA
| | - Rami Atat
- Neurology, Faculty of Medical Sciences Lebanese University, Beirut, LBN
- Neurology, Al Zahraa University Medical Center, Beirut, LBN
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4
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Sui Z, Zhu H, Luo J, Yu J, Li L, Zheng Q. Quantitative comparison of the efficacy of clinical drug treatments for primary progressive multiple sclerosis. J Clin Neurosci 2023; 113:45-53. [PMID: 37178621 DOI: 10.1016/j.jocn.2023.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 03/25/2023] [Accepted: 04/03/2023] [Indexed: 05/15/2023]
Abstract
OBJECTIVE This study proposes a comprehensive quantitative evaluation of the efficacy of drugs and placebo in clinical trials for primary progressive multiple sclerosis (PPMS). METHODS A literature search was conducted using the PubMed, EMBASE, and Cochrane library databases and the clinical studies reporting drug efficacy in the treatment of PPMS were included in the analyses. The cumulative proportion of patients without confirmed disability progression (wCDP%) was used as the main efficacy endpoint. The model-based meta-analysis method was used to describe the time course of each drug (as well as placebo) in order to rank the drug efficacy for the treatment of PPMS. RESULTS Fifteen studies involving 3779 patients were included, of which, nine were placebo-controlled and six were single-arm trials. Twelve drugs were included in the study. The results showed that, except for biotin, interferon β-1a, and interferon β-1b, whose efficacy was comparable to the placebo, the efficacy of the other 9 drugs were significantly better than placebo. Among these, ocrelizumab showed outstanding performance, with wCDP% of 72.6 at 96 weeks, while the proportions of rest of the drugs ranged between approximately 55-70%. CONCLUSION The results of this study provide the necessary quantitative information for both the rational clinical use of drugs and future clinical trials in primary progressive multiple sclerosis.
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Affiliation(s)
- Zichao Sui
- Center for Drug of Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haoxiang Zhu
- Center for Drug of Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jieren Luo
- Center for Drug of Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiesen Yu
- Center for Drug of Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Lujin Li
- Center for Drug of Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
| | - Qingshan Zheng
- Center for Drug of Clinical Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Alatrash R, Golubenko M, Martynova E, Garanina E, Mukhamedshina Y, Khaiboullina S, Rizvanov A, Salafutdinov I, Arkhipova S. Genetically Engineered Artificial Microvesicles Carrying Nerve Growth Factor Restrains the Progression of Autoimmune Encephalomyelitis in an Experimental Mouse Model. Int J Mol Sci 2023; 24:ijms24098332. [PMID: 37176039 PMCID: PMC10179478 DOI: 10.3390/ijms24098332] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 04/27/2023] [Accepted: 05/02/2023] [Indexed: 05/15/2023] Open
Abstract
Multiple sclerosis (MS) is an incurable, progressive chronic autoimmune demyelinating disease. Therapy for MS is based on slowing down the processes of neurodegeneration and suppressing the immune system of patients. MS is accompanied by inflammation, axon-degeneration and neurogliosis in the central nervous system. One of the directions for a new effective treatment for MS is cellular, subcellular, as well as gene therapy. We investigated the therapeutic potential of adipose mesenchymal stem cell (ADMSC) derived, cytochalasin B induced artificial microvesicles (MVs) expressing nerve growth factor (NGF) on a mouse model of multiple sclerosis experimental autoimmune encephalomyelitis (EAE). These ADMSC-MVs-NGF were tested using histological, immunocytochemical and molecular genetic methods after being injected into the tail vein of animals on the 14th and 21st days post EAE induction. ADMSC-MVs-NGF contained the target protein inside the cytoplasm. Their injection into the caudal vein led to a significant decrease in neurogliosis at the 14th and 21st days post EAE induction. Artificial ADMSC-MVs-NGF stimulate axon regeneration and can modulate gliosis in the EAE model.
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Affiliation(s)
- Reem Alatrash
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Maria Golubenko
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Ekaterina Martynova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Ekaterina Garanina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Yana Mukhamedshina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
- Department of Medical Biology and Genetics, Kazan State Medical University, 420012 Kazan, Russia
| | - Svetlana Khaiboullina
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Albert Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
| | - Ilnur Salafutdinov
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
- Department of Medical Biology and Genetics, Kazan State Medical University, 420012 Kazan, Russia
| | - Svetlana Arkhipova
- Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia
- Department of Medical Biology and Genetics, Kazan State Medical University, 420012 Kazan, Russia
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Zayed MA, Sultan S, Alsaab HO, Yousof SM, Alrefaei GI, Alsubhi NH, Alkarim S, Al Ghamdi KS, Bagabir SA, Jana A, Alghamdi BS, Atta HM, Ashraf GM. Stem-Cell-Based Therapy: The Celestial Weapon against Neurological Disorders. Cells 2022; 11:3476. [PMID: 36359871 PMCID: PMC9655836 DOI: 10.3390/cells11213476] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 10/15/2022] [Accepted: 10/24/2022] [Indexed: 09/01/2023] Open
Abstract
Stem cells are a versatile source for cell therapy. Their use is particularly significant for the treatment of neurological disorders for which no definitive conventional medical treatment is available. Neurological disorders are of diverse etiology and pathogenesis. Alzheimer's disease (AD) is caused by abnormal protein deposits, leading to progressive dementia. Parkinson's disease (PD) is due to the specific degeneration of the dopaminergic neurons causing motor and sensory impairment. Huntington's disease (HD) includes a transmittable gene mutation, and any treatment should involve gene modulation of the transplanted cells. Multiple sclerosis (MS) is an autoimmune disorder affecting multiple neurons sporadically but induces progressive neuronal dysfunction. Amyotrophic lateral sclerosis (ALS) impacts upper and lower motor neurons, leading to progressive muscle degeneration. This shows the need to try to tailor different types of cells to repair the specific defect characteristic of each disease. In recent years, several types of stem cells were used in different animal models, including transgenic animals of various neurologic disorders. Based on some of the successful animal studies, some clinical trials were designed and approved. Some studies were successful, others were terminated and, still, a few are ongoing. In this manuscript, we aim to review the current information on both the experimental and clinical trials of stem cell therapy in neurological disorders of various disease mechanisms. The different types of cells used, their mode of transplantation and the molecular and physiologic effects are discussed. Recommendations for future use and hopes are highlighted.
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Affiliation(s)
- Mohamed A. Zayed
- Physiology Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Physiology Department, Faculty of Medicine, Menoufia University, Menoufia 32511, Egypt
| | - Samar Sultan
- Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Regenerative Medicine Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hashem O. Alsaab
- Department of Pharmaceutics and Pharmaceutical Technology, College of Pharmacy, Taif University, Taif 21944, Saudi Arabia
| | - Shimaa Mohammad Yousof
- Physiology Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Medical Physiology Department, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Ghadeer I. Alrefaei
- Department of Biology, College of Science, University of Jeddah, Jeddah 21589, Saudi Arabia
| | - Nouf H. Alsubhi
- Department of Biological Sciences, College of Science & Arts, King Abdulaziz University, Rabigh 21911, Saudi Arabia
| | - Saleh Alkarim
- Embryonic and Cancer Stem Cell Research Group, King Fahad Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Biology Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Embryonic Stem Cells Research Unit, Biology Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Kholoud S. Al Ghamdi
- Department of Physiology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 31441, Saudi Arabia
| | - Sali Abubaker Bagabir
- Genetic Unit, Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia
| | - Ankit Jana
- School of Biotechnology, Kalinga Institute of Industrial Technology (KIIT) Deemed to be University, Campus-11, Patia, Bhubaneswar 751024, Odisha, India
| | - Badrah S. Alghamdi
- Department of Physiology, Faculty of Medicine, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Hazem M. Atta
- Clinical Biochemistry Department, Faculty of Medicine in Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia
- Medical Biochemistry and Molecular Biology Department, Faculty of Medicine, Cairo University, Cairo 11562, Egypt
| | - Ghulam Md Ashraf
- Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, University City, Sharjah 27272, United Arab Emirates
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7
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Willison AG, Meuth SG. [Multiple sclerosis: interventions to halt disease : Which patients can be considered for autologous stem cell transplantation]. DER NERVENARZT 2022; 93:987-999. [PMID: 35951049 DOI: 10.1007/s00115-022-01358-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 06/28/2022] [Indexed: 12/01/2022]
Abstract
BACKGROUND Autologous hematopoietic stem cell transplantation (aHSCT) for treatment of multiple sclerosis (MS) is gaining increasing prominence in the therapeutic landscape. This review article focuses on describing the evidence and European guidelines for aHSCT so that neurologists in Germany can consider this treatment option for appropriate MS patients. In this context, it must be taken into consideration that in every case a cost transfer must be individually applied for. AIM To provide information for neurologists considering aHSCT for patients with MS. MATERIAL AND METHODS In this narrative review articles from PubMed were pooled and analyzed. RESULTS AND DISCUSSION High quality data from randomized, controlled clinical trials are required to compare the efficacy of aHSCT to the currently available highly effective disease-modifying therapies (DMT) so that reliable conclusions can be drawn regarding the relationship between the risks and benefits of aHSCT in MS; however, the studies discussed in this review provide important points of reference for patient selection and the transplantation protocol. Further advice is available from the European Society for Blood and Marrow Transplantation (EBMT) for experienced centers considering aHSCT. The available data and the European guidelines suggest that patients aged less than 45 years, an expanded disability status scale (EDSS) ≤ 5.5, highly active MS, a disease duration of less than 10 years, an ineffective course of DMT or rapidly progressive MS may be eligible for aHSCT and should be referred to an experienced center for further assessment.
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Affiliation(s)
- A G Willison
- Klinik für Neurologie, Universitätsklinikum Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Deutschland.
| | - S G Meuth
- Klinik für Neurologie, Universitätsklinikum Düsseldorf, Moorenstraße 5, 40225, Düsseldorf, Deutschland.
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Autologous Hematopoietic Stem-Cell Transplantation in Multiple Sclerosis: A Systematic Review and Meta-Analysis. Neurol Ther 2022; 11:1553-1569. [PMID: 35902484 PMCID: PMC9333355 DOI: 10.1007/s40120-022-00389-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 07/14/2022] [Indexed: 12/13/2022] Open
Abstract
INTRODUCTION In 1995, the use of autologous hematopoietic stem-cell transplantation (AHSCT), which was previously used to treat hematological tumors, was introduced for severe autoimmune diseases such as multiple sclerosis (MS). AHSCT has proven its safety over the past few years due to technical advances and careful patient selection in transplant centers. While most studies have reported that AHSCT led to decreased Expanded Disability Status Scale (EDSS) scores, some patients reported increased EDSS scores following the procedure. Given the contradictory results, we aimed to conduct a comprehensive systematic review and meta-analysis to investigate the efficacy and safety of AHSCT. METHODS PubMed, Web of Science, and Scopus were searched in March 2022 using a predefined search strategy. We included cohort studies, clinical trials, case-control studies, and case series that investigated the efficacy or safety of AHSCT in patients with MS. PICO in the present study was defined as follows: problem or study population (P): patients with MS; intervention (I): AHSCT; comparison (C): none; outcome (O): efficacy and safety. RESULTS After a two-step review process, 50 studies with a total of 4831 patients with MS were included in our study. Our analysis showed a significant decrease in EDSS score after treatment (standardized mean difference [SMD]: -0.48, 95% CI -0.75, -0.22). Moreover, the annualized relapse rate was also significantly reduced after AHSCT compared to the pretreatment period (SMD: -1.58, 95% CI -2.34, -0.78). The pooled estimate of progression-free survival after treatment was 73% (95% CI 69%, 77). Furthermore, 81% of patients with MS who received AHSCT remained relapse-free (95% CI 76%, 86%). Investigating event-free survival, which reflects the absence of any disease-related event, showed a pooled estimate of 63% (95% CI 54%, 73%). Also, the MRI activity-free survival was 89% (95% CI 84%) among included studies with low heterogeneity. New MRI lesions seem to appear in nearly 8% of patients who underwent AHSCT (95% CI 4%, 12%). Our meta-analysis showed that 68% of patients with MS experience no evidence of disease activity (NEDA) after AHSCT (95% CI 59%, 77). The overall survival after transplantation was 94% (95% CI 91%, 96%). In addition, 4% of patients died from transplant-related causes (95% CI 2%, 6%). CONCLUSION Current data encourages a broader application of AHSCT for treating patients with MS while still considering proper patient selection and transplant methods. In addition, with increasing knowledge and expertise in the field of stem-cell therapy, AHSCT has become a safer treatment approach for MS.
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9
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The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis. J Neurol 2022; 269:3937-3958. [PMID: 35399125 PMCID: PMC8995166 DOI: 10.1007/s00415-022-11063-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 03/02/2022] [Accepted: 03/03/2022] [Indexed: 11/01/2022]
Abstract
AbstractAutologous haematopoietic stem cell transplantation (aHSCT) is gaining traction as a valuable treatment option for patients affected by severe multiple sclerosis (MS), particularly the relapsing–remitting form. We describe the current literature in terms of clinical trials, observational and retrospective studies, as well as immune reconstitution following transplantation, with a focus on the conditioning regimens used for transplantation. The evidence base predominantly consists of non-randomised, uncontrolled clinical trials or data from retrospective or observational cohorts, i.e. very few randomised or controlled trials. Most often, intermediate-intensity conditioning regimens are used, with promising results from both myeloablative and lymphoablative strategies, as well as from regimens that are low and high intensity. Efficacy of transplantation, which is likely secondary to immune reconstitution and restored immune tolerance, is, therefore, not clearly dependent on the intensity of the conditioning regimen. However, the conditioning regimen may well influence the immune response to transplantation. Heterogeneity of conditioning regimens among studies hinders synthesis of the articles assessing post-aHSCT immune system changes. Factors associated with better outcomes were lower Kurtzke Expanded Disability Status Scale, relapsing–remitting MS, younger age, and shorter disease duration at baseline, which supports the guidance for patient selection proposed by the European Society for Blood and Marrow Transplantation. Interestingly, promising outcomes were described for patients with secondary progressive MS by some studies, which may be worth taking into account when considering treatment options for patients with active, progressive disease. Of note, a significant proportion of patients develop autoimmune disease following transplantation, with alemtuzumab-containing regimens associated with the highest incidence.
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10
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Patti F, Chisari CG, Toscano S, Arena S, Finocchiaro C, Cimino V, Milone G. Autologous Hematopoietic Stem Cell Transplantation in Multiple Sclerosis Patients: Monocentric Case Series and Systematic Review of the Literature. J Clin Med 2022; 11:jcm11040942. [PMID: 35207216 PMCID: PMC8875789 DOI: 10.3390/jcm11040942] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 02/01/2022] [Accepted: 02/02/2022] [Indexed: 02/05/2023] Open
Abstract
Multiple sclerosis (MS) is a chronic, inflammatory and immune-mediated disease of the central nervous system (CNS), commonly affecting young adults and potentially associated with life-long disability. About 14 disease-modifying treatments (DMTs) are currently approved for the treatment of MS. However, despite the use of highly effective therapies, some patients exhibit a highly active disease with an aggressive course from onset and a higher risk of long-term disability accrual. In the last few years, several retrospective studies, clinical trials, meta-analyses and systematic reviews have investigated autologous hematopoietic stem cell transplantation (AHSCT) as a possible therapeutic option in order to address this unmet clinical need. These studies demonstrated that AHSCT is a highly efficacious and relatively safe therapeutic option for the treatment of highly active MS. Particularly, over recent years, the amount of evidence has grown, with significant improvements in the development of patient selection criteria, choice of the most suitable transplant technique and clinical experience. In this paper, we present six patients who received AHSCT in our MS center and we systematically reviewed recent evidence about the long-term efficacy and safety of AHSCT and the placement of AHSCT in the rapidly evolving therapeutic armamentarium for MS.
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Affiliation(s)
- Francesco Patti
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95125 Catania, Italy; (S.T.); (S.A.); (C.F.)
- Correspondence: (F.P.); (C.G.C.); Tel.: +39-09-5378-2620 (F.P.)
| | - Clara Grazia Chisari
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95125 Catania, Italy; (S.T.); (S.A.); (C.F.)
- Correspondence: (F.P.); (C.G.C.); Tel.: +39-09-5378-2620 (F.P.)
| | - Simona Toscano
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95125 Catania, Italy; (S.T.); (S.A.); (C.F.)
| | - Sebastiano Arena
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95125 Catania, Italy; (S.T.); (S.A.); (C.F.)
| | - Chiara Finocchiaro
- Department of Medical, Surgical Sciences and Advanced Technologies “G.F. Ingrassia”, University of Catania, 95125 Catania, Italy; (S.T.); (S.A.); (C.F.)
| | - Vincenzo Cimino
- IRCCS Centro Neurolesi “Bonino Pulejo”, 98124 Messina, Italy;
| | - Giuseppe Milone
- Hematology and Bone Marrow Transplant Unit, Azienda Policlinico-Vittorio Emanuele, 95124 Catania, Italy;
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11
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Sen MK, Almuslehi MSM, Shortland PJ, Coorssen JR, Mahns DA. Revisiting the Pathoetiology of Multiple Sclerosis: Has the Tail Been Wagging the Mouse? Front Immunol 2020; 11:572186. [PMID: 33117365 PMCID: PMC7553052 DOI: 10.3389/fimmu.2020.572186] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Accepted: 08/27/2020] [Indexed: 12/18/2022] Open
Abstract
Multiple Sclerosis (MS) is traditionally considered an autoimmune-mediated demyelinating disease, the pathoetiology of which is unknown. However, the key question remains whether autoimmunity is the initiator of the disease (outside-in) or the consequence of a slow and as yet uncharacterized cytodegeneration (oligodendrocytosis), which leads to a subsequent immune response (inside-out). Experimental autoimmune encephalomyelitis has been used to model the later stages of MS during which the autoimmune involvement predominates. In contrast, the cuprizone (CPZ) model is used to model early stages of the disease during which oligodendrocytosis and demyelination predominate and are hypothesized to precede subsequent immune involvement in MS. Recent studies combining a boost, or protection, to the immune system with disruption of the blood brain barrier have shown CPZ-induced oligodendrocytosis with a subsequent immune response. In this Perspective, we review these recent advances and discuss the likelihood of an inside-out vs. an outside-in pathoetiology of MS.
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Affiliation(s)
- Monokesh K Sen
- School of Medicine, Western Sydney University, Penrith, NSW, Australia
| | - Mohammed S M Almuslehi
- School of Medicine, Western Sydney University, Penrith, NSW, Australia.,Department of Physiology, College of Veterinary Medicine, University of Diyala, Baqubah, Iraq
| | - Peter J Shortland
- School of Science, Western Sydney University, Penrith, NSW, Australia
| | - Jens R Coorssen
- Departments of Health Sciences and Biological Sciences, Faculties of Applied Health Sciences and Mathematics & Science, Brock University, St. Catharines, ON, Canada
| | - David A Mahns
- School of Medicine, Western Sydney University, Penrith, NSW, Australia
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Autologous Haematopoietic Stem Cell Transplantation in Multiple Sclerosis: a Review of Current Literature and Future Directions for Transplant Haematologists and Oncologists. Curr Hematol Malig Rep 2020; 14:127-135. [PMID: 30828772 PMCID: PMC6510794 DOI: 10.1007/s11899-019-00505-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Purpose of Review We summarise the current development of autologous haematopoietic stem cell transplantation (AHSCT) in treating multiple sclerosis (MS) and discuss future directions for the general neurologist, transplant haematologist and oncologist. Recent Findings AHSCT was initially performed to treat MS over 20 years ago. Over recent years, the evidence base has grown, especially in relapsing-remitting MS (RRMS), with significant improvements in safety and efficacy through better patient selection, choice of transplant technique and increase in centre experience. Summary AHSCT is now a treatment option in very carefully selected patients with severe, treatment-resistant RRMS. However, it is important for transplant haematologists and oncologists to work closely with specialist MS neurologists in patient selection, during transplant and in long-term follow-up of patients. Data should be registered into international transplant registries and, ideally, patients should be enrolled on prospective clinical trials in order to build the evidence base and refine transplant techniques.
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Lycke J, Lenhoff S. Intensive immunosuppression followed by autologous hematopoietic stem cell transplantation for the treatment of multiple sclerosis. Ther Adv Neurol Disord 2020; 13:1756286420929467. [PMID: 32636931 PMCID: PMC7315665 DOI: 10.1177/1756286420929467] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Accepted: 03/22/2020] [Indexed: 12/20/2022] Open
Abstract
Autologous hematopoietic stem cell transplantation (AHSCT) to treat multiple sclerosis (MS) has mostly been used in devastating cases as the last option to stop further neurological deterioration. However, evidence from several retrospective clinical trials indicates that young, less disabled patients with highly inflammatory active MS are the most likely to benefit from AHSCT, and after moving from high-intensity to nonmyeloablative procedures the tolerability of AHSCT has increased and its associated risk and mortality have declined considerably. Recent meta-analyses and randomized clinical trials show that AHSCT is more effective than currently approved disease-modifying therapies (DMTs), with suppression of disease activity in 70-90% of patients and long-term cessation of disease activity in two-thirds of treated patients. The rationale for AHSCT is to eliminate autoimmunity and achieve immune resetting by intense immunosuppression followed by infusion of autologous hematopoietic stem cells. Similar effects on the immune system have been suggested for cladribine and alemtuzumab treatment and, together with AHSCT, they constitute the induction or immune-reconstitution therapies for MS. Although, further randomized controlled trials of AHSCT for MS are needed, it has become clear that improved patient selection and lower intensity conditioning regimens have reduced AHSCT associated risks and mortality and strengthened the position of AHSCT among other DMTs. Do we have enough experience and scientific support for AHSCT in MS to move from an exclusive treatment for aggressive, treatment-resistant MS and acquire broader indications, similar to other effective DMTs?
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Affiliation(s)
- Jan Lycke
- Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, The Sahlgrenska Academy, University of Gothenburg, Gröna stråket 11, 3 tr, Sahlgrenska University Hospital, Gothenburg, 415 45, Sweden
| | - Stig Lenhoff
- Department of Hematology, Oncology and Radiophysics, Skane University Hospital, Lund, Sweden
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Huang H, Chen L, Mao G, Sharma HS. Clinical neurorestorative cell therapies: Developmental process, current state and future prospective. JOURNAL OF NEURORESTORATOLOGY 2020. [DOI: 10.26599/jnr.2020.9040009] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Clinical cell therapies (CTs) for neurological diseases and cellular damage have been explored for more than 2 decades. According to the United States Food and Drug Administration, there are 2 types of cell categories for therapy, namely stem cell-derived CT products and mature/functionally differentiated cell-derived CT products. However, regardless of the type of CT used, the majority of reports of clinical CTs from either small sample sizes based on single-center phase 1 or 2 unblinded trials or retrospective clinical studies showed effects on neurological improvement and the ability to either partially or temporarily thwart the deteriorating cellular processes of the neurodegenerative diseases. There have been only a few prospective, multicenter, randomized, double- blind placebo-control clinical trials of CTs so far in this developing novel area that have shown negative results, and more clinical trials are needed. This will expand our knowledge in exploring the type of cells that yield promising results and restore damaged neurological structure and functions of the central nervous system based on higher level evidence-based medical data. In this review, we briefly introduce the developmental process, current state, and future prospective for clinical neurorestorative CT.
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Kvistad SAS, Lehmann AK, Trovik LH, Kristoffersen EK, Bø L, Myhr KM, Torkildsen Ø. Safety and efficacy of autologous hematopoietic stem cell transplantation for multiple sclerosis in Norway. Mult Scler 2019; 26:1889-1897. [DOI: 10.1177/1352458519893926] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Background: Hematopoietic stem cell treatment (HSCT) is a promising treatment option for multiple sclerosis (MS), but detailed safety and efficacy measures are still scarce. Objective: To evaluate the efficacy and safety of HSCT in MS. Methods: Retrospective single-center observational study of all MS patients that underwent HSCT in Norway during January 2015 to January 2018. The primary outcome was no evidence of disease activity (NEDA-3) status. Results: A total of 30 patients with a median follow-up time of 26 months (range: 11–48) were evaluated. In total, 25 (83%) achieved NEDA-3 status, and none received disease-modifying treatment after HSCT. For 13 (43%) of the patients, there were sustained improvement in Expanded Disability Status Scale (EDSS) score, and 10 (33%) were working full time after the treatment, compared to only 1 (3%) before treatment. There were no serious treatment-related complications and was no mortality. Five patients (17%) were diagnosed with an autoimmune thyroid disease after the procedure, and 10 (43%) of the women had amenorrhea lasting >12 months and symptoms of ovarian failure. Conclusion: HSCT in MS is an effective and relatively safe treatment option, with few serious complications and no mortality in Norway, so far. However, long-term adverse event with amenorrhea is a common problem.
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Affiliation(s)
- Silje Agnethe Stokke Kvistad
- Department of Immunology and Transfusion Medicine, Haukeland University Hospital, Bergen, Norway/Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | | | | | | | - Lars Bø
- Norwegian Multiple Sclerosis Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway/Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Kjell-Morten Myhr
- Department of Clinical Medicine, University of Bergen, Bergen, Norway/Norwegian Multiple Sclerosis Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Øivind Torkildsen
- Department of Clinical Medicine, University of Bergen, Bergen, Norway/Norwegian Multiple Sclerosis Competence Centre, Department of Neurology, Haukeland University Hospital, Bergen, Norway
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Mansoor SR, Zabihi E, Ghasemi-Kasman M. The potential use of mesenchymal stem cells for the treatment of multiple sclerosis. Life Sci 2019; 235:116830. [PMID: 31487529 DOI: 10.1016/j.lfs.2019.116830] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 08/23/2019] [Accepted: 09/01/2019] [Indexed: 12/21/2022]
Abstract
Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system (CNS). In attempt to identify an appropriate treatment for improving the neurological symptoms and remyelination process, autologous and allogenic transplantation of mesenchymal stem cells (MSCs) have been introduced as an effective therapeutic strategy in MS. MSCs are a heterogeneous subset of pluripotent non-hematopoietic stromal cells that are isolated from bone marrow, adipose tissue, placenta and other sources. MSCs have considerable therapeutic effects due to their ability in differentiation, migration, immune-modulation and neuroregeneration. To date, numerous experimental and clinical studies demonstrated that MSCs therapy improves the CNS repair and modulates functional neurological symptoms. Here, we provided an overview of the current knowledge about the clinical applications of MSCs in MS. Furthermore, the major challenges and risks of MSCs therapy in MS patients have been elucidated.
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Affiliation(s)
- Sahar Rostami Mansoor
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Ebrahim Zabihi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Maryam Ghasemi-Kasman
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; Neuroscience Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
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Karussis D, Petrou P. Immune reconstitution therapy (IRT) in multiple sclerosis: the rationale. Immunol Res 2019; 66:642-648. [PMID: 30443887 DOI: 10.1007/s12026-018-9032-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Immunotherapy of multiple sclerosis (MS) and other neuroimmune diseases is rapidly evolving. For the past 25 years, there has been an accelerating inclusion of new immunomodulating drugs. Based on their molecular construction and their basic mechanism of action, immunotherapeutic agents belong to the following categories: (1) cytotoxic drugs, (2) synthetic immunomodulators, (3) monoclonal antibodies, (4) vaccines (T cell vaccines, antigen vaccines), (5) oral tolerizing agents, (6) modalities that act as indirect immunosuppressants (plasmapheresis, intravenous immunoglobulins [IVIG]), and (7) cellular therapies. MS immunotherapies may also be classified in a different way, into treatments that are given continuously (chronic treatments) and medications that are applied intermittently (IRTs). The principle behind the latter is depletion of the immune system that allows it to rebuild itself. Upon its reconstitution/resetting, the immune system regains the ability to respond to infections and survey the periphery for cancer. An IRT by definition is given at short intermittent courses and not continuously. IRT modalities were shown to induce long-term remission of MS that, in some cases, is close to the definition of a "cure." There are cohorts of patients having been treated with the IRTs, alemtuzumab, and HSCT, who experience-under these modalities-no evidence of disease activity (NEDA) for over 10 years. Most importantly, IRTs cause radical changes in the lymphocyte repertoire after the reconstitution phase that may explain the long-term beneficial effects of IRT and the possibility of re-induction of self-tolerance to self/myelin antigens. In comparison, a chronic treatment cannot result in cure of the autoimmune reactivity, because it only blocks the immune system, as long as it is given; it cannot therefore radically affect the immunopathogenesis of the disease. The risks of adverse events related to immune suppression (such as opportunistic infections and secondary malignancies) with IRTs are lower and front-loaded, whereas the common side effects of chronic immunomodulation are higher and accumulate with time. In conclusion, IRT provides a novel concept for MS therapy with substantial advantages over chronic immunosuppression. IRT therapies have shown a significantly higher level of efficacy in MS. The "Holy grail" of the treatment of autoimmunity, which is to re-induce the disrupted self-tolerance, seems to be achievable-at least in part-with this approach. Moreover, the benefits of IRT, administered in short pulses, include significantly higher adherence to treatment and lower risks for accumulative side effects that are typically associated with chronic immunosuppression.
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Affiliation(s)
- Dimitrios Karussis
- MS Center and Unit of Neuroimmunology, Department of Neurology, Hadassah Medical Center, Jerusalem, Israel.
| | - Panayiota Petrou
- MS Center and Unit of Neuroimmunology, Department of Neurology, Hadassah Medical Center, Jerusalem, Israel
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Autologous Hematopoietic Cell Transplantation in Multiple Sclerosis: Changing Paradigms in the Era of Novel Agents. Stem Cells Int 2019; 2019:5840286. [PMID: 31341484 PMCID: PMC6612973 DOI: 10.1155/2019/5840286] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 04/22/2019] [Accepted: 06/13/2019] [Indexed: 12/29/2022] Open
Abstract
Autologous hematopoietic stem cell transplantation (AHSCT) is established as a standard of care for diseases ranging from hematological malignancies to other neoplastic pathologies and severe immunological deficiencies. In April 1995, our group performed the first AHSCT in progressive multiple sclerosis (MS). Since then, a plethora of studies have been published with encouraging but controversial results. Major challenges in the field include appropriate patient selection, improvements in AHSCT procedure, and timing of this treatment modality. Beyond AHSCT, several new intravenous or oral agents have been developed and approved over the last 20 years in MS. The emergence of multiple effective therapies for MS has created a challenging scenario for both treating physicians and patients. Novel cell-based therapies other than AHSCT are also currently investigated in MS patients with promising results. Our review is aimed at summarizing state-of-the-art knowledge on basic principles and results of AHSCT in MS and its role compared to novel agents.
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Kubsik-Gidlewska A, Klupiński K, Krochmalski M, Krochmalski J, Klimkiewicz P, Woldańska-Okońska M. CD34+ Stem Cell Treatment for Knee Osteoarthritis: A Treatment and Rehabilitation Algorithm. JOURNAL OF REHABILITATION MEDICINE - CLINICAL COMMUNICATIONS 2018; 3:1000012. [PMID: 33884126 PMCID: PMC8011677 DOI: 10.2340/20030711-1000012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Accepted: 11/14/2018] [Indexed: 11/24/2022]
Abstract
Osteoarthritis is a group of multiple overlapping pathological conditions that cause destruction of articular cartilage and other structures of the joint. It is a progressive disease that leads to limitations of physical activity. New forms of treatment are therefore sought to alleviate the clinical symptoms of osteoarthritis and avoid surgery. Stem cell based therapy is an emerging field in orthopaedics. This study describes the treatment of knee osteoarthritis with CD34+ stem cells at the Medical Magnus Outpatient Clinic in Lodz, Poland, together with the treatment and rehabilitation algorithm developed for maximum effectiveness of this procedure. The algorithm includes 3 rehabilitation stages: preoperative, hospitalization and outpatient periods.
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