Adult Stem Cell Treatment for Rheumatoid Arthritis

Sang Youn Jung

doi:10.4078/jrd.2018.25.3.158

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Jung: Adult Stem Cell Treatment for Rheumatoid Arthritis

Review Article

J Rheum Dis 2018;25(3):158-168.

Published online: 31 July 2018

DOI: https://doi.org/10.4078/jrd.2018.25.3.158

Adult Stem Cell Treatment for Rheumatoid Arthritis

Sang Youn Jung

Division of Rheumatology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea

Corresponding to: Sang Youn Jung http://orcid.org/0000-0002-0168-8906 Division of Rheumatology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea. E-mail: jungsy7597@cha.ac.kr

Received 21 May 201829 May 2018 Accepted 30 May 2018

This is a Open Access article, which permits unrestricted non-commerical use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Since methotrexate began to be used in the treatment of rheumatoid arthritis (RA) 30 years ago, RA treatments have advanced rapidly from only reducing joint pain and inflammation to suppressing disease progression and joint destruction. In particular, the development of biologics and targeted anti-rheumatic drugs has almost made it possible to induce remission in patients with RA. On the other hand, the current RA treatments are still limited by adverse effects and treatment failure. Stem cell therapy has been suggested as an alternative treatment of RA, and preclinical studies and clinical trials using representative adult stem cells (ASCs), hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), are currently underway. HSC therapy in RA has mostly progressed based on the concept of ‘immune reset', in which the existing immune cells are replaced with healthy ones. HSC transplantation was completed relatively safely, and the patients showed a positive treatment response. Nevertheless, the treatment response of HSCs in RA depends on the conditioning regimen, and the efficacy did not persist for a long time. The MSCs possessed a hypo-immunogenicity, immune modulation effect and tissue regeneration capability, making them another promising candidate for the RA treatment. MSC transplantation in RA was found to be safe with few adverse effects, such as immune rejection or embolism, but it showed a partial and transient response. This review addresses the characteristics of ASCs, focusing specifically on HSCs and MSCs, and summarizes the results of preclinical studies and clinical trials of ASC therapy in RA.

Keywords: Rheumatoid arthritis, Adult stem cell, Hematopoietic stem cell, Mesenchymal stem cell, Clinical trial

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Table 1.

Types and characteristics of stem cells

Stem cell type	Cell source	Potency (target cells)	Strong point	Weak point	Ref.
Embryonic stem cell	Blastocyst of embryo	Pluripotent (all kinds of cells)	High replicable capability, Large quantity production	Immune rejection, Ethical issue, Tumor formation	[6,16]
Induced pluripotent stem cell	Skin fibroblast, keratinocyte, T cell, hepatocyte, other somatic cells	Pluripotent (all kinds of cells)	Patient-specific, Large quantity production, No ethical issue	Tumor formation, Contamination, High cost	[7,17]
Adult stem cell Hematopoietic stem cell	BM, UCB, peripheral blood	Multipotent (myeloid and lymphoid	Proven safety, No ethical issue, Restore blood cell	Limited differentiation, Limited quantity	[9,18,23]
Mesenchymal stem cell	BM, UCB, UC, placenta, adipose tissue, dental pulp, periosteum	blood cells) Multipotent (osteoblast, chondrocyte, adipocyte)	Proven safety, No ethical issue, Hypo-immunogenic, Immune modulation	production Limited differentiation, Limited quantity production, Tissue sequestration	[11,16,48]

Target cells are those cells in which the stem cells can be differentiate. BM: bone marrow, UCB: umbilical cord blood, UC: umbilical cord, Ref.: reference.

Table 2.

Maj jor clinical trials o of hematopoietic stem cell therapy i n rheumatoid arthritis

No. of patients	Transplantation type	Cell source (n)	Graft manipulation (n)	Conditioning regimen (n)	Response (n)	Ref.
8	Autologous	Peripheral blood	None	CYC 100 mg/kg (4) CYC 200 mg/kg (4)	Arthritis improving (8) – only lasting 2∼3 mo in CYC 100 mg/kg (4) – beyond 17∼19 mo in CYC 200 mg/kg (4)	[45]
4	Autologous	Peripheral blood	CD34+ selection	CYC 200 mg/kg +ATG (3)+TBI (1)	Arthritis improving (3) – ACR70 (3) within 3 mo – ACR70 (1), ACR50 (1) after 6 mo	[46]
6	Autologous	Peripheral blood	CD34+ selection	CYC 200 mg/kg	Arthritis improving (6) – ACR20 (3), ACR50 (2), ACR70	[47]
73	Autologous	BM (1) Peripheral blood (72)	Unmanipulated (28) CD34+ selection (45)	Various: CYC 200 mg/kg (62)	(1): all relapsed at 1.5∼9 mo ACR50 (49) HAQ score↓ Most restarted DMARDs within 6 mo	[43]

BM: bone marrow, CD: cluster of differentiation, CYC: cyclophosphamide, ATG: anti-thymocyte globulin, TBI: total body irradiation, ACR: American College of Rheumatology, HAQ: Health Assessment Questionnaire, ↓: decrease, DMARD: disease-modifying antirheumatic drug, Ref.: reference.

Table 3.

Major clinical trials of mesenchymal stem cell therapy in rheumatoid arthritis

No. of patients	Transplantation type	Cell source (n)	Total cell dose (n)	Follow-up duration (mo)	Response (n)	Ref.
3	Autologous	Adipose tissue	6×10⁸ (1)8×10⁸ (2)	3∼13	Pain VAS↓, KWOMAC↓ (1) Walking improving (2) Off steroid (2)	[68]
4	Allogeneic	Bone marrow (1) Umbilical cord (3)	1×10⁶/kg)	24	ESR↓, DAS28↓, Pain VAS↓ (3) EULAR response but relapse (2) No EULAR response (2) No DAS28 remission (4)	[69]
136	Allogeneic	Umbilical cord	4×10⁷ (112)8×10⁷ (24)	3∼8	DAS28 remission (68) DAS28 low-activity (40)	[70]
46	Allogeneic	Adipose tissue	3×10⁶/kg (20)6×10⁶/kg (20)12×10⁶/kg (6)	6	ACR20 (53), ACR50 (31), ACR70 (12) ACR20 (9), ACR50 (5), ACR70 (2) EULAR response (6) DAS28 low-activity (6)	[71]

VAS: visual analog scale, ↓: decrease, KWOMAC: Korean Western Ontario and McMaster Universities arthritis index, ESR: erythrocyte sedimentation rate, DAS28: 28 joints disease activity score, EULAR: The European League Against Rheumatism, ACR: American College of Rheumatology, Ref.: reference.

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