Role of stem cells in spondyloarthritis: Pathogenesis, treatment and complications

Accepted Manuscript Review Role of stem cells in spondyloarthritis: Pathogenesis, treatment and complications Rebecca S.Y. Wong PII: DOI: Reference:

S0198-8859(15)00475-9 http://dx.doi.org/10.1016/j.humimm.2015.09.038 HIM 9617

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Human Immunology

Received Date: Revised Date: Accepted Date:

6 June 2014 2 July 2015 26 September 2015

Please cite this article as: Wong, R.S.Y., Role of stem cells in spondyloarthritis: Pathogenesis, treatment and complications, Human Immunology (2015), doi: http://dx.doi.org/10.1016/j.humimm.2015.09.038

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Role of stem cells in spondyloarthritis: Pathogenesis, treatment and complications Rebecca S.Y. Wong1, § 1

Faculty of Medicine, SEGi University. No. 9, Jalan Teknologi, Taman Sains Selangor, Kota

Damansara, PJU 5, 47810 Petaling Jaya, Selangor, Malaysia.

§

Corresponding author

Phone: +603- 6145 2777 (ext 3616) Fax: +603-6145 2649 Email: [email protected]; [email protected]

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Abstract Spondyloarthritis (SpA) is a family of interrelated inflammatory arthritis that includes ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, arthritis related to inflammatory bowel disease and undifferentiated SpA. The classification, epidemiology, pathogenesis and treatment of SpA have been extensively reviewed in the published literature. Reviews on the use of stem cells in various autoimmune diseases in general are also common. However, a review on the role of stem cells in SpA is currently lacking. This review focuses on the involvement of stem cells in the pathogenesis of SpA and the application of different types of stem cells in the treatment of SpA. It also addresses some of the complications which may arise as a result of the use of stem cells in the treatment of SpA.

Key words: Spondyloarthritis, stem cells, pathogenesis, treatment, complications

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1. Introduction Spondyloarthritis or spondyloarthropathy (SpA) is a family of inflammatory arthritis including the prototype ankylosing spondylitis (AS) and several related diseases, namely, psoriatic arthritis, reactive arthritis, arthritis related to inflammatory bowel disease (enteropathic arthritis) and undifferentiated SpA. These diseases share various common features in their clinical presentation, as well as pathophysiology. To date, its classification [1-3], epidemiology [4-6], pathogenesis [7-12] and treatment [13-15] have been reviewed extensively in the published literature. In addition, there is an increasing interest and an expanding body of research concerning the use of stem cells of various origins in the treatment of autoimmune diseases including SpA. Several reviews have been carried out on the use of stem cells in autoimmune diseases in general [16-20] while reviews on the use of stem cells in inflammatory arthritis [21] or specific arthritic conditions such as rheumatoid arthritis (RA) [22] are also common. However, a specific review emphasising in the role of stem cells in SpA is lacking. Thus, this paper critically reviews and summarises the role of stem cells in SpA from the perspectives of pathogenesis, treatment as well as existing and potential complications arising from stem cellbased therapy.

2. Spondyloarthritis Spondyloarthritis or spondyloarhtropahty (SpA) refers to an interrelated group of rheumatic diseases which share some common features. Several sets of classification criteria used to classify SpA have been reviewed, which include the Assessment of SpondyloArthritis Society (ASAS) criteria, the modified New York criteria for ankylosing spondylitis (AS), the Amor criteria and the European Spondyloarthropathy Study Group

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(ESSG) criteria [1-3]. Diseases that are included in the SpA family include AS, reactive arthritis, psoriatic arthritis, enteropathic arthritis and undifferentiated SpA. Variations in the epidemiology of SpA are explained by the application of different sets of SpA classification criteria. Dean et al estimated that there were 1.30 to1.56 million and 4.63 to 4.98 million cases of AS in Europe and Asia respectively [6]. In the United States, the overall ageadjusted prevalence of definite and probable SpA by the Amor criteria was 0.9%, which corresponded to approximately 1.7 million persons, while the age-adjusted prevalence of SpA by the ESSG criteria was 1.4%, which corresponded to 2.7 million persons [23]. Despite wide variations in the prevalence of SpA geographically, the reported prevalence of SpA between 0.9% and 1.4% may represent an overestimation due to recruitment biases. Some studies have reported an overall prevalence of SpA as low as 0.3% in France [24, 25], 0.45% in southern Sweden [26] and 0.4% in North America [27]. Although SpA is a class of diseases that share some similarities with rheumatic arthritis (RA), some distinctive features of SpA differentiate it from the latter. In RA, there is symmetrical involvement of the joints of the hands and feet accompanied by the presence of erosions and absence of new bone apposition. Auto-antibodies such as rheumatoid factor (RF) and anti-citrullinated peptide antibody (anti CCOP) are often present in RA [14]. On the other hand, SpA is characterised by human leukocyte antigen (HLA)-B27 association, and asymmetrical, oligoarticular peripheral arthritis that predominantly occurs in the lower extremities. Other features that link the SpA group of diseases include sacroiliitis, spondylitis, dactylitis, enthesitis and an increased susceptibility for inflammatory eye disease [14, 28].

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The pathogenesis of SpA is not fully understood. Inflammation and new bone formation, especially in the spine, are two central themes of the disease [29]. Several factors and mediators have been associated with the disease. For example, HLA-B27, a major histocompatility complex (MHC) class I molecule encoded on chromosome 6p, was first described to be associated with AS in 1973 [30]. Several earlier studies have shown that more than 90% of patients with AS were HLA-B27 positive [31, 32] whereas reactive, psoriatic and enteropathic arthritis were less frequently associated with HLA-B27 [32, 33]. However, not all HLA-B27 positive persons in the general population will eventually develop AS. HLA-B27 positive individuals in the general European population had a 16-fold lower risk (1.3%) of developing AS when compared to those who were HLA-B27 positive relatives of HLA-B27 positive patients with spondylitis (21%) [31].The multiple HLA-B27 related mechanisms and theories involved in the pathogenesis of SpA have been reviewed by Colbert et al [8] and Chatzikyriakidou et al [7]. Other players in the pathogenesis of SpA include inflammatory cytokines such as tumour necrosis factor alpha (TNF-α) [34, 35], interleukin (IL)-1 [36], IL-6 [34, 37], IL-7 [38], IL-17 [39] and IL-23 [39, 40]. The role of inflammatory cytokines and biomarkers in the pathogenesis of SpA has been reviewed by Keller et al [9], Maksymowych [10] and Hreggvidsdottir et al [11], while their role in the structural remodeling in peripheral SpA by Vandooren et al [12]. Despite new advances, novel approaches and discoveries, the treatment of SpA is largely dependent on pharmacological agents. Non-steroidal anti-inflammatory drugs (NSAIDs) remain the first-line drugs, while traditional disease-modifying drugs (DMARDS) such as sulphasalazine and methotrexate and intra-articular injections of corticosteroids in local disease, are commonly and conventionally used in the treatment of SpA whereas newer approaches such as tumour necrosis factor (TNF)-α blockers (e.g. infliximab, etanercept, adalimunab and

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golimumab) have been used in the treatment of SpA (reviewed by Braun & Sieper; Papagoras & Drosos; Keith) [13-15].

Other supportive measures that play an important role in the

management of SpA include patient education and exercise [41, 42], as well as physical therapy, rehabilitation, surgical referrals, patient associations and self-help groups [41].

3. Role of stem cells in the pathogenesis of spondyloarthritis Several studies have pointed to the involvement of stem cells in the pathogenesis of SpA, with a majority of them involving the mesenchymal stem cells (MSCs) (Figure 1), which are multipotent cells capable of differentiating into osteoblasts, adipocytes and chondroblasts [43]. In one study, the bone marrow-derived MSCs (BMSCs) from 51 AS patients were studied [44]. Although BMSCs obtained from AS patients were shown to demonstrate normal proliferation, cell

viability,

surface

markers

and

multiple

differentiation

characteristics,

their

immunomodulatory potential were significantly reduced when compared to that of BMSCs from healthy donors. In addition, there was an increase in the frequencies of Treg and Fox-P3+ cells in the peripheral blood nuclear cells (PBMCs) of these patients, with an increase in CCR4+CCR6+ Th cells in comparison with healthy donors. The study concluded that the reduced immunomodulatory potential of BMSCs played a crucial role in the pathogenesis of AS as it induced CCR4+CCR6+ Th/Treg cell imbalance in peripheral blood [44]. Other than being functionally abnormal and contributing to CCR4+CCR6+ Th/Treg cell imbalance, the MSCs have also been found to affect bone mineralisation by influencing the activity of tissue-nonspecific alkaline phosphatase (TNAP), an enzyme encoded by the ALPL gene [45] which has been reported to play a role in bone mineralization [46]. Ding et al examined the effects of TNF-α and IL-1β on osteoblast differentiation and mineralisation in

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cultured human MSCs (hMSCs) in search of a possible explanation for the differences in bone changes observed in RA and SpA. Interestingly, it was demonstrated that TNF-α and IL-1β inhibited collagen expression and stimulated TNAP activity. The differential effects of these cytokines on collagen expression and TNAP activity in turn, may help explain why in RA, inflammation is associated with bone erosion but leads to new bone formation in SpA [47]. In addition, a more recent study further supported the role of TNF-α in osteoblastic function and excessive bone formation by demonstrating autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-α in human MSCs. TNF-α was shown to significantly increase the levels of Wnt10b and Wnt5a, accompanied by stimulation of TNAP and mineralisation, an effect which could be mimicked by activating the canonical β-catenin pathway [48], suggesting the effects of inflammation on bone formation may potentially be mediated by Wnt5a . This may help explain partly why anti-TNF-α therapy is inefficient in preventing excessive bone formation in AS as the process involves indirect stimulation of ossification via the MSCs. The effects of activated monocytes or macrophages on MSCs with respect to matrix mineralisation and osteogenesis were studied by Guihard et al [49]. It was demonstrated that the induction of osteogenesis in MSCs by monocytes or macrophages relied on oncostatin M (OSM), a cytokine belonging to the IL-6 family. Bone formation was induced by OSM via the recruitment of MSC type II receptor, activating the transcription factor STA3 and resulting in osteoblastic differentiation. It was, therefore, proposed that during bone inflammation, injury or infection, this IL-6 family signaling network is responsible for osteogenesis and bone formation. This was further supported by earlier evidence that over-expression of OSM in the joints of mice led to periosteal bone formation, suggesting its role in bone apposition in RA, juvenile arthritis and SpA such as psoriatic arthritis and AS [50,51].

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MSCs have been isolated, localised and characterised in ossified spinal ligaments [52, 53]. Besides their involvement in osteogenesis and excessive bone formation in SpA, it is believed that MSCs may play a role in abnormal osteoblastic differentiation that leads to entheseal ossification in diffuse idiopathic skeletal hyperostosis (DISH), which share similarities with some forms of AS. Such a belief has led to the inference of the possible contribution of MSCs in the pathogenesis of entheseal abnormalities observed in SpA. The role of mesenchymatous cells in the pathogenesis of hyperostosis has been reviewed by Berthelot et al [54]. Additionally, MSC-derived adipocytes may also play a role in SpA pathogenesis due to deranged regulatory functions. The role of adipose tissue as a potent source of inflammatory cytokines is not an uncommon phenomenon in autoimmune diseases [55]. Such adipocyte dysfunctions have been demonstrated in AS patients showing an increased level in resistin (an adipokine primarily defined in human adipocytes) [56], suggesting a role played by the adipocytes in SpA. Resistin has been linked to increased expression of several pro-inflammatory cytokines such as IL-12 and TNF-α in an NF-κB-dependent manner [57]. In AS patients, resistin has been correlated to inflammatory markers whereas visfatin (a proinflammatory adipokine) was correlated to worsening of the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) in one study. It was also shown to be predictive of subsequent radiographic spinal progression and syndesmophyte formation/ progression [58]. Other adipokines that may be involved in AS include leptin, adiponectin and apelin. However, some conflicting opinions exist in the published literature regarding the role of these substances in AS (reviewed by Genre et al) [59].

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Although stem cells have been shown to contribute to the pathogenesis of SpA, some studies have reported their protective effects in the bone marrow both in vitro and in vivo. The interplay of MSCs and regulatory T (Treg) cells within the bone marrow may play a protective role in the pathogenesis of spondyloarthritis, given the bone marrow’s close proximity with the entheses. As SpA is a chronic inflammatory disease affecting the musculoskeletal system, the outcome of the disease depends not only on immune changes but also bone tissue homeostasis and remodeling [60]. In addition, a balance between T helper 17 (Th17) cells and Treg cells have been implicated in autoimmune bone related diseases [61]. In animal studies, it has been demonstrated that defects in Th17 cells played a proinflammatory role whereas Treg cells are anti-inflammatory [62, 63]. Luz-Crawford et al demonstrated that MSCs were capable of suppression of the proliferation, activation and differentiation of CD4+ T cells induced to differentiate into Th1 and Th17 cells, which was accompanied by an increase in the percentage of functional induced CD4+CD25+Foxp3+ Treg cells and increased IL-10 secretion. The study further demonstrated suppression of Th17 cells and an increase in the percentage of CD4+CD25+Foxp3+ Treg cells following MSC injection in mice [64]. Besides their interactions with MSCs, Treg cells have also been found to provide immune privilege to the haematopoietic stem-cell niche. Fujisaki et al demonstrated the persistence of the haematopoietic stem/progenitor cells (HSPCs) from allogeneic donor mice (allo-HSPCs) in nonirradiated recipient mice, which was lost if the FOxP3 Treg cells were depleted. It was also demonstrated that HSPCs co-localised with Treg cells on the endosteal surface in the calvarial and trabecular bone marrow suggesting the role of Treg cells in allo-HSPC persistence. Hence such interactions between bone marrow HSPCs and the Treg cells may play a role in providing a

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relative sanctuary from immune attack as the accumulation of Tregs in the HPSC niche shield endogenous HSPCs from autoimmunity or excessive inflammation [65].

4. Role of stem cells in the treatment of spondyloarthritis The co-existence of an autoimmune disease and a haematological disease in some patients often provides a good opportunity to examine the effects of bone marrow or haemtopoietic stem cell transplantation (BMT/HSCT) on autoimmune diseases in these patients. Hence, reports on the effects of BMT or HSCT on autoimmune diseases are not uncommon and may be dated back a few decades ago [66]. There have also been incidences where HSCT was used for the treatment for severe autoimmune diseases in the absence of a haematological disease [16]. Both autologous and allogeneic transplant, and both myeloablative and non-myeloablative approaches have been reported. Other than the haematopoietic stem cells (HSCs), MSCs have also been used widely in the treatment of autoimmune diseases in various reports with variable outcomes. Both HSC- and MSC-based therapy in a wide range of autoimmune disease including RA, systemic lupus erythematosus (SLE), multiple sclerosis (MS), scleroderma etc. have been extensive reviewed in published literature [16-20, 66]. However, much fewer studies have been carried out on stem cell-based therapy on SpA. There have been several reports on the beneficial effects of HSCT on SpA in which a majority involving HSCT as a treatment for a haematological disease in patients with concomitant SpA. While reports on the HSCT effects on psoriasis in general are abundant [67-69], there are relatively fewer reports that focus specifically on psoriatic arthritis, ankylosis spondylitis or other forms of SpA. Slavin et al observed graft versus autoimmunity effects following allogenic myeloablative blood stem cell transplantation (STC) in a patient with chronic myelogenous

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leukaemia (CML), severe systemic psoriasis and psoriatic polyarthritis [70]. In 2006, Woods and Mants described a case of aplastic anemia with concomitant psoriatic arthritis in which the patient achieved amelioration of severe psoriasis and psoriatic arthritis for twenty years after allogeneic HSTC [71]. The patient had a brief remission followed by a long chronic disabilityfree period post HSTC. Another patient with psoariatic arthropathy achieved complete remission of psoriatic arthropathy after autologous HSCT for multiple myeloma [72]. The patient was reported to have a 15-year history of arhtralgias and oligoarticular SpA.

Following

myeloablation and autologous HSCT, complete regression of his psoriatic arthropathies and skin lesions was observed, although he eventually had a relapse of his myeloma. It is worth mentioning that although the presentation of AS can be severe, it is usually not life-threatening. Therefore, HSCT is rarely used in these patients. For those who did receive HSCT as a treatment for AS, a majority of these patients did so because they also had a concomitant haematological disease. Jantunen et al reported a case of autologous stem cell transplant (ASCT) in a patient with lymphoma and a long history of AS [73]. The patient underwent chemotherapy and ASCT for the treatment of lymphoma and successfully achieved clinical remission for both the lymphoma and AS. The first autologous HSCT for the intentional treatment of AS was reported recently in 2012 [74]. In this case, a HLA-B27 positive man received high-chemotherapy and autologous HSCT at the age of 46 years. The patient achieved complete clinical remission throughout the entire two-year follow up period. In another case report, a 39-year-old man with active AS and concomitant acute myeloid leukaemia (AML) was given pre-transplantation total body irradiation and cyclophosphamide followed by allogeneic peripheral blood SCT. He experienced clinical remission and partial radiological regression of

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cervical spine syndesmophytes, and remained medication- and symptom-free for three years after the transplantation [75]. More recently, other than stem cells of haematopoeitic origin, MSCs have also caught the attention of researchers. For instance, Huang et al [76] have investigated the inhibitory effects of human umbilical cord derived MSCs (hUCMSCs) on peripheral blood T cells from patients with SpA in vivo in search of their therapeutic potential. It was found that co-culturing of peripheral blood mononuclear cells (PBMNC) with hUCMSCs significantly reduced IL-17 production from peripheral blood T cells, suggesting that MSCs may be a good candidate for the treatment of SpA. On the other hand, Wang et al investigated the effects and safety of intravenous infusion (IVI) of allogenic MSCs in patients with AS who have failed non-steroidal anti-inflammatory drugs in a 20-week clinical trial [77]. In the study, 31 AS patients received four IVI of MSCs on days 0, 7, 17 and 21. It was reported that the percentage of Assessment in Ankylosing Spondylitis Response Criteria (ASAS 20) responders reached 77.4% at the end of 4th week with a mean response duration of 7.1 weeks. There was a reduction of the Ankylosing Spondylitis Disease Activity Score Containing C-reactive Protein (ASDAS-CRP) from 3.6±0.6 to 2.4±0.5 at th

th

the 4 week, followed by an increase to 3.2±0.8 at the 20 week. There was also a significant reduction in the average total inflammation extent (TIE) detected by MRI, while no adverse effects were noted. The study concluded that IVI of MSCs was safe, feasible and promising for the treatment of AS [77]. However, it is worth mentioning that the difference in ASDAS-CRP between baseline (3.6 +0.6) and 4 weeks (2.4 + 0.5) could be explained by regression to the mean and that a controlled study will better demonstrate the effectiveness of IVI MSCs in SpA. In addition, there are several registered clinical trials that involve the use of stem cells in SpA. Two clinical trials have been identified at www.clinicaltrial.gov (a registry and results

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database of publicly and privately supported clinical studies of human participants conducted around the world). The first is titled “Safety and Efficacy Study of Umbilical Cord/PlacentaDerived Mesenchymal Stem Cells to Treat Ankylosing Spondylitis” [78]. This is a phase I clinical trial lasting two to three years in which the patients in the experimental group will receive MSC transplant with disease modifying drugs (DMARDs) and patients in the control group will receive DMARDs alone. The second is titled “A Molecule Basic Study of Early Warning of New Pathogenic Risk of Ankylosing Spondylitis” [79], in which the investigators will inject human MSCs into active AS patient and study the gene expression profiles of their PBMCs and related pathogenesis before and after treatment. A third phase I/II clinical trial was retrieved at the Chinese Clinical Trial Registry titled “Clinical Study of Mecenchymal Stem Cells Transplantation in Ankylosing Spondylitis” [80] in which the investigators study the safety and the clinical effects of MSC transplantation in AS patients. The use of stem cells in SpA is summarised in Table 1.

5. Complications of the use of stem cells in autoimmune diseases To date, despite past success and promising results from various studies, stem cell-based therapy is still not the treatment of choice in SpA or other types of autoimmune diseases except in very severe diseases or where there is failure of traditional treatment options. Although evidence of complications of stem cell therapy in SpA is not abundant due to scarcity of the published literature, lessons can be learnt from complications of HSCT and other stem cell-based therapy in other diseases, particular autoimmune diseases. Some of the complications of HSCT in the treatment of autoimmune diseases have been reviewed [81], which include treatment-

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related mortality, infectious complications, treatment-associated toxicity, endocrinological complications, and secondary autoimmune diseases and malignancies after HSTC. Like a double-edged sword the use of stem cells to treat autoimmune diseases have been shown to give rise to the development of secondary autoimmune diseases and inflammatory arthritis. Autoimmune phenomenon of haematological, endocrinological, neurological and rheumatological nature has been reported. The wide range of secondary autoimmune conditions developed post HSCT includes arthritis, SLE, vasculitis, eosinophilic fasciitis, antiphospholipid antibody syndrome, thyroiditis, autoimmune haemolytic anaemia, pancytopenia scleroderma etc. [81-84]. This has led researchers to turn their attention to other types of stem cells such as the MSCs. However, MSC-based treatments are not without their complications. The immunosuppressive and immunomodulatory properties of MSCs make them promising therapeutic agents in autoimmune diseases [85]. Nevertheless, MSCs have been reported to be involved in leukaemogenesis and to support tumour growth in various types of cancers (reviewed by Wong; Wong & Cheong) [86, 87]. Interestingly, there have been several sporadic reports on the development of SpA after BMT or SCT. In 1997, after receiving syngeneic bone marrow from a psoriatic donor, a patient was reported to develop psoriasis. Recurrence of the psoriasis with arthropathy was observed after a second syngeneic BMT [88]. Similarly, a HLA-B27 negative patient with CML developed psoriasis and psoriatic arthritis after receiving bone marrow from his HLA-identical brother, who had psoriatic skin lesions [89].

In 2000, a case report described the first

manifestations of seronegative SpA following autologous SCT in three HLA-B27 positive patients, in which two were male patients with non-Hodgkin lymphoma and one, female patient with AML. Two of the three patients had X-ray evidence of sacroiliitis. All three patients had

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enthesopathy and were subsequently tested positive for HLA-B27. The development of these SpA manifestations took between 4 and 15.5 years after SCT [90]. In 2010, another case report described the development of undifferentiated SpA in a 26-year-old male patient following allogeneic SCT. The patient was diagnosed with acute pre-B lymphocytic leukaemia at 10 years of age and had received allogeneic SCT from his father. The patient developed signs of SpA 10 years after SCT and showed signs of axial disease with dactylitis insidiously [91].

6. Conclusion Several points can be concluded concerning the role of stem cells in SpA: •

The role of stem cells in the pathogenesis is not fully understood Further explorations on how stem cells, especially the MSCs contribute to the pathogenesis of SpA are necessary. It is also beneficial to elucidate the mechanisms of secondary autoimmune disease and SpA manifestations after HSCT.

•

There is insufficient data to support the role of stem cells in the treatment of SpA Data currently available is inconclusive to suggest whether stem cells can cure or significantly improve SpA symptoms. Most published clinical studies are short-term, involving a small number of patients or are mostly case reports. There may be publication biases in the relief of symptoms in some SpA patients as only striking improvements following STC or HSCT were being reported whereas those cases with poor outcomes may have been excluded from publication.

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•

Larger studies with longer follow-up periods are needed to support the use of stem cells in the treatment of SpA Clinical trials with a large sample size and long-term follow ups are crucial to prove the safety and efficacy of stem cell use in SpA treatment. This can provide insights into the sustainability of treatment, relapse of disease after treatment, as well as the long-term complications of stem cell-based therapy.

•

Not all stem cell types can be used in the treatment of SpA So far the effects of stem cells of haematopoietic origin and the MSCs have been reported in the treatment of SpA. Literature on the use of other types of stem cells in the treatment of SpA is scarce.

•

Stem cells therapy for SpA may not be suitable for all types of patients The careful choice of patients is important as not all patients are suitable candidates of stem cell therapy. Only those with very severe diseases who are not responsive to conventional treatment should be considered for such treatment.

•

The use of stem cells is not without risks and complications The benefits of the treatment must outweigh the risks as stem cell therapy is not without disadvantages. The complications caused by each type of stem cells have to be thoroughly studied before they become commonly used in SpA treatment.

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49. Guihard P, Danger Y, Brounais B, David E, Brion R, Delecrin J, Richards CD, Chevalier S, Rédini F, Heymann D, Gascan H,Blanchard F. Induction of Osteogenesis in mesenchymal stem cells by activated monocytes/macrophages depends on oncostatin M signaling. Stem Cells 2012;30(4):762-72. 50. de Hooge AS, van de Loo FA, Bennink MB de Jong DS, Arntz OJ, Lubberts E, Richards CD, vandDen Berg WB. Adenoviral transfer of murine oncostatin M elicits periosteal bone apposition in knee joints of mice, despite synovial inflammation and up-regulated expression of interleukin-6 and receptor activator of nuclear factor-kappa B ligand. Am J Pathol 2002; 160: 1733–43. 51. de Hooge AS, van de Loo FA, Bennink MB Arntz OJ, Fiselier TJ, Franssen MJ, Joosten LA, Van Lent PL, Richards CD, van den Berg WB. Growth plate damage, a feature of juvenile idiopathic arthritis, can be induced by adenoviral gene transfer of oncostatin M: A comparative study in gene-deficient mice. Arthritis Rheum 2003; 48: 1750–1761. 52. Asari T, Furukawa KI, Tanaka S, Kudo H, Mizukami H, Ono A, Numasawa T, Kumagai G, Motomura S, Yagihashi S, Toh S. Mesenchymal stem cell isolation and characterization from human spinal ligaments, Biochem. Biophys. Res. Commun 2012; 362: 1193-9. 53. Chin, S , Furukawa KI , Ono A , Asari T , Harada Y, Wada K , Tanaka T , Inaba W , Mizukami H , Motomura S , Yagihashi S, Ishibashi Y. Immunohistochemical localization of mesenchymal stem cells in ossified human spinal ligaments. Biochemand Biophys Res Commun 2013; 436(4): 698-704. 54. Berthelot JM, Le Goff B, Maugars Y. Pathogenesis of hyperostosis: a key role for mesenchymatous cells? Joint Bone Spine. 2013; 80(6): 592-6. 55. Jastrzebska M, Kontny E, Janicka I, Maslinski W, Maldyk P. Rheumatoid adipose tissue is a potent source of cytokines. Ann Rheum Dis 2010;69:A53 56. Kocabas H, Kocabas V, Buyukbas S, Melıkoglu MA, Sezer I, Butun B. The serum levels of resistin in ankylosing spondylitis patients: a pilot study. Rheumatol Int 2012; 32(3):699-702. 57. Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham NZ. Human resistin stimulates the pro-inflammatory cytokines TNF-alpha and IL-12 in macrophages by NF-kappaB-dependent pathway". Biochem Biophys Res Commun 2005; 334 (4): 1092–101. 58. Syrbe U, Callhoff J, Conrad K, Poddubnyy D, Haibel H, Junker S, Frommer KW, Müller-Ladner U, Neumann E, Sieper J. Serum adipokine levels in patients with ankylosing spondylitis and their relationship to clinical parameters and radiographic spinal progression. Arthritis Rheumatol. 2015; 67(3):678-85. 59. Genre F, López-Mejías R, Miranda-Filloy JA, Ubilla B, Carnero-López B, Blanco R, Pina T, González-Juanatey C, Llorca J, González-Gay MA.Adipokines, biomarkers of endothelial activation, and metabolic syndrome in patients with ankylosing spondylitis. Biomed Res Int 2014; 2014: 860651. 60. Luyten FP1, Lories RJ, Verschueren P, de Vlam K, Westhovens R. Contemporary concepts of inflammation, damage and repair in rheumatic diseases. Best Pract Res Clin Rheumatol 2006; 20(5):829-48. 61. Wang M1, Tian T, Yu S, He N, Ma D. Th17 and Treg Cells in Bone Related Diseases. Clin Dev Immunol. 2013;2013: 203705.

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62. Bettelli E1, Oukka M, Kuchroo VK. TH-17 cells in the circle of immunity and autoimmunity. Nat Immunol 2007;8(4):345-50. 63. Afzali B1, Lombardi G, Lechler RI, Lord GM. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol 2007; 148(1):32-46. 64. Luz-Crawford P, Kurte M, Bravo-Alegría J, Contreras R, Nova-Lamperti E, Tejedor G, Noël D, Jorgensen C, Figueroa F, Djouad F, Carrión F. Mesenchymal stem cells generate a CD4+CD25+Foxp3+ regulatory T cell population during the differentiation process of Th1 and Th17 cells. Stem Cell Res Ther 2013;4(3):65. 65. Fujisaki J, Wu J, Carlson AL, Silberstein L, Putheti P, Larocca R, Gao W, Saito TI, Lo Celso C, Tsuyuzaki H, Sato T, Côté D, Sykes M, Strom TB, Scadden DT, Lin CP. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature 2011;474(7350):216-9. 66. Hinterberger W, Hinterberger-Fischer M, Marmont A. Clinically demonstrable antiautoimmunity mediated by allogeneic immune cells favorably affects outcome after stem cell transplantation in human autoimmune diseases. Bone Marrow Transplant 2002; 30(11):753-9. 67. Eedy DJ, Burrows D, Bridges JM, Jones FGC. Clearance of severe psoriasis after allogeneic bone marrow transplantation. BMJ 1990; 300:908. 68. Kanamori H, Tanaka M, Kawaguchi H, Yamaji S, Fujimaki K, Tomita N, Fujisawa S, Ishigarshubo Y. Resolution of psoriasis following allogeneic bone marrow transplantation for chronic myelogenous leukemia: case report and review of the literature. Am J Hematol 2002; 71:41–4. 69. Windrum P, Jones FGC, McMullin MF. Adoptive immunotherapy after bone marrow transplantation in a patient with relapsed acute myeloid leukaemia and severe psoriasis. Bone Marrow Transplant 2004; 34:281–2. 70. Slavin S, Nagler A, Varadi G, Or R. Graft vs autoimmunity following allogeneic nonmyeloablative blood stem cell transplantation in a patient with chronic myelogenous leukaemia and severe systemic psoriasis and psoriatic polyarthritis. Exp Hematol 2000; 28(7):853-7. 71. Woods AC, Mant MJ. Amelioration of severe psoriasis with psoriatic arthritis for 20 years after allogeneic haematopoietic stem cell transplantation. Ann Rheum Dis 2006; 65:697 72. Braiteh F, Hymes SR, Giralt SA, Jones R.Complete remission of psoriasis after autologous hematopoietic stem-cell transplantation for multiple myeloma. J Clin Oncol 2008; 26(27):4511-3. 73. Jantumen E, Myllykangas‐Luosujärvi R, Kaipiainen‐Seppänen O, Nousiainen T. Autologous stem cell transplantation in a lymphoma patient with a long history of ankylosing spondylitis. Rheumatology (Oxford) 2000; 39 (5): 563-564. 74. Britanova OV, Bochkova AG, Staroverov DB, Feforenko DA, Bolotin DA, Memedove IZ, Turchaaninova MA, Putintseva EV, Kotlobay AA, Lukyanov S, Noviks AA, Lebedev YB,Chudakov DM. First autologous hematopoietic SCT for ankylosing spondylitis: a case report and clues to understanding the therapy. Bone Marrow Transplant 2012; 47: 1479 -81.

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75. Yang HK, Moon SJ, Shin JH, Kwok SK, Park KS, Park SH, Kim HY, Ju JH. Regression of syndesmophyte after bone marrow transplantation for acute myeloid leukemia in a patient with ankylosing spondylitis: a case report. J Med Case Rep 2012; 21;6(1):250. 76. Huang ZF, Zhu J, Lu SH, Zhang JL, Chen XD, DU LX, Yang ZG, Song YK, Wu DY, Liu B, Huang F. Inhibitory effect of human umbilical cord-derived mesenchymal stem cells on interleukin-17 production in peripheral blood T cells from spondyloarthritis patients. Zhongguo Shi Yan Xue Ye Za Zhi 2013; 21(2):455-9. 77. Wang P, Li Y, Huang L, Yang J, Yang R, Deng W, Liang B, Dai L, Meng Q, Gao L, Chen X, Shen J, Tang Y, Zhang X, Hou J, Ye J, Chen K, Cai Z, Wu Y, Shen H. Effects and safety of allogenic mesenchymal stem cells intravenous infusion in active ankylosing spondylitis patients who failed NSAIDs: A 20 week clinical trial. Cell Transplant. 2013. doi: http://dx.doi.org/10.3727/096368913X667727. 78. ClinicalTrials.gov. Safety and efficacy study of umbilical cord/placenta-derived mesenchymal stem cells to treat ankylosing spondylitis. ClinicalTrials.gov identifier: NCT01420432. Retrieved from www.clinicaltrials.gov on 26th May 2014. 79. ClinicalTrials.gov. A molecule basic study of early warning of new pathogenic risk of ankylosing spondylitis. ClinicalTrial.gov identifier: NCT01709656. Retrieved from www.clinicaltrials.gov on 26th May 2014 80. Chinese Clinical Trial Registry. Clinical study of mecenchymal stem cells transplantation in ankylosing spondylitis. Registration number: ChiCTR-TRC-11001417 Retrived from http://www.chictr.org/en/proj/show.aspx?proj=1572 on 26th May 2014 81. Daikeler T, Tichelli A, Passweg J. Complications of autologous hematopoietic stem cell transplantation for patients with autoimmune diseases. Pediatr Res 2012;71 (4 Pt 2):43944. 82. Barnabe CC, LeClercq SA, Fitzgerald AA.The development of inflammatory arthritis and other rheumatic diseases following stem cell transplantation. Semin Arthritis Rheum 2009;39(1):55-60. 83. Holbro A, Abinun M, Daikeler T. Management of autoimmune diseases after haematopoietic stem cell transplantation. Br J Haematol 2012; 157(3):281-90. 84. Khalil A, Zaidman I, Bergman R, Elhasid R, Ben-Arush MW. Autoimmune complications after haematopoeitic stem cell transplantation in children with nonmalignant disorders. ScientificWorldJournal 2014; 2014: 581657. 85. Abumaree M, Al Jumah M, Pace RA, Kalionis B. Immunosuppressive properties of mesenchymal stem cells. Stem Cell Rev 2012; 8(2):375-92 86. Wong RSY. Mesenchymal stem cells: Angels or demons? Journal of Biomedicine and Biotechnology, 2011; 2011: 459510. 87. Wong RSY, Cheong SK. Role of mesenchymal stem cells in leukaemia: Dr. Jekyll or Mr. Hyde? Clin Exp Med, 2013. doi 10.1007/s10238-013-0247-4. 88. Snowden JA, Heaton DC. Development of psoriasis after syngeneic bone marrow transplant from psoriatic donor: further evidence for adoptive autoimmunity. Br J Dermatol 1997; 137(1):130-2. 89. Daikeler T, Gunaydin I, Kotter I. Transmission of psoriatic arthritis by allogeneic bone marrow transplantation for chronic myelogenous leukemia from an HLA-identical donor. Rheumatology (Oxford) 1999;38(1):89-90.

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90. Koch B, Kranzhöfer N, Pfreundschu M, Pees HW, Trümper L. First manifestations of seronegative spondyloarthropathy following autologous stem cell transplanatation in JLB-B27 positive patients. Bone Marrow Transplant. 2000: 26(6): 673-5. 91. Karia VR, Cuchacovich R, Espinoza LR. Undifferentiated spondyloarthritis following allogeneic stem cell transplantation. BMC Musculoskelet Disord 2010; 11: 132.

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Figure legends Figure 1 Role of stem cells in the pathogenesis of spondyloarthritis. (AS= ankylosing spondylitis;

HSPCs=

haematopoietic

stem/progenitor

cells;

IL=

interleukin;

MSCs=

mesenchymal stem cells; SpA= spondyloarthritis; Th cells= T helper cells; TNF= tumour necrosis factor; TNAP= tissue non-specific alkaline phosphatase; Treg cells= Regulatrory T cells) Figure 2 (A) Complications of stem cell-based therapy in autoimmune disease or in general. (B) Development of SpA after bone marrow or stem cell transplantation.

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25

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Table 1 Use of stem cells in patients with spondyloarthritis Disease

Stem cell type

Remarks

Reference

Published literature Severe psoriasis with psoriatic polyarthritis

Allogenic myeloablative blood stem cell transplantation

The patient had concomitant chronic myelogenous leukaemia. Graft versus autoimmunity effects were observed following allogenic myeloablative blood stem cell transplantation

[68]

Severe psoriasis and psoriatic arthritis

Allogeneic haematopoietic stem cell transplantation

The patient had concomitant aplastic anemia. He experienced a brief remission followed by a long chronic disability-free period post HSTC

[71]

Psoriatic arthropathy and psoriasis vulgaris

Autologous myeloablative haematopoietic stem cell transplantation

The patient had concomitant multiple myeloma. He had complete regression of his psoriatic arthropathies and skin lesions and an eventual relapse of his myeloma

[72]

Angkylosing spondylitis

Autologous stem cell transplantation

The patient had concomitant lymphoma and underwent chemotherapy and ASCT for the treatment of lymphoma. Successful achievement of clinical remission for both lymphoma and AS.

[73]

Ankylosing spondylitis

Allogeneic peripheral blood stem cell transplantation

The patient also had concomitant acute myeloid leukaemia. He was given pre-transplantation total body irradiation and cyclophosphamide. He experienced clinical remission and partial radiological regression of cervical spine syndesmophytes.

[74]

Ankylosing spondylitis

Autologous haematopoietic stem cell transplant

The first reported case of intentional autologous HSCT for AS. A HLA-B27 positive man received high-chemotherapy and autologous HSCT and achieved complete clinical remission throughout the entire 2-year follow up period.

[75]

Ankylosing spondylitis

Intravenous infusion of allogenic mesenchymal stem cells

20-week clinical trial involving 31 AS patients who have failed NSAIDs. The percentage of ASAS 20 responders reached 77.4% at the 4th week with a mean response duration of 7.1 weeks. A reduction in ASDSCRP and TIE was observed. No adverse effects noted.

[77]

Registered clinical trials Ankylosing spondylitis

Human umbilical cordderived mesenchymal stem cells

A phase I clinical trial lasting two to three years in which the patients in the experimental group will receive MSC transplant with DMARDs and patients in the control group will receive DMARDs alone.

[78]

Ankylosing spondylitis

Human mesenchymal stem cells

Human MSCs injection into active AS patient to study the gene expression profiles of their PBMCs and related pathogenesis before and after treatment.

[79]

27

Ankylosing spondylitis

Mesenchymal stem cells

A phase I/II clinical trial to study the safety and clinical effects of MSC transplantation in AS patients.

[80]

AS= Ankylosing spondylitis; ASAS 20= Assessment in Ankylosing Spondylitis Response Criteria; ASCT= Autologous stem cell transplantation; ASDAS-CRP= Ankylosing Spondylitis Disease Activity Score Containing C-reactive Protein; DMARD= Disease-modifying drugs; MSC= Mesenchymal stem cells; NSAID= Non-steroidal anti-inflammatory drug; PBMC=Peripheral blood mononuclear cell; TIE= total inflammation extent

28