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Health Policy Advisory Committee on

Technology

New and Emerging Health Technology Report

Stem cell therapy for non-haematological (autoimmune)

indications

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© State of Queensland (Queensland Department of Health) 2015

This work is licensed under a Creative Commons Attribution Non-Commercial No Derivatives 3.0 Australia licence. In essence, you are free to copy and communicate the work in its current form for non-commercial purposes, as long as you attribute the authors and abide by the licence terms. You may not alter or adapt the work in any way.

To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/3.0/au/deed.en. For further information, contact the HealthPACT Secretariat at:

HealthPACT Secretariat

c/o Clinical Access and Redesign Unit, Health Service and Clinical Innovation Division Department of Health, Queensland

Level 2, 15 Butterfield St HERSTON QLD 4029

Postal Address: GPO Box 48, Brisbane QLD 4001

Email: HealthPACT@health.qld.gov.au Telephone: +61 7 3328 9180

For permissions beyond the scope of this licence contact: Intellectual Property Officer, Department of Health, GPO Box 48, Brisbane QLD 4001, email ip_officer@health.qld.gov.au, phone (07) 3328 9824.

Electronic copies can be obtained from: http://www.health.qld.gov.au/healthpact

DISCLAIMER: This Report is published with the intention of providing information of interest. It is based on information available at the time of research and cannot be expected to cover any developments arising from subsequent improvements to health technologies. This Report is based on a limited literature search and is not a definitive statement on the safety, effectiveness or cost-effectiveness of the health technology covered.

The State of Queensland acting through Queensland Health (“Queensland Health”) does not guarantee the accuracy, currency or completeness of the information in this Report. Information may contain or summarise the views of others, and not necessarily reflect the views of Queensland Health.

This Report is not intended to be used as medical advice and it is not intended to be used to diagnose, treat, cure or prevent any disease, nor should it be used for therapeutic purposes or as a substitute for a health professional's advice. It must not be relied upon without verification from authoritative sources. Queensland Health does not accept any liability, including for any injury, loss or damage, incurred by use of or reliance on the information.

This Report was commissioned by Queensland Health, in its role as the Secretariat of the Health Policy Advisory Committee on Technology (HealthPACT). The production of this Report was overseen by HealthPACT. HealthPACT comprises representatives from health departments in all States and Territories, the Australian and New Zealand governments and MSAC. It is a sub-committee of the Australian Health Ministers’ Advisory Council (AHMAC), reporting to AHMAC’s Hospitals Principal Committee (HPC). AHMAC supports HealthPACT through funding.

This Report was prepared by Prof Paul Scuffham, Dr Tracy Comans, Nicole Moretto and Tom Elliott from The Centre for Applied Health Economics, School of Medicine, Griffith University

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Table of contents

HealthPACT Advisory ... iii

Executive summary ... iv

Background ... 1

Patient indication ... 1

Description of the technology ... 1

Reason for assessment ... 4

Stage of development in Australia ... 4

Licensing, reimbursement and other approval ... 4

Impact ... 5

Multiple Sclerosis ... 6

Systemic Sclerosis ... 10

Systemic lupus erythematosus ... 12

Current technology ... 14

Diffusion of technology in Australia ... 18

Cost infrastructure and economic consequences ... 19

Cost analysis ... 19

Ethical, cultural, access or religious considerations ... 23

Evidence and Policy ... 24

Safety and effectiveness for multiple sclerosis ... 24

Haemopoietic stem cell transplantations for multiple sclerosis ... 24

Mesenchymal stem cell therapy for multiple sclerosis ... 44

Safety and effectiveness for systemic sclerosis ... 48

Haemopoietic stem cell transplantations for systemic sclerosis ... 48

Safety and effectiveness for systemic lupus erythematosus ... 57

Haemopoietic stem cell transplantations for SLE ... 57

Mesenchymal stem cell therapy for SLE ... 63

Economic evaluation ... 71

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Summary of findings ... 80

References ... 84

Search Strategy ... 93

HTA sites ... 93

Number of studies included ... 93

Appendices ... 94

Appendix A Estimation of the number of patients with relapsing remitting multiple sclerosis failing interferon beta and alemtuzumab, or alemtuzumab only ... 94

Appendix B Profiles of all included studies for HSCT and MSCT for multiple sclerosis ... 95

Appendix C Cochrane risk of bias assessment of the direct randomised trials of HSCT for systemic sclerosis ... 100

Appendix D Profiles of included observational studies for SSc ... 101

Appendix E Profiles of included studies for SLE ... 102

Appendix F MS Australia statement on Autologous Hematopoietic Stem Cell Transplant (HSCT) treatment. ... 105

Appendix G MS Australia’s statement on stem cells ... 107

Appendix H NHMRC warns of the risks associated with unproven stem cell therapies in Australia and overseas ... 109

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HealthPACT Advisory

This report was commissioned by HealthPACT in response to jurisdictions noting an increase in the number of patients seeking stem cell transplantation treatment overseas outside of clinical trials, especially in response to extensive press coverage. Many of these patients have not exhausted all of the available medical options to treat their condition and therefore would not fit the selection criteria for stem cell transplantation clinical trials conducted in Australia.

Patients seeking this treatment need to be fully informed as to the potential risks and

benefits, including that stem cell transplantation is not considered curative but rather aimed at ameliorating disease.

It should be noted that although both mesenchymal and haemopoietic stem cells are being used in the treatment of immunological conditions including multiple sclerosis, systemic sclerosis and systemic lupus erythematosus, the use of haematopoietic stem cells is more effective in comparison to mesenchymal but associated with more adverse events.

The evidence base for the treatment of severe systemic sclerosis is the most mature and is now an accepted treatment option for this disease based on data from two randomised controlled trials. One of these trials has confirmed a clear benefit of long term mortality for haematopoietic stem cell transplantation in systemic sclerosis. Trials to refine clinical protocols for use in systemic sclerosis are likely to continue.

HealthPACT recommends that the treatment of patients with multiple sclerosis and systemic lupus erythematosus with stem cell transplantation should only be conducted under the auspices of an ethics approved controlled trial with informed consent Careful selection of patients for such clinical trials is required, with only those patients who are currently in an active inflammatory phase of the disease, and are therefore most likely to benefit from stem cell transplantation, being considered for enrolment in units with expertise in stem cell transplantation for autoimmune disease.

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Executive summary

This new and emerging health technology report was prepared for HealthPACT with the aim of providing a brief overview of the evidence on the safety, effectiveness and feasibility of stem cell transplantation for (non-haematological) autoimmune diseases within an

Australian context. The focus of the report was haemopoietic stem cell transplantation (HSCT) and mesenchymal stem cell therapy (MSCT) for patients with multiple sclerosis (MS), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Both autologous (auto) and allogeneic (allo) forms were assessed. The reason for assessment was the increasing

evidence base for autologous haemopoietic stem cell transplantation (auto-HSCT) as a treatment for SSc, mounting pressure from the public for stem cell transplantation for MS and the potential for a major cost impact on the public health system.

Description and estimate of patient numbers Multiple sclerosis

MS is a chronic autoimmune disease of the central nervous system which can lead to a considerable level of disability. The most common subtypes of MS are relapsing remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), primary progressive multiple sclerosis (PPMS) and relapsing progressive multiple sclerosis (RPMS). There are also other rare variants of the condition. The prevalence of MS in Australia in 2010 was estimated to be 95.6 per 100,000 population in Australia. It is postulated that of the estimated 850 new cases of RRMS each year, approximately 125 to 187 patients would be refractory to interferon and alemtuzumab, or alemtuzumab only and may be assessed for eligibility for auto-HSCT across Australia. It is difficult to estimate the number of patients with SPMS with inflammatory disease that may be suitable for auto-HSCT.

Systemic sclerosis

SSc, also known as systemic scleroderma, is recognised as the most severe connective tissue disorder. SSc affects many different systems throughout the body with the most severe form involving major organs including the pulmonary, cardiac and renal systems. SSc carries a highly increased mortality risk with the major cause of mortality being cardiopulmonary

events including interstitial lung disease and pulmonary arterial hypertension.1 The median

survival for patients with SSc related interstitial lung disease is 5 to 8 years.2 The true

prevalence of SSc is difficult to determine with international estimates ranging from three to 24 per 100,000 people. A systematic review of epidemiology suggests an incidence of SSc in Australia of 15 to 23 persons per million per year using data from three Australian sources covering 1993 to 2002. Based on Australian registry data and epidemiology of SSc,

approximately 30 to 65 patients per year may be a reasonable approximation of the likely demand for stem cell treatment for SSc.

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Systemic lupus erythematosus

SLE is a chronic autoimmune disease characterised by inflammation across multiple organ systems, a clinical pattern of flares/relapses and remissions, and the presence of

autoantibodies. Most patients with SLE have symptoms of the skin and joints, although life-threatening manifestations can arise in the kidney, lungs, the central nervous system, gastrointestinal system, ophthalmic system, cardiovascular system and haematologic system. Inflammation of the kidney can cause lupus nephritis which can lead to significant illness and can even be fatal. The incidence of SLE in Australia is not well reported although a number of studies have reported the prevalence in population subgroups. The prevalence of SLE in Aboriginal peoples (52.0−92.8 cases per 100,000 population) has been reported to

be higher than in non-Aboriginal peoples (19.3−39.0 cases per 100,000 population).3 Lupus

nephritis is a severe form of SLE affecting renal function and therefore would be likely to be the main population requiring stem cell transplantation. The prevalence of lupus nephritis in Australia was found to be 5.5 per 100,000 population. Based on the current population, about 1,200 to 1,300 people would be living with the severe form of SLE in Australia. It is unclear how many of these people would be likely to benefit from stem cell therapies. Diffusion of technology in Australia

In Australia, auto-HSCT is widely used as a treatment for disorders of the blood and immune system and as supportive treatment for blood-related cancers. There have been over 60 auto-HSCT for autoimmune disease performed at St. Vincent’s Hospital since 1996. The use

of allogeneic-HSCT for the treatment of autoimmune diseases has been extremely limited.4

The major concern with allogeneic transplants is the potential for graft-versus-host disease, a severe and potentially life threatening complication which has limited the diffusion of the technology.

The technology to produce and use mesenchymal cells for therapy is available in Australia and has been used to treat a variety of conditions. There has been limited use of MSCT for the treatment of autoimmune disease in Australia with one small study published in Crohn’s disease. There have been attempts to engage in early phase trials of mesenchymal stem cell therapy in MS in Australia.

Cost infrastructure and economic consequences

Little economic information was available on stem cell therapies for autoimmune diseases in Australia. This is likely due to the lack of mainstream use of stem cell therapy for

autoimmune diseases. It was estimated that the direct cost to government for health and community care for MS in 2010 was $10,721 per patient, with an additional cost of $4,384 and $3,697 attributable to residential care and direct patient out-of-pocket costs,

respectively.5 No cost of illness estimates were available for SSc in Australia. An estimate of

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cost of $5,038 per patient (2007 Can$)6. This cost, converted to 2013 Australian dollars using

the OECDa purchasing parity index,7 was $6,328. The Canadian cohort in this study included

a wider range of patients than those likely to benefit from HSCT therefore the cost of patients with severe disease would be higher than this estimate.

No cost of illness studies were found that reported costs for SLE in Australia. A UK report estimated the cost of a patient with severe SLE as £4,652 per annum equivalent to AUD $10,963. According to the selection criteria of the SLE studies, $10,963 would be a reasonable estimate of the yearly cost of a patient eligible for HSCT as only severe SLE patients are considered for stem cell transplantations.

A cost analysis was performed for the purposes of this report only. The average national cost of a primary auto-HSCT for MS was estimated to range from AUD $30,364 to $50,765. It was assumed that the same procedure is similar across the three autoimmune diseases. This estimate was based on the cost of undergoing an auto-HSCT in one major transplant centre in Australia and may not reflect the cost of undergoing the procedure in other centres throughout Australia.

Costs may also differ depending on the types of medications used in the protocol, the severity of patients, and the type of autoimmune condition. For example, there are

biosimilar medications for the granulocyte-colony stimulating factor, such as pegfilgrastim, which are less costly than filgrastim. The cost estimate in this report was based on the medications used in a current clinical trial in Australia.

The average cost per patient with different autoimmune conditions is relatively similar; however, patients with SSc require an extra day in hospital for the insertion of specialised central venous catheter.

For the MSCT procedure, an additional cost of $10,000 to $20,000 per treatment course for the manufacture of mesenchymal stem cells in an accredited facility. However, the costs

associated with chemotherapy, in-patient and support costs are less than HSCT.

Based on the incidence rates of the three autoimmune diseases and the recommended patient selection for auto-HSCT, it is unclear whether there would be capacity within existing hospitals across Australia to accommodate the anticipated increase in demand for stem cell therapies these diseases. However, there would be a significant increased burden on hospital staff.

The strong centre effect observed in the European registry and American registry data, which demonstrates that more experienced centres are associated with improved safety and clinical outcomes, highlights the need to limit the procedure to a few specialised sites across Australia.

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Review of the clinical evidence

A literature search was conducted for each of the three conditions, MS, SSc, and SLE, for HSCT and MSCT. For MS, fifteen studies based on HSCT and four studies based on MSCT, published between 2009 and 2014, were included in this report. For SSc, three randomised controlled trials (RCTs) and six other relevant observational trials, published between 2007 and 2014, were included. For SLE, six studies published between 2009 and 2014 were included for HSCT which consisted of four case series and two comparative studies with concurrent controls. A further six case series studies, published between 2010 and 2014, were found for MSCT for SLE.

Summary of multiple sclerosis

Interpreting the evidence for stem cell transplantations for MS is challenging as the studies contain different treatment protocols, conditioning regimens, sources of stem cells and definitions for clinical outcomes. There is also limited long-term follow-up data.

Most of the fifteen studies of HSCT for MS included in this report used autologous stem cells derived from peripheral blood. The median follow-up ranged from 31 months to 11.3 years. For the case series, the 100-day treatment-related-mortality (100 day TRM) ranged from zero per cent to four per cent and the treatment-related-mortality (TRM) ranged from zero to 14 per cent. For the retrospective analyses, the 100-day TRM and TRM ranged from two to four per cent and from 2.7 to 3.8 per cent, respectively. This reflects the European

experience,8 which reported a fall in mortality associated with autologous HSCT from 7.3 per

cent from 1995 to 2000 down to 1.3 per cent from 2001 to 2007. This may have been due to improved patient selection and a reduction in the high-intensity conditioning regimens. Progression-free survival was estimated to be between 47.6 to 100 per cent at three years, 45 to 82 per cent at five years, 29.2 to 65 per cent at six years, 48 per cent at nine years and 25 per cent at 15 years. Disease free survival was estimated to be between 62 to 78.4 per cent at three years and 68 per cent at five years. Relapse-free survival was estimated to be 76 per cent to 86.3 per cent at approximately three years and between 85 to 87 per cent at five years. Only three studies reported magnetic resonance imaging (MRI) event-free survival which was estimated to be 100 per cent at 6-12 months, 92 per cent at two years, 100 per cent at three years and 85 per cent at five years.

Disability at baseline, as measured by the median score on the Kurtzke expanded disability status scale (EDSS), ranged from 3.1 to 8.0. Disability progression was observed in zero to 58 per cent of patients whilst stabilisation or improvement was shown in 42 to 100 per cent of patients. New gadolinium-enhanced (Gd+) and/or T2 lesions were observed in zero to 24 per cent of patients at follow-up post-transplantation. Quality of life was found to

significantly improve as early as six months post-transplantation (p<0.05) and improvements were observed in most of the domains at follow-up.

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Stem cell transplantation is more efficacious in patients in the inflammatory stages of the condition (i.e. RRMS, and SPMS with episodes of relapsing remitting). As the condition progresses to SPMS, the disease shifts to a neural degenerative disorder and the treatment

is no longer effective. According to updated guidelines,4 the ideal target patient indications

for auto-HSCT for MS, are patients with MS in the relapsing remitting phase (characterised by clinical manifestations of high inflammatory activity and the presence of Gd+ enhancing lesions and/or new T2 lesions on MRI imaging scans) with aggressive progression failing one or more lines of treatment. Patients with severe ‘malignant’ MS would also be suitable candidates for the procedure. Patients with SPMS who have evidence of some inflammatory disease activity and who have deteriorated may also be considered for auto-HSCT. If the disease has progressed to a point where the patient have lost the ability to walk

(approximately EDSS >6), auto-HSCT is no longer a suitable treatment option (except for ‘malignant’ forms of MS).

Only four small case series for MSCT for MS met criteria for inclusion in this report. All included studies used autologous stem cell transplantation using mesenchymal stem cells derived from bone marrow. Common adverse events were fever, headaches, difficulty walking/standing and infections with no deaths reported across any of the four studies. Disease progression, as measured by the EDSS, significantly reduced in one study and was shown to improve in 34 per cent (13 patients), stabilise in 55 per cent (21 patients) and worsen in 11 per cent (4 patients) of patients in the other three included studies at six months with nearly 80 per cent improved or stable at 12 months. At follow-up, new T2, enlarging lesions or Gd+ lesions were found in zero to 71 per cent of patients.

There is some research emerging on the combined effects of multiple therapies including stem cell transplantations in conjunction with other therapies as treatment for MS. For example, recent studies have explored the combination of non-myeloablative HSCT with a

consolidation therapy of mitoxantrone,9 HSCT with infusion of mesenchymal stem cells,10

and failed non-myeloablative HSCT followed by natalizumab.11 This area of research is still in

its infancy, however may provide possible treatment options in the future.

MS is generally not considered to be a fatal disease unlike the severe forms of SSc and SLE and the current TRM of auto-HSCT for MS at one to two per cent remains a significant concern. Auto-HSCT remains a relatively experimental treatment for MS and should only be performed in a clinical trial setting, under the guidance of a human research ethics

committee and with full informed consent.

The safety and efficacy of stem cell therapies for autoimmune disorders and its benefits compared to existing standard therapies needs to be demonstrated through RCTs prior to becoming an accepted treatment option. Currently this level evidence is only available for SSc.

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Summary of systemic sclerosis

The results in trials to date support HSCT as an effective treatment for severe SSc. Patient selection is critical with high TRM in patients with cardiopulmonary involvement and in current and previous smokers.

From the available evidence, auto-HSCT had a worse short term safety profile than the comparison (cyclophosphamide) with more short term mortality and serious adverse events, particularly haematologic, respiratory, cardiovascular and common viral infections. TRM ranged from 0 to 23 per cent across the RCTs and observational studies.

Auto-HSCT has a clear benefit on long term mortality. In the one RCT (van Laar et al. 2014)12

reporting a comparison of mortality, a significant benefit was found for auto-HSCT at five years despite the increased early mortality due to treatment. Mortality at around five years was similar in the RCTs to the observational studies at around 20 per cent. This compares favourably to estimates of mortality in SSc with major organ involvement of around 40 to 50 per cent at five years.13

The results of longer term follow up support the hypothesis that HSCT is safer if baseline cardiac assessment is favourable and HSCT should be instituted before the SSc has caused cardiac abnormalities in order to maximise the benefit.

The transplantation procedure used to treat patients with SSc has undergone changes since it was first implemented, primarily related to the increased screening of patients for cardiac complications to reduce TRM. In order to appropriately ascertain risk, screening should include echocardiogram, confrontational right heart catheterisation, including a fluid

challenge test and cardiac MRI, however screening will increase the cost of the procedure.14,

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The improved procedures should have an impact on reducing the early mortality associated with auto-HSCT therefore making it a safer treatment option.

Summary of systemic lupus erythematosus

HSCT and MSCT are both promising treatments for SLE, though they are still in the naïve stages of being proven clinically effective. The evidence available for this report came from six HSCT studies and six MSCT studies. Only two studies included an alternative treatment, a conventional treatment, which diminished the ability of this report to comment on the

effectiveness of the treatments.16, 17 No RCTs comparing HSCT or MSCT to standard

treatment were found.

The safety of HSCT and MSCT differed greatly across the 12 studies, supporting the claim of a strong centre effect / learning curve being involved in stem cell transplantation

therapies.18 The 100-day TRM of the HSCT studies varied from zero per cent in Song et al.

(2011)17 to 12.94 per cent in Farge et al. (2010).19 Only Farge et al. (2010)19 judged deaths

within their study to be by TRM. Song et al. (2011)17 was unable to prove that HSCT was

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progression free survival was significantly improved in the HSCT group, suggesting patients

stay in remission longer due to HSCT.17 The MSCT studies did not judge any death to be

TRM, although Wang et al. (201420 and 201321) reported a 100-day TRM of 2.5 per cent and

2.29 per cent, respectively. The MSCT studies had an overall mortality range of 0.0 per cent (follow-up of 8.25 and 17.2 months) to 7.5 per cent (follow-up of 12 months).

A number of parameters were used to demonstrate the decrease in disease activity after HSCT or MSCT. In both HSCT and MSCT studies, each study which reported the systemic lupus erythematosus disease activity index (SLEDAI) analysis, found the average SLEDAI score to significantly decrease after transplantation. Decreasing SLEDAI scores represent diminishing disease activity, with remission reached at SLEDAI scores < three. The MSCT studies found 24h proteinuria, serum albumin levels and anti-dsDNA levels to positively change, representing statistically significant decreases in disease activity after treatment. There is no economic information available on SLE and stem cell transplantations in

Australia. No Australian data exists to estimate number of potential SLE patients that would meet the treatment criteria, and be able to estimate the cost per annum.

Cost-effectiveness analysis

A search of health technology assessment (HTA) databases revealed stem cell

transplantations for each of the relevant conditions, revealed three health technology assessments for MS, one health technology assessment for SLE, and no health technology assessments for SSc. Of these, only one publication was available which reported on an exploratory effectiveness analysis in the UK evaluated the incremental

cost-effectiveness of auto-HSCT versus mitoxantrone in the treatment of patients with SPMS. The results of the cost-utility analysis revealed auto-HSCT as cost-effective compared with mitoxantrone at a threshold accepted by policy makers in the UK. These results are not generalisable for auto-HSCT as a treatment for other subtypes of MS (e.g. RRMS) due to different comparators, other autoimmune diseases, or other types of stem cell

transplantations (e.g. MSCT). Ongoing research

Stem cell transplantation is an intervention currently of high interest to research teams with a large volume of research currently underway. For MS, 42 studies were found on clinical trial registries on stem cell transplantation for MS of which 30 studies are registered as active/recruiting/complete; 12 studies (HSCT), 21 studies (MSCT), and 3 studies (other). One multi-centre RCT (MIST phase) based in USA, Sweden, Brazil and the UK comparing auto-HSCT versus standard of care treatment is currently underway and will provide pivotal evidence on the outcomes of HSCT.

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There are 22 studies on stem cell transplantation for SSc of which 15 studies are registered as active/recruiting, three trials registered as complete and four trials registered as either terminated or withdrawn. Two RCTs are underway with results expected in 2017-2018. For SLE, 14 studies on stem cell transplantation were found. Most of the current trials were based on HSCT. There are no RCTs registered for HSCT for SLE. There is one double blind RCT comparing MSCT versus cyclophosphamide which will be first clinical trial with the ability to judge the efficacy of MSCT in SLE patients.

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Background

Register ID WP 194

Technology name Stem cell therapy for non-haematological (autoimmune) indications

Patient indication Patients with multiple sclerosis, systemic sclerosis and systemic lupus erythematosus

Description of the technology

Stem cells are a type of cell that are defined by their ability to multiple themselves (self-renew) and change into different types of specialist cells (differentiate). There are two main groups of stem cells: tissue stem cells and pluripotent stem cells (Table 1). Tissue stem cells are (multipotent) have the ability to differentiate into a limited number of cell types. Tissue stem cells include adult stem cells, cord blood stem cells and fetal stem cells. Pluripotent stem cells are able to differentiate into any type of cell and include embryonic stem cells and induced pluripotent stem cells.

Table 1 Classification and types of stem cells

Group Description Type of stem cells Source of stem cells

Tissue stem cells Differentiation into a limited number of cell types

Adult stem cells Part of human body (e.g. bone marrow) Cord blood stem cells Umbilical cord blood

Fetal stem cells Aborted fetuses

Pluripotent stem cells

Differentiation into any type of cell

Embryonic stem cells Embryos

Induced pluripotent stem cells Part of human body (e.g. skin)

The current report will focus on treatment involving tissue stem cells, specifically adult stem cells, which can be isolated from the bone marrow. These are sub-classified into

haemopoietic and mesenchymal stem cells.

Stem cell therapy refers to transplanting stem cells into the body (stem cell transplantation) and drug therapies that target stem cells in the body. Stem cell transplantations have been proposed as a treatment for severe autoimmune diseases. The objective of the treatment is remove the autoreactive immune cells and to introduce stem cells (either from the patient or a donor) to reset or replace the patient’s immune system. The two main types of stem cell transplantations for autoimmune diseases are haemopoietic and mesenchymal (Figure 1). Haemopoietic stem cell transplantation (HSCT) refers to the transplantation of

multipotent haemopoietic stem cells derived from bone marrow, peripheral blood, or umbilical cord blood. Mesenchymal stem cell therapy (MSCT) refers to the transplantation

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of multipotent mesenchymal stromal cells derived from bone marrow, umbilical cord,

adipose tissue, placenta, teeth and menstrual fluid.7, 22 For stem cell transplantations, stem

cells may be obtained from the patient (autologous), a matched donor (allogeneic), or an identical twin (syngeneic).

Figure 1 Common types of stem cell transplantations in autoimmune diseases

The autologous haemopoietic stem cell transplantation (auto-HSCT) procedure is outlined in Figure 2 and involves the following steps:

1. Mobilising

- Mobilising of haemopoietic stem cells from bone marrow or peripheral

blood, typically with granulocyte-colony stimulating factor and cyclophosphamide.

2. Collecting or harvesting

- Collecting or harvesting the haemopoietic stem cells by

leukaphersis/plasmapheresis and selection for CD34+ cells.

- Purifying and concentrating of the haemopoietic stem cells in the

laboratory.

- Freezing or ‘cryopreserving’ the cells in the laboratory.

3. Conditioning and reinfusing

- Immunoablative conditioning (chemotherapy) to destroy the immune

system, typically with cyclophosphamide with or without anti-thymocyte globulin.

- Reinfusing the thawed haemopoietic stem cells into the patient.

Stem cell transplantation / stem cell therapy

Haemopoietic stem cell transplantation (HSCT) Autologous (auto-HSCT) Allogeneic/syngeneic (allo-HSCT) Mesenchymal stem cell therapy (MSCT) Autologous (auto-MSCT) Allogeneic/syngeneic (allo-MSCT)

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Figure 2 Illustration of autologous haemopoietic stem cell transplantation procedure23

The conditioning regimens include myeloablative conditioning (cyclophosphamide with total body irradiation or busulfan) and nonmyeloablative conditioning (cyclophosphamide with or without anti-thymocyte globuline. Myeloablative conditioning is associated with higher treatment-related-mortality (TRM) and is less suitable for patients with autoimmune disease. The auto-HSCT procedure is relatively similar across multiple sclerosis (MS), systemic sclerosis (SSc) and systemic lupus erythematosus (SLE). Allogeneic haemopoietic stem cell transplantation (allo-HSCT) involves mobilisation, collection, and the harvest of haemopoietic stem cells from a human leukocyte antigen matched healthy donor.

MSCT using bone marrow derived mesenchymal stem cells involves the aspirate of a small volume of bone marrow and then the isolation and culture expansion of the mesenchymal stem cells in an accredited manufacturing facility. Administering the mesenchymal stem cells to the patient can be via injection using the following methods:

 intravenous (vein);

 intrathecal (space around spinal cord); or

 intraparenchymal (brain).

Company or developer

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Reason for assessment

The technology of stem cell transplantations for autoimmune diseases has been assessed in this new and emerging health technology report for a number of reasons including:

- increasing evidence for auto-HSCT as superior to the current treatment for severe

SSc;

- mounting pressure from the public for stem cell transplantation to be made

available to treat patients with MS; and

- results of the current phase III trial for auto-HSCT for MS which are expected to be

released over the next few years. If the results are considered to have significant health benefits in a subgroup of patients with MS, it is likely that there would be a major cost impact on the public health system as multiple sclerosis is a large patient group associated with significant morbidity.

Stage of development in Australia

Yet to emerge Established

Experimental Established but changed indication

or modification of technique

Investigational Should be taken out of use

Nearly established

Licensing, reimbursement and other approval

The Therapeutic Goods Administration (TGA) is the regulatory authority for all devices, drugs and biological in Australia and is responsible for the regulation of the importation, manufacture and supply of stem cells. Stems cells intended to be used for therapeutic purposes are required to be listed on the reference database of the TGA, the Australian Register of Therapeutic Goods. Under the Therapeutic Goods Act 1989, Therapeutic Goods

(Excluded Goods) Order No. 1 of 2011, human tissues and cells intended for use in humans

are exempt from regulation by the TGA for medical practices with registered medical

practitioners under specified medical conditions.b

In partnership with the Australian Health Practitioner Regulation Agency, the Medical Board of Australia is responsible for the regulation of medical practice in Australia. Before new stem cell treatments are made available to the public, clinical trials should be used to establish their safety and efficacy. In Australia and overseas, clinical trials should be

b

Human tissue and cells, intended for use in humans, are declared not to be therapeutic goods if they are collected from a patient who is under the clinical care and treatment of a medical practitioner registered under a law of a State or an internal Territory; and manufactured by that medical practitioner, or by a person or persons under the professional supervision of that medical practitioner, for therapeutic application in the treatment of a single indication and in a single course of treatment of that patient by the same medical practitioner, or by a person or persons under the professional supervision of the same medical practitioner. For more information, see the Therapeutic Goods Administration website at

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registered with World Health Organization (WHO) approved clinical trial registries.

According to the National Health and Medical Research Council (NHMRC), HSCT is the only stem cell treatment that is recognised as a safe and effective treatment to re-establish the

blood and immune system for specific medical conditions.24 The NHMRC has released

information guidelines25 for medical practitioners on stem cell treatments in Australia in

which it states that there are some medical practitioners in Australia and overseas that are providing stem cell treatments that may not have been shown to be effective.

Australian Therapeutic Goods Administration approval

Yes ARTG number (s)

No

Not applicable

Technology type Procedure

Technology use Therapeutic

Speciality Haematology

Technology setting Specialist hospital

Impact

Alternative and/or complementary technology

Additive and substitution (i.e. technology can be used as a substitute in some cases, but may be used in combination with current technologies in other instances).

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Patient Indication and Setting Multiple Sclerosis

Disease description and associated mortality and morbidity

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (i.e. the brain, spinal cord and optic nerves). It is characterised by demyelination caused by the body’s immune system attacking its own myelin sheaths (covering that surrounds the axons of the nerve fibres). The resulting inflammation and damaged myelin and axons lead to a disruption of the transmission of electrical signals to the brain. The symptoms of MS are dependent upon the areas of the central nervous system involved and can vary significantly between patients. Symptoms include numbness, tiredness, muscle weakness, sensitivity to heat, problems with balance and co-ordination, bladder and bowel symptoms, cognitive changes, and visual disturbances.

The cause of MS remains largely unknown, however it has been proposed that

autoimmunity (auto-reactive T and B cells), genetics and environmental factors (such as Epstein-Barr virus, human herpes virus 6, low vitamin D levels, smoking, and sun exposure) may all play a role.

The most common subtypes of multiple sclerosis are outlined in Table 2 below, and include:

 relapsing remitting multiple sclerosis (RRMS);

 secondary progressive multiple sclerosis (SPMS);

 primary progressive multiple sclerosis (PPMS);

 relapsing progressive multiple sclerosis (RPMS); and

 other rare MS variants (e.g. Marburg’s disease (malignant MS), Balo’s concentric

sclerosis, Schilder’s diffuse sclerosis, relapsing optic neuritis).

The latest diagnostic criterion for MS is the revised 2010 McDonald criteria (previously Poser and Schumacker criteria). It is estimated that approximately 75 per cent of patients with multiple sclerosis are female. The average age of onset of MS in Australia is usually between 20 to 40 years of age.

(20)

Table 2 Overview of types of multiple sclerosis

Type of MS Features Disease course

Relapsing remitting multiple sclerosis (RRMS)

Fluctuation of symptoms with periods when symptoms worsen (relapses) and periods when symptoms improve (remission). 85 per cent of patients are initially diagnosed with RRMS.

Secondary progressive multiple sclerosis (SPMS)

Initial RRMS disease course, followed by steady worsening of disease with or without occasional relapses and remissions.

Primary progressive multiple sclerosis (PPMS)

Steady worsening of disease without any remissions. PPMS is less common.

Relapsing progressive multiple sclerosis (RPMS)

Steady worsening of disease from onset with relapses (with or without partial recovery).

In 2012, a total of 149 deaths (53 males and 96 females) were registered with MS being the underlying cause and 249 registered deaths (83 males and 166 females) were associated

with multiple causes, including MS, in Australia.26 In general, MS is not considered to be a

fatal condition and does not significantly reduce life expectancy.27 MS can often lead to a

considerable level of disability. The Kurtzke expanded disability status scale (EDSS)28 is a scale used to measure the severity of the disability in neurological impairment in people with MS. The EDSS scale is based on eight functional systems (pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual, cerebral and other) and ranges from 0 (normal function) to 10 (death) with higher scores representing greater levels of disability (Figure 3). The scale has 0.5 unit increments. An EDSS score of 1.0 to 4.5 refers to fully ambulatory patients whilst patients with impairments in walking are indicated by a score of 5.0 to 9.5.

(21)

Figure 3 Kurtzke expanded disability status scale (EDSS) (MS Decisions)29

Number of patients

The 2009 Australian Bureau of Statistics (ABS) Survey of Disability, Ageing and Carers

estimated the number of people living with MS in Australia to be 23,700 individuals (0.1% of the population) with the true prevalence estimated to be between 21,150 and 26,250

individuals.30 Of the estimated 23,700 Australians with MS in 2009, core-activity limitation

was reported as profound (19.8%), severe (28.2%), moderate (11.9%), mild (15.5%), or no disability (22.7%). It is estimated that the number of people diagnosed with MS will increase

by four per cent per year.31

The prevalence of MS in Australia in 2010 was estimated to be 95.6 per 100,000 based on pharmaceutical prescription data for MS prescription medications which is similar to an estimate of 89.3 per 100,000 based on client membership of the Multiple Sclerosis Society

database.5 Based on the pharmaceutical data, the number of people living with MS in

Australia in 2010 was estimated to be 21,283 people (Table 3). The number is likely to be underestimated as not all people diagnosed with MS may be on medication due to being in remission.

Table 3 Number of people with multiple sclerosis in Australia, 2010, based on prescriptions, by state

NSW Vic Qld SA WA Tas ACT NT TOTAL

Number of people with MS 6,268 6,637 3,179 1,760 2,313 718 360 49 21,283

Percentage of cases of MS by State 29.5% 31.2% 14.9% 8.3% 10.9% 3.4% 1.7% 0.2% 100%

Abbreviation: MS: multiple sclerosis

A recent Australian study32 used pharmacoepidemiology of MS disease-modifying drugs for

RRMS between 2005 and 2008 to estimate the overall prevalence of MS (all subtypes) to be 68.4 per 100,000 people and the prevalence of RRMS in Australia to be 31.1 per 100,000

(22)

(Figure 4). This data supports a latitude gradient effect with the prevalence lower in the northern states of Australia and higher in the southern states of Australia.

Figure 4 Map of Australia illustrating the mean prevalence of treated RRMS by state, 2005 to 200832

MS is a disease of the nervous system (International Classification of Diseases, ICD-10 code G35) and (ABS code 607). In 2011−2012, the number of separations (episodes of care) of

patients with a primary diagnosis of MS admitted to Australian hospitals was 19,587.33

According to updated guidelines,4 the ideal target patient indications for auto-HSCT for MS,

are ambulatory patients (i.e. approximately EDSS <6) patients with:

- rapidly progressing RRMS refractory to one or more lines of treatment;

- SPMS with inflammatory activity who have deteriorated; and

- severe ‘malignant’ MS.

Based on an incidence of 1,000 new cases of MS (all subtypes) per year, 85 per cent would be diagnosed with RRMS. It is estimated that of the 850 new cases of RRMS, approximately 125 to 187 patients would be refractory to interferon and alemtuzumab, or alemtuzumab only (Appendix A) and may be assessed for eligibility for auto-HSCT across Australia. A proportion of these patients who are referred by their neurologist for auto-HSCT, who met all of the inclusion/exclusion criteria, and agree to undergo the procedure, may be eligible for the auto-HSCT treatment. It is difficult to estimate the number of patients with SPMS with inflammatory disease that may be suitable for auto-HSCT.

Mean prevalence of treated RRMS (per 100,000 people)

(23)

Systemic Sclerosis

Disease description and associated mortality and morbidity

Systemic sclerosis (SSc), also known as systemic scleroderma, is part of a group of conditions known as scleroderma and is recognised as the most severe connective tissue disorder. The aetiology of SSc remains unknown. SSc is an autoimmune disorder that involves

endothelium dysfunction and excessive production of collagen due to altered fibroblasts.34

This results in fibrosis of the skin and internal organs which in severe cases leads to organ

failure and death.35 SSc is sub-categorised depending on the extent of skin involvement:

limited cutaneous SSc affects mainly the fingers, toes and face and the diffuse form affects large areas of the skin including the torso. A third subset with no skin involvement, sine scleroderma, is sometimes used. Figure 5 outlines the types of scleroderma.

Figure 5 Types of scleroderma

Localised forms of the disease affect only the skin and related tissues, and will not progress to the systemic form. These localised forms, while they can have a severe impact on quality of life depending on the extent of skin involvement, are not life threatening.

Similar to other autoimmune disorders, SSc is more common among females with around

4:1 females to males.36 SSc affects many different systems throughout the body.

Complications of SSc include digital vasculopathy (Raynaud’s phenomenon, digital ulcers), pulmonary arterial hypertension, interstitial lung disease, scleroderma renal crisis and

gastrointestinal disease.37 Less than one third of those with this form of the disease will go

on to develop the severe form.36

Scleroderma

Localised scleroderma

Morphea scleroderma Linea

Systemic sclerosis Limited cutaneous systemic sclerosis Diffuse cutaneous systemic sclerosis

(24)

SSc carries a highly increased mortality risk. Scleroderma renal crisis develops in 10 to 15 per

cent of patients and was a major cause of mortality before ACE inhibitorsc became widely

available in the 1980s.36 Renal crisis is currently managed well with optimal medical

therapy. The major cause of mortality is now attributable to cardiopulmonary events

including interstitial lung disease and pulmonary arterial hypertension.1 The median

survival for patients with SSc related interstitial lung disease is 5 to 8 years.2 Interstitial lung

disease occurs in both diffuse and limited cutaneous forms of the disease38 and is found in

around 40 per cent of patients with SSc.34

Long term data shows a 2.5 times higher risk of death compared to the general population

based on 40 years of observational studies.35 This risk has remained relatively stable over

time although there is a trend towards longer survival of patients in the last few decades

due to the improvement in the treatment of renal crisis.39

Number of patients

The true prevalence of SSc is difficult to determine with international estimates ranging

from three to 24 per 100,000 people.40 There are no estimates for the prevalence of SSc in

Australia; however, there are an estimated 100,000 people with SSc in the United States.36

The Australian Rheumatology Association maintains the Australian Scleroderma Interest Group (ASIG) database. This database recruits patients from 12 sites across Australia and

has over 1,000 Patients with SSc enrolled.41 As of 2011, 88 per cent of patients were female

and 26 per cent had diffuse disease. Twenty-four per cent of the cohort had significant interstitial lung disease and 11 per cent had pulmonary arterial hypertension using gold

standard right heart catheterisation.41

A systematic review of epidemiology suggests an incidence of SSc in Australia of 15 to 23 persons per million per year using data from three Australian sources covering 1993 to

2002.40 Based on the current population of 23.7 million people, this predicts that there will

be 356 to 545 new cases of SSc diagnosed yearly in Australia. Based on the proportion in the Australian registry approximately 85 to 130 of these new cases will develop significant interstitial lung disease. Given that a proportion will respond well to current therapies and a proportion would be ineligible due to major organ involvement precluding stem cell

treatment or for other medical reasons, it is estimated that between 30 to 65 patients may be a reasonable estimate of likely demand for stem cell services per year.

(25)

Systemic lupus erythematosus

Disease description and associated mortality and morbidity

There are two main types of lupus; discoid lupus erythematosus (DLE) and SLE. DLE is the most common form of the condition confined to the skin. SLE is a chronic autoimmune disease characterised by inflammation across multiple organ systems, clinical pattern of flares/relapses and remissions, and the presences of autoantibodies. Most patients with SLE have symptoms in the skin and joints, although life threatening manifestations can arise in the kidney, lungs, the central nervous system, gastrointestinal system, ophthalmic system, cardiovascular system and haematologic system. Inflammation of the kidney can cause lupus nephritis which can lead to significant illness and can even be fatal. The vast variation in clinical and serological manifestations, led by a series of dysregulated immune processes, makes SLE a very heterogeneous disease which can affect any combination of organs in an individual. Due to the complexity of the disease, the primary causes of SLE remain unclear. A

number of contributing factors have been identified as:42

 generalised T-cell dysregulation causes immune activity through multiple pathways;

 various B-cell defects cause damage to host tissue by means of loss of immune

tolerance, dysregulation of cytokines and production of autoantibodies;

 the response of the innate immune system to pathogens, which leads to increased

effects of interferon-α; and

 defects in the complement system and/or programmed cell death impair the

clearing of immune debris, and in so doing, prolong inflammation.

Epidemiological studies on SLE show marked variations in gender, age and race, as well as hormonal, genetic and environmental disease triggers. There are striking gender disparities in SLE burden, with the disease generally affecting females in 80 to 90 per cent of the cases. In 20 per cent of patients with SLE, symptoms arise prior to the age of 16 years. Childhood-onset SLE is known to confer a worse prognosis than adult disease in terms of disease

activity, organ damage and mortality.43 Studies of racial tendencies showed that SLE more

frequently affects non-Caucasian individuals than Caucasian individuals.

The literature on mortality and morbidity of SLE in Australia is limited and primarily reported in comparison studies of Caucasian and non-Caucasian population groups. A small study reported Aboriginal peoples (n=18) to have a mortality rate of 11.1 per cent compared to zero per cent for Caucasians (n=6).3 Multiple reports have shown Asian patients with SLE are more affected then their Caucasian counterparts with respect to disease severity, renal

involvement, photosensitivity, laboratory characteristics and flares.44-46 No study has been

able to confirm a difference in mortality rates of SLE between Asian Australians and non-Asian Australians. Several adverse effects of SLE on pregnancy have been reported including

(26)

Number of patients

The incidence of SLE in Australia is not well reported although a number of studies have reported the prevalence in population subgroups. The prevalence of SLE in Aboriginal peoples (52.0−92.8 cases per 100,000 population) has been reported to be higher than in

non-Aboriginal peoples (19.3−39.0 cases per 100,000 population).3 Mackie et al. (2014)

reported the first incidence data for paediatric SLE (younger than 16 years) in Australia and

found 0.32 cases per 100,000 population per annum.43

Lupus nephritis is a severe form of SLE affecting renal function and therefore would be likely to be the main population requiring stem cell transplantation. The prevalence of lupus nephritis in Australia was found to be 5.5 per 100,000 population. The prevalence of Caucasian lupus nephritis was lower (4.0 per 100,000 population) compared to Asian lupus

nephritis (27.9 per 100,000 population).49 Based on the current population, about 1,200 to

1,300 people would be living with the severe form of SLE in Australia. It is unclear how many of these people would be likely to benefit from stem cell therapies.

(27)

Current technology

Multiple sclerosis

Disease modifying therapies for MS are medications aimed at decreasing the frequency and severity of relapses/attacks and reducing the disability progression of the disease. Disease modifying therapies are only available for clinically isolated syndrome (i.e. first episode of neurologic symptoms), RRMS and relapses in SPMS. The type of treatment used depends on the disease course and the treatment response. Currently, there are nine therapies listed on the Pharmaceutical Benefits Scheme (PBS) in Australia and three therapies approved by Pharmac in New Zealand (Table 4).

Table 4 Therapies approved for multiple sclerosis in Australia and New Zealand

Drug (trade name)

Listed on PBS (Australia)

Approved by PHARMAC

(New Zealand) Dose / frequency Approved indications CIS RRMS Relapses in SPMS

Interferon-b 1a IM ✔ ✔ 30μg weekly ✔ ✔ ✔

Interferon-b 1a S/C ✔ 44μg 3 times / week ✔ ✔ ✔

Interferon-b 1b S/C ✔ ✔ 250μg alternate days ✔ ✔ ✔

Glatiramer acetate ✔ ✔ 20mg daily ✔ ✔

Natalizumab ✔ 300mg every 4 weeks ✔

Fingolimod ✔ 0.5mg daily ✔ ✔

Teriflunomide ✔ 14mg daily ✔ ✔

Dimethyl Fumarate ✔ 240mg twice daily ✔ ✔

Alemtuzumab 2015 12mg two courses ✔

Abbreviations: CIS: clinically isolated syndrome; IM: intramuscular; IV: intravenous; PBS: Pharmaceutical Benefits Scheme; RRMS: relapsing remitting multiple sclerosis; S/C: subcutaneous; SPMS: secondary progressive multiple sclerosis.

Treatments for MS include immunomodulators, corticosteroids and immunosuppressants. The therapeutic approaches to disease modifying therapies for MS in adults have been reviewed by the Multiple Sclerosis Neurology Group of the Australian and New Zealand

Association of Neurologists.50-52The first-line treatments for MS are immunomodulators

including:

 interferon beta

- RRMS: moderate reduction in relapses and disability in the short-term.

- SPMS: slight reduction in change of experiencing relapses.

- PPMS: not effective in preventing disability from getting worse.

 glatiramer acetate

- RRMS: slightly reduces the chance of relapse.

- RRMS/SPMS/PPMS: does not prevent disability getting worse.

Second-line treatments for MS may include immunosuppressants such as natalizumab and

fingolimod. Due to the potential serious risks of drug-induced leukaemia and cardiotoxicity

associated with chemotherapy treatment, this treatment is reserved for aggressive MS refractory to therapy. The escalation of treatment beyond the first-line treatments are more

(28)

potent and may have a greater effect on the disease; however, there are more serious side effects, higher costs and limited evidence on long-term outcomes and the types of MS that may benefit. Alemtuzumab was recently approved by the TGA in December 2013 as a first-line treatment option for active RRMS and is awaiting listing on the PBS in Australia. Alemtuzumab has been shown to be superior to interferon beta in reducing the frequency of relapses and delaying the progression of disability in some patients with active MS. It is not recommended for patients who are stable on their current treatment or who have inactive disease. Side effects of alemtuzumab include infusion-associated reactions, lowered blood cell counts, infections, overactive or underactive thyroid gland, and immune

thrombocytopenic purpura (ITP). As this can be fatal, monitoring is required for the early detection and treatment of ITP. Other promising disease-modifying therapies in late phase

development for MS have been published.53

Systemic sclerosis

Due to the involvement of multiple organs and systems in SSc, many different therapies are used in the management of this condition. No current therapy is curative. A large range of vasodilators, vasoactive therapies, immunomodulators and antifibrotics have been used to

treat the symptoms of SSc.37

Table 5 lists the most common complications and recommended therapies from the

European league against rheumatism (EULAR) scleroderma trials and research group.37 This

list includes the therapies that have the most evidence available but is not a comprehensive list of all therapies available.

Table 5 Recommended therapies for treatment of major systemic sclerosis complications

Systemic sclerosis complication Therapy Evidence Digital vasculopathy (Raynaud’s phenomenon, digital ulcers)

Calcium antagonists (nifedipine), prostanoids (intravenous iloprost)

Bosentan if failure of calcium antagonists and prostanoid therapy

Reduces the frequency and severity of Raynaud’s phenomenon attacks

Heals digital ulcers Prevention of digital ulcers Pulmonary Arterial

Hypertension

Bosentan, sitaxentan, sildenafil

Intravenous epoprostenol for severe symptoms

Improves exercise capacity, functional class and some haemodynamic measures

Skin involvement Methotrexate Improves skin score

Interstitial lung disease Cyclophosphamide Improves lung function

Scleroderma renal crisis ACE inhibitors Prevent renal crisis

Gastrointestinal disease Proton pump inhibitors, prokinetic drugs and

rotating antibiotics Poor evidence available but may improve symptoms of reflux, ulcers and strictures, gastric motility and reduce bacterial overgrowth causing malabsorption

Source: Topal and Dhurat (2013)37

Abbreviations: ACE inhibitors = angiotensin-converting-enzyme inhibitors

Treatments used for SSc lung involvement (the most frequent cause of mortality) have included prednisone, azathioprine, cyclophosphamide, rituximab and mycophenolate

mofetil.2 Oral cyclophosphamide is the only treatment to have been tested in randomised

(29)

lung disease. In a systematic review including three RCTs, a meta-analysis found that cyclophosphamide significantly improved the diffusing lung capacity of carbon monoxide (3.74, 95% CI [0.09, 7.40]) and showed a positive trend to improving forced vital capacity

(4.15, 95% CI [-0.51, 8.80]).54 These benefits were modest and below what could be

considered clinically relevant.

Cyclophosphamide treatment carries considerable risk of toxicity and close monitoring of haematological status is required. Myelosuppression can lead to leukopenia, neutropenia, thrombocytopenia (higher risk of bleeding events), and anaemia. Immunosuppression can cause serious and sometimes fatal infections. Renal, cardiac and pulmonary systems can also be affected with severe consequences. Secondary malignancies, sterility and

genotoxicity are also possible. The usual dose for immunosuppressive therapy as used for

SSc is 1 to 3mg/kg orally depending upon response and toxicity.55

In conclusion, there is no one therapy available to treat all aspects of the disease process. Systemic lupus erythematosus

The current treatment methods have created a dramatic improvement in prognosis for patients with SLE, though improving the prognosis of refractory patients with SLE continues to be an obstacle. The guidelines presented by the EULAR recommend the use of

antimalarial and/or glucocorticoids on patients not displaying major organ involvement.42

Glucocorticoids are still the foundation of SLE treatment, despite their well-known

side-effects.56 In non-responsive patients or those requiring a higher than acceptable use of

steroids, immunosuppressive agents are recommended.

Lupus nephritis is a common and challenging manifestation of SLE. This variety of SLE is treated in two phases; aggressive immune suppression (induction phase), and a long term, less aggressive immune suppression (maintenance phase). The aim of the induction phase is to get the life threatening SLE flare under control with limited side-effects. The most

common induction phase therapies include the use of cyclophosphamide or mycophenolate mofetil, often with concurrent use of corticosteroids. The maintenance phase regimens consist of continued less frequent use of cyclophosphamide, mycophenolate mofetil or azathioprine.

The aim of biological treatments is to use the knowledge of the different dysregulated immunological pathways involved in SLE to develop target specific therapies. There are many biological therapies in clinical trials or development. Only two biological therapies are being used as treatments; belimumab and rituximab. Belimumab has current TGA approval for add-on therapy in adult patients with active, autoantibody-positive SLE with a high degree of disease activity. It also has United States Food and Drug Administration (FDA) approval. It is not currently listed on the PBS and therefore will currently have very limited use in Australia. Rituximab is not approved in Australia or the United States for use in SLE;

(30)

Rituximab is used off-label in the United States for patients with refractory SLE in addition to immunosuppressive treatment; however, RCTs have failed to find a clinical benefit.

The current therapies in use for SLE are summarised in Table 6.

Table 6 Current therapies used in the management of systemic lupus erythematosus

Abbreviations: SLE: systemic lupus erythematosus.

The high morbidity of cyclophosphamide and the building evidence of mycophenolate mofetil efficacy are creating a considerable push for mycophenolate mofetil to be the first-line immunosuppressant in the induction and maintenance phase therapy for lupus

nephritis. Studies have shown that as a treatment for lupus nephritis, mycophenolate

mofetil is at least equal in efficacy and has fewer side effects than cyclophosphamide.66-68

Severity of SLE

Therapy type Common

medications

Evidence

Mild Antimalarials Hydroxychloroquine First-line treatment effective in treatment of and preventing future mild manifestations but is ineffective against severe SLE manifestations.57

Mild to moderate

Glucocorticoids Prednisone Methylprednisolone

Supresses SLE fever. 58, 59

Treatment of pulmonary manifestations of SLE with Glucocorticoids showed 60−80 per cent survival rates.

Ineffective as sole therapy for gastrointestinal, neurological, ophthalmologic and haematologic manifestations of SLE.56

Serious adverse events with long term use including osteoporotic fractures; symptomatic coronary artery disease; cataracts; diabetes; pulmonary fibrosis; cognitive impairment/psychosis.60-62

Moderate to Severe Maintenance for mild Immunosuppressing agents

Azathioprine Azathioprine has superior efficacy to corticosteroids in the treatment of lupus nephritis, but less effective than other immunosuppressing agents.57

Moderate lupus arthritis

Methotrexate Treatment of joint involvement especially for lupus arthritis. Two clinical trials have shown an association between methotrexate therapy and articular improvement.63, 64

Side effects mild and controllable.

Does not have a place in the treatment of SLE with major organ involvement.

Severe lupus nephritis

Cyclophosphamide Has been first-line treatment for lupus nephritis, often in conjunction with steroid therapy.

Predominantly used in the induction phase due to its aggressive side effects. Long-term exposure to cyclophosphamide can cause bladder cancer, bone marrow suppression, haematologic malignancies, infections, myelodysplasia and premature gonadal failure.65

Severe lupus nephritis

Mycophenolate mofetil

Newer treatment for lupus nephritis equal in efficacy and with fewer side effects then cyclophosphamide.66-68

Moderate to

severe SLE Biological treatments Belimumab Two phase III trials showed superiority on the SLE responder index, however the overall effect size was modest.69, 70

Adverse events across the treatment groups were not noticeably different.

Severe SLE (active central nervous system or nephritis) patients were not included in the clinical trials so benefit is not clear in this group of patients.

Severe SLE Rituximab A clinical trial failed to show benefit in primary and secondary endpoints.71

Several open-label or retrospective studies suggest that adding rituximab to standard treatment regimen is beneficial.72

Common side effects are mild Infusion infection, while neutropenia and severe infections were reported in 10 per cent of treated patients.73

(31)

The adverse events associated with mycophenolate mofetil are primarily mild, consisting of

gastrointestinal events and infections.57

Although mycophenolate mofetil may become the appropriate first-line treatment for lupus nephritis and therefore be the main comparator to stem cell transplantation, in the relevant clinical trials the inclusion criteria was primarily failure of cyclophosphamide treatment.

Diffusion of technology in Australia Haemopoietic stem cell transplantation

Autologous haemopoietic stem cell transplantation

In Australia, auto-HSCT is widely used as a treatment for disorders of the blood and immune system (e.g. leukaemia and lymphoma) and as supportive treatment for blood-related cancers.

To date, less than 40 patients with MS have undergone auto-HSCT across several sites in Australia including St Vincent’s Hospital in Sydney, the Sir Charles Gairdner Hospital in Perth

and the Canberra Hospital in Canberra.74 St Vincent’s Hospital is currently the only site

providing auto-HSCT for patients with MS and other severe autoimmune diseases (including SSc and SLE) in Australia where the procedure is being performed as part of phase II clinical trials using strict eligibility criteria. There have been over 60 auto-HSCT for autoimmune diseases performed at St. Vincent’s Hospital since 1996.

Information on blood stem cell transplants performed in Australia and New Zealand are collected by the Australasian Bone Marrow Recipient Registry, which is hosted at St. Vincent’s Hospital.

Allogeneic haemopoietic stem cell transplantation

The use of allo-HSCT for the treatment of autoimmune diseases has been extremely

limited.4 The major concern with allogeneic transplants is the potential for graft versus host

disease, a severe and potentially life threatening complication which has limited the diffusion of the technology.

Mesenchymal stem cell therapy

Autologous and allogeneic mesenchymal stem cell therapy

For allogeneic bone marrow derived mesenchymal stem cells manufactured in Western Australia (WA) under TGA license, there have been approximately 400 infusions performed in about 90 patients throughout Australia. There have been 10 clinical trials originating from WA using mesenchymal stem cells to treat a variety of conditions. There has been limited use of MSCT for the treatment of autoimmune disease in Australia with one small study

published in Crohn’s disease.75 There have been attempts to engage in early phase trials of

(32)

Cost infrastructure and economic consequences

Estimate of the ratio and number of patients eligible for autologous haemopoietic stem cell transplantation

Data from the European Group for Blood and Marrow Transplantation (EBMT) registry shows that the majority of auto-HSCT treatments reported to the registry from 2005 to 2007 were severe cases of MS (49%), whilst SSc and SLE accounted for 25 per cent and five per cent of cases, respectively (Table 7). Other autoimmune conditions such as rheumatoid arthritis, juvenile idiopathic arthritis and haematologic immune cytopenia accounted for the remaining 21 per cent of auto-HSCT treatments during that period. Recent data suggests that auto-HSCT is now rarely used for rheumatoid arthritis as newer biological treatments have proved effective. Updated registry figures of the total number of HSCTs registered with

the EBMT by condition have been published;4 however, the relative progression in the

number of procedures over time cannot be elicited.

Table 7 Number and proportion of autologous haemopoietic stem cell transplantation performed for severe autoimmune diseases reported to the European Group for Blood and Marrow Transplantation registry from 2005 to 2007

Year MS SSc SLE Othera Total number of

auto-HSCT

2005 35/80 (44%) 17/80 (21%) 6/80 (8%) 22/80 (28%) 80

2006 52/99 (53%) 22/99 (22%) 4/99 (4%) 21/99 (21%) 99

2007 30/61 (49%) 21/61 (34%) 2/61 (3%) 8/61 (13%) 61

Total 117/240 (49%) 60/240 (25%) 12/240 (5%) 51/240 (21%) 240

Abbreviations: auto-HSCT: autologous haemopoietic stem cell transplantation; MS: multiple sclerosis; SSc: systemic sclerosis; SLE: systemic lupus erythematosus; a other conditions include rheumatoid arthritis, juvenile idiopathic arthritis, haematologic immune cytopenia and other autoimmune diseases. It is likely that Australian patients would share similar characteristics with a European cohort and therefore it is reasonable to assume that these MS, SSc and SLE would represent around 80 per cent of auto-HSCT for autoimmune (non-haematological diseases) required in

Australia. Cost analysis

Limited economic information was available on stem cell treatments for autoimmune diseases in Australia. This is likely due to the lack of mainstream use of stem cell transplantations for autoimmune diseases.

It was estimated that the direct cost to government for healthcare and community care for MS in 2010 was $10,721 per patient, with an additional cost of $4,384 and $3,697

attributable to residential care and direct patient costs, respectively.5

If hospitalised for MS, the relevant diagnosis-related groups (DRGs) are B68A/B for MS and cerebellar ataxia, at a cost of $11,136 and $1,731 with (+CC ) and without (-CC)

Figure

Figure 1  Common types of stem cell transplantations in autoimmune diseases
Figure 4  Map of Australia illustrating the mean prevalence of treated RRMS by state, 2005 to 2008 32
Table 6  Current therapies used in the management of systemic lupus erythematosus
Table 8  Estimated cost per autologous haemopoietic stem cell transplantation for multiple sclerosis
+7

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