Autologous stem cell transplantation against systemic sclerosis / high dose treatment with autologous stem cell support, HMAS
Treatment with own (autologous) stem cells has been tested among some of the hardest affected Systemic sclerosis, diffuse form
- Demand is due to the fact that some with systemic sclerosis have particularly poor prognosis with a very serious, rapidly increasing disease course, subsequent manifestations of internal organs, pain, reduced quality of life and early death.
- The treatment is demanding and involves high doses of chemotherapy (cyclophosphamide / Sendoxan) that knock out the immune system. Stem cells previously taken from the person's own blood are given intravenously after chemotherapy
- The body gradually builds up the immune system again. Experiences from systemic sclerosis show the effect of the treatment, but also that up to 10% die after a short time, often related to the drugs in the treatment regimen.
- However, long-term survival (more than 4 years) is better than with other treatments (Sendoxan monthly) when taking into consideration that treatment is given to those with the poorest prognosis. The treatment results are likely to gradually improve with more experience
- In the foreseeable future, the treatment will still be an option for a small proportion of patients with systemic sclerosis
Systemic sclerosis is divided into one begrenset and a diffuse form. The diffuse form is most rare, but often attacks faster and more extensively. Compared to many others Autoimmune diseases we still lack good drug treatment options for systemic sclerosis. The treatment aims to stop disease-related damage to the lungs, heart, kidneys and other internal organs. Drugs that stop the skin changes have not yet been developed.
Autologous stem cell treatment
Autologous means that the cells are taken from the patient himself and not from other individuals (this option is called allogeneic). (Transplant from animal to human is called Xero-transplant). The advantage of using own cells (autologous) stem cells is that they are well tolerated and rejections are rare. Thus, immunosuppressive maintenance treatment is not necessary in the same way as by other transplants.
Stem cells are immature cells that can develop into different specialized cells, and they can divide into multiple stem cells. Stem cells can be harvested from bone marrow, fatty tissue or blood. Thus, cells from blood are best suited.
It is very important that all organ functions, including the heart, are thoroughly examined before treatment begins. Both echocardiography and MRI examinations of the heart may be relevant. Latent infections must also be ruled out.
The treatment procedure extends over several phases (according to Van Laar at all 2014)
- Stem cells from bone marrow and blood are "mobilized" (made available) by a growth factor such as Granulocyte colony stimulating (GCSF) factor is given, usually in combination with a chemotherapy (cyclophosphamide /Sendoxan infusions most commonly used). The cellular lymphatic system itself can at the same time affect the rheumatic disease
- Stem cells are collected (harvested) using a laboratory technique (leukoferese) separating stem cells from the blood. Often, leukapheresis is combined with a "immunomagnetic method"
- After the stem cell harvest, the cells are "purified" by immunological techniques such that CD34 + T cells remain. These cells are particularly important for building a new immune system
- The actual disease treatment takes place with extremely large doses of chemotherapy in the form of cyclophosphamide (Sendoxan), (for example, total 200mg / kg intravenously over 4 days)
- To reduce the risk of rejection reaction, antibodies are given (anti-thymocyte globulin) and methylprednisolone (SoluMedrol)
- The harvested CD34 + stem cells are given back as blood infusion
- Over a period of 10 - 20 days, the immune system remains significantly weakened (aplastic phase) with an increased risk of infections before it gradually resumes its effect.
- Infections including Sepsis (Blood poisoning), viral infections and fungal infections (Aspergillus and more) occur more easily in the weeks following treatment and may be fatal. One checks for example signs of EB virus with PCR technology in the process. Use prevention of antibiotics, antivirals and fungicides is common
- Chemotherapy (cyclophosphamide / Sendoxan) are central to the treatment and is given in high doses
- Nausea and vomiting are common
- Significant hair loss may be expected
- Damage to the heart, kidneys and muscles
- Infertility (inability to have children) as a result of treatment is common
- Increased risk of cancer can occur in the long term
- Inflammation of the mucous membranes in the oral cavity is often painful but rarely life threatening
- Blood clots may occur, but are counteracted by plentiful fluid supply
- Men, reduced heart function (left ventricle) and old age are considered risk factors for complications (van Bijnen S, 2020)
Scientific basis for autologous stem cell treatment for systemic sclerosis
Current studies completed (per 2018)
- ASTIS study (156 patients): Van Laar 2014)
- ASSIST (19 patients, Lancet 2011)
- SCOT (75 patients, NEMJ 2018)
Autologous stem cell transplant / stem cell support is given as treatment in many autoimmune diseases, such as Multiple sclerosis (MS), Systemic lupus erythematosus (SLE), Myositis, Rheumatoid arthritis (RA), Juvenile arthritis (JIA), Inflammatory bowel disease in addition to systemic sclerosis (Farge D Tyndall A 2010). For many of the diseases, the knowledge of treatment outcomes is limited by the lack of good scientific studies.
- For systemic sclerosis there is a European published study that is a scientifically solid, controlled, phase 3 study. It is based on autologous stem cell transplantation in 79 selected patients with systemic sclerosis Diffuse form and short duration of illness (less than 4 years) and well functioning internal organs. The treatment was compared to chemotherapy (cyclophosphamide / Sendoxan, 12 infusions) given to 77 corresponding patients. The study and treatment results are published (Van Laar et al., JAMA, June 25, Vol. 311, No 24). The patients in the study had been ill for an average of 1,7 years and 86% had lung affection. The results showed that there were 8 deaths (10%) related to the treatment. There were no similar deaths in the control group. In the long run, however, the treatment with stem cells showed a better effect on the development of skin symptoms, severe affection of the lung, other internal organs, physical function and quality of life. Survival was also better in the long run than those who received other treatment (cyclophosphamide / Sendoxan). Among the eight who died from the treatment were seven former smokers. It has long been known that smoking is unfavorable for the prognosis of the disease.
- From the USA, the treatment is compared with "cytotoxic drugs" in the form of cyclophosphamide (Sendoxan) as an alternative for very serious prognosis. Stem cell treatment appeared to be most effective, but with higher treatment-related mortality (3-6% after 54 and 72 months, respectively) (Reference: Sullivan KM, 2018).
- The treatment is risky and offered only a small sample of patients
- It is required, among other things:
- The diagnosis is systemic sclerosis, diffuse form with disease progression and medical examination findings indicating particularly poor prognosis
- Internal organs and immune system are (still) well functioning
- Age under 65 years
- That the patient can withstand / carry out the treatment
- It is required, among other things:
Autologous stem cell transplant / stem cell support has been shown to be effective in severe diffuse form of systemic sclerosis
- There is currently no other treatment that has shown equally good effect
- The treatment is offered to selected patients with a diffuse form of systemic sclerosis, a serious disease course, but with the absence of major organ damage
- However, the treatment involves the risk of adverse events that may lead to early death, but with a strict selection of current patients, the complication rate may be reduced
- It may seem that earlier smokers tolerate the treatment the worst (increased mortality)
It is estimated that 1-3 cases in Norway annually may be relevant for autologous stem cell transplant / stem cell support for systemic sclerosis. Corresponding treatment has been given by Multiple myeloma (a malignant blood disease) for several years.
- Sullivan KM, 2018
- Cras A, 2015
- Van Laar, 2014
- More about organ transplants here (in Danish) (Wikipedia)
- Grans Compendium in Rheumatology